Current Diagnosis & Treatment in Infectious Diseases

Section IV - Viral Infections

39. Hepatitis

Lawrence W. Drew MD, PhD

The causes of hepatitis are varied and include viruses, bacteria, and protozoa, as well as drugs and toxins (eg, isoniazid, carbon tetrachloride, and ethanol). The clinical symptoms and course of acute viral hepatitis can be similar, regardless of etiology, and determination of a specific cause depends primarily on the use of laboratory tests (Box 39-1). Hepatitis may be caused by at least six different viruses whose major characteristics are summarized in Table 39-1. Non-A–non-B (NANB) hepatitis is a term previously used to identify cases of hepatitis not caused by hepatitis A or B. With the discovery of hepatitis viruses C, E, and G, most of the viral etiologies of NANB disease can be identified. Other viruses, such as Epstein-Barr virus and cytomegalovirus, can also cause inflammation of the liver, but hepatitis is not the primary disease they cause. Yellow fever is a form of hepatitis but is now rare. The relative contributions of the hepatitis viruses to acute and chronic viral hepatitis are shown in Table 39-1 and Table 39-2.

HEPATITIS A

Essentials of Diagnosis

• Increased risks in promiscuous homosexual men, travelers to underdeveloped areas, and institutionalized individuals.
• Malaise, anorexia, fever, dark urine, pale stools, jaundice, right upper quadrant pain, and tender hepatomegaly.
• Increased liver enzymes (ALT, AST), bilirubin, prothrombin time, and globulin.
• Serum positive for hepatitis A immunoglobulin M (IgM) antibody.
• May have history of recent (ie, 3–6 weeks previously) ingestion of undercooked shellfish or sewage-contaminated water.

General Considerations

1. Epidemiology.Hepatitis A virus is the cause of what was formerly termed infectious hepatitis or short-incubation hepatitis. It was first detected in the early 1970s in stools of patients incubating the disease. Humans appear to be the major natural hosts of hepatitis A virus. Several other primates (including chimpanzees and marmosets) are susceptible to experimental infection, and natural infections of these animals may occur.

The major mode of spread of hepatitis A is fecal-oral. Inoculation of infectious material intramuscularly can produce disease; transmission through blood transfusion rarely, if ever, occurs. Most cases of hepatitis A occur sporadically rather than being linked to a single contaminated source. The disease is common under conditions of crowding, and it occurs at high frequency in mental hospitals, schools for the developmentally disabled, and daycare centers. Because a chronic carrier state has not been observed with hepatitis A, perpetuation of the virus in nature presumably depends on sporadic subclinical infections and person-to-person transmission. Outbreaks of hepatitis A have been linked to the ingestion of undercooked shellfish from waters contaminated with human feces. Common-source outbreaks related to other foods, including vegetables, have also been reported.

The disease is widespread, but seroepidemiologic studies have shown marked variation in infection rates among different population groups. For example, rates are higher among those of lower socioeconomic status and among male homosexuals. Less than one-half of the general population of the United States now has serologic evidence of prior hepatitis A virus infection. Rates have been decreasing since 1970, apparently because of better sanitation and less crowding. In contrast, in many underdeveloped countries, > 90% of the adult population shows evidence of previous hepatitis A infection; in most cases, however, the evidence is of asymptomatic infection during childhood. The risk of overt disease is much higher in nonimmune infected adults than in children; travelers from developed countries who enter endemic areas are particularly susceptible.

1. Microbiology.Hepatitis A virus is an unenveloped, single-stranded small RNA (picorna)virus with cubic symmetry and a diameter of 27 nm (Figure 39-1). It is not inactivated by ether and is stable at -20°C and low pH. These properties are similar to those of enteroviruses (see Chapter 27), but hepatitis A virus is distinct and now classified in a separate genus, Hepatovirus.The virus has been successfully cultivated in cell cultures but grows poorly.
2. Pathogenesis.The virus is believed to replicate initially in the enteric mucosa. It can be demonstrated in feces by electron microscopy for 10–14 days before onset of disease. In most patients with symptoms of the disease, complete virus is no longer found in fecal specimens; however, viral antigen has been demonstrated in feces for ≤ 14 days thereafter. Multiplication in the intestines is followed by a period of viremia with spread to the liver. The response to replication in the liver consists of lymphoid cell infiltration, necrosis of liver parenchymal cells, and proliferation of Kupffer cells. The extent of necrosis often coincides with the severity of disease. A variable degree of biliary stasis may be present. Detectable levels of IgG antibody to hepatitis A virus persist indefinitely in serum, and patients with anti-hepatitis A virus antibodies are immune to reinfection.

