General Considerations

Although the hepatitis viruses have been characterized extensively, the pathogenesis, diagnosis, and treatment of chronic viral hepatitis continue to be the focus of research. Sensitive and specific assays are available for all five forms (A–E) of viral hepatitis (Table 40–1). Nevertheless, at least approximately 5–10% of cases of acute and chronic hepatitis cannot be attributed to any of the known forms of viral hepatitis and do not appear to result from toxic, metabolic, or genetic conditions. A specific cause cannot be identified for approximately 50% of cases of fulminant hepatitis. Whether additional unidentified viruses cause acute or chronic liver disease remains an unanswered question; to date, despite intense investigation, no other hepatitis viruses have been identified. This chapter focuses on clinical features of the five known viruses that cause almost all recognized cases of acute and chronic hepatitis (Table 40–2).

Clinical Findings

A. Acute Viral Hepatitis

1. Symptoms and signs

Symptoms of acute viral hepatitis are usually nonspecific and include malaise, fatigue, nausea, anorexia, and arthralgias. Fever, if present, is usually low grade. With disease progression, pruritus, dark urine, scleral icterus, and jaundice may occur.

2. Laboratory findings

In any acute viral hepatitis, serum aminotransferase levels typically exceed 500 units/L and often 1000 units/L, with the alanine aminotransferase (ALT) characteristically higher than the aspartate aminotransferase (AST). Elevation of aminotransferase levels begins in the prodromal phase and precedes the rise in bilirubin level in patients with icteric hepatitis. Serum alkaline phosphatase may be normal or only mildly elevated. Serum bilirubin may be normal (anicteric cases) or elevated (icteric cases), but albumin and prothrombin time are generally normal unless the acute hepatitis is sufficiently severe to impair hepatic synthetic function. In most instances, bilirubin is divided equally between conjugated and unconjugated fractions; values above 20 mg/dL that persist late into the course of acute viral hepatitis are more likely to be associated with severe disease. Prolongation of the prothrombin time (>3 seconds above the control value or international normalized ratio [INR] >1.7) should raise concern and prompt close monitoring of the patient for worsening hepatic function and impending hepatic failure. Neutropenia and lymphopenia are transient and followed by a relative lymphocytosis. Hypoglycemia occurs occasionally in severe acute hepatitis. A mild and diffuse elevation of the γ-globulin fraction is common, especially in patients with acute hepatitis A.

3. Imaging findings

Radiologic imaging studies are rarely necessary unless biliary tract disease is suspected. For example, for patients with profound cholestasis (such as occurs in hepatitis A and even more commonly in hepatitis E), ultrasonography may be helpful in excluding extrahepatic biliary tract obstruction.

4. Histologic evaluation

Liver biopsy is rarely necessary in acute viral hepatitis except when the diagnosis is questionable or when chronic hepatitis is suspected.

B. Chronic Viral Hepatitis

1. Symptoms and signs

Chronic viral hepatitis may be and is often asymptomatic; many patients are unaware of their condition until the diagnosis is made incidentally or until progression to advanced liver disease results in systemic symptoms and clinical features of hepatic dysfunction.

2. Laboratory findings

The most telling laboratory markers are the aminotransferase levels, which may be elevated continuously or may fluctuate; typically, ALT levels are higher than AST levels until cirrhosis develops, when AST levels tend to be higher. Otherwise, laboratory values that reflect hepatic function (bilirubin, albumin, prothrombin time) may be normal unless and until hepatic decompensation ensues.

3. Imaging findings

Ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) are useful to evaluate liver parenchyma and to assess for the existence of varices, reversal of portal hepatic flow, ascites, splenomegaly, and other signs of portal hypertension; hepatic vein occlusion and other vascular abnormalities; and focal mass lesions.

4. Histologic evaluation

Although its role is evolving and being supplanted gradually by noninvasive serum and imaging markers of fibrosis, liver biopsy is useful for grading the activity and for staging the progression of disease, for identifying clinically relevant histologic features (eg, steatosis, iron deposition, pathognomonic features of autoimmune liver injury, granulomatous inflammation, etc), or for adding helpful information in diagnostically challenging cases.

