The term hepatitis refers to any inflammatory process of the liver. The most common etiology of acute hepatitis is viral infection (Table 3). In North America, hepatitis A, hepatitis B and hepatitis C are the commonest causes of viral hepatitis. Viral hepatitis occurs less commonly with infections such as Epstein-Barr virus, cytomegalovirus, adenovirus, herpes simplex and Coxsackie virus. In these cases, the clinical picture is usually dominated not by the hepatitis but by other features of the viral illness.

The clinical course of acute hepatitis varies from mild symptoms requiring no treatment to fulminant liver failure requiring liver transplantation. In the last decade, the treatment of acute viral hepatitis has not progressed as rapidly as our understanding of these hepatitis viruses' epidemiology and molecular biology. The mainstay of treatment is still supportive care, because the inflammation is self-limited in most cases. Postexposure prophylaxis is possible for some of the hepatitis viruses.

4.1.1 HEPATITIS A VIRUS (HAV)

Previously termed "infectious hepatitis," hepatitis A virus (HAV) is an RNA virus that belongs to the enterovirus family. It is present in the stool of patients during the prodrome or pre-icteric phase until about two weeks after the onset of jaundice. Both IgM and IgG antibodies to the virus (anti-HAV) can be detected, with the most helpful sign being the demonstration of an elevated IgM antibody, indicating recent infection (Figure 2).

HAV infection infection is common. The anti-HAV IgG can be detected in 30-40% of the population in developed countries and 90% of the population in developing countries. HAV is usually transmitted by the fecal-oral route. Thus, food or water contamination may lead to epidemic outbreaks. Several outbreaks have been associated with ingestion of raw clams and oysters from polluted water. Person-to-person spread results in sporadic cases. Parenteral transmission is also possible, especially in intravenous drug users, but is much less common.

Infection can occur at any age but is most common in younger age groups. Infection can present as a gastrointestinal illness and therefore diagnosis can be missed. In countries with good water supplies and sanitation, more symptomatic hepatitis A is seen in older age groups, since fewer adults are exposed to hepatitis A as children. The incubation period is about one month, and rarely is longer than 40 days. The mortality rate - usually from fulminant hepatitis - is very low (0.1%). There is no evidence for a chronic carrier state or the development of chronic liver disease.

In 1965, an antibody in a hemophiliac patient was found to react with an antigen in the serum from an Australian aborigine; this antigen was subsequently found in patients with viral hepatitis. This antigen was termed the Australian antigen and is now known to be the surface coat of the hepatitis B virion, now called the hepatitis B surface antigen (HB_sAg).

HBV is a unique DNA virus that replicates through reverse transcription of its mRNA. It behaves more like a retrovirus than a DNA virus. HBV consists of a 28 nm central core containing the genome (a single molecule of partially double-stranded DNA) and a specific DNA polymerase with a surrounding core protein shell. The core is commonly found in the nuclei of infected hepatocytes, with the outer HB_sAg coat being acquired from the cytoplasm of the hepatocyte. The core antigen is antigenically distinct from the HB_sAg. This allows separate detection of core antibody (anti-HB_c) and surface antibody (anti-HB_s). A further viral antigen, termed HB_eAg, can be detected in the serum, together with DNA polymerase. HB_eAg is a subunit of HB_cAg. HB_eAg positivity implies viral replication and is an indicator of high infectivity. Mutants that do not produce HB_eAg exist; these "pre-core mutants" can cause severe hepatitis.

The typical course of HBV infection, appearance of the viral antigens and host immune response are shown in Figure 3. The significance of HBV markers and their importance in interpretation is summarized in Table 4.

In North America, HBV infection occurs primarily in adolescents and adults. High-risk groups for HBV infection are summarized in Table 5. The transmission may be sexual, vertical or parenteral (most commonly through inoculation by contaminated needles in intravenous drug users). Hepatitis B infection from transfusion has been almost completely eliminated by routine screening by the use of volunteer blood donors. Vertical transmission is common in developing countries, passing from a mother who is a chronic hepatitis B carrier to a fetus or newborn; the infection is acquired at the time of birth or shortly thereafter. This vertical transmission of HBV results in the vast majority of chronic carriers worldwide.

