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Hepatitis B

Essentials of Diagnosis

  • Malaise, anorexia, fever, dark urine, pale stools, jaundice, right upper quadrant pain, and tender hepatomegaly.
  • Increased risk in promiscuous homosexual men, injection drug users, transfusion recipients, hemophiliacs, hemodialysis patients, and patients with Down’s syndrome.
  • Increased liver enzymes (ALT, AST), bilirubin, prothrombin time, and globulin.
  • Serum positive for hepatitis B core IgM antibody.
  • Chronic hepatitis may be caused by hepatitis B and be diagnosed by the presence of hepatitis B surface antigen (HbsAg) in blood.

Hepatitis B

General Considerations


Hepatitis B infection is found worldwide, with prevalence rates varying markedly among countries. Chronic carriers constitute the main reservoir of infection: in some countries, particularly in the Far East, ~ 5-15% of all persons carry the virus, though most are asymptomatic. Of patients with HIV infection, 10% are chronic carriers of hepatitis B.

In the United States, it is estimated that 1.5 million people are infected with hepatitis B, and it is estimated that 300,000 new cases occur annually. Approximately 300 of these individuals die with acute fulminant hepatitis, and 5-10% of infected patients become chronic hepatitis B virus carriers. As many as 4000 people die yearly of hepatitis B-related cirrhosis, and 1000 of hepatocellular carcinoma. Approximately 50% of infections in the United States are sexually transmitted, and the occurrence of hepatitis B surface antigen (HBsAg) is higher in certain populations, such as male homosexuals, patients on hemodialysis or immunosuppressive therapy, patients with Down’s syndrome, and injection drug users.

Routine screening of blood donors for HBsAg has markedly decreased the incidence of post-transfusion hepatitis B; > 90% of cases developing after transfusion are now caused by other NANB hepatitis viruses. Multiple-pool blood products occasionally cause cases, and inadequately sterilized, blood-contaminated needles are still significant vehicles of transmission. Exposure by direct contact with blood or other bodily fluids, probably through small lesions, has resulted in hepatitis B infection of medical personnel. Attack rates are also high in spouses and sexual partners of infected patients.

Hepatitis B

Most hepatitis B infections of infants do not appear to be transplacentally transmitted to the fetus in utero, but are acquired during the birth process by the swallowing of infected blood or fluids or through abrasions. The rate of virus acquisition is high (~ 90%) in infants born to mothers who have acute hepatitis B infection or who carry HBsAg and hepatitis B e antigen (HBeAg). Most infants do not develop clinical disease; however, infection in the neonatal period is associated with failure to produce antibody to HBsAg and, thus, with chronic carriage in ~100% and perpetuation of infection by transmission in the family setting.

Hepatocellular carcinoma has been strongly associated with persistent carriage of hepatitis B virus, by serologic tests and detection of viral nucleic acid sequences integrated in tumor cell genomes. In many parts of Africa and Asia, primary liver cancer accounts for 20-30% of all types of malignancies, but only 1-2% in North and South America and Europe. The estimated risk of developing the malignancy for persons with chronic hepatitis B is increased between 10- and 300-fold in different populations. The mechanism of the association is unclear.


Hepatitis B virus is an enveloped DNA virus belonging to the family Hepadnaviridae. It is unrelated to any other human virus; however, related hepatotropic agents have been identified in woodchucks, ground squirrels, and kangaroos. A schematic of the hepatitis B virus is illustrated in Figure 39-2. The complete virion is a 42-nm, spherical particle that consists of an envelope around a 27-nm core. The core comprises a nucleocapsid that contains the DNA genome.

The viral genome consists of partially double-stranded DNA with a short, single-stranded piece. It comprises 3200 nucleotides, making it the smallest DNA virus known. Closely associated with the viral DNA is an RNA-dependent DNA polymerase, ie reverse transcriptase. Other components of the core are a hepatitis B core antigen (HBcAg) and HBeAg, which is a low-molecular-weight glycoprotein.

The envelope of the virus contains HBsAg, which is composed of one major and two other proteins. Antigenically there exist a group-specific determinant, termed a, and a number of subtypes that are important in epidemiologic typing, but not in immunity, because there is antigenic cross-reactivity and cross-protection between subtypes. Aggregates of HBsAg are often found in great abundance in serum during infection. They may assume spherical or filamentous shapes with a mean diameter of 22 nm and may contain portions of the nucleocapsid. Hepatitis B DNA can also be detected in serum and is an indication that infectious virions are present there. In infected liver tissue, evidence of HBcAg, HBeAg, and hepatitis B DNA is found in the nuclei of infected hepatocytes, whereas HBsAg is found in cytoplasm.