Differential Diagnosis

A. Acute Viral Hepatitis

Infections with other viruses, such as cytomegalovirus, Epstein-Barr virus, herpes simplex or zoster, and coxsackie viruses, can result in an acute viral hepatitis syndrome and elevated serum aminotransferase levels. Toxoplasmosis and leptospirosis may also share clinical features with acute hepatitis. If the results of serologic tests for the known hepatitis viruses (discussed later) are negative, and if clinical features are suggestive, serologic tests for these agents should be considered.

Several drugs and anesthetic agents can produce a picture similar to that of acute hepatitis; therefore, taking a careful drug history is important. A past history of unexplained and repeated episodes of hepatitis raises the possibility of underlying chronic hepatitis.

Alcoholic hepatitis is associated with a history of ethanol abuse and usually with clinical stigmata of alcoholism. In patients with alcoholic liver disease, serum aminotransferase levels rarely rise above 300 units/L, and, typically, serum AST levels exceed serum ALT levels.

When abdominal pain is prominent, acute viral hepatitis may be confused with acute cholecystitis, choledocholithiasis, ascending cholangitis, pancreatitis, or other abdominal disorders. Careful clinical and radiologic evaluation will assist in making the correct diagnosis and thereby avoiding unnecessary surgery. Cholestatic viral hepatitis may be confused with obstructive jaundice resulting from pancreatic carcinoma, common bile duct stone, other disorders that obstruct the biliary tree, or hepatic infiltrative disorders (eg, fatty infiltration, primary or metastatic tumor infiltration, extramedullary hematopoiesis, granulomatous disorders).

Clinical features help to distinguish acute hepatitis from congestive hepatopathy and acute ischemic injury, which tend to be associated primarily with aminotransferase, not alkaline phosphatase, elevations. Uncommonly, inherited metabolic disorders, such as Wilson disease, mimic acute viral hepatitis.

B. Chronic Viral Hepatitis

In the differential diagnosis of chronic viral hepatitis are autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, genetic disorders such as Wilson disease, hemochromatosis, α₁-antitrypsin deficiency, alcoholic liver disease, nonalcoholic fatty liver disease, and chronic drug hepatotoxicity. Serology, biochemical testing, and liver histopathology help in arriving at the correct diagnosis in most instances.

General Considerations

Hepatitis A virus (HAV) is a 27-nm nonenveloped RNA virus (genus Hepatovirus) that is transmitted by the fecal-oral route through ingestion of contaminated food (eg, shellfish, strawberries, onions) or water. The incubation period is 2–6 weeks, the duration of viremia is short (5–7 days), and chronic infection does not occur; therefore, percutaneous transmission is exceedingly rare.

Infection is more prevalent in areas of low socioeconomic status characterized by insufficient sanitation and poor hygienic practices, which facilitate the spread of enteric infections. In developing countries, hepatitis A is endemic, infecting most children before the age of 5–10. In developed countries, improved socioeconomic conditions and sanitation have led to an increase in the mean age of infection and a reduction in the prevalence of HAV exposure, as reflected by serum antibodies to HAV (anti-HAV) in the population.

Pathogenesis

As is true for all hepatitis viruses, viral replication of HAV occurs primarily within hepatocytes. Except in extraordinary circumstances, hepatitis viruses are not cytopathic; instead, liver cell damage results from host cell–mediated cytotoxicity. In hepatitis A, the necroinflammatory changes and mononuclear cell infiltrates are prominent in periportal areas, but lobular focal necrosis, ballooning hepatocytes, and apoptosis are regular features as well. In some cases, centrilobular cholestasis may be severe, particularly in adults. Serum neutralizing antibodies protect against HAV infection. HAV antigen can be demonstrated by immunohistochemical staining as fine granules in the cytoplasm of hepatocytes and Kupffer cells.