Hepatitis C virus is a recently discovered single-stranded RNA virus of less than 80 nm in diameter that has been classified as a member of the flavivirus family. The virus itself has not been isolated or visualized, although the majority of its genome has been cloned and sequenced. It is worldwide in distribution. The prevalence of HCV infection in the general population is approximately 1%. However, prevalence is highly variable among different risk groups. Hemophilia patients have a prevalence rate as high as 90%, whereas health-care workers have a prevalence rate of 1%.

The principal mode of HCV transmission is parenteral exposure, but a significant percentage of patients do not have identifiable risk factors. Parenteral exposure accounts for at least 90% of cases of post-transfusion hepatitis (previously labeled as non-A non-B hepatitis), but these cases make up only 10% of the total hepatitis C cases. Intravenous drug use is the main cause of hepatitis C infection, but interestingly, the exposure may predate clinical hepatitis by decades. HCV also accounts for 12-25% of cases of sporadic hepatitis.

The incubation period is 5 to 10 weeks (mean 7 weeks), with the acute phase being clinically mild and the majority of cases being anicteric. The elevated aminotransferase pattern may be monophasic or multiphasic with the latter suggesting chronicity, which develops in over 75% of cases. Histologically, it is not possible to distinguish between progressive and nonprogressive forms of hepatitis C, and liver biopsy is not suggested.

Serologic testing for this virus has developed rapidly following its discovery in 1989. The third-generation ELISA (enzyme-linked immunosorbent assay) and RIBA (recombinant immunoblot assay) identify antibodies to the nonstructural as well as structural epitopes of the virus. The ELISA test is very sensitive but not specific, and therefore all positives must be confirmed with the highly specific RIBA or another confirmatory test. From Red Cross blood donor data, about 50% of individuals who have normal liver enzymes and are anti-HCV positive by ELISA will be negative on subsequent RIBA testing. Hypergammaglobulinemia is a common reason for a false-positive ELISA test. An additional problem with the ELISA test for anti-HCV is that the antibody cannot be detected in the circulation for approximately three months following the onset of acute hepatitis C, as opposed to six to eight weeks for RIBA testing. Moreover, only 60-70% of patients with acute HCV infection will ever develop anti-HCV ELISA positivity.

Studies detecting HCV-RNA using the highly sensitive polymerase chain reaction have shown that 80% of antibody-positive individuals have viremia and are potentially infectious. In contrast to hepatitis B, sexual and vertical transmission is uncommon. HCV infection from contaminated needles in health-care workers occurs in less than 5%.

HDV is a defective RNA virus that requires the presence of hepatitis B surface antigen for its expression. HDV utilizes the HB_sAg protein as its external coat to attach to and enter hepatocytes. It is found worldwide, but Italy, Eastern Europe, the Middle East, the South Pacific, South America and Africa have the highest incidence. In North America, less than 1% of HB_sAg-positive patients have evidence of HDV infection, whereas in parts of Italy 14-50% of HB_sAg-positive patients are co-infected with HDV. In the United States and Canada, HDV infection is found almost exclusively among intravenous drug abusers and their sexual partners.

Hepatitis D infection may originate as a co-infection with hepatitis B or as a superinfection in a patient who is already a chronic HBV carrier. Co-infection produces a more severe acute hepatitis than that caused by hepatitis B alone, but it is usually self-limited. Superinfection often results in more severe chronic hepatitis than hepatitis B alone. The delta virus circulates in association with the delta antigen, but until more sensitive assays are developed, this antigen can be detected only during the early phases of infection. The serologic marker for acute and chronic hepatitis D infection is the antibody to delta antigen (anti-HDV).

Hepatitis E (epidemic hepatitis) appears to be due to a single-stranded RNA virus of 27-34 nm in size. It shares many similarities with hepatitis A. Although HEV was previously included in the group labeled non-A non-B hepatitis, it has now been classified as an enteric virus transmitted by contaminated water supplies or by the fecal-oral route. Cases of HEV infection may be part of an epidemic or may be isolated, sporadic cases. HEV is the leading cause of acute viral hepatitis in young to middle-aged adults in many developing countries. It is associated with a high mortality rate (approaching 20%) in infected pregnant women in the third trimester. It is seen only rarely in North America and almost exclusively in travelers returning from endemic regions. The incubation period is 10-50 days. There are no distinctive clinical features, with secondary cases being rare. Chronicity of infection does not develop. Testing for anti-HEV is available at reference laboratories.

An as yet unidentified virus is believed to be associated with some cases of fulminant hepatitis that are negative for all other viral serology. Most such cases are fatal without a liver transplant.