BOX 39-1 Hepatitis Infection

Children Adults More Common · Hepatitis A, B especially in underdeveloped countries and Far East · Hepatitis A, B, C Less Common · Hepatitis C, G · Hepatitis D, E, G

Clinical Findings

1. Signs and Symptoms.In hepatitis A virus infection, an incubation period of 10–50 days (mean, 25 days) is usually followed by the onset of fever, poor appetite, nausea, pain in the right upper abdominal quadrant, and, within several days, jaundice. The patient may notice dark urine and clay-colored stools 1–5 days before the onset of clinical jaundice. The liver is enlarged and tender. Many persons who have serologic evidence of acute hepatitis A infection are asymptomatic or only mildly ill, without jaundice (anicteric hepatitis A). The infection-to-disease ratio is dependent on age; it may be as high as 20:1 in children and approximately 4:1 in adults. Most (99%) of cases of hepatitis A are self-limiting.
2. Laboratory Findings.Serum aminotransferase levels are elevated as a result of hepatic inflammation and damage. The serum bilirubin levels and prothrombin time are also elevated, the latter being a sensitive marker of hepatocyte damage. The total leukocyte count is low because of neutropenia. Alkaline phosphatase is elevated especially in patients with a cholestatic picture, but it tends to subsequently decrease even when the bilirubin is still rising.

Table 39-1. Relative contribution of hepatitis viruses to acute viral hepatitis—United States.

Type Portion (%) of All Hepatitis Infections A 47% B 33% C 15% D 2% Other 3%

Table 39-2. Relative contribution of hepatitis viruses to chronic viral hepatitis—United States.

Type Cases/Year Deaths/Year from Chronic Liver Disease A 0 0 B 1 × 106 5,000 C 1 × 105 8–10,000 D 7 × 104 1,000 E 0 0

1. Imaging.Radiographic and radionucleotide studies may show hepatomegaly. Gall bladder and common bile duct examinations are usually normal.
2. Differential Diagnosis.All of the causes of acute hepatitis mentioned in the introduction to this chapter must be considered, but epidemiologic, age, and risk factors may help to predict a probable cause. See also Table 39-3.
3. Complications.In 0.1% of cases, fulminant fatal hepatitis associated with extensive liver necrosis may occur.

Figure 39-1. Diagram of the proposed structure of the hepatitis A virus. The protein capsid is made up of four viral polypeptides (VP1 to VP4). Inside the capsid is a single-stranded (ss) molecule of RNA (molecular weight 2.5 × 106), which has a genomic viral protein (VPG) on the 5′ end. (Reprinted from Ryan KJ et al: Sherris Medical Microbiology, 3rd ed. McGraw-Hill, 1994. McGraw-Hill, 1994; and by permission of Dr. J. A. Hoofnagle and of Abbott Laboratories, Diagnostic Division, North Chicago, Illinois.)

Table 39-3. Comparative features of viral hepatitis.