Despite extensive attempts, hepatitis B virus has not been propagated in the laboratory. Humans appear to be the major host; however, as with hepatitis A, infection of subhuman primates has been accomplished experimentally.

The replication of hepatitis B virus involves a reverse transcription step and, as such, is unique among DNA viruses. In viral replication, full-length positive viral RNA transcripts are inserted into maturing core particles late in the replicative cycle. These mRNA strands form a template for a reverse transcription step in which negatively stranded DNA is synthesized. The RNA template strands are then degraded by ribonuclease activity. A positive-stranded DNA is then synthesized, although this step is not completed before virus maturation and release. This results in the variable-length short positive DNA strands found in the virions together with complementary negative long strands. Release is by a secretory mechanism (reverse endocytosis) and does not cause cell lysis.


In the past, hepatitis B was known as post-transfusion hepatitis or as hepatitis associated with the use of illicit parenteral drugs (serum hepatitis). Over the past few years, however, it has become clear that the major mode of acquisition is through close personal contact with body fluids of infected individuals. HBsAg has been found in most body fluids, including saliva, semen, and cervical secretions. Transmission by person-to-person contact has been documented, as has vertical mother-to-child transmission, usually at the time of birth. Under experimental conditions, as little as 0.0001 mL of infectious blood has produced infection. Transmission is therefore also possible by vehicles such as inadequately sterilized hypodermic needles or instruments used in tattooing and ear piercing.

The factors determining the different clinical manifestations of acute hepatitis B are largely unknown; however, some appear to involve immunologic responses of the host. The serum sickness-like rash and arthritis that may precede the development of symptoms and jaundice appear related to circulating immune complexes that activate the complement system. Antibody to HBsAg is protective and associated with resolution of the disease. Cellular immunity also may be important in the host response, because patients with depressed T lymphocyte function have a high frequency of chronic infection with the hepatitis B virus. Antibody to HBcAg, is present in chronic carriers with persistent hepatitis B virion production and it does not appear to be protective.

The morphologic lesions of acute hepatitis B resemble those of hepatitis A and NANB hepatitis. In chronic active hepatitis B, the continued presence of inflammatory foci of infection results in necrosis of hepatocytes, collapse of the reticular framework of the liver, and progressive fibrosis. The increasing fibrosis can result in the syndrome of postnecrotic hepatic cirrhosis.

Integrated hepatitis B viral DNA can be found in nearly all hepatocellular carcinomas. The virus has not been shown to possess a transforming gene but may well activate a cellular oncogene. It is also possible that the virus does not play such a direct molecular role in oncogenicity, because the natural history of chronic hepatitis B infection involves cycles of damage or death of liver cells interspersed with periods of intense regenerative hyperplasia. This significantly increases the opportunity for spontaneous mutational changes that may activate cellular oncogenes. Whatever the mechanism, the association between chronic viral infection and hepatocellular carcinoma is clear, and liver cancer is a major cause of disease and death in countries in which chronic hepatitis B infection is common. The proven success of immunization in aborting hepatitis B infection makes hepatocellular carcinoma of the liver a potentially preventable disease.

Clinical Findings

Signs and Symptoms

The clinical picture of hepatitis B is highly variable. The incubation period is from 45 days to as long as 160 days (mean, ~10 weeks). Acute hepatitis B is usually manifested by the gradual onset of fatigue, loss of appetite, nausea and pain, and fullness in the right upper abdominal quadrant. Early in the course of disease, pain and swelling of the joints and occasionally frank arthritis may occur. Some patients develop a rash. With increasing involvement of the liver, there is increasing cholestasis and, hence, clay-colored stools, darkening of the urine, and jaundice. Symptoms may persist for several months before finally resolving.

In general, the symptoms associated with acute hepatitis B are more severe and more prolonged than those of hepatitis A; however, anicteric disease and asymptomatic infection regularly occur. The infection-to-disease ratio, which varies according to age and method of acquisition, has been estimated to be approximately 6:1 or 7:1.

Laboratory Findings

In acute illness, the laboratory findings are as with hepatitis A; persistence of blood abnormalities beyond 6 months may indicate the development of chronic hepatitis B disease.


As with hepatitis A

Differential Diagnosis

As with hepatitis A


Chronic hepatitis occurs in ~10% of all patients with hepatitis B infection The risk of chronic hepatitis B infection is much higher for newborns (100%), children (50%), and immunocompromised patients. Chronic infection is associated with ongoing replication of virus in the liver and usually with the presence of HBsAg in serum. Chronic hepatitis may lead to cirrhosis, liver failure, hepatocellular carcinoma, or some combination of these. It is estimated that 10% of all chronic liver disease in the United States and Canada is caused by hepatitis B. Fulminant hepatitis, leading to extensive liver necrosis and death, develops in ~0.1% of cases.


