PopSugar

Bella Book: The Japanese Skincare Revolution

BellaSugar — Wed, 28 Jan 2009 14:00:24 -0800

When it comes to beauty, I'll admit that I can always learn more about having a healthy complexion. So when I heard of a book that Japanese women consider to be their go-to guide to skin care, I took notice. Esthetician Chizu Saeki's The Japanese Skincare Revolution ($14) has recently been translated to English, and it draws upon her 45 years of beauty industry experience.

Focusing on a simple, cost-effective approach, the majority of this short read centers on positive thinking (quit zeroing in on those spots and fine lines) and ideas for tweaking products you already have. The most important tool for beauty? Your hands, says Saeki.

What separates this book from others is her fun ideas: a DIY lotion mask made with cotton pads, a honey lip treatment, a shower cap steam pack (scary looking, but effective), and a water bottle face massage that I'm dying to try. Interactive and engaging, Saeki also includes surveys to help you determine what type of skin you have and tests to determine elasticity, moisture levels, and symmetry of the face (my right side is the "slacker" side). We all know we don't need to spend a fortune to look like a million bucks, and I'm all for Saeki's feel-good message. It's like having an older, sage relative dishing advice. "Take in beauty with all your senses," she says. And now I'm off to practice my facial exercise routine by reciting the five Japanese vowels: ah-ay-ee-oh-oo.

Hepatitis

FitSugar — Wed, 08 Oct 2008 17:35:31 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

In 2006, the FDA approved telbivudine (Tyzeka), a new type of nucleoside analog drug, for treatment of chronic hepatitis B. There are now six drugs approved for hepatitis B treatment.
In 2007, the FDA approved HepaGam B, an intravenous immune globulin drug, for preventing hepatitis B recurrence following liver transplantation.

Drug Warning

In 2007, the FDA revised the prescribing label for entecavir (Baraclude), a drug used to treat hepatitis B. The new label advises against using entacavir in patients infected with both hepatitis B and HIV who are not receiving antiretroviral (anti-HIV) therapy.

Hepatitis C May Increase Lymphoma Risk

Hepatitis C infection increases the risk for developing non-Hodgkin’s lymphoma (NHL) by 20 - 30%, according to a 2007 study of male war veterans published in the Journal of the American Medical Association.

Causes of Death in Hepatitis B and C

Liver disease in general, and liver cancer in particular, is the leading cause of death in patients infected with hepatitis B, according to a 2006 study in the Lancet. Hepatitis B is the leading cause of liver cancer.
Patients with hepatitis C are also at high risk for death from liver disease. However, the Lancet study indicated that young women with hepatitis C face an even higher risk of dying from illegal intravenous drug use.

Drug Research

Adefovir (Hepsera) is commonly used to treat hepatitis B, but many patients eventually develop drug resistance. A 2006 study suggested that adefovir works well for about 5 years, with resistance occurring in about 20% of patients.
Combination treatment with pegylated interferon and ribavirin is an effective treatment for hepatitis C, but causes many side effects. Researchers are studying whether some patients may be able to succeed with a shorter course of treatment. Unfortunately, a 2007 New England Journal of Medicine study suggested that 16 weeks of treatment does not work as well as the standard 24-week course.

Introduction

Hepatitis is a disorder in which viruses or other mechanisms produce inflammation in liver cells, resulting in their injury or destruction. The liver is the largest organ in the body, occupying the entire upper right quadrant of the abdomen. It performs over 500 vital functions including:

The liver processes all of the nutrients the body requires, including proteins, glucose, vitamins, and fats.
The liver manufactures bile, the greenish fluid stored in the gallbladder that helps digest fats.
One of the liver's major contributions is to render harmless potentially toxic substances, including alcohol, ammonia, nicotine, drugs, and harmful by-products of digestion.
Old red blood cells are removed from the blood by the liver and spleen, and the iron contained in them is recycled to the bone marrow to make new red blood cells.

The esophagus, stomach, large and small intestine -- aided by the liver, gallbladder, and pancreas -- convert the nutritive components of food into energy and break down the non-nutritive components into waste to be excreted.

Damage to the liver can impair these and many other processes. Hepatitis varies in severity from a self-limited condition with total recovery to a life-threatening or life-long disease. It can occur from many different causes:

In the most common hepatitis cases (viral hepatitis), specific viruses incite the immune system to fight off infections. Specific immune factors become over-produced that cause injury.
Hepatitis can also result from an autoimmune condition, in which abnormal immune factors attack the body's own liver cells.
Inflammation of the liver can also occur from medical problems, drugs, alcoholism, chemicals, and environmental toxins.

No matter what the cause of hepatitis, it can take either an acute (short term) or chronic (long term) form. In some cases, acute hepatitis develops into a chronic condition, but chronic hepatitis can also occur on its own. Although chronic hepatitis is generally the more serious condition, patients having either condition can experience varying degrees of severity.

Acute Hepatitis. Acute hepatitis can begin suddenly or gradually, but it has a limited course and rarely lasts beyond 1 or 2 months. Usually, there is only spotty liver cell damage and evidence of immune system activity. Rarely, acute hepatitis can cause severe, even life-threatening, liver damage.

Chronic Hepatitis. The chronic forms of hepatitis last for prolonged periods. Doctors usually categorize chronic hepatitis by indications of severity:

Chronic persistent hepatitis is usually mild and nonprogressive or slowly progressive, causing limited damage to the liver.
Chronic active hepatitis involves extensive liver damage and cell injury beyond the portal tract.

Click the icon to see an image of aggressive hepatitis.

Most cases of hepatitis are caused by viruses that infect liver cells and begin replicating. They are defined by the letters A through G:

Hepatitis A, B, and C are the most common viral forms of hepatitis. Investigators are still looking for additional viruses that may be implicated in hepatitis unexplained by the current known viruses.
Other hepatitis viruses include hepatitis E and hepatitis G. Like hepatitis A, hepatitis E is caused by contact with contaminated food or water. It is not serious except in pregnant women, when it can be life threatening. Hepatitis G is always chronic and most likely has the same modes of transmission as hepatitis C. It does not appear to have serious effects.

Scientists do not know exactly how these viruses actually cause hepatitis (inflammation in the liver). As the virus reproduces in the liver, several proteins and enzymes, including many that attach to the surface of the viral protein, are also produced. Some of these may be directly responsible for liver damage. Researchers are investigating elevated levels of specific immune factors, including T cell sub-types in the liver of hepatitis C and B patients. T cells are important infection fighters in the immune system that in some cases release powerful inflammatory substances (tumor necrosis factor and interferon gamma) that can cause considerable damage leading to hepatitis B or C.

Autoimmune chronic hepatitis accounts for about 20% of all chronic hepatitis cases. Like other autoimmune disorders, this condition develops because a genetically defective immune system attacks the body's own cells and organs (in this case the liver). The attack is triggered by an environmental factor, probably a virus. Suspects include the measles virus, a hepatitis virus, or the Epstein-Barr virus, which causes mononucleosis. It is also possible that a reaction to a drug or other toxin that affects the liver also triggers an autoimmune response in susceptible individuals. In about 30% of cases, autoimmune hepatitis is associated with other disorders that involve autoimmune attacks on other parts of the body.

Alcohol. About 10 - 35% of heavy drinkers develop alcoholic hepatitis. In the body, alcohol breaks down into various chemicals, some of which are very toxic to the liver. After years of drinking, liver damage can be very severe, leading to cirrhosis in about 10 - 20% of cases. Although heavy drinking itself is the major risk factor for alcoholic hepatitis, genetic factors may play a role in increasing a person's risk for alcoholic hepatitis. Women who abuse alcohol are at higher risk for alcoholic hepatitis and cirrhosis than are men who drink heavily. High-fat diets may also increase the risk in heavy drinkers.

Drugs. Because the liver plays such a major role in metabolizing drugs, hundreds of medications can cause reactions that are similar to those of acute viral hepatitis. Symptoms can appear anywhere from 2 weeks to 6 months after starting drug treatment. In most cases, they disappear when the drug is withdrawn, but in rare circumstances they may progress to serious liver disease. Drugs most noted for liver interactions include halothane, isoniazid, methyldopa, phenytoin, valproic acid, and the sulfonamide drugs. Very high doses of acetaminophen (Tylenol) have been known to cause severe liver damage and even death, particularly when used with alcohol.

Nonalcoholic fatty liver disease (NAFLD) affects between 10 - 24% of the population. It covers several conditions, including nonalcoholic steatohepatitis (NASH). NAFLD has features similar to alcoholic hepatitis, particularly a fatty liver, but it occurs in individuals who drink little or no alcohol. Severe obesity and diabetes are the major risk factors for NAFLD as well as complications from NAFLD. NAFLD is usually benign and very slowly progressive. In certain patients, however, it can lead to cirrhosis, liver failure, or liver cancer. [For more information, see In-Depth Report #75: Cirrhosis.]

Diagnosis

In people suspected of having or carrying viral hepatitis, doctors will measure certain substances in the blood.

Bilirubin. Bilirubin is one of the most important factors indicative of hepatitis. It is a red-yellow pigment that is normally metabolized in the liver and then excreted in the urine. In patients with hepatitis, the liver cannot process bilirubin, and blood levels of this substance rise. (High levels of bilirubin cause the yellowish skin tone, known as jaundice.)
Liver Enzymes (Aminotransferases). Enzymes known as aminotransferases, including aspartate (AST) and alanine (ALT), are released when the liver is damaged. Measurements of these enzymes, particularly ALT, are the least expensive and most noninvasive tests for determining severity of the underlying liver disease and monitoring treatment effectiveness. Enzyme levels vary, however, and are not always an accurate indicator of disease activity. (For example, they are not useful in detecting progression to cirrhosis.)

Blood is drawn from a vein (venipuncture), usually from the inside of the elbow or the back of the hand. A needle is inserted into the vein, and the blood is collected in an air-tight vial or a syringe. Preparation may vary depending on the specific test.

Radioimmunoassays. To identify the particular virus causing hepatitis, blood tests called radioimmunoassays are performed. Typically, radioimmunoassays identify particular antibodies, which are molecules in the immune system that attack specific antigens. (Antigens are any molecules that the body considers threatening or dangerous and which can be targeted by antibodies.) Some of these tests can pinpoint hepatitis antigens directly. These tests, however, have limitations:

There may not be sufficient numbers of antibodies to be detectable by blood tests for up to weeks or months after hepatitis develops. Blood tests that are taken too early may miss these signs of infection.
Antibodies also linger after patients recover, so a positive antibody test can indicate a previous infection but does not necessarily determine if the infection is active.

The assays for individual hepatitis viruses may differ.

Polymerase Chain Reaction. In some cases of hepatitis C, a polymerase chain reaction (PCR), may be performed. PCR is able to make multiple copies of the virus’ genetic material to the point where it is detectable.

A liver biopsy may be performed for acute viral hepatitis caught in a late stage or for severe cases of chronic hepatitis. No laboratory tests for enzyme or viral levels can truly determine the actual damage to the liver. A biopsy helps determine treatment possibilities, the extent of damage, and the long-term outlook.

The biopsy requires abdominal surgery, most often laparoscopy. This procedure takes about an hour. It requires general anesthesia and involves the following steps:

The surgeon makes one or more small incisions (about 0.5 - 1.0 inch) in the abdomen.
Carbon dioxide or nitrous oxide is delivered through the incision to inflate the abdomen so that the involved area is visible.
The surgeon inserts a thin tube, called a laparoscope, which contains a tiny camera. Surgical instruments are also inserted through the incision to remove the liver tissue for biopsy.

Click the icon to see an explanation of liver biopsy.

A less invasive procedure, called a minilaparoscopy, uses a smaller scope and may prove to reduce the time of the procedure.

Patients with cirrhosis are usually screened for liver cancer using tests for a substance called alpha-fetoprotein (AFP) and ultrasound. It is not known, however, if such screening has much impact on survival, since it is not very sensitive and has a high rate of false positives (suggesting the presence of cancer when it is not actually present). Screening is not necessary in patients without cirrhosis.

Hepatitis A

About a third of the U.S. population has antibodies to hepatitis A, indicating previous infection by the virus. The hepatitis A virus infects up to 200,000 Americans every year and causes symptoms in about 134,000 of them. Almost 30% are children under age 15.

Hepatitis A (formerly called infectious hepatitis) is excreted in feces and transmitted by contaminated food and water. Eating shellfish taken from sewage-contaminated water is a common means of contracting hepatitis A. Infected people can transmit it to others if they do not take strict sanitary precautions. Hepatitis A is infectious for 2 - 4 weeks before symptoms develop and for a few days afterward.

People at risk for passing the infection along or being infected include:

International travelers. Hepatitis A is the hepatitis strain people are most likely to encounter in the course of international travel. In fact, in spite of the availability of a vaccine, the increase in travel to underdeveloped countries has kept the incidence of hepatitis A steady in Western nations. The incidence may even be increasing.
Day care employees and children. It is estimated that between 11 - 16% of hepatitis A cases occur among day care employees and children who attend day care. The risk for children attending day care is very low, however, if hygienic precautions are used, particularly when changing babies and handling diapers.
Sexually active homosexual men.
Intravenous drug users.
Health care, food industry, and sewage workers.

A fly may act as a mechanical vector of diseases such as hepatitis A, which means the fly carries the infective organism on its feet or mouth parts and contaminates food or water which a person then consumes. A biological vector actually develops an infective organism in its body and passes it along to its host, usually through its saliva. A fly can be a biological vector, as in the transmission of leishmaniasis by the sandfly.

Symptoms of acute viral hepatitis may begin suddenly or develop gradually. They may be so mild that patients mistake the disease for the flu. They include:

Nearly all patients experience some fatigue and often have mild fever.
Gastrointestinal problems are very common, including nausea, vomiting, a general feeling of discomfort in the abdomen, or a sharper pain that may occur in the upper right area of the abdomen. This pain tends to increase during jerking movements, such as climbing stairs or riding on a bumpy road.
Gastrointestinal problems can also lead to loss of appetite, weight loss, and dehydration.
After about 2 weeks, dark urine and jaundice (a yellowish color in the skin and whites of the eyes) develops in some, but not all, patients. (Children tend not to develop jaundice.)
About half of all patients have light colored stools, muscle pain, drowsiness, irritability, and itching, usually mild.
Diarrhea and joint aches occur in about a quarter of patients.
The liver may be tender and enlarged, and most people have mild anemia.
In about 10% of patients, the spleen is enlarged.

Travelers should take the following precautions:

Get vaccinated against hepatitis A and possibly B if traveling for long periods of time to countries where epidemics occur.
Use only carbonated bottled water for brushing teeth and drinking. (Remember that ice cubes can carry infection.) Boiling water is the best method for eliminating infectious organisms. Bringing the water to a good boil for at least a minute generally renders it safe to drink.
Heated food should be hot to the touch and eaten promptly.
Don’t buy food from street vendors.
Beware of sliced fruit that may have been washed in contaminated water. Travelers themselves should peel all fresh fruits and vegetables.
Avoid dairy products.
Avoid raw or undercooked meat and fish.

Two vaccines (Havrix, Vaqta) are now available, both very safe and effective for preventing hepatitis A (HAV). They can be given along with immune globulin and other vaccines. A combination Hep A - Hep B vaccine (Twinrix) that contains both Havrix and Engerix-B (a hepatitis B vaccine) is also available.

Click the icon to see a discussion of hepatitis A vaccine.

Candidates for HAV Vaccinations. Vaccinations for hepatitis A are recommended for:

Children age 12 - 23 months (the U.S. Centers for Disease Control and Prevention recommends that children receive the first dose of the hepatitis A vaccine when they are 12 months old, and a second dose 6 months later). Hepatitis A used to affect mostly children, but now occurs mostly in adults.
Travelers to developing countries. (Travelers should also receive immune globulin if they are visiting high-risk areas within 4 weeks of the vaccination.)
Sexually active homosexual men
Illegal drug users, especially those who inject drugs
Health care workers
People with chronic liver disease
People with hemophilia or other blood-clotting disorders

Side Effects. Although there are few side effects, allergic responses from the vaccination can occur. Hair loss has been reported in very few people after a second administration. There may be pain at the injection site. (Havrix causes more pain at the injection site than Vaqta.)

Symptoms are usually mild, especially in children, and generally appear between 2 - 6 weeks after exposure to the virus. Adult patients are more likely to have fever, jaundice, and itching that can last up to several months.

Hepatitis A is the least serious of the common hepatitis viruses. It does not directly kill liver cells, and there is no risk for a chronic form. Severe (fulminant) hepatitis is the only major concern, but even if it develops, it is almost always less dangerous than with other viral types. Only 1 in a 1,000 patients is at risk for death from this complication. If hepatitis A infection occurs in patients with hepatitis C, however, superinfections can occur, even without cirrhosis, leading to a life-threatening form of fulminant hepatitis. (Infection of patients with hepatitis B who do not have cirrhosis does not appear to be as dangerous.)

Radioimmunoassays are generally used to identify IgM antibodies, first produced to fight hepatitis A. They appear early in the course of the disease and usually can be identified as soon as symptoms appear. IgM antibodies disappear during recovery, but those known as IgG antibodies persist, and their presence can be used to indicate a previous infection.

The primary goals for managing acute viral hepatitis are to provide adequate nutrition, to prevent additional damage to the liver, and to prevent transmission to others.

Precautions for Preventing Transmission of Hepatitis A. Because hepatitis A and hepatitis E are usually passed through contaminated food, people with these viruses should not prepare food for others. Unfortunately, these viruses are most contagious before symptoms appear.

Using hot water when cleaning utensils or clothing is essential. Heating a contaminated article for 1 minute kills the virus. Simple household bleach is effective for disinfecting hard surfaces. Sterilizing is not necessary. Still, even with strong precautions, utensils used by the patient for eating and cooking should be kept separate from those used by others.
Abstain from sexual activity or take strict precautions.
Abstain from alcohol. Moderate drinking after recovery is not harmful for most people.

Hepatitis B and D

Hepatitis B and D were formerly called serum hepatitis. Hepatitis B is mainly transmitted through blood transfusions, contaminated needles, and sexual contact. Blood screening has reduced the risk from transfusions. It can also be passed from cuts, scrapes, and other breaks in the skin. Hepatitis D virus can replicate only by attaching to hepatitis B and therefore cannot exist without the B virus being present.

Risk Factors for Hepatitis B. About 1.2 million Americans are chronically infected with hepatitits B and between 20 - 30% acquired the infection when they were children. Men are at higher risk than women. Among ethnic groups living in the United States, Asians are at highest risk, due to the high rate of hepatitits B in Asian countries. Fortunately, in the US the number of new infections has declined dramatically -- by 67% between 1990 and 2002. In 2003, 7,526 cases were reported compared to over 20,000 in 1990. The greatest decrease has occurred in children. Among young adults and people living in the Northeast, however, the incidence has increased since 1999. This may indicate that sexual activity is an important route for viral transmission and that the protective effect of the vaccine has not yet reached older, high-risk groups. Also, as with hepatitis A, the increase in travelers to underdeveloped nations may be responsible for the steady rate.

Hepatitits B is far more common overseas and about 600,000 people die each year from conditions, such as liver cancer or cirrhosis, that are related to chronic hepatitis B. Nearly 70% of these infections were acquired during infancy or early childhood.

People at risk include:

Drug users who share needles.
Children of infected mothers. Pregnant women with hepatitis B can transmit the virus to their babies. Even if they are not infected at birth, unvaccinated children of infected mothers run a 60% risk of developing hepatitits B before age 5. Children are more likely than adults to become chronic carriers, although between 6 - 12% of children spontaneously recover each year.
People with multiple sex partners or other high-risk sexual behavior.
Hospital workers and others exposed to blood products. Contaminated medical instruments, including fingerstick devices used for more than one individual, have been known to transmit the virus.
Staff members and clients of institutions for the developmentally disabled.
Prisoners.
Immigrants from areas where the disease rate is high. (International travelers who spend long periods in such areas may also be at risk.)

People at highest risk for becoming chronic carriers of the virus include:

Children infected before age 5, including newborns, most of whom become carriers.
Infected people with damaged immune systems, such as AIDS patients.

Risk Factors for Hepatitis D. Hepatitis D occurs only in people with hepatitis B. It is not common in the U.S. and the incidence of this hepatitis is declining rapidly overseas. Experts anticipate that it will be extremely rare in the near future. Those who recover from hepatitis B are immune to further infection from both hepatitis B and D viruses.

The following are some precautions for preventing the transmission of hepatitits B or hepatitits C:

All objects contaminated by blood from patients with hepatitis B or C must be handled with special care. (Restrictions on food preparation are not necessary for these hepatitis viruses.)
Patients with viral hepatitis should abstain from sexual activity or take strict precautions. Infected patients should use condoms and contraceptives that prevent passage of the virus, possibly even in relationships that last for years. Women partners or infected women should abstain from sexual activity during menstruation. Either partner with infections that cause bleeding in the genital or urinary areas should avoid sexual activity until the infection is no longer active.
Couples with an infected partner or people sharing household with an infected person should avoid sharing personal items, such as razors or toothbrushes.

Note: There is no evidence that the viruses can be passed through casual contact, or other contact without exposure to blood, including kissing, hugging, sneezing, or coughing or by sharing eating utensils or drinking glasses. People infected with chronic hepatitis B or C should not be excluded from work, school, play, childcare or any social or work settings on the basis of their infection.

Symptoms appear long after the initial infection, usually 4 - 24 weeks. Many patients may not even experience them or they may be mild and flu-like. About 10 - 20% of patients have a fever and rash. Nausea is not common. Sometimes there is general aching in the joints. The pain can resemble arthritis, affecting specific joints and accompanied by redness and swelling.

Most people with hepatitis B recover from the virus. The risk of progressing to the chronic form of hepatitis B is age dependent. Only 2 - 6% of people who are older than 5 years old when they acquire the virus will develop chronic hepatitis B. The risk for chronic hepatitis in children age 1 - 5 years is 30%, and the risk for infants under the age of 1 is up to 90%. In the U.S., about 1.25 million people are chronically infected with hepatitis B. Worldwide, about 400 million people are chronically infected.

Chronic hepatitis B infection significantly increases the risk for liver damage, including cirrhosis and liver cancer. In fact, hepatitis B is the leading cause of liver cancer worldwide. According to a 2006 Lancet study, liver disease, especially liver cancer, is the main cause of death in people with chronic hepatitis B. Because of these high risks, it is very important that patients with chronic hepatitis B receive regular screenings for liver cancer.

Patients with hepatitis B who are co-infected with hepatitis D may develop a more severe form of acute infection than those who have only hepatitis B. Co-infection with hepatitis B and D increases the risk of developing acute liver failure. Patients with chronic hepatitis B who develop chronic hepatitis D also face high risk for cirrhosis. Hepatitis D occurs only in people who are already infected with hepatitis B.

A diagnosis of hepatitis B relies on measuring the liver enzymes aspartate (AST) and alanine (ALT) -- released when the liver is damaged -- assays to identify the viral DNA, and a liver biopsy.

Doctors must then determine if the condition is chronic but inactive or whether it is more aggressive. This is done by identifying a specific antigen called HBsAg, which is a protein that is found in the blood in early stages of hepatitis B and suggests the presence of a viral replication. Most people develop antibodies to this antigen during convalescence. Their condition is referred to as HBeAG negative, or anti-HBe, and suggests that infection is on the wane. About 5 - 10% of people do not clear the infection but become carriers of the antigen (called HBsAG-positive). Evidence of its persistence for more than 6 months suggests that the condition is chronic.

Tests can identify specific genetic types of hepatitis B virus (designated A to G). It is not clear how significant they are in treating patients with hepatitits B.

It is important to remember, however, that viral levels are not an accurate measure of actual liver damage. Only a biopsy can determine this.

To diagnose hepatitis D using an antibody test, hepatitis B must already have been identified.

General precautions for preventing hepatitis B when traveling are the same as those for hepatitis A. In infected people, precautions for preventing transmission are similar to those for hepatitis C.

Vaccinations for Prevention of Hepatitis B. Several inactivated virus vaccines, including Recombivax HB, GenHevac B, Hepagene, and Engerix-B, can prevent hepatitis B and are safe even for infants and children. A triple-antigen hepatitis B vaccine (Hepacare) is proving to be effective for people who do not respond to the standard vaccines. Vaccination programs are also helping to reduce the risk for liver cancer. A combination vaccine (Twinrix) that contains Engerix-B and Havrix, a hepatitis A vaccine, is now approved for people with risk factors for both hepatitis A and B.

Click the icon to see an image discussing hepatitis B vaccine.

Until recently, the vaccine contained a mercury-based preservative called thimerosal. In response to concerns, professional organizations recommended suspending vaccinations in infants with noninfected mothers. In 1999, a thimerosal-free vaccine became available, and medical centers are now urged to continue vaccinations. Unfortunately, even after the thimerosal-free vaccine became available, a number of hospitals still have not restored vaccination of all infants. This is a safe vaccine. Parents should be sure their children are immunized.

Candidates for Hepatitits B Vaccinations. Experts now recommend that all infants and children not previously vaccinated be immunized by the time they reach seventh grade.

Typical schedules for hepatitis B vaccinations in childhood are as follows:

All infants should receive the hepatitis B vaccine soon after birth and before hospital discharge. (The first dose may be given by age 2 months if the mother has no evidence of infection. Infants of mothers infected with hepatitits B should be treated with immune globulin plus the hepatitis vaccine within 12 hours of birth. Vaccinating the newborn prevents infection from being transmitted from mother to child.)
The second dose should be given at least 4 - 6 weeks after the first dose. The third dose is given at least 8 weeks after the second dose (typically when the baby is 6 - 23 months old).
Children who are 11 - 12 years old and who have not been immunized should receive two or three doses of the vaccine (depending on the brand) given over a few months.

Hepatitis B vaccine protection lasts at least 10 years. Booster shots after that may be recommended, depending on continuing risk such as sexual exposure.

The following adults are at very high risk and should be vaccinated:

Health care and public safety workers who may be exposed to blood products. Such individuals have a risk for hepatitis B virus that ranges from 15 - 30%.
People in the same household as hepatitits B infected individuals. (Unvaccinated people who have had intimate exposure to people with hepatitits B may be protected with immune globulin, which is sometimes administered with the vaccine.)
Travelers to developing countries.
Patients who require transfusions and have not been infected with hepatitits B. (Those with blood clotting disorders should have the vaccination administered under the skin, not injected in the muscle.)
Sexually active homosexual or heterosexual individuals with multiple partners or who engage in high-risk sexual behavior.
People with any sexually transmitted diseases.

Other people at risk who may benefit from vaccinations include:

Patients and workers in mental institutions and morticians.
Patients on hemodialysis. (People on hemodialysis may need larger doses or boosters. They also may need to be re-vaccinated if blood tests indicate they are losing immunity.)
People who use injected drugs.
Pregnant women at risk for the virus should be vaccinated. There is no evidence that the vaccine is dangerous to the fetus.
People receiving treatments or who have conditions that suppress the immune system may need the vaccination, although its benefits for this group are unclear except for those at high risk, such as people with HIV or spleen abnormalities.

The regimen in adults is typically three doses given over 6 months. People with alcoholism may need high doses.

Soreness at the injection site is the most common side effect. There have been some reports of nerve inflammation after vaccinations for hepatitis B, and there has been some concern about three small studies associating the vaccine with an insignificant increase in multiple sclerosis. Recent studies, however, have found no evidence to support these concerns. Nonetheless, some groups oppose the vaccination in children who are not in high-risk groups. It should be strongly stressed that worldwide 65 million people with chronic hepatitis are expected to die from liver disease. Vaccinations save lives. For example, in Taiwan, where infection rates are high and infants are at risk for hepatitis B from infected mothers, vaccination programs have significantly reduced the risk for liver cancer.

Six drugs are currently approved in the United States for treatment of chronic hepatitis B:

Peginterferon alfa-2a (Pegasys)
Interferon-alfa-2b (Intron)
Adefovir (Hepsera)
Lamivudine (Epivir)
Entecavir (Baraclude)
Telbivudine (Tyzeka)

These drugs block the replication of hepatitits B in the body. Some also help boost the immune system. A doctor will decide which drug to prescribe based on a patient’s age, disease severity, and other factors. Each drug has various advantages and disadvantages in terms of cost, efficacy, side effects, and likelihood of drug resistance. A combination of drugs may also be prescribed.

Peginterferon alfa-2a. Peginterferon alfa-2a (Pegasys) was approved in 2005 for treatment of chronic hepatitis B. (Peginterferon is also called pegylated interferon.) The drug was previously approved in 2002 for treatment of chronic hepatitis C. Pegasys prevents the hepatitis B virus from replicating and also helps boost the immune system. It is given as a weekly injection. Peginterferon is sometimes prescribed in combination with lamivudine (Epivir).

Interferon Alpha. For many years, interferon alfa-2b (Intron) was the standard drug for hepatitis B. The drug is usually taken by injection every day for 16 weeks. (It does not appear to help hepatitis D.) Unfortunately, even in hepatitis B, the virus recurs in almost all cases, although this recurring mutation may be weaker than the original strain. Administering the drug for longer periods may produce sustained remission in more patients while still being safe. Interferon is also effective in eligible children, although long-term effects are unclear.

Lamivudine,Entecavir, and Telbivudine. These drugs are classified as nucleoside analogs. Lamivudine (Epivir or 3TC) is an antiretroviral drug that is used to treat human immunodeficiency virus (HIV) as well as hepatitis B. Studies suggest that lamivudine reduces viral count in over half of hepatitis B patients who take it as sole therapy for about a year. It is less expensive than interferon-alfa and has fewer side effects, but may not work as well as interferon-alfa for long-term therapy. A major problem with lamivudine is the development of mutated viral strains that become resistant to the drug, particularly in areas where the virus is common. About 20% of patients who take lamivudine develop drug resistance.

In 2005, the FDA approved entecavir (Baraclude) for treatment of adults with chronic hepatitis B. In clinical trials, entecavir worked better than lamivudine for treating hepatitits B. Entecavir appears to have less risk of drug resistance than lamivudine. Studies also suggest that it may be a good alternative treatment for patients who have developed resistance to lamivudine. Questions have been raised about the drug’s possible cancer risks. Ongoing studies are evaluating this risk.

In 2006, the FDA approved telbivudine (Tyzeka), the newest nucleoside analog drug, for treatment of chronic hepatitis B.

Adefovir. Adefovir (Hepsera) belongs to a class of antiviral drugs called nucleotide analogs. (Nucleotides are related to nucleosides but have a slightly different chemical structure.) Nucleotide analogs block an enzyme involved in the replication of viruses. Adefovir costs more than lamivudine, but may be effective against lamivudine-resistant strains of hepatitits B. The drug must be taken on a long-term basis. A 2006 study indicated that when patients stopped taking adefovir after 48 weeks, the hepitatis B virus resumed replication. Patients who took the drug for a longer period (144 weeks) continued to benefit from treatment. Another 2006 study indicated that for some patients, adefovir remains effective for up to 5 years, although resistance occurs in about 20% of patients.

Drug Warnings. In 2004, the FDA issued two drug warnings for patients with hepatitits B. The HIV drug tenofovir (Viread) should not be used to treat patients with HIV who are co-infected with hepatitits B as the drug may increase hepatitis severity. The lymphoma drug rituximab (Rituxan) may reactivate hepatitits B. Patients with lymphoma should be screened for hepatitits B. In 2007, the FDA revised the label for entecavir (Baraclude); patients who are co-infected with hepatitits B and HIV should take entecavir only if they are also taking antiretroviral HIV drugs.

Investigational Drugs.

Emtricitabine is a nucleoside analog drug used to treat HIV and AIDS. It is being investigated for chronic hepatitits B.
Pegylated interferon alfa-2b (Peg-Intron) and alfa-2a (Pegasys) are approved for treatment of chronic hepatitis C. They are being investigated alone and in combination with other drugs, such as ribavirin (Copegus, Rebetol), for treatment of hepatitits B. The combination of pegylated interferon and ribavirin is the standard treatment for hepatitis C.
Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a substance derived from the thymus gland (which is responsible for maturation of immune factors called T-cells). It appears to be safe for hepatitis B patients when used alone or in combination with interferon. It is approved in many countries, but not the United States.

Liver Transplantation. If the disease progresses to liver failure, liver transplantation may be an option. It is not foolproof, however. Viral recurrence is high in patients with hepatitis B. However, regular, lifelong injections of hepatitis B immune globulin (HepaGam B) can reduce the risk for re-infection following liver transplantation.

Hepatitis C

Hepatitis C is spread by contact with infected human blood. It is the most common blood-borne infection in the country. Until blood screening began in 1990, the hepatitis C virus was primarily transmitted through blood transfusions. Now, hepatitis C is transmitted mainly through intravenous drug use and sharing needles. Nearly half of people infected with hepatitis C have a history of injecting drugs. People who received a blood transfusion before 1992 are also at high risk, as are people who have had 20 or more sexual partners. Hepatitis C can also be passed from an infected mother to her baby during birth. (Breast-feeding does not increase the risk of transmission.)

Click the icon to see an image discussing hepatitis C.

About 4 million Americans have had an initial hepatitis C infection and an estimated 3.2 million have chronic hepatitis C. Hepatitis C affects about 170 million people worldwide. Most people with chronic hepatitis C are unaware that they have it. It is not possible to predict which patients will develop the chronic form of hepatitis C.

Ethnic Groups. In general, hepatitis C occurs most commonly in non-Caucasian men ages 30 - 49 years. Over 6% of African-Americans are infected with hepatitis C, about two to three times the risk for Caucasians.

Most patients with hepatitis C do not experience symptoms. If they appear at all, symptoms develop about 1 – 2 months after a person is infected. Symptoms of progressive chronic viral hepatitis may be very subtle. In some patients, itchy skin is the first symptom. Overall, fatigue is the most common symptom. Many patients do not experience any symptoms at all. Chronic hepatitis C can be present for 10 - 30 years, and cirrhosis or liver failure can sometimes develop before patients experience any clear symptom.

Some evidence suggests, however, that patients with chronic hepatitis C often experience an impaired quality of life, mostly from fatigue. Fatigue can impair daily function, vitality, and mood in ways that are similar to other chronic diseases. The severity of the fatigue is not necessarily related to the degree of liver injury. Some patients develop pain in small joints in the body (such as the hand) that may be nearly indistinguishable from symptoms of rheumatoid arthritis, fibromyalgia, or carpal tunnel syndrome. Recent research suggests that sexual dysfunction may be common among men with chronic hepatitis C. Other nonspecific symptoms include abdominal discomfort, loss of appetite, depression, and difficulty concentrating.

Acute Form. Acute hepatitis C is rarely recognized, since there are no symptoms in up to 80% of patients. About 15 - 45% of acute cases clear up on their own without becoming chronic. Early treatment with interferon drugs can significantly reduce the risk for progression to chronic hepatitis.

Chronic Form. About 55 - 85% of infected people develop chronic hepatitis. Chronic hepatitis C poses a risk for cirrhosis, liver cancer, or both.

Five - 20% of patients with chronic hepatitis C develop cirrhosis over a period of 20 – 30 years. The longer the patient has had the infection, the greater the risk. Patients who have had hepatitis C for more than 60 years have a 70% chance of developing cirrhosis.
Seventy percent of patients with chronic hepatitis C eventually develop chronic liver disease.
Of these patients, 4% eventually develop liver cancer. (Liver cancer rarely develops without cirrhosis first being present.)

About 1 - 5% of people with chronic hepatitis C eventually die from liver diseases (cirrhosis or liver cancer). However, according to a 2006 Lancet study, intravenous drug-related deaths are more common than liver-related deaths among younger female patients (ages 15 - 24) infected with hepatitis C or hepatitis C and B.

Patients with chronic hepatitis C may also be at higher risk for non-liver disorders, including the following:

Cryoglobulinemia (a disorder in which protein clumps form in the blood). This can cause skin rash and ulcers, kidney problems, arthritis, and sensations (such as tingling or pain) in the hands and feet. People with such symptoms may have particular difficulties with interferon, which can have similar side effects.
Porphyria cutanea tarda (a disorder that causes skin color and texture changes and sensitivity to light).
Certain autoimmune disorders, particularly hypothyroidism and rheumatoid arthritis.
Type 2 diabetes, particularly among younger people with hepatitis C who are overweight.
Some experts believe that hepatitis C may infect the central nervous system in certain patients, possibly accounting for the fatigue, depression, or both experienced by patients who have even relatively mild cases.
Certain types of lymphomas (cancers of the lymphatic system). According to a 2007 study in the Journal of the American Medical Association, hepatitis C infection increases the risk of developing non-Hodgkin’s lymphoma by 20 - 30%. The risk for a particular type of non-Hodgkin’s lymphoma, Waldenstrom’s macroglobulinemia, increases by 300%. However, this study only evaluated male Vietnam War veterans, so these risks may not apply to the general public.

Tests for Liver Enzymes. Blood tests showing elevated liver enzymes, particularly alanine aminotransferase (ALT), plus symptoms of hepatitis (jaundice, fatigue) are often first signs of acute hepatitis. In chronic hepatitis, however, liver enzymes may be normal or fluctuate. They also can be elevated even after the virus has cleared.

Tests to Identify the Virus. The standard first test for diagnosing hepatitis C is known as enzyme-linked immunosorbent assay (ELISA or EIA). The antibody for hepatitis C is used to identify the virus. The antibody may not show up for 6 weeks to 1 year after the onset of the disease, however, so its absence is not necessarily an indication of a healthy liver. A test called an immunoblot assay (called RIBA) may also be used to confirm the presence of the virus. An accurate home test (Hepatitis C Check) is now available. It supplies a lancet for obtaining a drop of blood, which is sent to the laboratory for EIA and possibly RIBA analysis. Results take about a week.

Tests to Identify Genetic Types and Viral Load. Additional tests called hepatitis C RNA assays may be used to confirm the diagnosis. They use a polymerase chain reaction (PCR) to detect the RNA (the genetic material) of the virus. Such tests may be performed if there is some doubt about a diagnosis but the doctor still firmly believes the virus is present.

hepatitis C RNA assays also determine virus levels (called viral load). Such levels do not reflect the severity of the condition or speed of progression, as they do for other viruses, such as HIV. However, high viral loads suggest a poorer response to treatment with interferons.

Such techniques may also help determine the genotype of the virus, which can be helpful in determining a treatment approach. There are six main genetic types of hepatitis C and more than 50 subtypes. They do not appear to affect the rate of progression of the disease itself, but they can differ significantly in their effects on response to treatment. Genotype 1 is the most difficult to treat and is the cause of up to 75% of the cases in the U.S. The other common genetic types are types 2 (15%) and 3 (7%), which are more responsive to treatment. People with hepatitis C need to have their genotype tested so that doctors can make appropriate treatment recommendations.

Researchers are working on developing a genetic test to identify patients with chronic hepatitis C who are most at risk of developing cirrhosis. In 2007, scientists announced they had made progress on a test that measures variations in seven genes to calculate a “Cirrhosis Risk Score.” The researchers hope that this experimental test may eventually help doctors decide which patients should receive early treatment with alpha-interferon and ribavirin.

Liver Biopsy. Only a biopsy can determine the extent of injury in the liver. Some doctors now recommend biopsies for all patients with chronic hepatitis C, regardless of severity, because of the risk for liver damage even in patients without symptoms. If a biopsy does not show any scarring and liver enzymes are normal, patients can be assured that the outlook is very favorable.

No vaccines are available, but immune globulin helps protect against developing hepatitis C after transfusions. Periodic doses of immune globulin in sexual partners of infected people also appear to be protective. In infected people, preventing transmission is similar to those for hepatitis B.

Interferons. Interferons are natural proteins that activate certain immune functions in the body and have anti-viral properties. The natural interferons used for chronic hepatitis B and C are called type I interferons. They are given by injection, need to be taken three times a week, and include the following:

Interferon alfa 2b (Intron A). Used for both hepatitis B and C.
Interferon alfa 2a (Roferon-A). Mostly used for hepatitis C.
Interferon alfa-n1 (Wellferon). Approved but mostly used in Canada for hepatitis C.

Newer synthetic interferons have been developed that are showing some advantages over the natural forms:

Pegylated interferon (PegINF). Pegylated interferons use a small molecule called polythelene glycol (PEG), which attaches to a protein and extends the activity of the interferon. This action allows the drug to be taken only once a week. Drugs available include pegylated interferon alfa-2b (Peg-Intron) and alfa-2a (Pegasys).
Interferon alfacon-1 (Infergen). This drug is called a consensus interferon (CIFN) because it was genetically developed using the most commonly occurring amino acid sequences from each of the natural type 1 alpha interferons. It is 5 - 10 times more biologically active than natural type 1 interferons. CIFN is usually given three times a week when used as initial treatment for hepatitis C.

Interferon Candidates. The best candidates for interferon treatments are patients who are at greatest risk for cirrhosis. Factors suggesting a higher risk for cirrhosis include:

Detectable virus levels as determined by an assay test.
High levels of aminotransferase enzyme for more than 6 months.
Indication of liver scarring on biopsy.

Patients who are not good candidates for interferon and are usually ineligible include:

Women who are pregnant or planning to become pregnant soon.
Patients with advanced cirrhosis. (It is unclear if the drug improves survival in patients with advanced cirrhosis and, in any case, it may be dangerous for them.)
Patients with fluid in the abdomen (ascites).
Patients with anemia or risk factors for anemia should not take the combination treatments, although they may be candidates for interferon alone.

Several kinds of patients are ineligible for treatment because of the high risk for noncompliance and the severe psychiatric effects of the drugs. They include patients with psychiatric and medical problems and substance abusers. Some doctors believe that these patients could benefit from treatment.

Side Effects and Complications of Treatment with Interferon. Common side effects of any interferon are flu-like symptoms (fever, chills, muscle aches) that usually occur within 6 hours and gradually decline over 1 - 2 weeks. (Pegylated interferon may pose a higher risk for these symptoms than the natural interferons.)

Chronic or more serious effects include:

Emotional and mental changes. Depression can be very severe, and cases of suicidal thoughts have been reported. Other mental and emotional symptoms include anxiety, amnesia, confusion, irritability, impaired concentration, decreased alertness, memory problems, and mental slowing.
Changes in sensation.
Weight loss.
Skin rashes.
Hair loss.
Gastrointestinal problems, including nausea, vomiting, and diarrhea, and, in severe cases intestinal bleeding and ulcers.
Fatigue and general weakness.
Back pain.
Complications in the lungs, including worsening of asthma. In severe cases, interferon can cause shortness of breath, inflammation in the lungs, and pneumonia.
Possible negative effects on cholesterol and lipid levels.
Heart rhythm disturbances, which, in rare cases, can be serious.
Mild anemia.
Drop in platelet and white blood cell counts, increasing susceptibility to bacterial infections.
May trigger an autoimmune response, possibly causing anemia, diabetes, lupus-like symptoms, hypothyroidism, or even autoimmune hepatitis.
Complications in the eye, including bleeding that, in some cases, may lead to loss of vision if not detected promptly.
Rare reports of acute pancreatitis.
In children, interferon therapy temporarily disrupts growth.

Patients have a difficult time with prolonged therapy. Over 20% drop out if treatment lasts longer than 2 years. Depression is the most common reason for stopping the treatment.

Several different methods of administering interferons are under investigation to help reduce some of the problems associated with injections. These methods include pills, pumps, and controlled release implants.

Interferons in Combination with Ribavirin. Ribavirin, a nucleoside analog drug, does not work alone, but it can double sustained response rates when combined with an interferon.

Pegylated interferon combined with ribavirin is the gold standard treatment for chronic hepatitis C in both adults and children. It achieves response rates of up to 50% for patients infected with hepatitis C genotype 1 (the most common genotype form in the U.S.) and up to 80% for patients infected with genotypes 2 or 3. Interferon alone is usually reserved for patients who cannot tolerate ribavirin.

A 2005 study suggested that some patients with hepatitis C genotypes 2 or 3 may be able to benefit from a shorter course of combination treatment (12 weeks) than the standard 24-week treatment duration. A shorter treatment time may reduce the risk of side effects. However, a 2007 study in the New England Journal of Medicine found that 16 weeks of combination therapy in patients with these genotypes did not work as well as the 24-week regimen. Given the significant side effects associated with combination pegylated interferon and ribavirin treatment, particularly anemia, researchers are actively investigating how to identify which patients may be able to succeed with shorter treatment duration.

PegINF combinations may help slow progression of scarring, and have even achieved improvement in some patients who already have cirrhosis. Whether the combination treatment protects against future liver cancer is still unclear. (A higher total dose, rather than a longer duration of treatment, may be the critical factor for protection.)

Side Effects of Combination Treatment. The side effects of the combination include those of both interferon and ribavirin. Interferon side effects may occur more often in the combination treatment. Combination treatment side effects may include:

Anemia occurs in about 22% of patients who take combination treatment versus 1% who take interferon alone. This complication is reversible and usually stabilizes after 1 - 2 months of treatment. However, some patients may become so anemic that they have to stop the medication. Since anemia can worsen heart disease, patients with a history of significant heart problems should not be treated with ribavirin. Other nucleoside analogues are being investigated that may have a lower risk for anemia than ribavirin.
Flu-like symptoms such as fever, headaches, and muscle aches are the most common side effect.
Reduced white blood cell count.
Skin disorders such as dry skin and rash.
Coughing and shortness of breath.
Gastrointestinal symptoms (nausea, indigestion, lack of appetite).
Emotional and psychological symptoms, such as severe sleep disturbances, depression, irritability, and anxiety.
Combination treatment in pregnant women poses a very high risk for birth defects.

Determining Treatment Success. Doctors measure treatment success and approaches based on the patient’s response to the treatments:

Early Response. These are patients who respond to the drug right away. This means that their viral count drops very rapidly within the first few weeks of treatment and is still undetectable at 12 weeks. (One difficulty in deciding when to stop treatment, even in responders, is the inability to predict at 12 weeks which of these patients will relapse and which ones will have a sustained response.)
Sustained Response. Patients who are free of the virus longer than 6 months are considered to be sustained responders. The overall sustained response rates with the current standard combination of pegylated interferon and ribavirin is over 50%, with certain factors predicting higher or lower response rates.
Relapse. In relapse, the virus comes back again and requires retreatment. This is usually due to the development of mutant strains that are resistant to the drugs or because the original dose was too low.
Nonresponse. Patients are considered to be nonresponders if the virus is still detectable 12 weeks after interferon alone or after 24 weeks of combination therapy. Treating these patients again has achieved only a 15% response.

People at Risk for Poor Response to Combination Treatment. The following patients have a greater risk for not responding to combination treatment with interferon and ribavirin:

People at high risk for aggressive hepatitis C.
Having a high viral count.
Having a specific genetic type of the virus. Patients with genotype 1 do not respond as well to combination treatment as patients with genotypes 2 or 3.
Older age (especially older than 60 years).
African-Americans are less responsive to treatment than Caucasians or Asians. The reasons for this are unclear.

Failure can be due to other, modifiable factors, which should be assessed before stopping treatment, particularly in patients who had interferon alone. They include:

Interferon dose was too low.
Patient did not comply fully with the treatment.
Patient was consuming alcohol.
Treatment time was too short. Some evidence suggests that response can significantly improve for many patients with genotype 1 if treatment time is extended to 48 weeks.

Even if viral levels linger, interferon treatment may still have benefits. For example, patients with normal liver enzyme levels appear to have almost no risk for liver damage, even if viral levels persist after treatment. Evidence also suggests that interferon reduces liver scarring and may reduce the risk for liver cancer in some patients, even if the treatment does not eliminate the virus. More research is needed, however, to confirm these findings.

Investigational Drugs for Hepatitis C. The current drugs used for hepatitis C still do not meet the needs of all patients. They are expensive, have significant side effects, do not work in half the patients who take them, and are unsuitable in many others. Investigation is ongoing to find better solutions. Drugs that may show promise include:

Albinterferon alfa-2b (Albuferon). This long-acting form of interferon-alfa may have fewer side effects and require less dosing than pegylated interferons. It is currently being tested in combination with ribavirin in Phase II trials for patients with genotype 1 chronic hepatitis C.
Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors called T cells). It is being used for hepatitis B and is under investigation for hepatitis C in combinations interferon.
Celgosivir. Celgosivir is a new type of antiviral drug, which blocks alpha-glucosidase, an enzyme involved in viral replication. Celgosivir is being studied in combination with pegylated interferon alfa-2b and ribavirin. The drug is derived from the Australian chestnut tree.
Eltrombopag (Revolade). Thrombocytopenia, reduced production of blood platelets, is a condition that affects patients with hepatitis C and cirrhosis. Patients with thrombocytopenia cannot tolerate standard antiviral therapy. Researchers hope that eltrombopag, a drug that stimulates platelet production, may help normalize platelet levels so that they can start antiviral drug treatment.
Statins. Statin drugs are used for the treatment and management of cholesterol. Researchers are studying whether they may help improve liver enzyme levels in patients with hepatitis C.

Other drugs under investigation include vaccines, genetic therapies known as antisense oligonucleotides or monoclonal antibodies, and drugs that will help prevent or reduce progression of liver scarring or progression to liver cancer. Even if successful, none of these drugs will be available for many years.

Liver Transplantation for Hepatitis C. If the disease progresses to the point where it becomes life-threatening, liver transplantation may be an option. Nearly 40% of liver transplant patients are infected with hepatitis C. However, liver transplantation is not a cure for hepatitis C. The virus nearly always returns. One study of patients with hepatitis C reported 5-year risks for viral recurrence of 80% and for cirrhosis of 10%. A 2004 study found that the hepatitis C virus comes back with more severity in livers from living donors than livers taken from cadavers. Researchers are investigating retreatment with antiviral drugs.

In both hepatitis B and C, the disease often persists or returns despite treatment. The virus continually generates many “mutant viruses” that differ just slightly from the parent virus. These mutated viruses may be resistant to interferons and so, over time, the drugs become ineffective.

Autoimmune Hepatitis

Autoimmune chronic hepatitis typically occurs in women ages 20 - 40 who have other autoimmune diseases, including:

Systemic lupus erythematosus
Rheumatoid arthritis
Sjögren's syndrome
Inflammatory bowel disease
Glomerulonephritis
Hemolytic anemia

Some research indicates that the postmenopausal period may be another peak in incidence of autoimmune hepatitis among women. About 30% of patients are men, however, and in both genders there is often no relationship to another autoimmune disease. In general, researches have not discovered major risk factors for this condition.

About 85% of people with chronic active autoimmune hepatitis do not have severe symptoms. When symptoms occur, they range from minimal to severe, and include fatigue, jaundice, fever, and weight loss. The liver and spleen are often enlarged. In addition, patients with this condition may experience skin disorders, including palmar erythema (red palms) and spider angioma (a blood-red spot, the size of a pinhead, from which tiny blood vessels radiate like spider legs). Itching is not common, however. The abdomen or legs may be swollen due to the accumulation of fluid.

If a patient has symptoms of chronic active hepatitis for 6 months or more and a virus cannot be identified, doctors usually suspect autoimmune hepatitis. Other autoimmune liver diseases, however, can confuse a diagnosis. To help confirm this condition, test results may show high levels of immune factors called serum globulins or certain antibodies to liver proteins. In some cases, a successful trial of steroid drugs may be the only way to diagnose autoimmune hepatitis.

Autoimmune hepatitis is usually benign and causes little trouble. There is a very small risk that it can evolve into the active form. One study reported a 10-year survival rate of 95%, which was similar to the same age group in the general population. However, it the condition evolves into the chronic active form, 5-year survival may be only 50% if the disease is not treated. (The survival rate can be higher in people with milder symptoms and less liver damage.)

Although very uncommon, severe autoimmune hepatitis can be life-threatening and require intensive therapy, possibly including liver transplantation. The risk for liver failure and bleeding in the stomach and esophagus is highest in the early years after disease onset. This risk diminishes over time but is replaced by an increase in liver cancer rates and bleeding in the stomach and intestines. The risk for liver cancer is not as high, however, as with chronic viral hepatitis.

Patients with autoimmune hepatitis who have mild symptoms and slight inflammation of the liver do not require any treatment except to relieve symptoms. They should be monitored, however, for any signs of disease progression. Severe autoimmune hepatitis is a life-threatening condition and requires intensive therapy.

Because of effective treatment options and in spite of a high rate of relapse, long-term survival rates in patients with autoimmune hepatitis are excellent. Drugs that block factors in the immune system and help reduce inflammation and symptoms of autoimmune hepatitis are most often used.

Corticosteroids. The corticosteroid prednisone (Deltasone, Orasone, Sterapred, generic) is the standard drug for treating autoimmune hepatitis. It produces remission of symptoms in about 80% of patients with autoimmune hepatitis. For most patients, steroids also reduce symptoms within 3 months, improve liver function within 6 months, and restore liver health within 2 years. Between 10 - 20% of patients continue to deteriorate despite steroid treatment, although higher doses may help some of these people. (Steroids are generally not useful for chronic hepatitis B or C. Suppressing the immune system in these patients can actually encourage the viruses to multipy more quickly.)

Treatment usually needs to continue for about 2 years before the disease is in complete remission. Usually, steroids are stopped when disease symptoms have disappeared, when blood tests show that aminotransferase (AST) levels are less than two times normal, and liver biopsies reveal no active cell damage. Steroid medications must be withdrawn very slowly. Patients who are very elderly or who have advanced (decompensated) cirrhosis are not good candidates for this treatment.

Unfortunately, remission rarely lasts more than 3 years. About half of patients relapse within 6 months, and only about 20% of patientsare disease-free for more than 5 years. A 2007 study indicated that AST, gamma-globulin, and immunoglobulin-G (IgG) levels are helpful in predicting which patients may relapse and which patients have the best chance for maintaining remission. Still, most patients with autoimmune hepatitis will eventually have a relapse. Re-administering prednisone therapy after relapse achieves another remission in about 80% of patients.

Corticosteroid side effects can be very distressing and sometimes serious. They include weight gain, skin problems, moon-shaped face, high blood pressure, diabetes, cataracts, mental disturbances, infections, and osteoporosis.

Azathioprine. Doctors often prescribe the drug azathioprine (Imuran) along with steroids to help reduce severe side effects caused by using steroids alone. When azathioprine is given in combination with prednisone, the prednisone dose can be reduced, thereby lowering the corticosteroid’s side effects. Azathioprine also suppresses the immune system and helps prevent relapse, but the drug will not induce remission by itself.

Other Drugs. Other immunosuppressant drugs, such as mycophenylate mofetil (MMF), cyclosporine (Neoral), or tacrolimus (Prograf) are sometimes prescribed for patients who are not helped by standard treatment.

Liver Transplantation and Autoimmune Hepatitis. If all therapies fail and the disease becomes life threatening, liver transplantation may be performed. Liver transplantation can be a successful option for many people. Survival rates are about 90% after 1 year, and 70 - 80% after 5 years.

Symptom Management

The primary goals for managing viral hepatitis are to provide adequate nutrition, to prevent additional damage to the liver, and to prevent transmission to others. For mild cases of acute viral hepatitis, no drug therapy or other treatment is either available or necessary. Hospitalization is needed only for people at high risk for complications such as pregnant women, elderly people, patients with other serious conditions, or those who have severe nausea and vomiting and need to have fluids administered intravenously.

The following tips may be useful:

All patients should abstain from alcohol and sexual contact during the acute phase.
Although most patients with hepatitis experience fatigue and require more rest than usual, they can be as physically active as they want without affecting recovery. In fact, patients should be encouraged to be as active as they can.
Depression is common, particularly in people used to an active life. Patients should be reassured that in the majority of hepatitis cases, recovery is complete.
The liver processes many types of medications. As soon as hepatitis is diagnosed, patients should stop taking all drugs (including over-the-counter-medication) except those prescribed or recommended by their doctors. Specific nonsteroidal anti-inflammatory drugs (NSAIDs) that should be avoided include ibuprofen (Advil, Motrin) and acetaminophen (Tylenol). Ibuprofen (Advil, Motrin) may increase liver enzymes and cause liver damage in patients with hepatitis C. Acetaminophen (Tylenol) may cause sudden liver failure in patients with hepatitis A or B. Acetaminophen can also damage the liver if taken in combination with alcohol.

After the onset of acute hepatitis, periodic visits to the doctor for repeat blood tests are necessary, the frequency of which depends on how well the patient feels. If symptoms still occur after 3 months and laboratory tests still indicate active presence of the virus, the patient should be evaluated every month. If symptoms persist beyond 6 months, a liver biopsy may be required to determine any liver damage.

Dietary Factors to Protect the Liver. In general, no vitamins or special diets have been proven to be particularly beneficial. The following may be helpful, however:

Eating many small snacks during the day, with larger ones in the morning, may help prevent weight loss while reducing the severity of nausea. Patients might be able to tolerate high-caloric drinks to supplement their regular diet.
One small Japanese study suggested that vitamin E might help protect against liver damage in patients with hepatitis C.
Thiamine binds to iron and helps reduce iron load in the liver. One small study suggested it may be helpful for patients with chronic hepatitis B. Pork is high in the vitamin, but more healthy sources include dried fortified cereals, oatmeal, corn, nuts, cauliflower, sunflower seeds and vitamin pills.
Some research suggests that supplements of omega-3 fatty acids (found in fish oil and evening primrose oil) may help protect the diseased liver.
Higher coffee intake has been shown to reduce the risk for cirrhosis.

Manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Patients should always check with their doctors before using any herbal remedies or dietary supplements.

Popular herbal remedies for hepatitis include ginseng, glycyrrhizin (a compound in licorice), catechin (found in green tea), and silymarin (found in milk thistle). Aside from milk thistle, there has been no evidence that these herbs are helpful for hepatitis. Studies on milk thistle’s benefit have been mixed. Some studies have indicated that milk thistle may help improve liver enzyme levels. However, a 2005 review found that the herb did not reduce deaths from liver disease caused by hepatitis B or C.

Patients with hepatitis should be aware that some herbal remedies may cause liver damage. In particular, kava (an herb used to relieve anxiety and tension) may be dangerous for people with chronic liver disease.

Outlook

In most cases of acute viral hepatitis, recovery is complete and the liver returns to normal within 2 - 8 weeks. In a small number of cases of hepatitis B or C, the condition can be prolonged and recovery may not occur for a year. About 5 - 10% of these patients will have a flare-up of milder symptoms before full recovery. A few of these patients may go on to develop chronic hepatitis. People who have been infected with a hepatitis virus continue to produce antibodies to that specific virus. This means that they cannot be reinfected with the same hepatitis virus again. Unfortunately, they are not protected from other types.

Serious consequences of acute viral hepatitis are rare, but can be life threatening if they occur. Pregnant women with acute hepatitis B, C, or E are at higher risk for complications of acute hepatitis.

In very rare cases, within 2 months of onset of acute hepatitis, a very serious condition known as fulminant hepatitis can develop. In this event, the liver fails with catastrophic consequences. The following events may develop:

A large swollen abdomen (known as ascites) and a peculiar hand-flapping tremor (called asterixis).
These symptoms may be followed by stomach and intestinal bleeding and mental confusion, stupor, or coma caused by brain injury (encephalopathy).

No medications, including corticosteroids, have any effect against the condition itself. Liver transplantation is currently the only life-saving treatment for fulminant acute hepatitis and has survival rates of up to 60%. Without liver transplantation, the chance of survival is only 20%.

Other serious and rare consequences of acute viral hepatitis are aplastic anemia (which can be fatal), pancreatitis, hypoglycemia, and polyarteritis, a serious inflammation of blood vessels.

Chronic Persistent Hepatitis. Chronic persistent hepatitis is usually mild and nonprogressive or slowly progressive, causing limited damage to the liver. Cell injury in such cases is usually limited to the region of portal tracts, which contains vessels that carry blood to the liver from the digestive tract. In some cases, however, more extensive liver damage can occur over long periods of time and progress to chronic active hepatitis.

Chronic Active Hepatitis. If damage to the liver is extensive and cell injury occurs beyond the portal tract, chronic active hepatitis can develop. Significant liver damage has usually occurred by this time. Nearly every bodily process is affected by a damaged liver, including digestive, hormonal, and circulatory systems. Symptoms can significantly impair daily life.

Cirrhosis. If liver cells are destroyed between the portal tract and the central veins in the liver, progressive cell damage can build a layer of scar tissue over the liver, resulting in the condition known as cirrhosis. In such cases, the entire liver is threatened with malfunction and failure. If cirrhosis develops, the average survival time is about 10 years. The risk for cirrhosis is much higher in patients with hepatitis C than in those with hepatitis B. [For more information, see In-Depth Report #75: Cirrhosis.]
Liver Cancer. The risk for liver cancer in patients with cirrhosis is about 14% but varies widely depending on the cause of hepatitis. (Liver cancer is rare in patients who do not develop cirrhosis.)

Click the icon to see an image of cirrhosis of the liver.

Liver transplantation may be indicated for the following patients:

Those who have developed life-threatening cirrhosis and who have a life expectancy of more than 12 years.
Patients with liver cancer that has not spread beyond the liver.

Current 5-year survival rates after liver transplantation are 55 - 80%, depending on different factors. Patients report improved quality of life and mental functioning after liver transplantation. Unfortunately, in about half of all patients with chronic hepatitis, the disease recurs after transplantation.

Patients should consider medical centers that have performed more than 50 transplants per year and produced better-than-average results. Unfortunately, there are far more people waiting for liver donors than there are available organs. [For more information on liver transplantation, see In-Depth Report #75: Cirrhosis.]

Resources

www.cdc.gov/hepatitis -- Centers for Disease Control and Prevention
www.hepfi.org -- Hepatitis Foundation International
www.hepb.org -- Hepatitis B Foundation
www.liverfoundation.org -- American Liver Foundation
www.aasld.org -- American Association for the Study of Liver Diseases
www.gastro.org -- American Gastrointestinal Association
www2.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
www.immunize.org -- Immunization Action Coalition
www.hivandhepatitis.com -- Hepatitis and HIV
www.unos.org -- United Network for Organ Sharing

References

Amin J, Law MG, Bartlett M, Kaldor JM, Dore GJ. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet. 2006 Sep 9;368(9539):938-45.

Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007 May 9;297(18):2010-7.

Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006 Dec;131(6):1743-51. Epub 2006 Sep 20.

Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT, et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):297-306.

Montano-Loza AJ, Carpenter HA, Czaja AJ. Improving the end point of corticosteroid therapy in type 1 autoimmune hepatitis to reduce the frequency of relapse. Am J Gastroenterol. 2007 May;102(5):1005-12. Epub 2007 Feb 23.

Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007 Jul 12;357(2):124-34.

Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007 Jul 15;166(2):196-203. Epub 2007 May 11.

Review Date:
8/31/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, In-Depth Reports; Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2009 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

adam.com

Stress

FitSugar — Wed, 08 Oct 2008 17:35:26 -0700

In This Report

Highlights
Introduction
The Body's Response
Complications
Conditions with Similar Sym...
Treatment
Risk Factors
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Some people are pre-programmed for a heightened response to stress by conditions in the womb. Pregnant women under stress who eat a diet high in protein and low in carbohydrates have babies with higher cortisol levels. Later on, these levels increase in response to stress.
The impact of stress on the heart and circulation system is becoming more clear. Stress causes the body to release inflammatory markers that may worsen heart and circulatory diseases as well as inflammatory disease, such as rheumatoid arthritis. High levels of inflammatory markers are associated with increased risk of heart attack and stroke. Extreme stress can also produce a condition that mimics a heart attack, but is reversible. People under severe stress can experience irregular heart beats that make them susceptible to sudden cardiac death.
Stress also increases the risk of developing type 2 diabetes in women.
Traumatic stress has long been known to cause amnesia, emotional numbness, nightmares, and memory problems. Now it is known that traumatic emotional stress can cause permanent changes in the brain that interfere with the normal way information is accepted, coded, and retrieved.
The good news is that our physical response to stress is increasingly understood. Knowing what occurs at the cellular level may help researchers find more ways to counteract the detrimental physical and emotional effects of stress.

Introduction

Stress affects most people in some way. Acute (sudden, short-term) stress leads to rapid changes throughout the body. Almost all body systems (the heart and blood vessels, the immune system, the lungs, the digestive system, the sensory organs, and brain) gear up to meet the perceived danger.

These stresses could prove beneficial in a critical, life-or-death situation. Over time, however, repeated stressful situations put a strain on the body that may contribute to physical and psychological problems. Chronic (long-term) stress can have real health consequences and should be addressed like any other health concern.

Fortunately, research is showing that lifestyle changes and stress-reduction techniques can help people learn to manage their stress.

People can experience stress from external or internal factors.

External stressors include adverse physical conditions (such as pain or hot or cold temperatures) or stressful psychological environments (such as poor working conditions or abusive relationships). Humans, like animals, can also experience external stressors.
Internal stressors can also be physical (infections, inflammation) or psychological (such as intense worry about a harmful event that may or may not occur). As far as anyone can tell, internal psychological stressors are rare or absent in most animals except humans.

Stressors can also be defined as short-term (acute) or long-term (chronic).

Acute Stress. Acute stress is the reaction to an immediate threat, commonly known as the fight or flight response. The threat can be any situation that is perceived, even subconsciously or falsely, as a danger.

Common acute stressors include:

Noise (which can trigger a stress response even during sleep)
Crowding
Isolation
Hunger
Danger
Infection
High technology effects (playing video games, frequently ringing mobile phones)
Imagining a threat or remembering a dangerous event

Under most circumstances, once the acute threat has passed, levels of stress hormones return to normal. This is called the relaxation response.

Chronic Stress. Frequently, modern life poses ongoing stressful situations that are not short-lived. The urge to act (to fight or flee) must therefore be controlled. Stress, then, becomes chronic.

Common chronic stressors include:

On-going highly pressured work
Long-term relationship problems
Loneliness
Persistent financial worries

The Body's Response

The best way to envision the effect of acute stress is to imagine yourself in a primitive situation, such as being chased by a bear.

In response to seeing the bear, a part of the brain called the hypothalamic-pituitary-adrenal (HPA) system is activated.

Release of Steroid Hormones and the Stress Hormone Cortisol. The HPA systems trigger the production and release of steroid hormones (glucocorticoids), including the primary stress hormone cortisol. Cortisol is very important in organizing systems throughout the body (including the heart, lungs, circulation, metabolism, immune systems, and skin) to deal quickly with the bear.

Release of Catecholamines. The HPA system also releases certain neurotransmitters (chemical messengers) called catecholamines, particularly those known as dopamine, norepinephrine, and epinephrine (also called adrenaline).

Catecholamines activate an area inside the brain called the amygdala, which appears to trigger an emotional response to a stressful event. In the case of the bear, this emotion is most likely fear.

Release of Neuropeptide S. The brain releases neuropeptide S, a small protein that modulates stress by decreasing sleep and increasing alertness and a sense of anxiety. This gives the person a sense of urgency to run away from the bear.

Effects on Long- and Short-Term Memory. During the stressful event, catecholamines also suppress activity in areas at the front of the brain concerned with short-term memory, concentration, inhibition, and rational thought. This sequence of mental events allows a person to react quickly, either to fight the bear or to flee from it. It also interferes with the ability to handle difficult social or intellectual tasks and behaviors during that time.

On the other hand, neurotransmitters at the same time signal the hippocampus (a nearby area in the brain) to store the emotionally loaded experience in long-term memory. In primitive times, this brain action would have been essential for survival, since long-lasting memories of dangerous stimuli (such as the large bear) would be critical for avoiding such threats in the future.

The stress response also affects the heart, lungs, and circulation:

As the bear comes closer, the heart rate and blood pressure increase instantaneously.
Breathing becomes rapid, and the lungs take in more oxygen.
The spleen discharges red and white blood cells, allowing the blood to transport more oxygen throughout the body. Blood flow may actually increase 300 - 400%, priming the muscles, lungs, and brain for added demands.

The effect on the immune system from confrontation with the bear is similar to organizing a defensive line of soldiers to potentially critical areas. The steroid hormones reduce the activity in parts of the immune system, so that specific infection fighters (including important white blood cells) or other immune molecules can be repositioned. These immune-boosting troops are sent to the body's front lines where injury or infection is most likely to occur, such as the skin and the lymph nodes.

As the bear gets closer, fluids are diverted from nonessential locations, including the mouth. This causes dryness and difficulty in talking. In addition, stress can cause spasms of the throat muscles, making it difficult to swallow.

The stress effect moves blood flow away from the skin to support the heart and muscle tissues. This also reduces blood loss in the event that the bear causes a wound. The physical effect is a cool, clammy, sweaty skin. The scalp also tightens so that the hair seems to stand up.

Stress shuts down digestive activity, a nonessential body function during short-term periods of hard physical work or crisis.

Once the threat has passed and the effect has not been harmful (for example, the bear has not wounded the human), the stress hormones return to normal. This is known as the relaxation response. In turn, the body's systems also return to normal.

Complications

In prehistoric times, the physical changes in response to stress were an essential adaptation for meeting natural threats. Even in the modern world, the stress response can be an asset for raising levels of performance during critical events, such as a sports activity, an important meeting, or in situations of actual danger or crisis.

If stress becomes persistent and low-level, however, all parts of the body's stress apparatus (the brain, heart, lungs, vessels, and muscles) become chronically over- or under-activated. Such chronic stress may produce physical or psychological damage over time. Acute stress can also be harmful in certain situations, particularly in individuals with preexisting heart conditions.

Studies suggest that the inability to adapt to stress is associated with the onset of depression or anxiety. In one study, two-thirds of subjects who experienced a stressful situation had nearly 6 times the risk of developing depression within that month.

Some evidence suggests that repeated release of stress hormones produces hyperactivity in the hypothalamic-pituitary-adrenal (HPA) system, and disrupts normal levels of serotonin, the nerve chemical that is critical for feelings of well-being. Some people appear to be more at risk for an overactive HPA system under stress, including those with the personality traits that cause perfectionism. Certainly, on a more obvious level, stress reduces the quality of life by reducing feelings of pleasure and accomplishment. In addition, relationships are often threatened in times of stress.

The full impact of mental stress on heart disease is just coming to light, but the underlying mechanisms are not always clear. Stress can certainly influence the activity of the heart when it activates the automatic part of the nervous system that affects many organs, including the heart. Such actions and others could theoretically affect the heart badly in several ways:

Sudden stress increases the pumping action and rate of the heart, while at the same time causing the arteries to constrict (narrow). This restricts blood flow to the heart. A 2002 study suggested that such actions may be responsible for some cases of acute stress that have been associated with a higher risk for serious heart problems. These problems include heart rhythm abnormalities and heart attacks, and even death in people with heart disease.
Emotional effects of stress alter the heart rhythms, which could pose a risk for serious arrhythmias (rhythm abnormalities) in people with existing heart rhythm disturbances.
Stress causes blood to become stickier (possibly in preparation of potential injury), increasing the likelihood of an artery-clogging blood clot.
Stress appears to impair the clearance of fat molecules in the body, raising blood-cholesterol levels, at least temporarily.
Stress that leads to depression appears to be associated with increased intima-medial thickness, a measure of the arteries that signifies worsening blood vessel disease.
Chronic stress may lead to the production of immune factors called cytokines, although study results vary widely. Cytokines produce an inflammatory response that is now believed to be responsible for damaging the arteries. Such damage contributes to heart disease. New studies indicate that some people under stress may have increased levels of C-reactive protein (CRP), a risk marker for heart attack. Each 1 mg/L increase in CRP has been linked to a 20% increased risk of myocaridal ischemia, a condition that signals poor blood flow to the heart muscle.
Stress causes the body to release inflammatory markers into the bloodstream. These markers may worsen heart disease or increase the risk of heart attack or stroke.
Studies have reported an association between stress and high blood pressure, which may be more pronounced in men than in women. According to some evidence, people who regularly experience sudden spikes in blood pressure (caused by mental stress) may, over time, develop injuries in the inner lining of their blood vessels. In one 20-year study, for example, men who periodically measured highest on the stress scale were twice as likely to have high blood pressure as those with normal stress.

Evidence is still needed to confirm any clear-cut relationship between stress and heart disease. For example, a 2002 study in Scotland found no greater risk for actual heart disease or heart events even in men who reported higher mental stress. In fact, higher stress was associated with fewer heart events. Men with high stress levels did tend to complain of chest pain and to go to the hospital for it more often than those with lower stress. They also went to the hospital more often.

Evidence links stress to heart disease in men, particularly in work situations where they lack control. The association between stress and heart problems in women is weaker, and there is some evidence that the ways women cope with stress may be more heart-protective. In one study, men were more apt than women to use alcohol or eat less healthily in response to stress, which might account for their higher heart risks from stress. Different stressors may affect genders differently. In one study, work stress was associated with a higher risk for heart disease in men, but marital stress -- not work stress -- was associated with more severe heart disease in women with existing heart problems.

A condition called stress cardiomyopathy (or Takotsubo cardiomyopathy) is widely recognized. In this disease, intense emotional or physical stress causes severe but reversible heart dysfunction. The patient experiences chest pain, and EKGs and echocardiograms indicate a heart attack, but further tests show no underlying obstructive coronary artery disease.

Acute emotional stress can create abnormal heartbeats. MRI studies show that asymmetric brain activity may play a role in making a stressed heart susceptible to ventricular arrhythmias by creating electrical instability. In some patients, this can cause sudden cardiac death.

Psychological stress is also recognized as a possible cause of acute coronary syndrome (ACS), a collection of symptoms that signify heart attack or approaching heart attack. In one study of men who suffered ACS at work or up to 2 hours after work, many of the men were found to have anger and negative emotions. A 2007 review of studies on blood qualities, coagulation, fibrinolysis, and platelet reactivity found that high levels of psychological stress are associated with harmful changes to the blood. The research suggests that stress has the potential to trigger ACS, particularly in patients with heart disease. The studies also suggest that the risk is greatest immediately after the stressful incident, rather than during it.

Stress Reduction and Heart Disease. Studies suggest that treatments that reduce psychological distress improve long-term outlook in people with heart disease, including after a heart attack. Evidence indicates that stress management programs may reduce the risk of heart attacks by up to 75% in people with heart disease. Specific stress management techniques may help some problems but not others. For example, acupuncture in one study helped people with heart failure but had no effect on blood pressure. Relaxation methods, on the other hand, may help people with high blood pressure.

One survey revealed that men who had a more intense response to stressful situations, such as waiting in line or problems at work, were more likely to have strokes than those who did not report such distress. In some people, prolonged or frequent mental stress causes an exaggerated increase in blood pressure.

Chronic stress affects the immune system in complicated ways, and may have various results.

Susceptibility to Infections. Chronic stress appears to blunt the immune system's response to infections, and may even impair a person's response to immunizations. Several studies have shown that people under chronic stress have low white blood cell counts and are vulnerable to colds. Once a person catches a cold or flu, stress can make symptoms worse. People who carry the herpes virus or HIV may be more susceptible to viral activation following exposure to stress. Even more serious, some research has found that HIV-infected men with high stress levels progress more rapidly to AIDS when compared to those with lower stress levels.

Inflammatory Response. Some evidence suggests that chronic stress triggers an over-production of certain immune factors called cytokines. In excess levels, these chemicals can have very damaging effects. A recent study found that students unable to cope with stress had high levels of TNF-alpha, an inflammatory cytokine. Such findings may partly explain the association between chronic stress and numerous diseases, including heart disease and asthma.

Whether or not stress causes or aggravates cancer is not entirely clear. One study reported no association between stressful life events and recurrence in women who had been treated for breast cancer. Nevertheless, some animal studies suggest that lack of control over stress (not simply stress itself) had negative effects on immune function and contributed to tumor growth.

That being said, a 2007 study found that stress activates a gene that may cause metastatic cancer, as measured by increasing levels of the marker AGR2.

Although stress reduction techniques have no effect on survival rates, studies show that they are very helpful in improving a cancer patient's quality of life. Stress is also known to be one cause of hyponatremia (low plasma sodium levels) in cancer patients. Fortunately, this imbalance can be corrected with drugs called AVP-receptor agonists, developed for use in heart failure.

The brain and intestines are strongly related, and are controlled by many of the same hormones and parts of the nervous system. Indeed, some research suggests that the gut itself has features of a primitive brain. It is not surprising then that prolonged stress can disrupt the digestive system, irritating the large intestine and causing diarrhea, constipation, cramping, and bloating. Excessive production of digestive acids in the stomach may cause a painful burning.

Irritable Bowel Syndrome. Irritable bowel syndrome (or spastic colon) is strongly related to stress. With this condition, the large intestine becomes irritated, and its muscular contractions are spastic rather than smooth and wave-like. The abdomen is bloated, and the patient experiences cramping and alternating periods of constipation and diarrhea. Sleep disturbances due to stress can make irritable bowel syndrome even worse.

Peptic Ulcers. It is now well-established that most peptic ulcers are either caused by the H. pylori bacteria or the use of nonsteroidal anti-inflammatory (NSAID) medications (such as aspirin and ibuprofen). Nevertheless, studies still suggest that stress may predispose someone to ulcers, or sustain existing ulcers. Some experts estimate that social and psychological factors play some contributing role in 30 - 60% of peptic ulcer cases, whether they are caused by H. pylori or NSAIDs. In any case, some experts believe that the anecdotal relationship between stress and ulcers is so strong that attention to psychological factors is still warranted.

Inflammatory Bowel Disease. Although stress is not a cause of inflammatory bowel disease (Crohn's disease or ulcerative colitis), there are reports of an association between stress and symptom flare-ups. One study, for example, found that while short-term (over the previous month) stress did not significantly exacerbate ulcerative colitis symptoms, long-term perceived stress tripled the rate of flare-ups compared to patients who did not report feelings of stress.

Stress can have varying effects on eating problems and weight.

Weight Gain. Often stress is related to weight gain and obesity. Many people develop cravings for salt, fat, and sugar to counteract tension. As a result, they gain weight. Weight gain can occur even with a healthy diet, however, in some people exposed to stress. In addition, the weight gained is often abdominal fat, a predictor of diabetes and heart problems.

The release of cortisol, a major stress hormone, appears to encourage abdominal fat and may be the primary connection between stress and weight gain. Cortisol is a glucocorticoid. These hormones, along with insulin, appear to be responsible for stress-related food cravings. A 2005 study showed that hormonally induced cravings for "comfort foods" may have a biological benefit for managing stress. Eating comfort foods appears to reduce the negative hormonal and behavioral changes associated with stress, which might lessen the impact of stress on an individual. Carbohydrates in particular have been found to significantly increase levels of tryptophan and large neutral amino acids. This produces serotonin, which improves mood and performance under stress.

A 2007 study proposes a "reward-based stress eating" model. In this theory, stress and tasty, high-calorie foods cause the brain to make chemicals called endogenous opioids. These neurotransmitters help protect against the harmful effects of stress by slowing activity of a brain process called the hypothalamic-pituitary-adrenal (HPA) axis, thus weakening the stress response. Repeated stimulation of the reward pathways through stress-induced HPA stimulation, eating tasty food, or both, may lead to changes in the brain that cause compulsive overeating.

Weight Loss. Some people suffer a loss of appetite and lose weight during periods of stress. In rare cases, stress may trigger hyperactivity of the thyroid gland, stimulating appetite but causing the body to burn up calories at a faster than normal rate.

Eating Disorders. Chronically elevated levels of stress chemicals have been observed in patients with anorexia and bulimia. Some studies, however, have not found any strong link between stress and eating disorders. More work is needed to determine if changes in stress hormones are a cause or result of eating disorders.

Chronic stress has been associated with the development of insulin resistance, a condition in which the body is unable to use insulin effectively to regulate glucose (blood sugar). Insulin resistance is a primary factor in diabetes. In the Healthy Women Study, a large population of healthy women was studied for 15 years. Very stressful life events and severe depression greatly increased the risk of developing insulin resistance.

In another study of more than 33,000 Swedish workers, the development of type 2 diabetes was strongly correlated with work stress and low emotional support. However, the effect was seen in women, but not in men.

Stress can also exacerbate existing diabetes by impairing the patient's ability to manage the disease effectively.

Researchers are attempting to find the relationship between pain and emotion, but the area is complicated by many factors, including effects of personality types, fear of pain, and stress itself. A recent study suggests that chronic pain may impair the action of neutrophils, thereby weakening the immune response.

Muscular and Joint Pain. Stress may intensify chronic pain caused by arthritis and other conditions. According to a study on patients with rheumatoid arthritis, however, stress management techniques do not appear to have much effect on arthritic pain. Psychological distress also plays a significant role in the severity of back pain. Some studies have clearly associated job dissatisfaction and depression to back problems, although it is still unclear if stress is a direct cause of the back pain.

Headaches. Tension-type headaches are highly associated with stress and stressful events. Sometimes the headache does not start until long after the stressful event has ended. Additionally, stress can contribute to the development of headaches or cause headaches to occur more often.

Some research suggests that people who suffer from tension-type headaches may have some biological predisposition for translating stress into muscle contractions. Among the wide range of possible migraine triggers is emotional stress (although the headaches often erupt after the stress has eased). One study suggested that women with migraines tend to have personalities that over-respond to stressful situations.

The tensions of unresolved stress frequently cause insomnia, generally keeping the stressed person awake or causing awakening in the middle of the night or early morning. This appears to be due to the fact that stress causes physiological arousal during non-rapid eye movement (NREM) sleep.

Sexual Function. Stress can lead to diminished sexual desire and an inability to achieve orgasm in women. Stress response can cause androgen levels to drop, causing temporary impotence in men. Part of the stress response involves the release of brain chemicals that constrict the smooth muscles of the penis and its arteries. This constriction reduces the blood flow into and increases the blood flow out of the penis, which can prevent erection.

Premenstrual Syndrome. Some studies indicate that the stress response in women with premenstrual syndrome may be more intense than in those without the syndrome.

Fertility. Stress may even affect fertility. Stress hormones have an impact on the hypothalamus gland, which produces reproductive hormones. Severely elevated cortisol levels can even shut down menstruation. One small study reported a significantly higher incidence of pregnancy loss in women who had both high stress and prolonged menstrual cycles. Another reported that women with stressful jobs had shorter periods than women with low-stress jobs.

Effects on Pregnancy. Old wives' tales about a pregnant woman's emotions affecting her baby may have some credence. Stress may cause physiologic alterations, such as increased adrenal hormone levels or resistance in the arteries, which may interfere with normal blood flow to the placenta. Maternal stress during pregnancy has been linked to a higher risk for miscarriage, lower birth weights, and increased incidence of premature births. Some evidence also suggests that stress experienced by expectant mothers can even influence the way in which the baby's brain and nervous system will react to stressful events. Indeed, one study found a higher rate of crying and low attention in infants of mothers who had been stressed during pregnancy.

Menopause. A drop in estrogen levels during perimenopause and menopause may be responsible for changes in mood precipitated by stress. Estrogen replacement therapy can soften this response to stressful events.

Stress affects the brain, particularly memory, but the effects vary widely depending on whether the stress is acute or chronic.

Effect of Acute Stress on Memory and Concentration. Studies indicate that the immediate effect of acute stress impairs short-term memory, particularly verbal memory. On the plus side, high levels of stress hormone during short-term stress have been associated with enhanced memory storage and greater concentration on immediate events. The difference in effect may be due to how cortisol impacts glucocorticoid receptors in the hippocampus and prefrontal cortex. In a study of 20 men and 20 women, those whose cortisol levels increased in response to unpleasant, emotionally arousing photos had less memory recall later than those whose cortisol levels did not rise.

Effect of Chronic Stress on Memory. If stress becomes chronic, sufferers often experience loss of concentration at work and home, and they may become inefficient and accident-prone. In children, the physiologic responses to chronic stress can clearly inhibit learning. Chronic stress in older people may play an even more important role in memory loss than the aging process. In one study, for example, older adults with low stress hormone levels tested as well as younger adults in cognitive tests; those with higher stress levels tested 20 - 50% lower.

Studies have connected long-term exposure to excess amounts of cortisol (a major stress hormone) to shrinking of the hippocampus, the brain’s memory center. For example, two studies reported that groups who suffered from post-traumatic stress disorder (Vietnam veterans and women who suffered from sexual abuse) displayed up to 8% shrinking of the hippocampus. It is not yet known if this shrinking is reversible.

Allergies. Stress has been related to skin allergies. Some research suggests that stress, not indoor pollutants, may actually be a cause of the so-called sick-building syndrome. Sick-building syndrome produces allergy-like symptoms, such as eczema, headaches, asthma, and sinus problems, in office workers.

Compulsive Hoarding. People with obsessive-compulsive disorder (OCD) and compulsive hoarding are far more likely to have experienced a traumatically stressful event than people with OCD who are not hoarders. Hoarders who have experienced traumatic events have significantly more severe hoarding than those who have not been traumatized. The strongest association with traumatic stress is found in the clutter factor of compulsive hoarding, rather than in difficulty discarding objects.

Chronic Fatigue. Stress increases the risk of developing chronic fatigue syndrome, although studies suggest that high levels of emotional instability may genetically predispose someone to the syndrome.

Skin Disorders. Stress plays a role in worsening numerous skin conditions, including hives, psoriasis, acne, rosacea, and eczema, and is one of the most common causes of eczema. Unexplained itching may also be caused by stress. Evidence suggests that experiencing the stress of a traumatic event (parental divorce or separation, or a severe disease in a family member) before age 2 increases the risk of developing eczema.

Unexplained Hair Loss (Alopecia Areata). Alopecia areata is hair loss that occurs in localized (individual) patches. The cause is unknown, but stress is suspected as a player in this condition. For example, hair loss often occurs during periods of intense stress, such as mourning.

Teeth and Gums. Stress has now been implicated in increasing the risk for periodontal disease, which is disease in the gums that can cause tooth loss.

People under chronic stress often turn to alcohol abuse or tobacco use for relief. The damage these self-destructive habits cause under ordinary circumstances is compounded by the physiological effects of stress itself. Many people also resort to abnormal eating patterns or passive activities, such as watching television. The results of a national survey, released in February 2006, show that: "Americans engage in unhealthy behaviors such as comfort eating, poor diet choices, smoking and inactivity to help deal with stress."

Alcohol affects receptors in the brain that reduce stress. Lack of nicotine increases stress in smokers, which creates a cycle of dependency on smoking. One study indicated that nicotine has calming effects in women but not in men. In fact, in the study, smoking increased aggression in men.

The cycle is self-perpetuating: a sedentary routine, an unhealthy diet, alcohol abuse, and smoking all promote heart disease. They also interfere with sleep patterns, and lead to increased rather than reduced tension levels. Drinking four or five cups of coffee, for example, can cause changes in blood pressure and stress hormone levels similar to those produced by chronic stress. Animal fats, simple sugars, and salt are known contributors to health problems.

Conditions with Similar Symptoms

The physical symptoms of anxiety disorders mirror many symptoms of stress, including:

A fast heart rate
Rapid, shallow breathing
Increased muscle tension

Anxiety is an emotional disorder, however, and is characterized by feelings of apprehension, uncertainty, fear, or panic. Unlike stress, the triggers for anxiety are not necessarily or even usually associated with specific stressful or threatening conditions. Some individuals with anxiety disorders have numerous physical complaints, such as headaches, gastrointestinal disturbances, dizziness, and chest pain. Severe cases of anxiety disorders are debilitating, and interfere with career, family, and social spheres.

Depression can be a disabling condition, and, like anxiety disorders, may result from chronic stress. A 2005 study of Canadian workers found that individuals with a high level of work-related stress are more than twice as likely to experience a major depressive episode, compared with people under less stress. Evidence also suggests that certain people may be genetically susceptible to depression after stressful life events. Depression also mimics some of the symptoms of stress, including changes in appetite, sleep patterns, and concentration. Serious depression, however, is distinguished from stress by feelings of sadness, hopelessness, loss of interest in life, and, sometimes, thoughts of suicide. Acute depression is also accompanied by significant changes in the patient's functioning. Professional therapy may be needed in order to determine if depression is caused by stress, or if it is the primary problem.

Post-traumatic stress disorder (PTSD) is a reaction to a very traumatic event, and it is actually classified as an anxiety disorder. The event that brings on PTSD is usually outside the norm of human experience, such as intense combat or sexual assault. The patient struggles to forget the traumatic event and frequently develops emotional numbness and event-related amnesia. Often, however, there is a mental flashback, and the patient re-experiences the painful circumstance in the form of dreams and disturbing thoughts and memories. These thoughts and dreams resemble or recall the trauma. Other symptoms may include lack of pleasure in formerly enjoyed activities, hopelessness, irritability, mood swings, sleep problems, inability to concentrate, and an excessive startle-response to noise.

Treatment

Perhaps the best general approach for treating stress can be found in the elegant passage by Reinhold Niebuhr, "Grant me the courage to change the things I can change, the serenity to accept the things I can't change, and the wisdom to know the difference." The process of learning to control stress is life-long, and will not only contribute to better health, but a greater ability to succeed in one's own agenda.

Stress can be a factor in a variety of physical and emotional illnesses, which should be professionally treated. Many stress symptoms are mild and can be managed by over-the-counter medications (for example, aspirin, acetaminophen, or ibuprofen for tension headaches; antacids, anti-diarrhea medications, or laxatives for mild stomach distress). A physician should be consulted, however, for physical symptoms that are out of the ordinary, particularly those that get worse or wake a person up at night. A mental health professional should be consulted for unmanageable acute stress or for severe anxiety or depression. Often short-term therapy can resolve stress-related emotional problems.

In choosing specific strategies for treating stress, several factors should be considered.

No single method is always successful: A combination of approaches is generally most effective.
What works for one person does not necessarily work for someone else.
Stress can be positive as well as negative. Appropriate and controllable stress provides interest and excitement and motivates the individual to greater achievement. A lack of stress may lead to boredom and depression.

Stress may play a part in making people vulnerable to illness. A physician or psychologist should be consulted if there are any indications of accompanying medical or psychological conditions, such as heart symptoms, significant pain, anxiety, or depression.

People often succeed in relieving stress for the short term. However, they go back to previous ways of stressful thinking and behaving because of outside pressure, long-held beliefs, or habits. The following are some obstacles to managing stress:

The fight or flight urge: The very idea of relaxation can feel threatening, because it is perceived as letting down one's guard. For example, an over-demanding boss may put a subordinate into a psychological state of fighting-readiness, even though there is no safe opportunity for the subordinate to fight back or express anger. Stress builds up, but the worker has the illusion, even subconsciously, that the stress itself is providing safety or preparedness. For this reason, the employee does nothing to correct the condition.
Many people are afraid of being perceived as selfish if they engage in stress-reducing activities that benefit only themselves. The truth is that self-sacrifice (in the form of not reducing one’s stress) may be inappropriate and even damaging, if the person making the sacrifice is unhappy, angry, or physically unwell.
Some people believe that certain emotional responses to stress, such as anger, are natural and unchangeable features of personality. Research has shown, however, that with cognitive behavioral therapy, individuals can be taught to change their emotional reactions to stressful events.

It is essential to remember that reducing stress and staying relaxed clears the mind, so it can begin appropriate actions to get rid of the stress-ridden conditions.

Although treating stress cannot cure medical problems, stress management can be a very important part of medical treatment. Specific stress reduction approaches may benefit different medical problems. For example, acupuncture in one study helped reduce harmful heart muscle actions in people with heart failure, but it had no effect on blood pressure. Relaxation methods, on the other hand, may help people with high blood pressure. Stress reduction may improve well-being and quality of life for many patients who are experiencing stress because of severe or chronic medical conditions.

Important Note: Never use stress reduction techniques as the only treatment, or in place of proven treatments, for any medical condition.

Risk Factors

At some point in their lives virtually everyone will experience stressful events or situations that overwhelm their natural coping mechanisms. In one poll, 89% of respondents indicated that they had experienced serious stress in their lives. Some people are simply biologically prone to stress. Many outside factors influence susceptibility as well.

Conditions Most Likely To Produce Stress-Related Health Problems. Conditions that are most likely to be associated with stress and negative physical effects include the following:

An accumulation of persistent stressful situations, particularly those that a person cannot easily control (for example, high-pressured work plus an unhappy relationship)
Persistent stress following a severe acute response to a traumatic event (such as an automobile accident)
Acute stress accompanying serious illness, such as heart disease

Factors That Influence the Response to Stress. People respond to stress differently, depending on different factors:

Early nurturing: Abusive behavior towards children may cause long-term abnormalities in the hypothalamus-pituitary system, which regulates stress.
Personality traits: Certain people have personality traits that cause them to over-respond to stressful events.
Genetic factors: Some people have genetic factors that affect stress, such as having a more or less efficient relaxation response. One study found a genetic abnormality in serotonin regulation that was connected with a heightened reaction of heart rates and blood pressure in response to stress. (Serotonin is a brain chemical involved with feelings of well-being.)
Immune regulated diseases: Certain diseases that are associated with immune abnormalities (such as rheumatoid arthritis or eczema) may actually weaken a response to stress.
The length and quality of stressors: Naturally, the longer the duration and more intense the stressors, the more harmful the effects.

Individuals at Higher Risk for Stress. Studies indicate that the following people are more vulnerable to the effects of stress than others:

Older adults: As people age, achieving a relaxation response after a stressful event becomes more difficult. Aging may simply wear out the systems in the brain that respond to stress, so that they become inefficient. The elderly, too, are very often exposed to major stressors such as medical problems, the loss of a spouse and friends, a change in a living situation, and financial worries. No one is immune to stress, however, and it may simply go unnoticed in the very young and old.
Women in general and working mothers specifically: Working mothers, regardless of whether they are married or single, face higher stress levels and possibly adverse health effects, most likely because they bear a greater and more diffuse work load than men or other women. This has been observed in women in the U.S. and in Europe. Such stress may also have a domino and harmful effect on their children. It is not clear, however, if stress has the same adverse effects on women's hearts as it does on men's.
Less educated individuals.
Divorced or widowed individuals: Numerous studies indicate that unmarried people generally do not live as long as their married contemporaries.
Anyone experiencing financial strain, particularly long-term unemployed and those without health insurance.
People who are isolated or lonely.
People who are targets of racial or sexual discrimination.
People who live in cities.

Children are frequent victims of stress because they are often unable to communicate their feelings accurately. They also have trouble communicating their responses to events over which they have no control. Certain physical symptoms, notably repeated abdominal pain without a known cause, may be indicators of stress in children.

Various conditions can affect their susceptibility to stress.

Low Birth Weight. One study reported that low birth weight and slow growth up until age 7 was related to stress in adulthood.

Parental Stress. Parental stress, especially in mothers, is a particularly powerful source of stress in children, even more important than poverty or overcrowding. In a 2002 study, for example, young children of mothers who were highly stressed (particularly if they were depressed) tended to be at high risk for developing stress-related problems. This was especially true if the mothers were stressed during both the child's infancy and early years. Some evidence even supports the old idea that stress during pregnancy can have adverse effects on the infant's mood and behavior. Older children with stressed mothers may become aggressive and anti-social. One study suggested that stress-reduction techniques in parents may improve their children's behavior.

Gender Differences in Adolescent Stress. Adolescent boys and girls experience equal amounts of stress, but the source and effects may differ. Girls tend to become stressed from interpersonal situations, and stress is more likely to lead to depression in girls than in boys. For boys, however, specific events, such as changing schools or getting poor grades, appear to be the major sources of stress.

A report issued in October 2006 by the American Academy of Pediatrics recommends more unstructured play time for children. The report notes that today’s overscheduled, hurried lifestyle that many children experience is a source of stress and anxiety in some children.

In a 1999 study of 46,000 workers, health care costs were 147% higher in workers who were stressed or depressed than in others who were not. Furthermore, according to one survey, 40% of American workers describe their jobs as very stressful, making job-related stress an important and preventable health hazard.

Several studies are now suggesting that job-related stress is as great a threat to health as smoking or not exercising. Stress impairs concentration, causes sleeplessness, and increases the risk for illness, back problems, accidents, and lost time from work. Work stress can lead to harassment or even violence while on the job. At its most extreme, chronic stress places a burden on the heart and circulation that in some cases may be fatal. The Japanese even have a word for sudden death due to overwork, karoushi.

Not all work stress is harmful. However, studies suggest the following job-related stressors may increase people's -- particularly men's -- health risks:

Having no say in decisions that affect one's responsibilities
Unrelenting and unreasonable performance demands
Lack of effective communication and conflict-resolution methods among workers and employers
Lack of job security
Night-shift work, long hours, or both
Too much time spent away from home and family
Wages not matching levels of responsibility

Reducing Stress on the Job. Many institutions within the current culture, while paying lip service to stress reduction, put intense pressure on individuals to behave in ways that increase tension. Yet, there are numerous effective management tools and techniques available to reduce stress. Furthermore, treatment for work-related stress has proven benefits for both the employee and employer. In one study, at the end of 2 years, a company that instituted a stress management program saved nearly $150,000 in workers compensations costs (the cost of the program was only $6,000). Other studies have reported specific health benefits resulting from workplace stress-management programs. In one of the studies, workers with hypertension experienced reduced blood pressure after even a brief (16-hour) program that helped them manage stress behaviorally.

In general, however, few workplaces offer stress management programs, and it is usually up to the employee to find their own ways to reduce stress. Here are some suggestions:

Seek out someone in the Human Resources department or a sympathetic manager and communicate concerns about job stress. Work with them in a non-confrontational way to improve working conditions, letting them know that productivity can be improved if some of the pressure is off.
Establish or reinforce a network of friends at work and at home.
Restructure priorities and eliminate unnecessary tasks.
Learn to focus on positive outcomes.
If the job is unendurable, plan and execute a career change. Send out resumes or work on transfers within the company.
If this isn't possible, be sure to schedule daily pleasant activities and physical exercise during free time.

It may be helpful to keep in mind that bosses are also victimized by the same stressful conditions they are imposing. For example, in one study of male managers in three Swedish companies, those who worked in a bureaucracy had greater stress-related heart risks than those who worked in companies with social supports.

Caregivers of Family Members. Studies show that caregivers of physically or mentally disabled family members are at risk for chronic stress. One study reported that overall mortality rates were over 60% higher in caregivers who were under constant stress. Spouses caring for a disabled partner are particularly vulnerable to a range of stress-related health threats, including influenza, depression, heart disease, and even poorer survival rates. Caring for a spouse with even minor disabilities can induce severe stress.

Specific risk factors that put caregivers at higher risk for severe stress, or stress-related illnesses, include:

Caregiving wives: Some studies suggest that wives experience significantly greater stress from caregiving than husbands do.
Having a low income.
Being African-American: African-American people tend to be in poorer physical health, and have lower incomes, than Caucasians. They therefore face greater stress as caregivers to their spouses than their white counterparts.
Living alone with the patient.
Helping a highly dependent patient.
Having a difficult relationship with the patient.

Intervention programs that are aimed at helping the caregiver approach the situation positively can reduce stress, and help the caregiver maintain a positive attitude. A 2002 program also demonstrated that moderate-intensity exercise was very helpful in reducing stress and improving sleep in caregivers.

Health Professional Caregivers. Caregiving among the health professionals is also a high risk factor for stress. One study, for example, found that registered nurses with low job control, high job demands, and low work-related social support experienced very dramatic health declines, both physically and emotionally.

People who are less emotionally stable or have high anxiety levels tend to experience specific events as more stressful than others. Some doctors describe an exaggerated negative response to stress as "catastrophizing" the event (turning it into a catastrophe). Nevertheless, a 2003 study of patients with anxiety disorder did not find any differences in actual physical response to stress (heart rate, blood pressure, release of stress hormones) compared to people without anxiety.

The lack of an established network of family and friends predisposes one to stress disorders and stress-related health problems, including heart disease and infections. A study, meanwhile, reported that older people who maintain active relationships with their adult children are buffered against the adverse health effects of chronic stress-inducing situations, such as low income or lower social class. Another study suggested this may be because people who live alone are unable to discuss negative feelings as a means to relieve their stress.

Studies of people who remain happy and healthy despite many life stresses conclude that most have very good networks of social support. One study indicated that support even from strangers reduced blood pressure surges in people undergoing a stressful event. Many studies suggest that having a pet helps reduce medical problems aggravated by stress, including heart disease and high blood pressure.

Lifestyle Changes

A healthy lifestyle is an essential companion to any stress-reduction program. General health and stress resistance can be enhanced by regular exercise, a diet rich in a variety of whole grains, vegetables, and fruits, and by avoiding excessive alcohol, caffeine, and tobacco.

Of interest, a 2003 study suggested that fish oil, which has been associated with a lower risk for heart disease and stroke, may blunt some of the harmful effects of mental stress on the heart.

In one study, high doses of vitamin C reduced stress levels and blood pressure. The doses given were higher than the recommended upper limit of 2,000 mg per day. High doses may cause headaches and diarrhea. Long-term use increases risk for kidney stones and has other adverse effects in specific individuals.

Exercise in combination with stress management techniques is extremely important for many reasons:

Exercise is an effective distraction from stressful events.
Exercise may directly blunt the harmful effects of stress on blood pressure and the heart (exercise protects the heart in any case).

Usually, a varied exercise regime is more interesting, and thus easier to stick to. Start slowly. Strenuous exercise in people who are not used to it can be very dangerous and any exercise program should be discussed with a physician. In addition, half of all people who begin a vigorous training regime drop out within a year. The key is to find activities that are exciting, challenging, and satisfying. The following are some suggestions:

Sign up for aerobics classes at a gym.
Brisk walking is an excellent aerobic exercise that is free and available to nearly anyone. Even short brisk walks can relieve bouts of stress.
Swimming is an ideal exercise for many stressed people, including pregnant women, individuals with musculoskeletal problems, and those who suffer exercise-induced asthma.
Yoga or Tai Chi can be very effective, combining many of the benefits of breathing, muscle relaxation, and meditation while toning and stretching the muscles. The benefits of yoga may be considerable. Numerous studies have found it beneficial for many conditions in which stress is an important factor, such as anxiety, headaches, high blood pressure, and asthma. It also elevates mood and improves concentration and the ability to focus.

As in other areas of stress management, making a plan and executing it successfully develops feelings of mastery and control, which are very beneficial in and of themselves. Start small. Just 10 minutes of exercise three times a week can build a good base for novices. Gradually build up the length of these every-other-day sessions to 30 minutes or more.

Cognitive-behavioral techniques (CBT) are among the most effective ways of reducing stress. A 2005 study found that CBT training can have a long-term impact one’s ability to cope with stress. In the study, participants received CBT training and were exposed to a stressful situation 4 months later. The participants who had received CBT training had significantly less stress-induced cortisol responses compared with individuals who had received no stress management training. This effect was observed in both men and women, although the CBT had a greater effect on men. CBT may be particularly helpful when the source of stress is chronic pain or a chronic disease. In fact, in a study of patients with HIV, CBT was more helpful than support groups for improving well-being and quality-of-life.

A typical CBT approach includes identifying sources of stress, restructuring priorities, changing one's response to stress, and finding methods for managing and reducing stress.

Identifying Sources of Stress. One key component in most CBT approaches is a diary that keeps an informal inventory of daily events and activities. While this exercise might itself seem stress producing (and yet one more chore), it need not be done in painstaking detail. A few words accompanying a time and date are usually enough to serve as reminders of significant events or activities.

The first step is to note activities that put a strain on energy and time, trigger anger or anxiety, or precipitate a negative physical response (such as a sour stomach or headache).

Also note positive experiences, such as those that are mentally or physically refreshing or produce a sense of accomplishment.

After a week or two, try to identify two or three events or activities that have been significantly upsetting or overwhelming.

Questioning the Sources of Stress. Individuals should then ask themselves the following questions:

Do these stressful activities meet my goals or someone else's?
Have I taken on tasks that I can reasonably accomplish?
Which tasks are under my control and which ones aren't?

Restructuring Priorities: Adding Stress Reducing Activities. The next step is to attempt to shift the balance from stress-producing to stress-reducing activities. Eliminating stress is rarely practical or feasible, but there are many ways to reduce its impact.

Consider as many relief options as possible. Examples include:

Listen to music. Music is an effective stress reducer in both healthy individuals and people with health problems. In one study, for example, students who listened to a well-known gentle classical piece of music during a stressful task had reduced feelings of anxiety, heart rate, and blood pressure.
Take long weekends or, ideally, vacations.
If the source of stress is in the home, plan times away, even if it is only an hour or two a week.
Replace unnecessary time-consuming chores with pleasurable or interesting activities.
Make time for recreation. This is as essential as paying bills or shopping for groceries.
Own a pet. In a study of people with high blood pressure, pet owners had much lower blood pressure increase in response to stress than non-owners. Note that owning a pet was beneficial only for people who like animals to begin with.

Discuss Feelings. The concept of communication and letting your feelings out has been so excessively promoted and parodied that it has nearly lost its value as good psychological advice. Nevertheless, feelings of anger or frustration that are not expressed in an acceptable way may lead to hostility, a sense of helplessness, and depression.

Expressing feelings does not mean venting frustration on waiters and subordinates, boring friends with emotional minutia, or wallowing in self-pity. In fact, because blood pressure may spike when certain chronically hostile individuals become angry, some therapists strongly advise that just talking, not simply venting anger, is the best approach, especially for these people.

The primary goal is to explain and assert one's needs to a trusted individual in as positive a way as possible. Direct communication may not even be necessary. Writing in a journal, writing a poem, or composing a letter that is never mailed may be sufficient.

Expressing one's feelings solves only half of the communication puzzle. Learning to listen, empathize, and respond to others with understanding is just as important for maintaining the strong relationships necessary for emotional fulfillment and reduced stress.

Keep Perspective and Look for the Positive. Reversing negative ideas and learning to focus on positive outcomes helps reduce tension and achieve goals. The following steps, using an example of a person who is alarmed at the prospect of giving a speech, may be useful:

First, identify the worst possible outcomes (forgetting the speech, stumbling over words, humiliation, audience contempt).
Rate the likelihood of these bad outcomes happening (probably very low or that speaker wouldn't have been selected in the first place).
Envision a favorable result (a well-rounded, articulate presentation with rewarding applause).
Develop a specific plan to achieve the positive outcome (preparing in front of a mirror, using a video camera or tape recorder, relaxation exercises).
Try to recall previous situations that initially seemed negative but ended well.

Use Humor. Research has shown that humor is a very effective mechanism for coping with acute stress. Keeping a sense of humor during difficult situations is a common recommendation from stress management experts. Laughter not only releases the tension of pent-up feelings and helps keep perspective, but it appears to have actual physical effects that reduce stress hormone levels. It is not uncommon for people to recall laughing intensely even during tragic events, such as the death of a loved one, and to remember this laughter as helping them to endure the emotional pain.

Relaxation Methods. Since stress is here to stay, everyone needs to develop methods to promote the relaxation response, the natural unwinding of the stress response. Relaxation lowers blood pressure, respiration, and pulse rates, releases muscle tension, and eases emotional strains. This response is highly individualized, but there are certain approaches that seem to work.

Combinations are probably best. For example, in a study of children and adolescents with adjustment disorder and depression, a combination of yoga, a brief massage, and progressive muscle relaxation effectively reduced both feelings of anxiety and stress hormone levels. A 2005 study of organ transplant recipients showed that training in meditation and gentle yoga led to significant improvements in quality of sleep and lessened anxiety and depression.

No one should expect a total resolution of stress from these approaches, but if done regularly, these programs can be very effective.

Acupuncture. Some evidence suggests that acupuncture may also be helpful. It might even improve some physical factors associated with stress and health problems. For example, in a study of heart failure patients, acupuncture improved stress-related heart muscle activity, which could be an important benefit in these patients. However, acupuncture had no effect on stress-related blood pressure or heart rate.

Hypnosis. Hypnosis may also benefit some people with severe stress. In one study of patients with irritable bowel, stress reduction by hypnosis correlated with improvement in many bowel symptoms.


*Deep Breathing Exercises.* During stress, breathing becomes shallow and rapid. Taking a deep breath is an automatic and effective technique for winding down. Deep breathing exercises consciously intensify this natural physiologic reaction and can be very useful during a stressful situation, or for maintaining a relaxed state during the day.	Inhale through the nose slowly and deeply to the count of 10. Make sure that the stomach and abdomen expand, but the chest does not rise. Exhale through the nose, slowly and completely, also to the count of 10. To help quiet the mind, concentrate fully on breathing and counting through each cycle. Repeat five to 10 times, and make a habit of doing the exercise several times each day, even when not feeling stressed.
*Muscle Relaxation.* Muscle relaxation techniques, often combined with deep breathing, are simple to learn and very useful for getting to sleep. In the beginning it is useful to have a friend or partner check for tension by lifting an arm and dropping it. The arm should fall freely. Practice makes the exercise much more effective and produces relaxation much more rapidly. Small studies have reported beneficial effects on blood pressure in patients with high blood pressure who use this technique.	After lying down in a comfortable position without crossing the limbs, concentrate on each part of the body. Maintain a slow, deep breathing pattern throughout this exercise. Tense each muscle as tightly as possible for a count of five to 10, and then release it completely. Experience the muscle as totally relaxed and lead-heavy. Begin with the top of the head and progress downward to focus on all the muscles in the body. Be sure to include the forehead, ears, eyes, mouth, neck, shoulders, arms and hands, fingers, chest, belly, thighs, calves, and feet. Once the external review is complete, imagine tensing and releasing internal muscles.
*Meditation.* Meditation, used for many years in Eastern cultures, is now widely accepted in this country as a relaxation technique. The goal of all meditative procedures, both religious and therapeutic, is to quiet the mind (essentially, to relax thought). Small studies have suggested that regular meditation can benefit the heart and help reduce blood pressure. Better research is needed, however, to confirm such claims. Some recommend meditating for no longer than 20 minutes in the morning after awakening and then again in early evening before dinner. Even once a day is helpful. Note: Meditating before going to bed may cause some people to wake up in the middle of the night, alert and unable to return to sleep. New practitioners should understand that it can be difficult to quiet the mind, and should not be discouraged by lack of immediate results. Several techniques are available. A few are discussed here. The only potential risks from meditating are in people with psychosis, in whom meditating may trigger a psychotic event.	Mindfulness Meditation. Mindfulness is a common practice that focuses on breathing. It employs the basic technique used in other forms of meditation. Sit upright with the spine straight, either cross-legged or sitting on a firm chair with both feet on the floor, uncrossed. With the eyes closed or gently looking a few feet ahead, observe the exhalation of the breath. As the mind wanders, simply note it as a fact and returns to the "out" breath. It may be helpful to imagine your thoughts as clouds dissipating away. Transcendental Meditation (TM). TM uses a mantra (a word that has a specific chanting sound but no meaning). The person meditating repeats the word silently, letting thoughts come and go. In one study, TM was as effective as exercise in elevating mood. Mini-Meditation. The method involves heightening awareness of the immediate surrounding environment. Choose a routine activity when alone. For example: While washing dishes, concentrate on the feel of the water and dishes. Allow the mind to wander to any immediate sensory experience (sounds outside the window, smells from the stove, colors in the room). If the mind begins to think about the past or future, or fills with unformed thoughts or worries, redirect it gently back. This redirection of brain activity from your thoughts and worries to your senses disrupts the stress response and prompts relaxation. It also helps promote an emotional and sensual appreciation of simple pleasures already present in a person's life.
*Biofeedback.* Biofeedback is a technique that measures bodily functions, like breathing, heart rate, blood pressure, skin temperature, and muscle tension. By watching these measurements, you can learn how to alter these functions by relaxing or holding pleasant images in your mind.	During biofeedback, electric leads are taped to a subject's head. The person is encouraged to relax using methods such as those described above. Brain waves are measured and an audible signal is emitted when alpha waves are detected, a frequency which coincides with a state of deep relaxation. By repeating the process, subjects associate the sound with the relaxed state and learn to achieve relaxation by themselves.
*Massage Therapy.* A 2005 report that reviewed data from multiple studies showed that massage therapy decreases cortisol levels. Another 2005 study showed that massage from a stable romantic partner can reduce physiological responses to a subsequent stressful event. In the study, women who received instructed shoulder-neck-massage from their partners before being exposed to stress had lowered cortisol responses, and smaller heart rate increases after the stressful event. Interestingly, massage was more beneficial than receiving social support from the partner, indicating the power of physical touch in managing stress. Several massage therapies are available.	Many massage techniques are available, such as the following: Swedish massage is the standard massage technique. It uses long smooth strokes, and kneading and tapping of the muscles. Shiatsu applies intense pressure to the same points targeted in acupuncture. It can be painful, but people report deep relaxation afterward. Reflexology manipulates acupuncture points in the hands and feet.

Some people who experience chronic stress seek herbal or natural remedies. It should be strongly noted, however, that just as with standard drugs, so-called natural remedies can cause problems, sometimes serious ones.

Probiotics. Probiotics are helpful bacterial strains that by themselves may provide a barrier against harmful bacteria. They do so through various mechanisms, such as excreting certain acids (for example, lactate, acetate) that inhibit harmful bacteria. They may also compete with them for nutrients. Stress reduces levels of these bacteria. Research even suggests that probiotics may help maintain remission in patients with IBD. In one small study, people suffering from stress and exhaustion significantly reduced their stress symptoms and gastrointestinal complaints when they took a probiotic supplement for 6 months. The specific bacteria that might be beneficial, however, are not fully known. The most well-known probiotics are the lactobacilli strains, such as acidophilus, which is found in yogurt and other fermented milk products. Others, however, may prove to be more important, such as bifidobacteria and GG lactobacilli. Other probiotics include the lactobacilli rhamnosus, casel, plantarium, bulgaricus, and salivarius, and also Enterococcus faecium and Streptococcus thermophilus.

Aromatherapy. The smell of lavender has long been associated with a calming effect. In a Japanese study, 14 women who were put in a room with a lavender scent experienced reduced mental stress. Several aromatherapies are now used for relaxation. Use caution, however, as some of the exotic plant extracts in these formulas have been associated with a wide range of skin allergies.

Valerian. Valerian is an herb that has sedative qualities and may reduce stress and associated physical effects. This herb is on the FDA's list of generally safe products. Of note, however, the herb's effects could be dangerously increased if it is used with standard sedatives. Other interactions and long-term side effects are unknown. Side effects include vivid dreams. High doses of valerian can cause blurred vision, excitability, and changes in heart rhythm.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, however, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been numerous reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

Special Warning on Kava. Kava has been commonly used to reduce anxiety and stress. It is now highly associated with liver injury and even liver failure in a few cases. Experts now strongly warn against its use.

People seeking relief from stress should be wary of things that promise a quick cure, or plans that include the purchase of expensive treatments. These treatments may be useless and sometimes even dangerous.

Resources

www.nimh.nih.gov -- National Institute of Mental Health
www.nami.org -- National Alliance for the Mentally Ill
www.nmha.org -- National Mental Health Association
www.amtamassage.org -- American Massage Therapy Association
www.cognitivetherapynyc.com -- American Institute for Cognitive Therapy
www.aabt.org -- Association for the Advancement of Behavior Therapy
www.healthyminds.org -- The American Psychiatric Association
www.naswdc.org -- The National Association of Social Workers
www.aacap.org -- American Academy of Child and Adolescent Psychiatry
www.stress.org -- The American Institute of Stress

References

Ginsburg KR and the Committee on Communications and Committee on Psychosocial Aspects of Child and Family Health. Clinical Report: The Importance of Play in Promoting Healthy Child Development and Maintaining Strong Parent-ChildBonds.Last accessed on 17 October, 2006.

Dallman MF, Pecoraro NC, la Fleur SE. Chronic stress and comfort foods: self-medication and abdominal obesity. Brain Behav Immun. 2005;19:275-280.

Wang J. Work stress as a risk factor for major depressive episode(s). Psychol Med. 2005;35:865-871.

Hammerfald K, Grau M, et al. Persistent effects of cognitive-behavioral stress management on cortisol responses to acute stress in healthy subjects-A randomized controlled trial. Psychoneuroendocrinology. 2005 Sep 22; epub ahead of print.

Kreitzer MJ, Gross CR, Ye X, et al. Longitudinal impact of mindfulness meditation on illness burden in solid-organ transplant recipients. Prog Transplant. 2005;15:166-172.

Field T, Hernandez-Reif M, Diego M, et al. Cortisol decreases and serotonin and dopamine increase following massage therapy. Int J Neurosci. 2005;115:1397-1413.

Ditzen B, Neumann I, Bodenmann G, et al. Romantic Partner Interaction Reduces Endocrine and Autonomic Stress Responses in Women. New Research Abstracts, Annual Meeting of the American Psychiatric Association. Washington, D.C. 2005. Abstract NR140.

Review Date:
10/16/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Gout

FitSugar — Wed, 08 Oct 2008 17:35:16 -0700

In This Report

Highlights
Introduction
Symptoms
Causes and Risk Factors
Triggers
Diagnosis
Treatment: Acute Gout Attac...
Treatment: Preventing Attac...
Other Treatments
Lifestyle Changes
Complications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Types of Gout:

There are two types of gout -- primary and secondary.

Primary gout: The cause is usually unknown. However, primary gout is likely the result of a combination of genetic, hormonal, and dietary factors.
Secondary gout: Secondary gout is caused by medications or medical conditions that cause an increase in the serum (blood) levels of uric acid.

Risk Factors:

Risk factors for gout include:

Advancing age
Male gender
Family history of the condition
Obesity
Use of certain drugs, including diuretics, aspirin, cyclosporine, or levodopa
Drinking a large amount of alcohol, particularly beer
Exposure to lead
Organ transplants
Thyroid problems

Symptoms of a Gout Attack:

Symptoms of a gout attack include:

Severe pain at and around the joint
- May feel like "crushing" or a dislocated bone
- Walking and the weight of bed sheets may be unbearable
- Usually takes 8 - 12 hours to develop
- Occurs late at night or early in the morning and may wake you up
Swelling that may extend beyond the joint
Red, shiny, tense skin over the affected area, which may peel after a few days
Chills and mild fever, loss of appetite, and feelings of ill health

Research News

A large study found that people with gout are at an increased risk of having metabolic syndrome. Metabolic syndrome is a collection of problems, such as abdominal obesity, high blood pressure, and low "good" cholesterol. This syndrome increases a person's risk of heart disease and diabetes.

Introduction

Gout is a painful and common type of arthritis. About 1 in 100 people develop gout. The condition is usually associated with a long-lasting, abnormally high amount of uric acid in the blood, called chronic hyperuricemia.

The rate of gout has increased in recent decades, not only in America but also in other developed countries. The increase is possibly due to dietary and lifestyle changes, greater use of medications that cause hyperuricemia, and aging populations. Gout is very uncommon in developing countries.

Click the icon to see an animation about gout.

Metabolism of Purines. The process leading to hyperuricemia and gout begins with the metabolism of purines, nitrogen-containing compounds that are important for energy. Purines can be divided into two types:

Endogenous purines are manufactured within human cells.
Exogenous purines are obtained from foods.

The process of breaking down purines results in the formation of uric acid in the body. Most mammals have an enzyme called uricase, which breaks down uric acid so it can be easily removed from the body. Because humans lack uricase, uric acid is not as easily removed, and can build up in body tissues.

Uric Acid and Hyperuricemia. Purines in the liver produce uric acid. The uric acid enters the bloodstream, and most of it eventually goes through the kidneys and is excreted in the urine. The remaining uric acid travels through the intestines, where bacteria help break it down.

Normally these actions keep the level of uric acid in the blood plasma (the liquid part of the blood) at a healthy level, which is below 6.8 mg/dL. But under certain circumstances, the body produces too much uric acid or removes too little. In either case, concentrations of uric acid increase in the blood. This condition is known as hyperuricemia.

If concentrations of uric acid reach 7 mg/dL and above, needlelike crystals of a salt called monosodium urate (MSU) form. As MSU crystals build up in the joints, they trigger inflammation and pain, the characteristic symptoms of gout.

Symptoms

The specific symptoms of gout depend on the stage of the disease. Gout is often divided into four stages:

Asymptomatic hyperuricemia
Acute gouty arthritis
Intercritical gout
Chronic tophaceous gout

Asymptomatic means there are no symptoms. Asymptomatic hyperuricemia is considered the first stage of gout. MSU levels slowly increase in the body. This stage lasts for an average of 30 years.

Note: Hyperuricemia does not inevitably lead to gout. In fact, less than 20% of cases develop the full-blown arthritic gout disease.

Acute gouty arthritis occurs when the first symptoms of gout appear. Sometimes the first signs of gout are brief twinges of pain (petit attacks) in an affected joint. These attacks can precede the actual full-blown condition by several years.

MSU crystals form at normal body temperature when the concentration of uric acid in the blood reaches 7 mg/dL. At lower temperatures, MSU crystals form at lower concentrations of uric acid. Since blood temperature falls the further blood gets from the heart, gout strikes the toes and fingers first.

Symptoms of acute gouty arthritis include:

Severe pain at and around the joint
- May feel like "crushing" or a dislocated bone
- Walking and the weight of bed sheets may be unbearable
- Usually takes 8 - 12 hours to develop
- Occurs late at night or early in the morning and may wake you up
Swelling that may extend beyond the joint
Red, shiny, tense skin over the affected area, which may peel after a few days
Chills and mild fever, loss of appetite, and feelings of ill health

Most often symptoms start in one joint.

Monoarticular Gout. Gout that occurs in one joint is called monoarticular gout. About 60% of all first-time monoarticular gout attacks in middle-aged adults occur in the big toe. This occurrence is known as podagra. Symptoms can also occur in other locations, such as the ankle or knee.

Polyarticular Gout. If more than one joint is affected, the condition is known as polyarticular gout. Multiple joints are affected in only 10 - 20% of first attacks. Older people are more likely to have polyarticular gout. The most frequently affected joints are the foot, ankle, knee, wrist, elbow, and hand. The pain usually occurs in joints on one side of the body and it is usually, although not always, in the lower legs and the feet. People with polyarticular gout are more likely to have a slower onset of pain and a longer delay between attacks. People with polyarticular gout are also more likely to experience low-grade fever, loss of appetite, and a general feeling of poor health.

An untreated attack will typically peak 24 - 48 hours after the first appearance of symptoms, and go away after 5 - 7 days. However, some attacks last only hours, while others persist as long as several weeks.

Intercritical gout is the term used to describe the periods between attacks. The first attack is usually followed by a complete remission of symptoms, but, if left untreated, gout nearly always returns. Over two-thirds of patients will have at least one further attack within 2 years of the first attack. By 10 years, over 90% of the patients are likely to have repeat attacks.

Chronic Tophaceous Gout and Tophi. After several years, persistent gout can develop into a condition called chronic tophaceous gout. This long-term condition often produces tophi, which are solid deposits of MSU crystals that form in the joints, cartilage, bones, and elsewhere in the body. In some cases, tophi break through the skin and appear as white or yellowish-white, chalky nodules that have been described as looking like crab eyes.

Click the icon to see an image of tophi gout.

Without treatment, tophi develop about 10 years after the initial onset of gout, although the occurence can range from 3 to 42 years. Tophi are more likely to appear early in the course of the disease in older people. In the elderly population, women appear to be at higher risk for tophi than men. Certain people, such as those who are receiving cyclosporine after a transplant, have a high risk of developing tophi.

Development of Chronic Pain. When gout remains untreated, the intercritical periods typically become shorter and shorter, and the attacks, although sometimes less intense, can last longer. Over the long term (about 10 - 20 years) gout becomes a chronic disorder characterized by constant low-grade pain and mild or acute inflammation. Gout may eventually affect several joints, including those that may have been free of symptoms at the first appearance of the disorder. In rare cases, the shoulders, hips, or spine are affected.

Location of Tophi. Tophi generally form in the following locations:

Curved ridge along the edge of the outer ear
Forearms
Elbow or knee
Hands or feet -- older patients, particularly women, are more likely to have gout in the small joints of the fingers.
Around the heart and spine (rare)

Tophi are generally painless. However, they can cause pain and stiffness in the affected joint. Eventually, they can also erode cartilage and bone, ultimately destroying the joint. Large tophi under the skin of the hands and feet can give rise to extreme deformities.

Uric Acid Nephrolithiasis (Kidney Stones). Persons who have kidney stones that formed from uric acid are more likely to have higher levels of uric acid in their blood than in their urine. This suggests that gout is responsible for this type of kidney stones. Uric acid stones and other forms of kidney stones are present in 10 - 25% of patients with primary gout, a rate of more than 1,000 times that of the general population. In gout caused by other conditions (called secondary gout), the reported rate reaches 42%.

Click the icon to see an image of nephrolithiasis.

Not all of the kidney stones in patients with gout are made of uric acid. Some are made from calcium oxalate, calcium phosphate, or substances combined with uric acid. Uric acid stones can also form when you do not have gout or hyperuricemia.

Chronic Uric Acid Interstitial Nephropathy. Chronic uric acid interstitial nephropathy occurs when crystals slowly form in the structures and tubes that carry fluid from the kidney. It is reversible and not likely to injure the kidneys.

