Ohio GI [Hepatitis B]

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INTRODUCTION The liver is an organ that is located in the right upper abdomen, beneath the rib cage. It performs many functions that are essential to life including:

Removal of toxins from the blood
Metabolizing medications
Producing blood proteins that are essential for normal blood clotting
Manufacturing albumin, a protein required for maintaining normal fluid balance in the body
Producing fluids and enzymes required for normal digestion

The term "hepatitis" is used to describe a common form of liver injury. Hepatitis simply means "inflammation of the liver" (the suffix "itis" means inflammation and "hepa" means liver). Hepatitis B is a specific type of hepatitis that is caused by a virus.

It is estimated that there are more than 300 million carriers of the hepatitis B virus in the world, with over 500,000 dyinig annually from HBV-related liver disease.

Fortunately, treatments for chronic hepatitis B are available, and many new treatments are in development. Vaccines have been developed that can prevent infection, and are now given routinely to newborns and children in the United States and in many other countries. Vaccination is highly recommended for adults who are at risk for acquiring the infection.

TRANSMISSION The hepatitis B virus can be transmitted in a many ways. In the United States, the virus is most commonly transmitted by needle sharing during injection drug use or by unprotected sexual intercourse; in regions of the world where hepatitis B is prevalent, perinatal transmission (transmission from a mother to her baby) is the most common type of transmission.

Transmission by contaminated needles Any activity that transfers blood or body fluids beneath the skin can transmit the hepatitis B virus. This includes tattooing, acupuncture, and ear piercing, if these procedures are performed with contaminated instruments. Needle sharing among injection drug users is another cause of transmission.

Sexual transmission Transmission by unprotected sexual intercourse is the most common type of transmission of hepatitis B in developed countries. Sexual transmission accounts for about 30 percent of acute (new) cases of hepatitis B virus infection in the United States.

Perinatal transmission Perinatal transmission refers to transmission from a mother to her baby near the time of birth. Transmission usually occurs during or shortly after delivery. There is no evidence that cesarean section prevents maternal-infant transmission, and breast-feeding does not appear to increase the risk of transmission. Infants of mothers known to have hepatitis B are usually given hepatitis B immunoglobulin (HBIG) and the hepatitis B vaccine as soon as possible after birth to reduce the chance that the infant will become infected. Babies who are infected around the time of birth have a 90 percent chance of developing chronic infection.

During pregnancy, all women should have a blood test for a marker of hepatitis B virus, called hepatitis B surface antigen (HBsAg). This marker is produced by HBV and indicates that the woman is currently or has previously been infected with HBV. If the mother's HBsAg test is positive, the infant should receive an injection of hepatitis B immunoglobulin (HBIG) soon after birth. HBIG is a passive immunization that temporarily helps to protect the infant from infection. The infant should also recieve the hepatitis B vaccine at birth, at 1 to 2 months, and at 6 months. The infant should have a blood test for hepatitis B infection at 9 to 18 months of age; if the test is negative, a fourth dose of the vaccine should be given at that time.

Transmission by close contact Hepatitis B transmission can occur through close personal contact. Infection most likely occurs when body fluids containing the virus enter tiny breaks in the skin or the membranes of the eyes and mouth. This type of transmission often occurs between children. Because the virus can survive outside the body for long periods of time, transmission can also occur by sharing household items that carry the virus, including toys, toothbrushes, and razors.

Blood transfusion Blood transfusion is now an uncommon route for the transmission of hepatitis B virus. Blood donors are carefully screened, and all donated blood is tested for markers of hepatitis infection. These procedures detect most contaminated units of blood, but a very small percentage of these units go undetected. As a result, people who require many blood transfusions during their lifetime (for conditions such as hemophilia or thalassemia) have an increased risk of hepatitis B. ( See "Patient information: Blood donation and transfusion" ).

Transmission in the hospital setting In the hospital setting, hepatitis B virus can be transmitted from patient to patient or from patient to health care provider through contaminated needles or instruments. Transmission from health care providers to patients is extremely rare. Measures to reduce this risk include using gloves, eye protection, a face mask, and hand washing, when appropriate.

