Lancet 1998;351:1643; Gastroenterologist 1996;4:107

Cause: The hep A virus, a small, nonenveloped RNA virus of the genus Hepatovirus. There are 4 stable human genotypes and 1 serotype.

Epidem: (J Infect Dis 1995;171[suppl 1]:S2) Hep A is commonly acquired before age 5 yr in developing nations of Africa, Asia, and Latin America, where seroprevalence is greater than 90% before adulthood. In Western nations, the seroprevalence is falling and is about 43% in the U.S. The spread is fecal-oral with secondary attack rates of about 20-50% in households. The incubation period is 15-50 days. The virus can be found in feces for about 2 weeks prior to and up to several weeks after the onset of clinical illness. Risk factors for hep A in the U.S. include (1) household or sexual contact of a pt, (2) employee or participant in day care, (3) traveler, and (4) food (including bivalve shellfish) or waterborne outbreaks. There is no risk factor present in 45% of cases (Am Fam Phys 1996;54:107). There has been a marked decrease in incidence in the 17 U.S. states where routine vaccination of children has been practiced (Jama 2005;294:194) and a fall in mortality from hep A in the vaccination era (J Infect Dis 2008;197:1282).

Pathophys: After oral ingestion, the virus is transported across the intestinal epithelium and into hepatocytes. The virus replicates within hepatocytes. Hepatocellular damage results from the host’s immune response against infected cells (J Clin Lab Immunol 1993;40:47). Once jaundice occurs, viral titers fall as antibodies are produced against the virus.

Sx: A prodrome of fever, malaise, anorexia, nausea, and vomiting is usually seen in adults. The prodromal sx recede and jaundice develops. In children, the illness is usually anicteric and presents with flu-like sx of pharyngitis, cough, runny nose, photophobia, and headache. Diarrhea is seen in 50% of children but is uncommon in adults.

Si: Jaundice and hepatomegaly are usually noted, but splenomegaly is less common. Spider angiomata may develop but recede after the illness. Posterior cervical nodes may be seen. A cutaneous vasculitis is rare. Impending hepatic failure may be heralded by confusion, irritability, and asterixis.

Crs: The case fatality rate is quoted at 0.35%. However, so many cases go unrecognized that this is probably an overestimate. About 70% of the fatalities occur in the 8% of pts infected after age 50 yr. The typical course is a 3- to 6-month clinical illness. Jaundice usually lasts 6-8 weeks. LFTs resolve with the clinical sx. Fulminant hepatic failure develops in 0.14-0.35% of pts hospitalized for hep A. These pts develop worsening LFTs, markedly prolonged PT, and change in mental status. About 70-95% of them go on to develop cerebral edema, multiple organ failure, and death. Relapsing hep A occurs in 3-20% of all cases. These pts make an apparent clinical recovery, and weeks to months later develop recurrent illness with worsening LFTs and viral shedding. They ultimately recover (J Clin Gastro 1999;28:355). Prolonged cholestatic hep A is seen in 3-5% of pts. These pts have bilirubin >10 mg/dL, alk phos 3-5 times normal, and recover after an illness lasting months (Ann IM 1984;101:635).

Cmplc: Pancreatitis (Am J Gastro 1992;87:1648), renal failure (Clin Nephrol 1993;39:156), cholecystitis (Ann IM 1994;120:398), fulminant hepatic failure, Guillain-Barrè syndrome (Intern Med 1994;33:799), thrombocytopenic purpura (J Clin Gastro 1993;17:166), vasculitis, and arthritis may occur.

Diff Dx: See p 26.

Lab: The dx is made by demonstrating the presence of the IgM ab to hep A, which is always present during acute illness and which persists for 3-6 months. The presence of IgG ab without detectable IgM indicates prior infection and current immunity. Transaminases range from 500-5000 U/L. Bilirubin is usually less than 10 mg/dL but may go to 20 mg/dL in uncomplicated disease. A PT should be obtained as a marker of severity. Atypical lymphocytes are common.

X-ray: US or MRCP may be indicated if obstructive jaundice is a clinical question.

Rx: In most pts the rx is on an outpatient basis with abstinence from alcohol, moderate activity, and diet as tolerated. Bed rest is unnecessary (Nejm 1969;281:1421). Enteric precautions to minimize household spread are crucial.

Two vaccines are commercially available in the U.S., and others are under development. They are killed, attenuated virus vaccines that induce an antibody response in almost all healthy pts within a month. Havrix or VAQTA are given to adults in a dose of 1.0 mL im, followed by a booster of 1.0 mL 6-12 months later. They are indicated for travelers to endemic areas, those who live in endemic areas (including many American states), pts with chronic liver disease (especially hep C [Nejm 1998;338:286]), pts with clotting disorders (because of concentrated blood product use), in community outbreaks, for men who have sex with men, and for illicit drug users. Other high-risk occupations might be targeted (sewage workers, day-care workers). Universal vaccination has been proposed, but many practical barriers exist. A combination hep A and hep B vaccine (Twinrix) in a dose of 1.0 mL at 0, 1, and 6 months may be useful for adults needing both vaccines. The vaccine can also be used to prevent secondary spread (NNT = 18 to prevent 1 secondary case) (Lancet 1999;353:1136), but a direct comparison to immunoglobulin in this setting has notbeen done.