Feature Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis G Incubation period 2–6 weeks (average 4 weeks) 6–23 weeks (average 10 weeks) 6–12 weeks 4–8 weeks Virus 27-nm RNA virus 42-nm DNA virus RNA, flavivirus Incomplete RNA virus RNA similar to Calicivirus RNA similar to Hepatitis C virus Onset Abrupt (variable) Insidious (variable) Insidious (variable) Abrupt (variable) Acute ? Transmission Fecal-oral IDU, sexual IDU, sexual (?)/ household IDU, sexual Fecal-oral Severity of acute infection Self-limiting Occasionally severe (up to 25% icteric) Usually subclinical Coinfection occasionally severe; superinfection often severe Self limiting, fulminant in pregnancy ? Fulminant Hepatitis Very rare (~0.1%) Rare (<1% of icteric patients) Very rare, if ever Occurs with simultaneous hepatitis B In pregnancy Symptoms Fever, malaise, headache, anorexia, vomiting, dark urine, jaundice (often asymptomatic) As with A but 10–20% with serum sickness like reaction As with A As with A As with A Carrier state % carriers in U.S. None 0 Yes 0.1% Yes 0.3–2% Yes Very rare ? Yes 1–2% Chronicity 0% 5–10% Up to 75%; cirrhosis (25–33%); hepatoma Up to 30% of those with chronic hepatitis B No Transmission by blood transfusion Very rare Rare with screening Rare with screening Rare with Hepatitis B screening Probably not Yes Diagnosis Anti-HAV, IgM/IgG HbsAg; Anti-Hbc, IgM; Anti-Hbs, IgG Anti-HCV, IgG; HCV RNA Anti-HDV, IgM Anti-HEV, IgM HGV, RNA Prevention Immune globulin, killed vaccine HBIG/Hepatitis B vaccine Immune globulin(?) Prevent B Immune globulin Associated w/ cirrhosis No Yes Yes, 20% Yes, 40% No Rare Associated w/ hepatoCellular cancer No Yes Yes ? No ? Treatment of chronic disease None Interferon alpha; ? 3TC Interferon alpha & ribavirin Interferon alpha ? None indicated

Diagnosis

The best method for documentation of acute hepatitis A virus infection is the demonstration of high titers of virus-specific IgM antibody in serum drawn during the acute phase of illness. Because IgG antibody persists indefinitely, its demonstration in a single serum sample is not indicative of recent infection; a rise in titer between acute and convalescent sera must be documented. Immune electron microscopic identification of the viral antigen in fecal specimens and isolation of the virus in cell cultures remain research tools. Past infection is best demonstrated by anti-HAV IgG but absent IgM.

Treatment

There is no specific treatment for patients with acute episodes of hepatitis A infection (Box 39-2). Supportive measures include adequate nutrition and rest.

BOX 39-2 Treatment of Chronic Hepatitis Infection

Children Adults First Choice · Hepatitis B: interferon, 15–30 million U weekly · Hepatitis C: interferon, 9–10 million U weekly plus ribavirin · Hepatitis D: interferon, 5–10 million U daily · Hepatitis A, E: no known treatment · Hepatitis G: no treatment indicated Second Choice · Hepatitis B: possibly 3TC (Lamivudine), famciclovir Penicillin Allergic

Prognosis

The prognosis is excellent for > 99% of patients with hepatitis A infection. Only 0.1% of patients develop fatal acute hepatic necrosis.

Prevention & Control

1. Passive Immunization.Passive (ie, antibody) prophylaxis for hepatitis A has been available for many years. Immune serum globulin (ISG), manufactured from pools of plasma from large segments of the general population, is 80–90% protective if given before or during the incubation period of the disease. In some cases, infection occurs, but disease is ameliorated; that is, the patient develops anicteric, usually asymptomatic, hepatitis A.

At present, ISG should be administered to household contacts of hepatitis A patients and those known to have eaten uncooked foods prepared or handled by an infected individual. Once clinical symptoms have appeared, the host is already producing antibody, and administration of ISG is not indicated. Persons from areas of low endemicity who travel to areas with high infection rates may receive ISG before departure and at 3- to 4-month intervals as long as potential heavy exposure continues, but active immunization is preferable (see below).

1. Active Immunization.For hepatitis A, live attenuated vaccines have been evaluated but have demonstrated poor immunogenicity and have not been effective when given orally. Formalin-killed vaccines induce antibody titers similar to those of wild-virus infection and are almost 100% protective. Use of this vaccine is preferable to passive prophylaxis for those with prolonged or repeated exposure to hepatitis A.

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.

General Considerations

1. Epidemiology.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.

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.

Figure 39-2. Schematic diagram of hepatitis B virion. The 42-nm particle is the “Dane Particle” or the hepatitis B virus. The 22-nm particles are the filamentous and circular forms of hepatitis B surface antigen or protein coat. (Reprinted from Ryan KJ et al: Sherris Medical Microbiology, 3rd ed. McGraw-Hill, 1994.)

2. Microbiology.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.

1. Pathogenesis.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

1. 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.