In 1995, a new virus that causes hepatitis was cloned. It is known as the GB agent, so named after the initials of a surgeon who contracted this infection. It is similar to flaviviruses and shares 25% homology with hepatitis C. It persists as a mild chronic hepatitis. Very little is known about this new virus or group of viruses.

A paramyxo-like virus has been identified in a small number of patients with severe acute liver disease who usually died of liver failure or underwent liver transplantation. The presumptive diagnosis is made by liver biopsy where multinucleated giant cells are present. Paramyxo-like virus particles can also be seen on electron microscopy of the specimen. The epidemiology, presumed infectious agent, response to treatment and forms of prevention have yet to be defined.

Acute viral hepatitis causes inflammation of the liver involving primarily the parenchyma. There is evidence of hepatocellular degeneration (ballooning, acidophilic bodies, spotty necrosis), inflammation (lobular and portal mononuclear infiltrate) and hepatocyte regeneration (Figure 4). More severe cases demonstrate bridging necrosis between central veins and portal tracts (Figure 5 and Figure 6). Because there is usually preservation of the reticular framework, the liver completely restores itself with hepatocyte regeneration. Liver biopsy is not generally helpful in distinguishing between the different types of acute hepatitis, as the histology is quite similar.

Most viral hepatitis infections are asymptomatic, especially in younger individuals. When symptomatic, initial symptoms are those of any viral infection, beginning with malaise, nausea, vomiting, fatigue and a low-grade fever. More characteristic are severe anorexia, an aversion to smoking, and the passing of dark urine. Right upper quadrant discomfort is common in acute hepatitis, but severe abdominal pain is not a feature. After several days, jaundice appears, often preceded by dark urine and light-colored stool. The convalescent stage is usually 7 to 10 days, with the total illness lasting 2 to 6 weeks. Physical findings are usually minimal, aside from jaundice and a tender, enlarged liver.

Acute viral hepatitis can be suspected by the presence of viral prodrome symptoms, which often precede the more classical symptoms (including jaundice, dark urine and pruritus). Of diagnostic importance are a history of exposure to jaundiced persons, recent intravenous drug use or transfusions, sexual orientation and sex practices, travel history, drug or toxin exposure (including herbs) and the absence of significant abdominal pain.

If viral hepatitis is suspected clinically, laboratory evaluation will help confirm the presence of acute liver injury, may define the etiology and may help monitor the course and prognosis of hepatitis. Characteristically, the serum aminotransferase level is significantly elevated, often to levels >1,000 IU/L (normal is 10-40 IU/L), with the alkaline phosphatase only mildly to moderately elevated. The serum bilirubin is mainly conjugated and reflects the severity of the hepatitis. The INR/prothrombin time defines the extent of liver injury in the acute stage, with an increasing INR/PT implying a poor prognosis and the need for referral to a regional liver center. Initial serologic testing should include only HAV-IgM and HB_sAg. Anti-HCV should be done at the onset only if specific risk factors are present (especially intravenous drug use) or subsequently if the HAV and HBV serology is negative.

The differential diagnosis should include other viral infections (such as infectious mononucleosis or cytomegalovirus infection), drug-induced liver disease, autoimmune hepatitis and Wilson's disease. Biliary tract disease (including cholecystitis and cholangitis) is distinguished by the presence of fever and significant abdominal pain. If doubt exists as to the diagnosis of hepatitis, abdominal ultrasound to investigate extrahepatic biliary obstruction and even liver biopsy may be necessary. In general, however, liver biopsy is rarely required in patients with acute hepatitis.

Most patients with viral hepatitis recover completely. The most important complication is the development of chronicity, which may follow hepatitis B, C, D and G. Most other complications are fortunately rare.

This is defined as the development of acute liver cell injury proceeding to liver failure and hepatic encephalopathy within eight weeks in a patient without any known previous liver disease. Clinically, the patient deteriorates with development of deep jaundice, confusion and drowsiness. The encephalopathy can progress into deep coma. Because of massive liver necrosis, there is deficiency of clotting factors, and hence the INR/PT is always increased. At this stage, mortality is greater than 50% unless a liver transplant can be performed. Death may occur from infection, hypoglycemia, increased intracranial pressure with cerebral edema, or renal failure. Massive hepatic necrosis with architectural collapse is seen histologically (Figure 7 and Figure 8). Despite this, if regeneration occurs, histologic recovery is the rule.