Organ transplantation Hepatitis B virus can be transmitted in donated livers and other organs. However, organ donors are routinely screened for hepatitis, which usually prevents this type of transmission.

SYMPTOMS The symptoms of hepatitis B differ during acute (new) hepatitis and chronic (long-standing) hepatitis. Within these categories, the symptoms also vary widely from person to person. Most infected people, even those with progressive disease, have no specific symptoms for many years. However, the absence of symptoms does not necessarily mean that the infection is under control. All persons who have chronic infection with hepatitis B are at increased risk of developing complications that include the development of liver scarring (which in its advanced stage is termed cirrhosis) and liver cancer. ( See "Patient information: Cirrhosis" ).

Acute hepatitis B The symptoms of acute hepatitis B usually appear one- to four-months after infection. The first symptoms may be non-specific, including fever, skin rash, and joint pain and inflammation. Although many people have no symptoms at all, symptoms of acute hepatitis may include fatigue, loss of appetite, nausea, jaundice (yellowing of the skin), and pain in the upper right abdomen (where the liver is located). Acute hepatitis can be severe, with symptoms lasting for many weeks or months. Less commonly, acute hepatitis is life-threatening or "fulminant," in which the liver is so badly damaged that it can no longer function. The only treatment for fulminant hepatitis is liver transplantation.

The symptoms of acute hepatitis B usually resolve within three months as the body eliminates the virus or brings the virus under control. People with acute hepatitis rarely experience complications in other organs and tissues, and a very small percentage of people (0.1 to 0.5 percent) develop severe liver failure.

Most people with acute hepatitis B recover uneventfully. However, in about 5 percent of adults (1 in 20) the virus makes itself at home in the liver, where it continues to make copies of itself for many years. People who continue to harbor the virus are referred to as "carriers" while liver damage associated with longstanding infection is referred to as "chronic hepatitis."

Chronic hepatitis B The symptoms of chronic hepatitis B can vary widely and can last for many years. Many people who carry the virus have no symptoms at all; other people have symptoms of ongoing liver inflammation, such as fatigue and loss of appetite. Some people with chronic hepatitis B experience sudden, temporary worsening of symptoms.

About 10 to 20 percent of people with chronic hepatitis B develop complications in other organs and tissues outside the liver; vascular inflammation and kidney disease are the two most common complications. People with chronic hepatitis B who develop cirrhosis or liver cancer may experience symptoms such as fatigue, weight loss, fluid accumulation in the abdomen and legs, bleeding, mental confusion, and abdominal pain.

Chronic hepatitis B develops more commonly in people who are infected with the virus at an early age, such as at birth. Unfortunately, this is a common event in some parts of the world such as in southeast Asia, China, and sub-Saharan Africa, where as many as 1 in 10 people have chronic infection.

DIAGNOSIS The diagnosis of hepatitis B is based upon a careful review of a person's medical history, the signs and symptoms noted during a physical examination, and the results of diagnostic tests.

Medical history A detailed medical history may suggest the presence of hepatitis B and the likely route of infection. A healthcare provider will ask about risk factors for hepatitis B, including unprotected sexual intercourse and injection drug use, country of birth and any family history of hepatitis B. The clinician will also ask about any symptoms that have developed.

Physical examination A physical examination is important to detect signs of acute hepatitis, including fever, yellowing of the eyes and skin (jaundice), a tender, slightly enlarged liver, and a skin rash. Most patients with chronic hepatitis B do not have any abnormal findings on examination. However, patients with advanced disease (such as those who have developed cirrhosis) can have a number of findings on physical examination as a result of the underlying liver problem. These include:

Jaundice
Confusion
A distended, fluid-filled abdomen (ascites)
An enlarged spleen
Edema of the legs
Enlarged breast tissue (in men)
Redness of the palms (palmar erythema)
Small, spider-like veins, usually on the chest and back (spider angiomas)
Muscle wasting
Atrophy of the testes
Asterixis (spontaneous flapping of the hands when outstretched with the palms facing forward)

Liver tests Liver tests are blood tests that provide information about the presence of liver damage and help determine the severity of damage and whether it has stopped or is ongoing.