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.
2. Imaging.As with hepatitis A
3. Differential Diagnosis.As with hepatitis A
4. Complications.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.

Diagnosis

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.

Figure 39-3. Sequence of appearance of viral antigens and antibodies in acute self-limiting cases of hepatitis B. HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; anti-HBc, antibody to hepatitis B core antigen; anti-HBe, antibody to HBeAg; anti-HBs, antibody to HBsAg. (Reprinted from Ryan KJ et al: Sherris Medical Microbiology, 3rd ed. McGraw-Hill, 1994.)

Treatment

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 39-2). 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.

Prognosis

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.

HEPATITIS D (DELTA HEPATITIS)

Essentials of Diagnosis

• Occurs only in patients with preexisting or concurrent hepatitis B.
• Occurs in the same groups at risk for hepatitis B.
• May be associated with fulminant hepatitis or rapid progression of chronic hepatitis B.
• Diagnosed by presence of IgM antibody to hepatitis D antigen or by IgG seroconversion to this antigen.

General Considerations

1. Epidemiology.Delta hepatitis is spread just as hepatitis B and is most prevalent in groups at high risk of hepatitis B infection. Injection drug users are those at greatest risk in the western world, and ~ 50% of such individuals may have IgG antibody to the delta virus antigen. Delta virus infection is rare in the U.S., northern Europe, and Japan but largely prevalent in southern Europe, Africa, and South America. Because blood is not yet routinely screened for the delta agent, blood products and dialysis transmission are possible sources for those who have prior hepatitis B. Nonparenteral and vertical transmission can also occur.
2. Microbiology.Delta hepatitis is caused by the hepatitis D virus. This small single-stranded RNA virus requires the presence of hepatitis B to provide its protein shell and is thus found only in persons with acute or chronic hepatitis B infection.
3. Pathogenesis.The method of replication of hepatitis D viral RNA is not clear. Associated with the RNA are proteins of 27 and 29 kDa that constitute the delta antigen. This protein-RNA complex is surrounded by HBsAg (Figure 39-4). Thus, although the delta virus produces its own antigens, it utilizes HBsAg in assembling its coat.

Clinical Findings

1. Signs and Symptoms.Two major types of delta infection have been noted.

• Simultaneous delta and hepatitis B infection: This infection is clinically identical to acute hepatitis A or B, except for a higher rate of fatal hepatic necrosis than is seen with hepatitis B alone.
• Delta superinfection in those with chronic hepatitis B: This infection increases the severity and progression of chronic hepatitis B. Death due to liver disease may occur in 20% of superinfected patients.

• Laboratory Findings.Similar to hepatitis A and B
• Imaging.Similar to hepatitis A and B
• Differential Diagnosis.Simultaneous infection with both delta and hepatitis B results in clinical hepatitis that is indistinguishable from acute hepatitis A or B; however, fulminant hepatitis is much more common than with hepatitis B virus alone.
• Complications.Persons with chronic hepatitis B who acquire infection with hepatitis D suffer relapses of jaundice and have a high likelihood of developing chronic cirrhosis. Rapidly progressive liver disease and death may occur in ≤ 20% of doubly infected persons.

Figure 39-4. Schematic of delta hepatitis virus. Note outer layer derived from hepatitis B surface antigen. (Reprinted from Ryan KJ et al: Sherris Medical Microbiology, 3rd ed. McGraw-Hill, 1994.)

Diagnosis

Diagnosis of hepatitis D is made by demonstrating IgM or IgG antibodies, or both, to the delta antigen in serum. IgM antibodies appear within 3 weeks of infection and persist for several weeks. IgG antibodies persist for years.

Treatment

Response to interferon alpha treatment is less than in patients who have only hepatitis B. Recommended doses are higher (5–10 million U daily).

Prognosis

Superinfection with hepatitis D worsens the prognosis of preexisting hepatitis B, increasing the rate and rapidity of developing cirrhosis.

Prevention & Control

Because the capsid of delta hepatitis is HbsAg and hepatitis D depends on hepatitis B for its replication, measures aimed at limiting the transmission of hepatitis B, for example, through vaccination, prevent the transmission of delta hepatitis.

