Viral Hepatitis Background Hepatitis or inflammation of the liver can be caused by infectious and noninfectious problems. Infectious etiologies include viruses, bacteria, fungi and parasites. Noninfectious causes include certain medications, toxins such as alcohol, and autoimmune diseases. Of the viral hepatitis viruses, hepatitis A accounts for 30% of acute infections in the United States, hepatitis B for 40% and hepatitis C for 30%. The clinical presentation of acute hepatitis varies from asymptomatic or mildly symptomatic to serious illness or death. It is the leading cause of fulminant liver failure in the US causing 4,000 to 5,000 deaths each year. Chronic infection is possible with hepatitis B or C and causes approximately 16,0000 deaths/year. Seventy percent of chronic hepatitis in the US is due to hepatitis C, 20% from hepatitis B and 10% from a coinfection with both B and C. Phases of Infection There are four recognized phases in patients infected with viral hepatitis. Phase one is the viral replication stage during which the patient is asymptomatic. Serologic testing is positive and liver function tests may be abnormal. In phase 2, the prodromal stage, the patient complains of nonspecific symptoms such as fever chills, nausea, vomiting, anorexia, alteration in taste, malaise, arthralgias, headache and fatigue. They may experience itching or rash and develop an aversion to smoking cigarettes. If medical care is sought during this phase, the patient is often diagnosed with a viral syndrome or gastroenteritis. In phase three, the icteric phase, the patient develops dark urine and light-colored stools. The skin and eyes become jaundiced. Gastrointestinal symptoms worsen and right upper quadrant pain develops. A painful, enlarged, firm liver may be noted on examination. In the convalescent phase, phase 4, symptoms and icterus resolve and the liver function tests normalize. Hepatitis A Approximately 1/3 of cases of acute viral hepatitis reported in the US are caused by hepatitis A. The highest incidence is in children age 5 to 14 years. HAV exists in highest concentrations in the stool of infected patients and is transmitted from person-to-person mainly via the fecal-oral route. Contaminated food such as shellfish collected from
sewage-contaminated water has also been implicated. HAV may spread through infected serum but this is much less common. Infection occurs worldwide, but risk is greatest in developing countries, areas of low socioeconomic status and areas without sufficient sanitation. Because of the increased incidence of fecal-oral spread, daycare centers are also sites of increased transmission. Other groups at high risk include travelers to Africa, Asia, Central and South America and the Middle East, intravenous drug abusers, homosexual men and military personnel stationed in foreign countries. Close contacts to infected persons are also at risk. Maternal-neonatal transmission does not occur. The incubation period of HAV is two to six weeks and clinical symptoms develop more rapidly than in the other forms of viral hepatitis. The most common symptoms are fatigue, nausea, vomiting, fever, enlarged liver, jaundice, dark urine, loss of appetite and rash. HAV is usually a mild self-limited disease that confers lifelong immunity. However, the older the patient, the more severe the illness is likely to be. Complications include fulminant liver failure (rare) and relapsing hepatitis (15%). With relapsing hepatitis, the patient experiences episodic symptoms for six to nine months. Chronic infection does not occur. The mortality rate from acute hepatitis A infection is extremely low (0.2-0.6%). Improved sanitation, strict personal hygiene and frequent hand washing especially after using the restroom, changing diapers or when preparing food, may help prevent transmission of HAV. Travelers to endemic areas should not drink water or eat raw seafood. In addition, they should cook and peel all fruits and vegetables. A vaccine to prevent HAV infection was produced in 1995 and is > 90% effective. The vaccine is recommended for those traveling to areas of increased risk, homosexual men, intravenous drug abusers, and patients with chronic liver disease. Hepatitis B Hepatitis B is the most virulent form of acute viral hepatitis. It is estimated that 400 to 500 million people worldwide are carriers of HBV and one million deaths occur each year due to liver disease caused by hepatitis B. In the United States, approximately 1,250,000 people are chronically infected and 50,000 to 250,000 become newly infected each year. HBV is primarily a disease of adults and adolescents. Transmission occurs parenterally, sexually and perinatally. Saliva, serum and semen are all potentially infectious. Percutaneous exposures causing transmission include transfusion of HBV-infected blood or blood products, intravenous drug use with shared needles,
hemodialysis and needlesticks. Sexual contact is the cause for 50% of acute HBV infections in the US. Intravenous drug use accounts for another 20%. The risk of acquiring hepatitis B from a blood transfusion is 1/250,000 due to a screening test in use since the early 1970s. Dialysis patients and hemophiliacs are at increased risk. Perinatal transmission is a major cause of HBV worldwide. Infection occurs due to direct contact with the mother s contaminated blood during the delivery process and not transplacentally. Though hepatitis B is less common in the pediatric patient, 95% of children with HBV infection become chronically infected. The incubation period for hepatitis B is 30 to 180 days. Patients then enter the prodromal phase, developing the gradual onset of malaise, fatigue and loss of appetite. Liver enzymes start to rise as the liver becomes inflamed. The patient may begin to experience pain in the right upper quadrant. Next the patient enters the icteric phase during which the liver becomes tender to palpation and jaundice arises. Nausea, vomiting, and itching also occur. The patient may notice dark urine and light stools. The remainder of the clinical course is variable. Ninety-five percent of adult patients have a fairly rapid improvement of their symptoms and develop antibodies to HBV that confer lifelong immunity. Approximately 5% of adults become chronically infected. They are carriers who have virus present in their blood for > six months. Of those with chronic infection, 70-90% are asymptomatic but contagious. Ten to thirty percent develop chronic hepatitis with increased liver enzymes in their blood and abnormal liver cells noted on biopsy. These patients can also remain symptom free though some have chronic fatigue and dyspepsia. Patients with chronic hepatitis are at increased risk for cirrhosis and liver cancer. A small subset of patients (0.5-1%) with acute hepatitis B infection develops rapid progression to fulminant hepatic failure, which is acute liver failure in the setting of hepatic encephalopathy. Fulminant hepatic failure may resolve, but > 50% of cases end in death unless urgent liver transplantation is performed. Immunization with the three-dose recombinant DNA hepatitis B vaccine may prevent infection. This vaccine is recommended for all children and healthcare workers. Non-immunized persons in close contact with infected patients or those who experience a significant occupational exposure should receive the HBV immune globulin as well as the vaccine as this combination prevents 80-95% of transmission in these settings.