Clinical Findings

A. Acute HAV Infection

Although more than 70% of adults infected with HAV have symptoms, approximately 70% of infections in young children are asymptomatic. When hepatitis A is clinically apparent, patients present with fatigue, malaise, right upper quadrant and epigastric discomfort, loss of appetite, and, in icteric cases, dark urine and jaundice. Less commonly, HAV infection may be profoundly cholestatic and accompanied clinically by marked jaundice, acholic stools, and pruritus. This cholestatic variant of acute hepatitis A may be protracted but, ultimately, is self-limited.

Hepatitis A results very rarely in fulminant hepatitis and does not cause chronic liver disease, although extraordinarily rare reports suggest that acute hepatitis A can trigger autoimmune hepatitis in susceptible persons. Approximately 10% of patients can have a relapsing course lasting several months (resumption of fecal viral excretion and aminotransferase elevation after initial, apparent resolution) and invariably culminating in eventual recovery. Systemic manifestations are uncommon and include arthritis and, very rarely, transverse myelitis, aplastic anemia, and leukocytoclastic vasculitis, although reports of these complications are not linked reliably to hepatitis A. Concomitant meningoencephalitis has been reported rarely.

B. Serologic Assays

The diagnosis of acute HAV infection depends on the detection of IgM antibodies to HAV (IgM anti-HAV). IgM anti-HAV occurs as a primary immune response and persists for approximately 3 months, sometimes extending to 6 months after acute HAV infection. As IgM anti-HAV declines, it is replaced by immunoglobulin G (IgG) anti-HAV, which correlates with subsequent lifelong immunity. Thus, if a patient who presents with acute hepatitis has IgG anti-HAV, the acute illness is not caused by HAV.

Prevention

General measures to prevent the spread of HAV infection include a safe water supply and proper environmental hygiene (eg, sewage disposal, elimination of overcrowded housing, etc). Killed HAV vaccines have a protective efficacy of 94–100% after two doses, with negligible side effects. Two such vaccines were licensed in the United States in 1995–1996 and are available worldwide. Their introduction in the United States coincided with a decline in new, reported cases of hepatitis A in the United States from an annual average of 12 cases per 100,000 population in 1995 to 1 case per 100,000 in 2007. In 2006, because of residual clusters of hepatitis A cases, including severe and even fatal instances in otherwise healthy adults, the Advisory Committee on Immunization Practices of the US Public Health Service recommended routine hepatitis A vaccination of children at 1 year of age. Recommendations for vaccination of other persons in groups at increased risk for hepatitis A are listed in Table 40–3.

Immunoglobulin has also been shown to be safe and effective as both preexposure and postexposure prophylaxis against HAV infection. For preexposure prophylaxis, if immediate protection is required, travelers should receive passive immunization with immunoglobulin and begin a course of active immunization with vaccine; in this setting, preexposure passive immunization requires a single intramuscular dose of immunoglobulin (0.02 mL/kg). For postexposure prophylaxis, the same dose, given within 10–14 days of exposure, has an efficacy of approximately 85% and usually aborts or reduces the severity of, and renders clinically inapparent, HAV infection (yielding a combination of passive immunization and the durable immunity that follows acute infection). In the absence of concomitant active immunization, the passive protection offered by immunoglobulin lasts only a few months; currently, hepatitis A vaccination is preferred over immunoglobulin for postexposure prophylaxis in healthy children and adults.

Treatment

Treatment is largely supportive and consists of discontinuation of potentially hepatotoxic medications and restriction of alcohol intake. Neither bed rest nor dietary restrictions are effective. Most patients do not require hospitalization, which is recommended for those with advanced age, serious underlying medical conditions, chronic liver disease, malnutrition, pregnancy, immunosuppressive therapy, hepatotoxic medications, severe vomiting that prevents adequate oral intake, and clinical and laboratory findings that suggest fulminant hepatitis. The occasional patient with fulminant hepatic failure, defined as the onset of coagulopathy and encephalopathy within 8 weeks of the onset of symptoms, should be referred for consideration of liver transplantation.