Kidney Failure. Sudden overproduction of uric acid can occasionally block the kidneys and cause them to fail. This occurrence is very uncommon but can develop after any of the following:

Chemotherapy for leukemia or lymphoma
Severe heat stress from vigorous exercise
Epileptic seizures
Corticosteroid therapy for severe allergic reactions

Causes and Risk Factors

Gout is classified as either primary or secondary, depending on what causes the high levels of uric acid in the blood (hyperuricemia).

More than 99% of primary gout cases are referred to as idiopathic, meaning that the cause of the hyperuricemia cannot be determined. Primary gout is most likely the result of a combination of genetic, hormonal, and dietary factors. Secondary gout is caused by drug therapy or by medical conditions other than a metabolic disorder.

The following factors increase your risk for gout:

Advancing age
Male gender
Family history of the condition
Obesity
Use of certain drugs, including diuretics ("water pills"), aspirin, cyclosporine, or levodopa
Drinking a large amount of alcohol, particularly beer
Exposure to lead
Organ transplants
Thyroid problems
Other serious illness

Each risk factor is discussed in more detail below.

Middle-Aged Adults. Gout usually occurs in middle-aged men, peaking in the mid-40s. It is most often associated in this age group with obesity, high blood pressure, unhealthy cholesterol levels, and heavy alcohol use.

Elderly. Gout can also develop in older people, when it occurs equally in men and women. In this group, gout is most often associated with kidney problems and the use of diuretics. It is less often associated with alcohol use.

Children. Except for rare inherited genetic disorders that cause hyperuricemia, gout in children is rare.

Men. Men are significantly at higher risk for gout. In males, uric acid levels rise substantially at puberty. In about 5 - 8% of American men, levels exceed 7 mg/dL (indicating hyperuricemia). However, gout typically strikes after 20 - 40 years of persistent hyperuricemia, so men who develop it usually experience their first attack between the ages of 30 and 50.

Women. Before menopause, women have a significantly lower risk for gout than men, possibly because of the actions of estrogen. This female hormone appears to facilitate uric acid excretion by the kidneys. (Only about 15% of female gout cases occur before menopause.) After menopause the risk increases in women. At age 60 the incidence is equal in men and women, and after 80, gout occurs more often in women.

According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, up to 18% of people with gout have a family history of the condition. Some people with a family history of gout have a defective protein (enzyme) that interferes with the way the body breaks down purines.

Researchers report a clear link between body weight and uric acid levels. In one Japanese study, overweight people had two to more than three times the rate of hyperuricemia as those who maintained a healthy weight. Children who are obese may have a higher risk for gout in adulthood.

Thiazide diuretics are "water pills" used to control hypertension. The drugs are strongly linked to the development of gout. In fact, 75% of patients who develop gout at an older age report the use of diuretics.

Several other medications can increase uric acid levels and raise your risk for gout. These include:

Aspirin -- low doses of aspirin reduce uric acid excretion and increase the chance for hyperuricemia. This may be a problem for older people who take baby aspirin (81 mg) to protect against heart disease.
Niacin (used to treat cholesterol problems)
Pyrazinamide (used to treat tuberculosis)

Drinking excessive amounts of alcohol can raise your risk of gout. Beer is the kind of alcohol most strongly linked with gout, followed by spirits. Moderate wine consumption does not appear to increase the risk of developing gout.

Alcohol use is highly associated with gout in younger adults. Binge drinking particularly increases uric acid levels. Alcohol appears to play less of a role among elderly patients, especially among women with gout.

Alcohol increases uric acid levels in the following three ways:

Providing an additional dietary source of purines (the compounds from which uric acid is formed)
Intensifying the body's production of uric acid
Interfering with the kidneys' ability to excrete uric acid

Chronic occupational exposure to lead is associated with build-up of uric acid and a high incidence of gout.

Kidney transplantation poses a high risk for renal insufficiency and gout. In addition, other transplantation procedures, such as heart and liver, increase the risk of gout. The procedure itself poses a risk of gout, as does the medication (cyclosporine) used to prevent rejection of the transplanted organ. Cyclosporine also interacts with indomethacin, a common gout treatment.

The kidneys are responsible for removing waste from the body, regulating electrolyte balance and blood pressure, and stimulating red blood cell production.

Treatment of several other conditions can cause significant elevations of uric acid in the blood, and therefore a gout attack. These conditions include:

Leukemia
Lymphoma
Psoriasis

Triggers

Triggers are events or conditions that can set off a gout attack. Certain risk factors, including a purine-rich diet, are also considered a trigger. Triggers include:

Joint injury
Overindulging in alcohol or purine-rich foods
Over-strenuous exercise
Severe illness or infection
Stress
Sudden weight loss
Surgery
Using certain drugs

Hot and humid weather may also be strongly associated with recurrent gout attacks. Such weather can cause sweating and, ultimately, dehydration, which has long been recognized as a potential trigger for gout attacks.

Drinking more water and fluids when it's warm outside could help persons with gout prevent future attacks.

Diagnosis

The first step in diagnosing the disease is to determine which joints are affected. A physical examination and medical history can help confirm or rule out gout. For example, gout is more likely if arthritis first appears in the big toe.

The speed of the onset of pain and swelling is also important. Symptoms that take days or weeks (rather than hours) to develop probably indicate a disorder other than gout.

Abnormal enlargements in joints that had been affected by previous injury or osteoarthritis are possible signs of gout. This is particularly significant in older women who take diuretics ("water pills").

A blood test is usually done to measure uric acid levels and detect hyperuricemia. A low level of uric acid in the blood makes a diagnosis of gout much less probable, and a very high level increases the likelihood of gout, especially if patient has symptoms of gout. Nevertheless, uric acid levels in the blood during an attack of gout can be within or below the normal range, and the presence of hyperuricemia does not necessarily mean someone has gout. However, most doctors feel that closer monitoring of blood uric acid levels in people with gout may help reduce gout flares.

Synovial fluid examination is the most accurate method for diagnosing gout. The synovial fluid is the lubricating liquid that fills the synovium (the membrane that surrounds a joint and creates a protective sac). The fluid cushions joints and supplies nutrients and oxygen to the cartilage surface that coats the bones. This exam also helps detect gout during intercritical periods.

The health care provider uses a needle attached to a syringe to draw out fluid from the affected joint. This is called aspiration. Local anesthesia is not used because it can reduce the effectiveness of the procedure. However, the procedure is usually only mildly uncomfortable. Afterwards, there can be some minor discomfort in the area where the needle was inserted, but it usually goes away quickly.

The fluid sample is sent to a laboratory for analysis. Testing can reveal the presence of monosodium urate (MSU) crystals, which will nearly always confirm a diagnosis of gout. The laboratory can also test the sample for infection.

The procedure itself can cause infection, though this occurs in less than 0.1% of patients. Aspiration sometimes eases the patient's symptoms by reducing swelling and pressure on the tissue surrounding the joint.

Synovial fluid analysis is a method to look at the fluid that cushions a joint. It is done to help diagnose and treat joint-related problems such as gout.

It is sometimes helpful to gauge the amount of uric acid found in a patient's urine, particularly if the patient is young and has pronounced hyperuricemia that might be related to a metabolic disorder. If uric acid in the urine exceeds a particular value, further tests for an enzyme defect or other identifiable cause of gout should be performed. Greater-than-normal amounts of uric acid in the urine also mean that the patient is more likely to develop uric acid kidney stones.

Typically, a 24-hour urine test is performed. The patient discards the first urination sample on the day of the test. Afterward all urine passed over the next 24 hours is collected into a special container, including the first urination on the morning of day two. The container is delivered to the patient's health care provider or sent directly to the laboratory.

The urine is collected during an intercritical period, after the patient has been placed on a purine-reduced diet. The patient is also asked to temporarily stop using alcohol and any medications that can interfere with the test. The patient should not change any of his or her usual eating or drinking patterns when performing this test.

Click the icon to see an image of a uric acid test.

X-Rays. For the most part, x-rays do not reveal any problems during the early stages of gout. Their usefulness lies in assessing the progress of the disorder in its chronic phase and identifying other health problems with symptoms similar to gout. Tophi can be seen on x-rays before they become apparent on physical examination.

Advanced Imaging Techniques. Advanced imaging techniques being investigated for identifying tophi include computed tomography (CT), magnetic resonance imaging (MRI), and Doppler ultrasonography.

As part of the diagnosis, other disorders that produce gout-like symptoms or cause hyperuricemia should be ruled out. In general, it is easy to distinguish acute gout that occurs in one joint from other arthritic conditions. The two disorders that may confuse this diagnosis are pseudogout and septic arthritis. Pseudogout is a condition most likely to be confused with gout.

Chronic gout can often resemble rheumatoid arthritis. Several other conditions may at some point in their course resemble gout.

Pseudogout (also called calcic gout and calcium pyrophosphate dihydrate deposition disease) is a common inflammatory arthritis among older adults. It is very similar to gout, but is caused by deposits of calcium pyrophosphate dihydrate crystals in and around the joints.

Although symptoms of pseudogout resemble gout in some ways, there are differences:

The first attack typically strikes the knee. Other joints commonly affected are the shoulders, wrists, and ankles. At least two-thirds of cases affect more than one joint during a first attack. Pseudogout may involve any joint, although the small joints in the fingers or toes are not commonly affected.
The symptoms of pseudogout also appear more slowly than those of gout, taking days rather than hours to develop.
Pseudogout is more likely to first develop in elderly people, particularly those with osteoarthritis. (It affects 10 - 15% of people over 65.)

Pseudogout is more likely to occur in the autumn while gout attacks are most common in the spring.

Conditions that are associated with a higher risk for pseudogout in elderly patients include underlying acute medical conditions, trauma, or surgery. Medical conditions associated with pseudogout include hypothyroidism, diabetes, gout, and osteoarthritis. Liver transplantation also may increase the risk.

There is no cure for pseudogout. It is a progressive disorder that can eventually destroy joints. Treatments for pseudogout are similar to those for gout and are aimed at relieving the pain and inflammation and reducing the frequency of attacks.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for treating inflammation and pain from pseudogout.
For acute attacks in large joints, fluid aspiration alone or with corticosteroids may help.
Colchicine may be used for acute attacks.
Magnesium carbonate may help dissolve crystals, but existing hard deposits may remain.
Surgery may be required for joint replacement.

Rheumatoid Arthritis. Rheumatoid arthritis can distort the joints of the finger and cause inflammation and pain that may mimic gout. In older people, it is particularly difficult to distinguish chronic gout from rheumatoid arthritis. A proper diagnosis can be made with a detailed medical history, laboratory tests, and identification of MSU crystals.

Osteoarthritis. Gout can coincide and be confused with osteoarthritis in older people, particularly when it occurs in arthritic finger joints in women. In general, gout should be suspected if the joints in the fingertips are unusually enlarged.

Click the icon to see an image of osteoarthritis.

Infections. Joint infections can have features that resemble gout. A correct diagnosis is critical for appropriate treatment. For example, some cases of gout have been confused with infection after joint replacement. On the other hand, joint infection not associated with surgery might indicate sepsis, which is a widespread and potentially life-threatening bacterial infection that can cause inflamed joints, chills, and a spiking fever. The severity of the fever and a high white blood cell count in the joint fluid helps diagnose a septic infection, while urate crystals in the joint are a good indicator of gout.

Charcot Foot. Between 1 - 2.5% of people with diabetes have Charcot foot or Charcot joint (medically referred to as neuropathic arthropathy). This condition is caused by problems in the nerves in the feet. Early changes may resemble gout, with the foot becoming swollen, red, and warm. Recognition and treatment of this condition is very important. A seriously affected foot can become deformed. The bones may crack, splinter, and erode, and the joints may shift, change shape, and become unstable.

Bunions. A bunion is a foot deformity that usually occurs at the head of the first of five long bones (the metatarsal bones) that extend from the arch and connect to the toes, and may be confused with gout. The first metatarsal bone is the one that attaches to the big toe. A bunion begins to form when the big toe is forced in toward the rest of the toes, causing the head of the first metatarsal bone to jut out and rub against the side of the shoe. The underlying tissue becomes inflamed, and a painful bump forms. As this bony growth develops, the bunion is formed as the big toe is forced to grow at an increasing angle towards the rest of the toes.

Click the icon to see an illustrated series detailing bunion removal.


Disease	Specific Subtypes
Osteoarthritis
Infectious Arthritis	Lyme disease, septic arthritis, bacterial endocarditis, mycobacterial and fungal arthritis, viral arthritis, osteomyelitis
Postinfectious or Reactive Arthritis	Reiter syndrome (a disorder characterized by arthritis and inflammation in the eye and urinary tract), rheumatic fever, inflammatory bowel disease
Pseudogout
Rheumatic Autoimmune Diseases	Rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, scleroderma, Still's disease (also called juvenile rheumatoid arthritis)
Fibromyalgia
Other Diseases	Chronic fatigue syndrome, hepatitis C, familial Mediterranean fever, cancers, AIDS, leukemia, bunions, Whipple's disease, dermatomyositis, Behcet's disease, Henoch-Schonlein purpura, Kawasaki's disease, erythema nodosum, erythema multiforme, pyoderma gangrenosum, pustular psoriasis

Treatment: Acute Gout Attack

Acute attacks of gout and long-term treatment of gout and hyperuricemia require different approaches. Treatment usually involves medication. After the first attack, some health care providers advise their patients to keep a supply of medications on hand so that self-medication can begin at the first sign of symptoms of a second acute attack. There are also specific treatments for conditions associated with gout, including uric acid nephropathy and uric acid nephrolithiasis.

Many patients do not require medications. During the period between gout attacks, patients are advised to avoid foods high in purines and to maintain a healthy weight. Patients should also avoid alcohol and reduce any stress.

Drug treatments for acute attacks of gout are aimed at relieving pain and reducing inflammation. They should be started as early as possible.

Medications used in the treatment of gout include:

NSAIDs (nonsteroidal anti-inflammatory drugs)
Colchicine
Corticosteroids

Powerful forms of nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice for an acute attack in younger, healthy patients with no serious health problems, particularly problems that affect the kidneys, liver, or heart. Usually indomethacin is prescribed for 2 - 7 days.

There are dozens of NSAIDs available. Over-the-counter NSAIDs include:

Low-dose Ibuprofen (Motrin IB, Advil, Nuprin)
Naproxen (Aleve)
Ketoprofen (Actron, Orudis KT)

Prescription NSAIDs include:

Ibuprofen (Motrin)
Naproxen (Naprosyn, Anaprox)
Flurbiprofen (Ansaid)
Diclofenac (Voltaren)
Tolmetin (Tolectin)
Ketoprofen (Orudis, Oruvail)
Dexibuprofen (Seractil)
Indomethacin (Indocin)

Indomethacin (Indocin) is typically the first choice of treatment for patients who have no medical conditions that would interfere with its use. Usually 2 - 7 days of high-dose indomethacin is enough to treat a gout attack. The first dose of indomethacin usually begins to act against the pain and inflammation within 24 hours and often much sooner.

Ibuprofen, naproxen, sulindac, or NSAIDs are good alternatives, particularly for elderly patients who might experience confusion or bizarre sensations with indomethacin. (Aspirin is an NSAID, but is associated with a higher risk for gout and should be avoided.)

Regular use of even over-the-counter NSAIDs can cause certain health problems, such as:

Ulcers and gastrointestinal bleeding
Increased blood pressure -- people with hypertension, severe vascular disease, kidney, or liver problems and those taking diuretics must be closely monitored if they need to take NSAIDs.
Delayed emptying of the stomach, which could interfere with the actions of other drugs. The elderly are at special risk.
Dizziness
Tinnitus (ringing in the ear)
Headache
Skin rash
Depression
Confusion or bizarre sensation (in some higher-potency NSAIDs, notably indomethacin)
Kidney damage

NSAIDs can cause kidney problems, especially in the elderly and those with kidney disease. When caught early enough, these problems generally resolve if the drugs are stopped. Any sudden weight gain or swelling should be reported to a physician. Anyone with kidney disease should avoid these drugs.

Patients with diabetes who take hypoglycemics by mouth may need to adjust their medication dosage if they also take NSAIDs, because of possible harmful interactions between these classes of drugs.

Some studies reported that ibuprofen (but not other NSAIDs) may reduce the heart-protective effects of low-dose aspirin. Additional research is needed to confirm these findings.

Long-term use of NSAIDs is a common cause of ulcers. NSAID-related bleeding and stomach problems may be responsible for over 100,000 hospital admissions and over 15,000 deaths each year. Because there are usually no gastrointestinal symptoms from NSAIDs until bleeding begins, health care providers cannot predict which patients taking these drugs will develop bleeding.

Those at high risk for NSAID-related bleeding include the elderly, anyone with a history of an ulcer or gastrointestinal bleeding, patients with serious heart conditions, those who drink too much alcohol, and persons on certain medications, such anticoagulants (blood thinners), corticosteroids, or bisphosphonates (drugs used for osteoporosis).

Preventing NSAID-Related Ulcers. Switching to alternative pain relievers is the first step in preventing or healing ulcers caused by NSAIDs. If people cannot change drugs, they should use the lowest NSAID dose possible.

In addition, medications are available that may help prevent ulcers in people who need to take NSAIDs. Proton-pump inhibitors (PPIs) are the first drug of choice for preventing ulcers in high-risk individuals. They have been shown to reduce NSAID-ulcer rates by as much as 80% compared with no treatment. Types of these drugs include omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex ), and pantoprazole (Protonix). Prevacid is the first proton-pump inhibitor specifically approved for protecting against ulcers in chronic NSAID users.

Arthrotec is a combination of an ulcer-protective drug called misoprostol and the NSAID diclofenac. It too may reduce the risk for gastrointestinal bleeding.

Colchicine is a derivative of the autumn crocus (also called the meadow saffron). It has been used against gout attacks for centuries. It is highly effective, although it is no longer the first drug of choice because of its frequent, unpleasant, and sometimes very serious side effects.

Colchicine may be given to a healthy adult within 48 hours of an attack. It should not be used by elderly patients or those with kidney, liver, or bone marrow disorders. It can also affect fertility and should not be used during pregnancy. The drug can cause gastrointestinal side effects at high dose, including nausea, vomiting, diarrhea, and abdominal cramps. Low doses do not pose as high a risk for gastrointestinal symptoms, and can prevent further attacks, including attacks in patients who are starting anti-hyperuricemic therapies.

Colchicine may be taken by mouth or given by an intravenous line. Those who take it by mouth need doses every hour until either symptoms improve or side effects develop. Improvement should be seen by the tenth dose. It usually eliminates the pain of an acute attack within 48 hours. The intravenous route has some serious side effects, however, and poses an increased risk for injury to the kidney, liver, central nervous system, and bone marrow.

The antibiotic erythromycin, or H2 blockers such as famotidine (Pepcid AC), cimetidine (Tagamet), or ranitidine (Zantac) may intensify the gastrointestinal side effects of colchicine.

Warning Note: Overdose of colchicine can be dangerous, and there have even been reports of death. The drug may also suppress blood cell production and cause nerve and muscular injury in certain people, sometimes even in those not taking high doses.

Corticosteroids may be used in patients who cannot tolerate NSAIDs and they may be particularly beneficial for elderly patients. Injections into an affected joint provide effective relief for many patients, but this is not useful for patients who have multiple affected joints. Steroids taken by mouth may be used for patients who cannot take NSAIDs or colchicine and who have gout in more than one joint. Corticosteroids include triamcinolone and prednisone.

Treatment: Preventing Attacks

After an acute attack some patients remain at high risk for another attack for several weeks during the intercritical period. Such patients include those with kidney insufficiency or those with congestive heart failure who are on diuretics. Low doses of colchicine or NSAIDs may be used to during this period for prevention of another attack. They should be taken in low doses for 1 - 2 months after an attack, or for longer periods in patients who have experienced frequent attacks.

Antihyperuricemic medications reduce levels of uric acid in the body. The decision whether to use an antihyperuricemic medicine and at what point is not entirely clear. Some health care providers do not prescribe them if hyperuricemia is mild, or until a patient has had two gout attacks. Others prescribe them immediately after a single attack. Most of the time, antihyperuricemic therapy means taking a drug routinely throughout life, which many people find difficult.

Experts do not recommend treatment for hyperuricemia that causes no symptoms. Asymptomatic hyperuricemia often does not lead to gout or other health problems. In addition, the drugs used to treat it are expensive and carry certain risks. In unusual circumstances treatment may be justified, for example in patients with very high uric acid levels that threaten the kidney or those with a personal or strong family history of gout, kidney stones, or kidney damage.

Before treatment, some experts recommend a 24-hour urine collection sample in patients with frequent gout attacks to determine whether they are over-producers or under-excreters of uric acid. Also, before starting one of these drugs, any previous acute attack should be completely controlled and the joints should not be inflamed. Some health care providers prefer to wait about a month after an attack.

Low doses of NSAIDs or colchicine are used during several months after introducing anti-hyperuricemic therapies to prevent gout attacks. It should be noted that NSAIDs, particularly aspirin and similar drugs, reduce the effectiveness of uricosurics. These are drugs given to under-excreters of uric acid (see below). Patients taking uricosurics should avoid NSAIDs, if possible.

Long-term treatment of hyperuricemia may be recommended for people who have:

A risk for tophaceous gout
Had more than two or three acute attacks of gout in the past
Unusually severe attacks, or attacks that affect more than one joint
Joint damage from gout, as shown on x-rays
Hyperuricemia caused by an identifiable inborn metabolic deficiency

Uricosurics. These drugs prevent the kidney from reabsorbing uric acid, and therefore increase the amount excreted in the urine. They are appropriate when gout is caused by under-excretion of uric acid, which occurs in about 80% of gout cases. They are not used for patients with reduced kidney function or those with tophaceous gout. Uricosurics are usually the choice for preventing gout in the following patients:

Those under 60 years of age
Those with normal diets
Those who have normal kidney function
Those who have no risk of kidney stones

Uricosuric drug candidates should produce no more than 700 - 800 mg of uric acid in the urine over a 24-hour period.

Probenecid (Benemid, Probalan) and sulfinpyrazone (Anturane) are the standard uricosurics. A more potent uricosuric, benzbromarone, may work for people with severe tophaceous gout and kidney impairment when other drugs do not. In some studies, benzbromarone was equal to or even more effective than allopurinol, another type of antihyperuricemic drug. Because benzbromarone can cause liver failure in some patients, it is available in the U.S. only with special authorization. A uricosuric combined with allopurinol may be beneficial in some cases.

Probenecid is taken two to three times a day, and sulfinpyrazone begins at twice a day and increases to three or four times daily. The initial doses should be low and gradually increased. Probenecid combined with colchicine is more effective than probenecid alone, but everyone responds differently, so the dose should be carefully individualized.

The possible side effects of probenecid and sulfinpyrazone include skin rashes, gastrointestinal problems, anemia, and kidney stone formation. To help reduce acidity and the risk for kidney stones, patients should drink plenty of fluids (ideally water, not caffeinated beverages). Sodium bicarbonate supplemented by acetazolamide can also reduce acidity and the risk for stones.

NSAIDs, particularly aspirin, as well as other salicylate drugs, interfere with uricosuric drugs and reduce effectiveness. Patients who require minor pain relief should instead take acetaminophen (Tylenol). Uricosurics interact with many other drugs, and a patient should be sure to inform their health care provider of all medications they are taking.

People who take these drugs should have normal kidney function. This therapy may not be as beneficial in many elderly patients, who often have some kidney insufficiency.

Allopurinol (Lopurin, Zyloprim). Allopurinol blocks uric acid production. It is the drug most often used in long-term gout treatment for older patients and those who overproduce uric acid.

Allopurinol is taken by mouth once a day in doses of 100 - 600 mg, depending on the patient's response to treatment. When it is first used, allopurinol can trigger further attacks of gout. Therefore, during the first months (or longer) of therapy, the patient also takes an NSAID or colchicine to reduce that possibility.

Allopurinol has positive effects on "bad" cholesterol levels, so it may be better than other drugs for patients with both gout and coronary artery disease.

Side effects, which can be severe, include:

Rash
Diarrhea
Headache
Fever
Leukopenia (a reduction in the number of white blood cells)
Thrombocytopenia (a reduction in the number of platelets)
Cataracts

In rare cases, the rash can become severe and widespread enough to be life threatening (this condition is called toxic epidermal necrolysis, or TEN). Allergic individuals who experience only a mild rash may be able to build up their tolerance for the drug by undergoing a desensitization process.

Allopurinol interacts with certain other drugs, such as azathioprine.

Puricase (PEG-Uricase). This is an experimental drug that has been shown to rapidly reduce excess uric acid. If approved, it may help those who have failed other treatments.

It should be noted that many drugs used for gout can also precipitate acute gout symptoms and so should not be used until symptoms have subsided. The patient should then start treatment with small doses that gradually increase.

Hypertensive Agents. People with gout have a higher risk for high blood pressure. Some of the drugs used to treat hypertension, such as thiazide diuretics, can increase the risk for gout attacks. Newer agents, such as losartan (an angiotensin II receptor antagonist), and amlodipine (a calcium channel blocker), may have beneficial effects on both high blood pressure and gout.

Febuxostat. Febuxostat is the first drug to emerge in many decades as a potential new treatment for chronic gout. It may prove to be an alternative for patients who are allergic to allopurinol. The drug is awaiting approval from the U.S. Food and Drug Administration (FDA).

Other Treatments

Surgery. Large tophi that are draining, infected, or interfering with the movement of joints may need to be surgically removed. When infection is present, the procedure carries a high risk for complications. People most likely to have surgery also tend to have other medical conditions that might worsen their outlook. In one study, experts suggested that better preventive measures, such as the use of allopurinol, could reduce the need for surgery.

Several other surgical procedures are available for relieving pain and improving the function of affected joints. It is sometimes necessary to replace joints.

Hot and Cold Therapy. Rest and protecting the affected joint with a splint can also promote recovery. One study reported that applying ice packs for 30 minutes four times daily significantly reduced pain. However, a different study recommended applying warm water continuously and moving the joint. The theory behind this advice was that the pain in a gout attack is due to grinding from the crystals and that warmth would help dissolve the crystals and relieve pain.

Lifestyle Changes

Any activities that increase energy demands on the body also increase metabolism of purines, which produces uric acid. Avoiding stress and staying healthy are important for the prevention of attacks.

Because uric acid levels are only mildly affected by diet, dietary therapy does not play a large role in the prevention of gout. Still, people who have had an attack of gout may benefit from reducing their intake of purine-rich foods, particularly if they eat unusually large quantities of such foods.

While meat and certain types of seafood and shellfish do produce high levels of purines in the blood, research has suggested that not all purine-rich foods are associated with gout. Eating a moderate amount of purine-rich vegetables (spinach, cauliflower, mushrooms, legumes) does not appear to increase the risk of gout.

Dairy products, especially low-fat products (low-fat yogurt and skim milk), may actually protect against gout. Researchers have also found that taking 500 mg a day of vitamin C significantly reduces uric acid levels. They are investigating whether vitamin C can be used to prevent or treat gout.

Foods to Avoid:

Organ meats (liver, kidneys, sweetbreads)
Red meat (beef, pork, lamb)
Meat extracts (soup, broth, gravies)
Seafood (anchovies, sardines, herring, fish roe, canned tuna fish, shrimp, lobster, scallops, mussels)
Yeast products (beer and baked goods)

A supervised weight-loss program may be a very effective way to reduce uric acid levels in overweight patients. Crash dieting, on the other hand, is counterproductive because it can increase uric acid levels and may cause an acute attack.

Drinking plenty of water and other nonalcoholic beverages helps remove MSU crystals from the body.

Alcohol should be avoided, since it promotes purine metabolism and uric acid production. It also may reduce excretion of uric acid. Heavy drinking, especially binge drinking of beer or distilled spirits, should be avoided.

People with gout should also attempt to avoid activities that cause repetitive joint trauma, such as wearing tight shoes.

Travel is an example of an activity that increases the risk for gout. It not only increases stress, but eating and drinking patterns may change. Before traveling, patients should discuss preventive measures with their health care providers. The doctor may prescribe a prednisone tablet to be taken immediately at the first sign of a gout attack. In most cases, this stops the episode.

Complications

Properly treated gout rarely poses a long-term health threat, though it can be a cause of short-term pain and incapacity for thousands of Americans.

Left untreated, gout can develop into a painful and disabling chronic disorder. Persistent gout can destroy cartilage and bone, causing irreversible joint deformities and loss of motion. Survey results released in 2006 show that two-thirds of persons with gout consider the pain of attacks among the worst they've ever experienced. An estimated 75% of those surveyed said flare-ups made walking very difficult, and about 70% reported trouble putting on shoes or playing sports.

Tophi are firm chalky, gritty clumps of uric acid crystals that build up in tissue surrounding a joint. If gout is not treated, tophi can grow to the size of golf balls and can destroy bone and cartilage in the joints, similar to the process in rheumatoid arthritis. If they lodge in the spine, tophi can cause serious damage including compression, although this is very rare. In extreme cases, joint destruction results in complete disability.

Kidney Stones. Kidney stones occur in 10 - 40% of gout patients, and can occur at any time after the development of hyperuricemia. Although the stones are usually composed of uric acid, they may also be mixed with other materials.

Kidney stones result when urine becomes too concentrated, and substances in the urine crystallize to form stones. Symptoms occur when the stones begin to move down the ureter and cause intense pain. Kidney stones may form in the pelvis or calyces of the kidney or in the ureter.

Kidney Disease. About 25% of patients with chronic hyperuricemia develop progressive kidney disease, which sometimes ends in kidney failure. It should be noted, however, that many experts believe that chronic hyperuricemia is unlikely to be a common cause of kidney disease. In most cases, the kidney disease comes first and causes high concentrations of uric acid.

Gout is found in higher rates in people with high blood pressure, coronary artery disease, and heart failure. Hyperuricemia, in fact, has been associated with a higher risk of death from heart conditions. A large study published in 2007 found an association between gout and having the metabolic syndrome -- a collection of problems, such as abdominal obesity, high blood pressure, high triglycerides levels, and low "good" cholesterol levels. This syndrome increases a person's risk of heart disease and diabetes.

A study published in the August 2006 journal Arthritis & Rheumatism found that gout increases the risk of heart attacks in men with no previous history of heart problems. According to some studies, hyperuricemia may be associated with heart disease, but there is not enough data to confirm such an association.

Click the icon to see an image of coronary artery blockage.

The following are some conditions that are associated with long-term gout:

Cataracts
Dry eye syndrome
Complications in the lungs (in rare cases, uric acid crystals occur in the lungs)

Resources

www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.rheumatology.org -- American College of Rheumatology
www.arthritis.org -- The Arthritis Foundation
www.gouteducation.org -- The Gout & Uric Acid Education Society

References

Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2007;57(1):109-15.

Huang HY, Appel LJ, Choi MJ et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum. 2005 Jun;52(6):1843-7.

Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk of acute myocardial infarction. Arthritis Rheum. 2006 Aug;54(:2688-96.

Underwood M. Diagnosis and management of gout. BMJ. 2006;332(7553):1315-9.

Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1301-11.

Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-24.

Zhang YQ, Chaisson CE, Chen CA, McAlindon TE, Hunter DJ. High Humidity and High Temperature Increase the Risk of Recurrent Gout Attacks: The Online Case-crossover Gout Study. Presentation Number 707. American College of Rheumatology Annual Scientific Meeting, Washington, DC, November 2006.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Immunizations

FitSugar — Wed, 08 Oct 2008 17:35:29 -0700

In This Report

Highlights
Introduction
Diphtheria, Tetanus, and Pe...
Measles, Mumps, and Rubella...
Varicella-Zoster Virus (Chi...
Varicella-Zoster Virus (Shi...
Hepatitis A
Hepatitis B
Pneumococcal Pneumonia
Poliomyelitis
Viral Influenza
Haemophilus Influenzae Type...
Human Papillomavirus (HPV)...
Rotavirus
Smallpox
Other Vaccinations
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Vaccines

The Centers for Disease Control and Prevention now recommends that children receive 2 doses of the varicella-zoster (Chickenpox) vaccine: the initial vaccine between ages 12 - 15 months, and a booster between 4 - 6 years. Children aged 12 and older and adults who have not had the vaccine should receive 2 doses. Immunization guidelines were changed following research that indicated the effectiveness of the vaccine declines over time. A 2007 study indicated that children who were vaccinated 5 or more years earlier were 2.6 times more likely to have a moderate-to-severe breakthrough case of chickenpox than those who had been vaccinated more recently.
A study finds that the conjugate pneumococcal vaccine, which was introduced for children in 2000, has reduced hospital admissions for pneumonia in children under age 2 by about 39%. The vaccine has also caused hospital admissions to drop 26% among adults aged 18 - 39. Another study found that recurrent ear infections have fallen by 28% since the introduction of the vaccine.
In April 2007, the U.S. Food and Drug Administration approved the first vaccine against the avian flu virus. The avian flu vaccine is designed for people ages 18 - 64 who are at risk for exposure to the virus. The vaccine is given in 2 shots, spaced about 1 month apart. The U.S. government is stockpiling the vaccination in case of an avian influenza outbreak, but the vaccine is not available to the general public.
Research finds that the human papillomavirus (HPV) vaccine (Gardisil) is 100% effective against cervical, vaginal, and vulvar diseases caused by 4 types of HPV (6, 11, 16, and 18).

Introduction

Immunizations against childhood diseases have saved millions of lives. American vaccination rates are now at an all-time high. Disease and death from diphtheria, pertussis, tetanus, measles, mumps, rubella, and Haemophilus influenzae (H. influenzae) type b are at or near record lows. In adults, immunizations against influenza (the flu), pneumococcal pneumonia, hepatitis, and other ailments have likewise saved many lives and prevented many more cases of serious illness. A new vaccine has been shown to be highly effective for preventing the virus that leads to cervical cancer.

More than 70 bacteria, viruses, parasites, and other infectious microbes cause major human disease. Fortunately, vaccines are either available or being developed against many of them. With the advent of new or newly feared biological threats, emerging infections, and bacterial resistance to common antibiotics, immunizations are assuming an increasingly important role in maintaining the health of billions of people worldwide.

Immunizations (vaccinations) are given to initiate or augment resistance to an infectious disease. Immunizations provide a specialized form of immunity that provides long-lasting protection against specific antigens, which cause disease.

Routine Childhood Vaccines. Experts recommend that all children be routinely vaccinated against the following diseases:

Measles
Mumps
Rubella (German measles)
Diphtheria
Tetanus
Pertussis (whooping cough)
Poliomyelitis (polio)
Varicella (chickenpox)
Hepatitis B
Hepatitis A
H. influenzae type B (a cause of meningitis)
Influenza (children aged 6 - 59 months)
Pneumococcal disease
Meningococcal disease (for selected populations)
Rotavirus (children aged 6 - 32 weeks)

Many vaccinations are first given during infancy. Even premature infants can, in most cases, be given vaccinations on a normal schedule. There is even some evidence that doing so may offer some slight protection against sudden infant death syndrome. Note: These facts pertain to children in the United States. Children from other countries have not been well studied. Parents who adopt internationally may want to have their children's immunity assessed by a physician. Some evidence suggests that their medical records may not correctly reflect immunization status and that many adopted children, such as those from China, have not had many important vaccinations.

Click the icon to see an animation about vaccines.

Common Adult Vaccines. Vaccinations against the following disorders are also recommended routinely for certain adults:

Influenza (flu). Every year in high-risk adults under 49 and everyone over 50. When supplies are limited, as with the 2004 - 2005 flu season, the vaccine should be administered preferentially to adults only over age 65 and to individuals with heart disease, lung disease, and other significant chronic illnesses. Health care providers with direct patient contact, child care providers, and residents of long-term care facilities should also be vaccinated.
Pneumococcal pneumonia. One dose in high-risk adults under 64 and a first dose or a revaccination in everyone over 65.
Hepatitis A and B and Meningococcal vaccine. Given to high-risk individuals.
Tetanus. Adults need a booster shot every 10 years.
Measles, mumps, rubella. Typically given to adults under 56 who are unsure of their vaccination history. High-risk individuals may receive two doses.
Diphtheria and pertussis are now recommended with tetanus (Tdap vaccine) booster every 10 years until age 65.
Herpes zoster (shingles) vaccine. One dose for adults 60 and older.
Human papillomavirus (HPV). Three doses in young women aged 11 - 26.

Vaccines are currently taken by mouth (orally) or given by a shot (injection). Vaccines are usually made of one of two agents that cause the body to produce antibodies that attack a specific disease. A vaccine may contain:

A live but weakened virus. Live-virus vaccines provide longer immunity than inactivated ones, but they can cause serious infection in people with weakened immune systems and have also been associated with severe medical disorders in rare instances.
Inactivated bacteria, viruses, or toxoids. Inactivated vaccines are safe even in people with impaired immune systems.

Click the icon to see an image of antibodies.

The weakened or inactivated agent in the vaccine teaches the immune system to recognize the real, harmful substance and attack it when the person becomes exposed to the infection. The antibodies remain in the body, preventing future illness from the disease. This is called immunity.

Combination Vaccines. The American Academy of Pediatrics and American Academy of Family Physicians recommend that health care providers use, whenever possible, combination vaccines instead of individual components. Combination shots containing vaccines for diphtheria, tetanus, and pertussis (DTaP), and for measles, mumps, and rubella (MMR), have been available for years. New combinations that cover up to 5 vaccinations are being developed and are proving to be safe and well tolerated in infants as young as 2 months. For example, one that combines DTaP, hepatitis B, and the polio vaccine (Pediarix) has been approved and should simplify the immunization process.

There is some concern that increasing use of combinations may reduce the potency of some of the vaccines. Some parents are also worried about increased side effects. Studies to date, however, are reporting that combinations are effective and safe.

Passive Immunity. Another form of protection against disease is called passive immunity. This approach uses immune globulin, which are blood products containing antibodies. Immune globulin is generally used for people who cannot be vaccinated, when immediate protection is required, or to prevent severe complications of the disease. In some circumstances, passive immunity can interfere with active vaccinations, particularly live-virus vaccines, so, if possible, they should not be administered within weeks or even months of each other.

General Information on Side Effects. Vaccines can have side effects, such as swelling at the injection site or fever, which are nearly always mild. There have been a number of reports in the popular press about alarming side effects in many vaccines. Anti-vaccine groups vocally oppose immunizations in children. Although it is true that no vaccine is 100% safe, childhood infections have not been wiped out. Without immunization, children risk diseases that have in the past killed millions of young children.

Thimerosal is a preservative used in many vaccines. It has been in use since the 1930s. The preservative contains small amounts of mercury. Some people are concerned about possible neurologic consequences from cumulative doses of mercury contained in vaccines given to infants. A 2003 study did report an association between thimerosal in DTaP vaccines and a higher risk for problems in neurologic development, including autism and speech problems.

In 2004, the Institute of Medicine (IOM) Safety Review Committee reported the results of studies in the U.S. and several European countries evaluating a possible association between thimerosal and autism. They concluded that scientific studies did not find that thimerosal caused autism.

In any case, manufacturers have been removing this preservative from vaccines. At the time of this report, all vaccines recommended for children age 6 or younger contain either no thimerosal or only trace amounts, with the exception of the inactivated influenza vaccine (although a limited supply of a version of the vaccine containing only trace amounts of thimerosal is available for use in infants, children, and pregnant women). A trace amount means that a given dose of vaccine contains less than 1 part per million.

Inactivated-virus and toxoid vaccines are usually safe in pregnant women, although any vaccination should be delayed, if possible, until the second or third trimester. Because of a possible risk to the fetus, live-virus vaccines should not be given to pregnant women or those likely to become pregnant within 28 days unless such women need immediate protection against life-threatening diseases, such as yellow fever, that are only prevented using live-virus vaccines. The live-virus MMR combination, which vaccinates against measles, mumps, and rubella, is not given to pregnant women because of the theoretical risk of the live-rubella vaccine on the fetus.

Click the icon to see an image of rubella syndrome.

Live-virus vaccines are not usually given to people whose immune system has been compromised by illness or the use of medication such as long-term corticosteroids. They include:

Click the icon to see an image of HIV.

Persons who have immune deficiency diseases (such as HIV or AIDS).
Patients with active leukemia or lymphoma.
Patients who are taking treatments that suppress the immune system, such as corticosteroids, alkylating drugs, antimetabolites, or radiation. (There are important exceptions, however, which are noted in the discussion of individual vaccinations below.) Short-term corticosteroids (given for less than 2 weeks) do not suppress the immune system and so should not affect any live-virus vaccination. It should be noted that some topical corticosteroids are suppressive. Patients who need vaccinations and who take long-term or high-dose topical steroids should check with their physicians.

In general, vaccines are not completely effective for patients whose immune systems are compromised by disease or medications. Often, such patients are given immune globulin if they are exposed to infection. It may take 3 months to 1 year before a person who has stopped taking immunosuppressant drugs regains the full ability to be successfully immunized against disease.

People who are traveling to developing countries should check with the US Centers for Disease Control (www.cdc.gov/travel) for up-to-date information on immunization requirements for their destination.

Below are some general guidelines for vaccinations, immunizations, and other preventive steps for travel:

Everyone should be up-to-date on any recommended vaccinations for childhood diseases, regardless of their age. Booster shots may be required for travelers to developing countries even if they have completed the initial series. Vaccinations may include polio, H. influenzae, the series for diphtheria, pertussis, and tetanus (DTaP), hepatitis B, rotavirus, measles, and varicella-zoster (chickenpox). If children have not completed their DTaP series, parents should consider having it completed while overseas.
Pregnant women should have vaccinations that are appropriate to their trimester. Not all vaccinations are safe during pregnancy.
Older adults may not respond to a vaccination as quickly as younger people or they may have a higher risk for side effects. They should check with their physicians.
Upper respiratory infections are very common after foreign travel. The flu vaccine may be recommended when traveling to any country during flu season, particularly for the elderly and people at risk for serious illness. This group may also need the pneumococcal vaccine.
Travelers to areas where there are tuberculosis (TB) outbreaks should have skin tests before traveling; those with negative tests should have a repeat test 2 - 4 months after they return.
Vaccination against hepatitis A is recommended for all travelers to developing countries. Some expert groups believe that such travelers should have hepatitis B vaccinations as well, but the CDC does not generally recommend them at this time except under certain circumstances.
Travelers to countries with malaria should take preventive agents.
Some countries may require vaccinations against yellow fever, meningitis, typhoid, cholera, Japanese encephalitis, and rabies under certain circumstances. Some of these vaccinations are covered in this report.
Studies indicate that multiple vaccines may be given at the same time to most adults without significantly increasing adverse effects.

[For more information, see In-Depth Report #1: Travel to developing countries.]

Childhood Immunization Schedule**
Age	Chickenpox (Varicella Zoster)	Diphtheria, Tetanus, Pertussis (DTaP)*	Haemophilus influenzae type (Hib)	Hepatitis A	Rotavirus
Birth
2 months		DTaP*	Hib		Rotavirus
4 months		DTaP*	Hib		Rotavirus
6 months		DTaP*	Hib (Depending on brand. For example, no third dose is required for PedvaxHIB or ComVax.)		Rotavirus
12 to 15 months	Varicella	DTaP* (Typically between 15 and 18 months. May be given as early as 12 months in high-risk children as long as 6 months have passed since the third dose.)	Hib (Sometime between 12 and 15 months.)	HepA (In 2 does, between 12 and 23 months)
2 years old				In children who have not been fully vaccinated.
4 to 6 years	Varicella	DTaP
11 to 12 years	Varies. (If previously missed, two doses should be given at least four weeks apart.)			In adolescents through age 18 in selected areas.

Age	Hepatitis B (Hep-B)*	Measles, Mumps, Rubella (MMR)	Pneumococcal Vaccine (PCV7)	Polio (Inactive virus) (IPV)*	Human Papillomavirus (HPV)
Birth	Hep-B immediately after birth. (This is very important when mothers are infected.) No later than 2 months in children of noninfected mothers. *
2 months	Hep-B some time between 1 and 4 months depending on risk. *		PCV7	IPV*
4 months			PCV7	IPV*
6 months	Hep-B some time between 6 and 18 months. *		PCV7	IPV* (Advised at some point between 6 and 18 months.) *
12 to 15 months	Varies.	MMR (Some time between 12 and 15 months.)
2 years old			PCV7 -- 1 dose for children not previously vaccinated.
4 to 6 years		MMR	PCV7 -- 1 dose in high-risk children.	IPV*
11 to 12 years	Hep-B (If vaccinations were previously missed). Two or 3 doses a few months apart.	MMR (If vaccinations were previously missed).			HPV (Females)
* A one-shot combination vaccine (Pediarix) has been approved that covers polio, hepatitis B, diphtheria, pertussis, and tetanus (DTaP) and should simplify the immunization process. It would be given as a single injection at 2, 4, and 6 months with booster shots given at 12 to 15 months and 4 to 6 years. **All children aged 6 - 59 months should receive an annual flu shot. Children older than 5 years of age who have chronic medical conditions should also receive the influenza vaccination. The flu shot is not approved for children younger than 6 months of age.

Of great concern are anti-immunization organizations and websites, which were formed mostly because of unsubstantiated reports linking small numbers of serious problems to some vaccines. The following watchdog systems are now in effect to monitor side effects from vaccination:

VAERS (Vaccine Adverse Event Reporting System) is a government service that registers all adverse events reported after vaccination, including those not related to the vaccine. It is useful for surveillance but has limitations. For example, the service may record the same case more than once. In addition, more serious events that occur after a vaccination are more likely to be reported than later and milder events, and such events are not necessarily linked to the vaccine.
VSD (Vaccine Safety Datalink) is a linked database that analyzes the records of more than 5 million patients each year. It is more accurate than VAERS, although the information it contains is not as timely.
The CDC has established the national network of Clinical Immunization Safety Assessment (CISA) Centers. It will provide services to physicians to help them evaluate and manage patients who may have had a side effect.

Studies using these systems are ongoing and none to date have confirmed reports of any significant association between most vaccines and severe side effects that would outweigh the benefits of these important and lifesaving agents.

No vaccine is 100% safe. Allergic and serious reactions are possible. In 2 cases, the early polio vaccine and the rotavirus vaccine, problems did occur, and some were serious. It is important to note, however, that even in these cases, the vaccines were withdrawn and the severe events still were far fewer than the number of lives saved.

The focus on vaccination side effects is ironic due to the fact that reports of such adverse effects outnumber the number of actual infections. Because vaccinations have been in existence for so long, today's parents have no direct knowledge of the consequences of these dreaded infections, which killed or severely sickened millions of children in the past.

It should be noted that studies are reporting that the risk for infection increases significantly in children who are not vaccinated. There is also a rise in infections among immunized children, suggesting resistance to the vaccines.

Infants often accept the first injection easily, since they are not expecting it. It gets more difficult, however, with each additional shot. Simply providing love and warmth can help children of all ages tolerate immunizations.

Additional tips:

Do not lie and tell an older child that a shot will be painless. Some health care providers suggest telling them that it stings a little and to count to 5 while it is being administered.
Ask the doctor if it is OK to give the child a dose of acetaminophen (Tylenol) before or after a shot. Ibuprofen (Motrin, Advil) or other non-aspirin pain relievers may be acceptable alternatives. (Children should NEVER take aspirin after vaccinations.)
Ask the doctor about EMLA cream, a topical anesthetic containing lidocaine and prilocaine. This product can be applied about an hour before the injection. (Note: EMLA may interact with acetaminophen and certain vaccinations, so be sure to check with the doctor first.)
A cooling spray may work as well as EMLA and have fewer side effects.
Longer needles, rather than shorter ones, may help reduce pain. One study reported that using longer needles decreased redness at the injection site by about two-thirds. Parents may want to ask their doctor about this study.
Have your child take a deep breath right before the shot and blow out very hard while it is being given. One study reported very good results with this breathing technique.
Give a sweet fluid before the shot and a little reward, such as a lollipop, immediately after the shot. Sugar actually has mild pain relieving properties for infants.

Diphtheria, Tetanus, and Pertussis

Diphtheria. Diphtheria is caused by the bacterium Corynebacterium diphtheriae, which can occur as either a toxic or nontoxic strain. When only the skin is involved, it is known as cutaneous diphtheria, and is likely to be a nontoxic strain. If the toxic strain affects the mucus linings in the body, such as the throat, diphtheria becomes life threatening. Between 1900 and 1925, diphtheria infected 200,000 people every year and killed between 5 - 10% of them, mostly the very young and very old. Because of immunizations, only one case was reported in 2000.

Tetanus. Tetanus is a disease that causes severe muscular contractions and convulsions. It is caused by a powerful toxin secreted by the bacterium Clostridium tetani. The bacterium is anaerobic, which means it lives without oxygen. People become infected by this dangerous bacterium through wounds in the skin. It is fatal in 15 - 40% of cases. Only 35 cases were reported in the U.S. in 2000, mostly in adults. One case, however, occurred in a 12-year-old boy whose parents refused to vaccinate him.

Pertussis. Pertussis (whooping cough) was a very common childhood illness throughout the first half of the 1900s. The disease is very easily spread from one person to another, and it is most severe in babies. Because of immunizations, which began in the 1940s, cases of whooping cough reached an all-time low of 1,010 in 1976 in the U.S. The incidence has risen recently, with almost 25,837 cases reported in 2004. Many more cases are reported worldwide. Nearly half of pertussis cases now occur in people 10 years of age or older, perhaps due to waning immunity in adolescents and adults. Such cases may be greatly underreported. One study suggested that as many as 25% of adults who see a doctor for persistent cough may actually have pertussis, but it may go undiagnosed because symptoms are usually mild and adults are unlikely to have the classic whooping cough. This is of some concern, because such adults may unknowingly infect unvaccinated children. The younger the patient, the higher the risk for severe complications, including pneumonia, seizures, and even death. Children younger than 6 months are at particular risk because even with vaccination, protection is incomplete.

The Initial Vaccination. Diphtheria, tetanus, and pertussis (DTaP) are very different disorders, but a combination injection has been routinely given to children since the 1940s. Since the early 1990s, the standard vaccine is DTaP, which uses a form of the pertussis component known as acellular pertussis that consists of a single weakened toxoid. (The older vaccine, DTP, includes a pertussis vaccine that contains multiple toxins against different variants of the disease. DTaP is just as effective but has fewer side effects than DTP.)

Pertussis is increasing among adults; the Centers for Disease Control data indicate that there were more than 25,000 cases of pertussis in 2004.

The Booster. Protection against diphtheria and tetanus from the vaccine lasts about 10 years. At that point a booster may be given against tetanus and diphtheria (Td). The Td vaccine contains the standard dose against tetanus and a less potent one against diphtheria and does not contain the pertussis component. In April 2005, the FDA approved the first pertussis booster shot ("Boostrix") for kids aged 10 - 18. Boostrix is a lower dose of infant pertussis vaccine. The infant pertussis vaccine can start to wear off after about 5 years, and some previously immunized teens and adults can get a mild form of the disease. The booster shot may help reduce the number of pertussis cases in adolescents and adults. The FDA also approved in 2005 another novel booster vaccine called Adacel for protection against tetanus, diphtheria and pertussis from adolescence through adulthood.

DTaP Schedule in Childhood. All children younger than 7 years old should receive the DTaP vaccine. In general, the vaccinations are given as follows:

Infants receive a series of three vaccinations at 2, 4, and 6 months of age (doctors may delay a vaccination in infants with suspected neurologic problems until their neurologic situation is clarified, but no later than their first birthday). Children with neurologic problems that have been corrected can be vaccinated.
A fourth dose is given between 15 and 18 months. (Infants at higher risk, such as those exposed to an outbreak of pertussis, may be given this vaccination earlier.) Of note, children who receive their third shot late in the schedule are at higher risk for skipping the fourth dose than children who were on schedule. Parents should be sure to adhere to a schedule that includes the fourth shot, even if they were late on the third.
A fifth dose is given at 4 - 6 years. This fifth shot now usually includes a vaccine against H. influenzae as well.
Children between the ages of 11 and 15 years old should receive a tetanus and diphtheria (Td) booster shot.
Boostrix is a single-dose booster that can be given to children age 10 - 18 years.
Adacel is a single-dose booster Tdap for people age 11 - 64 years.

If a child has a moderate or severe current or recent fever-related illness, vaccinations should be postponed until after recovery. Colds or other mild respiratory infections are no cause for delay. Parents should not be unduly concerned if the interval between shots is longer than that recommended. The immunity from any previous vaccinations persists, and the doctor does not have to start a new series from scratch.

Recommendations for Adults. All vaccinated adults should have a Td booster at least every 10 years throughout their lifetimes. One study reported that fewer than half of adult Americans ages 20 and older were protected against both tetanus and diphtheria, and immunity rates were even lower in those over 70. The results indicate that many people are not getting routine boosters.

Other recommendations for adults are as follows:

Adults who did not receive the primary childhood vaccinations should have the tetanus, diphtheria, and pertussis (Tdap) vaccine, approved in 2005, every 10 years.
Unvaccinated pregnant women should receive two doses of Td, properly spaced, and previously vaccinated women should have a booster.

Preventing Tetanus in Individuals with Wounds. Wounds that put patients at highest risk for tetanus are puncture wounds or wounds contaminated with dirt, feces, or saliva. However, any patient who requires medical care for any wound is a candidate for tetanus immunity.

Some considerations for tetanus vaccinations in wounded people are as follows:

A booster is needed if the last shot was 5 or more years before the injury.
Children under 7 are usually given DTP if they are not fully vaccinated.
Most individuals are given the Td vaccination if they have been vaccinated.
Older patients who had experienced an allergic response to a previous tetanus booster may be given the tetanus immune globulin (TIG).

Allergic Reactions. In rare cases, people may be allergic to the older diphtheria, tetanus, and pertussis vaccine, DTP. Parents should tell their doctor if their children have any allergies. The newer vaccine, DTaP, may pose a slightly higher risk for an allergic reaction than the older vaccine, DTP. Children who have severe responses should not be given further vaccinations. A rash that occurs after a dose of DTP is of little consequence. In fact, it does not usually indicate an allergic response but only a temporary immune reaction and does not usually recur with subsequent shots. It should be noted that no deaths have been reported from allergic reactions, even severe (anaphylactic) ones, to the DTP vaccine.

Pain and Swelling at the Injection Site. Children may feel pain at the injection site. In some cases, a small lump may remain at the site for several weeks. Placing a clean, cool washcloth over any swollen, hot, or red area can help. Children should not be covered or wrapped tightly in clothes or blankets.

The risk for swelling, including of the whole arm or leg, increases with subsequent injections, particularly the fourth and fifth doses. If possible, parents should request that their children receive the same vaccine brand each time to help reduce the risk of side effects.

Feverand Other Symptoms. A child may develop a mild fever, irritability, drowsiness, and loss of appetite after a shot.

The following remedies may be helpful:

Acetaminophen (for example, Children's Tylenol) and a sponge bath in lukewarm -- NOT cold -- water may help relieve fever and pain.
The doctor may suggest that children who have had previous high fevers or other reactions to the shot be given acetaminophen at the time of the vaccination and every 4 hours afterward for 24 hours. (The doctor will determine the dosage according to the weight of the child.)
Children should NEVER be given aspirin.

Fevers that should cause concern include the following:

The older DTP vaccine posed some risk for fever-related seizures on the day of vaccination. The newer DTaP has significantly reduced this side effect. Any very high fever in children (over 105° F) that causes convulsions should be reported immediately to the doctor. Although frightening, such fever-related seizures are uncommon and rarely have any long-term effect, and a recurrence after a subsequent vaccination is very unlikely.
A new fever that develops 24 hours after the vaccination, a fever that persists for longer than 24 hours, or seizures without fever are most likely due to other causes.

Hypotonic-Hyporesponsive Episode (HHE). HHE is an uncommon response to the pertussis component and occurs within 48 hours of the injection in children under 2. The child usually starts out feverish and irritable and then becomes pale, limp, and unresponsive. Breathing is shallow, and the child's skin may turn bluish. The reaction lasts an average of 6 hours and, although it is frightening, virtually all children return to normal. This side effect is less common since the introduction of the DTaP vaccine, but it can still occur.

Neurologic Effects in Pertussis Component. Of concern have been a few reports of permanent neurologic abnormalities that have occurred after children have been vaccinated. Such reports include attention deficit disorder, learning disorders, autism, brain damage (encephalopathy), and even death.

It is well known that the diphtheria and tetanus components cause no adverse neurologic effects, so some people suspect the pertussis component. However, many major studies, including an important statistically sound analysis in 2002, found no causal relationship between neurologic problems and the pertussis vaccination. In fact, one study indicated that children who received pertussis vaccine had fewer problems in school than those who were not vaccinated, regardless of family income levels. Studies on the newer DTaP have reported no safety concerns to date.

There may be some exceptions. Studies now suggest that in cases where neurologic problems have been strongly linked to the vaccination, high fevers -- not immunization -- are responsible. Children with known neurologic abnormalities may also be at risk for an outbreak of symptoms 2 or 3 days after the vaccination. Such a temporary worsening of their disease rarely poses a danger to the child. (Some experts suggest that children who have new neurologic events following their shot may already have a preexisting impairment, such as epilepsy, which is revealed -- but not caused -- by the vaccine.) To date, there is no proof that the pertussis vaccine causes these neurologic events, which, in any case, are so infrequent as to be nearly statistically unmeasurable.

Important Note: Unwarranted fears of side effects from vaccinations can be dangerous. In England such fears have caused a significant decline in immunization rates since the 1970s. Outbreaks of whooping cough have occurred as a result, causing a number of deaths and brain damage in many children. Small babies are particularly endangered if they become infected from older unvaccinated children (who usually have a mild disease).

Call the doctor immediately if a child has any of the following symptoms.

Extremely High Fever. A rectal temperature of 105° F or higher. (Temperatures taken under the arm or by mouth often register lower than actual temperatures.)
Inconsolable Crying. The child has been crying for over 3 hours without stopping or has a cry that isn't normal, such as being high-pitched.
Convulsions. The child's body starts shaking, twitching, or jerking. This is usually in response to a high fever. Place the child face down with the head to one side, protecting the head from hitting anything hard. Be sure the child can breathe freely. Seizures caused by fevers usually last less than 15 minutes.
Shock. The child collapses, turns pale, and becomes unresponsive.
Severe Allergic (Anaphylactic) Reaction. Swelling in the mouth and throat, wheezing and breathing difficulties, dizziness. The child collapses or is pale and limp.

Call the doctor if the following symptoms persist for more than 24 hours:

The injection site is still red and tender.
Fever does not go down.
The child is still fussy.

Measles, Mumps, and Rubella

Measles. Measles, one of the most contagious of all human infections, used to be a very common childhood disease. Most cases go away without serious complications. In severe cases, however, measles can cause pneumonia, and in about 1 out of 1,000 cases it can lead to encephalitis (inflammation in the brain) or death. The risk for these severe complications is highest in the very young and very old. In pregnant women, measles increases the rates for miscarriage, low birth weight, and birth defects.

Measles outbreaks still occur in the United States, usually among groups of people who do not believe in immunizations or in areas where immunization levels have fallen below the critical level. It is a fairly serious childhood infection that is recognized by the rash (as seen here), Koplik spots (small white spots on red background), red eyes, photophobia (sensitivity to light), and coughing.

Aggressive vaccination programs have reduced the incidence of measles in the U.S., to a low of 86 cases in 2000, most imported from other countries. Full-blown measles cases among unvaccinated children still remain a serious international problem, with 42 million cases and over 1 million deaths in small children each year.

Mumps. Mumps is at record lows in the US, with only 338 cases reported in 2000. In about 15% of cases, mumps affects the lining of the brain and spinal cord, although this is usually not ultimately harmful. Swelling of the testicles occurs in between 20 - 30% of males who have reached puberty, although sterility is rare. Deafness in one ear occurs in one patient out of 20,000 with mumps.

Click the icon to see an image of the meninges of the brain.

Rubella (German Measles). When rubella, commonly known as German measles, infects children or adults, it causes a mild illness that includes a rash, enlarged lymph nodes, and sometimes a fever. If a pregnant woman is infected during her first trimester, however, her baby has a 80% chance for developing birth defects, including heart abnormalities, cataracts, mental retardation, and deafness.

Click the icon to see an image of a cataract.

Before the vaccine became available, about 56,000 cases of rubella occurred annually in the U.S. Vaccination programs have dramatically reduced the number of cases to a low of 176 in 2000, but between 6 - 11% of adults are still susceptible, particularly unvaccinated Hispanic Americans who were born outside of the U.S.

Click the icon to see an image of rubella.

Safe and effective live-virus vaccines for measles, mumps, and rubella have been developed over recent decades. They are usually combined in children as the measles, mumps, and rubella (MMR) vaccine. Individual live-virus vaccines or the combined MMR may be given to adults, depending on their risk factors.

Measles-Mumps-Rubella (MMR) Vaccine in Early Childhood. The combined MMR vaccine should be given in two doses:

Between ages 12 and 15 months for the first dose. (Some doctors believe that the vaccine may be effective and safe in children younger than 9 months who are in areas of measles outbreaks. It should be noted that there were only 86 reported cases of measles in the U.S. in 1999.)
Between ages 4 and 6 years for the second dose. (Children who receive only one dose at 15 months or older have five times the risk of measles compared to those who had two doses.)

Measles-Mumps-Rubella (MMR) Vaccine in Adolescents and Adults. The general recommendations for adult MMR vaccinations are as follows:

Most people born before 1957 have experienced these once-common childhood diseases and do not require vaccination.
All unvaccinated people born after 1956 who did not already have measles and mumps should be given two doses of the live MMR vaccine administered at least 1 month apart.
Many people received an inactivated measles-virus vaccine in the early 1960s or an inactivated mumps-virus vaccine between 1950 and 1978; such people need revaccination with two doses of the live MMR vaccine. (This will cause no harm even if someone had a previous live-virus-mumps vaccination.)
The American Academy of Pediatrics now recommends the live-virus MMR vaccine for HIV-infected children, teenagers, and young adults, except for those who are severely immunocompromised. At this time, however, the vaccine appears to be safe in HIV-infected children, and it should be stressed that measles is very dangerous in this population.

Rubella Vaccinations During Pregnancy. It is particularly important for any unvaccinated nonpregnant woman who wants children to be vaccinated against rubella. It is recommended that women wait at least 28 days after vaccination to start trying to conceive. Except under very special circumstances, no live-virus vaccine, especially MMR, is given to an already pregnant woman, since there is a theoretical risk for birth defects from the rubella vaccine. Fortunately, the risk is low. In fact, studies have reported no increase in birth defects in women who were inadvertently vaccinated for rubella early in their pregnancy.

Common side effects from the MMR vaccination include fever, rash, and joint pain. Children are more likely to experience such side effects from the second dose (at 10 - 12 years) than from the first (at 4 - 6 years).