Alanine and aspartate aminotransferases During acute hepatitis B, blood levels of two liver enzymes, alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT), are usually elevated. High levels of these enzymes signal ongoing liver inflammation. In most people with acute hepatitis, levels return to normal within one to four months. The persistence of high ALT levels after six months suggests that a person is developing chronic hepatitis. Liver enzyme levels may be more than 1000 IU/L during acute hepatitis but may vary from normal (less than 40 IU/L) to a few hundred in patients with chronic infection. Liver enzyme levels may fluctuate during the course of chronic infection.

Bilirubin High blood levels of bilirubin (a substance produced mostly from red blood cells and metabolized by the liver) often signal more severe liver damage. High bilirubin levels give rise to jaundice, which is yellowing of the skin and eyes and darkening of the urine.

Albumin Low blood levels of albumin, a protein synthesized by the liver, often signal chronic liver damage.

Prothrombin time An abnormally long prothrombin time (a measure of the time required for blood clotting) or high international normalized ratio (INR, another way of reporting prothrombin time) suggests more severe liver damage. The results of a prothrombin time are the best predictor of outcome in acute hepatitis B.

Hepatitis markers Levels of several hepatitis markers found in the blood can confirm hepatitis B infection and differentiate acute from chronic infection. These markers include substances produced by the hepatitis B virus (called antigens) and substances produced by the immune system to control and eliminate the virus (called antibodies).

The diagnosis of acute hepatitis B is based upon the presence of the hepatitis B surface antigen (HBsAg) and hepatitis B core IgM antibody. The diagnosis of chronic hepatitis B is based on the presence of the HBsAg marker for at least six months; hepatitis B core IgM antibody is usually negative.

Hepatitis B surface antigen In acute hepatitis, HBsAg can be detected soon after infection; falling levels of this marker and the appearance of hepatitis B surface antibodies (HBsAb or anti-HBs) signal recovery. In chronic hepatitis, HBsAg can be detected for many years, and HBsAb may never appear.

Hepatitis B e antigen Hepatitis B e antigen (HBeAg) is present when the hepatitis B virus is actively multiplying. In acute hepatitis, HBeAg can be detected soon after infection; falling levels of this marker and the appearance of hepatitis B e antibodies (HBeAb or anti-HBe) signal recovery. In most patients with chronic hepatitis, HBeAg can be detected for many years. With time, the immune system may suppress the virus to such low levels that HBeAg is no longer detected and HBeAb is present. Loss of HBeAg and appearance of HBeAb (also called HBeAg seroconversion) is usually an indication that the virus is suppressed and the liver disease becomes inactive. However, some HBV mutants that cannot make HBeAg have been described (precore mutants). In this case, patients may be HBeAg negative but still have high levels of virus and active liver disease.

Hepatitis B virus DNA Detection of hepatitis B virus DNA in a blood sample signals that the virus is actively multiplying. In acute hepatitis, HBV DNA can be detected soon after infection; falling levels of HBV DNA signal recovery, and levels usually become undetectable over time. In chronic hepatitis, levels of HBV DNA often remain high for many years and then decrease as the immune system gains control over the virus. In some patients, HBV DNA levels fluctuate due to alterations in balance between the immune system and the virus.

Antibodies to Hepatitis B core antigen In acute hepatitis, a specific class of antibodies (IgM) directed against the hepatitis B core antigen (anti-HBc) appears early in infection. There are two classes of this antibody (core IgG and core IgM). The IgM class appears first during the acute phase of hepatitis and then gradually switches to the IgG type.

Antibodies to Hepatitis B surface antibody (anti-HBs) is a marker of immunity or protection. Persons who develop immunity to hepatitis B after vaccination have anti-HBs only while those who develop immunity after recovery from acute hepatitis B have anti-HBs and the IgG type of anti-HBc.