Course & Prognosis

The overall case fatality rate for HAV infection is very low (~0.3–0.8%), although higher in adults older than age 60 (2.6%). In some reports, morbidity and mortality were increased in the presence of a hepatitis A superinfection in patients with underlying chronic liver disease.

General Considerations

More than 350 million people worldwide—5% of the world’s population—are currently HBsAg-reactive, indicating that they are currently infected with hepatitis B virus (HBV), and as many as 50% of the world’s population have had HBV infection, as reflected by the presence of anti-HBs. HBV is endemic in areas containing 45% of the world’s population. In endemic areas, rates of current infection range from 8% to 25%, and exposure rates (based on the presence of anti-HBs) range from 60% to 85%. In low prevalence areas such as the United States, the prevalence of chronic HBV infection is 0.1–0.2% (1.25 million), and the annual incidence of new HBV infections is 200,000–300,000.

HBV is transmitted primarily by perinatal, percutaneous, and sexual routes. The virus can also be transmitted by inapparent percutaneous routes and close person-to-person contact, presumably via open cuts and sores, especially among children in endemic areas (eg, sub-Saharan Africa, which has a prevalence of chronic HBV infection of nearly 10%). In the United States, most HBV infections occur in adolescence and early adulthood, and the most common modes of transmission are sexual and percutaneous (exposure to contaminated instruments and needles, eg, via injection drug use). In contrast, in Asia, the most common mode is perinatal transmission to infants of mothers with chronic HBV infection; in sub-Saharan African countries, in addition to perinatal spread, another common mode of transmission is horizontal spread between young children. Injection drug users are at high risk of acquiring not only HBV infection but also other blood-borne hepatitis agents, hepatitis C and D (see later sections).

Pathogenesis

HBV is a partially double-stranded, partially single-stranded DNA virus (hepadnavirus type 1) that replicates via reverse transcription through an RNA intermediate. Although HBV is strongly hepatotropic, viral sequences, including HBV replicative intermediates, are present in extrahepatic tissues (lymph nodes, peripheral blood mononuclear cells); however, the vast bulk of—and the only pathophysiologically relevant—HBV replication is confined to the liver. The HBV genome contains four open reading frames that encode four major proteins: (1) the S gene, which codes for the envelope protein, HBsAg; (2) the C gene, which codes for the nucleocapsid proteins hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg); (3) the P (or pol) gene, which codes for the DNA polymerase, which, in turn, catalyzes transcription and reverse transcription steps involved in viral replication; and (4) the X gene, which codes for the X protein, a protein of limited clinical relevance but which upregulates the transcription of host cellular and viral genes, including those of other viruses such as HIV.

The envelope protein of the virus, HBsAg, in serum is the primary marker of HBV infection. In the hepatocyte, HBsAg is expressed in the cytoplasm and can be recognized histologically by the presence of ground-glass hepatocytes. Eight HBV genotypes (A–H) have been identified; the prevalence of HBV genotype varies depending on geographic location. In the United States the prevalences of genotypes A, B, C, D, and others are 35%, 22%, 31%, 10%, and 2%, respectively. Recent data suggest that HBV genotypes may play an important role in progression of HBV-related liver disease as well as in response to interferon therapy. Similar associations have not been clarified definitively in patients treated with oral agents (nucleoside and nucleotide analogs); therefore, the testing of HBV genotype has not yet been adopted routinely as a prelude to antiviral therapy (see later discussion).

