Geographic Distribution and Sources of Exposure

The prevalence of hepatitis B varies markedly around the world. In highly endemic regions, such as Southeast Asia (excluding Japan), China, and much of Africa, 8% or more of the population are chronic HBV carriers, and the lifetime risk of infection ranges from 60% to 80%.² In these areas, perinatal transmission and horizontal spread among children are the major sources of infection. Approximately 60% of the world’s population reside in these areas where HBV is highly endemic.³ Regions of intermediate risk include parts of southern and eastern Europe, the Middle East, Japan, the Indian subcontinent, much of the former Soviet Union, and northern Africa. In intermediate-risk areas, the lifetime risk of infection is between 20% and 60%. Persons of all age groups are infected, but as in high-risk areas, most infections occur during infancy or early childhood. Regions of low prevalence are North America, western Europe, certain parts of South America, and Australia. In these areas, the lifetime risk of HBV infection is less than 20%, and transmission is primarily horizontal (i.e., between young adults). Sexual transmission is the main mode of transmission in Europe and North America, and injection drug use is a major contributor to new cases as well.⁴

Transmission of infection from an HBV carrier mother to her neonate accounts for the majority of new infections in the world today. Sixty to ninety percent of hepatitis B surface antigen (HBsAg)-positive mothers who are hepatitis B e antigen (HBeAg)-positive transmit the disease to their offspring, whereas mothers who are positive for antibody to HBeAg (anti-HBe) transmit the disease less frequently (15% to 20%) (see later discussion of diagnosis). Other less common sources of infection are household contact with an HBV carrier, hemodialysis, exposure to infected health care workers, tattooing, body piercing, artificial insemination, and receipt of blood products or organs. Since routine screening of the blood supply was implemented in the early 1970s, transfusion-associated hepatitis B has become rare in the United States. Hepatitis B can be transmitted by blood that tests negative for HBsAg but positive for antibody to hepatitis B core antigen (anti-HBc) because of low levels of circulating HBV DNA in such blood.⁵ HBsAg-negative blood that is positive for anti-HBc is excluded from the donor pool in the United States and many countries around the world. In 0% to 30% of persons who are seropositive for anti-HBc alone, HBV DNA is detectable in serum by polymerase chain reaction (PCR) testing.⁶

HBV is transmitted efficiently by percutaneous and mucous membrane exposure to infectious body fluids. The virus is 100 times as infectious as human immunodeficiency virus (HIV) and 10 times as infectious as hepatitis C virus (HCV). HBeAg seropositivity indicates a higher risk of transmission from mother to child, after needlestick exposure, and in the setting of household contact. HBV DNA has been detected by sensitive techniques such as PCR testing in most body fluids, except for stool that has not been contaminated with blood. Although HBV replicates primarily in hepatocytes, the presence of replicative intermediates and virally encoded proteins in other sites, such as the adrenal gland, testis, colon, nerve ganglia, and skin, suggests that a vast extrahepatic reservoir for infectious virus exists.⁷ Small amounts of HBV DNA have been demonstrated in peripheral mononuclear cells and liver tissue years after apparent resolution of chronic infection.^8,9 Extrahepatic localization of low levels of replicating virus explains the relatively high rate of transmission of infection from anti-HBc–positive organ donors.¹⁰

Rates of Infection in the United States

The incidence of hepatitis B has been declining in the United States over the past decade because of universal vaccination of newborns, adult vaccination programs for high risk persons, changes in sexual lifestyle, refinements in blood screening procedures, and the availability of virus-inactivated blood components.¹¹ Most striking has been the decrease among children and health care workers, groups with the highest rates of vaccination. Data from the Centers for Disease Control and Prevention (CDC) indicate that more than 95% of pregnant women in the United States are tested for HBsAg, and infant vaccine coverage levels are now equivalent to those of other vaccines in the childhood schedule. Nonetheless, an estimated 78,000 new HBV infections occurred in 2001, with the highest incidence rates among sexually active young adults (20 to 29 years old) and higher rates occurring among black and Hispanic persons than in white persons.¹² Since 1995, approximately 40% of cases of acute hepatitis B reported to the CDC were caused by intimate contact among heterosexuals, 15% to 20% were related to intravenous drug use, and 12% occurred in men who have sex with men. No identifiable source of exposure was demonstrated in approximately 15% of cases. Nearly one third of prison inmates have been infected with hepatitis B, and 2% are chronically infected.