Liver biopsy During a liver biopsy, a small sample of liver tissue is collected for microscopic examination. A liver biopsy is not routinely needed to diagnose hepatitis B. Liver biopsy is used for monitoring the progression of liver damage in people with chronic hepatitis, helping to decide if treatment is needed, and for detecting cirrhosis or liver cancer. ( See "Patient information: Liver biopsy" ).

TREATMENT There is no specific treatment for acute hepatitis B; in 95 percent of adults, the immune system controls the infection and eliminates the virus within about six months. Antiviral treatment may be considered in the rare patient with very severe acute or prolonged acute hepatitis B. In people who develop chronic hepatitis, the goals of treatment are to stop the virus from multiplying to reduce or reverse liver damage.

General measures All persons with chronic hepatitis B should be vaccinated against hepatitis A unless they are known to be immune. Pneumococcal vaccine is recommended every five years, and influenza vaccination is recommended once per year. Patients with liver disease should also receive standard immunizations, including diphtheria and tetanus booster immunizations every ten years. ( See "Patient information: Adult immunizations" ).

Regular screening for liver cancer is also recommended, particularly for older individuals, those with cirrhosis, and patients with family history of liver cancer. In general, this entails an annual or biannual ultrasound examination and blood test for the alpha fetoprotein level (a protein produced by some liver tumors, which is detectable in blood). The best approach to screening for liver cancer has not been determined.

Antiviral therapy Six drugs that can slow or stop multiplication of the hepatitis B virus are available: lamivudine, adefovir, entecavir, telbivudine, interferon-alpha, and pegylated interferon-alpha. Not all hepatitis B patients will benefit from these treatments. The physician and the patient should discuss treatment options after a careful assessment of the individual's conditions. Regular monitoring is needed during treatment to monitor for response, side effects and drug resistance, and for relapse after treatment is stopped. Some patients benefit from treatment when hepatitis becomes more active, which requires that the patient is monitored periodically.

Lamivudine Lamivudine (Epivir-HBVÿ) is effective in decreasing virus activity and ongoing liver inflammation. It is safe in patients with liver failure and long-term treatment can decrease the risk of liver failure and liver cancer.

Lamivudine is taken by mouth, usually at a dosage of 100 mg/day. The major problem with lamivudine is that a resistant form of hepatitis B virus (referred to as a YMDD mutant) frequently develops in people who take lamivudine for long-term treatment. Appearance of the mutant virus may be accompanied by a marked increase in virus level and a flare of hepatitis, and in rare instances, liver failure. Lamivudine is used less commonly in patients who require long-term treatment because new drugs are available that are less likely to cause resistance.

Adefovir Adefovir (Hepseraÿ) is an alternative initial choice for people who have detectable virus activity and ongoing liver inflammation. An advantage of adefovir compared to lamivudine is that resistance to the drug occurs at much lower rates. In addition, adefovir can suppress lamivudine- resistant hepatitis B mutants. Adefovir has been associated with kidney problems when used in high doses or for long durations, so kidney function needs to be monitored before and during treatment. Adefovir acts slowly in some patients, additional treatment may be needed in those with little or no decrease in HBV DNA levels after six months of adefovir.

Adefovir is taken orally, at a dosage of 10 mg/day, for at least one year. Most patients will need long-term treatment to maintain control of the hepatitis B virus.

Entecavir Entecavir (Baracludeÿ) is a relatively new drug, so its benefits and safety are still being determined. An advantage compared with lamivudine, telbivudine, and adefovir is its greater potency against the hepatitis B virus. To date, resistance seems to be rare. A disadvantage is its relatively higher cost, relative to the other oral HBV drugs. It is also effective against lamivudine-resistant hepatitis B, although it is not as potent as adefovir for this condition.

Entecavir is taken orally, at a dosage of 0.5 mg daily for patients who have no prior treatment and 1.0 mg daily for patients who have resistance to lamivudine, for at least one year. Most patients will need long-term treatment to maintain control of the hepatitis B virus.