Fever. About 5 - 15% of people who are vaccinated with any live measles virus vaccine develop a fever of 103° F or greater, usually between 5 and 15 days after the vaccination. It usually lasts 1 or 2 days but can persist up to 5 days. In very young children, seizures can occur from high fever 8 - 14 days after vaccination, but they are rare and almost never have any long-term effects.

Swollen Glands. The live-mumps vaccine can cause mild swelling in the glands that are situated near the ears.

Joint Pain. Up to 25% of women have joint pain 1 - 3 weeks after a vaccination with a live-rubella virus; it lasts for 1 day to 3 weeks. Such pain does not usually interrupt daily activities. Rarely, it recurs or becomes persistent.

Allergic Reaction. People who have known anaphylactic allergies (very severe reactions) to eggs or neomycin are at high risk for a severe allergic response to the MMR vaccine. People with allergies that do not cause anaphylactic shock to these substances are not at higher risk for a serious allergic reaction to the vaccine. Mild allergic reactions may occur in some people, including rash and itching. A rash occurs in about 5% of people who are vaccinated with a live-measles vaccine. A live-mumps vaccination has caused rash and itching, but these symptoms are usually mild.

Interaction with Tuberculosis Test. The live-measles vaccine may interfere with a tuberculosis test, so the two should be administered at least 4 - 6 weeks apart. No evidence exists that the vaccine has an adverse effect on tuberculosis itself.

Mild Infection. One study suggests that a mild form of measles that has no symptoms may develop in previously immunized people who are exposed to the virus, although this mild infection may not be significant.

Idiopathic Thrombocytopenic Purpura (ITP). In about 1 in 22,300 doses, MMR can cause a rare bleeding disorder called idiopathic thrombocytopenic purpura (ITP). This can cause a purple, bruise-like discoloration that can spread across the body, nose bleeds, or tiny red spots. It is nearly always mild and temporary. (Of note, the risk for ITP is much higher with the actual infections, particularly rubella.)

Note: Unsubstantiated Reports of Neurologic Side Effects and Decline in Immunization. Much controversy has arisen over unsubstantiated reports of neurologic side effects attributable to MMR. This is of great concern since such reports have resulted in a decline in immunizations in certain areas, notably affluent areas in England where the vaccination rate has dropped from 92% in 1996 to 84% currently. Here, measles outbreaks are now climbing, and doctors fear that unless immunization rates increase rapidly, case numbers will significantly increase. In these and other regions, some parents mistakenly believe that the dangers of immunization outweigh a dangerous childhood illness that only older people remember. It should be strongly noted that measles still cause about 745,000 deaths in unvaccinated children who live in underdeveloped countries, primarily in Africa.

Most publicity has centered on a possible link between the MMR vaccine, which was introduced in 1988, and a variant of autism that includes inflammatory bowel disease (IBD) and impaired behavioral development. Such findings have been rigorously reviewed and refuted in a number of well-conducted studies. Of special note, a 2002 analysis of vaccination records of children born between 1979 and 1998 found no higher incidence in autism, with or without behavioral problems and gastrointestinal disorders. In the study, there was a link between impaired behavioral development and bowel problems, but they were not related to the vaccine.

Despite considerable publicity, there is no evidence linking MMR vaccination with the development of autism. The Centers for Disease Control & Prevention website provides extensive information on this matter. The popular media has incorrectly reported the possible link between autism and MMR as causing a split in the scientific community, but virtually all experts refute any association. In fact, reports of symptoms related to autism increased only after widespread publicity of this supposed side effect.

The potential benefits from receiving the MMR vaccine far outweigh the potential adverse effects. Measles, mumps, and rubella are all very serious illnesses and each may have complications resulting in lifetime disabilities or even death. The incidence of such complications, related to having the actual diseases, is far greater than the potential of developing serious, or even moderate, adverse effects due to the MMR vaccine.

Click the icon to see an image of inflammatory bowel disease.

Varicella-Zoster Virus (Chickenpox)

Chickenpox (caused by the varicella-zoster virus) is one of the most contagious childhood diseases. Nearly every unvaccinated child becomes infected with it. The affected child or adult may develop hundreds of itchy, fluid-filled blisters that burst and form crusts.

The infection rarely causes complications in healthy children, but it is not always harmless. Five out of every 1,000 children are hospitalized and, in rare cases, it can be fatal. Before the vaccination became widespread, chickenpox resulted in about 11,000 hospitalizations and 100 deaths a year.

This is a close-up picture of chickenpox. Early chickenpox lesions consist of small red papules that quickly fill with a yellowish or straw colored fluid to form small blisters (vesicles), as seen in this photograph. Later, these vesicles will rupture, forming shallow erosions that crust over and then ultimately heal.

Click the icon to see an x-ray of pneumonia following exposure to chickenpox.

Chickenpox can be especially severe in adults and very serious in anyone with a compromised immune system. In addition, the varicella virus (which persists after the childhood disease) erupts as a painful and distressing condition called herpes zoster (shingles) in about 20% of adults with a history of chickenpox. Chickenpox itself usually occurs only once, although a few cases of mild second infections, marked by the telltale rash, have been reported in older children years after their first infection.

Click the icon to see an image of the shingles.

A live-virus vaccine (Varivax) produces persistent immunity against chickenpox. Data show that the vaccine can prevent chickenpox or reduce the severity of the illness even if it is used within 3 days, and possibly up to 5 days, after exposure to the infection.

Recommendations for the Vaccine in Children. The vaccine against chickenpox is now recommended in the U.S. for all children between the ages of 18 months and adolescence who have not yet had chickenpox. Children are given one dose of the vaccine. Two doses 1 - 2 months apart are given to people over 13 years of age. To date, more than 75% of children have been vaccinated.

Doctors recommend that the chickenpox vaccine be given at the same time as the measles-mumps-rubella (MMR) vaccine or that there is a delay of at least 1 month between the two vaccinations. (If the chickenpox vaccination is given within that 30-day period -- but not at the same time -- there is a higher risk for a breakthrough infection later on.)

A chickenpox vaccine is part of the routine immunization schedule. It is about 100% effective against moderate or severe illness, and 85 - 90% effective against mild chickenpox. Parents often express concern that the immunity from the vaccine might not last. The chickenpox vaccine, though, is the only routine vaccine that does not require a booster.

Recommendations for the Vaccine in Adults.

Some doctors suggest that every healthy adult without a known history of chickenpox be vaccinated. In general, however, the following adults should consider vaccinations:

Older people without a history of chickenpox and who are at high risk of exposure or transmission (such as hospital or day care workers and parents of young children)
People who live or work in environments in which viral transmission is likely
Nonpregnant women of childbearing age
Adolescents and adults living in households with children
International travelers

As with other live-virus vaccines, the chickenpox vaccine is not recommended for the following:

Pregnant women (including the 3 months prior to pregnancy). Of note, an encouraging study suggested that pregnant women who were inadvertently vaccinated did not face a higher risk for birth defects in their offspring.
People whose immune systems are compromised by disease or drugs (such as after organ transplantation). The vaccine is being studied, however, for its safety in some of these patients, particularly children with cancer or other high-risk conditions. Experts report that it is safe in children with acute lymphoblastic leukemia (ALL), who should receive two doses. Certain children who are HIV positive may be candidates for the vaccine. An inactivated varicella vaccine may be safe and effective in patients undergoing bone marrow transplants, when given before and after the operation.
Most patients who cannot be vaccinated but are exposed to chickenpox are given immune globulin antibodies against varicella virus. This helps prevent complications of the disease if they become infected.

Discomfort at the Injection Site. About 20% of vaccine recipients have pain, swelling, or redness at the injection site.

Mild Rash and Risk of Transmission. The vaccine may produce a mild rash within about a month of the vaccination, which has been known to transmit chickenpox to others. Individuals who have recently been vaccinated should avoid close contact with anyone who might be susceptible to severe complications from chickenpox until the risk for a rash has passed.

Severe Side Effects. Between 1995 and 2001, 759 serious adverse effects were reported. Such events included seizures, pneumonia, anaphylactic reaction, encephalitis, Stevens-Johnson syndrome, neuropathy, herpes zoster, and blood abnormalities. Anecdotal reports have found a higher association of side effects when varicella vaccine is given at the same time as the measles, mumps, and rubella (MMR) vaccination. Because combined vaccinations are being developed, such effects should be closely studied.

There is intense debate over the long-term protection of the vaccine. The incidence of breakthrough infections after vaccination stimulates the controversy. It should be noted, however, that evidence is showing improvements in quality of life and better survival rates since the introduction of the vaccine. Any negative studies to date on long-term effectiveness simply raise the question of the need for booster or higher doses -- not the elimination of the vaccine altogether.

Long-Term Protection in Vaccinated Children. Most studies suggest that the vaccine is not wholly effective in up to 30% of vaccinated children. However, they also report if chickenpox occurs, more than 95% of the cases are mild. It is also usually less contagious. In such people, the infection appears to be caused by a wild virus, not a reactivation of the vaccine. (Of concern was a 2002 study of a day care center reporting a much higher rate -- 56% -- of break-through infection, with only 86% of cases being mild. The implications of this study are unclear.) The longer the interval since vaccination occurs, the higher the risk for a breakthrough infection.

This does not necessarily mean, however, that children who are vaccinated eventually lose total immunity. A breakthrough infection is often due to issues with the primary vaccine (improper storage, low potency, the duration between the chickenpox and measles, mumps, and rubella vaccines being less than a month) or the child's history (having asthma, being less than 14 months at the time of vaccination). Nevertheless, there is also some evidence that either having the vaccination or even having chickenpox itself is not as protective against a later infection as experts have thought.

Long-Term Protection in Vaccinated Adults. The protective effects for adults are even less clear. An encouraging 2002 study of adults vaccinated between 1979 and 1999 reported that 9% developed chickenpox months to years after their last vaccination. The length of time since the vaccination did not seem to affect whether the adults would catch chickenpox or not. (Nearly half of those had been exposed to the disease in their homes.) In all cases, infection was mild, with none of the serious complications of adult chickenpox.

Vaccine's Effect on Shingles. A primary concern is whether the vaccine protects against shingles later on, particularly in people who have breakthrough infections -- however mild. As more and more children get vaccinated, the actual protection of the vaccine and the implication of the breakthrough infection will become clearer.

[For more information, see In-Depth Report #82: Shingles and chickenpox (Varicella-zoster virus).]

In September, 2005, the Food and Drug Administration approved a combination vaccine to protect against measles, mumps, rubella, and chickenpox. Proquad, produced by Merck & Co., protects against all four infections with one shot, thus sparing young children from multiple painful injections. Proquad is approved for use in children from 12 months to 12 years of age. Proquad was studied in four randomized trials involving 5,446 healthy children aged 12 - 23 months received Proquad. Proquad’s immune response rates were 97.4% for measles, 95.8 - 98.8% for mumps, 98.5% for rubella, and 91.2% for chickenpox, similar to the rates induced by the concomitant administration of single doses of M-M-R II and Varviax at separate injection sites in 2,038 children.

Varicella-Zoster Virus (Shingles)

Shingles is a painful infection caused by the varicella zoster virus, the same virus responsible for chickenpox. Once a person has chickenpox, the virus lies dormant in the body. It can emerge years later as shingles.

Shingles causes a painful, red, and sometimes blistery rash to form on the body or face. The disease can cause intense pain, called post herpetic neuralgia. Other symptoms include fever, headache, and chills. In rare cases, complications, such as pneumonia, blindness, and brain inflammation (encephalitis), can occur. Shingles is most common in adults over age 50.

In May 2006, the U.S. Food and Drug Administration licensed the herpes zoster vaccine (Zostavax) for the prevention of shingles. The vaccine can reportedly cut the incidence of shingles in half for adults over age 60.

Recommendations for the Vaccine in Adults. All adults age 60 or older should get a single dose of the herpes zoster vaccine, regardless of whether they have previously had shingles.

The following people should not receive the herpes zoster vaccine:

Anyone who has a weakened immune system due to HIV/AIDS or cancer of the lymph, bone, or blood, or due to treatments such as radiation or corticosteroid drugs
Women who are pregnant, or anyone who is in close contact with a pregnant woman who has not had chickenpox
Children -- they should receive only the chickenpox vaccine

Redness, pain, and swelling. About 1 out of every 3 people who get the vaccine have mild redness, soreness, swelling, or itching at the injection site.

Headache. About 1 in 70 people experience headache after taking the vaccine.

There have been no serious side effects reported with the shingles vaccine.

Research has found that the herpes zoster vaccine reduces the incidence of shingles by about 50%. The benefit is as high as 64% in people ages 60 - 69. In people who are vaccinated but still develop shingles, the vaccine reduces the duration of the pain involved with the disease.

One 2007 study found that doing tai chi might boost the immune response to the vaccine. According to the study, people aged 59 - 86 who took part in a 16-week tai chi program had immunity similar to that of 30- and 40-year-old adults who had been vaccinated. Combining tai chi with the vaccine increased the effects of the vaccine by about 40%.

Hepatitis A

The hepatitis A virus infected an estimated 56,000 people in 2004. Hepatitis A, formerly called infectious hepatitis, is always acute and never becomes chronic. The virus is excreted in feces and transmitted by contaminated food and water. Eating shellfish taken from sewage-contaminated water is a common means of contracting hepatitis A. It can also be acquired by close contact with individuals infected with the virus. It is estimated that 11 - 16% of reported cases occur among children or employees in daycare centers or among their contacts. The hepatitis A virus does not directly kill liver cells, and experts do not yet know how the virus actually injures the liver.

A fly may act as a mechanical vector of diseases such as hepatitis A. The fly may carry the infective organism on its feet or mouth parts and contaminate food or water, which a person then consumes. A biological vector actually develops an infective organism in its body and passes it along to its host, usually through its saliva. A fly can be a biological vector, as in the transmission of leishmaniasis by the sandfly.

All children should get 2 doses of the hepatitis A vaccine starting at 1 year, according to CDC recommendations. The doses should be given at least 6 months apart. Others who should be vaccinated against hepatitis A include travelers to developing countries, people living in communities where outbreaks occur, people with blood-clotting disorders, sexually active homosexual men, and health care workers exposed to the virus. People with chronic liver disease, including those with hepatitis C, should also be vaccinated, particularly if they have not been exposed to hepatitis A, since the infection can cause liver failure in these patients.

The hepatitis A vaccine can be given along with immune globulin and other vaccines. Individuals should also receive immune globulin if they are exposed within 4 weeks of the vaccination. A combined vaccine against both hepatitis A and B is now available as well for those at high risk for both these infections. People should get 3 doses of this vaccine, and the last dose should be given 6 months after the first dose.

Side Effects. The vaccine is very safe and effective, although allergies can occur. The most common side effects reported are soreness at the injection site, headache, and general malaise.

Click the icon to see an image about hepatitis A immunization.

Hepatitis B

About 2 billion people have been infected with the hepatitis B virus (HBV) worldwide, and each year 1 million people die, mostly due to cirrhosis and liver cancers that develop in the chronic form of this disease. In the U.S., about 1.25 million people have chronic hepatitis B.

Hepatitis B is also known as serum hepatitis. It spreads through blood and sexual contact. The infection is seen with increased frequency among intravenous drug users who share needles and among the homosexual population. This photograph is an electronmicroscopic image of hepatitis B virus particles. (Courtesy of the CDC.)

Pregnant women with hepatitis B can transmit the virus to their babies. Even if they are not infected at birth, unvaccinated children of infected mothers run a 60% risk of developing hepatitis B before age 5. Although hepatitis B infections have dropped 95% since routine immunization began in the early 1990s, there are still children who aren't immunized, and the disease persists. Universal vaccination against this disease during childhood is very important.

Several inactivated virus vaccines, including Recombivax HB, GenHevac B, Hepagene, and Engerix-B, can prevent hepatitis B. Twinrix is a vaccine against both hepatitis A and B. They are safe, even for infants and children. Vaccination programs are proving to reduce the risk for liver cancer.

Click the icon to see an image of hepatitis B.

Hepatitis B Vaccine for Early Childhood. Experts now recommend that all infants and children not previously vaccinated be immunized by the time they reach seventh grade. Typical schedules for hepatitis B vaccinations in childhood are as follows:

All infants should receive the hepatitis B vaccine soon after birth and before hospital discharge. (The first dose may be delayed if the mother has no evidence of infection, but only with the doctor's permission.) The second dose should be given at 1 - 2 months; and the third between 6 and 18 months (at least 16 weeks after first dose and 8 weeks after second dose). (A fourth dose may also be given if any of the previous doses was a combination vaccine.) This is a safe vaccine, even in newborns, and parents should be sure their infants are immunized.
Infants of mothers infected with hepatitis B should be treated with immune globulin plus the hepatitis vaccine within 12 hours of birth. The second dose should be given at 1 - 2 months and the third at 6 months. Infants should be tested for antibody status at 9 - 18 months to see if they are chronic virus carriers or need to be revaccinated. Immunization rates are still too low in this group.
When it is not known if a mother is infected, the infant should receive the vaccine within 12 hours of birth. The mother's blood should then be tested right away. If she is infected, the infant should receive immune globulin within 1 week of birth.
Children who are 11 - 12 and who have not been immunized should receive 2 or 3 doses of the vaccine (depending on the brand) given over a few months.

Hepatitis B vaccine protection may wane over time. According to a 2007 study, 40% of adolescents who had received a first dose of the vaccine as newborns had declining immunity to the disease by age 14. As of now, routine booster shots are not recommended because more research is needed on the subject. Booster shots may be recommended for those at risk, such as from sexual exposure.

Hepatitis B Vaccine for Adults. The following adults are at very high risk and should be vaccinated:

Health care and public safety workers who may be exposed to blood products. Such individuals have a risk for hepatitis B that ranges from 15 - 30%.
People in the same household ashepatitis B-infected individuals. (Unvaccinated people who have had intimate exposure to people with hepatitis B may be protected with immune globulin, which is sometimes administered with the vaccine.)
Travelers to countries with a high incidence of hepatitis B infection.
Patients who require transfusions and have not been infected with hepatitis B. (Those with blood clotting disorders should have the vaccination administered under the skin, not injected in the muscle.)
Sexually active individuals with multiple partners.
People with any sexually transmitted diseases.

Other people at risk who would benefit from vaccinations include:

Patients and workers in mental institutions
Morticians
Patients undergoing hemodialysis. (These people may need larger doses or boosters; they also may need to be revaccinated if blood tests indicate they are losing immunity.)
People who use injected drugs
Pregnant women at risk for the virus. (There is no evidence that the vaccine is dangerous to the fetus.)
People receiving treatments or who have conditions that suppress the immune system may need the vaccination, although its benefits for this group are unclear except for those at high risk, such as people with HIV or spleen abnormalities.

Click the icon to see an image of the immune system structures.

The regimen in adults is typically 3 doses given over 6 months. One study reported that older adults would benefit from a fourth dose without incurring serious side effects. People who abuse alcohol may need higher doses.

A small percentage of people do not develop immunity, even after a vaccine has been given repeatedly. A more potent vaccine is proving to be effective for these people; it loses its effect after 5 years in about one-third of those who receive it.

Soreness. Soreness at the injection site is the most common side effect.

Nerve Inflammation. There have been some reports of nerve inflammation after vaccinations for hepatitis B, and some questions about multiple sclerosis. A review article published in 2006 found no evidence that hepatitis B vaccine is associated with multiple sclerosis, sudden infant death syndrome, or chronic fatigue syndrome. Earlier studies also found no evidence linking the vaccine to multiple sclerosis. A 2007 study found that the vaccine doesn't increase the risk for rheumatoid arthritis.

Because of even a small theoretical risk of nerve damage in infants, some groups oppose the vaccination in children who are not in high-risk groups. Worldwide, 65 million people with chronic hepatitis are expected to die from liver disease and vaccinations are saving lives. For example, in Taiwan, where infection rates are high and infants are at risk for hepatitis B from infected mothers, vaccination programs have significantly reduced the risk for liver cancer. [For more information see In-Depth Report #59: Hepatitis.]

Pneumococcal Pneumonia

The pneumococcal bacterium (also called Streptococcus pneumoniae or S. pneumoniae ) is responsible for many respiratory infections in the upper and lower airways. This bacterium is dangerous for people with serious underlying chronic medical conditions and illnesses and is the leading cause of ear infections and sinusitis in children. The most serious complication is pneumonia.

More than 200,000 people in the U.S. are hospitalized each year for pneumonia-related complications. Although the majority of pneumonias respond well to treatment, the infection can still be a very serious problem. It kills approximately 36,000 people each year. Together with influenza, pneumonia is the eighth leading cause of death in the U.S.

Of particular concern is the increasing prevalence of pneumococcal bacteria that are resistant to many standard antibiotics. This has created a great sense of urgency in the medical community to find effective measures for preventing infection.

This picture shows the organism pneumococci. These bacteria are usually paired (diplococci) or appear in chains. Pneumococci are typically associated with pneumonia, but may cause infection in other organs, such as the brain (pneumococcal meningitis) and bloodstream (pneumococcal septicemia). (Courtesy of the CDC.)

The pneumococcal vaccine protects against S. pneumoniae (also called pneumococcal) bacteria, the most common cause of respiratory infections. There are 2 effective vaccines available: The 23-valent polysaccharide vaccine (Pneumovax, Pnu-Immune) for adults and the 7-valent conjugate vaccine Prevnar (PCV7) for infants and young children. Experts are now recommending that more people, including healthy elderly people, be given the pneumococcal vaccine, particularly in light of the increase in antibiotic-resistant bacteria.

The 7-valent conjugate vaccine Prevnar (PCV7) is very effective in children. Research finds that the vaccine, which was introduced in 2000, has reduced hospital admissions for pneumonia in children under age 2 by about 39%. The vaccine has even lowered hospital admissions 26% among adults aged 18 - 39 the study found, likely because they are parents of young children who might otherwise have developed the disease. Another study found that the vaccine also has benefited children who regularly get ear infections. Recurrent ear infections have fallen by 28% since the introduction of the vaccine.

Click the icon to see an image of pneumococcal pneumonia.

The pneumococcal vaccine is now recommended by many experts for the following groups:

Children up to age 2. The vaccine is very effective in children. In one study, a similar vaccine under investigation not only protected children in day care from serious respiratory infections, but their younger unvaccinated siblings had fewer infections as well.
Children up to age 5 who are at risk for pneumonia or complications of influenza, such as children with sickle cell disease, those with immune deficiencies, a damaged spleen or no spleen, or children with chronic medical conditions. One study has found that the rate of pneumococcal disease among children with sickle cell disease has dropped 90% since the vaccine was introduced.
Other children ages 2 - 5 who are at higher risk for serious pneumococcal infections should be considered for vaccinations. They include African- or Native Americans, children in group child care, socially or economically disadvantaged children, or those who have had frequent or complicated acute middle ear infections within the past year.

Pneumococcal Vaccine in Older Children and Adults. The vaccine is proving to be effective in reducing the rate of pneumonia in young adults, although not to the degree that it protects young children. The benefit for the elderly -- other than protection against bloodstream infection -- is unclear. Still, pneumonia is declining among adults, which may be due to fewer infections being transmitted from vaccinated young children. Many experts now recommend the vaccine for the following older children or adults:

All people over 65 years old. Some experts believe that all adults 50 - 64 should also be vaccinated. Unfortunately, although the vaccination is protective against pneumococcal bacteremia (invasive infection) in people over 65, evidence suggests that it does not appear to protect against community-acquired pneumonia.
Adults with any chronic condition that increases the risk for pneumonia. This includes patients with heart disease (such as congestive heart failure), chronic lung disease (COPD or emphysema, but not asthma), or diabetes.
Individuals with immune deficiencies (such as HIV) or those undergoing treatments that suppress the immune system.
Patients with autoimmune diseases, such as rheumatoid arthritis and lupus. Unfortunately, studies show the vaccine may not be as effective in these patients as in those with healthy immune systems. Nevertheless, they are at high risk for serious respiratory infections and should be vaccinated.
Patients with kidney disease or kidney transplants. Older people who have had transplant operations or those with kidney disease may require a revaccination after 6 years.
Patients with problems in the spleen.
Alcoholics, especially those with cirrhosis.
People living in long-term care facilities.
Alaska Natives or American Indians, who may be at increased risk for pneumonia.

The safety of the pneumococcal vaccine hasn't been proven during the first trimester of pregnancy; however, there have been no adverse effects reported. When the vaccine is administered to pregnant women, it may actually protect their infants against certain respiratory infections.

Protection lasts for more than 6 years in most people, although the protective value may be lost at a faster rate in elderly people than in younger adults. Anyone at risk for serious pneumonia should be revaccinated 6 years after the first dose, including those who were vaccinated before age 65. Subsequent booster doses, however, are not recommended.

The recommended schedule of immunization for Prevnar (PCV7) is 4 doses, given at 2, 4, 6, and 12 - 15 months of age. Infants starting immunization between 7 and 11 months should have 3 doses. Children starting their vaccinations between 12 and 23 months only need 2 doses. Those who are over 2 years old need only 1 dose.

Side effects include pain and redness at the injection site, fever, and joint aches. Children are more likely to have fever within 48 hours if they receive other vaccines at the same time, and also after the second dose. Fortunately, severe reactions are very rare, even if a person is mistakenly revaccinated before the effects of the first vaccination have worn off. Allergic reactions are also very rare.

Poliomyelitis

Poliomyelitis, more commonly known as polio, is a disorder caused by a virus and marked by potentially paralyzing nerve-related damage, which can be fatal. Fifty years ago it was a major killer of children, and it remains a threat in parts of Asia and Africa today. Vaccination programs eliminated the disease in the Americas in 1994, with the last case of wild poliovirus in the U.S. reported in 1979. As of 2004, polio has been eradicated in the Americas, the Western Pacific, and Europe.

Poliomyelitis is a communicable disease caused by viral infection and occurs through direct contact with infected secretions. Polio is found worldwide, but immunization has reduced the incidence. Clinical polio affects the central nervous system (brain and spinal cord). Disability is more common than death.

Two poliovirus vaccines have been available in the U.S.: oral poliovirus vaccine (OPV), a live-virus vaccine, and inactivated poliovirus vaccine (IPV), a killed vaccine that is administered by a shot. Both produce immunity in more than 95% of people. The live-virus used in the vaccine, however, has, in some cases, reverted to a form that can cause polio in unvaccinated people. This is a particular danger in developing countries where vaccination rates are low. The Centers for Disease Control and Prevention now recommends only the inactivated IPV vaccine for children. The schedule is 4 doses of IPV at ages 2 months, 4 months, 6 - 18 months, and 4 - 6 years.

Poliovirus Vaccine in Older Children and Adults. The poliovirus vaccine is not usually recommended for people over 18. Exceptions are unvaccinated health care workers, laboratory technicians, or others exposed to polioviruses. Travelers to developing countries where outbreaks of poliovirus have been reported should be vaccinated. Adults should also be given the inactivated poliovirus vaccine (IPV).

Allergic Reactions. The inactivated poliovirus vaccine (IPV) contains small amounts of streptomycin and neomycin, so people allergic to these antibiotics can also have an allergic response to this vaccine. Patients should report any allergies to their physician.

Paralysis. Rare cases of paralysis have occurred in people taking the oral live poliovirus vaccine or in those exposed to recipients of this vaccine. It should be stressed the risk is very small, with only 1 case occurring out of 2.4 million doses. Since the introduction of the current recommended series that uses only IPV, no cases have been reported.

Contamination by Simian Virus 40. The public was alarmed by reports of contamination of polio vaccines given between 1955 and 1963 by a virus known as SV40. The virus has been detected in certain rare cancers, including mesothelioma (a lung cancer normally associated with asbestos exposure), osteosarcoma, some brain tumors, and non-Hodgkin's lymphoma.

Click the icon to see an image of a brain tumor.

Still, about 98 million people may have been exposed, and most of these cancers are very rare (although some, including non-Hodgkin's lymphoma, are increasing). At least 40 years of observation have raised no red flags that indicate any serious problem. However, polio, once a major killer of children, has nearly been wiped out worldwide.

Viral Influenza

Influenza, commonly called the flu, is always caused by a virus.

Influenza, also known as the flu, is caused by a virus.

There are different strains of influenza:

Influenza A is the most widespread and most severe strain. It can affect both animals and humans. Influenza A is the cause of the worldwide epidemics (pandemics) of the flu that have occurred. More than 200,000 hospitalizations per year are due to this strain of the flu. Influenza A is usually further categorized by 2 subtypes based on 2 substances that occur on the surface of the viruses: hemagglutinin (H) and neuraminidase (N).
Avian Influenza A (called “bird flu”) was first detected in humans in 1997 in China and the region of Hong Kong. Bird flu is spread easily from bird to bird. Humans usually contract the flu from contact with infected domesticated birds, such as chickens, turkeys, and ducks. The World Health Organization confirms that there were, as of the publishing of this report, 331 cases of bird flu in humans and 203 deaths. The greatest number of cases have occurred in Indonesia, followed by Vietnam, Egypt, Thailand, and China. In April 2007, the U.S. Food and Drug Administration approved the first vaccine against the avian flu virus.
Influenza B infects only humans. It is less common than type A, but is often associated with specific outbreaks, such as in nursing homes. Flu caused by this strain tends to be milder than that caused by Influenza A.

Based on a final analysis of the 2005 - 2006 flu season, nearly 80% were type A and about 20% were type B. Influenza A usually causes more severe disease than type B. However, because influenza B has been less common in the past few years, there is concern that some people -- particularly small children -- may have fewer antibodies to it and so may be at higher risk for severe infection. (See Flu Vaccines in this report.)

Complications of the Flu. In general, the flu is usually self-limited and not serious. It is responsible, however, for 15 - 30% of the excess number of hospitalizations that occur in winter. More than 200,000 people who contract the flu end up in the hospital, and an estimated 36,000 people currently die each year of flu-related complications. The highest risks for serious complications occur in people age 65 and older and in those who are already sick with another disease. There have also been reports of flu-related deaths in very young children.

Pneumonia is the major serious complication of the flu and can be very serious. It can develop about 5 days after viral influenza. It is an uncommon event, however. It nearly always occurs in high-risk individuals, such as the very young or very old, and hospitalized or immunocompromised patients.

Note on Pandemics. Every year, flu strikes millions of people worldwide. Influenza epidemics are most serious when they involve a new strain against which most people are not immune. Such so-called pandemics can infect more than one fourth of the world's population within a 3-month period. For example, the Spanish flu in 1918 and 1919 killed 20 million people in the U.S. and Europe, and 17 million people in India. Although pandemics are still of great concern, there have been major improvements in private and public health since then, including the discovery of antibiotics to treat bacterial complications, new antiviral agents and vaccines, and intensive worldwide surveillance of outbreaks.

Description of Vaccines. Vaccines against the flu use inactivated (not live) viruses. The influenza vaccine is commonly called a "flu shot." It is designed to provoke the immune system to attack antigens contained on the surface of the virus. (Antigens are foreign molecules that the immune system specifically recognizes as alien and so targets for attack.)

Click the icon to see an image of antigens.

Unfortunately, the antigens in these influenza viruses undergo genetic alterations (called antigenic drift ) over time, so they are likely to become resistant to a vaccine that worked in the previous year. Vaccines are redesigned annually to match the current strain.

Influenza A. The influenza A virus is further categorized by primary molecular antigens (hemagglutinin and neuraminidase), which serve as the targets for the vaccines. Influenza A is a particular problem because it can infect other species, such as pigs or chickens, and undergo major genetic changes.
Influenza B viruses tend to be more stable than influenza A viruses, but they, too, vary. Although influenza B has been far less common than A, a vaccine for type B is important because experts are concerned that small children will not have developed any immunity to the virus and will experience severe flu if they are exposed to type B.

Until recently the vaccine has been administered only by injection. A vaccine (FluMist) that can be delivered in a nasal spray has now been approved for people aged 5 - 49. The vaccine contains live viruses that have been engineered to replicate in the cool temperatures of the nasal passages, but not in the warmer lungs and lower airways. Its presence in the nasal passages boosts the specific immune factors in the mucous membranes that fight off the epidemic viruses. Studies in 2003 reported protection against the flu that ranged from 66 - 92%, depending on whether the flu was type A or type B. (The lower rates were those observed for influenza B, particularly a new variant.) A 2007 study found that children aged 6 months - 5 years who had the nasal spray had 55% fewer cases of the flu than those given the injection. However, the vaccine is not approved for children in this age group. A preservative-free intramuscular injectable vaccine (Fluzone) is also now available.

The avian flu vaccine is designed for people aged 18 - 64 who are at risk for exposure to the avian H5N1 virus. The vaccine is given as 2 shots, spaced about 1 month apart. In studies, the vaccine appeared to be effective and well tolerated. Currently, the government is stockpiling the vaccination in case of an avian influenza outbreak. The vaccine is not available to the general public.

Ideally, appropriate candidates should be vaccinated every October or November. However, it may take longer for a full supply of the vaccine to reach certain locations. In such cases, the high-risk groups should be served first.

Antibodies to the flu virus usually develop within 2 weeks of vaccination, and immunity peaks within 4 - 6 weeks, then gradually wanes.

Because children under age 9 do not develop strong immune responses to 1 dose, the CDC recommends 2 vaccinations given 1 month apart.
Early research also suggests that it may be equally effective to administer children’s vaccinations in the spring and fall, rather than 1 month apart; further study is ongoing.
It should be noted that if an individual develops flu symptoms and is accurately diagnosed in time, vaccination of the other members of the household within 36 - 48 hours affords effective protection to those individuals, according to a 2004 Canadian analysis of multiple studies.

In healthy adults, immunization typically reduces the chance of getting the flu by about 70 - 90%. The current flu vaccines may be slightly less effective in certain patients, such as the elderly and those with certain chronic diseases. Some evidence suggests, however, that even in people with a weaker response, the vaccine is usually protective against serious flu complications, particularly pneumonia. The major outstanding question is whether the vaccination prevents complications of serious illness. One 2003 study, for instance, reported no reduction in severity of chronic lung diseases among vaccinated patients with asthma, emphysema, or chronic bronchitis. Some evidence suggests, on the other hand, that among the elderly, a flu shot may help protect against stroke, adverse heart events, and death from all causes.

Children Who Should Be Vaccinated. The following children over 6 months should be vaccinated against the flu:

The American Academy of Pediatrics (AAP) and the CDC recommend flu shots for all healthy children ages 6 - 23 months. In addition, any child over age 2 years who has a condition that requires regular medical care or who has been hospitalized for a serious illness (particularly lung or kidney disease, diabetes, sickle cell disease, or immune deficiencies).
Children who are receiving long-term aspirin therapy should also receive a flu shot. Children who get the flu are at higher risk for Reye syndrome, a life-threatening disease.
Some doctors now advocate flu shots for all school-age children. Research indicates that children are responsible for transmitting the vast majority of cases of the flu, and that routine vaccination of school-age children would considerably reduce transmission rates throughout communities.

There has been some question concerning flu shots because of some reports that vaccines may worsen asthma. Recent and major studies have been reporting, however, that the vaccination is safe for children with asthma. It is also very important for these patients to reduce their risk for respiratory diseases. Yet many children with asthma are not vaccinated. One study by the CDC found that fewer than one-third of children with asthma were vaccinated during the 2004-2005 flu season.

Older Children and Adults Who Should Be Vaccinated. The following, in order of priority, are the population groups who should be vaccinated each year. The first 2 groups have the highest need for flu shots and are given top priority:

All adults 65 years and older. Older adults who get a flu shot have lower hospitalization rates than those who do not. Evidence now suggests that vaccination may help protect against adverse heart events (including after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two-thirds of people in this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.
People of any age at high risk for serious complications from the flu. Such people include those with heart disease, lung problems, immune deficiencies, diabetes, kidney disease, or chronic blood disease. Those with any condition that may compromise respiratory function or the handling of respiratory secretions, including people with cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders, are included in this group. (There have been concerns about the safety of the vaccinations in certain high-risk patients, such as those with HIV or asthma. Studies now suggest that the vaccine is generally safe in these patient groups. Furthermore, their risk for serious complications from the flu outweighs any potential adverse effects from the vaccines.)
Adults aged 50 - 64 who have chronic medical conditions. The U.S. Advisory Committee on Immunization Practices (ACIP) suggests that all adults over age 50 should be vaccinated, although this is not a recommendation of the CDC.
All health care workers should be vaccinated, according to the ACIP’s 2005 recommendations.
Household members in contact with individuals who are at high risk for complications from the flu should be vaccinated.

Other adults who should consider flu shots include:

People at risk for complications of the flu who are traveling to the tropics at any time or to the Southern Hemisphere between April and September.
Pregnant women who are at risk for complications of the flu and who will be in their second or third trimester during flu season. Women who are pregnant should receive only the inactivated flu vaccine. (Vaccinations should usually be given after the first trimester. Exceptions may be women who are in their first trimester during flu season, because their risk from complications of the flu is higher than any theoretical risk to the baby from the vaccine.)
People such as firemen or policemen who are critical for public safety.

Possible side effects of the flu vaccine include:

Allergic Reaction. Newer vaccines contain very little egg protein, but an allergic reaction still may occur in people with strong allergies to eggs.
Soreness at the Injection Site. Up to two-thirds of people who receive the influenza vaccine develop redness or soreness at the injection site for 1 or 2 days afterward.
Flu-like Symptoms. Some people actually experience flu-like symptoms, called oculo-respiratory syndrome, which include conjunctivitis, cough, wheeze, tightness in the chest, sore throat, or a combination. Such symptoms tend to occur 2 - 24 hours after the vaccination and generally last for up to 2 days. It should be noted that these symptoms are not the flu itself but an immune response to the virus proteins in the vaccine. (Anyone with a fever at the time the vaccination is scheduled, however, should wait to be immunized until the ailment has subsided.)
Guillain-Barre Syndrome. Isolated cases of a paralytic illness known as Guillain-Barre syndrome have occurred, but if there is any higher risk, it is very small (one additional case per 1 million people), and does not outweigh the benefits of the vaccine.

Haemophilus Influenzae Type B

Haemophilus influenzae (H. influenzae) type B is a bacterium, which, despite its name, is entirely different from the viruses that cause influenza (the flu). Before vaccination, H. influenzae type B (Hib) was the most common cause of childhood bacterial meningitis, killing 600 American children every year and leaving others deaf, mentally retarded, or epileptic. It is rarely troublesome for adults, although it can be dangerous for anyone with chronic lung disease and those susceptible to infections.

This is a Gram stain of spinal fluid from a person with meningitis. The rod-like organisms seen in the fluid are Haemophilus influenza, one of the most common causes of childhood meningitis (prior to the widespread use of the H. influenza vaccine). The large red-colored objects are cells in the spinal fluid. A vaccine to prevent infection by Haemophilus influenza type B is available as one of the routine childhood immunizations (Hib), typically given at 2, 4, and 12 months.

Three equally effective inactivated bacterial vaccines (commonly called Hib vaccines) are available for H. influenzaetype B. All children under 5 should be vaccinated against H. influenzae type B. The vaccine is administered as an injection at 2 and 4 months. Depending on the vaccination preparation, a third shot in the series is administered at 6 months. A booster is required at some time between 12 and 15 months of age.

Click the icon to see an image of Hib immunization.

In children older than 12 months, the Hib and DTaP vaccines are being combined in a single injection. This combined injection can be given as a booster, but not as the initial Hib immunization.

Evidence suggests that in infants, this combined vaccine using acellular pertussis (the current DTaP standard) is less effective in protecting against Hib than one that uses the older form with whole-cell pertussis. The booster at 1 year should help maintain protection, however.

The Hib vaccine may benefit older people who have had their spleen removed or illnesses that put them at risk for pneumonia, including sickle cell disease, leukemia, and HIV infection.

Click the icon to see an image of sickle cells.

Side effects of the Hib vaccine include redness and pain at the injection site, moderate fever, and, in rare cases, weakness, nausea, and dizziness.

Human Papillomavirus (HPV)

In 2006, the U.S. Advisory Committee on Immunization Practices( ACIP) voted to recommend the use of the first vaccine (Gardasil) to protect against human papillomavirus (HPV). This group of 100 viruses includes some 40 sexually transmitted viruses. Some HPV viruses can significantly increase the risks of cervical cancer, as well as cancers of the vulva, vagina, anus, and penis.

HPV is a very common virus; an estimated 20 million people in the U.S. have it. At least half of all sexually active men and women will eventually develop the virus.

A 2007 study indicated that the Gardasil vaccine is 100% effective against cervical, vaginal, and vulvar diseases caused by 4 types of HPV (6, 11, 16, and 18); however, it does not protect against the other types of the virus. It is less effective in women who were exposed to the virus before they were vaccinated. A 2007 study indicated that the vaccine is effective for 5 years after women receive the initial dose. The manufacturer has applied to the FDA for approval of the vaccine to also help prevent cancers of the vagina and vulva.

A new experimental vaccine, called Cervarix, has been shown in research to be effective for 5 1/2 years against the 2 most prevalent strains of HPV. Research is also indicating that the vaccine might be effective against more types of infections than the Gardasil vaccine. Researchers are studying the vaccine further, and they're looking at whether Cervarix is effective in women over age 25.

Girls ages 11 - 12 should get the vaccine, but they can get it as early as age 9. Adolescents and women ages 13 - 26 also should get the vaccine if they haven't already received it. Young women should ideally get the vaccine before they are sexually active, but it is still effective in sexually active women who haven't yet been infected with HPV. Currently there is no research to confirm the vaccine's effectiveness in women over 26, so there is no recommendation yet for this age group. Gardasil is not recommended for pregnant women.

Young women should get 3 doses of the vaccine. They should get the second dose 2 months after the first dose, and the third dose 6 months after the first dose.

Studies have shown no significant side effects from the HPV vaccine. The most common side effect was soreness at the injection site.

Rotavirus

Rotavirus is the most common cause of diarrhea, cramps, and vomiting in infants, and affects about 3.5 million children in the U.S. each year. As many as 80% of small children become infected with the virus. Although most cases in this country are mild, more than 50,000 American children are hospitalized and as many as 125 die from severe diarrhea every year. Worldwide the virus can be devastating, causing more than 600,000 infant deaths annually. There is also some strong evidence that the virus can lead to childhood diabetes.

An oral vaccine (Rotashield) has been withdrawn after reports of a severe and even life-threatening condition called intussusception following use of the vaccine. Intussusception occurs when the bowel slips inside itself like a telescope and obstructs the intestine. The risk was very small and occurred within a week or two of the vaccination. Any child who previously had the vaccination no longer incurs any increased risk. Preliminary reports suggest that newer rotavirus vaccines may be highly effective in preventing infection among infants, although more research is needed to confirm these findings and to determine their safety record in a large number of children. The association between diabetes and the virus itself raises some alarm that the vaccine might also increase the risk in children who are genetically susceptible to type 1 diabetes.

The U.S. Food and Drug Administration (FDA) approved a new oral rotavirus vaccine (Rotavirus, Live, Oral, Pentavalent vaccine -- trade name RotaTeq) early in 2006, and the Advisory Committee on Immunization Practices (ACIP) recommended that all infants should be immunized (3 liquid doses by mouth at 2, 4, and 6 months of age). In February 2007, the FDA announced there had been 28 reports of intussusception in infants who received the vaccine. After carefully monitoring cases of intussusception and other adverse effects associated with RotaTeq the FDA announced in March 2007 that the vaccine does not pose an increased risk of intussusception.

Because this is a deadly virus for many children worldwide, international groups believe that the few cases of intussusception do not warrant withdrawing its use, at least for countries where the infection is so common and deadly.

Click the icon to see an x-ray of intussusception.

Smallpox

Vaccination against smallpox used to be routine in the U.S. until 1972, and most older Americans bear the telltale small round smallpox vaccination scar on their upper arms. Immunity may last 10 years or longer. The last case of smallpox, a highly contagious and deadly disease caused by the variola virus, occurred in a laboratory worker in the U.K. in 1978.

However, the growing threat of bioterrorism has raised fears that smallpox could be used as a biological weapon, and in 2002 the US government issued plans for vaccinating every citizen against the disease in the event of an outbreak. The vaccination, however, carries some risks. Currently, then, vaccination continues to be recommended only for laboratory workers and scientists who work with the virus.

If an outbreak occurs, guidelines from the CDC call for a so-called "ring vaccination" approach. This involves identifying anyone who comes into contact with an infected person and vaccinating them and their contacts with a single dose of vaccine. This includes people of all ages and even those at risk for vaccine complications. The vaccine may work even if given within the first few days of infection.

Those at increased risk of vaccine complications but who should still be immunized if they are actually exposed to an outbreak include the following:

Children younger than a year. About 42 infants out of a million will develop brain swelling that may result in retardation or death. A severe, body-wide rash may also occur, especially if children touch the vaccination site.
Pregnant women. There is a small risk of miscarriage or premature delivery, although smallpox itself in pregnant mothers has more serious implications.
People with skin conditions, particularly eczema. They may develop a widespread blistering rash called eczema vaccinatum, which is fatal in 1 - 6% of cases, and they should not be vaccinated unless they've been exposed to the disease. They should also avoid others who have been vaccinated until those persons' vaccination scabs heal and fall off. People with non-chronic skin conditions, such as allergic rashes, severe burns, or chickenpox, may be vaccinated once their skin condition clears up.
People with suppressed immunity due to HIV, organ transplants, high-dose steroids, cancer chemotherapy, or other conditions.
Should a severe rash or other complication develop, patients should notify their doctors immediately. Two investigational medications, vaccine immune globulin (derived from the blood of people who have been vaccinated against smallpox) and an antiviral drug called cidofovir (Vistide), may be administered intravenously in the hospital should serious complications arise.
In the event of an outbreak, current plans specify that vaccination against smallpox will remain voluntary, although unvaccinated people who are exposed to the disease may be quarantined for 18 days to help contain the spread of disease.

Other Vaccinations

Many other types of vaccinations are available.

Rabies is a frequently fatal, acute viral infection that is transmitted to humans by infected animals (often dogs or bats) via a bite or exposing broken skin to an infected animal's saliva. In the past, human cases in the U.S. usually resulted from a dog bite, but more cases of human rabies have been linked to bats. Meanwhile, there have not been any rabies cases caused by dog bites for a number of years. Few cases occur in the U.S. because of extensive animal vaccination programs.

Anyone who is exposed to bats or to secretions of an animal suspected of having rabies should receive the rabies vaccine. Exposed individuals should also receive immune globulin unless they were previously vaccinated. Veterinarians and animal handlers should be vaccinated. This does not eliminate the need for treatment if they are exposed to rabies, but it reduces the intensity of the treatment.

Side effects include pain, redness, swelling at the injection site, headache, nausea, stomach pain, muscle aches, and dizziness. Allergic response can occur after the first shot and as many as 21 days after a booster shot. Rare cases of neurologic disorders that cause pain and paralysis in the legs and arms have also been reported. These neurologic disorders usually clear up in about 12 weeks.

Click the icon to see an image of rabies.

Plague is a severe, and potentially deadly, infection. It is caused by the organism Yersinia pestis. Wild rodents, like rats, spread the disease to humans. Plague is spread among rodents by a flea bite. Humans may get the plague when they touch or eat the infected animal, or when they come in contact with its feces. Certain forms of the plague can be spread from human to human. Plague is rare in the United States, but has been known to occur in parts of California, Utah, Arizona, Nevada, and New Mexico.

Veterinarians and assistants in the western U.S. or anyone who works with potentially plague-infected animals and travelers to developing countries where outbreaks have occurred should be vaccinated. The plague vaccine is not 100%y protective; it may only lessen severity of the disease. Preventive antibiotics are needed for anyone exposed. Side effects include headache, malaise, fever, swollen lymph nodes, and, occasionally, non-infected abscesses. Allergic reactions may occur, particularly in those sensitive to beef, soy, milk, and phenol.

Anthrax is an infectious disease caused by the spore-forming bacteria called Bacillus anthracis. Infection in humans most often involves the skin, the gastrointestinal tract, or the lungs.

Anthrax commonly affects hoofed animals such as sheep and goats, but humans who come in contact with the infected animals can get sick from anthrax, too. Historically, the populations most at risk for anthrax included farm workers, veterinarians, and tannery and wool workers. Anthrax is a potential agent for use as a biological weapon or for bioterrorism. In 2001, bioterrorist activities involving the U.S. Postal Service infected 22 people with anthrax; 7 survivors had confirmed cutaneous anthrax disease.

Military personnel and vaccine researchers, as well as people who work with imported animal hides, furs, bone meal, wool, animal hair (especially goat hair), and bristles, should receive an anthrax vaccine. The anthrax vaccine appears to be safe and effective, even after exposure, but requires 6 shots over 18 months. Up to half of recipients develop temporary soreness; some develop fever. Pregnant women should not get the anthrax vaccine.

Click the icon to see an image of cutaneous anthrax.

Click the icon to see an image of tuberculosis.


Disease	Who Should Get It?	Additional Information
Adenovirus	Military personnel.	Vaccine given orally for the prevention of respiratory illness.
Yellow Fever	Travelers to developing countries where outbreaks have occurred, currently parts of Africa and Central and South America. Residents of these areas, particularly children.	Vaccinations safe and effective for the prevention of jaundice and kidney and liver failure. Anaphylactic reactions in those allergic to eggs. Very rarely, may cause a potentially fatal illness resembling yellow fever, with fever and diarrhea, particularly in seniors. Lower immunity when given with cholera vaccine; the vaccines should be given three weeks apart.
Cholera	Travelers to developing countries where outbreaks have occurred.	Recently developed vaccines (Dukoral, Mutacol) are more effective than previous ones, which provided little protection. Not recommended or available, however, in the US.
Typhoid	Travelers to developing countries where outbreaks have occurred.	Oral vaccines include: (Ty21a, Vivotif). The oral vaccines are not effective against parathyroid fever. One-shot vaccine (Typhim Vi). Can be taken as early as two weeks before travel. Vi-rEPA is a newer injected vaccine that is safe in children and may be more effective-than other vaccines to date. No vaccine is 100% effective. The response to the typhoid vaccine tends to be lower in older people.
Tuberculosis	Individuals exposed to infected people.	Bacille Calmette-Guerin vaccine has been the standard vaccine, but its effectiveness has been questioned. No longer recommended in US except for certain high-risk children. A new recombinant BCG vaccine, shown in early trials to be more effective, is now licensed for use and is undergoing continued study.
Meningitis caused by meningococcal bacteria	U.S. Advisory Committee on Immunization Practices (ACIP) recommendations now call for routine vaccination of all young adolescents (aged 11 - 12) as well as those previously defined as at increased risk: People exposed to single cases or outbreaks; freshmen college students living in dorms; military recruits; travelers to developing countries where outbreaks have occurred; patients with problems in the spleen.	Vaccines are available against four subtypes of meningococcal bacteria but not for serogroup B, which causes up to 40% of meningococcal disease in the U.S. Among young people, fatalities have been higher in 15- to 24-year-olds than those younger than 15.

Resources

www.immunize.org -- Immunization Action Coalition
www.cdc.gov/vaccines/ -- The National Immunization Program
www.fda.gov/cber/vaers/vaers.htm -- Vaccine Adverse Event Reporting System
www.909shot.com/Issues/Injury_Compensation.htm -- National Vaccine Injury Compensation Program
www.immunizationinfo.org -- The National Network for Immunization Information
www.vaccine.chop.edu -- Vaccine Education Center, Children's Hospital of Philadelphia
www.vaccinesafety.edu -- Institute for Vaccine Safety, Johns Hopkins School of Public Health
www.whathealth.com -- National Partnership for Immunization
www.immunofacts.com -- Information on vaccinations
www.vaccines.org -- The Vaccine Page

References

American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedule: United States, 2005. Pediatrics. 2005 Jan;115(1):182.

Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). Mor Mortal Wkly Rep. June 2007;56:1-40.

Centers for Disease Control and Prevention. Recommended Immunization Schedule for Ages 0-6 Years, United States, 2007.

Chaves SS, Gargiullo P, Zhang JX, Civen R, Guris D, Mascola L. Loss of vaccine-induced immunity to varicella over time. NEJM. March 15, 2007;356:1121-1129.

Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. NEJM. May 10, 2007;356:1928-1943.

Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. April 7, 2007;369:1179-1186.

Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005 Jul 29;54(RR-8):1-40.

Poehling KA, Szilagyi PG, Crijalva CG, Martin SW, LaFleur B, Mitchel E, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics. April 4, 2007;119:707-715.

Prevention of influenza in the general population: Recommendation statement from the Canadian Task Force on Preventive Health Care. CMAJ. 2004;171:10.

American Academy of Pediatrics Committee on Infectious Diseases. Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric patients. Pediatrics. 2005 Aug;116(2):496-505.

Pneumococcal vaccine cuts severe bacterial disease in US. Mor Mortal Wkly Rep CDC Surveill Summ 2005;54:893-896.

Wise R, Iskander J, Pratt D, et al. Postlicensure Safety Surveillance for 7-Valent Pneumococcal Conjugate. JAMA. 2004; 292:1702-1710.

Krym VF, MacDonald RD. Global efforts to eradicate polio. CMAJ. 2004 Jan 20;170(2):189-90.

Zuckerman JN. Protective efficacy, immunotherapeutic potential, and safety of hepatitis B vaccines. J Med Virol. 2006 Feb;78(2):169-77.

Review Date:
10/1/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Hypothyroidism

FitSugar — Wed, 08 Oct 2008 17:35:30 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Diagnosis
Risk Factors
Complications
Treatment
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Congenital Hypothyroidism and Maternal Hyperthyroidism

Thyroid-lowering medications used for treating Graves’ disease, the most common cause of hyperthyroidism (overactive thyroid), can cause babies to be born with hypothyroidism (underactive thyroid). Research presented at the 2006 annual meeting of the American Thyroid Association suggests that hyperthyroidism can be effectively managed during pregnancy without causing newborn hypothyroidism. The researchers suggest that:

Pregnant women with Graves’ disease should take the lowest possible dose of their thyroid medication
It is safe for women with Graves’ disease to maintain thyroid levels in the upper-normal range while pregnant

Low-Normal Thyroid and Metabolic Syndrome

Thyroid levels in the low-normal range may increase the risk of unhealthy cholesterol levels, high blood sugar, and abdominal obesity -- indicators of metabolic syndrome -- according to a 2006 study in the Journal of Clinical Endocrinology and Metabolism.
Metabolic syndrome is a cluster of conditions, (including abdominal obesity, high blood sugar, and unhealthy cholesterol levels), which increases the risk for heart disease. However, many experts do not believe that treating subclinical hypothyroidism (mildly underactive thyroid) can help prevent heart problems. More research is underway.

Subclinical Hypothyroidism and Mood

A large study of elderly people, published in the Annals of Internal Medicine, suggests that subclinical hypothyroidism does not cause depression, anxiety, or impaired cognition. The study included nearly 6,000 people age 65 years and older.

Introduction

The thyroid is a small, butterfly-shaped gland located in the front of the neck that produces hormones, notably thyroxine (T4) and triiodothyronine (T3), which stimulate vital processes in every part of the body. These thyroid hormones have a major impact on the following functions:

Growth
Use of energy and oxygen
Heat production
Fertility
The use of vitamins, proteins, carbohydrates, fats, electrolytes, and water
Immune regulation in the intestine

These hormones can also alter the actions of other hormones and drugs.

The thyroid gland, a part of the endocrine (hormone) system, plays a major role in regulating the body's metabolism.

Regulating thyroid function is a complex and important process that involves several factors, including iodide and four thyroid hormones. Any abnormality in this intricate system of hormone synthesis and production can have far-reaching consequences on health.

Iodide. An understanding of the multi-step thyroid hormone process begins with iodide, a salt that is extracted from the blood and trapped by the thyroid gland. Iodide is converted to iodine in the thyroid gland. (Eighty percent of the body's iodine supply is stored here.) Iodine is the material used to make the hormone thyroxine (T4).

Thyroid Hormones. Four hormones are critical in the regulation of thyroid function:

Thyroxine (T4) and Triiodothyronine (T3). Thyroxine (T4) is the key thyroid hormone. Low levels of T4 produce hypothyroidism, and high levels produce hyperthyroidism. Thyroxine converts to triiodothyronine (T3), which is a more biologically active hormone. Only about 20% of triiodothyronine is actually formed in the thyroid gland. The rest is manufactured from circulating thyroxine in tissues outside the thyroid, such as those in the liver and kidney. Once T4 and T3 are in circulation, they typically bind to substances called thyroid hormone transport proteins, after which they become inactive.
Thyrotropin. Thyrotropin (also called thyroid-stimulating hormone or TSH) is another very important hormone in the process. Secreted by the pituitary gland, this hormone directly influences the process of iodine trapping and thyroid hormone production. When thyroxine levels drop even slightly, the pituitary gland goes into action to pump up secretion of thyrotropin so that it can stimulate thyroxine production. So, when T4 levels fall, TSH levels increase.
Thyrotropin-releasing hormone (TRH), the final critical thyroid hormone, is produced in a region in the brain called the hypothalamus, which monitors thyrotropin levels.

Click the icon to see an image of the pituitary gland.

Click the icon to see an image of the pituitary gland and TSH.

Hypothyroidism occurs when thyroxine (T4) levels drop so low that body processes begin to slow down. Hypothyroidism was first diagnosed in the late nineteenth century when doctors observed that surgical removal of the thyroid resulted in the swelling of the hands, face, feet, and tissues around the eyes. They named this syndrome myxedema and correctly concluded that it was the outcome of the absence of substances, thyroid hormones, normally produced by the thyroid gland. Hypothyroidism is usually progressive and irreversible. Treatment, however, is nearly always completely successful and allows a patient to live a fully normal life.

Subclinical hypothyroidism (mildly underactive thyroid), also called early-stage hypothyroidism, is a condition in which thyrotropin (TSH) levels have started to increase in response to an early decline in T4 levels in the thyroid. However, blood tests for T4 are still normal. The patient may have mild symptoms (usually slight fatigue) or none at all. Mildly underactive thyroid is very common (affecting about 10 million Americans) and is a topic of considerable debate among professionals because it is not clear how to manage this condition.

For instance, mildly underactive thyroid does not progress to the full-blown disorder in most people. Experts estimate that each year approximately 2 - 5% of people with mildly underactive thyroid will go on to develop overt hypothyroidism. Other factors associated with a higher risk include being an older woman (up to 20% of women over age 60 have subclinical hypothyroidism), having a goiter (enlarged thyroid gland) or thyroid antibodies, or harboring immune factors that suggest an autoimmune condition.

Mildly underactive thyroid is determined on the basis of the TSH laboratory blood tests. According to a 2004 consensus statement from the American Thyroid Association, the American Association of Clinical Endocrinologists, and the Endocrine Society, the normal range of TSH concentration falls between 0.45 and 4.5 mU/L. Patients with mildly underactive thyroid have TSH levels between 4.5 mU/L and 10mU/L. Patients with levels greater than 10mU/L are considered to have overt hypothyroidism and should be treated with medication.

For patients in the mildly underactive thyroid range, treatment decisions are less clear. The consensus committee recommended against routine treatment for patients with mildly underactive thyroid , but did suggest repeat screenings of thyroid function every 6 - 12 months to detect any changes in TSH levels. However, these are general guidelines, and individual cases and risk factors may differ. Patients should discuss with their doctor the course of action that is most appropriate for them.

Causes

Many permanent or temporary conditions can reduce thyroid hormone secretion and cause hypothyroidism. About 95% of hypothyroidism cases occur from problems that originate in the thyroid gland. In such cases, the disorder is called primary hypothyroidism. (Secondary hypothyroidism is caused by disorders of the pituitary gland. Tertiary hypothyroidism is caused by disorders of the hypothalamus.)

The two most common causes of primary hypothyroidism are:

Hashimoto's thyroiditis. This is an autoimmune condition in which the body's immune system attacks its own cells.
Overtreatment of hyperthyroidism (an overactive thyroid).

Hashimoto's thyroiditis, atrophic thyroiditis, and postpartum thyroiditis are all autoimmune diseases of the thyroid. An autoimmune disease occurs when the immune system mistakenly attacks the body's own healthy cells. In the case of autoimmune thyroiditis, a common form of primary hypothyroid disease, the cells under attack are in the thyroid gland.

All forms of thyroid autoimmunity typically start with T and B cells:

Important immune factors called T and B cells infiltrate the thyroid gland in equal numbers. These white blood cells are the primary infection-fighting immune cells. T cells identify invasive molecules, such as viral proteins, and help B cells to produce antibodies that are designed specifically to attack these invaders.
In cases of autoimmunity, T cells are tricked into classifying molecules on the body's own cells as invaders. In such cases, B cells then produce antibodies, called autoantibodies, which attack those cells.
In most cases of thyroid autoimmunity, the autoantibodies launch an attack on a thyroid protein called thyroid peroxidase; this attack appears to destroy thyroid cells.

Experts do not know why the immune system starts the process that injures the thyroid. Some theories follow:

One theory starts with a virus that has a protein resembling a thyroid protein. During an infection, T cells induce B cells to secrete specific antibodies that attack the invasive viral protein. Unfortunately, the T cells are also tricked into inducing a B-cell attack on the similar thyroid protein.
Genetic factors most likely play some role in autoimmune thyroiditis. For example, many patients with Hashimoto's thyroiditis express a gene called the Fas gene, which interacts with thyroid cells and triggers a process called apoptosis, in which the cells begin to self-destruct. The Fas gene is linked to genes that regulate tumor necrosis factors, which are products of the immune system that trigger a damaging inflammatory response in cells.
In some women, thyroid autoimmunity may have developed while they were pregnant. In such cases, some evidence suggests that fetal cells accumulated in the mother's thyroid gland, triggering an immune attack.
In some cases of Hashimoto's thyroiditis, antibodies block a receptor on thyroid cells that bind to thyrotropin (TSH). This effect is more likely to be involved in worsening the disorder, but does not explain initial destruction.
Some evidence suggests that excess iodine intake triggers the process leading to Hashimoto's thyroiditis.

Hashimoto's Thyroiditis. The most common form of hypothyroidism in the U.S. is Hashimoto's thyroiditis, a genetic disease named after the Japanese doctor who first described thyroid inflammation. It occurs in about 0.3 - 5 people per 1,000 per year, and women are 15 - 20 times more likely than men to develop this disease.

Click the icon to see an image of Hashimoto's thyroiditis.

An enlargement of the thyroid gland, called a goiter, is almost always present and may appear as a cyst-like or fibrous growth in the neck. Hashimoto's thyroiditis is permanent and requires lifelong treatment. Both genetic and environmental factors appear to play a role in its development.