HEPATITIS C

Essentials of Diagnosis

• Acute hepatitis C usually is asymptomatic.
• First recognition of chronic hepatitis C is the presence of elevated liver enzymes in an asymptomatic patient.
• Unexplained chronic hepatitis is most commonly caused by hepatitis C.
• Diagnosis is by presence of hepatitis C IgG antibody.

General Considerations

Most NANB hepatitis is caused by an RNA virus termed hepatitis C virus. Its existence and role in the etiology of hepatitis was identified by preparing numerous complementary DNA clones from the presumed RNA virus in infectious serum. Peptides encoded by these clones were then tested for reaction with sera from cases of NANB hepatitis, and one was found to be highly specific.

3. Epidemiology.The transmission of hepatitis C by blood is well documented: indeed, it caused the great majority of post-transfusion NANB hepatitis. It is estimated that 2% of U.S. citizens have been infected with hepatitis C. Screening of donor blood for hepatitis C has markedly decreased transmission of the virus by blood products. Currently, the major mechanism of transmission is by intravenous drug abuse. Transmission of this virus in nontransfusion, community-acquired cases is less well understood. It may be sexually transmitted but to a much lesser degree than hepatitis B, and vertical transmission may occur. In the United States, 3.5 million people have antibody to hepatitis C, but the number of new cases of hepatitis C has decreased from 80,000 to ~30,000 yearly. Since the 1980s, outbreaks of what is now known as hepatitis C have been associated with intravenous immune globulin (IVIG). To reduce this risk, all U.S.-licensed IVIG products now have viral inactivation steps included in the manufacturing process. In addition all immunoglobulin products (including intramuscular immunoglobulin products that have not been associated with hepatitis C) that lack viral inactivation steps are now excluded if hepatitis C virus is detected by polymerase chain reaction (PCR) analysis.
4. Microbiology.Hepatitis C virus is an RNA virus in the flavivirus family (other members include the agents of yellow fever and dengue). It has a very simple genome consisting of just three structural and five nonstructural genes. There are at least six major genotypes, two of which have subtypes (1a and b, 2a and b). These genotypes have quite different geographic distributions and may be associated with differing severities of disease as well as response to therapy.
5. Pathogenesis.Hepatitis C does not cause acute hepatic cellular necrosis. Rather, there is an insidious infection with a progressive inflammatory response, leading to, in many cases, hepatic fibrosis and cirrhosis. The determinants of progression are not understood.

Clinical Findings

1. Signs and Symptoms.The incubation period of hepatitis C averages 6–12 weeks. The infection is usually asymptomatic or mild and anicteric but results in a chronic carrier state in 70–85% of adults. The average time from infection to the development of chronic hepatitis is 13–18 years. Cirrhosis is a late sequela of chronic hepatitis, which may occur in 15–33% of infected adults and is the leading reason for liver transplants. Chronic hepatitis tends to wax and wane and is often asymptomatic.
2. Laboratory Findings.Hepatitis C may be associated with elevated or normal ALT values in serum.
3. Complications.The risk of hepatocellular carcinoma is 1–5% after 30 years of chronic infection. Cirrhosis may occur in 15–33% of hepatitis C-infected adults.

Diagnosis

Antigens of hepatitis C are not detectable in blood, so diagnostic tests consist of attempts to demonstrate antibody. Unfortunately, the antibody responses in acute disease remain negative for 1–3 weeks after clinical onset and may never become positive in ≤ 20% of patients with acute, resolving disease. These antibody assays can be helpful in chronic hepatitis, especially when multiple antigens are sought. The first test developed to assist the diagnosis of hepatitis C measured antibody to the C-100 antigen of the virus. It is now acknowledged that this antibody is an inaccurate marker for the disease, and current second-generation tests measure antibodies to multiple hepatitis C antigens by either enzyme immunoassay or immunoblot testing. Even with these newer assays, IgG antibody to hepatitis C may not develop for ≤ 4 months, making the serodiagnosis of acute hepatitis C difficult. Assays of hepatitis C virus RNA by PCR or other methods may be used for diagnosis, estimating prognosis, predicting interferon responsiveness, and monitoring therapy.