Interferon-alpha Interferon-alpha is an appropriate treatment for people with chronic hepatitis B infection who have detectable virus activity, ongoing liver inflammation,and no cirrhosis. Both conventional interferon (which has to be given daily or three times a week) and pegylated interferon are approved in the United States. Interferon-alpha is not appropriate for people with cirrhosis who have liver failure or for people who have a recurrence of hepatitis after liver transplantation.

Interferon is given for a finite duration (4 to 12 months) in contrast to the oral HBV drugs which are given for many years until a desired response is achieved. Drug resistant mutations to interferon have not been reported.

Interferon-alpha must be taken by injection. The drug triggers a flare of hepatitis in 30 to 50 percent of people who are HBeAg positive, although flares are uncommon in those who are HBeAg negative. These flares usually do not cause symptoms but in rare cases, usually in patients with cirrhosis, can be fatal. The disadvantage of interferon-alpha is that it can cause many side effects. Interferon-alpha may be considered in young patients who do not have advanced liver disease and do not wish to be on long-term treatment.

Telbivudine Telbivudine (Tyzekaÿ) is similar (but slightly more potent) than lamivudine. Unfortunately, it is associated with a high rate of resistance, similar to lamivudine.

Liver transplantation Liver transplantation may be the only option for those who have developed advanced cirrhosis. The transplantation process is elaborate, involving an extensive screening process to ensure that a person is a good candidate. Thus, not all patients with cirrhosis are eligible, and only those with the most advanced cirrhosis and otherwise good medical and social conditions will be put on the transplant waiting list.

PROGNOSIS As discussed above, the clinical course of hepatitis B can vary widely. Certain factors help predict prognosis.

Likelihood of developing chronic infection The likelihood of acute hepatitis progressing to chronic hepatitis largely depends on a person's age at the time of infection. Chronic infection develops in about 90 percent of children who are infected at birth, in 20 to 50 percent of children who are infected between the ages of 1 and 5 years, and in less than 5 percent of people infected during adulthood.

Factors that influence prognosis Several factors affect the prognosis of chronic hepatitis. Prognosis is largely influenced by the extent of viral multiplication and the immune system's ability to control the infection. Other factors that appear to worsen the course of hepatitis include male gender, habitual alcohol consumption, and coinfection with other hepatitis viruses.

TIPS TO MAINTAIN LIVER HEALTH As discussed above, the majority of people with acute hepatitis B spontaneously clear the infection. Those who develop chronic infection should be evaluated by a physician with expertise in liver disease (usually a gastroenterologist or hepatologist) who can discuss treatment options. In addition to the routine vaccinations discussed above and the need to screen for liver cancer, a number of other issues may be discussed:

Diet No specific diet has been shown to improve the outcome in patients with hepatitis B. The best advice is to eat a normal healthy and balanced diet.

Alcohol Alcohol should be avoided since it can worsen liver damage. All types of alcoholic beverages can be harmful to the liver. Patients with liver disease may worsen even with small amounts of alcohol.

Exercise Exercise is good for overall health and is encouraged, but it has no effect on the virus.

Prescription and nonprescription drugs Many medications are broken down by the liver. Thus, it is always best to check with a healthcare provider or pharmacist before starting a new medication. As a general rule, unless the liver is already scarred, most drugs are safe for people with hepatitis B. An important possible exception is acetaminophen (Tylenolÿ); the maximum recommended dose in those with liver disease should be no more than 2 grams (650 milligrams per dose) in 24 hours.

Herbal medications Although many claims about herbal medications have been made (particularly on the internet), no herbal treatment has been proven to improve outcomes in patients with hepatitis B, and some can cause serious liver toxicity.

Support Sharing concerns with others infected with hepatitis B can provide support. A number of organizations are available around the world. ( See " Where to get more information" below ).

IMPLICATIONS FOR THE FAMILY Acute and chronic hepatitis B are contagious. Thus, people with hepatitis B should discuss measures to reduce the risk of infecting others. This usually involves minimizing blood and bodily fluid exposure, testing immediate family and household members, and vaccinating those at risk for acquiring the infection. ( See "Patient information: Adult immunizations" ).