According to the third National Health and Nutrition Examination Survey (1988 to 1994), one or more serologic markers of HBV infection were demonstrated in 4.9% of the U.S. population, and the prevalence of chronic infection was 0.2%.¹³ Traditional estimates based on the results of blood donation screening in the late 1970s also indicated a prevalence rate for chronic infection of 0.2% to 0.4% in the United States. Although traditional estimates are that the number of HBV carriers in the United States is between 1.25 and 1.5 million, this figure is likely to be a serious underestimate because of changing immigration patterns and underrepresentation of certain minority groups in field surveys. For example, 15 million Asians live in the United States, and even a conservative estimate that the prevalence in this group is 5% would raise the overall number of HBV carriers in the United States by more than 750,000.

Definitions

In common usage, the term HBV carrier has often been used to refer to persons persistently infected with HBV who have normal serum aminotransferase levels. (They are sometimes inappropriately referred to as “healthy” HBV carriers.) Because the nomenclature is potentially confusing, the proposal has been made that the carrier state be categorized as inactive or active. Inactive carriers are patients who have evidence of HBV replication on a PCR-based assay only (but not with a less sensitive non–PCR-based assay) and normal or only mildly elevated serum aminotransferase values (see later).¹⁴ Long-term follow-up of inactive carriers suggests that the majority of these patients do not have progressive liver disease and do not experience complications. Some of these patients, however, ultimately have one or more episodes of reactivated hepatitis in which the levels of viremia and serum aminotransferase activity increase. Also, some patients with the inactive carrier state may demonstrate HCC. Active carriers, on the other hand, have evidence of HBV replication on non–PCR-based assays for HBV DNA, intermittently or persistently elevated serum aminotransferase levels, and evidence of chronic hepatitis in a liver biopsy specimen.

Clinical Sequelae of Acute Hepatitis B Virus Infection

The age at which a person becomes infected with HBV is a principal determinant of the clinical outcome. HBV infection in adults with an intact immune system is likely to cause clinically apparent acute hepatitis B; only 1% to 5% of these persons become chronically infected.⁴ By contrast, as many as 95% of infected neonates become chronic HBV carriers because of immunologic tolerance to the virus.

In adults, fulminant liver failure caused by acute hepatitis B occurs in less than 1% of cases, but this group still accounts for 5% of all cases of acute liver failure and approximately 400 deaths annually in the United States.¹⁵ Rapid viral elimination may result in clearance of HBsAg from serum by the time of initial presentation. In these cases, the accurate diagnosis of fulminant hepatitis B may require testing with immunoglobulin (Ig) M antibody to hepatitis B core antigen (HBcAg) (IgM anti-HBc) (see later discussion of serologic markers of infection).¹⁶ The rate of spontaneous survival in acute liver failure caused by hepatitis B is only approximately 20%. Liver transplantation has resulted in survival rates of 50% to 60%. Recurrent disease in the allograft is now uncommon because of administration of hepatitis B immune globulin (HBIG) and potent orally administered antiviral agents (see later and Chapters 93 and 95).

Clinical Sequelae of Chronic Hepatitis B Virus Infection

Chronic hepatitis B develops in 2% to 5% of persons who acquire HBV infection in adulthood. Progressive liver disease (including cirrhosis and HCC) can be expected to develop in one quarter to one third of people who acquire infection in the first few years of life. An estimated 15% to 25% of patients ultimately die of liver-related causes, with the greatest risk in male HBV carriers.

The presence of active viral replication and long-standing necroinflammatory liver disease caused by HBV strongly influences the rate of progression to cirrhosis. The major determinant of survival is the severity of the liver disease when the patient first comes to medical attention.¹⁷ Cirrhosis is associated with decreased survival and an increased frequency of HCC. Five- and 20-year survival rates of 55% and 25%, respectively, have been reported in patients with cirrhosis at presentation, whereas rates of 97% and 63%, respectively, have been reported for those with mild (noncirrhotic) disease.¹⁸ Survival rates differ most dramatically between patients with compensated and decompensated cirrhosis. In one study, an 84% five-year survival rate was reported for patients with compensated HBV-related cirrhosis, compared with 14% for patients with cirrhosis complicated by ascites, jaundice, encephalopathy, or a history of variceal bleeding.¹⁹ Multivariate analyses in several large cohort studies have identified age, ascites, hyperbilirubinemia, and other features of advanced liver disease as correlating independently with survival in patients with HBV-related cirrhosis. Interferon-induced clearance of HBeAg (see later) has been associated with prolongation of survival without complications or the need for liver transplantation.²⁰