Prophylaxis with immunoglobulin is used for postexposure prophylaxis of household contacts and as primary prevention in infants where vaccine experience is limited.
Immunoglobulin is given in a dose of 0.02 mL/kg as a single im injection as soon as the index case is recognized (Am Fam Phys 1996;54:107). It provides protection if given within 2 weeks of exposure and lasts about 4-6 weeks. Doses of 0.06 mL/kg provide protection for travelers for up to 6 months, but vaccine is preferable.

Clin Gastroenterol Hepatol 2008;6:1315; Nejm 2008;359:1486; Clin Gastroenterol Hepatol 2004;2:87

Cause: The hep B virus (HBV), a DNA virus of the hepadnaviridae family. The virus is made up of a circular, partly double-stranded piece of DNA that is surrounded by a core called the nucleocapsid, which is then surrounded by an envelope. The envelope is antigenic (the hep B surface antigen, or HBsAg), and the nucleocapsid is antigenic (the hep B core antigen, or HBcAg). Immunity to HBsAg is protective and is the basis of natural and vaccine-induced immunity. The hep B e antigen (HBeAg) is derived from the core gene, which is modified and exported from liver cells. It is a marker for active replication of virus and is seen in pts with circulating HBV DNA.

Epidem: In endemic areas (Africa, Southeast Asia, China), 50% of the population become infected and 8% become chronic carriers. Infection is spread from mother to neonate (vertical transmission) or from child to child. In low-prevalence areas (North America, Europe), disease is spread sexually between young adults. Other risks in developed nations are iv drug use, occupational exposure, blood exposure, dialysis, or nosocomial transmission (Nejm 1992;326:721). About 20-30% of pts have no identified risk. Transmission from infected surgeons to pts has been reported (Nejm 1997;336:178). The U.S. prevalence is 0.35% for chronic infection and 5% for lifetime risk of infection. HBV is the leading cause of cirrhosis and HCC worldwide.

Pathophys: (Mayo Clin Proc 2007;82:967) In acute infection, clinical hepatitis results from the inflammatory response generated by the host in response to viral antigens presented on the surface of hepatocytes. If the immune response is vigorous, infected hepatocytes are rapidly cleared after an incubation period of 6 weeks to 6 months. This is the typical course for more than 95% of immunocompetent adults. However, if the immune response is ineffective, the pt develops chronic hepatitis. There are 4 phases of chronic HBV infection. Most pts do notgo through all 4 phases, and pts may transition back and forth between some of them.

In Phase 1, immune tolerance, pts have notyet developed an effective immune response. This is the case in most pts infected as neonates (95%) and many infected as young children (30%). There are high levels of viral replication as evidenced by high levels of circulating HBV DNA and a positive HBeAg. In this phase there is no clinical hepatitis and ALT levels are normal.

In Phase 2, HBeAg-positive chronic hepatitis, the maturing immune system starts to clear infected hepatocytes. Levels of HBV DNA fall but are still high. ALT rises and there is inflammation and developing fibrosis in the liver. For some pts, this leads to cirrhosis. Some pts will successfully inhibit viral replication and undergo seroconversion in which they lose HBeAg positivity and usually develop HBeAb.

In Phase 3, inactive HBsAg carrier state, after seroconversion the inflammation subsides, ALT levels normalize, and HBV DNA levels become low or undetectable. These pts have an overall good prognosis. However, a minority will revert back to HBeAg positivity and active viral replication with a flare of hepatitis. The rate of clearance of HBsAg in this stage is relatively low at about 0.1-2% per yr. Some inactive carriers redevelop active disease when given immunosuppressive rx for other diseases. Even in pts who clear HBsAg there is a risk of cirrhosis and HCC.

In Phase 4, HBeAg-negative chronic hepatitis, about 20-30% of inactive carriers will develop active disease with mutant viruses that do notexpress HBeAg. These viruses have mutations in the precore and core-promoter portions of the genome. Some pts enter this phase of disease directly from Phase 2. These pts develop a flare of hepatitis with elevated ALT levels and detectable HBV DNA, though typically at lower levels than in Phase 2 pts. These pts are usually older and have more advanced disease.

Sx: About half of pts with acute hep B have a subclinical illness. Those with clinically detectable illness usually present with jaundice, malaise, anorexia, and fever. Those with chronic hep B are usually asymptomatic but may complain of fatigue or malaise.