One theory proposes that Hashimoto's thyroiditis and Graves' disease (a form of hyperthyroidism) are caused by a similar immunologic dysfunction. Similar immune system substances called antibodies are present in both diseases, and some experts believe that the predominance of one or another antibody determines which of the diseases become manifest. The two diseases, then, are essentially two sides of a single coin.

Click the icon to see an image of Grave's disease.

Atrophic Thyroiditis. Atrophic thyroiditis is similar to Hashimoto's thyroiditis, except a goiter is not present.

Riedel's Thyroiditis. Riedel's thyroiditis is a rare autoimmune disorder, in which scar tissue progresses in the thyroid until it produces a hard stony mass that suggests cancer. Hypothyroidism develops as the scar tissue replaces healthy tissue. Surgery is usually required, although early stages may be treated with tamoxifen, corticosteroids, or other immunosuppressive drugs.

Autoimmune Thyroiditis Due to Pregnancy. Hypothyroidism may also occur in women who develop antibodies to their own thyroid during pregnancy, causing an inflammation of the thyroid after delivery.

Subacute thyroiditis is a temporary condition that passes through three phases: hyperthyroidism, hypothyroidism, and a return to normal thyroid levels. Patients may exhibit symptoms of both hyperthyroidism and hypothyroidism (rapid heartbeat, nervousness, weight loss), and they can feel extremely sick. Symptoms last about 6 - 8 weeks and then resolve in most patients, although each form carries some risk for becoming chronic. Experts estimate that subacute thyroiditis is responsible for 10% of all cases of hypothyroidism.

The three forms of subacute thyroiditis follow a similar course:

Painless Postpartum Subacute Thyroiditis. Postpartum thyroiditis is an autoimmune condition that occurs in up to 10% of pregnant women and tends to develop between 4 - 12 months after delivery. In most cases, a woman develops a small, painless goiter. Although 80% of women with this condition have normal thyroid function within a year, some evidence suggests that half of women with this condition develop permanent hypothyroidism within 7 years. Women who have had recurrent episodes after previous pregnancies and women who have other autoimmune disorders are at higher risk for this form of subacute thyroiditis. It is generally self-limiting and requires no therapy unless the hypothyroid phase is prolonged. In such cases, therapy may be thyroxine replacement for a few months. A doctor will prescribe beta blockers if the hyperthyroid phase requires treatment.

Painless Sporadic, or Silent, Thyroiditis. This painless condition is very similar to postpartum thyroiditis except it can occur in both men and women and at any age. About 20% of patients with silent thyroiditis may develop chronic hypothyroidism. Treatment considerations are the same as for postpartum subacute thyroiditis.

Painful, or Granulomatous, Thyroiditis. This condition comes on suddenly with flu-like symptoms and severe neck pain and swelling. It generally occurs in the summer and is five times more common in women. It recurs in about 2% of patients. Hypothyroidism persists in about 5%. Treatments typically include pain relievers and, in severe cases, corticosteroids.

Up to half or more of patients who receive radioactive iodide treatments for an overactive thyroid develop permanent hypothyroidism within a year of therapy. This is the standard treatment for Graves' disease, which is the most common form of hyperthyroidism, a condition caused by excessive secretion of thyroid hormones.

By the end of 5 years, about 65% of treated patients have developed hypothyroidism, after which the rate of this condition levels off to about 1% a year. Such patients need to take thyroid hormones for the rest of their lives. Other forms of treatment for overactive thyroid glands using either antithyroid drugs or surgery may also result in hypothyroidism.

Too much or too little iodide can cause hypothyroidism. If there is a deficiency of iodide, the body cannot manufacture thyroxine. About 200 million people around the world have hypothyroidism because of insufficient iodine in their diets. Too much iodide is a signal to inhibit the conversion process of thyroxine to T3. The end result in both cases is inadequate production of thyroid hormones. Some evidence suggests that excess iodine triggers the process leading to Hashimoto's thyroiditis.

Complete removal (total thyroidectomy) of the thyroid to treat thyroid cancer requires a lifetime of treatment with an appropriate dosage of thyroid hormone. Removing one of the two lobes of the thyroid gland (hemithyroidectomy), usually because of benign growths on the thyroid gland, rarely produces hypothyroidism. The remaining thyroid lobe will generally enlarge so that it can produce sufficient amounts of thyroid hormone for normal function. Many doctors recommend thyroid hormone treatment, however, to prevent the formation of additional nodules.

Click the icon to see an illustrated series detailing thyroid removal.

A small percentage of Graves disease patients who require surgery to remove most of both thyroid lobes (subtotal thyroidectomy) may develop hypothyroidism. It is important to find an experienced surgeon for this procedure and to have the thyroid checked at 6- or 12-month intervals.

Researchers have identified several additional syndromes that also cause hypothyroidism. These generally involve abnormalities in thyroid hormone itself or genetic deficiencies in certain proteins that impair thyroid hormone conversion processes or responses.

Lithium. Lithium, a drug widely used to treat psychiatric disorders, has multiple effects on thyroid hormone synthesis and secretion. Up to 50% of patients who take lithium develop a goiter, with 20% developing symptomatic hypothyroidism, and another 20 - 30% developing hypothyroidism without symptoms.

Amiodarone. The drug amiodarone (Cordarone), which is used to treat abnormal heart rhythms, contains high levels of iodine and can induce hyper- or hypothyroidism, particularly in patients with existing thyroid problems. Hypothyroidism occurs in 20% of patients and is the more common effect in the U.S. and other countries where dietary iodine is abundant. Hyperthyroidism is a less common effect in these regions.

Other Drugs. Drugs used for treating epilepsy, such as phenytoin and carbamazepine, can reduce thyroid levels. Certain antidepressants may cause hypothyroidism, although this is rare. Interferons and interleukins are used for treating hepatitis, multiple sclerosis, and other conditions. Evidence suggests that these drugs increase antibodies that put patients at risk for hypo- or hyperthyroidism. Some drugs used in cancer chemotherapy, such as sunitinib (Sunent) or imatinib (Gleevec), can also cause or worsen hypothyroidism.

High-dose radiation for cancers of the head or neck and for Hodgkin's disease causes hypothyroidism in up to 65% of patients within 10 years after treatment.

In rare instances, usually due to a tumor, the pituitary gland will fail to produce thyrotropin (TSH), the hormone that stimulates the thyroid to produce its hormones. In such cases, the thyroid gland withers. When this happens, secondary hypothyroidism occurs.

Hypothyroidism in newborns (known as congenital hypothyroidism) occurs in one in every 3,000 - 4,000 births, making it the most common hormonal disorder in infants. In 90% of these cases, it persists throughout life.

Permanent Congenital Hypothyroidism. In up to 85% of permanent congenital hypothyroidism cases, the thyroid gland is missing, underdeveloped, or not properly located. In most cases the cause or causes of these conditions are unknown. In about 10 - 15% of cases, processes involved in hormone production are impaired, most likely because of genetic abnormalities. In less than 5% of cases, the pituitary or hypothalamus function abnormally.

Temporary Hypothyroidism in Infants. Temporary hypothyroidism can also occur in infants. In about 20% of cases, the cause remains unknown. The known causes stem from various immunologic, environmental, and genetic factors, including those in the mother:

Hypothyroidism. Women who have an underactive (“low”) thyroid, including those who develop the problem during pregnancy, are at increased risk for delivering babies with congenital (newborn) hypothyroidism. Maternal hypothyroidism can also cause premature delivery and low-birth weight.
Hyperthyroidism. Graves disease is the most common cause of maternal hyperthyroidism (overactive or “high” thyroid). Some of the drugs used to treat hyperthyroidism can cause hypothyroidism in the infant. Some research indicates that using the lowest possible dose of thyroid-lowering medication can minimize the risk of congenital hypothyroidism. (The research also suggests that it is safe for women with Graves’ disease to remain in a mildly hyperthyroid state during pregnancy.
Iodine deficiency. This may cause temporary hypothyroidism. (Exposure to too much iodine immediately after birth, for example, from iodine-containing disinfectants or medicines, can also cause thyroid dysfunction.)
Being premature.
Kidney disease. Temporary hypothyroidism in infants can occur in premature babies and, rarely, in those with kidney disease.
The central nervous system connections between the hypothalamus and pituitary gland may also mature late; this condition generally resolves 4 - 16 weeks after birth.

Children with temporary congenital hypothyroidism should be followed-up regularly during adolescence and adulthood for possible thyroid problems. The risk for further thyroid problems is highest in these adult women during pregnancy. Newborn siblings of these children should also be screened for possible thyroid defects.

Symptoms

Early Symptoms. Early symptoms of hypothyroidism are subtle and, in older people, can be easily mistaken for symptoms of stress or aging. They include:

Chronic fatigue
Sensitivity to cold
Headache
Muscle and joint aches
Weight gain, despite diminished appetite
Constipation
Dry skin

In premenopausal women, early symptoms can interfere with fertility. They may experience heavy periods or, in rare cases, a milky discharge from the breasts. A history of miscarriage may be a sign of impending hypothyroidism. Studies suggest that even if thyroid levels are normal, women who have a history of miscarriages often have antithyroid antibodies during early pregnancy and are at risk for developing autoimmune thyroiditis over time.

Later Symptoms. As free thyroxine levels fall over the following months, other symptoms may develop:

Impaired mental activity, including concentration and memory, particularly in the elderly.
Depression. Some experts believe that even mild thyroid failure may increase susceptibility to major depression.
Muscle weakness, numbness, pain, and cramps. This can cause an unsteady gait. Muscle cramps are common, and carpal tunnel syndrome or symptoms similar to arthritis sometimes develop. In some cases, the arms and legs may feel numb.
Numbness in the fingers.
Hearing loss.
Husky voice.
Continuing weight gain and possible obesity, in spite of low appetite.
Some people experience less sweating, and their skin becomes pale.
Skin and hair changes. Skin becomes pale, rough, and dry. Patients may sweat less. Hair coarsens and even falls out. Nails become brittle.
Snoring and obstructive sleep apnea (a condition in which in the soft palate in the throat collapses at intervals during sleep, thereby blocking the passage of air).

Secondary hypothyroidism, caused by tumors or other growths on the pituitary, produces the usual symptoms of primary hypothyroidism. In addition, sexual drive and fertility may be impaired in both men and women. Patients may also feel exhausted, crave salt, and have low blood pressure. Headaches and visual disturbances may develop, which are directly related to the pituitary tumor.

Hypothyroidism occurs when the thyroid gland is underactive. The condition may affect all body functions. The rate of metabolism slows, causing mental and physical sluggishness. Myxedema, a medical emergency, is the most severe form of hypothyroidism. A problem with the thyroid itself (primary) or malfunction of the pituitary gland (secondary) or hypothalamus (tertiary) can cause hypothyroidism.

All babies are now screened for hypothyroidism in order to prevent retardation that can occur if treatment is delayed. Symptoms of hypothyroidism in children vary depending on when the problem first develops.

Most children who are born with a defect that causes congenital hypothyroidism have no obvious symptoms. Symptoms that do appear in newborns may include jaundice (yellowish skin), noisy breathing, and an enlarged tongue.
Early symptoms of undetected and untreated hypothyroidism in infants include feeding problems, failure to thrive, constipation, hoarseness, and sleepiness.
Later on, symptoms in untreated children include protruding abdomens; rough, dry skin; and delayed teething. Rarely, in advanced cases, yellow raised bumps (called xanthomas) may appear under the skin, the result of cholesterol build-up.
If they do not receive proper treatment in time, children with hypothyroidism may be extremely short for their age, have a puffy, bloated appearance, and have below-normal intelligence. Any child whose growth is abnormally slow should be examined for hypothyroidism.

Diagnosis

Advances in diagnostic methods now make it possible to detect hypothyroidism in almost all cases before severe symptoms develop. Doctors can diagnosis hypothyroidism after completing a history and physical exam of the patient and performing sensitive laboratory tests on the patient's blood.

The doctor will check the heart, eyes, hair, skin, and reflexes for signs of hypothyroidism.

Goiter. The presence of a goiter (an enlarged thyroid), especially a rubbery, painless one, may be an indication of Hashimoto's disease. If the thyroid is tender and enlarged but not necessarily symmetrical, the doctor may suspect subacute thyroiditis. A diffusely enlarged gland may occur in hereditary hypothyroidism, in postpartum patients, or from use of iodides or lithium. Goiters may also develop in people with iodide deficiency.

Thyroid Neck Check. Women who are experiencing menopausal symptoms that may be masking those of hypothyroidism should perform a simple self-examination called the Thyroid Neck Check:

Hold a mirror in front of the area of the neck where the thyroid gland is located. This area is just below the Adam's apple and right above the collarbone. (Note: The Adam's apple is not the thyroid location.)
Tip the head back.
Take a drink of water and swallow, watching the neck during the process.
Check for any bulging or protrusions. If any is detected, call a doctor for a check up.

In diagnosing hypothyroidism, blood tests measuring hormone levels are needed to make a correct diagnosis. In some cases, antibody tests are also helpful.

Thyroxine (T4). Hypothyroidism is a condition marked by low thyroxine (T4) hormone levels, and a test can measure levels of this hormone in the blood. However, this test is usually inadequate for the following reasons:

T4 levels can be normal early in the disease process leading to hypothyroidism. If hypothyroidism is suspected, other tests are needed.
T4 levels can be low in patients who do not have hypothyroidism. For instance, thyroxine can be extremely variable in very elderly or seriously ill patients and during pregnancy.

Measuring thyroxine is usually performed using a process called a T3 resin uptake to correct for the presence of medications (such as birth control pills, aspirin, and others) that could distort the results. Other tests are needed to confirm a diagnosis of hypothyroidism.

Thyrotropin (Thyroid-Stimulating Hormone or TSH). Measuring TSH is the most sensitive indicator of hypothyroidism. (As with thyroxine levels, however, TSH levels can vary in pregnant women and patients who are ill with other conditions.) In general, results indicate the following:

TSH levels over 10mU/L. This is a clear indicator of hypothyroidism if T4 levels are low -- and, in most cases, even if they are normal. Patients usually require thyroxine (T4) replacement therapy. They should also be tested for high cholesterol levels and antithyroid antibodies.
Levels between 4.5 mU/L - 10 mU/L. Patients with signs and symptoms of hypothyroidism usually need thyroxine replacement therapy. Patients without symptoms have subclinical hypothyroidism and should be rechecked every 6 - 12 months. Antibody tests may also be performed.
TSH levels between 0.45 mU/L - 4.5 mU/L. These indicate normal thyroid function. (Abnormally low levels suggest hyperthyroidism, which is overactive thyroid.)
Specific TSH measurement -- even if it is significantly higher than 10 mU/L -- is not associated with the severity of the condition. This can be determined only by measuring thyroxine levels and evaluating the patient's symptoms.

Antithyroid Antibodies. If TSH levels suggest hypothyroidism or subclinical hypothyroidism, the doctor may choose to perform a blood test for specific antithyroid antibodies that act against a factor called thyroperoxidase (TPO). Tests can also check for antibodies to thyroglobulin. Results depend on the patient's condition:

Patients with confirmed hypothyroidism (TSH levels over 10 mU/L). Positive test results in such patients confirm the need for thyroxine replacement therapy. (Even if antibody results are negative, these patients usually require thyroxine replacement therapy.) About 90% of patients with Hashimoto's thyroiditis test positive for antibodies to thyroperoxidase, and up to half have thyroglobulin antibodies.
Patients with subclinical hypothyroidism (TSH between 4.5 mU/L - 10 mU/L). If antibody levels are high, thyroxine therapy is usually warranted, since it indicates an underlying autoimmunity condition that poses a high risk for later thyroid failure. If the tests are negative, but patients have thyroid-related problems (such as high cholesterol, female infertility), they should be monitored annually with hormone tests.

About 10% of the American population and 25% of women over 60 years old carry these antibodies, and the majority of these women have no thyroid problems. Only about 0.5% have full-blown hypothyroidism, and 10% have subclinical hypothyroidism. In one 10-year study, however, people with normal thyroid results and high levels of antibodies still had an annual risk of 2 - 4% for developing hypothyroidism.

Other Hormone Tests Used for Thyroid Function. Other hormone tests are done if hyperthyroidism is suspected. They include tests for triiodothyronine (T3) and thyroglobulin (also called thyroid binding globulin). Such measurements, however, may also be helpful in detecting sudden temporary increases in thyroid hormone (thyrotoxicosis) that can precede certain forms of autoimmune thyroiditis.

Thyroid Scintigraphy. Thyroid scintigraphy tests scan the thyroid and pick up images highlighted by small amounts of radioactive substances. Thyroid scans can be used to determine whether the thyroid is producing normal amounts of hormone. The patient drinks a small amount of radioactive iodine or technetium and waits until the substance has passed through the thyroid. Images of a properly functioning thyroid would show uniform levels of absorption throughout the gland. Overactive areas show up white, and underactive areas appear dark. Thyroid scans are usually unnecessary unless the doctor needs to rule out suspected cancer.

Ultrasound. Ultrasound has limited value, but it can visualize the thyroid and specific abnormalities, such as nodules. (It cannot measure the thyroid gland's function, however.)

Click the icon to see an image of thyroid ultrasound.

More Advanced Imaging Tests. If laboratory tests suggest that a pituitary or hypothalamus problem is causing hypothyroidism, the doctor will usually order brain imaging procedures using computed tomography (CT) scans or magnetic resonance imaging (MRI). MRIs may also be used for determining the extent of thyroid cancers and of goiters. MRIs are also being used for investigating hypothyroidism in infants and for determining widespread effects of autoimmune thyroiditis (such as Hashimoto's hypothyroidism).

Needle aspiration biopsy is used to obtain thyroid cells for microscopic evaluation. It may be useful to rule out thyroid cancer in patients with suspected Hashimoto's hypothyroidism, especially if they have difficulty swallowing or develop a goiter. Much like drawing blood, the doctor injects a small needle into the thyroid gland and draws cells from the gland into a syringe. The cells are put onto a slide, stained, and examined under a microscope.

Cholesterol levels need to be checked. Other blood tests may be performed to detect levels of calcitonin, calcium, prolactin, and thyroglobulin and to check for anemia and liver function, all of which may be affected by hypothyroidism.

Screening in Older Adults. Some doctors believe that because thyroid problems are so common in the elderly and thyroid hormone tests are so inexpensive, blood tests for thyroid function should be routine. Undiagnosed hypothyroidism in elderly patients can develop into a serious and even life-threatening situation. Hyperthyroidism also poses many health risks. In fact, during the period around menopause, the symptoms of menopause and hypothyroidism are similar and can easily be confused with each other.

Professional organizations differ widely on screening recommendations. Most do not recommend widespread screening for healthy adults:

The American College of Physicians recommends that women over 50 years old be screened for thyroid disorders every 5 years. The American Academy of Family Physicians believes that adults do not have to be screened until they are over 60.
The American Thyroid Association, however, recommends that all adults, both men and women, begin their screening at age 35 and every 5 years thereafter. Experts in this organization argue that such early screening is inexpensive and would prevent progression to hypothyroidism, and therefore possibly heart disease, in people with subclinical hypothyroidism. Such an approach would also eliminate the need for expensive anti-cholesterol drugs.

Screening in Pregnant Women. Untreated hypothyroidism in a pregnant woman, particularly in the first trimester, may cause premature delivery and birth defects. Birth defects can affect a baby’s intelligence, mental development, and motor skills. Subclinical hypothyroidism also increases the risk for premature delivery and birth defects.

Some experts propose that screening be done on any woman who is planning a pregnancy to help determine those who may be at increased risk for hypothyroidism and, if needed, begin treatment as early as possible during the critical first trimester. Women who have a personal or family history of hypothyroidism should have their thyroid checked within the first weeks of pregnancy and should be retested during each trimester.

Screening in Infants. It is very difficult to diagnose hypothyroidism in newborns by symptoms alone. Fortunately, almost all newborns with hypothyroidism are identified shortly after birth through an effective national screening program using a thyroid blood test.

Because the symptoms of hypothyroidism are so similar to common conditions, including aging, diagnosis can be difficult.

Conditions That Cause Thyroid Abnormalities. Some conditions may cause thyroid abnormalities without symptoms and must be differentiated from subclinical hypothyroidism. They include, although are not limited to:

Inadequate response to thyroid therapies in people with hypothyroidism
Recovery from a severe illness that is unrelated to thyroid disorders
Chronic kidney failure
Failure of the adrenal gland

Aging-Related Disorders. Some symptoms of hypothyroidism and aging are very similar. Menopausal symptoms often resemble hypothyroidism. Many other problems related to aging -- such as vitamin deficiencies, Parkinson's and Alzheimer's diseases, and arthritis -- also have characteristics that can mimic hypothyroidism.

Obesity. Many people who are overweight believe that they have an underactive thyroid gland, but only a very small percentage of obese people actually have hypothyroidism. Patients with hypothyroidism generally show only a moderate weight increase of 5 - 10 pounds, mainly from accumulation of fluid, and in fact they often have a decreased appetite.

Depression. A lack of interest in personal relationships, drowsiness, an increase in sleep, slowing of speech, and general apathy are signs of clinical depression as well as hypothyroidism. The two disorders often coexist, particularly in older women, so diagnosing one does not rule out the presence of the other.

Diseases of Muscles and Joints. Joint and muscle aches may be the first symptoms of hypothyroidism. Most likely, however, such pain is not caused by hypothyroidism if other thyroid symptoms remain absent. Numerous conditions can cause muscle and joint pain, and if thyroid levels are normal the doctor should look for other causes.

Risk Factors

About 15 million Americans have unrecognized thyroid disease, mostly subclinical hypothyroidism (mildly underactive thyroid). Less than 2% of the U.S. population has full-blown hypothyroidism.

Women. Women have 10 times the risk of hypothyroidism as men, with the difference being significant after age 34. In one study, nearly 6% of women over 60 had hypothyroidism, and some experts estimate that as many as 20% of women in this age group have a subclinical condition. Because the symptoms of hypothyroidism and menopause are so similar, hypothyroidism may easily be missed.

Pregnancy is a major factor in the higher risk in women. It affects the thyroid in a number of ways and poses a high risk for hypothyroidism, both during pregnancy and afterward. For one, iodine requirements are high in both the mother and the fetus. Changes in reproductive hormones also cause changes in thyroid hormone levels. In addition, some women develop antibodies to their own thyroid during pregnancy, causing a condition known as postpartum autoimmune, or subacute, thyroiditis. This occurs in up to 10% of pregnant women and tends to develop between 4 - 12 months after delivery. It is a limited condition and nearly always clears up. However, it does pose a risk for the development of permanent hypothyroidism later on.

Age. The elderly are most susceptible, but hypothyroidism can affect people of all ages. For example, 1 in every 3,000 - 4,000 infants is born with congenital hypothyroidism. Female infants are at higher risk than males.

Ethnicity. African-Americans may be less likely to have thyroid disease than Caucasians and Asians.

Genetics plays a role in many cases of underactive and overactive thyroid. The genetics involved with hypothyroidism are complicated, however. Certain genetic features, for example, appear to play a role in Hashimoto's thyroiditis and postpartum thyroiditis in Caucasians, but others affect different ethnic groups. Thyroid disease will often skip generations. For example, someone with an underactive thyroid may have healthy parents but have grandparents who had thyroid troubles. Some people inherit a tendency to thyroid problems but never become ill, while others become very sick.

Smoking significantly increases risk for thyroid disease, particularly autoimmune Hashimoto's thyroiditis and postpartum thyroiditis. Chemicals in cigarette smoke called thiocyanates appear to have especially harmful effects on the thyroid. Smoking also increases the negative effects of hypothyroidism, notably on the arteries and heart.

People with certain medical conditions have a higher risk for hypothyroidism. These conditions include:

Autoimmune diseases. People with many autoimmune diseases have a higher risk for hypothyroidism. Type 1 (insulin-dependent) diabetes poses a higher risk and is a special problem since hypothyroidism can affect insulin requirements. Women with other autoimmune diseases, including systemic lupus erythematosus, pernicious anemia, and rheumatoid arthritis, are also at higher risk for hypothyroidism. Pregnant women with autoimmune conditions have a 25% risk for hypothyroidism during gestation.
Breast cancer. There may be a link between breast cancer and thyroid levels, but the evidence is unclear. Some studies have indicated that women with breast cancer may be more susceptible to hypothyroidism. Other studies suggest the opposite. Several studies indicate that hypothyroidism itself may protect against breast cancer. In addition, when women with hypothyroidism develop breast cancer, it is often a less aggressive and more easily treated form.
Gout. Hypothyroidism and gout often coexist and may have biologic mechanisms in common.
Addison's disease.
Myasthenia gravis.
Polycystic ovarian syndrome.
Anorexia or bulimia. People with eating disorders are at risk for hypothyroidism. In these cases, however, reduced thyroid function may be an adaptation to malnutrition and, therefore, some experts think that only the eating disorder should be treated, not hypothyroidism.
Turner syndrome. As many as half of patients with Turner syndrome have hypothyroidism, usually in the form of Hashimoto's thyroiditis. This inherited condition is one of the most common genetic diseases in women.
Glaucoma. A 2004 study of male veterans suggested that hypothyroidism may be associated with increased risk for developing open-angle glaucoma.

Click the icon to see an animation about gout.

Click the icon to see an image of polycystic ovarian syndrome.

Many drugs affect the thyroid, so anyone being treated for a chronic disease, patients who are taking thyroid medication, and those who are at risk for a thyroid disorder should discuss the impact these drugs may have on their thyroid.

Hypothyroidism is associated with premature gray hair and left-handedness.

Complications

Hypothyroidism carries serious physical and mental risks for all ages. Studies indicate that subtle adverse health effects occur even with subclinical hypothyroidism, a condition in which the patient has no symptoms but blood tests indicate hypothyroidism. Fortunately, hypothyroidism is now easily diagnosed, and treatment will restore normal thyroid function and relieve symptoms and physical signs of the disease. With treatment, a patient should expect to live a normal life, free of harmful consequences. Iodine deficiency and goiter are still major problems in less developed nations and cause varying degrees of mental retardation in millions of people.

Myxedema Coma. Myxedema coma is a rare, life-threatening complication of untreated hypothyroidism. Symptoms include a severe drop in body temperature (hypothermia), delirium, reduced lung function, slow heart rate, constipation, urine retention, seizures, stupor, fluid build-up, and finally coma. It is uncommon, but may develop in untreated patients subjected to severe stress, such as infection, surgery, or extreme cold. Certain drugs (such as sedatives, painkillers, narcotics, amiodarone, and lithium) may increase the risk. Emergency treatment is required. Mortality rates are high (between 30 - 60%) with the highest risks in older patients and those with persistent hypothermia or heart problems.

Suppurative Thyroiditis. Suppurative thyroiditis is a life-threatening infection of the thyroid gland. It is very rare, since the thyroid is normally immune to infection. People with pre-existing thyroid diseases, such as Hashimoto's thyroiditis, however, may be at higher than average risk for it. It often begins with an upper respiratory infection. Symptoms include fever, neck pain and rash, and trouble swallowing and speaking. Immediate treatment is critical.

Thyroid hormones, notably triiodothyronine (T3), affect the heart directly and indirectly. They are closely linked with heart rate and heart output. T3 provides particular benefits by relaxing the smooth muscles of blood vessels. This helps keep the blood vessels open so that blood flows smoothly through them.

Hypothyroidism is associated with:

Unhealthy cholesterol levels. Hypothyroidism raises levels of total cholesterol, LDL (the so-called bad cholesterol), triglycerides, and other lipids (fat molecules) associated with heart disease. Treating the thyroid condition with thyroid replacement therapy can significantly reduce these levels.
Mild high blood pressure. Hypothyroidism may slow the heart rate to less than 60 beats per minute, reduce the heart's pumping capacity, and increase the stiffness of blood vessel walls. All of these effects may lead to high blood pressure. Indeed, patients with hypothyroidism have triple the risk of developing hypertension. All patients with chronic hypothyroidism, especially pregnant women, should have their blood pressures checked regularly.
Heart failure. Hypothyroidism can affect the heart muscle’s contraction and increase the risk of heart failure in people with existing heart disease.

The evidence for subclinical hypothyroidism and heart disease is mixed. Some studies suggest that subclinical hypothyroidism increases the risks for coronary artery disease and heart failure. A 2007 study indicated that low-normal thyroid function may increase the risk for metabolic syndrome (a cluster of symptoms that include abdominal obesity, high blood sugar, and unhealthy cholesterol levels). However, a 2006 study in the Journal of the American Medical Association found that while subclinical hypothyroidism was associated with atrial fibrillation (irregular heart beat), it was not associated with other types of heart disease. Many experts believe that treatment of subclinical hypothyroidism will not help prevent or improve heart problems. More research is underway.

Depression. Depression is common in hypothyroidism and can be severe. Some psychiatrists suspect that even subclinical hypothyroidism may contribute to depression. The two disorders may have some common physiological basis. Adding thyroid hormones to antidepressants may hasten a depressed patient's recovery, even in some patients who have not been diagnosed with hypothyroidism. Hypothyroidism should be considered as a possible cause of any chronic depression, particularly in older women.

Mental and Behavioral Impairment. Untreated hypothyroidism can, over time, cause mental and behavioral impairment and eventually, even dementia. Whether treatment can completely reverse problems in memory and concentration is uncertain, although many experts believe that only mental impairment in hypothyroidism that occurs at birth is permanent.

A 2006 study of nearly 6,000 people age 65 years and older concluded that subclinical hypothyroidism is not associated with depression, anxiety, or mental impairment in elderly patients.

The following medical conditions have been associated with hypothyroidism. Often the causal relationship is not clear in such cases:

Iron deficiency anemia.
Respiratory problems.
Kidney function.
Glaucoma. (Some research has associated hypothyroidism with an increased risk for glaucoma.)
Headache. (Hypothyroidism may worsen headaches in people predisposed to them.)
Thyroid lymphoma. (Patients with Hashimoto's thyroiditis are at higher risk for this rare form of cancer.)
Joint stiffness. (Women with hypothyroidism may actually have fewer problems with joint stiffness than women with normal thyroid.)

Most women with hypothyroidism fail to produce eggs, and many younger women with hypothyroidism are diagnosed with the condition for the first time during a fertility evaluation. A pregnant woman with hypothyroidism has a fourfold risk for miscarriage. In one study, nearly 40% of women with a history of miscarriages and normal thyroid levels had antithyroid antibodies (immune factors that attack thyroid tissue). Those who continue to have hypothyroidism near the time of delivery are in danger of developing high blood pressure and premature delivery. They are also prone to postpartum thyroiditis, which is said to be a contributor to postpartum depression.

Children of Untreated Mothers. Children born to untreated pregnant women with hypothyroidism are at risk for impaired mental performance, including attention problems and verbal impairment. Studies on the effects on children of women with subclinical hypothyroidism are less clear, with some reporting lower IQs in such children and others reporting no significant problems.

Effects of Hypothyroidism During Infancy. Transient hypothyroidism is common among premature infants. Although temporary, severe cases can cause difficulties in neurologic and mental development.

Infants born with permanent congenital (inborn) hypothyroidism need to receive treatment as soon as possible after birth to prevent mental retardation, stunted growth, and other aspects of abnormal development (a syndrome referred to as cretinism). It has been estimated that untreated infants can lose up to three to five IQ points per month during the first year. An early start of lifelong treatment avoids or minimizes this damage. Even with early treatment, however, mild problems in memory, attention, and mental processing may persist into adolescence and adulthood.

Effects of Childhood-Onset Hypothyroidism. If hypothyroidism develops in children older than 2 years, mental retardation is not a danger, but physical growth may be slowed and new teeth delayed. If treatment is delayed, adult growth could be affected. Even with treatment, some children with severe hypothyroidism may have attention problems and hyperactivity.

Two million Americans, mostly children, received x-ray treatments to the head or neck between 1920 - 1960 for acne, enlarged thymus gland, recurrent tonsillitis, or chronic ear infections. The risk of developing thyroid nodules and thyroid cancers is increased in these individuals, especially if they have hypothyroidism. Cancer can develop as late as 40 years after the original treatment. Everyone who has had head and neck radiation should be sure to have their thyroid glands examined regularly.

Treatment

Various tests are used when deciding whether to treat a patient for hypothyroidism:

First, an elevated TSH (thyrotropin) level should be confirmed and thyroxine (T4) level determined.
Testing for antithyroid antibodies and determining cholesterol levels is also important.

Treating Hypothyroidism. Patients with full-blown hypothyroidism, indicated by clear symptoms and blood tests that show high TSH (generally 10 mU/L and above) and low thyroxine (T4) levels, must be treated with thyroid replacement.

Treating Subclinical Hypothyroidism. Considerable debate exists about whether to treat patients with subclinical hypothyroidism (slightly higher than normal TSH levels, normal thyroxine levels, and no obvious symptoms). Some doctors opt for treatment because of the following benefits, although evidence remains uncertain:

Preventing progression to full-blown hypothyroidism. Treating subclinical hypothyroidism will prevent progression to overt hypothyroidism. Only a minority of people with subclinical hypothyroidism go on to develop the active condition, however.
Preventing heart disease. Some studies have shown that treating subclinical hypothyroidism lowers cholesterol levels and may improve other heart functions, including blood pressure, endothelial function, and heart rate. However, current research from 2006 suggests that subclinical hypothyroidism poses little risk for heart disease and that untreated subclinical hypothyroidism will not increase heart disease risks.
Improving well-being. Some studies report that treating subclinical hypothyroidism may improve mild psychological symptoms, such as impaired mental functioning and depression. About 25% of patients with subclinical hypothyroidism report feeling better after taking thyroid medication even if they have not previously reported symptoms.

It is not clear, then, if the benefits of treating subclinical hypothyroidism outweigh the higher costs of testing and treatments. Experts against treatment argue that thyroid levels can vary widely, and subclinical hypothyroidism may not persist. In such cases, overtreatment leading to hyperthyroidism is a real risk.

In spite of such uncertainties, three out of four major medical organizations recommend treatment for subclinical hypothyroidism, particularly in patients who have:

High total or LDL cholesterol levels
Blood tests that show autoantibodies indicating a future risk for Hashimoto's thyroiditis or other forms of other autoimmune hypothyroidism·
Blood tests that show TSH levels greater than 10 mU/L
Goiter

Experts also recommend treating subclinical hypothyroidism in:

Pregnant women
Women with infertility that may be associated with subclinical hypothyroidism

Treatment is optional in patients with subclinical hypothyroidism who have no obvious symptoms and normal cholesterol levels. If they forego treatment, however, they should be tested yearly for TSH and thyroxine.

Treating Patients with Hypothyroidism Symptom and Normal Thyroid Tests. Some doctors treat patients who have a normal or below normal thyroid function test. Some experts believe it is irresponsible to treat such patients with thyroid replacement since such symptoms can occur with many physical and psychological conditions. In any case, studies have not found any benefits from T4 replacement therapies in this group.

In the 19th century, doctors observed the relationship between myxedema (swelling of the hands, face, feet, and tissues around the eyes) and surgical removal of the thyroid gland. Some doctors began to feed patients with myxedema with whole or powdered extracts of animal thyroid glands. Using thyroid hormone to treat hypothyroidism was one of the first successful medical treatments based on careful scientific observation. With only some modifications, this approach has varied little for over a century.

A synthetic thyroid hormone called levothyroxine is currently the treatment of choice for hypothyroidism. This drug is a synthetic derivative of T4 (thyroxine), and it normalizes blood levels of TSH, T4, and T3. Nevertheless, the therapeutic principle for hypothyroidism is the same as it was more than 100 years ago: To provide the body with replacement thyroid hormone when the gland is not able to produce enough itself.

Brand Names. A number of levothyroxine brands are available in the U.S. and overseas. Synthroid is the oldest brand and has been used for over 40 years. In the past, manufacturers of levothyroxine have not had to meet as strict standards as in the production of other drugs. This resulted in thyroid products with varying quality. The FDA has issued stronger requirements that have largely corrected this problem.

Generics versus Brand-Name Products. Generic brands are available and are subject to the same guidelines as brand-name products. There is still considerable debate over whether generic thyroid preparations are as effective as brand products.

In addition, the amount of T4 in some generic products is outside the FDA range, which requires additional testing of thyroid hormone levels. Many doctors, then, prefer to use brand-name products, noting that the cost difference between brand and generic thyroid drugs is not substantial. Regardless of which type is used, once a patient has been stabilized, doctors generally recommend sticking with one type or brand since potency often varies from one drug to the next.

Natural Thyroid Hormone. Dried powdered thyroid hormone (Armour Thyroid, S-P-T, Thyrar, Thyroid Strong) is made from animal glands. It was once the most common form of thyroid therapy but is no longer generally recommended because potency varies. Some people argue that with stricter FDA regulations, this natural form is better controlled and may even reduce the risk of developing autoimmunity factors. Dried thyroid also contains both T3 and T4 and is favored as a natural treatment by many alternative practitioners. However, studies need to be conducted to evaluate its benefits.

T3 and T4 Combinations. Triiodothyronine (T3), the other important thyroid hormone, is not ordinarily prescribed except under special circumstances. Most patients respond well to thyroxine (T4) alone, which is converted in the body into T3. In addition, the use of T3 may cause disturbances in heart rhythms. Some patients treated only with thyroxine continue to have mood and memory problems or other symptoms.

Combination products containing T4 and T3, such as liotrix (Thyrolar), are available, but there is some controversy concerning their benefits. Several 2005 studies suggested that although some patients may prefer combination therapy, T3 and T4 together do not work better than T4 alone. Patients might like the combined drugs because they cause more weight loss, or a placebo effect may be involved. It does not appear that combination products offer any advantage for normalizing TSH levels.

Levothyroxine only needs to be taken once a day. It is slowly assimilated by body organs, so it usually takes up to 6 weeks before symptoms improve in adults. Nevertheless, many patients feel better after 2 - 3 weeks of treatment. The speed at which specific symptoms improve varies:

Weight loss, less puffiness, and improved pulse usually occur early in the treatment.
Improvements in anemia and skin, hair, and voice tone may take a few months.
High LDL ("bad cholesterol") levels decline very gradually. HDL ("good cholesterol") levels are not affected by treatment.
Goiter size declines very slowly, and some patients may require high-dose thyroid hormone (called suppressive thyroid therapy) for a short period.

Levothyroxine reduces blood pressure in about half of hypothyroid patients with hypertension, although blood pressure medications may still be needed.

Appropriate Dosage Levels. Initial dosage levels are determined on an individual basis and can very wide depending on a person's age, medication condition, other drugs they are taking, and, in women, whether they are pregnant or not. For example, pregnant women with hypothyroidism may require higher than normal doses.

Starting out. Most individuals need to build up gradually until they reach a maintenance dose. In uncomplicated cases, the dose typically starts at 50 micrograms per day, which then increases in 3- to 4-week intervals until thyroid hormone levels are normal. Seniors and those with heart disease may start at 12.5 - 25 micrograms per day. On the other hand, young adults with a short history of hypothyroidism might be able to tolerate a full maintenance dosage right away.
Maintenance dose. Maintenance dose for most patients averages 112 micrograms but it can vary between 75 - 260 micrograms. If conditions such as pregnancy, surgery, or other drugs alter hormone levels, the patient's thyroid needs will have to be reassessed.

Daily Regimen. Because thyroid replacement is usually lifelong, setting up a regular daily routine is helpful. Here are some tips to remember:

Establish a habit of taking the medication at the same time each day. This may help prevent missed doses.
Levothyroxine is very forgiving. The hormone remains in the body for several days, so one missed dose should not cause a noticeable decline in well-being. The patient can safely take two doses the next day.
Fiber and common daily supplements, such as calcium, may interfere with thyroxine absorption. Although levothyroxine can be taken at any time of day either with or without food, some experts recommend taking thyroid hormone upon awakening and at least 30 minutes before consuming anything, including breakfast or supplements.

Annual Evaluation. Thyroid failure is an ongoing process and so is its treatment. Many factors can cause changes that require modifying the thyroxine dosages.

A dose that is appropriate for 1 year may be too low the next. To maintain normal thyroid levels, some patients may need to take gradually increasing doses of thyroid hormone every year or two. Experts recommend that patients be reevaluated 6 months after normal TSH levels have been reached and then once a year thereafter.

Specific factors, such as changes in health or diet, new medications for other conditions, or simply switching brands, can also cause changes in thyroid hormone levels that require different doses. If patients change dose levels or thyroxine brands then they should be checked again at least 6 weeks later.

Because levothyroxine is identical to the thyroxine the body manufactures, side effects are rare. Over- or under-dosing, however, is fairly common, although rarely serious in the short term.


Under-Dosing	Over-Dosing
Sluggishness	Heart symptoms (rapid heart beat, palpitations, and wide variations in pulse; possible angina or congestive heart failure)
Mental dullness	Agitation (tremor, nervousness, insomnia, excessive sweating)
Feeling cold	Pain (headache and muscle pain)
Muscle cramps	Intestinal and metabolic symptoms (change in appetite, diarrhea, weight loss)
	Fever and intolerance to heat

No Symptom Improvement When Normal Thyroid Levels Are Reached. Some patients fail to feel significantly better even when their thyroid levels become normal after taking thyroid replacement.

Some experts argue that many patients become symptom-free only if their thyroid replacement achieves high-normal T4 and low-normal TSH levels (rather than just normal levels). They believe that slightly higher thyroxine levels will not be harmful. Research is needed to confirm these claims.

Some patients with persistent symptoms may benefit from triiodothyronine (T3), the other important thyroid hormone. In such cases, either a combination of a lower-dose of thyroxine with a small amount of T3 or natural dried thyroid hormone, which contains T3, may be helpful.

Side Effects of Under-Dosing. If the levothyroxine dose is not sufficient to restore normal thyroid levels, or if the patient frequently forgets to take the medication, the patient may continue to experience symptoms of hypothyroidism. Even mild hypothyroidism without any symptoms can eventually lead to an increase in cholesterol levels. In a 2000 study, 40% of people taking thyroid medication still had abnormal levels of TSH. To avoid these problems, patients should take the proper dosage of levothyroxine as prescribed and have regular check-ups that include measurement of blood TSH.

Side Effects of Over-dosing: Thyrotoxicosis. Over-dosing can cause thyrotoxicosis, or the symptoms of hyperthyroidism. A patient with too much thyroid hormone in the blood is at an increased risk for abnormal heart rhythms, rapid heartbeat, congestive heart failure, and possibly a heart attack if the patient has underlying heart disease. Excess thyroid hormone is particularly dangerous in newborns, and their drug levels must be carefully monitored to avoid brain damage.

Side Effects of Long-Term Treatment. Patients with hypothyroidism usually receive lifelong levothyroxine therapy. There has been some concern that long-term use will increase the risk of osteoporosis, as suppression therapy does. Studies indicate that postmenopausal women who are taking long-term normal replacement thyroxine have no out-of-the-ordinary risk for osteoporosis.

Drug Interactions with Levothyroxine. Many drugs interact with levothyroxine and may either enhance or interfere with its absorption. These drugs include amphetamines, anticoagulants (blood thinners), tricyclic antidepressants, anti-anxiety drugs, arthritis medications, aspirin, beta-blockers, insulin, oral contraceptives, digoxin, and certain cancer drugs. Large amounts of dietary fiber may also reduce the drug’s effectiveness. People whose diets are consistently high in fiber may require larger doses of the drug. Since thyroid hormones regulate the metabolism and can affect the actions of a number of medications, dosages may also need to be adjusted if a patient is being treated for other conditions. Even changing thyroxine brands can have a different effect.

Suppressive thyroid therapy involves taking levothyroxine in doses that are high enough to block the production of natural TSH but too low to cause hyperthyroid symptoms. It may used for patients with large goiters or thyroid cancer.

Suppressive thyroid therapy places patients, particularly postmenopausal women, at risk for accelerated osteoporosis, a disease that reduces bone mass and increases risk of fractures. Some researchers suggest, however, that such bone loss is too slight to pose any significant risk for fracture. Furthermore, the cholesterol-lowering benefits of suppressive therapy outweigh this small risk. A small study found that premenopausal women taking suppressive therapy for more than 10 years were also at increased risk of bone loss by the time they reach menopause, although more research is needed to confirm this.

Bone density loss can be reduced or avoided by taking no higher a dose of thyroxine than necessary to restore normal thyroid function. In any case, doses of T4 must be continuously and carefully tailored in all patients to avoid adverse effects on the heart.

A number of medications are also available that can help preserve bone in postmenopausal women. Women on hormone replacement therapy may need to increase their dose of thyroid hormone.

Drugs that Inhibit Thyroid Hormone

Drugs that are Enhanced by Thyroid Hormone

Drugs that are Suppressed by Thyroid Hormone

Drugs that Reduce Natural Thyroid Hormone Levels and May Cause Hypothyroidism

Iron supplements (even low doses found in multivitamins)

Calcium carbonate supplements

Aluminum-containing antacids (Maalox)

Drugs used to reduce cholesterol levels by binding bile acids (colestipol and cholestyramine)

Estrogens in oral contraceptives and hormone replacement therapy (may need to increase thyroid hormone while taking estrogen)

Raloxifene (Evista), a designer-estrogen used for osteoporosis

Sucralfate (Carafate)

Epinephrine (adrenaline) injections. Thyroid hormone may increase the risk of serious side effects in heart disease patients given this drug.

Warfarin, a blood thinner. Doses of this medication may need to be reduced if thyroid treatment is started after blood thinning treatments have begun.

Many antidepressants. In some cases, potency of both antidepressants and thyroid hormones may increase.

Diabetes drugs. Patients taking thyroid hormone may need additional insulin or oral hypoglycemic drugs. Stopping or reducing thyroid hormone may increase the risk of low blood sugar.

Digoxin. Patients with heart disease may need to increase their dosage of digoxin.

Lithium. This drug, used for bipolar disorder, has multiple effects on thyroid hormone synthesis and secretion.

Amiodarone (Cordarone). This drug, used to treat abnormal heart rhythms, contains iodine and can induce hyper- or hypothyroidism, particularly in patients with an existing thyroid problem.

Antiseizure drugs used for epilepsy, including phenytoin and carbamazepine.

Interferons and interleukins used in hepatitis, multiple sclerosis, and other conditions.

Rifampin, used for tuberculosis.

Some drugs used for cancer chemotherapy.

Interferon.

Large doses of selenium, a dietary supplement.

Treating the Elderly and Patients with Heart Disease. Thyroid dysfunction is common in elderly patients, with most having subclinical hypothyroidism. There is no evidence that this condition poses any great harm in this population, and some experts recommend treating only high-risk patients. One study suggested many elderly patients have been treated unnecessarily for hypothyroidism for years. In the study, half the patients taking thyroid hormone were taken off the medication successfully. Such patients may have been inappropriately diagnosed years ago, when testing was less accurate. More sensitive tests available now should reduce this risk.

Elderly patients, particularly people with heart conditions, usually start with lower doses of thyroid replacement, since a large initial dose may be a shock to the heart. Thyroid treatment may aggravate angina in about 20% of patients with the heart condition. About 40% of patients who have heart disease must take lower-than-average maintenance doses. Experts do not recommend treatment for subclinical hypothyroidism in elderly patients with heart disease whose test show only minimal thyroid hormone abnormalities and who have no anti-thyroid antibodies. Such patients should be closely monitored, however.

Preliminary research indicates that in patients undergoing cardiac bypass surgery, administration of triiodothyronine at the time of surgery may improve blood flow, heart rate, and cardiac output. Patients with advanced heart failure may also benefit from supplementary thyroid hormone.

Treating the Mentally Ill. Patients with psychiatric illness often forget to take their medications regularly. In these patients, once- or twice-weekly dosing of thyroid medications is often safe and effective and may improve compliance.

Treating Newborns and Infants with Hypothyroidism. Babies who are born with hypothyroidism (congenital hypothyroidism) should be treated with levothyroxine (T4) as soon as possible to prevent complications. Early treatment can help improve IQ and other developmental factors. However, even with early treatment, mild problems in mental functioning may persist into adulthood. In general, children who are born with milder forms of hypothyroidism will fare better than those who have more severe forms.

Single oral doses of levothyroxine (T4) can usually restore normal thyroid hormone levels within 1 - 2 weeks. It is critical that normal levels are achieved within a 2-week period. If thyroid function is not normalized within 2 weeks, it can pose greater risks for developmental problems. Some experts urge treating newborns at slightly higher than recommended doses for the first 2 weeks and then reducing the dosage once normal thyroid levels have been reached. Infants should continue to be monitored closely to be sure that thyroxine levels remain as consistently close to normal as possible. These children need to continue lifelong thyroid hormone treatments.

Treatment During Pregnancy and for Postpartum Thyroiditis. Women who have hypothyroidism before becoming pregnant may need to increase their dose of levothyroxine during pregnancy. In very rare cases, women may develop hypothyroidism while pregnant and need to be treated with levothyroxine in full replacement doses to reduce the risk of stillbirth. The developing baby is not affected when the pregnant woman takes thyroid hormones. The pregnant woman with hypothyroidism should be monitored regularly and doses adjusted as necessary. If postpartum thyroiditis develops after delivery, any thyroid medication should be reduced or temporarily stopped during this period.

Treatment for Myxedema Coma. Myxedema coma is an emergency situation, and the patient should be given intravenous doses of thyroid hormone, which could be triiodothyronine, levothyroxine, or both. Lower doses may be safer in elderly patients. Oftentimes, hydrocortisone, a corticosteroid, is also administered. Any other accompanying critical condition, including low body temperature, slow heart rate, low blood sugar, and difficulty in breathing, should also be treated immediately.

Treatment of Secondary Hypothyroidism. The small percentage of patients who have hypothyroidism due to a pituitary or hypothalamus problem should take levothyroxine along with their other medication to treat the primary disorder. In secondary hypothyroidism, the adrenal gland is often impaired. This means that the increased activity in the metabolic rate that occurs after thyroid replacement therapy may trigger a severe and even life-threatening condition called addisonian crisis, which is caused by a sudden demand for the depleted stress hormones secreted by the adrenal gland. Before administering thyroid replacement, the doctor should initiate a test that stimulates release of ACTH, one of the hormones secreted by the adrenal gland. If there is insufficient ACTH, then before thyroid replacement is started, the patient is usually treated with cortisone acetate, a stress hormone.

In one study of those taking thyroid hormone, 12% of women and 29% of men took it inappropriately. In some cases of infertility, women with menstrual problems and repeated miscarriages and men with low sperm counts have been treated with thyroid hormones even when there was no evidence of thyroid abnormalities. (Women showing high levels of TSH, however, may benefit from levothyroxine therapy.)

Other inappropriate uses for thyroid hormones are for weight loss and to reduce high cholesterol levels. Thyroid hormones have also been given to treat so-called metabolic insufficiency. Vague symptoms suggesting low metabolism, such as dry skin, fatigue, slight anemia, constipation, depression, and apathy, should not be treated indiscriminately with thyroid hormone. No evidence exists that thyroid therapy is beneficial unless the patient has proven hypothyroidism. Indiscriminate use of thyroid hormones can weaken muscles and, over the long term, even the heart. One exception is the use of thyroxine to enhance drugs used for the treatment of severe depression.

Treating Hypothyroidism and Iodide Deficiency. People who are iodide deficient may be able to be treated for hypothyroidism simply by using iodized salt. In addition to iodized salt, seafood is a good source. Except for plants grown in iodine-rich soil, most other foods do not contain iodine. The current RDA for iodide is 150 micrograms for both men and women, with an upper limit of 1,100 micrograms to avoid thyroid injury.

Iodine Restriction in Patients with Hashimoto's Thyroiditis. Some evidence suggests that excess iodine triggers Hashimoto's thyroiditis. Small studies report that restricting iodine intake restored thyroid levels to normal in up to 75% of these patients. More research is needed.

Resources

www.aace.com -- American Association of Clinical Endocrinologists
www.thyroid.org -- American Thyroid Association
www.tsh.org -- Thyroid Foundation of America
www.endo-society.org -- Endocrine Society

References

Desai J, Yassa L, Marqusee E, George S, Frates MC, Chen MH, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006 Nov 7;145(9):660-4.

Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, et al. Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med. 2006 Oct 17;145(:573-81.

Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 2007 Feb;92(2):491-6.

Review Date:
3/20/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Colds and the flu

FitSugar — Wed, 08 Oct 2008 17:35:26 -0700

In This Report

Highlights
Introduction
Diagnosis
Complications
Risk Factors
Prevention
Treatment
Medications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Vaccine News:

On September 28, 2007, the U.S. Food and Drug Administration (FDA) approved a new brand of inactivated influenza ("flu") vaccine, Alfuria, for adults aged 18 years or older. This vaccine is given by injection.
On September 19, 2007, the FDA approved the use of the live flu vaccine (FluMist) in healthy children as young as 2 years of age. This vaccine, given in the form of a nose spray, was previously approved for healthy children and non-pregnant adults aged 5 - 49.

Drug Resistance:

The World Health Organization reports that resistance to the anti-viral drug oseltamivir (Tamiflu) can develop with extensive use. Oseltamivir is one of two drugs the CDC recommends for treating the flu. It is also the current recommended treatment for the H5N1 avian flu virus.

Drug Recalls:

In October 2007, drug manufacturers voluntarily withdrew from the market all oral cough and cold products, including decongestants, aimed at children under 2, due to potential harm from misuse. The U.S. Food and Drug Administration (FDA) recommends against using these products to treat children under age 2. The FDA is currently reviewing the safety of cough and cold medicines in children ages 2 - 11 years.

Emerging Virus:

A new, more virulent strain of adenovirus has reportedly emerged in the United States in 2006. The adenovirus family causes upper respiratory infections, pneumonia, and several other diseases. The new strain of adenovirus 14 causes severe respiratory illness that has resulted in several deaths.

Introduction

Upper respiratory tract infections affect the airways in the nose, ears, and throat.

Structures of the throat include the esophagus, trachea, epiglottis, and tonsils.

The infections can be caused by viruses, bacteria, or other microscopic organisms. In most cases, these infections lead to colds or mild influenza (flu) and are temporary and harmless. In rare cases, flu can be severe, or the infections may turn into pneumonia.

Organisms that cause these upper respiratory tract infections are generally spread by:

Direct contact (such as hand-to-mouth)
Coughing or sneezing

The common cold (medically known as infectious nasopharyngitis) is the most common upper respiratory tract infection. More than 200 viruses can cause colds. The most common cause is the rhinovirus, which is responsible for about half of all colds. Symptoms usually develop 1 - 3 days after being exposed to the virus.

A cold usually progresses in the following manner:

It nearly always starts rapidly with throat irritation and stuffiness in the nose.
Within hours, full-blown cold symptoms usually develop, which can include sneezing, mild sore throat, fever, minor headaches, muscle aches, and coughing.
Fever is low-grade or absent. In small children, however, fever may be as high as 103°F for 1 or 2 days. The fever should go down after that time, and be back to normal by the 5th day.
Nasal discharge is usually clear and runny the first 1 - 3 days. It then thickens and becomes yellow to greenish.
The sore throat is usually mild and lasts only about a day. A runny nose usually lasts 2 - 7 days, although coughing and nasal discharge can persist for more than 2 weeks.

A new, more virulent strain of adenovirus has reportedly emerged in the United States in 2006. The adenovirus family causes upper respiratory infections (it is one of the many viruses that cause the common cold). It also causes pneumonia, conjunctivitis, and several other diseases. The new strain of adenovirus 14 causes severe respiratory illness that has resulted in several deaths. Some patients who contracted this new viral disease had to be hospitalized, sometimes in intensive care units.

Every year, influenza strikes millions of people worldwide. Influenza epidemics are most serious when they involve a new strain, against which most people around the world are not immune. Such global epidemics (pandemics) can rapidly infect more than one fourth of the world's population. For example, the Spanish flu in 1918 and 1919 killed an estimated 20 million people in the U.S. and Europe and 17 million people in India. With modern society's dependence on air travel, an influenza pandemic could potentially inflict catastrophic damage on human lives, and disrupt the global economy.

The influenza virus mutates (changes) rapidly as it moves from species to species. Most Type A influenza strains (the most common strains) first develop in migratory waterfowl populations. While most avian influenza (bird flu) virus strains are relatively harmless, a few develop into "highly pathogenic avian influenza," which can be very deadly for domesticated poultry and livestock. As recent events have shown, these strains can also be deadly to humans. People can become infected by these bird flu strains through contact with contaminated chickens and pigs. The medical community is now greatly concerned about the H5N1 bird flu virus, which has infected and even killed people in several countries.

Symptoms of influenza. Patients usually feel sick 1 - 4 days after exposure to the influenza (flu) virus. The flu usually involves:

Abrupt onset of severe symptoms, which include headache, muscle aches, fatigue, and high fever (up to 104°F).
Cough (which is usually dry but can be severe) and sometimes a runny nose and sore throat.
Children may experience vomiting, diarrhea, and ear infections, as well as other flu symptoms.
The symptoms usually resolve in 4 - 5 days, although some people can experience coughing and feelings of illness for more than 2 weeks. In some cases, flu can become more severe or make other conditions worse.

Transmitting the Virus. The flu virus is spread primarily when a person with the flu coughs or sneezes near someone else. Adults with flu typically spread it to someone else from 1 day before symptoms start to about 5 days after symptoms develop. Children can spread the infection for more than 10 days after symptoms begin, and young children can transmit the virus 6 days or even earlier before the onset of symptoms. People with severely compromised immune systems can transmit the virus for weeks or months.

Flu Strains. A virus is a cluster of genes wrapped in a protein membrane, which is coated with a fatty substance that contains molecules called glycoproteins. Strains of the flu are identified according to the number of membranes and type of glycoproteins present.

Click the icon to see an image of a virus.

The two major flu strains are referred to as A and B:

Influenza A is the most widespread and can infect animals and humans. Influenza A is the cause of the major pandemics (worldwide epidemics) of influenza that have occurred so far. It is usually further categorized by two subtypes based on two substances that occur on the surface of the viruses: hemagglutinin (H) and neuraminidase (N).
Influenza B infects only humans. It is less common than type A, but is often associated with specific outbreaks, such as in nursing homes.

The vast majority of flu cases are type A. Influenza A usually causes more severe disease than type B. There is some concern, however, that since influenza B has been less common in the past few years, some people, particularly small children, may have fewer antibodies to it and so may be at higher risk for severe infection.

Although the risk of lethal viruses is generally low, scientists are greatly concerned about a particular virus called H5N1, which causes avian influenza. Since 1997, the H5N1 virus has triggered deadly outbreaks in poultry across Southeast Asia. As of Janaury 15, 2008, 350 people had been infected with the bird flu in 12 countries. Of these people, 217 have died, according to the World Health Organization. No cases have been seen in the United States.

So far, the virus has spread from birds to humans. The virus does not seem to be easily spread from person to person. However, scientists and public health officials are monitoring the spread of H5N1 and working to contain it. Efforts include slaughtering infected birds, developing new vaccines, and stockpiling antiviral drugs such as oseltamivir (Tamiflu). Many poor nations have limited resources and already contend with other serious health problems, including HIV-AIDS. If H5N1 does mutate and spread, the consequences could be especially severe for these countries.

In April 2007, the FDA approved a vaccine to protect humans from avian influenza. Currently this vaccine is not being used for routine immunization. However, if the avian flu develops the ability to spread fairly easily from human to human, this vaccine may be made available.

Diagnosis

Differentiating between a cold and flu may be difficult. Cold symptoms are nearly always less severe than those of the flu.


Symptoms	Cold	Flu
Fever	Rare	Common and high (102-104°F); lasts 3 - 4 days
Headache	Rare	Almost always present
General aches and pains	Mild, if they occur at all	Often severe
Fatigue, exhaustion, and weakness	Mild, it they occur at all	Extreme exhaustion is early and severe; can last 2 - 3 weeks
Stuffy nose	Nearly always	Sometimes
Sneezing	Very common	Sometimes
Sore throat	Common	Sometimes
Chest discomfort and cough	Mild-to-moderate, hacking cough	Common, can be severe
Source: National Institute of Allergy and Infectious Disease

Several available tests can isolate and identify the viruses responsible for some respiratory infections. They are generally not needed, since most cases of the flu are self-evident. However, such tests can be very helpful in confirming or ruling out the flu. If a doctor believes a diagnosis would help, samples using a swab should be taken from the nasal passages or throat within 4 days of the first symptoms.

A nasopharyngeal culture is a test used to identify disease-causing organisms in nasal secretions. Nasopharyngeal cultures are useful in identifying Bordetella pertussis and Neisseria meningitidis (types of bacteria). The culture may help determine appropriate antibiotic therapy.

Several rapid tests for the flu can produce results in less than 30 minutes, but vary on the specific strain or strains that they can detect. They are not as accurate as a viral culture, however, in which the virus is reproduced in the laboratory. Culture results can take 3 - 10 days. Blood tests can also document the infection several weeks after symptoms appear.

In February 2006, the U.S. Food and Drug Administration approved a new, faster test for diagnosing H5 strains of avian influenza in people suspected of having the virus. The test is called the Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set. The test gives preliminary results within 4 hours. Older tests required 2 - 3 days. It checks for the presence of the Influenza A H5 strain. If the presence of this strain is confirmed through the rapid test, further testing will be needed to determine the exact subtype of the virus. For example, the current strain of concern is H5, subtype N1, designated as H5N1 for short.

Ruling out Allergic Rhinitis. Symptoms of allergic rhinitis include nasal obstruction and congestion, which are similar to the symptoms of a cold. People with allergies, however, are likely to have the following:

Thin, clear, and runny nasal discharge
An itchy nose, eyes, or throat
Recurrent sneezing

There are two forms of allergic rhinitis:

Symptoms that appear only during allergy season are called allergic rhinitis, commonly known as hay or rose fever. [For more information, see In-Depth Report #77: Allergic rhinitis.]
Allergens in the house, such as house dust mites, molds, and pet dander, can cause year-long allergic rhinitis, referred to as perennial rhinitis.

Click the icon to see an image of common allergens.

Ruling out Sinusitis. The signs and symptoms suggestive of true acute sinusitis include the following:

A return of congestion and discomfort after initial improvement in a cold (called double sickening)
Purulent (pus-filled) nasal secretion
A lack of response to decongestant or antihistamine
Pain in the upper teeth or pain on one side of the head
Pain above or below both eyes when leaning over

Children with sinusitis are less likely to have facial pain and headache and may only develop a high fever or prolonged upper respiratory symptoms (such as a daytime cough that does not improve for 11 - 14 days). When the diagnosis is unclear or complications are suspected, further tests may be required. [For more information, see In-Depth Report #62: Sinusitis.]