Treatment

Interferon alpha is approved for the treatment of chronic hepatitis C, but it often provides only a transient benefit (see Box 39-2). The commonly used dose is 3 million U 3 times weekly for ≥ 6 months. Amino transferase levels decrease in only 40–70% of patients, but sustained improvement occurs in only 10–15% of patients. Responses are better in patients with genotypes other than 1 and those with low initial titers of viral RNA. Increasing dosage to 10 million U or extending treatment from 24 to 48 weeks may increase the number of sustained responses. Combination therapy with ribavirin appears to improve efficacy. Corticosteroids are not beneficial

Prognosis

Hepatitis C has a worse prognosis than, for example, hepatitis B, since such a high proportion of cases develop cirrhosis—≤ 33% of infected patients.

Prevention & Control

It is not clear whether prophylactic immune serum globulin protects against hepatitis C. Also, the development of a vaccine is complicated because of the antigenic variability of the virus and patients may be reinfected by different strains of wild-type virus. Reduction of needle sharing by intravenous drug users would greatly reduce the incidence of new cases. (Box 39-3.)

HEPATITIS E

General Considerations

Hepatitis E is the cause of another form of hepatitis, but this virus is spread by the fecal-oral route and therefore resembles hepatitis A. Hepatitis E virus is an RNA virus that appears similar to caliciviruses. The viral particles in stool are spherical, 20–32 nm in diameter, and unenveloped and exhibit spikes on their surface. Like hepatitis A, this virus causes only acute disease and may be fatal, especially in pregnant women. Most cases have been identified in India, Southeast Asia, the Middle East, and other areas with poor sanitation. Rarely have cases been identified in the United States, and these have been in visitors or immigrants from endemic areas.

BOX 39-3 Control of Hepatitis Infection

Prophylactic Measures Hepatitis A Preexposure: · Vaccination with killed vaccine · Immune serum globulin Postexposure: · Immune serum globulin Hepatitis B Preexposure: · Vaccination with recombinant hepatitis B vaccine Postexposure: · Hepatitis B immune globulin followed by vaccine Hepatitis D · Vaccination with recombinant hepatitis B vaccine Isolation Precautions · Hepatitis A, E: enteric precautions · Hepatitis B, C, D: needle, blood precautions

Diagnosis

Diagnosis of hepatitis E infection may be confirmed by demonstrating the presence of specific IgM antibody.

Treatment

No treatment is available for hepatitis E infection (see Box 39-2).

Prognosis

Hepatitis E does not appear to eventuate in chronic hepatitis, so the prognosis is good, except in the instance of fulminant hepatitis E of pregnancy, which may be fatal.

Prevention & Control

It is not known whether immune serum globulin provides protection.

HEPATITIS G

General Considerations

Although hepatitis C virus is the major cause of NANB hepatitis, additional etiologic agent(s) continue to be sought. In 1995 a newly discovered agent, hepatitis G, was identified in the sera of two patients. This agent is an RNA virus similar to hepatitis C and members of the flavivirus family. Up to 2% of volunteer blood donors are seropositive for hepatitis G antibody, and it is a transmissible blood-borne virus.

In addition to being closely related to hepatitis C, there are data to suggest that many patients infected by hepatitis C are also infected by hepatitis G. Given this close association, it has been difficult to ascertain the contribution of hepatitis G to clinical disease. Patients infected with both viruses do not appear to have worse disease than those infected by hepatitis C virus only.

Diagnosis

So far, it has not been possible to develop an antibody assay so that seroprevalence could be determined. Instead detection of infection with this virus requires a PCR assay for viral RNA in patients' sera.

Treatment

In very limited clinical studies, hepatitis G appears to be susceptible to interferon alpha treatment. Because it is not clear that hepatitis G virus causes disease, treatment is not currently indicated (see Box 39-2).

REFERENCES

de Franchis R et al: The natural history of asymptomatic hepatitis B. Ann Intern Med 1993;118:191–94. (A clinical and laboratory follow-up of HBsAg positive blood donors.).

Johnson Y, Lau N, Wright TL. Molecular virology and pathogenesis of hepatitis B. Lancet 1993;342:1335–39. (This short review covers details of molecular structure and replication of the virus.)

Sharara AI et al: Hepatitis C. Ann Intern Med 1996;125: 658–68.