Si: In acute infection, jaundice, tender hepatomegaly, and fever. There may be stigmata of chronic liver disease (p 26).

Crs: Most adult pts have an acute hepatitis that clears within 6 months. About 3-5% of infected adults develop chronic hepatitis. Up to half of acutely infected adults are symptomatic. Pts are said to have chronic hepatitis if they have HBsAg detectable in the serum for more than 6 months or have HBsAg with no evidence of IgM anti-HBc. About 95% of infected neonates and 30% of children under age 6 yr have an asymptomatic illness that becomes chronic. Those adults with chronic hepatitis have a risk of progression to cirrhosis of 20% at 4 yr (Gut 1991;32:294). Fulminant hepatitis with coagulopathy, encephalopathy, and cerebral edema occurs in <1% of cases of acute hep B (Nejm 1993;329:1862). Any of the complications of end-stage liver disease may occur (p 255). Pts with concurrent hep C infection have aggressive liver disease, but HIV-infected pts do nothave more severe liver disease than those notinfected (Ann IM 1992;117:837).

Cmplc: Hep D (Delta) infection, a passenger virus that requires hep B for replication and causes severe liver disease (p 225). HCC (p 247) complicates long-standing hep B infection. It usually occurs in those with cirrhosis 25-30 yr after the onset of infection. HCC can occur in inactive carriers. The incidence of HCC is much higher in Asians and Africans than whites because of a much higher incidence of childhood infection. Polyarteritis nodosa (HTN, eosinophilia, abdominal pain, rash, polyarthritis, and necrotizing vasculitis involving gut, kidneys, and CNS) is a rare but serious complication of hep B infection (Lupus 1998;7:238). Glomerulonephritis (Ann IM 1989;111:479) and leukocytoclastic vasculitis (J Clin Gastroenterol 1995;21:42) are uncommon complications.

Diff Dx: See p 26.

Lab: Acute infection is diagnosed by the presence of HBsAg and IgM anti-HBc in the serum. In some very early cases, IgM anti-HBc may be absent, and it becomes positive later in the course. In those recovering from acute infection, IgM core disappears while the IgG core ab appears. HBsAg is cleared in about 24 weeks and anti-HBs appears about 8 weeks later, indicating complete recovery and future immunity. During the gap between the disappearance
of HBsAg and the appearance of anti-HBs (the window), the dx is made by the presence of IgM anti-HBc. IgG antibody to the core antigen (anti-HBc) develops and usually lasts a lifetime. If IgM anti-HBc is present, the pt has likely been recently infected, because the IgM fraction usually clears within 8 months of infection. A small number of pts with a flare of chronic hep B will produce IgM anti-HBc. HBeAg is present during acute infection and clears early in the illness. In chronic infection, HBsAg is present in the serum for a period of greater than 6 months (by definition). The IgM anti-HBc is usually absent. The HBeAg is present, and DNA levels are high when viral replication is high. The precore and core-promoter mutants may produce active infection but do notmake the HBeAg and may escape laboratory detection unless DNA levels are checked. DNA levels are best measured by real-time PCR assays with high sensitivity and a broad range of accurate quantification. Testing for hep A immunity should be done to select pts for vaccination. Prior to consideration of rx in pts with chronic hepatitis, testing should be done for HBeAg, HBeAb, HBV DNA, hep C, hep D, and HIV. A urinalysis should be done to look for renal complications. Genotype testing can be done if interferon rx is being considered since response rates are higher in pts with genotypes A and B. The suggested upper limit of normal for ALT to be used in hep B monitoring is 30 IU/mL for men and 19 IU/mL in women. Many commercial laboratories report higher normal values. In pts with chronic hepatitis who are notbeing treated because ALT is normal, the ALT is followed every 3-6 months. In the inactive carrier state, ALT is followed every 6-12 months and HBV DNA is checked if ALT rises.

Liver bx in cases of chronic hepatitis shows variable portal zone inflammation, focal hepatocyte necrosis, and ground glass hepatocytes (containing HBsAg). As the degree of injury progresses, there is more severe necroinflammatory change with eventual bridging or multiacinar fibrosis (Am J Clin Pathol 2000;113:40). Older descriptive terms such as “chronic persistent hepatitis” or “chronic active hepatitis” are no longer used. Instead, pathologists describe the degree of both inflammation and fibrosis (categorized as mild, moderate, marked, and very marked). The histologic patterns have no correlation with sx. The utility of bx is variable, because the decision to treat is usually based on evidence of viral replication rather than histology. However, bx may be especially helpful in pts with normal ALT levels and age >35-40 yr to identify those with active disease (as they transition from the immune-tolerant phase) despite the normal ALT level.

Rx: (Clin Gastroenterol Hepatol 2008;6:1315, Clin Gastroenterol Hepatol 2004;2:87)