Acute Bronchitis. Acute bronchitis is usually caused by a virus and in most cases is self-limiting. The cough it causes typically lasts for about 7 - 10 days, but in about half of patients, coughing can last for up to 3 weeks, and 25% of patients continue to cough for over 1 month.

Atypical Pneumonia. Pneumonia caused by atypical organisms (for example, Mycoplasma pneumonia, chlamydia, Legionella) can cause symptoms similar to the flu. Only laboratory tests can diagnose the difference. [For more information, see In-Depth Report #64: Pneumonia.]

Ruling out More Serious Viral Infections. Respiratory syncytial virus (RSV) and, possibly human parainfluenza viruses (HPV), are proving to be important causes of serious respiratory infections in infants, the elderly, and people with damaged immune systems. (Both also cause mild conditions.) RSV may be a much more common cause of flu-like symptoms than previously thought.

Pertussis. Pertussis (whooping cough) was a very common childhood illness throughout the first half of the century. Although immunizations caused a decline in cases to only 1,700 in the U.S. in 1980, the incidence has risen recently, with almost 30,000 cases reported between 1997 and 2000 (17 infants died of the disease in 2000). Many more cases are reported worldwide.

Nearly half of pertussis cases now occur in people 10 years of age or older, perhaps due to waning immunity in adolescents and adults. Such cases may be greatly underreported. Up to 25% of adults who see a doctor for persistent cough may actually have pertussis. It may go undiagnosed, however, because symptoms are usually mild, and adults are unlikely to have the classic "whooping" cough. This is of some concern because such adults may unknowingly infect unvaccinated children. The younger the patient, the higher the risk for severe complications, including pneumonia, seizures, and even death. Children younger than 6 months are at particular risk because protection is incomplete, even with vaccination.

In addition to common cold viruses, other, less frequent causes of sore throat include the following:

Strep throat
Foodborne and waterborne infections (Streptococcus C and G)
An uncommon organism called Arcanobacterium haemolyticum (infection with this bacterium can mimic strep throat and may even cause a rash)
Infectious mononucleosis ("mono")
Herpesvirus 1

Group A Streptococcal bacteria is the most common bacterial cause of the severe sore throat known commonly as "strep throat." It occurs mostly in school age children, but people of all ages are susceptible. (Strep throat constitutes about 12% of all sore throat cases seen by doctors.)

The symptoms of strep throat include the following:

A sudden onset of severe sore throat
Difficulty in swallowing
Fever
Headache
Stomach pain
Vomiting

Only about half of patients with strep throat have such clear-cut symptoms. Furthermore, half of people who have these symptoms do not actually have strep throat.

How Is Strep Throat Diagnosed? Most cold-related sore throats are caused by viruses and require no treatment. They usually do not last more than a day. When the sore throat persists and is very painful the doctor will want to rule out or confirm the presence of the strep bacteria.

The doctor will look for redness and pus-filled patches on the tonsils and back of the throat. Enlarged tonsils are less likely to indicate a strep throat.
The doctor will feel the sides of the neck for swollen lymph nodes. If the lymph nodes are not swollen, it is less likely to be a strep throat.
A cotton swab is used to take a sample of pus in the throat for a throat culture.

A throat culture is the most effective and least expensive test for confirming the presence of strep throat. It takes 24 - 48 hours to obtain a result.

Rapid Antigen-Detection Test for Strep Throat. A faster test, called the rapid strep antigen test, uses chemicals to detect the presence of bacteria in a few minutes. A positive result nearly always means that streptococcal bacteria is the cause of the infection. The test, however, fails to detect 10 - 20% of cases, so a culture may still be necessary to catch any missed infections, particularly in children.

How Serious is Strep Throat? The use of antibiotics has removed the threat of most complications from streptococcus infection in the throat (strep throat). However, untreated strep throat could lead to the following complications:

Abscess in the tonsils
Scarlet fever
Rheumatic fever (rare in the U.S.)

How Is Strep Throat Treated? Strep throat infections require antibiotics. Antibiotics prevent a serious complication called rheumatic fever, which can result in permanent damage to the heart. Fortunately, this complication occurs rarely in United States anymore. If started on time, antibiotic treatment of strep throat will almost always prevent this complication. In addition, antibiotics shorten the recovery time from strep throat.

The following antibiotics are generally used to treat strep throat:

Penicillin is usually the antibiotic of choice unless the patient is allergic. A full 10 days may be necessary. Amoxicillin, a form of penicillin, is proving to be effective when taken in a single daily dose for 10 days.
Macrolide antibiotics. Erythromycin is known as a macrolide antibiotic and is the first choice for patients with penicillin allergies. A 10-day regimen is needed. Another macrolide, azithromycin, can be given as a single daily dose and may be effective in 5 days. It is expensive, however, and bacterial resistance to macrolides is growing, so it should not be given as a first choice.
Cephalosporins are very effective in eradicating the bacteria.

Antibiotics are very commonly inappropriately prescribed for non-strep sore throats. One study reported that an estimated 6.7 million American adults visited their doctors because of sore throat between 1989 and 1999, with 73% of them receiving antibiotics. Studies indicate, however, that fewer than half of adults and far fewer children with even strong signs and symptoms for strep throat actually have strep infections.

Parents should be comforted that a delay in antibiotic treatment while waiting for lab results does not increase the risk that the child will develop serious long-term complications, including acute rheumatic fever. If a patient is severely ill, however, it is reasonable to begin administering antibiotics before the results are back. If the culture is negative (there is no evidence of bacteria), the doctor should call the family to make certain the patient stops taking the antibiotics and any remaining pills are discarded.

Children who have a sore throat and who have had rheumatic fever in the past should receive antibiotics immediately, even before culture results are back. Children with a sore throat who have a family member with strep throat or rheumatic fever should also receive immediate antibiotic treatment.

Complications

Colds rarely cause serious complications. In about 1% of cases, a cold can lead to other complications, such as sinus or ear infections. It can also aggravate asthma and, in uncommon situations, increase the risk for lower respiratory tract infections.

Ear Infections. The rhinovirus infection, a major cause of colds, also commonly predisposes children to ear infections, possibly by obstructing the Eustachian tube, which leads to the middle ear. Viruses may even attack the ear directly.

Sinusitis. Between 0.5 - 5% of people with colds develop sinusitis, an infection in the sinus cavities (air-filled spaces in the skull). Sinusitis is usually mild, but if it becomes severe, antibiotics generally eliminate further problems. In rare cases, however, sinusitis can be serious.

Lower Respiratory Tract Infections. The common cold poses a risk for bronchitis and pneumonia in nursing home patients, and in other people who may be vulnerable to infection. Some experts believe that the rhinovirus may play a more significant role than the flu in causing lower respiratory infections in the vulnerable population.

Aggravation of Asthma. Rhinovirus infections can aggravate asthma in both children and adults. In fact, rhinovirus has been reported to be the most common infectious organism associated with asthma attacks. Colds may promote allergic inflammation of the airways, and increase the intensity their responsiveness for weeks.

The flu is usually self-limited and not serious. However, each year in the United States, more than 200,000 people are hospitalized due to complications of the flu. An estimated 36,000 people die each year of influenza-related complications. People at highest risk for serious complications are those over 65 years old and those with chronic medical conditions. Influenza A is the most severe strain. Influenza B tends to be milder.

Pneumonia. Pneumonia is the major serious complication of influenza and can be very serious. It can develop about 5 days after viral influenza. More than 90% of the deaths caused by influenza and pneumonia occur among older adults. Flu-related pneumonia nearly always occurs in high-risk individuals, such as the following:

People with weakened immune systems, such as AIDS patients
Elderly patients, particularly patients in nursing home
Very young children -- [it may be difficult to tell whether pneumonia is related to influenza or caused by respiratory syncytial virus (RSV)]
Hospitalized patients and anyone with serious medical conditions, such as diabetes, heart, circulation, or lung disorders, particularly chronic lung disease
Drug abusers who use needles

Combinations of these factors further increase the risk. It should be noted that pneumonia is an uncommon outcome of influenza in healthy adults.

Complications in the Central Nervous System in Children. Influenza increases the risk for complications in the central nervous system of small children. Febrile seizures are the most common neurologic complication in children The risks decline after a child turns 1 year old, but are still high in children aged 3 - 5 years old.

Risk Factors

The very young and the very old are at higher risk for upper respiratory tract infections and their associated complications.

Children. Young children are prone to colds and may have 8 to 12 of them every year. Millions of cases of influenza develop in American children and adolescents each year.

Before the immune system matures, all infants are susceptible to uppper respiratory infections, with a possible frequency of one cold every 1 - 2 months. Smaller nasal and sinus passages also make younger children more vulnerable to colds than older children and adults. Upper respiratory infections gradually diminish as children grow, until at school age their rate of such infections is about the same as an adult's. There is almost never cause for concern when a child has frequent colds, unless the colds become unusually severe or more frequent than usual.

The Elderly. The elderly have diminished cough and gag reflexes, and their immune systems are often weaker. They are therefore at greater risk for serious respiratory infections than the young and middle-aged adults.

The risk of respiratory infections is increased by exposure to cigarette smoke, which can injure airways and damage the cilia (tiny hair-like structures that help keep the airways clear). Toxic fumes, industrial smoke, and other air pollutants are also risk factors. Parental smoking increases the risk of respiratory infections in their children.

People with AIDS and other medical conditions that damage the immune system are extremely susceptible to serious infections.

Cancers, especially leukemia and Hodgkin's disease, put patients at risk. Patients who are on corticosteroid (steroid) treatments, chemotherapy, or other medications that suppress the immune system are also prone to infection.

People with diabetes are at a higher risk for the flu.

Certain genetic disorders predispose people to respiratory infections. They include sickle-cell disease, cystic fibrosis, and Kartagener syndrome (which results in malfunctioning cilia).

Much evidence suggests that stress increases one's susceptibility to a cold. In one study, people with high stress levels averaged 2.7 upper respiratory infections during a 6-month period and those reporting low stress averaged 1.5 infections. Another study found the duration of colds in children with chronic, year-round colds decreased with help of a stress management program. Stress appears to increase the risk for a cold regardless of lifestyle or other health habits. And once a person catches a cold or flu, stress can make symptoms worse.

It is not clear why these events occur. Some experts believe that stress alters specific immune factors, which cause inflammation in the airways. One study reported that the only people who got sick after experiencing short stress were those whose body responded to stress with high levels of cortisol, a stress hormone, coupled with a low immune response.

In people who already have colds, exercise has no effect on the illness' severity or duration of the infection. High-intensity or endurance exercises, however, appear to suppress the immune system while they are being performed. Some highly trained athletes, for instance, report being susceptible to colds after strenuous events. People should avoid strenuous physical activity when they have high fevers or widespread viral illnesses. Note: Very low fat diets appear to worsen this dampening effect on the immune system. A higher fat-diet may help correct this imbalance (omega-3 fatty acids, found in fish and canola oil, are preferred). Whether carbohydrate loading provides much additional value is not clear.

Colds and flus occur predominantly in the winter. Flu season typically starts in October and lasts into mid March.

The reasons for this seasonal bias are not due to the cold itself, but to other factors. Certainly, flus and colds are more likely to be transmitted in winter because people spend more time indoors and are exposed to higher concentrations of airborne viruses. Dry winter weather also dries up nasal passages, making them more susceptible to viruses. Some experts theorize that the high rates of viral infections in winter may be due to certain immune factors, which react to light and dark and affect a person's susceptibility to viruses.

Traveling in close contact with people, whether on trains, planes, or buses, can increase the risk for respiratory infections.

Children who attend day care may have an increased risk of colds. However, one study suggested that although children in day care centers incur higher rates of the common cold in the preschool years, they have lower cold rates in their first years of regular school. The colds they catch in day care, then, may bestow some immunity to future colds for a few years. By age 13, such protection has worn off. There is also some evidence that frequent colds in young children may help protect against future allergies and asthma.

Prevention

Because colds and flus are easily spread, everyone should always wash their hands before eating and after going outside. Ordinary soap is sufficient. Waterless hand cleaners that contain an alcohol-based gel are also effective for every day use and may even kill cold viruses. (They are less effective, however, if extreme hygiene is required. In such cases, alcohol-based rinses are needed.)

Antibacterial soaps add little protection, particularly against viruses. In fact, one study suggests that common liquid dish washing soaps are up to 100 times more effective than antibacterial soaps in killing respiratory syncytial virus (RSV), which is known to cause pneumonia. Wiping surfaces with a solution that contains one part bleach to 10 parts water is very effective in killing viruses.

Colds are not caused by insufficiently warm clothes or by going outside with wet hair.

Foods Containing Lactobacilli (Good Bacteria). Researchers are also studying the possible protective value of certain strains of lactobacilli bacteria found in the intestines. Some of these strains, particularly acidophilus, are used to make yogurt. According to one Finnish study, children attending day care who ate milk containing the strain lactobacilli GG 10 - 20% fewer respiratory infections. (The strain used was not the kind found in most commercial yogurt products.)

Vitamins. Studies are mixed whether vitamin supplements protect against upper respiratory infections. Large doses of vitamin C, for example, may help reduce the duration of a cold, but they do not appear to protect against one in the first place, even after exposure to a cold virus. Two studies on multivitamins reported opposite results, with one finding fewer infections and one finding no difference. It is possible that vitamin C or multivitamin supplements may be helpful in specific people, such those who are vitamin deficient or have medical problems that impair their immune systems.

Treatment

The following are some food and fluid recommendations. Most will not cure a cold, but they may help a person deal better with the symptoms:

Drinking plenty of fluids and getting lots of rest when needed is still the best bit of advice to ease the discomforts of the common cold. Water is the best fluid and helps lubricate the mucous membranes. (There is no evidence that drinking milk will increase or worsen mucus, although milk is a food and should not serve as fluid replacement.)
Chicken soup does indeed help congestion and body aches. The hot steam from the soup may be its chief advantage, although laboratory studies have actually reported that ingredients in the soup may have anti-inflammatory effects. In fact, any hot beverage may have similar soothing effects from steam. Ginger tea, fruit juice, and hot tea with honey and lemon may all be helpful.
Spicy foods that contain hot peppers or horseradish may help clear sinuses.
Foods rich in vitamins A and C are always recommended and may be helpful during a respiratory infection. They include oranges, kiwi, and tomatoes for vitamin C, and sweet potatoes, spinach, and broccoli for vitamin A.

Different studies have found that large doses of vitamin C may reduce the duration of a cold. Some precautions against taking high doses of vitamin C include the following:

High doses of vitamin C may cause headaches, intestinal and urinary problems, and even kidney stones.
Because vitamin C increases iron absorption, people with certain blood disorders, such as hemochromatosis, thalassemia, or sideroblastic anemia, should avoid high doses of this vitamin.
Large doses of vitamin C can also interfere with anticoagulant medications ("blood thinners"), blood tests used in diabetes, and stool tests.
Vitamin E or multivitamin supplements do not appear to be helpful in reducing symptoms of the cold.

Zinc appears to have certain important effects on the immune system and it may have a direct effect on viruses. How it works is not entirely clear, however. Zinc preparations in lozenge or nasal gel form are now available as cold treatments. Studies are very mixed on the effects of zinc on colds. The variance may be due to different zinc preparations. A review of available studies comparing zinc treatment to placebo ("sugar pill") found only one high-quality study, which showed that zinc nasal gels might provide a benefit. The overall benefit of zinc in the prevention of colds remains unproven. In any case, no one with an adequate diet and a healthy immune system should take zinc for prolonged periods, for the purpose of preventing colds.

Side Effects. Side effects, particularly of the lozenges form, include the following:

Dry mouth
Constipation
Nausea
Bad taste (possibly only with zinc gluconate lozenges)
Severe vomiting, dehydration, and restlessness (signs of overdose, seek medical help)
Allergic response (rare)

Food and Drug Interactions. Zinc may also interact with drugs or other elements:

It may reduce absorption of certain antibiotics.
Foods high in calcium or phosphorus may reduce zinc absorption.
In high doses and for long periods of time, zinc can cause copper deficiencies.

Many people take medications to reduce mild pain and fever. Adults most often choose aspirin, ibuprofen (Advil), or acetaminophen (Tylenol).

The following are recommendations for children:

Acetaminophen (Tylenol) or ibuprofen (usually Advil or Motrin) are the typical pain-relievers parents give their children. Most pediatricians advise such medications for children who run fevers over 101°F. Some suggest alternating the two agents, although there is no evidence that this regimen offers any benefits, and it might be harmful.
Aspirin and aspirin-containing products are virtually never recommended for children or adolescents. Reye syndrome, a very serious condition, has been associated with aspirin use in children who have flu symptoms or chicken pox.

Nasal strips (such as Breathe Right) are placed across the lower part of the nose and pull the nostrils open. These strips may open the nasal passages and ease congestion due to a cold, sinusitis, or hay fever. As of yet, there is no scientific evidence that they offer such benefits.

A nasal wash can be helpful for removing mucus from the nose. A saline solution can be purchased at a drug store or made at home. One study reported that neither a homemade solution (using one teaspoon of salt and one pinch of baking soda in a pint of warm water) nor a commercial hypertonic saline nasal wash had any effect on symptoms. Further, one preliminary study found that over-the-counter saline nasal sprays that contain benzalkonium chloride as a preservative may actually worsen symptoms and infection.

Some physicians, however, advocate a traditional nasal wash that has been used for centuries and is different from that used in most studies. It contains no baking soda and uses more fluid for each dose and less salt. The nasal wash should be performed several times a day.

A simple method for administering a nasal wash:

Lean over the sink head down.
Pour some solution into the palm of the hand and inhale it through the nose, one nostril at a time.
Spit the remaining solution out.
Gently blow the nose.

The solution may also be inserted into the nose using a large rubber ear syringe, available at a pharmacy. In this case, the process is the following:

Lean over the sink head down.
Insert only the tip of the syringe into one nostril.
Gently squeeze the bulb several times to wash the nasal passage.
Then press the bulb firmly enough so that the solution passes into the mouth.
The process should be repeated in the other nostril.

Nasal-delivery decongestants are applied directly into the nasal passages with a spray, gel, drops, or vapors. Nasal forms work faster than oral decongestants and have fewer side effects. They often require frequent administration, although long-acting forms are now available. Ingredients and brands of nasal decongestants include the following:

Long Acting Nasal-Delivery Decongestants. They are effective in a few minutes and remain so for 6 - 12 hours. The primary ingredient in long-acting decongestant is:

Oxymetazoline: Brands include Vicks Sinex (12-hour brands), Afrin (12-hour brands), Dristan 12-Hour, Good Sense, Nostrilla, Neo-Synephrine 12-Hour
Xylometazoline: Inspire, Otrivin, Natru-vent

Short-Acting Nasal-Delivery Decongestants. The effects usually last about 4 hours. The primary ingredients in short-acing decongestants are:

Phenylephrine: Neo-Synephrine (mild, regular, high-potency), 4-Way, Dristan Mist Spray, Vicks Sinex
Naphazoline (Naphcon Forte, Privine)

Dependency and Rebound. The major hazard with nasal-delivery decongestants, particularly long-acting forms, is a cycle of dependency and rebound effects. The 12-hour brands pose a particular risk for this effect. This effect works in the following way:

With prolonged use (more than 3 - 5 days), nasal decongestants lose effectiveness and even cause swelling in the nasal passages.
The patient then increases the frequency of their dose. The congestion worsens, and the patient responds with even more frequent doses, in some cases as often as every hour.
Individuals then become dependent on them.

Tips for Use. The following precautions are important for people taking nasal decongestants:

When using a nasal spray, spray each nostril once. Wait a minute to allow absorption into the mucosal tissues, and then spray again.
Keep the nasal passages moist. All forms of nasal decongestants can cause irritation and stinging. They also may dry out the affected areas and damage tissues.
Do not share droppers and inhalators with other people.
Use decongestants only for conditions requiring short-term use, such as before air travel or for a single-allergy attack. Do not take them more than 3 days in a row. With prolonged use, nasal decongestants become ineffective and result in the so-called rebound effect and dependence.
Discard sprayers, inhalators, or other decongestant delivery devices when the medication is no longer needed. Over time, these devices can become reservoirs for bacteria.
Discard the medicine if it becomes cloudy or unclear.

Oral decongestants also come in many brands, which mainly differ in their ingredients. The most common active ingredient is pseudoephedrine (Sudafed, Actifed, Drixoral).

Side Effects of Decongestants. Decongestants have certain adverse effects, which are more apt to occur in oral than nasal decongestants and include the following:

Agitation and nervousness
Drowsiness (particularly with oral decongestants and in combination with alcohol)
Changes in heart rate and blood pressure

Avoid combinations of oral decongestants with alcohol or certain drugs, including monoamine oxidase inhibitors (MAOI) and sedatives

Individuals at Risk for Complications from Decongestants. People who may be at higher risk for complications are those with certain medical conditions, including disorders that make blood vessels highly susceptible to contraction. Such conditions include the following:

Heart disease
High blood pressure
Thyroid disease
Diabetes
Prostate problems that cause urinary difficulties
Migraines
Raynaud's phenomenon
High sensitivity to cold
Emphysema or chronic bronchitis

Anyone with the above conditions should not use either oral or nasal decongestants without a doctor's guidance. In addition, people taking medications that increase serotonin levels, such as certain antidepressants, anti-migraine agents, diet pills, St. John's wort, and methamphetamine, should avoid decongestants. The combinations can cause blood vessels in the brain to narrow suddenly, causing severe headaches and even stroke.

Others who should use these drugs with caution are the following (consult your health care provider):

Anyone who is pregnant.
Children: Children appear to metabolize decongestants differently than adults. Decongestants should not be used at all in infants and small children under the age of 2, according to a new recommendation from an advisory panel of the Food and Drug Administration. These children are at particular risk for side effects that depress the central nervous system. Such symptoms cause changes in blood pressure, drowsiness, deep sleep, and, rarely, coma. Studies have also shown that these cough and cold products generally are not effective in the treatment of children under 6 years of age.

In October 2007, drug manufacturers voluntarily withdrew from the market all oral cough and cold products, including decongestants, aimed at children under 2, due to potential harm from misuse.

Major studies have indicated that over-the-counter cough medicines are not very effective, but they are also not harmful.

For thick phlegm, patients may try cough medications that contain guaifenesin (Robitussin, Scot-Tussin Expectorant), which loosens mucus. Patients should not suppress coughs that produce mucus and phlegm. It is important to expel this substance. To loosen phlegm, patients should drink plenty of fluids and use a humidifier or steamer.
For patients with a dry cough, a suppressant may be useful, such as one that contains dextromethorphan (Drixoral Cough, Robitussin Maximum Strength Cough Suppressant).

Medications that contain both a cough suppressant and an expectorant are not useful and should be avoided. Medicated cough drops that contain dextromethorphan are not very useful. A patient is just as likely to find relief from hard candy or lozenges.

Prescription cough medications with small doses of narcotics are available. They are usually reserved for lower respiratory infections with significant coughs.

Sore throats that are associated with colds are generally mild. The following may be helpful:

Cough drops, throat sprays, or gargling warm salt water may help relieve sore throat and reduce coughing.
Throat sprays that contain phenol (for example, Vicks Chloraseptic) may be particularly helpful. Phenol has antibacterial properties. In one study, patients with sore throat who used the spray experienced faster resolution of the cold itself, including fever, headache, and other symptoms compared to a placebo. The patients were not taking antibiotics.
Cough drops that contain menthol and mild anesthetics, such as benzocaine, hexylrescorincol, phenol, and dyclonine (the most potent), may soothe a mild sore throat.
People with sore throats from postnasal drip might try taking a teaspoon of liquid antacid. They shouldn't drink anything afterward, since the intention is to coat the throat and help neutralize the acid in the mucus that might be causing pain.

If soreness in the throat is very severe and does not respond to mild treatments, the patient or parent should check with the physician to see if a strep throat is present, which would require antibiotics. [See What is Strep Throat? in the Diagnosis section.]

Dozens of remedies are available that combine ingredients aimed at more than one cold or flu symptom. In general, they do no harm, but they have the following problems:

Some ingredients may produce side effects without even helping a cold.
In some cases, the ingredients conflict (such as a cough expectorant and a cough suppressant).
In other cases, a patient may wish to increase the dosage to improve one symptom, which serves to increase other ingredients that do no good and, in higher doses, may cause side effects.

Note on Antihistamines. Many combination remedies contain antihistamines. Antihistamines are used for allergies and are not generally recommended to relieve the symptoms of the common cold. Some evidence suggests, however, that they may have some value.

First-generation antihistamines may reduce cold symptoms. Their benefits for the cold are likely to be due to the drowsiness they cause. Such antihistamines include Benadryl, Tavist, and Chlor-Trimeton. The newer, second-generation antihistamines (Claritin, Allegra, Zyrtec) do not have these effects and also appear to have no benefits against colds.

Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been numerous reported cases of serious and even deadly side effects from herbal products.

The following are special concerns for people taking natural remedies for colds or influenza:

Echinacea is commonly taken to prevent onset and ease symptoms of cold or flu. A rigorous study, published in 2005 in the New England Journal of Medicine, determined that this herb does not help to prevent or treat colds. In addition, some people are allergic to echinacea. People who have autoimmune diseases or plant allergies should avoid it. There have been a few reports of people experiencing a skin reaction called erythema nodosum, which is characterized by tender, red nodules under the skin.
Chinese herbal cold and allergy products can contain trace amounts of aristolochic acid, a chemical that causes kidney damage and cancer. Many herbal remedies imported from Asia may contain potent pharmaceuticals, such as phenacetin and steroids, as well as toxic metals.

Medications

Vaccines are available to prevent influenza (See section on Viral Influenza Vaccines).

For mild influenza, symptom relief is similar to that for colds.

Two classes of antiviral agents have been developed to treat influenza: neuraminidase inhibitors and M2 inhibitors.

Brands and Benefits. Zanamivir (Relenza) and oseltamivir (Tamiflu) are neuraminidase inhibitors. They are newer agents that have been designed to block a key viral enzyme, neuraminidase, which is involved with viral replication. According to a major review of over 50 studies published in 2006, these drugs are effective against the flu in about 60% of cases.

Important points about the use of these drugs:

Neuraminidase inhibitors are effective for treating both A and B strains of influenza. (M2 inhibitors are effective only against type A.) However, their main benefit has been to reduce the length of symptoms by about one day, and only when started within 48 hours after symptoms become evident.
They may help reduce transmission of the virus.
They have a lower risk than M2 inhibitors for emerging viral strains that are resistant to their effects. However, The World Health Organization reports that viral resistance to oseltamivir (Tamiflu) can develop with extensive use. The level of resistance averaged 0.3% over 3 flu seasons surveyed in Japan (2003 - 2006). During that time, 35 million Japanese patients used the drug.
They have fewer serious side effects than the M2 inhibitors.
Both show some benefits for preventing influenza. Only oseltamivir has been approved for this purpose, however, and only in people over 13.
They may reduce complications of influenza, although this needs to be confirmed. It is not yet known if they have any effect on overall survival rates.
Oseltamivir is the only drug studied in avian flu cases. Although it is active in lab experiments, it has not been successful clinically. Experience is very limited, however, and it is not clear whether people infected with avian flu received the drug in time for it to be useful.

Limitations and Side Effects. Although they have many advantages compared to the M2 inhibitors, neuraminidase inhibitors are much more expensive. They also need to be taken within 2 days of the start of symptoms to be effective. Neither neuraminidase inhibitor is effective against influenza-like illness (one that is not caused by an influenza virus). There are also some differences between the two drugs that could be significant for some individuals:

Zanamivir is administered as a nasal spray or inhaler. People with asthma or other lung disorders may experience airway spasms and should use this drug with caution. Side effects are generally minor in most patients. It is important to make sure that elderly patients are able to properly use the zanamivir inhaler device.
Oseltamivir comes in capsule and liquid form. Side effects are also minor, but about 10 - 15% of patients experience nausea and vomiting. Patients with kidney dysfunction should take lower doses.

The current use of neuraminidase inhibitors in different age and patient groups is as follows:

Adults: Both drugs are approved for treatment in adult patients.
Children: Oseltamivir is approved for use in children age one and older. Studies report significant reduction in symptoms and in the incidence of ear infections in this population. However, studies from Japan point to the possibility of psychiatric side effects in children under 16 using oseltamivir. Zanamivir is approved for children over age 7, and studies are currently underway to determine its safety in younger children.
High-Risk Patients. Recent studies indicate neuraminidase inhibitors are safe and effective in patients with serious medical problems or other conditions that put them at risk for complications of flu.

Brands and Benefits. Amantadine (Symmetrel) and rimantadine (Flumadine) are M2 inhibitors. The following benefits may apply to the minority of strains of influenza A that remain sensitive to the drugs:

Both offer protection against influenza A and prevent severe illness if a person contracts the infection. (To be effective it must be administered within 2 days of onset.)
They may shorten the duration and lessen the severity of the flu if given within 48 hours of onset of symptoms.

Limitations. Drawbacks of M2 inhibitors include:

Viral resistance to these agents is rapidly emerging. For this reason, the Centers for Disease Control and Prevention Does not recommends M2 inhibitors for use during the 2007 - 2008 flu season in the United States.
M2 inhibitors are not effective against influenza B.
Neither drug has proven to reduce the risk for complications of the flu, including pneumonia and bronchitis.

Side Effects. Both M2 inhibitors occasionally cause nausea, vomiting, indigestion, insomnia, and hallucinations. Amantadine affects the nervous system and about 10% of people experience nervousness, depression, anxiety, difficulty concentrating, and lightheadedness. Rimantadine is less likely to do so. Rarely, amantadine can cause seizures, usually in elderly people already at risk for psychiatric symptoms.

Note: Amantadine is a standard treatment for Parkinson's disease and should be continued for that condition.

Flu Shots. These vaccines use inactivated (not live) viruses. They are designed to provoke the immune system to attack antigens contained on the surface of the virus. (Antigens are foreign molecules that the immune system specifically recognizes as alien and targets for attack.)

Unfortunately, the antigens in these influenza viruses undergo genetic changes (called antigenic drift) over time, so they are likely to become resistant to a vaccine that worked in the previous year. Vaccines are then redesigned annually to match the current strain.

Influenza A. The influenza A virus is further categorized by primary molecular antigens (hemagglutinin and neuraminidase), which serve as the targets for the vaccines. Influenza A is a particular problem, because it can infect other species, such as pigs or chicken, and undergo major genetic changes.
Influenza B viruses tend to be more stable than influenza A viruses, but they too vary. Although influenza B has been far less common than A, a vaccine for type B is important because experts are concerned that small children will not have developed any immunity to the virus, and will experience severe flu if they are exposed to type B viruses.

Intranasal (inside the nose) vaccine. A live but weakened intranasal vaccine (FluMist) is proving to be effective and safe in healthy, non-pregnant people aged 2 - 49 years and has been approved by the FDA. It is known as a live, attenuated, intranasal influenza vaccine (LAIV). The vaccine is engineered to grow only in the cooler temperatures of the nasal passages, not in the warmer lungs and lower airways. It boosts the specific immune factors in the mucous membranes of the nose that fight off the actual viral infections. FluMist is given using a nasal spray.

Timing and Effectiveness of the Vaccine. Ideally, people should be vaccinated every October or November. However, it may take longer for a full supply of the vaccine to reach certain locations. In such cases, the high-risk groups should be served first.

Antibodies to the influenza virus usually develop within 2 weeks of vaccination, and immunity peaks within 4 - 6 weeks, then gradually wanes.

Because children under age 8 do not develop strong immune responses to one dose, the CDC recommends two vaccinations given 1 month apart on the first year they receive the vaccine. If children under 8 received only 1 dose of the vaccine on their first immunization year, they should receive 2 doses the following year. Children under 8 who have received single doses for 3 or more years should continue to receive single doses.
It should be noted that if an individual develops influenza symptoms and is accurately diagnosed in time, vaccination of the other members of the household within 36 - 48 hours affords effective protection to those individuals.

In healthy adults, immunization typically reduces the chance of illness by about 70 - 90%. The current flu vaccines may be slightly less effective in certain patients, such as the elderly and those with certain chronic diseases. Even in people with a weaker response, however, the vaccine is usually protective against serious flu complications, particularly pneumonia. In fact, among the elderly, interesting studies are now suggesting that influenza vaccination may help protect against stroke, adverse heart events, and death from all causes.

Children Who Should Be Vaccinated. The following children over 6 months should be vaccinated against influenza:

The American Academy of Pediatrics (AAP) and the CDC recommend influenza vaccination in all healthy children between 6 and 59 months old.
In addition, any child over the age of 2 years with a condition that requires regular medical care or who has been hospitalized for a serious illness (particularly lung or kidney disease, diabetes, sickle-cell, or immune deficiencies). If parents are concerned about vaccines that contain the mercury preservative thimerosal, they can ask their doctor about reduced-thimerosal flu vaccine.
Children who come in direct contact with a person vulnerable to complications from influenza should also be vaccinated.
Children who are receiving long-term aspirin therapy should also be immunized against the flu because they are at higher risk for Reye syndrome, a life-threatening disease, if they get the flu.
Some experts now advocate flu shots for all school-age children. Emerging research indicates that children are responsible for transmitting the vast majority of cases of seasonal flu, and that routine vaccination of school-age children would considerably reduce transmission rates throughout communities.

Older Children and Adults Who Should Be Vaccinated. The following, in order of priority, are the population groups who should be vaccinated each year. The first two groups have the highest need for influenza vaccinations and are given top priority:

All adults 50 years and older. Vaccinated older adults have lower hospitalization rates than unvaccinated peers. Evidence now suggests that vaccination may help protect against adverse heart events (including those after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two thirds of the people in this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.
People of any age at high risk for serious complications from influenza. Such people include those with heart disease, lung problems, immune deficiencies, diabetes, kidney disease, or chronic blood disease. Those with any condition that may compromise respiratory function or the handling of respiratory secretions, including people with cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders, are included in this group. (There have been concerns about the safety of the vaccinations in certain high-risk patients such as those with HIV or asthma. Studies now suggest that the vaccine is generally safe in these patient groups. Furthermore, their risk for serious complications from influenza outweighs any potential adverse effects from the vaccines.)
All health care workers should be vaccinated, according to the ACIP's recommendations.
Household members in contact with individuals who are at high-risk for complications from influenza should be vaccinated.

Other adults who should consider influenza vaccinations include:

People at risk for complications for influenza and who are traveling to the tropics at any time or to the Southern Hemisphere between April and September.
Pregnant women who are at risk for complications of influenza, and who will be in their second or third trimester during flu season. (Vaccinations should usually be given after the first trimester. Exceptions may be women who are in their first trimester during flu season and their risk from complications of the flu is higher than any theoretical risk to the baby from the vaccine.)
Police officers, firefighters, and other public safety officials.

Negative Effects. Possible negative responses to the vaccines include:

Allergic Reaction. Newer vaccines contain very little egg protein, but an allergic reaction still may occur in people with strong allergies to eggs.
Soreness at the Injection Site. Up to two thirds of people who receive the influenza vaccine develop redness or soreness at the injection site for 1 - 2 days afterward.
Flu-like Symptoms. Some people actually experience flu-like symptoms, called oculo-respiratory syndrome, which include cough, wheezing, tightness in the chest, sore throat, or a combination. Such symptoms tend to occur 2 - 24 hours after the vaccination and generally last up to 2 days. These symptoms are not influenza itself but an immune response to the virus proteins in the vaccine. (Anyone with a fever at the time the vaccination is scheduled, however, should wait to be immunized until the ailment has subsided.)
Guillain-Barre Syndrome. Although iIsolated cases of a paralytic illness known as Guillain-Barre syndrome occurred in about one of every 100,000 people vaccinated with the swine-flu vaccine in 1976, it has not been a problem with subsequent vaccines.
There has been some question concerning influenza vaccinations because of some reports that vaccines may worsen asthma. Recent and major studies have been reporting, however, that the vaccination is safe for children with asthma. It is also very important for these patients to reduce their risk for respiratory diseases.

The FDA approved the first vaccine for humans against H5NI influenza virus in April 2007. The vaccine, which is made from a human strain of the virus, could be used in people ages 18 - 64 to prevent the spread of the virus from human to human. The vaccine requires two shots, given about a month apart. It will not be sold commercially, but instead is being purchased by the U.S. government to be stockpiled and distributed to public health officials in the event of an outbreak of avian flu.

In a study, 103 healthy adults received two g shots of the virus, 28 days apart. An additional group of 300 adults received the vaccine at a lower dose, while 48 people received placebo injections. The study showed that 45% of those who received the higher dose developed antibodies that may reduce their risk of getting the avian flu. The most common side effects reported were pain at the injection site, headache, and muscle pain. Research on the vaccine is continuing.

The intense and widespread use of antibiotics is leading to a serious global problem of antibiotic resistance. The inappropriate use of powerful newer antibiotics for conditions such as colds or sore throats poses a particular risk for resistant strains of bacteria. For example, the number of cases of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in people who have no known risk factors. (MRSA causes sometimes-fatal skin infections.) In 2006, rates of Neisseria gonorrhoeae resistance to the fluoroquinolone antibiotics family exceeded 10%. The CDC no longer recommends treating gonorrhea infections with fluoroquinolone first.

When Antibiotics Are Needed for Upper Respiratory Infections.

Antibiotics do not affect viruses and, in healthy individuals, these drugs are almost never necessary or helpful for influenza or colds, even with persistent cough and thick, green mucus. In one disturbing study, antibiotics were prescribed for nearly half of children who went to the doctor for a common cold.

Antibiotics may be required for upper respiratory tract infections only under certain situations, such as the following:

Patients, particularly small children or elderly people, who have medical conditions that put them at high risk for complications from any respiratory tract infections, should usually be given antibiotics.
Patients with severe sinusitis that does not clear up within 7 days (some experts say 10 days) and whose symptoms include one or more of the following: green and thick nasal discharge, facial pain, or tooth pain or tenderness.
Some children with middle ear infections, although experts differ on who will benefit. Some experts recommend that only children under the age of 2 years should be treated with antibiotics, and children over 2 should be treated on a case-by-case basis.
Patients with strep throat or severe sore throat that involves fever, swollen lymph nodes, and absence of cough. (Strep throat makes up only 10 - 15% of all sore throat cases.)
Patients who have an acute cough that is caused by pneumonia (but in few other cases, regardless of the duration of the cough). Experts estimate that, outside the hospital setting, less than 20% of prescriptions for persistent coughing are necessary.

Patients at Highest Risk for Infection with Resistant Bacteria Strains. Some patients are at greater risk for developing an infection resistant to common antibiotics. At this time, the average person is not endangered by this problem. Risk factors include:

Very old or very young age
Exposure to patients with drug-resistant infection
Hospitalization in intensive care
History of an invasive surgical procedure
Staying in the hospital
Prolonged course of antibiotics, particularly within the past 4 - 6 weeks
Serious wounds
Tubes down the throat, catheters, or intravenous (I.V.) lines
Immunosuppression

Children at higher risk for antibiotic resistance are those who attend day care, who are exposed to cigarette smoke, who were bottle-fed, and who had siblings with recurrent ear infections.

What the Health Care Community Is Doing. Prescribing antibiotics only when necessary is the most important step in restoring bacterial strains that are susceptible to antibiotics. Encouraging studies are reporting that inappropriate antibiotic prescriptions are on the decline. Prescriptions for other common respiratory infections, such as otitis media, sore throat, acute bronchitis, and colds and flus have been decreasing.

What Patients and Parents Can Do. Patients and parents can also help with the following tips:

Use home or over-the-counter remedies to relieve symptoms of mild upper respiratory tract infections.
Realize that antibiotics will not shorten the course of a viral infection. It is important for patients and parents to understand that although antibiotics may bring a sense of security, they provide no significant benefit for a person with viral infection, and overuse can contribute to the growing problem of resistant bacteria.
Don't pressure a doctor into prescribing an antibiotic if it is clearly inappropriate. The doctor very often will give in.
If a child needs an antibiotic, ask the doctor whether it is appropriate to use high-dose short-term antibiotics, which may lower the risk for developing resistant strains.
If an antibiotic is prescribed, take the full course, even if you feel better before finishing it.

Resources

www.cdc.gov/flu -- U.S. Centers for Disease Control and Prevention
www.niaid.nih.gov -- National Institute for Allergy and Infectious Diseases
www.who.int/csr/disease/influenza/en -- World Health Organization
www.cdc.gov/vaccines -- National Immunization Program
www.immunize.org -- Immunization Action Coalition
www.entnet.org -- American Academy of Otolaryngology -- Head and Neck Surgery
www.cdc.gov/flu/avian -- Avian Influenza Information

References

American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedule: United States, 2005. Pediatrics. 2005 Jan;115(1):182.

Caruso TJ, Prober CG, Gwaltney JM Jr. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis. 2007;45(5):569-74.

Centers for Disease Control and Prevention. Key Facts About Seasonal Influenza (Flu). Available online.

Centers for Disease Control and Prevention. 2007-08 Influenza Prevention & Control Recommendations: Vaccination of Specific Populations. Available online.

Centers for Disease Control and Prevention. Acute Respiratory Disease Associated with Adenovirus Serotype 14 -- Four States, 2006-2007. MMWR. 2007;56(45):1181-84.

Centers for Disease Control and Prevention. FDA Approves New Laboratory Test To Detect Human Infections With Avian Influenza A/H5 Viruses. February 3, 2006.

Hayden GF, Turner RB. Acute Pharyngitis. In: Behrman RE, Kliegman RM, Jenson HB, eds. Behrman: Nelson Textbook of Pediatrics, 17th ed. Philadelphia, Pa: Saunders; 2004.

Interagency Task Force on Antimicrobial Resistance. Executive Summary: 2006 Annual Report on Progress on "A Public Health Action Plan to Combat Antimicrobial Resistance." Draft release, June 2007. Available online.

Jefferson T, Demichelli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet 2006 Jan 28;367(9507):303-13.

Morantz CA. ACIP Updates Guidelines on Prevention and Control of Influenza. Am Fam Physician. 2005; 72(6); 1119-1127.

Reveiz L, Cardona AF, Ospina EG. Antibiotics for acute laryngitis in adults. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004783.

Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S. Effect of vitamin C on common cold: randomized controlled trial. Eur J Clin Nutr. 2006;60(1):9 - 17.

Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis. 2007;7(7):473-80.

Simasek M, Blandino DA. Treatment of the common cold. Am Fam Physician. 2007;75(4):515-20.

Taverner D, Latte J. Nasal decongestants for the common cold. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001953.

U.S. Food and Drug Administration: Nonprescription Drugs and Pediatric Advisory Committee Meeting. Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18-19, 2007. Available online.

World Health Organization: Neuraminidase Inhibitor Susceptibility Network. Monitoring of neuraminidase inhibitor resistance among clinical influenza virus isolates in Japan during the 2003-2006 influenza seasons. Weekly epidemiological record. 2007;82(17):149-50.

World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO. January 15, 2008. Available online.

Review Date:
1/18/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Parkinson's disease

FitSugar — Wed, 08 Oct 2008 17:35:13 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Complications
Diagnosis
Treatment
Levadopa (L-dopa)
Other Medications
Surgery
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

In 2007, the FDA approved the first skin patch drug for treatment of Parkinson’s disease. Transdermal rotigotine (Neupro) is a dopamine agonist drug that may help improve symptoms of early-stage Parkinson’s disease. The patch is applied daily.
Rivastigimine (Exelon), an Alzheimer’s disease drug, was approved in 2006 for treatment of mild-to-moderate dementia associated with Parkinson’s disease.

Drug Withdrawal

In 2007, the FDA withdrew the dopamine agonist pergolide (Permax) from the market due to safety concerns. Several articles published in 2007 in the New England Journal of Medicine indicated that pergolide and a similar drug, cabergoline (Dostinex), are associated with heart valve problems. Cabergoline is not approved in the U.S. for treatment of Parkinson’s disease.

Dietary Supplements

In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to study whether creatine may help slow the progression of Parkinson’s disease. Creatine is a nutritional supplement that is sometimes used to enhance exercise performance.
Coenzyme Q10, an antioxidant dietary supplement, does not help improve Parkinson’s disease symptoms, according to a study published in 2007 in the Archives of Neurology.

Deep-Brain Stimulation

Deep-brain stimulation outperformed drug therapy in a randomized trial comparing these two treatment approaches. In a study published in 2006 in the New England Journal of Medicine, patients who received deep-brain stimulation had better symptom and quality of life improvement than those who were treated with only medications. However, more serious side effects were reported in the deep-brain stimulation group. Deep-brain stimulation is a surgical technique that involves implanting electrodes in a target area of the brain.

Introduction

Parkinson's disease (PD) is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinson's disease is referred to as idiopathic, which means that the cause is unknown. This term distinguishes the primary disease from parkinsonism, which are the symptoms occurring from a known cause. In addition to its effects on motor control, Parkinson's disease is now recognized as a broader condition that can include cognitive and behavioral disturbances, sleep disorders, speech difficulties, and other problems.

Parkinson's disease occurs from the following process in the brain:

PD develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra.

Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.

Nerve cells in the substantia nigra send out fibers to the corpus stratia, gray and white bands of tissue located in both sides of the brain.
There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease.

Dopamine. Dopamine deficiency is the hallmark feature in PD. It is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease. Dopamine also appears to be important for efficient information processing, and deficiencies may also be responsible for problems in memory and concentration that occur in many patients.

Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, it is not clear what causes dopamine loss. The culprit is less likely to be a single cause than a combination of genetic and biologic factors, which are triggered by some environmental assault.

Other Changes. The PD disease process also appears to impair nerve endings in the heart to cause dysautonomia-- changes in the autonomic (also called sympathetic) nervous system. Such changes may impair the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress. Evidence suggests this may be responsible for the abrupt drops in blood pressure when standing that occur in PD. Further research is underway to determine if the loss of nerve terminals is confined to the heart or if it affects other organs as well.

Click the icon to see an animation about Parkinson's disease.

Apoptosis and Alpha Synuclein. Important research now suggests that three molecules are critical in the development of inherited PD: alpha synuclein, parkin, and ubiquitin, which all interact in the normal brain. Abnormally high levels of alpha synuclein, which is produced in dopamine-rich nerve cells, may play a central role. Normally, two other molecules, parkin and ubiquitin, are involved in the natural self-destruction of synuclein -- a natural process of programmed cell death called apoptosis. If this process goes awry, for instance, with a defective parkin gene, cell death fails to occur. If synuclein is not eliminated in these cells, it builds up and becomes toxic to dopamine. In such cases, synuclein accumulates in Lewy bodies, the deposits of fibrous tissue found in all patients with PD.

Another protein, beta amyloid, also increases the build-up of synuclein. Beta amyloid is a known factor in Alzheimer's disease, and may help explain the co-existence between Alzheimer's and Parkinson's disease in many patients.

Lewy Bodies. The fibrous deposits known as Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. They are found not only in the brains of patients with Parkinson's disease but, in rare cases, may show up in cells in other parts of the body (the heart, intestine), causing severe disabling symptoms. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.

The Mitochondria and Oxygen-Free Radicals. Some research has observed that certain patients with PD have significantly low levels of complex I, an enzyme found in the mitochondria, sausage-like structures that are the primary source of energy within cells. Some theories suggest that low amounts of complex I may make nerve cells vulnerable to the assault of oxygen free radicals (also called oxidants). Oxidants are unstable molecules that bind to other molecules in the body. They are normally produced by the natural chemical processes in the body. If the body is subjected to environmental stresses, however, they can be over-produced. In excess, they can damage any cell, including nerve cells in the brain, and even interfere with their DNA.

NMDA Receptors. Also of interest in PD are processes that occur in an area of the brain called the subthalamic nucleus. Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage.

Immune Factors and the Inflammatory Response. An over-responsive immune system triggered by initial damage may also play a role in perpetuating Parkinson's disease. When the immune system becomes overactive, it produces excessive numbers of potent factors called cytokines, which cause inflammation and further injury in brain cells. Important cytokines under investigation are interleukin-1 and tumor necrosis factor.

Specific genetic factors appear to play a strong role in early-onset Parkinson's disease, an uncommon form of the disease. Research from the last several years suggests that multiple genetic factors may also be involved in late-onset Parkinson’s disease. Several important studies, published in 2005, lay the groundwork for potential genetic screening for this disease. Researchers identified the leukine-rich repeat kinase 2 (LRRK2) gene, located on a region of chromosome 12 known as PARK8, as a key gene involved in inherited forms of Parkinson’s. The researchers estimate that a single gene mutation in LRRK2 may be responsible for 5% of inherited Parkinson’s cases and about 2% of isolated cases.

Early Onset PD. The cases of genetic early-onset Parkinson's disease have most often been detected in specific family groups.

Defective genes that regulate the molecules alpha synuclein and parkin, which are important in the PD disease process, may be responsible for a number of early-onset cases. For example, genetic abnormalities the alpha synuclein protein have been detected in some early-onset Parkinson's patients of European descent.
The parkin gene may be the cause of many cases of early-onset Parkinson's in young adults. (Parkinson's cases associated with this mutation tend to progress slowly and respond well to treatment, even after years of symptoms. Dementia is also rare with this form.)

Late Onset PD. Two landmark studies published in the Journal of the American Medical Association provided the first evidence of a genetic link to late-onset Parkinson’s disease. In these 2001 studies, researchers found that regions on chromosomes 5, 6, 8, 9, and 17 were implicated with Parkinson’s. The parkin gene (located on chromosome 6) and the tau gene (located on chromosome 17) were both found in families that had late onset Parkinson’s. Parkin was previously thought to be responsible only for early-onset Parkinson’s, but this research identified it in families that had both early- and late-onset disease forms. These studies also bolstered the theory that Parkinson’s does have a genetic component and is not caused solely by environmental factors. A 2005 study found that a G2019S mutation in the LRRK gene, located on the PARK8 region of chromosome 12, was definitively associated with late-onset Parkinson’s disease in North American and European families.

Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's.

Infectious Organisms. Some research has identified immune factors that suggest a viral presence in the Lewy bodies and swollen nerve pathways of Parkinson's brains. Influenza and other potent viruses have long been known to be a cause of parkinsonism. In one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.

Environmental and Industrial Chemicals. Intense exposure to certain environmental and industrial chemicals is also being studied.

Pesticides and Herbicides. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink private well water or are agricultural workers. A large 2000 study found a strong link between high exposure to insecticides and herbicides at home and a 50 - 70% increase in risk of Parkinson's.
Other Chemicals. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, a cause that is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear. High levels of iron content observed in critical parts of the brain in PD are under particular scrutiny.

Most, but not all, Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any excessive stress on these transporters might trigger Parkinson's disease in the aging, and more vulnerable, brain.

Symptoms

Parkinson's disease (PD) symptoms often start with tremor, which may occur in the following ways:

Tremors may first be only occasional, starting in one finger and spreading over time to involve the whole arm. The tremor is often rhythmic, 4 - 5 cycles per second, and frequently causes an action of the thumb and fingers known as pill rolling.
Tremors can occur when the limb is at rest or when it is held up in a stiff unsupported position. They usually disappear briefly during movement and do not occur during sleep.
Tremors can also eventually occur in the head, lips, tongue, and feet. Symptoms can occur on one or both sides of the body. In one study, 44% of patients reported experiencing internal tremors lasting less than half an hour, but occurring several times a week.

In younger patients tremor is usually predominant and often suggests a less aggressive form of the disease. Some evidence suggests that tremor in PD may occur from mechanisms in the brain that are different from those that cause other PD symptoms.

A number of PD symptoms involve motor impairment caused by the abnormalities in the brain that regulate movement:

Slowness of motion (bradykinesia) is one of the classic symptoms of Parkinson's disease. Patients may eventually develop a stooped posture and a slow, shuffling walk. The gait can be erratic and unsteady. After a number of years, muscles may freeze up or stall, usually when a patient is making a turn or passing through narrow spaces, such as a doorway.
Intestinal motility (the ability to swallow, digest, and eliminate) may slow down, causing eating problems and constipation.
Muscles may become rigid (akinesia). This symptom often begins in the legs and neck. Muscle rigidity in the face can produce a mask-like, staring appearance.
Motor abnormalities that limit action in the hand may develop in late stages. Handwriting, for instance, often becomes diminutive.
Normally spontaneous muscle movements, such as blinking, may need to be done consciously.

The traditional view of Parkinson's disease is shifting to reflect growing awareness that it is much more than a motor disease. Many non-motor components and their treatments are now under study. The following symptoms should be carefully monitored by doctors and caregivers:

Depression is the most common psychiatric problem associated with PD, affecting about 40% of patients. Because depression is a common problem in older people, it is likely not to be recognized as a symptom.
Anxiety affects about 30% of patients.
Dementia and paranoia are more common than previously understood.
Orthostatic hypotension -- some patients experience a sudden drop in blood pressure when they stand. This can cause dizziness and fainting.
Changes in sensations of temperature, hot flashes, and excessive sweating.
Daytime sleepiness and other sleep disorders are common.

Risk Factors

Parkinson's disease affects about 3% of Americans over 65 years old. Experts estimate that this percentage could double in the next 30 - 40 years. The symptoms of parkinsonism (tremor, gait disturbance, bradykinesia, and rigidity) occur in even more people, estimated to be 8 million over age 65. In a study that included very mild symptoms, parkinsonism occurred in about 15% of people 65 - 74 years of age, about 30% in those 75 - 84, and over half of people older than age 85.

The average age of onset of Parkinson's disease is 55. About 10% of Parkinson's cases are in people younger than 40 years old. Older adults are at higher risk for both parkinsonism and Parkinson's disease. There is some evidence, however, that the risk declines significantly after age 75 and that the very elderly are at low risk.

Some research indicates that men may face up to twice the risk as women. Estrogen may offer some protection for women up until menopause. A 2001 study, for example, reported a higher rate of Parkinson's disease in women who had undergone hysterectomy. Other studies suggest that the disease also progresses more rapidly in men than women. Older women seem to be more at risk for gait disturbance and men for rigidity and tremor.

People with siblings or parents who developed Parkinson's at a younger age are at higher risk for Parkinson's disease, but relatives of those who were elderly when they had the disease appear to have an average risk.

African- and Asian-Americans have a lower risk than Caucasians. Some evidence suggests that non-Caucasians may be more vulnerable to an atypical form of PD, which causes early impairment in thinking and has a poor response to levodopa, the primary PD treatment.

Increasing weight gain in middle age was associated with a higher risk of PD in a 2002 study.

Complications

Parkinson's disease (PD) is not fatal, but it can reduce longevity. The disease progresses more quickly in older than younger patients, and may lead to severe incapacity within 10 - 20 years. Older patients also tend to experience freezing and greater declines in mental function and daily functioning than younger people. If PD starts without signs of tremor, it is likely to be more severe than if tremor had been present. Having other family members with PD does not appear to have any effect on the severity of the disease.

Parkinson's disease can seriously impair the quality of life in any age group. The physical and emotional impact on the family should not be underestimated as the patient becomes increasingly dependent on their support.

Treatment advances are increasingly effective in alleviating symptoms and even slowing progression of the disease. Taking many of the medications over time, however, can produce significant side effects. Newer drugs may help reduce these occurrences.

The negative effect of overall motor and muscle impairment on daily life can be considerable. Some motor complications can be life-threatening.

Disturbed gait and unstable posture are common and serious problems in elderly patients, since they increase the risk for falling and injury. Some studies have suggested that the appearance of these symptoms early in the course of the disease predict a faster decline than having tremor as the predominant symptom.
Swallowing problems (dysphagia). The presence of dysphagia is associated with shorter survival time. Motor impairment of the muscles in the throat not only impairs swallowing but it also poses a risk for aspiration pneumonia.
Constipation is a major problem and occurs both as a result of the disease and a side effect of its treatment. Laxatives, stool softeners, and other medications may be prescribed.
Bladder control and urinary incontinence are also important complications of PD.
Speech problems occur in more than 70% of patients, by some estimates. Speech difficulty can be caused by rigidity of the facial muscles, loss of motor control, and impaired breath control. Tone can become monotonous, words may be repeated over and over, or the rate of speech may even be very fast.

Depression is extremely common, affecting up to 40% of patients with Parkinson's. PD poses multiple threats on the emotional health:

The disease process itself causes changes in chemicals in the brain that affect mood and well-being.
The complications of its symptoms have a profound impact on daily life that can be emotionally devastating without help and support.
Some drug treatments (levodopa combined with a dopamine agonist) can cause compulsive behavior, such as gambling, shopping, and increased sexuality. Patients who have pre-existing tendencies to novelty-seeking behavior, or a family or personal history of alcohol abuse, may be more likely to develop compulsive gambling. Deep brain stimulus (DBS) surgery may also increase the risk for compulsive gambling in patients who have a history of gambling.

Impaired Thinking (Cognitive Impairment). Defects in thinking, memory, language, and problem solving skills may occur early on in untreated patients or late in the course of the disease. Medications may play a role in thinking problems. In one study, for example, patients with PD were slower in detecting associations, although (unlike in Alzheimer's disease) once they discovered them they were able to apply this knowledge to other concepts. After they were taken off medication, however, they had no problems with the tasks.

Dementia. Dementia is three to six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. PD marked by muscle rigidity (akinesia), rather than tremor, and early hallucinations also increase the risk for dementia. (Visual hallucinations can also occur in about a third of patients from PD medication.) Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia.

A number of other problems associated with Parkinson's disease affect daily life:

Vision Problems. Vision is also affected, including impaired color perception and contrast sensitivity. These problems progress and can impair motor functioning.

Sleep Disorders. Excessive daytime sleepiness and other sleep disorders are common in PD, both from the disease itself and from the drugs that treat it. In general, patients have a 25% higher risk for daytime sleepiness, including suddenly falling asleep, than patients with other neurologic diseases.

Restless legs syndrome, an irresistible urge to move the calves, which often occurs at night, affects many patients. However, Parkinson's disease itself does not seem to increase the risk for RLS. Nor does RLS early in life predispose to Parkinson's later on. The common connection between RLS and Parkinson's disease may derive from iron deficiencies that can play a role in both conditions.

Many patients also suffer from nighttime leg cramps. And, some of the medications cause vivid dreams as well as waking hallucinations.

Impaired Sexuality. Although Parkinson's disease and its treatments can cause compulsive sexual behavior, the disease can also affect patients' self-esteem and inhibit sexuality. This is an area not often studied but which is important for many patients' well-being. A 2000 study reported that not only did sexual dysfunction occur, but also affectionate touching and expression of feelings were reduced, even though both partners maintained a desire for intimacy.

Worsened Sense of Smell. The sense of smell is impaired in about 70% of patients.

Osteoporosis. Parkinson’s disease may increase the risk for low bone density and osteoporosis. Both men and women are at risk. Experts recommend that patients with Parkinson’s disease get tested for osteoporosis, especially if they have problems with walking.

Diagnosis

It is difficult to diagnose Parkinson's in early stages. The disease is primarily diagnosed by its symptoms, and studies indicate that doctors make an incorrect initial diagnosis of Parkinson's disease in 8 - 35% of cases. Even neurologists have difficulties in correctly identifying the disease.

A medical and personal history should include any relevant symptoms as well as any medications taken, and information on exposure to environmental toxins.

Early Symptoms. Early treatment may help slow progression, so an early diagnosis of Parkinson's is highly desirable. Early symptoms are often mild, however, so Parkinson's disease can be missed, particularly in young adults. Repeated assessment of symptoms over time is important for improving the accuracy of diagnosis. Too often a younger person with Parkinson's may be diagnosed with mental illness, because the doctor associates the disease only with older people.

Parkinson's may be suspected in patients with the following symptoms:

Slowness and difficulty of movement. These are usually the first symptoms. The patient will be asked to walk and to get out of a chair, preferably a deep one. Early gait disturbance, however, often indicates a disease other than Parkinson's disease.
A tremor when their limb is relaxed. (As many as 25% of patients, however, will not have a tremor.)
Symptoms on one side of the body.

Later Symptoms. In later stages of Parkinson's disease, the symptoms are usually unmistakable, and the problem can often be diagnosed using simple physical tests and a medical and personal history.

The loss of smell is associated with loss of dopamine receptors in the brain. “Scratch and sniff” smell tests can help a doctor diagnose Parkinson’s disease. Smell tests can help differentiate Parkinson’s disease from other conditions with similar symptoms. Some patients with a very similar condition called multiple system atrophy will have a good initial response to levodopa, but it is not usually sustained.

Levodopa and apomorphine can confirm a diagnosis of Parkinson’s disease. If patients’ symptoms improve when they take these drugs, they likely have Parkinson’s, ruling out other neurological diseases.

According to 2006 guidelines from the American Academy of Neurology, there is not enough evidence to recommend for or against the use of imaging techniques such as computerized tomography (CT), magnetic resonance imaging (MRI), or positron-emission tomographic (PET) to diagnose PD.

When symptoms resemble Parkinson's disease but have an identifiable cause, the syndrome is known as parkinsonism. People who have parkinsonism, but not Parkinson's disease, often have additional neurologic symptoms. A number of conditions can also have similar or some of these symptoms.

Other Neurologic Conditions. Many medical conditions may cause symptoms of Parkinson's disease:

Hardening of the arteries (arteriosclerosis) in the brain can cause multiple small strokes, which can produce loss of motor control.

Click the icon to see an image of plaque in an artery.

Alzheimer's disease can be very similar. In one study 23% of people with Alzheimer's also met the criteria for Parkinson's disease. The two diseases often coexist, and research suggests that Alzheimer's and Parkinson's disease may sometimes share a common biologic origin, the accumulation of the protein alpha synuclein and Lewy bodies in the brain.
Lewy bodies variant (LBV), also called dementia with Lewy bodies, is a separate disease from both Alzheimer's and Parkinson's disease. It has similar symptoms to both but is marked by early dementia.
Encephalitis caused by influenza has been known to cause parkinsonism.
Primary progressive freezing gait is a progression condition, in which freezing gait occurs at the onset. Other Parkinson-like features, such as slow movement, often develop. Although very similar to PD, this condition does not respond to L-dopa or other PD medications.
Essential tremor, unlike the tremor of Parkinson's disease, often occurs in the head and voice and is usually worse during motion, as opposed to rest.
Progressive supranuclear palsy has similar symptoms, but involves less tremor and earlier rigidity, and it tends to affect both sides of the body symmetrically. Magnetic resonance imaging scans that measure parts of the midbrain may be a reliable method for distinguishing between PD and progressive supranuclear palsy.
Multiple system atrophy (previously called Shy-Drager syndrome) is a degenerative nerve disease that also affects movement and blood pressure and has many of the symptoms of Parkinson's disease. Some research suggests that a trial using the drug apomorphine may help differentiate between the two.
Other problems that may mimic Parkinson's disease include Wilson's disease, thyroid abnormalities, hydrocephalus, tumors, having the fragile X trait (but not the full disorder), and a number of degenerative neurologic diseases.