The C region has two initiation codons and therefore two gene transcripts (precore and core), the translation of which result in two protein products (HBeAg and HBcAg). HBcAg, the protein expressed on the 27-nm nucleocapsid core particles, is not secreted into serum but is localized predominantly to the hepatocyte nucleus and is expressed also in smaller quantities on the hepatocyte surface membrane. As such, HBcAg is the target of the host immune response to infection, playing an important role in the pathogenesis of HBV-induced liver damage. The other nucleocapsid protein, HBeAg, a low-molecular-weight nonparticulate protein, is encoded by the precore plus core region of the C gene, enters the secretory apparatus of the hepatocyte, and circulates in serum; the presence of HBeAg is indicative of active viral replication and correlates with increased infectivity and liver injury. The products of the same gene, HBcAg and HBeAg, have considerable amino acid homology and immune cross-reactivity at the T-cell level. Antibody to HBcAg (anti-HBc) appears at the onset of clinical hepatitis, shortly after the appearance of HBsAg, and may be the only marker detectable between the disappearance of HBsAg and the appearance of anti-HBs (less likely to be encountered now that the sensitivity of assays for HBsAg and anti-HBs are so high). During acute hepatitis B, anti-HBe appears as clinical symptoms and aminotransferase levels are waning; its appearance marks a transition to lower viral replication, infectivity, and liver injury.

HBeAg-negative variants result from mutations in the precore region of the C gene, with failure of HBeAg synthesis (the serologic marker linked to active virus replication) yet with continued high-level viral replication and liver injury. “HBeAg-negative” mutant HBV has been associated with fulminant hepatitis (rarely) and chronic hepatitis (commonly).

Liver injury associated with HBV infection is the product of a combination of innate and adaptive immune responses, the latter of which are affected by cytotoxic T cells directed at liver membrane complexes of host histocompatibility antigens and HBcAg. The clinical outcome of HBV infection depends on the balance between viral activity and the host immune response, as reflected by the robustness of the CD8⁺ cytotoxic T-cell response and the release of antiviral T-cell cytokines; however, other than certain clinical features (eg, age, infection at birth, immunocompetence), what distinguishes those who recover from those who progress to chronic infection remains poorly defined. In perinatally acquired infection, immaturity of the neonatal immune system and the presence of HBV on hepatocytes shortly after birth combine to produce a level of immunologic tolerance to HBV that limits the adequacy of the host immune response to HBV. This state of immunologic tolerance can persist indefinitely. In perinatally acquired HBV infection, no robust cytotoxic T-cell response occurs against HBV, no clinical illness ensues, but chronic infection is almost invariable (>90%). In contrast, among young adults with acute hepatitis B, the cytotoxic T-cell response to HBV expressed on hepatocyte membranes is substantial and efficient, leading to an acute hepatitis illness and, typically, recovery; chronicity after clinically apparent acute hepatitis B in healthy, immunocompetent young adults occurs in fewer than 1% of cases.

A. Hepatocellular Carcinoma

Epidemiologically and clinically, chronic HBV infection is linked strongly to the development of hepatocellular carcinoma (HCC), which can occur in up to 50% of patients with HBV-induced cirrhosis following lifelong infection acquired perinatally (see Chapter 50). The mechanism of viral oncogenesis has been studied extensively; viral integration into the host genome is required, but no consistent sites of integration have been identified (eg, adjacent to a host tumor promotor or suppressor gene). Cell turnover associated with chronic inflammation likely contributes to the pathogenesis of HCC, as do such cofactors such as alcohol use and environmental aflatoxin exposure.

B. Hepatitis B Virus Variants

1. Precore mutants or HBeAg-negative chronic HBV infection

A precore nucleotide mutation or core-promoter mutation can lead to premature termination of the precore protein, preventing production of HBeAg. HBeAg-negative HBV infection is found more frequently in HBV genotypes other than genotype A, and its prevalence was concentrated initially in Mediterranean countries. Currently, HBeAg-negative chronic hepatitis B is the predominant form of chronic hepatitis B in Europe and represents a growing proportion (~40%) of chronic hepatitis B infections in the United States. Wild-type (HBeAg-positive) chronic hepatitis B is associated with higher levels of HBV replication (≥10⁶ virions/mL) than HBeAg-negative chronic hepatitis B (≤10⁵ virions/mL), whereas HBeAg-negative chronic hepatitis B is more likely to be associated with fluctuating levels of HBV DNA and aminotransferase activity. In addition, in HBeAg-negative chronic hepatitis B, patients treated with antiviral therapy (see later discussion) cannot experience treatment-induced HBeAg seroconversion, which, in HBeAg-positive chronic hepatitis B, can be used as a treatment end point. Therefore, the ideal duration of therapy remains undefined in HBeAg-negative chronic hepatitis B.