Nonspecific findings in blood are elevations of hepatic enzymes, globulin, and prothrombin time and decreases of albumin and blood leukocytes. The sequential appearance of hepatitis B antigens and antibodies is shown in Figure 39-3. During the acute episode of disease, when there is active viral replication, large amounts of HBsAg and hepatitis B virus DNA can be detected in the serum, as can fully developed virions and high levels of DNA polymerase and HBeAg. Although HBcAg is also present, antibody against it invariably occurs and prevents its detection. With resolution of acute hepatitis B, HBsAg and HBeAg disappear from serum with the development of antibodies (anti-HBs and anti-HBe) against them. The development of anti-HBs is associated with elimination of infection and protection against reinfection. Anti-HBc is detected early in the course of disease and persists in serum for years. It is an excellent epidemiologic marker of infection but is not protective.

In patients with chronic hepatitis B, evidence of viral persistence can be found in serum. HBsAg can be detected throughout the active disease process, and anti-HBs does not develop, which probably accounts for the chronicity of the disease. Anti-HBc is, however, detected. Two types of chronic hepatitis can be distinguished. In one, HBsAg is detected, but not HBeAg; these patients usually show minimal evidence of liver dysfunction. In the other, both antigens are found; the process is more active with continued hepatic damage that may result in cirrhosis. The presence of HBsAg and hepatitis B DNA (HB DNA) is indicative of active viral replication. The laboratory diagnosis of acute hepatitis B is best made by demonstrating the IgM antibody to HBcAg in serum. HBsAg may also be detected in serum. Past infection with hepatitis B is best determined by detecting anti-HBc IgG, anti-HBs IgG, or both. Chronic infection with hepatitis B is best detected by persistence of HBsAg in blood for > 6-12 months. Vaccine recipients demonstrate an IgG antibody to HbsAg but not to HbcAg.


There is no specific treatment for typical acute hepatitis B. A high-calorie diet is desirable. Corticosteroid therapy has no value in uncomplicated typical acute viral hepatitis, and recent studies suggest that it may increase the severity of chronic hepatitis caused by hepatitis B virus. Chronic hepatitis B is a treatable disease. Interferon alpha, 5-10 million U thrice weekly for 4-6 months, provides long-term benefit in a minority (~ 33%) of patients with chronic hepatitis B infection (see Box 2). Those who already demonstrate an acute immune response with low serum viral-DNA levels are the most likely to respond to treatment. Lamivudine (3Tc), a potent inhibitor of human immunodeficiency virus (HIV), is also active against hepatitis B virus, both in vitro and in initial clinical trials, but the virus can become resistant to this agent.


Ninety percent of acute hepatitis B cases resolve within 6 months; 0.1% are fatal due to acute hepatic necrosis; and ~10% progress to chronic hepatitis. Of these, = 10% will develop cirrhosis, hepatocellular carcinoma, or both.

Prevention & Control

Both active prophylaxis and passive prophylaxis of hepatitis B infection can be accomplished. Most preparations of ISG contain only moderate levels of anti-HBs; however, specific hepatitis B immune globulin (HBIG) with significant protective activity is now available. HBIG is prepared from sera of subjects who have high titers of antibody to HbsAg but are free of the antigen itself. Administration of HBIG soon after exposure to the virus greatly reduces the development of symptomatic disease. Postexposure prophylaxis with HBIG should be followed by active immunization with vaccine.

Inactivated hepatitis B vaccines have been available for several years. The first was developed by purification and inactivation of HbsAg from the blood of chronic carriers, but this vaccine is no longer in use. The current vaccine is a recombinant product derived from HBAg grown in yeast. Excellent protection has been shown in studies on homosexual men and medical personnel. These groups and others, such as laboratory workers and injection drug users, who come into contact with blood or other potentially infected materials, should receive hepatitis B vaccine as the preferred method of preexposure prophylaxis. Recently, immunization of all children has been recommended.

A combination of active and passive immunization is the most effective approach to prevent neonatal transmission and, thus, the development of chronic carriage in the neonate. Most hospitals recommend routine screening of pregnant women for the presence of HbsAg. Infants born to women who are positive should receive HBIG in the delivery room followed by three doses of hepatitis B vaccine beginning 24 h after birth.

A similar combination of passive and active immunization is used for nonimmunized persons who have been exposed by needle-stick or similar injuries from a hepatitis BsAg positive individual.

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