Drugs. Certain drugs or medications account for about 4% of all cases of parkinsonism. According to some studies, patients who experience drug-induced parkinsonism may actually be at an increased risk of developing Parkinson's disease later in life. A number of drugs can cause these symptoms, including antipsychotic and antiseizure drugs. Anyone with parkinsonism should discuss their medications with their doctor.

The American Academy of Neurology (AAN) recommends the Beck Depression Inventory or the Hamilton Depression Rating Scale to screen for depression in patients with Parkinson’s disease. The AAN recommends the MMSE and CAMCOG tests to screen for dementia. During these tests, the patient answers a series of questions.

Treatment

Drugs, physical therapy, and surgical interventions can manage Parkinson's disease. The goals of treatment for Parkinson's disease are to:

Relieve disabilities
Balance the problems of the disease with the side effects of the medications

Treatment is very individualized for this complicated disease. Patients must work closely with doctors and therapists throughout the course of the disease to customize a program suitable for their particular and changing needs. Patients should never change their medications without consulting their doctor, and they should never stop taking their medications abruptly.

The American Academy of Neurology recommends the following therapies for the initial treatment of Parkinson’s disease:

Levodopa (L-dopa). Levodopa, or L-dopa, has been used for years and is the gold standard for treating Parkinson's disease. The drug increases brain levels of dopamine. It is used in nearly all phases of the disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, a drug that slows the breakdown of levodopa. Levodopa is better at improving motor problems than dopamine agonists but increases the risk of involuntary movements (dyskinesia).

Dopamine Agonists. Dopamine agonist drugs mimic dopamine to stimulate the dopamine system in the brain. These drugs include pramipexole (Mirapex), ropinirole (Requip), bromocriptine (Parlodel), and rotigotine (Neupro). The Food and Drug Administration (FDA) pulled the dopamine agonist pergolide (Permax) from the market in March 2007 over safety concerns that included potentially fatal heart valve damage.

Selegiline (Eldepryl) and rasagiline (Azilect). Selegiline is a monoamine oxidase B (MAO-B) inhibitor that may have some mild benefit as an initial therapy. However, unlike levodopa, it does not slow the progression of Parkinson’s disease. Another MAO-B inhibitor, rasagiline (Azilect), was approved in May 2006. Unlike selegiline, which needs to be taken by mouth twice a day, rasagiline needs to be taken only once a day.

Drug treatments for Parkinson disease do not consistently control symptoms. At certain points during the day, the beneficial effects of drugs wear off, and patients can experience a return of symptoms, such as uncontrolled muscular motor function, difficulty walking, and loss of energy. In 2006, the American Academy of Neurology (AAN) reviewed evidence for the various drugs used to treat “off time.” The AAN found that the following drugs had the strongest evidence for controlling off time symptoms:

Entacapone (Comtan) belongs to a class of drugs called catechol-o-methyl transferase (COMT) inhibitors. COMT inhibitors help prolong the effects of levodopa by blocking an enzyme that breaks down dopamine.
Rasagiline (Azilect) belongs to a class of drugs called monoamine oxidase (MAO) inhibitors. These drugs slow the breakdown of dopamine that occurs naturally in the brain and dopamine produced from levodopa.

The AAN also found good evidence for the dopamine agonists ropinirole (Requip) and pramipexole (Mirapex), and the COMT inhibitor tolcapone (Tasmar). Deep brain stimulation is a surgical treatment that may help improve motor fluctuations in some patients.

Both Levodopa and dopamine agonists can cause involuntary movements (dyskinesia). The AAN has not found any strong evidence to recommend any drug for treating dyskinesia. However, weak evidence suggests that the antiviral drug amantadine (Symmetrel) may help reduce stiffness and improve dyskinesia. There is also weak evidence that deep brain stimulation of the subthalamus area may be helpful.

Conditions associated with motor impairment and other symptoms of Parkinson's disease may require a variety of treatments.

Depression. Although depression is very common in PD, there have been surprisingly few controlled studies. Antidepressants used for PD include tricyclics, particularly amitriptyline (Elavil). Some studies have found that selective serotonin-reuptake inhibitors (SSRIs) -- which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) -- may worsen symptoms of Parkinson's. Doctors should monitor patients taking SSRIs.

Psychotic Side Effects. Studies indicate that clozapine (Clozaril) and quetiapine (Seroquel), antipsychotic drugs used to treat schizophrenia, may be the best drugs for treating psychosis in patients with Parkinson's disease. A similar drug, olanzapine (Zyprexa), should not be used for patients with PD because it can worsen their psychotic symptoms.

Dementia. The cholinesterase inhibitor drugs donepezil (Aricept) and rivastigmine (Exelon) are used to treat Alzheimer’s disease. Studies suggest that these drugs may also help treat dementia associated with Parkinson’s disease. In 2006, rivastigimine was approved for treatment of mild-to-moderate dementia associated with Parkinson’s disease.

Daytime Sleepiness. Modafinil (Provigil), a drug used to treat narcolepsy, is proving to be very helpful for patients with sleepiness related to their disease.

Drooling. In search of a simple solution for the problem of drooling, scientists have reported that injections of very small amounts of botulinum toxin effectively reduce saliva production and drooling. In such small amounts the toxin is safe.

Voice Loss. A relatively simple procedure using collagen injections in the neck appears to be a safe and effective method of improving the voice and speech disorders caused by PD. The procedure augments the collagen in the vocal fold and works best in patients who can still initiate speech. A 2001 study reported improvements that lasted from 2 - 7 months in 61% of patients.

Erectile Dysfunction. Sildenafil (Viagra) is proving to be very helpful for men who suffer from impotence from Parkinson's disease. However, the drug may worsen orthostatic hypotension, a side effect of some PD medications.

Eventually, symptoms such as stooped posture, freezing, and speech difficulties may not respond to drug treatment. (Total unresponsiveness is unlikely, however, even after 20 years of treatment.) The following approaches may be tried:

Simply increasing the dose of levodopa or its frequency raises an unacceptable risk of the distressing side effects. Some doctors have tried hospitalizing patients, totally withdrawing the levodopa, and then re-administering it. Benefits were seen for only a few months, however, and there were some dangerous risks to the process of withdrawal, including pneumonia and blood clots in the lungs.

An embolus is a blockage of an artery in the lungs by fat, air, tumor tissue, or blood clot.

Surgical treatments, including deep brain stimulation and pallidotomy, may help some patients.
Research is ongoing to develop drugs and procedures that will manage advanced disease and possibly even reverse the process.

Levadopa (L-dopa)

Levodopa, also called L-dopa, which is converted to dopamine in the brain, remains the gold standard for treating Parkinson's disease. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. Dosages vary, although the preparation is usually taken in three or four divided doses per day. In 2004, the FDA approved a new oral form of carbidopa-levodopa (Parcopa) that dissolves on the tongue.

In general L-dopa has the following effects on Parkinson's disease:

It is most effective against rigidity and slowness.
It produces less benefit for tremor, balance, and gait.

In many patients, levodopa significantly improves the quality of life for many years. If symptoms do not improve after 2 - 3 months, one of the following reasons may account for the failure:

Other neurologic problems may be causing the symptoms.
Some patients have abnormalities in other brain sites that do not respond to L-dopa.
Sometimes patients are so depressed they cannot tell if the drug is beneficial or not. Only a series of physical examinations by the doctor will indicate that the drug is actually helping.

Studies suggest that levodopa may help slow disease progression and protect against brain cell degeneration.

The toxic effects of levodopa with or without carbidopa are considerable.

Physical Side Effects. The physical side effects are as follows:

Low blood pressure. Low blood pressure is a common problem during the first few weeks, particularly if the initial dose is too high. The addition of extra supplements of carbidopa reduces this effect to some degree. The patient should drink lots of fluids and possibly increase salt intake to maintain normal blood pressure.
Arrhythmia. In some cases the drug may cause abnormal heart rhythms.
Gastrointestinal effects. Stomach and intestinal side effects are common even with carbidopa. Taking the drug with food can alleviate the nausea. However, proteins interfere with intestinal absorption of levodopa, and some doctors recommend not eating any protein until nighttime in order to avoid this interference. The drug can also cause gastrointestinal bleeding.
Effects in the lung. Levodopa can cause disturbances in breathing function, although it may benefit patients who have upper airway obstruction.
Hair loss.

Psychiatric and Mental Side Effects. The major adverse effects of the drug are psychiatric. Patients taking levodopa, especially in combination with other drugs, can experience:

Confusion.
Extreme emotional states, particularly anxiety.
Vivid dreams.
Visual and possibly auditory hallucinations. The drug may even unmask dementia that had not been previously noticed.
Effects on learning. L-dopa appears to have mixed effects on learning. It may improve working memory. However, some evidence suggests that it impairs areas of the brain related to other learning functions and social behavior.
Sleepiness and sleep attacks.

Levodopa causes fewer psychiatric side effects than other drugs used for Parkinson's disease, including anticholinergics, selegiline, amantadine, and dopamine agonists. Because psychiatric side effects often occur at night, if they are severe some doctors recommend reducing or stopping the evening dose.

Within 4 - 6 years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time (called the wearing-off effect) and the following pattern may occur:

Patients may first notice slowness (bradykinesia) or tremor in the morning before the next dose is due.
Less commonly, some experience painful dystonia, muscle spasms that can cause sustained contortions of various parts of the body, particularly the neck, jaw, trunk, and eyes and possibly the feet.
Patients must increase the frequency of levodopa doses. This puts them at risk for dyskinesia (the inability to control muscles), which usually occurs when the drug level peaks. Dyskinesia can take many forms, most often uncontrolled flailing of the arms and legs or chorea, rapid and repetitive motions that can affect the limbs, face, tongue, mouth, and neck. Dyskinesia is not painful, but it is very distressing.
In some people, eventually L-dopa is effective only for 1 - 2 hours and most patients start to experience motor fluctuations. In about 15 - 20% of patients such fluctuations become extreme, a phenomenon known as the on-off effect, which consists of unpredictable, alternating periods of dyskinesia and immobility. Sometimes the symptoms switch back in forth within minutes or even seconds. (The transition may follow such symptoms as intense anxiety, sweating, and rapid heartbeats.)

Reasons for the Wearing-Off Effect. Debate is ongoing about the cause of the wearing-off effect and dyskinesia. Some theories suggested for these effects are:

The disease progresses beyond the ability of levodopa to control it.
Some patients become tolerant to prolonged exposure to dopamine and, at the same time, the disease is progressing.
The brain's own dopamine neurons become incapable of storing dopamine. When the levodopa wears off, little or no natural dopamine remains.
Levodopa itself accelerates the disease by producing oxygen free radicals, unstable particles that increase injuries to the brain and dopamine degradation.

Preventing the Wearing-Off Effect. To reduce the effects of fluctuation and the wearing-off effect, it is important to maintain as consistent a level of dopamine as possible. Unfortunately, levodopa is poorly absorbed and may remain in the stomach a long time. A number of strategies are being developed to take care of these problems:

Some patients take multiple small doses on an empty stomach, crushing the pills and mixing them with a lot of liquid.
A liquid form of Sinemet may produce fewer fluctuations and a prolonged "on" time compared with the tablet.
A prolonged release version of levodopa and carbidopa (Sinemet CR) is also available to control fluctuations for some people. (Some evidence suggests that there is no actual difference in symptom control between the sustained and immediate release forms, but patients on Sinemet CR tend to experience a better quality of life.)

Other Medications

Selegiline (Eldepryl, Movergan, Zelepar), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B (MAO-B), an enzyme that degrades dopamine. Until recently, selegiline was the drug most commonly used in early-onset disease and in combination with levodopa for maintenance. A major 2002 study reported, however, that although selegiline delays the need for L-dopa by a few months, it has no effect on long-term progression.

Rasagiline (Azilect), another MAO-B inhibitor, was approved in May 2006 for the initial treatment of Parkinson’s disease. It is used alone during early-stage PD and in combination with L-dopa for moderate-to-advanced PD. Unlike selegiline, which is taken twice a day, rasagiline is taken once a day.

Other Adverse Effects. MAO-B inhibitors may have severe side effects:

One of the most important side effects is orthostatic hypotension, particularly in people taking Sinemet plus selegiline. This condition is a sudden drop in blood pressure that causes dizziness and lightheadedness when a patient stands up. Orthostatic hypotension can also occur with other Parkinson's drugs.
Can cause high blood pressure (hypertension) if combined with drugs that increase serotonin levels -- such drugs include nearly every major antidepressant. Patients suffering from depression and taking selegiline should discuss all treatment options with their doctor.
Can also cause a dangerous increase in blood pressure if patients eat foods rich in the amino acid tyramine. Patients should avoid the following foods while taking selegiline or rasagiline and for 2 weeks after stopping medication: aged cheeses, air-dried meats, pickled herring, yeast extract, aged red wines, draft beers, sauerkraut, and soy sauce

Debate over Mortality Rates. Some major studies have reported higher mortality rates in patients with advanced PD. Such findings may be due to adverse effects on the heart and blood vessels. Although other studies have not reported lower survival rates, some experts believe that, given its modest effects, selegiline may be a poorer drug choice than others, particularly in patients with risk factors for heart disease.

Dopamine agonists stimulate dopamine receptors in the substantia nigra, the part of the brain in which Parkinson's is thought to originate. Dopamine agonists are effective in delaying motor complications during the first 1 or 2 years of treatment.

Newer Dopamine Agonists. The most commonly prescribed dopamine agonists are pramipexole (Mirapex) and ropinirole (Requip). They are used either alone or in combination with L-dopa. Pramipexole appears to work better and have fewer side effects than ropinirole.

Studies still report, however, that L-dopa is superior for improving motor function. In one study, motor function was no different in disease progression among all of the drugs by the third year of treatment. Recent research suggests that L-dopa is better at improving motor disability and dopamine agonists are better at reducing motor complications. L-dopa has a higher risk for dyskinesia side effects than dopamine agonists, but dyskinesia can also occur with dopamine agonists.

Side Effects. Side effects of pramipexole and ropinirole vary but can be severe and include:

Gastrointestinal side effects (nausea and constipation). Nausea can be controlled by drugs, such as domperidone.
Headache
Orthostatic hypotension (sudden drop in blood pressure upon standing up)
Nasal congestion
Nightmares, hallucinations, and psychosis (more severe than with L-dopa for both drugs)
Sudden sleep attacks. These can be very serious, particularly if patients are driving. (Sleep attacks may occur -- although less commonly -- with other PD drugs.)

Other Dopamine Agonists.

Specific dopamine agonists that contain ergot alkaloids include bromocriptine (Parodel), pergolide (Permax), cabergoline (Dostinex), and lisuride (Dopergin). As of 2007, bromocriptine is the only ergot dopamine agonist approved for Parkinson’s treatment in the United States. In January 2007, the New England Journal of Medicine (NEJM) published two studies indicating that pergolide and cabergoline are associated with heart valve damage. In March 2007, due to these safety concerns, the FDA withdrew pergolide from the U.S. market. Cabergoline and lisuride are not approved in the U.S. for Parkinson’s disease treatment but are used for this purpose in other countries. The NEJM studies did not find any heart valve problems associated with bromocriptine or lisuride.
Rotigotine transdermal (Neupro) is a dopamine agonist that is delivered through a skin patch that is changed daily. In 2007, the FDA approved rotigotine transdermal for treatment of symptoms of early Parkinson’s disease. It is the first skin patch approved for Parkinson’s disease. Side effects are similar to those of other dopamine agonists.
Apomorphine is a dopamine agonist used as a "rescue" drug in people experiencing on-off effects severe enough to require going off L-dopa for a few days. In 2004, the FDA approved apomorphine for treating off-time episodes of Parkinson’s disease. Apomorphine is given by injection. Because it causes severe nausea and vomiting, it must be taken with an anti-nausea drug.

Catechol-O-methyl transferase (COMT) inhibitors increase concentrations of existing dopamine in the brain. Entacapone (Comtan, Stalevo) is the current standard COMT inhibitor. (Stalevo combines entacapone and levodopa into a single pill.) It improves motor fluctuations related to the wearing-off effect and has shown good results in improving on time and reducing the requirements for L-dopa. If the patient does not respond to the drug within 3 weeks, it should be withdrawn. No one should withdraw abruptly from these drugs.

Side Effects. Side effects include:

Involuntary muscle movements
Mental confusion and hallucinations
Cramps, nausea, and vomiting
Insomnia
Headache
Urine discoloration (a harmless side effect but should be reported to the doctor)
Diarrhea
Less commonly, constipation, susceptibility to respiratory infection, sweating, dry mouth

Of major concern are reports of a few deaths from liver damage in patients taking the COMT inhibitor tolcapone (Tasmar). The drug has been taken off the market in many countries and is recommended in the U.S. only for patients who cannot tolerate another other drugs. Entacapone does not appear to have the same effects on the liver and does not require monitoring. A 2003 3-year study suggested that the drug is safe and effective over the long term. Still, patients should watch out for symptoms of liver damage, including jaundice (yellowish skin), fatigue, and loss of appetite.

Jaundice is a condition produced when excess amounts of bilirubin circulating in the bloodstream dissolve in the subcutaneous fat (the layer of fat just beneath the skin), causing a yellowish appearance of the skin and the whites of the eyes. With the exception of normal newborn jaundice in the first week of life, all other jaundice indicates overload or damage to the liver, or inability to move bilirubin from the liver through the biliary tract to the gut.

Anticholinergics were the first drugs used for PD, but have largely been replaced by dopamine drugs. They are generally used only against tremor in the early stages. They are not as effective against bradykinesia and posture problems and may increase the risk for dementia in late stages. Among the many anticholinergics are trihexyphenidyl (Artane, Trihexy), benztropine (Cogentin), biperiden (Akineton), procyclidine (Kemadrin), and ethopropazine (Parisdol). Orphenadrine (Norflex) is a drug with anticholinergic properties, but is also a muscle relaxant and does not cause urinary retention.

Side effects of Anticholinergics. Anticholinergics commonly cause dryness of the mouth (which can actually be an advantage in some people who experience drooling). Other side effects are nausea, urinary retention, blurred vision, and constipation. These drugs can also increase heart rate and worsen constipation. Anticholinergics can sometimes cause significant mental problems, including memory loss, confusion, and even hallucinations. People with glaucoma should use these drugs cautiously.

Amantadine (Symadine, Symmetrel) stimulates the release of dopamine and may be used for patients with early mild symptoms. It has some benefit against muscle rigidity and slowness and may help some patients in advanced stages who are unresponsive to other drugs. It is less powerful than levodopa and may lose its effectiveness after 6 months. It may also reduce motor fluctuations brought on by levodopa, however, and these benefits appear to persist for at least a year. Large, well-conducted studies are still needed to determine its true benefits and safety.

Side Effects. Side effects are similar to those of anticholinergic drugs and also may include swollen ankles and mottled skin. It can also cause visual hallucinations. Overdose can cause serious and even life-threatening toxicity. Patients with Parkinson's should not withdraw from this drug abruptly. In rare instances, it can cause acute delirium or a life-threatening condition called neuroleptic malignant syndrome. Pregnant or nursing women should not use this drug.

Anticonvulsants. Zonisamide (Zonegran), a drug used to treat epilepsy, is showing promise in treating tremors, motor problems, and involuntary movements in patients with Parkinson’s disease.

Budipine and Other Glutamate Blockers. A number of experimental drugs are being investigated for Parkinson's disease because they block the actions of glutamate, an amino acid that is a particularly potent nerve cell killer. Some of these drugs block a receptor group to glutamate called N-methyl-D-aspartate (NMDA). Investigational NMDA antagonists include remacemide, memantine, riluzole, and budipine.

Stem Cell Transplantation. Scientists are investigating whether transplanting embryonic stem cells into the brain may help treat Parkinson’s disease. Researchers hope that the transplanted stem cells may be able to stimulate dopamine production. However, stem cell transplantation research is still in its very early stage. It will be many years before clinical trials will be conducted in humans.

Surgery

Surgical procedures are recommended for specific patients with advanced Parkinson’s disease who no longer respond to drug treatments. Surgical treatment cannot cure Parkinson's disease, but it may help control symptoms such as motor fluctuations and dyskinesia. Pallidotomy and thalamotomy are older procedures that destroy tissue in certain parts of the brain. Deep brain stimulation, the current standard surgical practice for Parkinson’s disease, has largely replaced the older operations.

In deep brain stimulation (DBS), also called neurostimulation, an electric pulse generator controls symptoms. The generator is similar to a heart pacemaker. It sends electrical pulses to specific regions of the brain. Candidates for surgery are generally patients who have responded well to levodopa drug treatment. Patients who have had PD for fewer than 16 years may experience greater benefit from DBS than patients who have had the disease longer.

Evidence indicates that DBS improves motor function and reduces dyskinesia best when the procedure targets the subthalamic nucleus (STN) of the brain. Many studies demonstrate the effectiveness of STN stimulation. Procedures that target the globus pallidus interna or ventral intermediate nucleus of the thalamus can also sometimes treat rigidity and tremors. However, there is not yet enough evidence to support stimulation of these parts of the brain.

The procedure is performed as follows:

The surgeon implants a tiny pulse generator near the collarbone, which is connected to four electrodes that have been implanted in the target area in the brain.
The generator delivers programmed pulses to this area, which the patient can turn on and off using a magnet held over the skin.
When on, the pulses suppress symptoms. Complications occur in 2 - 4% of operations. The most serious ones are bleeding in the brain and infection. Depression is common.

In a 2006 study of patients with advanced Parkinson’s disease and severe motor symptoms, patients who received DBS had better improvement in symptoms and quality of life than those who received only drug therapy. However, patients in the neurostimulation group had more serious side effects than those who were treated only with medications. Researchers are also studying whether DBS can benefit patients with earlier-stage Parkinson’s disease.

Pallidotomy and thalamotomy are surgical procedures that destroy brain tissue in regions of the brain associated with Parkinson’s symptoms such as dyskinesia, rigidity, and tremor. In these procedures, a surgeon drills a small hole in the patient’s skull and inserts an electrode to destroy brain tissue. Pallidotomy targets the global pallidus area. Thalamotomy targets the thalamus. Because these procedures permanently eliminate brain tissue, most experts now recommend deep brain stimulation instead of pallidotomy or thalamotomy.

Surgical complications may include behavioral or personality changes, trouble speaking and swallowing, facial paralysis, and vision problems. Weight gain after surgery is also common.

Scientists are investigating whether stem cells may eventually help treat Parkinson disease. Experimental surgery has shown promise using fetal brain cells rich in dopamine implanted in the substantia nigra area of the brain. Because the use of embryonic stem cells is controversial, researchers are studying alternative types of cells, including stem cells from adult brains and cells from human placentas or umbilical cords. Studies are also using gene therapies and other advanced treatments for transplanting dopamine-producing cells or nerve-protecting cells into the brain. All of this research is still in preliminary stages.

Lifestyle Changes

No special diets or natural foods have been shown to slow down the progression of Parkinson's disease, but there are some dietary recommendations.

Protein. High levels of proteins compete with levodopa for transport to the brain and reduce its effectiveness. Avoiding protein altogether is not the solution, since malnutrition can result. Most experts now recommend trying to maintain a carbohydrate-to-protein ratio of 7:1 throughout the day. This may be difficult to calculate and some doctors recommend simply keeping proteins to 12% of total daily calories.

As an aid in calculation, food labels indicate proteins in grams. One gram of protein equals four calories. Good control of protein intake may help minimize fluctuations and wearing-off and may allow some patients to reduce their daily levodopa dosage.

Fruits and Vegetables and Increasing Fiber. Eating whole grains, fresh fruits, and vegetables is the best approach for any healthy life. A diet rich in fruits and vegetables may help protect nerve cell function. Many of these foods are also often rich in fiber, which is particularly important for helping to prevent constipation.

Dietary fiber is the part of food that is not affected by the digestive process in the body. Only a small amount of fiber is metabolized in the stomach and intestine, the rest is passed through the gastrointestinal tract and makes up a part of the stool. There are two types of dietary fiber, soluble and insoluble. Soluble fiber retains water and turns to gel during digestion. It also slows digestion and nutrient absorption from the stomach and intestine. Soluble fiber is found in foods such as oat bran, barley, nuts, seeds, beans, lentils, peas, and some fruits and vegetables. Insoluble fiber appears to speed the passage of foods through the stomach and intestines and adds bulk to the stool. It is found in foods such as wheat bran, vegetables, and whole grains. Fiber is very important to a healthy diet and can be a helpful aid in weight management. One of the best sources of fiber comes from legumes, the group of food containing dried peas and beans.

People whose diets have been low in fiber should increase it gradually. It is best to obtain dietary fiber, soluble or insoluble, in the natural form of whole grains, nuts, legumes, fruits, and vegetables. If it proves difficult to do so, psyllium, a grain naturally found in India, is an excellent soluble fiber supplement (Metamucil, Fiberall, Perdiem Fiber). Fluids are particularly important in preventing constipation.

Fish Oil. Omega-3 fatty acids, which are found in oily fish, are proving to have powerful anti-inflammatory effects and may also be nerve protective.

Click the icon to see an image of foods that contain omega-3 fatty acids.

Dairy Products. A 2002 study reported a higher risk for Parkinson's disease in men (but not in women) who consumed high amounts of dairy products. This association was not linked to fats in dairy foods and high intake of calcium or protein from other sources did not increase the risk. A 2005 prospective study of men found that milk consumption in midlife was associated with increased risk of Parkinson’s disease. As with prior research, the researchers did not find that calcium itself carried a risk. They suggested that some unidentified neurotoxic contaminant in milk may be responsible.

Vitamins.

B Vitamins. Most B vitamins play important roles in the brain and central nervous system. Vitamin B6 (pyridoxine) theoretically has benefits for PD because it is necessary in the production and metabolism of dopamine. Folate deficiency may increase toxic effects against dopamine neural pathways, perhaps by increasing levels of homocysteine, an amino acid that may play a destructive role in many diseases, including heart and neurologic disorders. Some evidence suggests that L-dopa elevates homocysteine levels, so folate supplements may be particularly important for patients. Although the major food sources of B vitamins are meats and dairy products, which are high in protein, these vitamins are also found in whole grains and are added as supplements to commercial cereals.

Click the icon to see an image of the benefits of vitamin B6.

Click the icon to see an image of foods that contain vitamin B6.

Click the icon to see an image of foods that contain folate.

Vitamin E. Researchers have investigated antioxidant vitamins, especially vitamin E, for their effect on the brain. Some, but not all, studies have reported slower mental decline and lower risk for Parkinson's and Alzheimer's disease in people who ate large amounts of foods rich in vitamin E. Such foods include vegetable oils (particularly wheat germ oil), sweet potatoes, turnip greens, mangos, avocados, nuts, sunflower seeds, and soybeans. Vitamin E supplements, however, do not appear to be helpful for slowing disease progression or improving symptoms.

Both smoking and coffee drinking have been associated with lower risk for PD. Researchers are attempting to discover if these substances protect nerve cells. One interesting study suggested that the early disease process in PD produces changes in the dopamine pathway that actually protects an individual from caffeine and nicotine addiction, so that fewer patients have a history of smoking and caffeine. Research is needed to determine why these toxic substances protect against PD.

Smoking and Nicotine Replacement. Cigarette smokers appear to have a 40% lower risk for Parkinson's disease, indicating some protection by nicotine. This finding, of course, is no excuse to smoke, but such protection may help researchers develop new therapies. Studies on nicotine replacement, such as gum or patches, have been conflicting, however, with some short-term studies reporting no benefits. A 2002 study suggested that nicotine replacement may help smokers with early PD, but not nonsmokers.

Coffee Consumption. Studies have indicated that the risk for PD in coffee drinkers is about 30% lower than for non-coffee drinkers. In a 30-year study of Japanese-American men, coffee consumption was associated with a lower risk for Parkinson's disease, and the more coffee they drank, the lower their risk became. Coffee and tea can reduce fluids by increasing urination, however, and so may increase constipation in PD.

Regular use of ibuprofen may reduce the risk of Parkinson’s disease according to research presented at the 2005 annual meeting of the American Academy of Neurology. In this prospective study, people who took at least two ibuprofen tablets per week for at least 1 year lowered their risk of developing Parkinson’s by 35% compared to nonusers or irregular users. For those who took ibuprofen daily, the comparative risk was 38% lower. Other non-steroidal anti-inflammatory drugs (NSAIDS) did not appear to affect disease risk.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

The following dietary supplements are being studied for treatment of Parkinson's disease:

Creatine. Creatine is a nutritional supplement that is sometimes used to improve exercise performance. In 2007, the U.S. National Institutes of Health launched a large-scale clinical trial to study whether creatine can slow the progression of Parkinson’s disease. The trial will enroll patients who have been diagnosed with PD within the last 5 years and who have received levodopa therapy for no more than 2 years.

Coenzyme Q10 (Ubiquinone). Coenzyme Q10 (also called ubiquinone) is an antioxidant being studied for the treatment of Parkinson's disease. This enzyme is important for cellular energy, which may be impaired in PD. In one study, patients who took coenzyme Q10 had slower decline in daily activities and mental and motor skills compared to patients on placebo. However, a 2007 study found that small doses of coenzyme Q10 had no effect on improving Parkinson’s symptoms. Researchers are still investigating whether larger doses given over a long period of time may benefit patients.

Exercise early in adult life may help protect against later development of Parkinson’s disease. Exercise is also an important component of rehabilitation. Physical therapy is extremely important and usually includes active and passive exercise, gait training, practice in normal activities, and if needed, hot or cold treatments, water therapy, and electrical stimulation. Exercise is also essential for well-being and helps patients maintain productive years. To date, no specific approach has been proven to be better than others.

Exercise Programs. Exercise programs are defined as passive or active.

Passive exercise, mostly stretching and manipulation of muscles by a physical therapist, is aimed at preventing muscles from shortening. A passive exercise program that begins with slow and gentle exercises and becomes progressively more intense may improve mobility in patients with early and mid-stage Parkinson's disease.
Active exercises are used to help range-of-motion, coordination, and speed. Patients should continually make efforts to practice movement, even simple ones, such as marching in place, making circular arm movements, and raising the legs up and down while sitting. Patients who enjoy sports or the use of exercise equipment should continue with these activities even if their skills diminish, assuming there are no other medical conditions that would prevent participation.

Gait Training. Practicing new methods for standing, walking, and turning may help retain balance. The following tips may be helpful:

Take large steps when walking forward, raising the toes at the forward step, and hitting the ground with the heel.
Take small steps while turning.
When walking or turning, have the legs 12 - 15 inches apart to provide a wide base.
Do not wear rubber or crepe-soled shoes because they grip the floor and may cause the patient to fall forward.
Using devices that keep a rhythmic beat, such a metronome (a simple device used by musicians to keep time), may be very effective, possibly more than music itself, in helping patients to walk faster and take longer steps. One study found that setting a metronome rhythm to about 10% faster than the patient's fastest gait offers significant improvement over walking to no rhythm at all or to a rhythm that matches the gait.

Reducing Muscle Freezing. The patient should practice regular daily activities that simplify actions and reduce the incidence of muscle freezing. Most often, freezing occurs when a patient begins to move or is presented with an obstacle. The following tips may be helpful:

Rock from side to side.
If the legs feel frozen, lift the toes. This simple action may free spasm in some cases.
Hum marching tunes. In fact, music has been shown to help people move and to get out of bed in the morning. Some studies report that wearing a Walkman and turning music on in situations associated with freezing, such as crossing a street, is helpful.
Divide actions into separate events, which may prevent freezing that occurs from trying to coordinate too many physical operations at one time. For instance, when going through a doorway, approach the door, stop at the door, open it, stop, and then walk through the doorway.
A cane equipped with a laser pointer may be helpful, at least temporarily.
Simply being touched by another person can sometimes release the patient (although a patient with PD should never be pulled or pushed).

Sleep Deprivation Therapy. Sleep deprivation therapy may have a role in treating some cases of depression and some studies are finding some benefits on the depression, tremor, and rigidity experienced by patients. Scientists believe that sleep deprivation produces certain anticholinergic effects, which may improve both depression and Parkinson's symptoms.

Mental Tasks. Mental training may increase dopamine in the brain. Some studies indicate that being mentally fit may be as important for patients as being physically fit. Helpful approaches include:

Select and learn new hobbies that require finger and hand mobility, such as sewing, carpentry, fishing, or playing cards.
Practice deep breathing and relaxation exercises. These may help maintain proper speech control, control tremor, and reduce anxiety.
Both the patient and any caregivers should consider psychological therapy and support for depression and loss of motivation. If psychological therapy is too costly, inexpensive support programs and groups are widely available and can be invaluable for the patient and the family.

Speech Therapy. Speech therapy may help those who develop a monotone voice and lose volume, particularly in combination with medications. There are no well-conducted studies comparing specific speech therapies, but the Lee Silverman Voice Treatment (LSVT) appears to be an example of an effective technique. It has five major components:

Focus on the voice ("think loud/think shout")
High effort (pushes patients to overcome limitations)
Intensive treatment (16 sessions in 1 month)
Calibration (learning to know and accept the amount of effort needed to produce normal sound so it becomes automatic)
Quantification (continuous feedback to objectively document success)

LSVT may help swallowing as well as speech.

Equipment and Devices. A number of devices can be helpful for maintaining stability and preventing falls. The following are some examples:

Rails installed where the patient needs support in getting up or down, such as along the bed and in the bathroom.
Walkers with locking wheels. (Walkers do not appear to be helpful for freezing.)
Chairs with straight backs, firm seats, and arm rests.
Firm mattresses and satin sheets or less expensive sheets with high thread counts. (These are useful for helping patients slide out of bed.)

Resources

www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.aan.com -- American Academy of Neurology
www.apdaparkinson.org -- American Parkinson's Disease Association
www.pdf.org -- Parkinson's Disease Foundation
www.parkinson.org -- National Parkinson Foundation
www.michaeljfox.org -- Michael J. Fox Foundation for Parkinson's Research
www.wemove.org -- Worldwide Education and Awareness for Movement Disorders
www.parkinsonsaction.org -- Parkinson's Action Network

References

Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908.

Murata M, Hasegawa K, Kanazawa I. Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology. 2007 Jan 2;68(1):45-50.

Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007 Jan 4;356(1):29-38.

Schupbach WM, Maltete D, Houeto JL, du Montcel ST, Mallet L, Welter ML, et al. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007 Jan 23;68(4):267-71. Epub 2006 Dec 6.

Storch A, Jost WH, Vieregge P, Spiegel J, Grelich W, Durner J, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q10 in Parkinson disease. Arch Neurol. 2007 July;64.

Voon V, Thomsen T, Miyasaki JM, de Souza M, Shafro A, Fox SH, et al. Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease. Arch Neurol. 2007 Feb;64(2):212-6.

Watts RL, Jankovic J, Waters C, Rajput A, Boroojerdi B, Rao J. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology. 2007 Jan 23;68(4):272-6. Epub 2007 Jan 3.

Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med. 2007 Jan 4;356(1):39-46.

Review Date:
6/4/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Prostate cancer

FitSugar — Wed, 08 Oct 2008 17:35:05 -0700

In This Report

Highlights
Introduction
Prognosis
Risk Factors
Symptoms
Conditions with Similar Sym...
Screening and Diagnosis
Tests to Determine Severity...
Treatment
Treatment Options by Stagin...
Treatment for Localized Pro...
Surgery
Radiation Treatments
Options if Treatments Fail...
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

New Guidelines for Localized Prostate Cancer

In 2007, the American Urological Association (AUA) released updated guidelines for treatment of localized prostate cancer. The guidelines recommend that:

Patients should be classified as low, intermediate, or high risk, depending on their PSA levels, cancer stage, and tumor aggressiveness.
Doctors need to consider patients’ personal preferences and quality of life concerns as well as their clinical status.
Standard treatment options include active surveillance (watchful waiting), surgery, or radiation therapy. Initial androgen deprivation therapy (hormone therapy) is seldom recommended for localized prostate cancer.

New Guidelines for Androgen Deprivation Therapy

The American Society of Clinical Oncology (ASCO) 2007 guidelines recommend that doctors delay androgen deprivation therapy for advanced prostate cancer until patients develop symptoms. When treatment is started, ASCO recommends either removal of both testicles (orchiectomy) or luteinizing hormone releasing hormone (LHRH) drug treatment.
Androgen deprivation therapy can increase the risks for heart disease death and diabetes, according to a 2006 Journal of Clinical Oncology study.

Diagnosis

Experts do not recommend prostate specific antigen (PSA) tests for men over age 70, yet many of these men continue to receive unnecessary tests, indicates a 2006 Journal of the American Medical Association study.
A new investigational test for early prostate cancer antigen-2 (EPCA-2) may be more accurate than the PSA test and may eventually replace it, suggests a 2007 study in Urology.

Genetic Research

Researchers have identified a set of genetic variations that may account for about 68% of prostate cancer cases in African-American men. Scientists hope that further investigation of this chromosomal region may help in developing genetic tests for prostate cancer.

Introduction

Prostate cancer is a malignant tumor that arises in the prostate gland. As with any cancer, if it is advanced or left untreated in early stages, it can eventually spread through the blood and lymph fluid to other organs. Fortunately, prostate cancer tends to be slow growing compared to other cancers. As many as 90% of all prostate cancers remain dormant and clinically unimportant for decades. This high incidence of latent or incidental malignancy is unique to the prostate gland. Most older men eventually develop at least microscopic evidence of prostate cancer, but it often grows so slowly that, as one specialist has written, many men with prostate cancer "die with it, rather than from it."

The prostate gland is an organ that surrounds the urinary urethra in men. It secretes fluid which mixes with sperm to make semen.

Male hormones (androgens) play major roles in the development of prostate cancer. Some research, for example, reports a higher risk with increasing testosterone and a lower risk with increasing estrogen levels. Dihydrotestosterone (DHT) is the principal male hormone in the prostate gland. It affects the size of the prostate gland itself and may play a role in prostate cancer. Nevertheless, researchers have not yet fully clarified the specific mechanisms that may be important in the development of this disease. Most likely, genetic mutations affecting androgens trigger the process. Certain growth hormones, such as insulin-like growth factor-I, are unrelated to testosterone and may increase the risk for prostate cancer.

Description of the Prostate Gland

The prostate gland is located between the bladder and the rectum and wraps around the urethra (the tube that carries urine through the penis). It is basically composed of three different cell types:

Smooth muscle cells, which contract during sex and squeeze the fluid from the glandular cells into the urethra, where it mixes with sperm and other fluids to make semen
Glandular cells, which produce a milky fluid that liquefies semen
Stromal cells (which form the structure of the prostate)

The central area of the prostate that wraps around the urethra is called the transition zone. The entire prostate gland is surrounded by a dense, fibrous capsule.

Functions of the Prostate Gland

The prostate gland provides the following functions:

The glandular cells produce a milky fluid, and during sex the smooth muscles contract and squeeze this fluid into the urethra. Here, it mixes with sperm and other fluids to make semen.
The prostate gland also contains an enzyme, called 5 alpha-reductase, that converts testosterone to dihydrotestosterone, another male hormone that has a major impact on the prostate.

Changes During the Lifespan

The prostate gland undergoes many changes during the course of a man's life. At birth, the prostate is about the size of a pea. It grows only slightly until puberty, when it begins to enlarge rapidly, attaining normal adult size and shape, about that of a walnut, when a man reaches his early 20s. The gland generally remains stable until about the mid-forties, when, in most men, the prostate begins to enlarge again through a process of cell multiplication.

Click the icon to see an image of the male reproductive anatomy.

Prognosis

Prostate cancer is the most common male cancer in the U.S. Only lung cancer causes more cancer deaths in American men. The lifetime probability of developing prostate cancer is about 16%. Each year, approximately 218,890 men in the United States will be diagnosed with prostate cancer, and about 27,050 will die from the disease. According to the American Cancer Society, 5-year survival rates for all stages of prostate cancer have increased during the past 20 years from 67% to nearly 100%.

A survival rate indicates the percentage of patients who live a specific number of years after the cancer is diagnosed. For prostate cancer, the 10-year survival rate is 93% and the 15-year survival rate is 77%. After 15 years, survival rates stabilize. A 2006 study in the Journal of the American Medical Association found that men who are diagnosed with low-grade prostate cancers have a minimal risk of dying from prostate cancer up to 20 years after diagnosis. However, men diagnosed with more severe forms of prostate cancer have a higher risk of dying within 10 years.

Treatment of prostate cancer varies depending on the stage of the cancer (i.e., spread) and may include surgical removal, radiation, chemotherapy, hormonal manipulation or a combination of these treatments.

Because so many prostate tumors are low-grade and slow growing, survival rates are excellent when prostate cancer is detected in its early stages. Cure rates can be as high as 98% in some cases.

Click the icon to see an image of the pelvic lymph nodes.

Locally Advanced. If the disease is at the locally-advanced stage, in which it has spread beyond the prostate but only to nearby regions, it is more difficult to cure, but survival rates can be prolonged for years in many men. (When cancer has metastasized to the pelvic lymph nodes, the outlook is worse than if it has spread to other areas.)

Metastasized Cancer. If prostate cancer has spread to distant organs (metastasized), average survival time is 1 - 3 years, but some of these patients may live longer or die of other causes.

If cancer recurs after initial treatment for early-stage tumors, it is still potentially curable if it is contained within the prostate, although in most cases the cancer has spread. Hormone treatments for such recurring cancers can often prolong survival for years, although the cancer almost always returns again.

Risk Factors

The major risk factors for prostate cancer include genetic, dietary, and environmental factors that affect male hormones (androgens) and make a man more susceptible to this cancer.

Prostate cancer occurs almost exclusively in men over age 40 and most often after age 50. It is estimated that by age 70, about 65% of men have at least microscopic evidence of prostate cancers. Fortunately, the cancer is often very slow growing and older men with the cancer nearly always die of something else.

Heredity plays a role in some types of prostate cancers. Men with a family history of the disease have a higher risk of developing prostate cancer. Having one family member with prostate cancer doubles a man's own risk, and having three family members increases risk by 11-fold.

In 1998, scientists discovered a gene, located on chromosome 1, which may be involved in 1 in 500 cases of prostate cancer. They named this gene HPC1. (HPC stands for “hereditary prostate cancer.”) In 2005, scientists announced another major breakthrough in understanding the genetic components of prostate cancer. Research published in Science suggested that, in some cases, prostate cancer occurs when a specific set of genes merge. The genes are part of the ETS gene family and include ETV1, ETV4, and ERG.

In 2007, three separate studies published in Nature Genetics focused on DNA variations located on chromosome 8 in the 8q24 region. The research suggested that men who carry these genetic variations have a substantially increased risk of developing prostate cancer. The DNA variations may be associated with as many as 32% of prostate cancers in Caucasian men and 68% of prostate cancer cases in African-American men.

Doctors hope that future research will help develop genetic tests to identify men most at risk and, eventually, targeted drug therapy for prostate cancer.

A gene is a short segment of DNA which is interpreted by the body as a plan or template for building a specific protein. Genes reside within long strands of DNA which in turn make up the chromosomes.

African-American men have the world's highest risk for prostate cancer, more than 50% higher than the risk for Caucasian males. The disease is also more lethal among African-Americans. Men who live in Asia have lower risks for prostate cancer, but their risk increases if they move to North America. This indicates that there are unknown environmental or dietary factors that can alter a man's underlying genetic risk of developing this disease.

Socioeconomic Issues. The higher mortality rates in African-American men may be partly due to socioeconomic factors, such as lack of insurance, irregular screening and a late diagnosis, and unequal access to health care.

Dietary Factors. Dietary factors may play some small role in the higher risk in African-American men. This is suggested by the fact that prostate cancer is rare in many parts of Africa.

Biologic Factors. Evidence suggests that African-American and Asian men have certain genetic factors that may affect male hormones differently and may help account in part for the higher risk in the first group and the lower risk in the second.

Higher PSA Levels. African-American men also tend to have higher PSA levels than Caucasians. They are overdiagnosed with prostate cancer by 37% compared to 15% in Caucasians using PSA screening tests.

Chemicals. The relationship between prostate cancer and chemical exposure is controversial. Men whose work involves heavy labor and those exposed to certain metals and chemicals, including cadmium, dimethylformamide, and acrylonitrile, may be at higher risk for prostate cancer. Some studies have indicated that farmers might be at higher risk.

A 2001 study concluded that certain leisure activities may expose men to the same chemicals as those that pose a possible danger in the industrial setting. These chemicals included:

Home or furniture maintenance
Painting, stripping, or varnishing furniture
Activities that involved exposure to lubricating oils or greases, metal dust, or pesticides or garden sprays

Scientists think that specific genes that affect the body's response to viruses may be associated with certain types of prostate cancer. Some theories suggest that there may be a relationship between prostate cancer and infections, such as herpes virus, human papillomavirus, and cytomegalovirus. In 2006, scientists identified a new virus, XMRV, which is 30 times more common in men with prostate cancer who have a genetic mutation with the HPC1 gene. Scientists know that men who have the HPC1 genetic mutation are more likely to get prostate cancer. This new research suggests that the genetic mutation may make them more vulnerable to a virus that causes the cancer. Researchers will continue to investigate XMRV and other possible infectious causes of prostate cancer.

Obesity. Obesity may increase the risk for prostate cancer, particularly more aggressive forms of the disease. Obesity may also make prostate cancer more difficult to diagnose. A 2005 study found that overweight and obese men were more likely to be diagnosed with advanced prostate cancer and to die of the disease than normal-weight men.

Nonmelanoma Skin Cancers and Sunlight. Some studies report that patients with prostate cancer and a history of nonmelanoma skin may have a higher risk for a poorer outlook. Such skin cancers are highly associated with exposure to sunlight. However, sunlight triggers production of vitamin D in the body, which research indicates may help protect against prostate cancer. Prostate cancer rates are, in fact, lower in southern, sunny regions.

Vasectomy. Because testosterone levels remain higher for a longer period in men who had vasectomy, experts have theorized that such men have a greater chance for developing the cancer. While some studies have suggested a higher risk with vasectomy, other studies have reported no higher danger. A rigorous 2002 study from New Zealand, for example, which has the highest vasectomy rates in the world, found no increased risk of prostate cancer from the procedure, even 25 years after the operation. A 2002 study in California, in fact, reported a lower risk for prostate cancer in men who had had vasectomies. It is possible that the higher rates reported in earlier studies may have been due to earlier prostate screening in men who have had vasectomies. Indeed, one study reported that about 25% of doctors screened men with vasectomies earlier for prostate cancer than those without the operation. [See In-Depth Report #37: Vasectomy.]

Click the icon to see an illustrated series detailing a vasectomy.

Click the icon to see an animation on vasectomy.

A Western lifestyle is associated with prostate cancer, so obesity, high-meat intake, and dietary fats have been intensively studied. Results have been inconsistent, however. Certain factors, such as cancer-causing compounds in well-cooked meat or high-calorie intake, may help explain the associations between such dietary factors and cancer risk.

Click the icon to see an image on different types of weight gain.

Fats. Some studies have found an association between high fat-intake and prostate cancer. This association may be explained by other suspected dietary factors for prostate cancer, such as high-calorie diet, high meat intake, and calcium (found in dairy products), all of which are associated with fat intake. The effects of specific fatty acids (compounds that make up fats) may also help clarify the role of fats in prostate cancer. The omega-3 fatty acids in fish (EPA and DHA) and the omega-3 fatty acids found in certain vegetables (ALA) can all protect the heart, but they may have different effects on the prostate.

Marine Omega-3 Fatty Acids. Research indicates that docosahexanoic acid (DHA) and eicosapentaneoic acid (EPA), the omega-3 fatty acids found in fish, may be protective against prostate cancer. Some studies have reported a lower risk for prostate cancer in men who ate fish frequently (two or more times a week).
Alpha-Linolenic Acid. On the other hand, some research has indicated that alpha-linolenic acid (ALA), the omega-3 fatty acid found in certain plants and nuts (flaxseed, canola, walnuts), may increase the risk of prostate cancer. However, some studies suggest that flaxseed, a plant food that is also rich in omega-3 fatty acids, may help slow the growth of prostate tumors.

Meat and High-Temperature Cooking. Some evidence suggests that a high intake of red meat raises the risk for prostate cancer. Because red meat is high in saturated fat, such findings may explain the inconsistencies found in studies that simply look at fat content as a risk for prostate cancer. High-temperature cooking (grilling, broiling, or pan-frying) of meat or poultry has been specifically associated with increased risk for cancer in some studies. Over-cooking meat increases the amount of compounds called heterocyclic amines, which has been associated with cancerous changes in general and prostate cancer in particular, at least in some studies. Cooking meats in liquid does not appear to increase these compounds. As with all dietary studies, some have observed no association between high intake of well-cooked meat and prostate cancer.

Vegetarian Diet. Small studies suggest that a vegetarian diet may be protective. Specific foods may be especially helpful in reducing the risk of prostate cancer:

Whole grain cereals, seeds, and nuts have been associated with a lower risk for prostate cancer. Part of this protection may be due to their high fiber content. Fiber binds to sex steroids and is excreted, carrying the hormones with it. Whole grains also contain selenium, a trace mineral that may have some protective properties.
Many studies have reported a significantly lower risk for prostate cancer with high intake of cooked tomatoes, which are high in a beneficial plant chemical called lycopene. (However, other studies have not reported such protection.)
Soy may also be protective, which may partially explain the low rate of prostate cancer observed in Japanese men and vegetarians (who typically use soy as a protein replacement). Theoretically soy, which is a rich source of an estrogen-like plant compound, may inhibit hormones that promote prostate cancer. Laboratory studies are mixed on such effects, however.
Cruciferous vegetables (cauliflower and broccoli) may have cancer-fighting chemicals.
Boron-rich foods (nuts, red grapes, avocados, and dried fruits) may also be protective.
Green tea. Scientists have speculated that the antioxidants contained in green tea may help to inhibit prostate cancer growth. Investigators are researching the effects of both green tea and green tea extract supplements, but results to date have been inconclusive.

Dairy Products, Calcium, and Vitamin D. Studies have reported an association between consuming large amounts of dairy products and a modestly increased risk for prostate cancer. (Moderate intake has not been associated with a higher risk.) There is some evidence that calcium (contained in dairy products) may increase the risk for prostate cancer by reducing levels of the most active form of vitamin D (1,25 dihydroxyvitamin D). Many studies indicate that vitamin D may help protect against prostate cancer. Men should make sure they are getting enough vitamin D through sunlight exposure, food, or vitamin supplements.

Getting enough calcium to keep bones from thinning throughout a person's life may be made more difficult if that person has lactose intolerance or another reason, such as a tendency toward kidney stones, for avoiding calcium-rich food sources. Calcium deficiency also affects the heart and circulatory system, as well as the secretion of essential hormones. There are many ways to supplement calcium, including a growing number of fortified foods.

Click the icon to see an image of the benefits of vitamin D.

Click the icon to see an image of the sources of vitamin D.

There is some evidence that certain vitamin and mineral supplements (such as vitamin E and selenium) can protect against prostate cancer, and also some evidence that excessive use of supplements may increase risk. In a 2007 National Institutes of Health study, men who took multivitamin supplements more than seven times a week increased their risks for developing advanced prostate cancer and for dying from the disease. The risks were highest for men who had a family history of prostate cancer and for those who took individual supplements of selenium, beta-carotene, or zinc. However, using multivitamin supplements occasionally or once a day does not appear to increase prostate cancer risk.

The National Cancer Institute is conducting a large-scale clinical trial of more than 35,000 men to investigate whether selenium, vitamin E, or a combination of these two dietary supplements can help to prevent prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is the largest prostate cancer prevention trial ever initiated.

Click the icon to see an image of the benefits of vitamin E.

Click the icon to see an image of the sources of vitamin E.

In general, a healthy diet with nutritious fruits and vegetables is the best way to meet your daily requirement of vitamins and minerals.

Alcohol consumption does not appear to be associated with increased prostate cancer risk. A recent study, however, suggested a linear trend between red wine consumption and reduced risk of prostate cancer. In a study of over 1,400 newly diagnosed middle-aged patients with prostate cancer, researchers found that each additional glass of red wine consumed per week reduced the relative risk of prostate cancer by 6%. Researchers theorize that the flavonoids contained in red wine may inhibit tumor cell growth. More research is needed to confirm these results.

Regular physical activity may help reduce the risk of prostate cancer and slow the progression of the disease. The beneficial effects of exercise may be particularly important for older men. A 2006 study found that men ages 65 and older who exercised vigorously for at least 3 hours weekly had a 70% lower risk of being diagnosed with advanced prostate cancer.

Finasteride (Proscar) is a drug used to shrink the prostate in men with benign prostatic hyperplasia (BPH). It blocks an enzyme that converts testosterone to dehydroepiandrosterone (DHEA), the form of the male hormone that stimulates the prostate. Researchers are investigating whether finasteride may help prevent prostate cancer. In the 2003 Prostate Cancer Prevention Trial (PCPT), more than 18,000 men were randomly assigned to receive either finasteride or placebo. The men took the pills daily for 7 years. Results, published in 2003 in the New England Journal of Medicine, indicated that men who took finasteride were 25% less likely to develop prostate cancer than men who took placebo. However, although the finasteride group had fewer prostate cancers overall, those that did develop were higher-grade and more aggressive. Men who took finasteride had more sexual problems, including episodes of erectile dysfunction, but were less likely to have urinary problems, such as incontinence. It is still unclear if finasteride is an appropriate preventive approach.

Frequent ejaculations from masturbation or sexual activity have been associated with a lower risk for prostate cancer. Some experts speculate that certain carcinogens may be concentrated in prostate fluid, so that frequent ejaculation helps eliminate them. Of note, risky sexual activity, such as with multiple partners, increases the risk for sexually transmitted disease, which in turn may increase the risk for prostate cancer.

There is some evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) offer some protection against prostate cancer. NSAIDs suppress chemicals in the body called COX-2, a protein that may cause prostate cancer cells to spread. Standard NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve). However, NSAIDs taken on a long-term basis can increase the risk for heart and gastrointestinal problems.

Symptoms

Prostate cancer usually causes no symptoms in the early stages. As the malignancy spreads, it may constrict the urethra and cause urinary problems.

Urine flows from the kidney through the ureters into the urinary bladder where it is temporarily stored. As the bladder becomes distended with urine, nerve impulses from the bladder signal the brain that it is full, giving the individual the urge to void. By voluntarily relaxing the sphincter muscle around the urethra, the bladder can be emptied of urine. Urine then flows out through the urethra.

Later-stage urinary symptoms typically include:

Weak urinary stream
Inability to urinate
Blood in the urine
Interruption of urinary stream (stopping and starting)
Frequent urination (especially at night)
Pain or burning during urination

Significant pain in one or more bones may indicate the occurrence of metastases (spread of disease). This chronic pain occurs most often in the spine and sometimes flares in the pelvis, the lower back, the hips, or the bones of the upper legs. It may be accompanied by significant weight loss.

Conditions with Similar Symptoms

In up to half of men in their 40s, the prostate begins to enlarge through a process of cell multiplication called benign prostatic hyperplasia (BPH). The symptoms of BPH can mirror late-stage prostate cancer because the enlarging inner portion of the prostate puts pressure on the urethra, which can potentially cause urinary problems. About 80% of men eventually develop enlarged prostates, but only some experience significant symptoms. BPH is a normal condition and is not life-threatening. [See In-Depth Report #71: Benign prostatic hyperplasia.]

Benign prostatic hypertrophy (BPH) is a non-cancerous enlargement of the prostate gland, commonly found in men over the age of 50.

Relationship to Prostate Cancer. Because the prostate enlargement in BPH is affected by testosterone, many men are concerned that it may be related to prostate cancer. Fortunately, current evidence indicates that it has no effect one way or the other. The two conditions develop in different parts of the prostate. BPH occurs in the inner zone of the prostate, while cancer tends to develop in the outer area. A 10-year study found no higher risk for prostate cancer in men with BPH.

Click the icon to see an animation about benign prostatic hypertrophy.

Prostatitis is an inflammation of the prostate, often caused by bacterial infections. Symptoms include urgency, frequency, and pain in urination, sometimes accompanied by fever or blood in the urine.

Screening and Diagnosis

The prostate specific antigen (PSA) blood test is widely used for screening men for prostate cancer. However, there is great uncertainty over whether regular screening has major benefits for most men. The most recent guidelines from the U.S. Preventive Services Task Force report that there is no conclusive evidence that routine prostate screening saves lives. Indeed, it may lead to invasive testing, and to treatments for many men who, considering the slow growth of the cancer, might derive no benefits from them. It is a difficult subject, and men must discuss all aspects carefully with their doctor.

A 2006 study in the Archives of Internal Medicine also suggested that screening tests for prostate cancer may not reduce men’s risk of death. The small study of 1,000 men found no differences in survival between men who had prostate specific antigen tests or digital rectal exams, and men who were not screened. Doctors should inform men of the uncertainty of prostate cancer tests so that patients understand the relative risks and benefits of screening

Standard Screening Tests for Early Detection. Two standard tests are used for early detection of prostate cancer:

Digital rectal examination (DRE). With the DRE, a doctor palpates the prostate in order to feel lumps or masses.
PSA test. The PSA blood test measures the level of a protein called prostate-specific antigen. It is able to detect early prostate cancer, although it has limitations.

If the digital rectal examination indicates the possible presence of cancer, regardless of the PSA results, a doctor may also obtain a visual image of the prostate through an ultrasound procedure called transrectal ultrasonography (TRUS). Only a biopsy, however, in which a tiny sample of prostate tissue is surgically removed, can actually confirm a diagnosis of prostate cancer.

Candidates for Annual Screening. Until major studies report on the survival benefits of prostate screening, expert groups recommend the following:

Men ages 50 - 70 should be offered annual screening. (Some experts believe that men whose PSA levels are under 1.0 and possibly under 2.0 may safely be screened only every 2 years thereafter.)
Men with a family history of prostate cancer and all African-American men should consider annual screening at about age 45.
Experts agree that PSA testing is inappropriate for men over age 70. PSA testing in this age group can cause more harm than good by leading to overly aggressive treatment. Despite this fact, many elderly men continue to receive unnecessary PSA tests.

The best age to start annual screening is under debate. Some experts advocate performing a first PSA test in all men aged 40 and then monitoring anyone whose PSA levels are over 0.60 ng/mL. They argue that such men are at high risk for developing prostate cancer within 25 years. A study presented at the 2007 meeting of the American Urological Association suggested that even a small increase in PSA in men age 44 - 50 may predict whether advanced prostate cancer will develop later in life.

Researchers are working on developing more accurate tests that, hopefully, will one day replace the PSA test. A promising test in development measures a protein called early prostate cancer antigen-2 (EPCA-2). A 2007 study suggested that the EPCA-2 test is highly accurate. It can distinguish between benign prostatic hyperplasia (BPH) and prostate cancer and can evaluate whether or not a man has prostate cancer, regardless of what his PSA levels indicate. Researchers hope that this test may eventually provide better diagnoses of prostate cancer, and help prevent men from receiving unnecessary biopsies.


	DRE alone	PSA alone and in Combination with DRE
Chance of Cancer	Only 20% of men with abnormal DREs have cancer. Unfortunately, 70% of prostate cancers detected with DRE alone have already spread beyond the prostate gland.	The odds of cancer with PSA readings are: 3 ng/mL or below indicates 2% or less chance of cancer. 3 - 10 ng/mL indicates about a 25% chance of cancer. 10 ng/mL and over indicates a very strong chance. Men with abnormal results from both DRE plus PSA tests have a 60% chance for cancer.
Risk of Missed Cancers with Normal Results	About 60% of men who have prostate cancer have normal DRE results.	Some evidence suggests that only performing biopsies at levels above 4.0 would miss over 80% of cancers present below that level in men under 60 years and 65% in older men. As a result, some experts recommend biopsies with PSA levels at 3.0 or below in young men. Still, cancer at low PSA levels is very uncommon, particularly in younger men.

About 90% of all prostate cancers arise in the outer part of the prostate where they may be detected by a digital rectal exam (DRE), which is the simplest and most widely-performed screening procedure. The doctor inserts a gloved and lubricated finger into the patient's rectum and feels the prostate for bumps or other abnormalities. The exam is quick and painless but some men find it embarrassing. It is not very accurate in detecting early cancers, but studies indicate that regular DREs still save lives.

Prostate Cancer is the most common cancer in men in the United States. Prostate cancer forms in the prostate gland, and can sometimes be felt on digital rectal examination. This is one of the purposes of the digital rectal exam.

Prostate specific antigen (PSA) is a protein produced in the prostate gland that keeps semen in liquid form. Prostate cancer cells appear to produce this protein in elevated quantities. Measuring PSA levels increases the chance for detecting the presence of cancer when it is microscopic. There are many unresolved questions surrounding PSA testing. The test is not accurate enough to either completely rule out or confirm the presence of cancer. Relying too much on the test may lead to unnecessary biopsies. Not relying on it enough may miss cancers. It is still unclear if PSA testing is actually saving lives.

Click the icon to see an image of a PSA blood test.

Indications for Biopsy. A biopsy is usually performed to confirm or rule out cancer after screening tests that report:

PSA level of 4.0 ng/mL or higher. Some evidence indicates that men with an initial test showing PSA levels above 4.0 should take a second PSA test several weeks afterward before having a biopsy, since many non-malignant factors can increase PSA levels. (Some experts urge biopsies even if PSA levels fall below 4.0 mg, particularly in men under 60, since lower levels do not necessarily rule out cancer.)
Abnormal digital rectal examination (DRE).

Men with abnormal results from both tests have a 60% chance of prostate cancer. The chances for cancer if only one test is abnormal are considerably lower. To further complicate matters, biopsies themselves may miss very small cancers detected by PSA levels alone.