2. S mutants

A mutation in the S gene has been reported in infants who are born to HBV-infected mothers but acquire HBV infection after vaccination and in liver transplant recipients who acquire breakthrough HBV reinfection despite treatment with hepatitis B immunoglobulin (HBIG). These mutations alter the antigenicity of the HBV envelope, evading neutralizing anti-HBs. Fortunately, the frequency of such mutations—and their public health impact—is limited.

3. P mutants

Mutations in the polymerase gene are associated with resistance to HBV antiviral agents such as lamivudine, adefovir, and telbivudine (see later discussion).

Clinical Findings

A. Acute Hepatitis B

The incubation period of acute hepatitis B is between 4 weeks and 6 months. Clinical symptoms are similar to those described earlier for acute hepatitis A (eg, fatigue, anorexia, jaundice), and aminotransferase elevations are the biochemical hallmark of illness. In 5–10% of patients with acute hepatitis B, a serum sickness-like syndrome with arthralgias, rash, angioedema, and, rarely, proteinuria and hematuria may develop in the prodromal phase. In children, hepatitis B may present rarely as anicteric hepatitis associated with a nonpruritic papular rash on the face, buttocks, and limbs (papular acrodermatitis of childhood).

B. Chronic Hepatitis B

Progression from acute to chronic hepatitis may be suggested by the persistence of anorexia, weight loss, and fatigue, although most patients with chronic hepatitis B are asymptomatic. Physical findings may include hepatomegaly and splenomegaly. Laboratory findings include persistence of HBsAg, detectable HBeAg in HBeAg-positive hepatitis, and elevations of aminotransferase, bilirubin, and globulin levels. Histologic features include the presence of portal inflammation; bridging or, in severe cases, multilobular hepatic necrosis; and the presence of fibrosis.

Many patients with chronic HBV infection are inactive carriers who have no symptoms, normal serum aminotransferase activity, low-level HBV DNA (≤10³ virions/mL), circulating anti-HBe, and normal or near-normal liver histology.

Extrahepatic manifestations, when they occur, may include arthralgias, arthritis, Henoch-Schönlein purpura, generalized vasculitis (polyarteritis nodosa), glomerulonephritis, pleural effusions, pericarditis, and aplastic anemia (the latter not definitively linked to HBV infection, however). Uncommon complications of HBV infection include pancreatitis, myocarditis, atypical pneumonia, transverse myelitis, and peripheral neuropathy.

C. Serologic Assays

The diagnosis of HBV infection relies on the presence of HBsAg. Acute and chronic infections are distinguished by the presence of IgM versus IgG antibodies to HBcAg (anti-HBc). The presence of IgM anti-HBc indicates recent infection, generally within the previous 6 months. HBeAg appears early during acute hepatitis B, while viral replication is at peak levels, and in self-limited cases is replaced within 2–3 months by antibody to HBeAg (anti-HBe).

During chronic hepatitis B, in patients with wild-type HBV infection, the presence of HBeAg corresponds to a relatively highly replicative period, during which levels of HBV DNA exceed 10⁶ virions/mL, infectivity is substantial, and liver injury is pronounced. Over time, this highly replicative phase gives way to a relatively low replicative phase, characterized by low-level HBV DNA (≤10³ virions/mL) and negligible infectivity and liver injury. Patients in this phase are considered inactive carriers.

In patients with precore mutations (HBeAg-negative chronic hepatitis B), HBV DNA levels fluctuate between undetectable and approximately 10⁵ virions/mL, and anti-HBe is detectable in serum. In chronic hepatitis B, anti-HBc is of the IgG class (except, rarely, during reactivation of chronic hepatitis B [eg, seroreversion from anti-HBe-reactive back to HBeAg-reactive or during reactivation of clinically quiescent HBeAg-negative chronic hepatitis B], when IgM anti-HBc may reappear transiently). The presence of isolated anti-HBs is consistent with vaccine-induced immunity. Antibodies to both surface and core proteins (anti-HBs, anti-HBc, and anti-HBe) indicate prior HBV infection.