Hepatitis C Hepatitis C is five times as widespread as HIV, infecting 170 million people worldwide. An estimated 3.9 million Americans have been infected making it the most common blood borne infection in the United States. Of these, 2.7 million are chronically infected. Approximately 30,000 new cases of HCV infection occur annually. Many of these people are asymptomatic and, therefore, unaware that they are infected. In the US, HCV causes approximately 20% of acute hepatitis cases. Forty percent of chronic liver disease in this country is HCV related. It is the primary reason for liver transplantation. The highest rates of disease occur in intravenous drug abusers and hemophiliacs. Transmission mainly occurs parenterally with intravenous drug use accounting for 60%. Transfusion of infected blood, blood products or organs and needlestick exposures are also routes of transmission. Since testing of donors for HCV began in 1992, the risk of acquiring the infection is 1/100,000 per unit of blood transfused. Perinatal transmission occurs as well. Sharing paraphernalia used for intranasal substance abuse has also been noted to transmit the virus. Sexual contact with an infected partner is felt to be low risk. The incubation period for HCV is 15 to 150 days. Symptom onset is insidious. During acute infection, symptoms may be similar to those seen in acute HBV infection. However, up to 80% of patients with acute HCV are asymptomatic and anicteric. Chronic infection occurs in 75 to 85% of infected persons and as many as 70% of these develop chronic hepatitis. Of the patients who have chronic hepatitis, 20% develop cirrhosis over a period of ten to forty years. As with HBV infection, patients with chronic hepatitis and cirrhosis are at increased risk for primary liver cancer (hepatocellular carcinoma); 8,000 to 10,000 people die in the US per year secondary to end stage liver disease related to HCV infection. There is no vaccine to prevent hepatitis C nor is there any postexposure prophylaxis. Prevention is primarily aimed at eliminating high-risk behaviors such as intravenous drug use. Contacts of patients who are infected with HCV should not share any personal care items (e.g. razors or toothbrushes) that may have blood on them. Health care providers must use universal precautions. Though the risk of transmission from sexual contact is low, condoms are recommended for people with multiple sexual partners. Hepatitis D
HDV is an incomplete virus and requires the presence of the hepatitis B virus in order to replicate. Infection can occur concurrently with HBV infection or can be superimposed on a chronically infected hepatitis B patient. Transmission occurs via the same route as hepatitis B although perinatal transmission is rare. The incubation period of HDV is approximately 35 days. Patients coinfected with HBV and HDV often have more severe disease than do those with HBV alone. Thirty three to fifty percent develop fulminant hepatic failure. Chronic hepatitis and cirrhosis also occurs more frequently in the presence of infection with both viruses. Since the HDV can only infect a person when the HBV is present, transmission can be decreased by vaccinating against hepatitis B. There is no known way of preventing HDV infection in a person who is a carrier of hepatitis B. Treatment of Viral Hepatitis The treatment of viral hepatitis is mostly supportive with intravenous fluids to correct dehydration, analgesics for pain, and antiemetics for nausea. As the liver is a primary source of the factors needed in coagulation, patients may need blood products to correct any clotting problems they may have as a result of liver inflammation. Specific treatment for chronic infections caused by HBV and HCV do exist. Interferon alfa-2b is an effective treatment of adults with chronic hepatitis B or C virus infection who have ongoing liver inflammation as evidenced by elevated liver enzymes. It attaches to healthy cells and helps them defend themselves against viruses and also helps the immune system stop viral replication. One third of patients with chronic HBV treated with 5 million units per day experience remission and 10% become hepatitis B antigen negative (cured). Interferon has the disadvantage of intramuscular or subcutaneous administration. Lamivudine (Epivir) is also used in patients with chronic HBV infection. Lamivudine works by inhibiting HBV polymerase, the viral enzyme that mediates DNA synthesis, thereby stopping viral replication. By reducing the HBV viral levels, progressive liver inflammation is suppressed which decreases the risk of further damage to the liver. Fifty two percent of patients had decreased evidence of liver inflammation as compared to 36% of those taking interferon and 23-25% taking placebo. Studies evaluating combination treatment with interferon and lamivudine in chronic HBV patients are ongoing. Three million units of interferon given three times per week to patients with chronic HCV leads to remission in 50 to 70%; unfortunately most patients relapse after treatment is discontinued. Use of the antiviral medication ribavirin in combination with interferon
has been shown to provide a more sustained remission in chronic HCV patients. Ribavirin is felt to directly inhibit viral RNA replication and also cause mutation in the viral structure. Peginterferon, a chemically altered version of interferon with a longer half life, in combination with ribaviron produces a significantly higher sustained viral response and affords once a week treatment.