Occasionally acute viral hepatitis exhibits a cholestatic phase, in which the patient becomes intensely pruritic and jaundiced, and the enzyme pattern changes with a fall in the aminotransferase but with an increased alkaline phosphatase value. Biliary tract disease and drug toxicity should be ruled out. Resolution within a few weeks is the usual course. This occurs most commonly in hepatitis A.

Clinically, these patients are improving, only to have a recurrence of the signs and symptoms of their hepatitis. Resolution is almost always complete. This pattern is most characteristic of hepatitis A. In some cases of hepatitis B, the second phase is due to acute hepatitis D. Hepatitis C is characterized by continued and wide fluctuations in liver aminotransferase values, but a biphasic clinical course is uncommon.

In hepatitis B, about 5-10% of cases initially develop a serum-sickness - like syndrome (characterized by skin rash, angioedema and arthritis), which is due to circulating immune complexes of viral particles and antibody with complement activation. Other immunologic manifestations include pericarditis, aplastic anemia or neurologic abnormalities such as Guillain-BarrŽ syndrome. Chronic hepatitis B may have persisting circulating immune complex disease that leads to such diseases as membranous glomerulonephritis with nephrotic syndrome or polyarteritis nodosa. Chronic hepatitis C can cause cryoglobulinemia secondary to viral protein and antibody interaction.

Chronic hepatitis represents continued disease activity beyond six months. This complicates acute hepatitis B infrequently in adults but occurs in acute hepatitis C in over 75% of cases. It does not occur in hepatitis A or E. Chronic hepatitis can be suspected if there are persistent symptoms or persistent elevation of serum aminotransferase levels after six months.

Most cases of acute viral hepatitis resolve spontaneously and require no specific treatment. Strict bed rest is not necessary. The patient may undertake any activity that does not exacerbate symptoms. Diet can be liberal, encouraging a high calorie intake but excluding alcohol. Fatty foods are poorly tolerated and are best avoided. Hospitalization is not necessary. All drugs, especially tranquilizers and sedatives, should be avoided. Corticosteroids do not alter the degree of hepatitis or rate of healing and should be avoided to allow a normal immunologic response, which then can eliminate the virus. Indeed, their use in acute viral hepatitis may increase the risk of a chronic carrier state. Alpha-interferon may be useful in acute hepatitis C, but this approach remains investigational.

Return to work and activity should be guided by the patient's symptoms. Patient education will help alleviate anxiety. Specialist referral is not usually required. Prophylaxis and prevention of secondary spread is perhaps the most important aspect of treatment.

The control of hepatitis A is dependent on good sanitation and hygiene, because the virus is excreted in the stool early in the course of the infection. An attack of hepatitis A confers lifelong immunity. An effective vaccine has been developed for use by high-risk individuals such as those traveling to endemic areas or in institutions. Serum immunoglobulin (ISG) is also available. This should be provided to all household contacts, and is optimally given within one week of exposure at a dose of 0.02 mL/kg IM. Casual school or work contacts are not usually treated prophylactically unless an epidemic is identified.

A specific globulin preparation and a vaccine are available for HBV. Hepatitis B immunoglobulin (HBIG) should be given when there has been a clear-cut exposure such as inadvertent "needlestick" or sexual contact. It also should be given, along with hepatitis B vaccine, within 24 to 48 hours to the neonates of mothers with acute or chronic hepatitis B. Hepatitis B vaccine, originally manufactured from pooled donor sera, is now synthesized from recombinant DNA. Side effects are minimal with both forms. Vaccination targeted against high-risk groups such as homosexuals, health-care workers, IV drug users, family contacts of chronic carriers, chronic transfusion recipients and dialysis patients has surprisingly failed to affect the incidence of hepatitis B. Universal vaccination is therefore advocated and has been initiated in some provinces. Vaccination for hepatitis B is also protective against hepatitis D.

There is no vaccine or specific immunoglobulin available for hepatitis C. Pooled gamma globulin may reduce post-transfusion hepatitis C and thus it has been given empirically following high-risk exposures such as needlestick or transfusion from a known case of hepatitis C.

Table 6 summarizes the important features of the different types of viral hepatitis. Acute viral hepatitis is a self-limited disease and requires supportive care only. For the few patients who develop fulminant liver failure, liver transplantation may be required. Chronic infection can develop in patients with HBV, HCV, HDV and HGV infection.