Interpretation of isolated IgG anti-HBc positivity is difficult and may represent ongoing, low-level HBV infection, prior HBV infection, or a false-positive test. Isolated anti-HBc with ongoing low-level HBV infection is more common in persons from high-prevalence areas, with a history of injection drug use, and/or with HIV infection.

Prevention

Hepatitis B vaccine is protective in over 90% of normal adults and in almost 100% of newborns. Recombinant vaccines have largely supplanted the original plasma-derived vaccine in most parts of the world. Common adverse effects are local reactions at the injection site (soreness, tenderness, pruritus, and swelling). The immunogenicity of hepatitis B vaccines is reduced in adults older than 40 years; among younger healthy adults, approximately 2.5–5% do not acquire protective antibodies, and such nonresponsiveness has been shown to be genetically determined.

Despite the availability of highly effective vaccines for over 30 years, targeted vaccination programs for those at highest risk of infection have failed to reduce the frequency of HBV infection in the US population. Currently, the US Public Health Service recommends universal vaccination of all neonates and prepubertal teenagers. In addition, HBV vaccination is currently recommended for immunocompromised patients; hemodialysis patients; patients with coexisting chronic liver disease of other causes, including chronic hepatitis C; health care workers; injection drug users; and those with high-risk sexual exposures (see Table 40–3). Currently, booster immunization is not recommended routinely, although it may be useful in immunosuppressed persons who have lost detectable anti-HBs or in immunocompetent persons who sustain HBsAg inoculation after losing detectable antibody (although this subgroup appears to be protected even after loss of detectable anti-HBs).

Treatment

A. Fulminant Hepatitis B

In fulminant hepatitis B, intensive care in a specialized unit and early consideration for orthotopic liver transplantation are likely to reduce mortality. Only 25% of patients who have fulminant hepatitis B will survive without liver transplantation. Patients should be supported by maintaining fluid and electrolyte balance and cardiorespiratory function, controlling bleeding, treating prophylactically with broad-spectrum antibiotics, monitoring for cerebral edema, and managing other complications. Although antiviral treatment with interferon has not been shown to be of benefit in fulminant hepatitis B, treatment with oral nucleoside or nucleotide agents (described later) may be of benefit and would be recommended in most specialized treatment centers.

Corticosteroid therapy is not only ineffective but harmful, as demonstrated in clinical trials. Similarly, exchange transfusions, plasma perfusion, human cross-circulation, porcine liver cross-perfusion, and extracorporeal liver-assist devices have not been proven to be effective.

Orthotopic liver transplantation is being performed with increasing frequency, with excellent long-term results. Thus, patients should be supported maximally until spontaneous recovery or until prognostic factors indicate worsening outcome necessitating transplantation; the threshold for referring to a liver transplantation center should be very low. During and after transplantation, measures should be taken to prevent HBV infection of the graft (see later discussion).

B. Chronic Hepatitis B

The objectives of treatment for chronic hepatitis B are to suppress HBV replication and reduce liver injury. Among the end points of therapy are (1) profound reduction in circulating HBV DNA, preferably to levels undetectable by highly sensitive amplification assays; (2) in HBeAg-positive chronic hepatitis B, HBeAg seroconversion (loss of HBeAg and acquisition of anti-HBe); (3) normalization of ALT levels; (4) improvement in liver histology (reduction in the grade of necroinflammatory activity and limiting progression of, or even improving, the stage of fibrosis). Data suggest that successful antiviral therapy has the potential to prevent or delay progression to cirrhosis, hepatic decompensation, and even HCC. Recommendations for patients with chronic hepatitis B who are candidates for treatment are summarized in Table 40–4; seven therapies are approved and currently available for treatment of chronic hepatitis B (Table 40–5).

1. Interferon-α2b