Factors Affecting PSA Levels. A number of factors and noncancerous conditions can influence PSA levels:

Ethnicity. Normal levels in Caucasian males may be different from those for African-American or Asian men. For example, using PSA screening, one study suggested that 15% of Caucasians and 37% of African-Americans are overdiagnosed with prostate cancer based upon PSA results. Some experts believe that there should be different scales for determining risk among these groups, but there is still not enough information to determine a specific range for various ethnic groups.
Age. PSA levels tend to rise naturally with age, so an elevated level in a man who is 70 may be less serious than the same level in a younger man. Some experts believe that men older than 65 who have low PSA levels are at such low risk for prostate cancer that they may be able to forgo further testing.
Benign Prostatic Hyperplasia (BPH) and Its Treatments. Between 25 - 56% of patients with BPH have elevated PSA levels. Certain treatments for this condition can also elevate PSA.
Prostatitis. About half of men with elevated PSA levels but no signs of cancer on biopsy have signs of prostatitis as indicated by urine and prostate secretion tests. (Prostatitis simply means inflammation in the prostate. Inflammation is usually due to bacterial infection, but it can also be caused by nonbacterial factors.) In one study, screening for prostatitis increased the accuracy of the PSA test significantly and reduced the number of unnecessary biopsies.
Other Noncancerous Conditions. Other noncancerous conditions that can increase PSA levels include surgical procedures or drug treatments for BPH, acute urinary retention, digital rectal examinations, and prostate biopsies themselves.
Ejaculation. Ejaculation within 48 hours before testing can raise PSA levels.

Even with its limitation, the PSA test has increased the number of detectable early-stage and therefore treatable cancers. Because of the slow-growing nature of prostate cancer, however, it is not known whether all of these very early cancers will result in significant or life-threatening disease. It is possible that PSA screening could result in the detection of some possible cancers that would never have bothered the patient and would never have posed a threat to his life.

To improve the accuracy of the PSA tests, particularly when PSA levels have risen to an intermediate range of between 4 - 10 ng/mL, researchers are developing methods for measuring other factors. To date, no test has emerged as clearly superior to the PSA test.

Free PSA Test. A small amount of prostate specific antigen leaks out of the prostate into the bloodstream. There, PSA can circulate without binding to other proteins and is referred to as free PSA. It can also form chemical combinations with other proteins. If cancer is present, PSA is more likely to be bound, and so there is less free PSA in circulation. The free PSA blood test, then, is a ratio of free PSA to the total PSA (free PSA plus chemically bound PSA).

The following results are used to determine if an elevated PSA level could mean cancer:

A free-to-total PSA ratio of 20% or lower, plus total PSA levels of 4 - 10 ng/mL, are suggestive of prostate cancer. (Some experts use 25% as a cut-off, but studies suggest that using this cut-off would miss cancers in many African-American and older men.)
A free-to-total PSA level of more than 20% plus normal or even moderately elevated total PSA tend to indicate the presence of other, benign conditions, such as benign prostatic hyperplasia (but it still does not rule out cancer).

Some studies have reported that adding a test for free PSA may improve prostate cancer detection by roughly 40% and may also reduce the need for unnecessary biopsies. In addition, any cancers that the test misses would not develop into significant disease for many years, providing ample opportunity to identify them before they became serious. Not all studies support its advantages, however, compared to measuring total PSA alone, and to date there is no consensus among doctors for how it can be used.

Complexed PSA Test. Complexed PSA (cPSA) is a form of circulating PSA that is bound to a molecule called alpha1-antichymotrypsin. It represents about 90% of the total PSA in men and is significantly higher in men with prostate cancer than in those with BPH. To date, studies have reported conflicting results on its benefits for diagnosing prostate cancer.

Transition Zone PSA Test. Some tests have been developed to measure the density of the PSA in the transition zone of the prostate gland. (The transition zone is the central area of the prostate that wraps around the urethra.) A major comparison study in 2002 reported more accurate results than with complexed PSA.

An ultrasound procedure called transrectal ultrasonography (TRUS) provides a visual image of the prostate and is used if the DRE indicates the presence of cancer. Ultrasound is not effective as a diagnostic tool by itself because it cannot differentiate very well between benign inflammations and cancer, but the procedure may help to confirm an uncertain preliminary diagnosis and is useful as a guide for needle biopsies. Ultrasound enhancements, such as Doppler imaging or computer modeling techniques called artificial neural networks (ANN), may increase the accuracy of TRUS.

Initial Biopsies. If preliminary tests raise the suspicion of cancer, doctors will perform a biopsy. Biopsy is used to diagnose prostate cancer, and is a very accurate method for predicting the severity of an existing cancer. However, biopsies can still miss cancers if they are very small.

Core Biopsy. The standard method is called a core biopsy, which uses a spring-loaded biopsy device inserted into the rectum. The device propels a needle into the prostate, obtaining a core of tissue, which is examined by pathologists.
Fine Needle Aspiration. A more recent procedure, called fine needle aspiration, is less painful and may be as accurate as a core biopsy if the sample obtained is sufficient for analysis and if it is analyzed by a skilled pathologist.

More than half of the men who have a biopsy experience discomfort and anxiety, with men under 60 reporting higher levels of discomfort than older men. Taking a sedative 1 - 2 hours before the procedure can help reduce distress. Complications of biopsy are low, but urinary tract infection, fever, or bleeding occurs in 0.1 - 4% of men.

Repeat Biopsies. Because a biopsy can miss very small cancer cells, sometimes three or even more biopsies are recommended if cancer is still suspected after negative results, such as when:

PSA levels are high. Two or more biopsies may be taken if a man has very high PSA levels and still has normal results on a biopsy. Even men with mildly elevated PSA (between 4 - 10 ng/mL) who test negative may be given a repeat biopsy. Cancer will be detected in about 10% of this group. Whether a third biopsy is useful in these men if they still test negative after a second biopsy is uncertain.
DRE results are abnormal.
Ultrasound results are abnormal.
The initial biopsy yields microscopic findings that are suspicious.
The initial biopsy detects precancerous cells known as high-grade prostatic intraepithelial neoplasia (PIN). No treatment is necessary with this finding, but these patients should be rechecked every 3 - 6 months for the next 2 years, and then annually.

Doctors may also perform a lymph node biopsy to see if the cancer has spread.

Tests to Determine Severity of Cancer

Once cancer is diagnosed, PSA levels may help to determine its extent. If PSA levels are less than 20 ng/mL, it is possible that the cancer has not spread to distant sites. PSA levels over 40 ng/mL are a strong indicator that cancer has metastasized (spread throughout the body). PSA levels are also monitored after treatments begin. Changes in the level can show if a treatment is working or if the cancer has come back.

Doctors also monitor how quickly PSA levels rise over time. This rate is called PSA velocity (PSAV). The PSAV is very helpful in determining when treatment should begin and which treatment should be used. A high rate of PSAV is considered to be 2 ng/mL a year. Recent research suggests that men with early-stage prostate cancer who have a slow PSAV are more likely to live longer than men with rapidly rising PSA levels.

A number of biological factors are being used or investigated as markers for cancer or its severity:

Chromosomal Sets. The number of chromosomal sets in the nucleus of the tumor's DNA, known as its ploidy, is an important marker for patients in late stages of prostate cancer. Tumors with the normal two sets of chromosomes, called diploid tumors, usually have a more favorable outcome than tumors that have four sets of chromosomes (tetraploid tumors) or have an abnormal number of individual chromosomes (aneuploid tumors).

Blood Vessel Density. The density of blood vessels in the tumor is an important indicator of outcome. The greater the density, the more likely the tumor is to be aggressive.

Serum Acid Phosphatase. High levels of this enzyme indicate a more aggressive disease and the need for intensive treatments.

Testosterone Levels. Higher total testosterone levels may increase the risk for metastasis. A 2000 study found an association with low free testosterone and more extensive prostate cancer, suggesting free testosterone could be a marker for aggressive disease. (Free testosterone, as with free PSA, is not chemically bound.)

Genetic Markers. Researchers have identified a genetic marker (EZH2), which may prove to be an important marker for aggressive prostate cancer. It may, in fact, prove to be a better predictor of outcome than the tumor grade, stage, or surgical margins. Other genes being studied are those that regulate tumor growth (p53, p27, bcl-2).

Other Markers. Other markers being investigated for predicting cancer progression include prostate-specific membrane antigen, prostatic acid phosphatase, and growth factors.

The ProstaScint is a scanning technique that uses tiny amounts of radioactive material with a monoclonal antibody that can attach specifically to prostate cancer cells. A special camera then can detect tumor cells that cannot be detected with other diagnostic tools. It may help doctors make better treatment decisions. The role of this test in the routine management of prostate cancer is still being defined.

If the biopsy indicates cancer, the doctor will order other tests to determine whether or how far the cancer has spread.

Bone Scans and X-Rays. Bone scans and x-rays may reveal whether the cancer has invaded the bones. To perform a bone scan, doctors inject low doses of a radioactive substance into the patient's vein, which accumulates in bones that have been damaged by cancer. A scanner then reveals how much of the radioactive material has accumulated. Arthritis and infections may also produce positive scans. Patients with PSA levels below 20 ng/mL are unlikely to have scans that show cancer in the bone.

A radiotracer is injected into a peripheral vein. As the radiotracer decays, gamma radiation is emitted and is detected by a Gamma camera. When the tracer has collected in the target organ the area is scanned. Radionuclide scans can detect abnormalities such as fractures, bone infections, arthritis, rickets, and tumors that have spread, among other diseases.

Computed Tomography and Magnetic Resonance Imaging. Computed tomography (CT) or magnetic resonance imaging (MRI) scans can further pinpoint the location of cancer that has spread beyond the prostate. Advanced MRI techniques are showing promise for staging and planning treatments.

Click the icon to see an image of a CT scan.

Click the icon to see an image of a MRI.

Bone Metastasis Markers. Researchers are investigating chemical markers, such as amino-terminal propeptide of type I procollagen (PINP), as early indicators of bone metastasis.

Treatment

Because BPH rarely causes serious complications, men usually have a choice between treating it or opting for watchful waiting:

Watchful Waiting. Watchful waiting (also called active surveillance) involves lifestyle changes and an annual examination. Even when choosing watchful waiting, an initial examination is critical to rule out other disorders.
Treatment Options. The primary goals of treatment for BPH are to improve urinary flow and to reduce symptoms. Many options are available. They include drug therapies, minimally invasive procedures, and major surgery.

The choice between watchful waiting and treatment usually depends on a number of factors, such as urine flow rates, prostate size, and PSA levels. Men with BPH who develop symptoms at around age 50 are more likely to need treatment within their lifetimes than older men. Unfortunately, there is no current way to determine who specifically might be at risk for serious problems and need early treatment.

The development of the International Prostate Symptoms Score (IPSS) has made the evaluation of symptoms somewhat easier. This scoring service serves as a benchmark for determining severity. The decision to treat or not to treat is typically based on the guidelines described below, but the ultimate choice is often guided primarily by a man's perception of his own symptoms.

Mild, or No, Symptoms. Men with mild, or no, symptoms (IPSS scores of 7 or below) usually choose watchful waiting even if their prostates are enlarged. BPH eventually progresses to the point of needing treatment in about 15% of men with mild symptoms who wait.

Moderate Symptoms. The choice is most difficult for men with moderate symptoms (scores between 8 - 19) and may simply depend on a man's ability to tolerate them. Some studies have reported that up to 40% of men with moderate symptoms eventually seek treatment, and a quarter require surgery. In a small percentage of patients, symptoms improve.

Severe Symptoms. Men with severe symptoms (scores over 20) nearly always choose treatment, although if their prostate glands are small or normal-sized, symptoms may improve.

If a man opts for treatment, there are several choices. Most experts recommend a staged approach as follows:

Mild Symptoms. Medications are the best choice for men with mild symptoms who decide to have their condition treated. There are two standard choices: alpha-blockers and anti-androgens, nearly always finasteride (Proscar). Specific conditions determine the choice, although most men take an alpha-blocker. Men with mild symptoms who choose surgery only experience minor improvement afterward but face the same risks as patients with more severe symptoms.
Moderate-to-Severe Symptoms. Men with moderate-to-severe symptoms often respond to the same medications as men with mild symptoms. (Combinations of alpha-blockers and finasteride are under investigation.) Recent developments in drug therapy have reduced the number of surgical procedures needed and delayed their use. However, a quarter of men with moderate symptoms, and even more men with severe symptoms, eventually need surgery. If a man chooses surgery, there are many choices. Transurethral resection of the prostate (TURP) is the standard procedure, but less invasive procedures, particularly those using heat or lasers to destroy prostate tissue, are gaining prominence.

Click the icon to see an illustrated series detailing transurethral resection of the prostate surgery.

The most common reason for choosing surgery is obstruction of the bladder outlet, which causes urinary retention. Surgery is also typically a reasonable option when BPH is clearly related to one or more of the following conditions:

Recurrent urinary tract infection.
Hematuria (blood in the urine). Studies have suggested that when hematuria is left untreated, two-thirds of patients continue to bleed and one third require surgery. The drug finasteride may help some men with this condition and should probably be tried before surgery.
Bladder stones.
Kidney problems.
Some experts believe that surgery might benefit patients for whom an early diagnosis of prostate cancer is important. Unsuspected prostate cancer is detected during surgery in about 15% of cases.

The greatest improvements resulting from surgery are usually increased urinary flow and reduced urine retention. In one study, men who chose surgery reported more worry and depression before the procedure, but afterward they had less depression and anxiety than those who had chosen medication. Often, however, the benefits of surgery are not permanent.

Treatment Options by Staging and Grading

Stages indicate the extent of the cancer:

Stage I and stage II cancer are considered early stage. The cancer is localized and has not spread outside the prostate gland.
Stage III, locally advanced cancer, means that the cancer has spread into the seminal vesicles (glands at the base of the bladder, which are connected to the prostate gland and help produce semen).
Stage IV is advanced cancer. The cancer has spread to the lymph nodes and other tissues or organs.

Experts have devised treatments based on classification systems, including staging and tumor grade. However, there are no clear-cut answers on the best treatments for particular stages. In addition to staging, other factors must be considered. These factors include the patient’s age, overall health status, and personal preferences concerning side effects and quality of life. In addition to standard treatments, patients may also wish to consider enrolling in clinical trials of investigational treatments.

The U.S. National Cancer Institute recommends the following treatment options by cancer stage:

Tumors: T1a, N0, M0, G1, Stage A

Active surveillance
Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy after surgery
External beam radiation therapy
Implant radiation therapy (brachytherapy)
Clinical trial options include high-intensity focused ultrasound

Click the icon to see an illustrated series detailing prostatectomy surgery.

Tumors: T1a - c, N0, M0, any G, Stage A2, B1, or B2

Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy after surgery
Active surveillance
External beam radiation therapy with or without hormone therapy
Implant radiation therapy (brachytherapy)
Clinical trial options include radiation therapy with or without hormone therapy; ultrasound-guided cryosurgery; hormone therapy followed by radical prostatectomy

Tumors: T3, N0, M0, any G, Stage C

External beam radiation with or without androgen deprivation therapy (hormone therapy)
Androgen deprivation therapy
Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy following surgery
Radiation therapy, androgen deprivation therapy or transurethral resection of the prostate (TURP) to relieve symptoms
Clinical trial options include ultrasound-guided cryosurgery

Click the icon to see an illustrated series detailing transurethral resection of the prostate.

Tumors: Any T, any N, any M, any G, Stage D1 - D2

Androgen deprivation therapy
External beam radiation therapy with or without androgen deprivation therapy
Radiation therapy or transurethral resection of the prostate (TURP) to relieve symptoms
Active surveillance
Clinical trial options include radical prostatectomy with surgery to remove both testicles (orchiectomy)

Treatment options are dependent on various factors, including prior treatment, site of recurrence, coexistent illnesses, and individual patient considerations.

Patients whose cancer recurs locally after prostatectomy: Radiation therapy, androgen deprivation therapy.
Patients whose cancer recurs locally after radiation therapy: Androgen deprivation therapy, prostatectomy (very select patients).
Patients whose recurrent cancer has spread: See treatment options for stage IV.

Treatment for Localized Prostate Cancer

Choosing the best treatment for localized prostate cancer (T1 or T2) is generally based on the patient's age, the stage and grade of the cancer, overall health status, and the patient's personal preferences for the risks and benefits of each therapy.

Patients have three main options:

Active surveillance, also called watchful waiting, involves monitoring the tumor for cancer progression to determine if and when treatment should be started.
Surgery (radical prostatectomy) removes the prostate gland. The vessels that carry semen and surrounding tissue may also be removed. Studies indicate that compared to watchful waiting, radical prostatectomy may lower the risk of cancer recurrence and death, particularly for younger men with aggressive tumors.
Radiation therapy targets the tumor either externally (external beam radiation) or internally (implanted “seeds”).

In 2007, the American Urological Association (AUA) released guidelines for the treatment of localized prostate cancer. The guidelines recommend that patients should be classified as low, intermediate, or high risk. Doctors determine the risk category by using criteria such as PSA tests, tumor aggressiveness, and the clinical stage of the tumor.

Among the AUA’s treatment recommendations:

Compared with active surveillance, radical prostatectomy may lower the risk of cancer recurrence and death.
For men at intermediate and high risk, adding androgen deprivation therapy to external beam radiation may improve survival. A higher dose of external beam radiation also improves the odds for survival.
Initial (first-line) androgen deprivation therapy is seldom recommended for localized prostate cancer except for the relief of symptoms in patients with poor prognoses. Androgen deprivation therapy can increase the risks for diabetes and heart disease.
Patients with localized prostate cancer should have the opportunity to enroll in clinical trials investigating new types of therapy.

Conflicting Data on Survival Rates. To date, neither treatment nor active surveillance has emerged with a definitive survival advantage. Several studies from 2005 and 2006 suggested that treatment provides a survival advantage over watchful waiting for some men with early-stage prostate cancer. A 2005 New England Journal of Medicine study reported that men who had a radical prostatectomy before age 65 had a reduced risk of death from prostate cancer, death from other causes, localized cancer progression, and metastases than men who chose watchful waiting.

Similarly, research presented at the 2006 Prostate Cancer Symposium found in a study of nearly 50,000 men with early-stage prostate cancer that men who had radiation or surgical treatment had a 30% lower risk of death than men who were randomly assigned to watchful waiting. However, a 2005 Journal of the American Medical Association study advised against aggressive treatment for localized low-grade prostate cancer. The study found that men with low-grade prostate cancer had a small risk of cancer progression even after 20 years of watchful waiting or hormonal drug therapy

Imperfection of Classification System. The classification systems are not perfect. Even if tumors are rated in low stages and grades and are treated accordingly, undetected cancer cells may escape and spread beyond the prostate. Other factors, such as the man's age and medical condition, must be included in determining whether aggressive treatments or conservative measures are appropriate.

Specialty Bias. Patients should be aware that doctors may be biased to prefer a specific treatment depending on their specialty. For example, in one study the following treatments were favored for patients who were generally appropriate candidates for either surgery, radiation, or watchful waiting:

93% of urologists recommended radical prostatectomy.
72% of radiation oncologists recommended radiation. (And 82% thought that radical prostatectomy was overused.)
Virtually none of the doctors recommended watchful waiting for higher-risk disease. When in doubt, patients should always seek a second opinion to help them make this important choice.

Quality of Life. Surgery and radiation both have potentially distressing side effects, including the possibility of impotence, incontinence, or both. A man must weigh his own emotional responses to the possibility of these side effects versus the possible stress of watchful waiting.

In general, differences in quality of life after surgery or radiation treatment have to do with the specific effects of each type of treatment:

Radiotherapy generally causes more bowel problems than surgery, 30 - 35% versus 6 - 7%, according to a 2001 study. In a 2003 review, the risk for impotence from radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy.
Prostatectomy causes more urinary incontinence (39 - 49% versus 6 - 7% for radiotherapy patients) than radiotherapy. Risks for impotence range from 66% after nerve-sparing prostatectomy to 87% after cryotherapy. In spite of these adverse effects, a 2002 study reported no meaningful differences in well-being or quality of life during a 4-year period for men who chose surgery versus those who chose watchful waiting.
Active surveillance could lead to cancer growth that eventually obstructs the urinary tract (which can happen with the treatments as well). It may also impose an emotional burden on men who live with the possibility of progressive cancer and its difficult treatments. Some who decide to wait become what some doctors refer to as the "walking worried," men who are constantly concerned with their PSA levels. Because aggressive treatment reduces such anxiety, some studies reported that years after surgery, about 75% of men said they would chose it again, in spite of the significant side effects.

Watchful waiting involves lifestyle change and careful monitoring for cancer progression. Over the last several years, watchful waiting has evolved into a strategy called “active surveillance” or “delayed surgical intervention.” With this approach, patients have a digital rectal exam and PSA blood test every 6 - 12 months. If test results indicate cancer progression, then treatment options (surgery, radiation, drugs) are considered. Patients should exercise and eat healthy foods. Patients should report symptoms such as weight loss, pain, urinary problems, fatigue, or impotence to their doctors.

Candidates. Active surveillance may be most appropriate for the following patients:

Men in their late 70s and older. More aggressive therapies (surgery and radiation) are usually recommended for men in their 50s and younger. The choice for men in their 60s and early 70s is more problematic. The general recommendation is that aggressive therapy is suitable for those who have a life expectancy of more than 10 years and who have localized but mid- to high-grade tumors. The tumor grade may be the best guide for determining the risks in choosing watchful waiting.
Elderly men with early-stage (T0 - T2) low-grade tumors.
Men with low-to-moderate (3 - 13 ng/mL) PSA levels.

Some experts think that because prostate cancer grows so slowly, it is likely that older men will die from causes unrelated to the cancer. There is therefore little potential benefit from surgery or radiation, with both posing a risk for impotence and incontinence. However, some recent surveys suggest that more men are choosing treatment (especially surgery) over active surveillance. The choice is a difficult one. It is important that patients find a doctor who can provide them with all the necessary information so that they can make an informed decision.

In men whose cancer is confined to the prostate, surgical resection (radical prostatectomy) offers the potential for cure. Cure rates from initial surgery in men with localized cancer are about 70%, depending on tumor stage, tumor grade, and PSA levels. Research suggests that surgery provides long-term cancer control. Most patients can consider themselves disease-free if their PSA levels remain undetectable 10 years after surgery.

Candidates. Radical prostatectomy is a consideration for men who meet all of the following criteria:

In good health and with a life expectancy of 10 years or more. As average life expectancy in men has increased, more older men are becoming candidates for surgery. Complication rates are higher the older a man is, however.
The cancer has not spread beyond the prostate gland.
The cancer is potentially life threatening. (In general, a life-threatening tumor is indicated by volumes more than 0.2 cc and Gleason grade scores greater than 5.)

The procedure is more likely to cause incontinence (up to 50%) than radiation treatment but has fewer bowel complications. Impotence rates are about the same. Surgery for prostate cancer may be particularly difficult in men who have had transurethral resection of the prostate (TURP).

Radiation therapy (or radiotherapy) is administered as external beam radiation or as brachytherapy (radiation implants). It may be used as the sole primary treatment for localized prostate cancer; 5-year survival rates are similar to those of surgery.

Candidates. Radiation is considered for men with one or more of the following characteristics:

Being older and, particularly, having other medical problems.
Cancer has extended beyond the prostate capsule but has not spread to the lymph nodes or further.
Being a good surgical candidate, but having decided against an operation.

The risk for incontinence (less than 10%) is much lower than with surgery, although bowel problems occur in about a third of patients. Impotence rates are about the same.

Androgen Deprivation Therapy With Radiation. Hormonal (“androgen deprivation”) drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used. Hormone therapy can also be given at the same time or following radiation.

An important study published in 2004 in the Journal of the American Medical Association (JAMA) found that for men with localized prostate cancer, a 6-month course of androgen deprivation therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be given for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

A 2005 JAMA study suggested that PSA velocity (PSAV) may help doctors decide which patients should receive androgen deprivation drugs along with radiation therapy. PSAV lets doctors calculate how quickly a patient’s PSA level has risen. Researchers found that men who had at least a 2.0 ng/mL increase in PSA levels during the year before their cancer diagnosis had a high risk of dying after external beam radiation therapy, even though they had low-grade prostate cancer. The study suggests that men with this particular PSAV history should consider combining radiation therapy with androgen deprivation drugs.

Surgery

Radical prostatectomy is the surgical removal of the entire prostate gland along with the seminal vesicles (the vessels that carry semen) and surrounding tissue. The incision can be made in one of the following regions:

Retropubicly (through the abdomen and under the pubic bone, exposing the entire surface of the prostate).
Through the perineum (the skin between the scrotum and the anus).

The gland and other structures are then removed. The operation lasts 2 - 4 hours. Advanced surgical techniques, such as minilaparotomy and laparoscopy, are being developed for radical prostatectomy. These techniques use smaller incisions, are less invasive, and may cause fewer complications.

Click the icon to see an illustrated series detailing prostatectomy surgery.

Nerve-Sparing Techniques. Surgical procedures have been refined over the years, and many operations for localized low-grade prostate cancer now spare the nerves that control erection.

A bilateral nerve-sparing procedure saves the nerves on both sides of the sex organs.
A unilateral procedure saves nerves on only one side.

Nerve-sparing techniques can improve quality of life. The ability for sexual intercourse recovers in about a third of patients at 3 years and nearly 60% at 5 years after surgery. (Rates vary depending on certain factors, such as the patient's age -- the younger the better.) In cases where the tumor is bulky and undifferentiated, nerve-sparing techniques may not be appropriate.

Convalescence. Patients remain hospitalized for up to 2 weeks. A temporary catheter used to pass urine is kept in place when the patient is sent home and usually removed about 3 weeks after the operation. The convalescent period at home is about a month. In general, younger patients with early-stage cancers recover fastest and experience the fewest side effects.

Complication rates vary after radical prostatectomy and usually depend on the age of the patient and the experience of the surgeon and medical center. They can range from 4% in men in their 40s to 14% in men over age 70. Complication rates are 10 times higher in patients who have prostatectomy because of cancer recurrence after radiation treatment.

Complications include the usual risks of any surgery, such as blood clots, heart problems, infection, and bleeding. Complications specific to radical prostatectomy, (incontinence, impotence, and contracture of the bladder neck), are discussed below. The mortality rate is very low, about 0.4%.

Quality of life usually improves shortly after surgery, and recovery from certain complications, such as incontinence and sexual function, can continue to occur even over years.

Urinary Incontinence. Urinary incontinence is a common complication and a more distressing side effect of surgery for most men than sexual dysfunction. When the urinary catheter is first removed following surgery, nearly all patients lack control of urinary function and will leak urine for at least a few days and sometimes for months. Major medical centers report that continence returns within about 18 months for nearly all men younger than age 70 and in the great majority of men older than 70. The average time for return of continence in one center was just 1.5 months.

Click the icon to see an image of catheterization.

A number of approaches may help prevent or treat incontinence:

Nerve-sparing techniques can help prevent incontinence, although even in experienced centers, 8% of patients will have some postoperative incontinence, and this rate is much higher (up to 50%) in many community medical centers.
A procedure called endopelvic anterior urethral stitch (EAUS) used with prostatectomy appears to reduce urinary incontinence. In one small study, 75% of selected patients recovered continence in a month. The procedure requires a simple stitch at the front of the urethra.
Kegel exercises, contracting and relaxing the muscles used to shut off the urinary stream, strengthen the muscles on the pelvic floor and are reported to be very beneficial for many men.

If incontinence persists beyond a year, patients may require drug therapy or surgery. Collagen injections into the urethra, bladder neck suspension surgery, or a urinary sphincter implant may be helpful for men who have chronic incontinence. [See In-Depth Report #50: Urinary incontinence.]

Impotence. Studies suggest that about 40% of men have problems with erection after the procedure. In one study, however, more than 70% said they would have the procedure again. Nerve-sparing procedures are proving to be helpful in reducing impotence as well as incontinence.

Sildenafil (Viagra) may help restore potency on average in about a third of patients, but some men may do better than others. In one study, for example, 80% of younger men who were potent before surgery and had bilateral nerve sparing procedures responded to the drug. (Only 40% responded with only unilateral procedure.) Sildenafil is unlikely to be effective for men who had unilateral or no nerve sparing procedures. In those who respond, sildenafil may provide a benefit for years. Sildenafil may take 9 months or longer to become effective. Men who take it may benefit from alprostadil injections started right after surgery to preserve elasticity and help prevent scarring.

Early treatments with alprostadil injections may helpful in restoring erectile function in any case. This treatment maintains blood flow in the penis, and some research suggests that impotence after prostate surgery may be due in part to injury to these blood vessels. In one study, men administered injections every other night for 6 months. They then started taking sildenafil 3 months after surgery. At 6 months, 82% of these men achieved penetration compared to only 52% of men who took Viagra only. The vacuum pump may serve a similar purpose as the injections. [See In-Depth Report #15: Erectile dysfunction.]

Even when erectile function is preserved, men may experience other sexual problems:

Erections may not be as rigid as before the operation.
Orgasm and sexual sensation may be altered.
Patients who retain potency may suffer from retrograde ejaculation, also known as dry ejaculation. During ejaculation, semen travels backward into the bladder, causing infertility.

Fecal Incontinence. Radical prostatectomy can also cause fecal incontinence. The risk may actually be higher in men undergoing nerve-sparing procedures.

Contracture of the Bladder Neck. Another common postsurgical complication is contracture of the bladder neck at the point where it has been stitched to the remainder of the urethra. Contracture usually occurs within the first 3 months after the operation, causing a sharp decrease in urinary stream. The condition can be treated by dilation or surgery on the bladder neck, and rarely recurs.

Pelvic lymphadenectomy is the surgical removal of the pelvic lymph nodes. It is usually performed at the same time as prostatectomy. If the surgeon suspects that cancer has spread beyond the prostate, the surgeon will perform the lymphadenectomy as part of the operation. Some surgeons do this procedure as a matter of course when performing prostatectomy, since it has few complications and adds information on the state of the disease. The lymph nodes are removed through an incision in the lower part of the abdomen, using conventional surgery or laparoscopy, a less invasive variation. The nodes are immediately examined. If they show signs of cancer, metastasis has occurred. In such cases, the operation is usually stopped and the patient is offered radiation or hormone treatments.

Click the icon to see an image of the pelvic lymph nodes.

Transurethral resection of the prostate (TURP) involves removing a section of the prostate with a surgical instrument (resectoscope) that is inserted through the urethra. TURP may be used to control urinary symptoms in men who are not good candidates for curative therapy due to advanced age, health status, or other reasons. TURP is also used as a treatment for benign prostatic hyperplasia (BPH).

Cryosurgery is an alternative to standard prostatectomy. The goal of cryosurgery is destruction of the entire prostate gland and possibly surrounding tissue. Steel probes are inserted through the skin between the anus and the rectum and into the prostate. Liquid nitrogen is pumped through the probes to freeze all prostate cells, both healthy and cancerous. For success, cryosurgery requires a uniformly frozen area. The dead cells are absorbed and eliminated by the body. Patients can leave the hospital in 2 - 3 days.

Candidates. Cryosurgery may be considered for patients with:

Early stage local cancer
Cancer that has recurred after radiation treatments
Large primary tumors that the surgeon wishes to reduce
Possibly tumors that have spread beyond the prostate if they have not yet reached the lymph nodes

Strong predictors of treatment failure include:

A history of both hormonal and radiation treatments
Tumor grades 8 and above
PSA levels of more than 10 ng/mL

Complications. Complications are similar to those of standard prostatectomy, but incontinence rates are much lower. Impotence rates, however, are much higher. Nevertheless, 96% of patients report that they are satisfied with the results. Incontinence and other side effects may be higher in patients who have had previous radiation treatments. Other significant complications include scarring and narrowing of the urethra, and fistulas (abnormal passages from internal organs to the skin or between two internal organs).

Radiation Treatments

The two major radiation treatments are:

External beam radiation
Brachytherapy (internal radiation)

Both treatments have generally equal success rates. Research presented at the 2006 Prostate Cancer Symposium indicated that the two therapies work equally well for treating localized prostate cancer. In some cases, both techniques may be used in high-risk patients.

In external beam radiation therapy, a doctor focuses a beam of radiation directly on the tumor for 35 3-minute treatments given 5 times a week over 7 weeks. 3-D conformal techniques use computers and a three-dimensional image of the prostate to target the tumor precisely, using high-dose radiation beams. It poses a lower risk for inflammation. Men who have had transurethral resection of the prostate (TURP) or have a history of lower urinary tract symptoms may be particularly good candidates for 3D conformal techniques.

According to the 2007 American Urological Association guidelines for treatment of localized prostate cancer, patients considering external beam radiation should know that higher radiation doses may reduce the risk for cancer recurrence and improve survival outcome.

Brachytherapy is an outpatient technique that implants radioactive "seeds" directly into the prostate. Implants can be temporary or permanent. Temporary implants are usually accompanied by external beam radiation. This procedure requires more skill than external beam radiation therapy and, even with experienced doctors, the distribution of radioactive seeds is uneven in 15% of cases, increasing the risk for insufficient doses.

Computerized systems are being developed to help oncologists optimize seed placement and allow precise treatment for each patient and higher radiation doses. Eventually, it could improve tumor control, reduce side effects, and cut costs.

It is common for PSA levels to temporarily rise, or "bounce," following seed implantation without it being a signal for cancer recurrence. This effect can produce anxiety and can interfere with the diagnosis of true recurrence.

Candidates. Studies suggest that brachytherapy is useful for select patients, specifically those with prostate volumes less than 60 mL and who have early-stage prostate cancer (T1 or T2 tumors, a Gleason grade lower than 7, and PSA levels below 10 ng/mL). It may be beneficial in patients with inflammatory bowel disease or with cancer close to the bowel. Poorer candidates for brachytherapy include men who have had TURP and patients with advanced cancer, high-grade tumors, or very enlarged prostate glands.

The side effects of radiation therapy include most of those of surgery, but the risks for impotence and incontinence are considerably lower. A 2000 study concluded that adjuvant radiation therapy (given right after surgery) in moderate doses does not increase the risk for long-term urinary incontinence or sexual dysfunction beyond that of surgery alone.

Gastrointestinal Complications. Complications in the gastrointestinal are common. Short-term effects include nausea and loss of appetite. Diarrhea is a very common side effect and can last for the duration of therapy. It is usually treated with Lomotil. A few patients have diarrhea flare-ups for years afterwards. Less than 1% suffer more serious intestinal problems.

There is potential for injury to the rectum with brachytherapy. Ulcers in the rectum occur in more than 10% of patients, but the risk decreases with greater experience in the technique.

Urinary Problems. The risk for incontinence is about 7 - 20%. Patients treated with radiation may experience a painful, but usually temporary, urinary tract inflammation. About 10 - 15% of patients develop a long-term urgent and frequent need to void their bladder. Brachytherapy carries a lower risk for urinary incontinence.

Scarring and narrowing of the urinary tract (stricture) may occur, particularly in men who had TURP performed within a short time before radiation treatment. In such men, radiation treatments should be delayed by 4 - 6 weeks. If the prostate has been injured or damaged or the bladder is easily irritated, side effects with brachytherapy may actually be worse than with other procedures.

Impotence. In a 2003 review, the risk for impotence following radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy. Still, very few studies on brachytherapy have lasted more than 2 years, so more research is needed.

Sildenafil (Viagra) may help many men experiencing impotence following radiation therapy for local prostate cancer. Early use of both alprostadil injections and sildenafil may be even more effective. Other treatments may also be useful. [See In-Depth Report #15: Erectile dysfunction.]

Investigators are testing radiation treatments that use a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard proton radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions.

High-Intensity Focused Ultrasound (HIFU). Studies are reporting promising results with an intensive ultrasound procedure called transrectal high-intensity focused ultrasound (HIFU). It allows for very precise minimally invasive removal of tissue in local prostate cancers. It may eventually prove to be an alternative to radiation therapy. More research, with long-term follow up, is needed.

Radiofrequency. Radiofrequency is being used to heat and destroy the prostate. Early studies suggest that this is a promising approach.

Options if Treatments Fail

Rising PSA Levels. If prostate cancer has been eliminated, PSA levels should drop to 0.5 ng/mL or less after treatment. A sudden rise or persistently elevated PSA levels after treatment are often indications that prostate cancer persists:

If PSA levels are above 2.0 ng/mL, then cancer is most likely still present.
If PSA levels are between 0.5 - 2.0 ng/mL, the situation is less clear. One study indicated that measuring free PSA may help determine the status of the cancer in such patients. An average free PSA of 27% indicated that cancer had been eliminated, while an average of 15% meant that cancer was still present.

Note: It is common for PSA levels to temporarily rise following radiation seed implantation without signaling cancer recurrence.

Rising PSA levels do not necessarily mean that the cancer has spread or even that the cancer will recur during a man's lifetime. An actual cure is still possible if the cancer is localized within the prostate. In one study, 64% of patients with rising PSA levels after surgery still had cancer confined to the prostate. Indications of a poorer outlook in this study included:

Cancer penetration of the prostate capsule
Positive surgical margins (microscopic evidence of cancer cells at the very edge of the resected specimen)
Invasion of nearby vessels or lymph nodes

Still, among the men in the study, after 7 years only 3% of patients had died of prostate cancer. After 15 years, only 19% had evidence of recurrence. Other markers for persistent cancer are under investigation. For example blood tests that show low levels of acid phosphatase (ACP) before treatments may predict a higher chance for recurrence-free survival.

Treatment for recurring cancer is not always clear-cut. If the cancer recurs locally, cure may still be possible:

Surgery and androgen deprivation therapy may be considered for patients who were first treated with radiation.
For patients who were initially treated with surgery, radiation or androgen deprivation therapy are both options.

If the disease has already spread or if the doctor suspects that it may have spread, the patient is typically given androgen deprivation therapy. Chemotherapy drugs in combination with hormonal drugs are being investigated for patients who fail surgery or radiation.

A 2005 study in the Journal of the American Medical Association suggested three factors that may help doctors and patients decide if additional treatment is needed if cancer recurs after surgery:

How quickly PSA levels double after surgery (shorter time equals higher risk)
How quickly the cancer recurred after surgery (shorter time equals higher risk)
Gleason score (higher score suggests more aggressive tumors and greater risk)

Patients at high risk are more likely to die from the recurrent cancer and should be considered for additional treatments. Patients at low risk face a lower likelihood of death from prostate cancer and probably do not require more treatment. The study found that for patients at low risk, the time to death after cancer recurrence was very long, generally lasting more than 16 years.

Androgen Deprivation Therapy. Androgen deprivation therapy, also called androgen suppression therapy or hormone therapy, involves blocking the effect of male hormones such as testosterone through medical (drugs) or surgical castration. Androgen suppression therapy is not recommended as a first-line approach for most men with localized prostate cancer. It is usually given to patients with recurrent, progressive, or advanced prostate cancer. It may also be given for a relatively brief time in combination with external beam radiation.

Although androgen deprivation therapy slows the growth of most prostate cancers, it can have serious side effects. The American Society of Oncology’s (ASCO) 2007 guidelines do not recommend the early use of hormone therapy. However, ASCO does recommend that patients start therapy once they begin to experience cancer symptoms. Patients who defer therapy should have regular doctor visits every 3 - 6 months to monitor their condition.

Salvage Prostatectomy. Salvage prostatectomy is sometimes performed after unsuccessful radiation treatment if the cancer is still local. The odds of the procedure's success are only 10 - 64%. Many experts recommend against salvage prostatectomy in most cases of radiation failure. Severe complication rates for salvage prostatectomy are very high: 10 times that of men who have not had radiation. For example, incontinence after salvage prostatectomy is often untreatable with medications, collagen implants, or other standard treatment measures.

Salvage Cryosurgery. Salvage cryosurgery may be effective in certain patients who fail external beam radiotherapy. The best candidates are those with Stage II cancer or less and PSA levels below 10 ng/mL.

Adjuvant and Salvage Radiation. Radiation is proving to help patients who still show detectable levels of PSA after surgery (generally 2 ng/mL or less). It may even be useful years after surgery if PSA levels rise. Depending on timing, radiation after treatment failure is referred to as either:

Adjuvant radiation is radiation therapy performed within 6 months after radical prostatectomy. One area of controversy is whether to use adjuvant radiation after surgery on patients whose PSA levels are very low or undetectable but who have other test results that indicate the cancer is likely to spread. Patients with adverse findings and low PSA have to weigh the potential complications of radiation therapy against the odds of recurrence without it, which are about 20 - 30%. A small 2006 study found that adjuvant radiation worked much better than salvage radiation for men with advanced (stage III or IV) local prostate cancer. However, a 2007 study indicated that adjuvant radiation in men with advanced cancer may reduce the risk of cancer recurrence but does not improve length of survival.
Salvage radiation is radiation therapy more than 6 months after surgery. A 2004 study suggested that salvage radiation could be more beneficial than previously thought, even for men with aggressive prostate cancer. Researchers studied 501 men who had undergone radical prostatectomy (surgical removal of the prostate gland) and subsequently received radiation treatment for recurrent cancer (as indicated by rising PSA levels). Men with lower Gleason scores and lower PSA levels benefited the most from salvage radiation. However, even men with higher-grade cancers were able to delay metastatic cancer progression as long as they received radiation at an early stage while their PSA levels were relatively low (less than 2.0 ng/mL).

Other Treatments

Male hormones (called androgens), particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. When prostate cells, both healthy and cancerous, are deprived of androgens, they no longer proliferate and eventually die.

Androgen deprivation therapy (also called androgen suppression therapy or hormone therapy) uses drugs or surgery (orchiectomy) to suppress or block male hormones (androgen) -- particularly testosterone and dihydrotestosterone -- that stimulate the growth of prostate cells. Androgen deprivation therapy is used for advanced and metastatic cancer and may be used if treatment for localized prostate cancer has failed and cancer recurs (as indicated by rising PSA levels). Side effects can include decreased bone density, decreased muscle mass, hot flashes, depression, fatigue, weight gain, enlarged breasts, and high cholesterol levels. Evidence also indicates that androgen deprivation therapy increases the risk for diabetes and death from heart disease.

There has been some debate about when androgen deprivation therapy should be initiated. In 2007, the American Society of Clinical Oncology (ASCO) published clinical guidelines for androgen deprivation therapy in patients with recurrent, progressive, or advanced prostate cancer. The guidelines recommend that hormone therapy should, in general, be delayed until patients begin to experience symptoms from their cancer. However, when therapy is deferred, patients should regularly visit their doctors every 3 - 6 months for careful monitoring of their condition.

ASCO recommends either removal of both testicles (bilateral orchiectomy) or injections with luteinizing hormone-releasing hormone (LHRH) as initial androgen deprivation treatments. Combining nonsteroidal antiandrogen drug therapy with orchiectomy or LHRH may also be considered.

Doctors vary widely on their opinions of androgen deprivation therapy. A 2006 study found that the decision to use hormonal therapy depends more on a patient’s urologist than on the patient’s tumor or other factors.

Androgen deprivation therapy includes:

Hormonal Drugs. The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormone (LH-RH) agonists.

Orchiectomy. Orchiectomy is the surgical removal of the testicles. It is the single most effective method of reducing androgen hormones, but it is considered an extreme procedure. Studies do not indicate that it significantly improves survival rates. Orchiectomy plus radical prostatectomy may delay progression in patients with cancers that have spread only to the pelvic lymph nodes. Combining orchiectomy with antiandrogen drug therapy adds a modest benefit.

The median survival rate after the operation is about 55% over a 40-month period. An estimated 25% of patients survive 5 years or more. Nevertheless, orchiectomy, although irreversible, may produce fewer adverse effects than hormonal drugs, and interestingly, many patients report significantly higher quality of life after orchiectomy than those who opt for hormonal treatment, particularly total androgen ablation. Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose hormonal therapy to block androgens. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis.

Many men can still achieve erection after orchiectomy, but there is almost always a decline in sexual drive. Men who cannot achieve erection may be candidates for a penile implant. Patients do not experience a reversal of sex characteristics; the voice does not change and body hair is not affected.

Androgen Deprivation Therapy Before or With Radiation. Hormonal drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used.

An important study published in 2004 in the Journal of the American Medical Association found that for men with localized prostate cancer, a 6-month course of hormone therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be administered for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

Androgen Deprivation Therapy Before or After Surgery. Some studies suggest benefits from using hormone therapy before surgery (neoadjuvant therapy) to reduce the tumor size, although it is not clear yet if this approach has survival benefits. Hormonal treatment may be useful after surgery in men who have high-grade tumors or tumors that have invaded the semen-carrying vessels or lymph nodes. Such men have a risk for failure after surgery of 50 - 80%.

The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormones (LHRH) agonists. They include:

Leuprolide (Lupron, Leuprogel). Studies report that disease progression is prevented in 72% of men taking daily leuprolide and up to 89% of those taking monthly injections. Certain men, however, may not respond to injections. Drug delivery using implants is under investigation.
Goserelin (Zoladex). Partial responses of 60 - 80% have been reported. A controlled release formulation has been developed that increases the time between injections from 4 weeks to 3 months.
Buserelin.

LHRH drugs block the pituitary gland from producing hormones that stimulate testosterone production. Patients must have injections of LHRH agonists for the rest of their lives.

Testosterone and PSA Surges. Treatment with LHRH agonists produces a testosterone surge in the first week, which may actually intensify symptoms. After this phase, testosterone levels drop to near zero. Leuprogel, a newer leuprolide, may pose a lower risk for this effect. Researchers are investigating other drugs, such as GnRH antagonists, that do not produce this surge.

LH-RH agonists can also cause PSA levels to rise temporarily. Administering flutamide, a drug known as an antiandrogen, for 2 weeks prior to LH-RH agonists may not only prevent PSA surge but also induce early declines in PSA levels.

Side Effects. Side effects include hot flashes and occasionally nipple and breast tenderness.

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary gland to release luteinizing hormone-releasing hormones (LHRH). GnRH antagonist drugs such as abarelix (Plenais) and histrelin (Vanta) block this action. They have two advantages over LHRH agonists:

They do not cause the same testosterone surge that can temporarily worsen cancer symptoms.
They seem to reduce testosterone levels more quickly.

Anti-androgens are drugs used to block the effects of testosterone. They are used alone or in maximal androgen blockage (MAB), in which they are combined with LHRH agonists or orchiectomy to completely block androgen hormones. Anti-androgens are either steroidal or nonsteroidal.

Nonsteroidal Anti-androgens. Nonsteroidal anti-androgen drugs include:

Flutamide (Eulexin, Drogenil). Flutamide has produced extended response in some patients. Side effects may include diarrhea and liver damage, which has been fatal in rare cases; liver function must be monitored closely.
Nilutamide (Nilandron). Nilutamide is associated with reversible interstitial pneumonitis, nausea, alcohol intolerance, and visual disturbances.
Bicalutamide (Casodex). Bicalutamide is effective and appears to have fewer severe side effects than other anti-androgens, including loss of sexual interest, osteoporosis, visual disturbance, and interstitial pneumonia. This drug is proving to have survival rates equal to those of maximal androgen blockage.

Steroidal Antiandrogens. Steroidal antiandrogens act like female hormones and include:

Megestrol uppresses androgen production, but incompletely, and is generally not used as initial therapy.
Cyproterone combined with estrogen may prevent the testosterone surge that occurs with LH-RH agonists.

Men often experience fatigue, loss of energy, and emotional distress from androgen suppression treatment. Hormonal therapy may significantly impair quality of life, particularly in men who had no symptoms beforehand and whose cancer has not metastasized. Common side effects of androgen suppression drugs include:

Osteoporosis, the loss of bone density. This risk is higher with orchiectomy than with androgen suppressants. Some androgen suppressants, such as bicalutamide, may cause less bone loss. The use of estrogens may actually be bone protective. A number of medications, especially bisphosphonates, are available to help prevent or reduce bone loss.
Diarrhea
Loss of muscle mass
Psychological disturbances
Fatigue
Loss of sexual drive and sexual dysfunction
Swelling of the breasts (gynecomastia)
Nausea and vomiting
Hair loss
Anemia

In addition, there is growing evidence that androgen deprivation therapy increases the risks for diabetes and heart disease.

Prostate cancer that does not respond to hormonal treatment is called hormone-resistant, or hormone-refractory, cancer. There are various drug treatments for hormone-resistant cancer:

Docetaxel and Other Chemotherapy. Chemotherapy drugs for prostate cancer include docetaxel (Taxotere), mitoxantrone (Novantrone), estramustine (Emcyt), and various platinum-based drugs, such as carboplatin. These drugs are often combined with other cancer drugs (such as 5-fluorouacil) or corticosteroids (such as prednisone).

Docetaxel-based drug regimens are emerging as the main chemotherapy treatment for hormone-refractory prostate cancer. In 2004, the FDA approved docetaxel injection in combination with prednisone for treatment of patients with hormone-resistant prostate cancer. Patients who received this drug combination survived on average 2.5 months longer than patients who received mitoxantrone and prednisone. Another 2004 clinical trial found that a docetaxel and estramustine combination worked better than mitoxantrone and prednisone for advanced resistant prostate cancer. Side effects can be serious and may include gastrointestinal problems (nausea, vomiting, or diarrhea), fatigue, low blood cell counts, and increased risk for blood clots.

Researchers are continuing to investigate docetaxel combinations and compare them to other chemotherapy regimens. A large 2006 study reported that docetaxel and prednisone worked better than mitoxantrone plus prednisone in improving quality of life, pain relief, and survival. Docetaxel is also being investigated in combination with vitamin D-related drugs. A 2006 trial found that men with advanced prostate cancer who took docetaxel plus high-dose vitamin D (calcitriol) lived about 8 months longer than men who received docetaxel and placebo. Calcitriol also appeared to protect against docetaxel’s side effects, especially gastrointestinal problems and blood clots.

Doctors are also studying other ways to help patients cope with docetaxel’s side effects. Research presented at the 2006 Prostate Cancer Symposium suggested that patients may be able to take periodic breaks from docetaxel treatment instead of having continuous therapy. In the study, patients with advanced prostate cancer were given the option of suspending docetaxel treatment if their PSA levels improved within a certain range. Researchers found that patients were able to take 16-week breaks and still show improvement once they resumed treatment. This approach may work best for patients who experienced a good initial response to docetaxel.

Bisphosphonates. These drugs prevent bone loss and reduce bone pain in metastasized cancers. They are of particular interest because they may inhibit prostate cancer cell growth in the bone. The bisphosphonates showing most promise in prostate cancer are newer drugs called nitrogen-containing bisphosphonates (pamidronate, zoledronic acid).

Immunotherapies. The prostate organ offers special possibilities for genetic therapies because it contains highly specific antigens (factors that the immune system can target). There are a number of approaches currently under investigation, including:

Genetically designed vaccines (Provenge, Gvaz, JBT 1001) inject factors into prostate cancer cells that trick the immune system into attacking the cancer cells.
Antisense therapy for prostate cancer blocks expression of a protein called BCL-2, which tends to be genetically overexpressed in some patients with androgen-independent prostate cancer. This protein prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct).
Monoclonal antibodies (MAbs) are genetically designed immune factors that target foreign compounds called antigens for attack by the immune system. Monoclonal antibodies are being designed to target prostate-specific antigens.

Angiogenesis Inhibitors. Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis ). The spread of new blood vessels is controlled by compounds called growth factors, which may be important in cancer cell proliferation. Researchers are interested in drugs that turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In doing so, the drugs may be able to cut off cancer's life blood. Gefitinib (Iressa) and erlotinib (Tarceva) are angiogenesis inhibitors that target receptors of epidermal growth factors called tyrosine kinase. They are being used in lung cancer and are being investigated in a number of other cancers, include prostate cancer. Various drugs that inhibit angiogenesis in other ways (thalidomide, endostatin) are also under investigation.

Ketoconazole. Ketoconazole is an antifungal drug that blocks an enzyme that stimulates production of testosterone. It is effective in high doses but can have severe gastrointestinal effects, mainly nausea and anorexia. Long-term use can result in impotence, itchy skin, nail changes, and suppression of stress hormones. One center reported a consistent PSA response in more than 60% of patients who had failed other androgen deprivation treatments.

Aromatase Blockers. Aminoglutethimide (Cytadren) and similar drugs block aromatase, an enzyme important in estrogen production. Because the female hormone estrogen plays such a major role in the development of breast cancer, some experts think that blocking the small amount of estrogen found in men may also affect prostate cancer. Side effects include drowsiness and skin rash.

Atrasentan. Atrasentan is known as an ET(A)-receptor antagonist. It is showing promise in reducing bone loss and delaying progression of prostate cancer in men with advanced disease that no longer responds to hormone therapy. Side effects are relatively mild.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.prostatecancerfoundation.org -- Prostate Cancer Foundation
www.fightprostatecancer.org -- National Prostate Cancer Coalition
www.urologyhealth.org -- Urology Health
www.nccn.org -- National Comprehensive Cancer Network
www.cdc.gov/cancer/prostate -- CDC Cancer Prevention and Control
www.psa-rising.com -- PSA Rising: Prostate Cancer Survivor Info
www.ustoo.org -- Us Too! Prostate Cancer Education and Support
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007 Mar 20;146(6):416-24.

Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007 May;39(5):631-7. Epub 2007 Apr 1.

Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007 May;39(5):638-44. Epub 2007 Apr 1.

Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006 Sep 20;24(27):4448-56.

Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst. 2007 May 16;99(10):754-64.

Leman ES, Cannon GW, Trock BJ, Sokoll LJ, Chan DW, Mangold L, et al. EPCA-2: a highly specific serum marker for prostate cancer. Urology. 2007 Apr;69(4):714-20.

Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007 Apr 20;25(12):1596-605. Epub 2007 Apr 2.

Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, et al. Guideline for the management of clinically localized prostate cancer: 2007update. J Urol. 2007 Jun;177(6):2106-31.

Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006 Nov 15;296(19):2329-35.

Walter LC, Bertenthal D, Lindquist K, Konety BR. PSA screening among elderly men with limited life expectancies. JAMA. 2006 Nov 15;296(19):2336-42.

Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007 May;39(5):645-9. Epub 2007 Apr 1.

Review Date:
6/27/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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Prostate cancer

admin — Wed, 03 Sep 2008 17:49:18 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Prostate cancer is cancer that grows in prostate gland. The prostate is a small, walnut-sized structure that makes up part of a man's reproductive system. It wraps around the urethra, the tube that carries urine out of the body.

Alternative Names

Cancer - prostate

Causes, incidence, and risk factors

The cause of prostate cancer is unknown, although some studies have shown a relationship between high dietary fat intake and increased testosterone levels. When testosterone levels are lowered either by surgical removal of the testicles (castration, orchiectomy) or by medication, prostate cancer can slowly get better.

There is no known association with benign prostatic hyperplasia (BPH).

Prostate cancer is the third most common cause of death from cancer in men of all ages and is the most common cause of death from cancer in men over 75 years old. Prostate cancer is rarely found in men younger than 40.

Men at higher risk include African-America men older than 60, farmers, tire plant workers, painters, and men exposed to cadmium. The lowest number of cases occurs in Japanese men and those who do not eat meat (vegetarians).

Prostate cancers are grouped according to how quickly they spread and how different they are from the surrounding prostate tissue. This is called staging. There are several different ways to stage tumors, a common one being the A-B-C-D staging system, also known as the Whitmore-Jewett system:

Stage A: Tumor is not felt on physical examination, and is usually detected by accident after prostate surgery is done for other reasons.
Stage B: Tumor is only in the prostate and usually detected during a physical exam or with a blood test (PSA test).
Stage C: Tumor has spread beyond the prostate but is not in the lymph nodes.
Stage D: Tumor has spread (metastasized) to lymph nodes or other parts of the body, such as the bone and lungs.

This system also contains several substages.

Symptoms

With the advent of PSA testing, most prostate cancers are now found before they cause symptoms. Additionally, while most of the symptoms listed below can be associated with prostate cancer, they are more likely to be associated with non-cancerous conditions.

Urinary hesitancy (delayed or slowed start of urinary stream)
Urinary dribbling, especially immediately after urinating
Urinary retention
Pain with urination
Pain with ejaculation
Lower back pain
Pain with bowel movement

Additional symptoms that may be associated with this disease:

Signs and tests

A rectal exam often reveals an enlarged prostate with a hard, irregular surface. A number of tests may be done to confirm the diagnosis of prostate cancer.

PSA test may be high, although non-cancerous enlargement of the prostate can also increase PSA levels.
Free PSA may help tell the difference between BPH and prostate cancer.
Urinalysis may show blood in the urine.
Urine or prostatic fluid cytology may reveal unusual cells.
Prostate biopsy confirms the diagnosis.
CT scans may be done to see if the cancer has spread.
A bone scan may be done to see if the cancer has spread.
Chest x-ray may be done to see if the cancer has spread.

A newer test called AMACR is more sensitive for determining the presence of prostate cancer than the PSA test.

Treatment

The appropriate treatment of prostate cancer is often controversial. Treatment options vary based on the stage of the tumor. In the early stages, surgery and radiation therapy may be used to remove or kill the tumor.

Prostate cancer that has spread may be treated with drugs to reduce testosterone levels, surgery to remove the testes, or chemotherapy.

Surgery, radiation therapy, and hormonal therapy can interfere with sexual desire or performance on either a temporary or permanent basis. Discuss your concerns with your health care provider.

SURGERY

Surgery is usually only recommended after thorough evaluation and discussion of all treatment options. A man considering surgery should be aware of the benefits and risks of the procedure.

Removal of prostate gland (radical prostatectomy) is often recommended for treatment of stage A and B prostate cancers. This is a lengthy procedure, usually done using general or spinal anesthesia. An surgical cut is made through the abdomen or perineal area. You may remain in the hospital for 5 to 7 days. Possible complications include impotence and urinary incontinence, although nerve-sparing procedures may reduce the risk of these complications. This surgery should be done by a urologist with extensive experience doing this specific procedure.

Orchiectomy alters hormone production and may be recommended for metastatic cancer. There may be some bruising and swelling initially after surgery, but this will gradually go away. The loss of testosterone production may lead to problems with sexual function, osteoporosis (thinning of the bones), and loss of muscle mass.

RADIATION THERAPY

Radiation therapy is used primarily to treat prostate cancers classified as stages A, B, or C. Whether radiation is as good as prostate removal is a debatable topic, and the decision about which to choose can be difficult. In patients whose health makes the risk of surgery unacceptably high, radiation therapy is often the preferred alternative. Radiation therapy to the prostate gland is either external or internal:

External beam radiation therapy is done in a radiation oncology center by specially trained radiation oncologists, usually on an outpatient basis. Prior to treatment, a therapist will mark the part of the body that is to be treated with a special pen. The radiation is delivered to the prostate gland using a device that resembles a normal x-ray machine. The treatment itself is generally painless. Side effects may include loss of appetite, fatigue, skin reactions such as redness and irritation, rectal burning or injury, diarrhea, cystitis (inflamed bladder), and blood in urine. External beam radiation therapy is usually done 5 days a week for 6 - 8 weeks.
Internal radiation therapy places radioactive seeds inside you, directly in or near the tumor. This is called brachytherapy. A surgeon makes a small cut in the area to inject the seeds. They are so small, you don't feel them. The seeds can be temporary or permanent. Because internal radiation therapy is directed to the prostate, it reduces damage to the tissues surrounding the prostate. Side effects may include pain, swelling or bruising in your penis or scrotum, red-brown urine or semen, impotence, incontinence, and diarrhea.
Radiation is sometimes used for pain relief when cancer has spread to the bone.

MEDICATIONS

Medicines can be used to adjust the levels of testosterone. This is called hormonal manipulation. Since prostate tumors require testosterone to grow, reducing the testosterone level often works very well in preventing further growth and spread of the cancer. Hormone manipulation is mainly used to relieve symptoms in men whose cancer has spread. Hormone manipulation may also be done by surgically removing the testes.

The drugs Lupron or Zoladex are also being used to treat advanced prostate cancer. These medicines block the production of testosterone. The procedure is often called chemical castration, because it has the same result as surgical removal of the testes. However, it is reversible, unlike surgery. The drugs must be given by injection, usually every 3 months. Possible side effects include nausea and vomiting, hot flashes, anemia, lethargy, osteoporosis, reduced sexual desire, and erectile dysfunction (impotence).

Other medications used for hormonal therapy include androgen-blocking agents (such as flutamide) which prevent testosterone from attaching to prostate cells. Possible side effects include erectile dysfunction, loss of sexual desire, liver problems, diarrhea, and enlarged breasts.

Chemotherapy is often used to treat prostate cancers that are resistant to hormonal treatments. An oncology specialist will usually recommend a single drug or a combination of drugs. Chemotherapy medications that may be used to treat prostate cancer include:

Mitoxantrone
Prednisone
Paclitaxel
Docetaxel
Estramustine
Adriamycin

After the first round of chemotherapy, most men receive further doses on an outpatient basis at a clinic or physician's office. Side effects depend on the drug given and how often and how long you take it. Some of the side effects for the most commonly used chemotherapy drugs for prostate cancer include:

Blood clots
Bruising
Dry skin
Fatigue
Fluid retention
Hair loss
Lowering of your white cells, red cells or platelets
Mouth sores
Nausea
Tingling or numbness in hands and feet
Upset stomach
Weight gain

MONITORING

You will be closely watched to make sure the cancer does not spread. This involves routine doctor's check ups. Monitoring will include:

Serial PSA blood test (usually every 3 months to 1 year)
Bone scan or CT scan to check for spreading of the cancers
Complete blood count (CBC) to monitor for signs and symptoms of anemia
Monitoring for other signs and symptoms, such as fatigue, weight loss, increased pain, decreased bowel and bladder function, and weakness

Support Groups

The stress of illness may be eased by joining a support group whose members share common experiences and problems. See support group - prostate cancer.

Expectations (prognosis)

The outcome varies greatly, primarily because the disease is found in older men who may have a variety of other complicating diseases or conditions, such as cardiac or respiratory disease, or disabilities that immobilize or greatly decrease activities.

Complications

Impotence is a potential complication after prostatectomy or radiation therapy. Recent improvements in surgical procedures have made this complication occur less often. Urinary incontinence is another possible complication. Medications can have side effects, including hot flashes and loss of sexual desire.

Calling your health care provider

Call for an appointment if you are a man older than 50 who has:

Never been screened for prostate cancer (by rectal exam and PSA level determination)
Not had regular, annual exams
A family history of prostate cancer

You should discuss the advantages and disadvantages to PSA screening with your health care provider.

Prevention

There is no known prevention. Following a vegetarian, low-fat diet or one similar to the traditional Japanese diet may lower risk. Early identification (as opposed to prevention) is now possible by yearly screening of men over 40 or 50 years old through digital rectal examination (DRE) and PSA blood test.

There is a debate, however, as to whether PSA testing should be done in all men. There are several potential downsides to PSA testing. The first is that a high PSA does not always mean a patient has prostate cancer. The second is that health care providers are detecting and treating some very early-stage prostate cancers that may never have caused the patient any harm. The decision about whether to pursue a PSA should be based on a discussion between patient and health care provider.

Review Date: 9/11/2006

Reviewed By: Rita Nanda, M.D., Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

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