Clearance of HBsAg in patients with HBV-related cirrhosis has been associated with an excellent prognosis, including improvement in liver histology and function, a decreased chance of viral reactivation, and prolonged survival.¹⁷ Even HBsAg clearance, however, is not an absolute safeguard against the future development of HCC in persons who already have cirrhosis.²¹

Hepatitis B Virus Genotypes

A genetic classification based on comparisons of complete genomes has demonstrated eight genotypes of HBV, designated A through H (Table 78-1).²³ Several methods have been used for HBV genotyping, including a commercially available line probe assay. Genotypic differences are based on an intergroup divergence of 8% or more in the complete nucleotide sequence. Genotype A is the predominant genotype in northern Europe and the United States. Genotypes B and C are confined to populations in eastern Asia and the Far East, but changes in immigration patterns have resulted in an influx of Asian HBV carriers with these genotypes into the United States.²⁴ Genotype D is found worldwide but is especially prevalent in the Mediterranean area, Middle East, and south Asia. Genotype E is indigenous to western sub-Saharan areas, and genotype F prevails in Central America. Cases of genotype G have been reported in the United States and France. Genotype H has been described in Mexico.

Table 78-1 Hepatitis B Genotypes (A-H) and Their Possible Clinical Associations

Hepatitis B Surface Antigen Mutants

Mutations in the surface gene can result in changes in the antibody-binding domain. Accordingly, both virus neutralization by polyclonal antibody to HBsAg and testing for HBsAg by methods that depend on antibody binding can be affected. Large-scale vaccination programs in regions endemic for HBV have revealed a 2% to 3% frequency of vaccine escape mutants that result from alterations in the “a” determinant of the HBsAg protein, which is the major neutralizable epitope. The typical mutation results in the substitution of glycine for arginine at amino acid position 145; this substitution prevents binding of neutralizing antibodies (i.e., antibody to HBsAg [anti-HBs]). The clinical significance of these mutants for neonatal vaccination programs is highly controversial because the frequency of these variants among HBV-infected mothers whose infants respond to vaccination has been found to be similar to that of mothers whose infants do not respond. The “a” determinant mutants also are proposed to have clinical relevance after liver transplantation for hepatitis B. As many as 50% of patients in whom recurrent HBV infection develops despite the use of HBIG have been shown to have these escape mutants, and the rate at which the mutations are detected appears to correlate with the length of time over which HBIG is repeatedly administered.²⁶

Mutations in the Precore, Basal Core Promoter, and Core Genes

Mutations in the precore and basal core promoter regions of the HBV genome can influence the production of HBeAg. A precore mutation results in a stop codon at nucleotide 1896 that abolishes the synthesis of HBeAg,²⁷ whereas mutations in the basal core promoter at nucleotides 1762 and 1764 decrease HBeAg synthesis by approximately 70% while maintaining pregenomic RNA levels.²⁸ Both types of mutations have been observed in cases of severe or fulminant hepatitis, which has been attributed to the loss of the immune-tolerizing effects of HBeAg antigen (see later). The presence of core promoter mutations has been linked to a significantly increased risk of HCC.²⁹ Precore and basal core promoter mutants have been described in the same patients and are particularly common in Asian and European patients with chronic hepatitis B.³⁰ A large serosurvey of HBV carriers residing in the United States has found that precore and core promoter mutations are common (frequencies of 27% and 44%, respectively), depending on the ethnicity and places of birth of the patients. Both mutant forms of HBV were observed to occur far more commonly in HBeAg-negative patients (precore mutation in 38% of HBeAg-negative versus 9% of HBeAg-positive patients; core promoter mutation in 51% versus 36%).³¹ In addition to these mutations, upstream mutations in the core gene can influence immunologic responses to HBV. Core gene mutations have been shown to block recognition of HBV by cytotoxic T lymphocytes (CTLs), a key mode of viral clearance. Therefore, the mutations contribute to HBV immune escape and possibly influence the response to interferon.³² Core gene mutations within the immunodominant epitopes of the HBV nucleocapsid also can affect CD4⁺ T-cell reactivity.³³

In patients with perinatally acquired chronic hepatitis B, a prolonged immune tolerant phase with minimal to absent hepatic necroinflammatory activity is typically seen for the first 20 to 30 years of HBV infection. Sequencing studies have shown stable core gene sequences during this phase. Precore mutations are also uncommon during this phase. Core gene mutations become more common as patients pass from the immune tolerant phase, at which time a growing number of mutations are observed in the region of the core gene that includes many B- and T-cell epitopes. Both precore stop codon mutants and core gene mutants have been associated with a poor response to interferon therapy.

Hepatitis B Virus DNA Polymerase Mutants

The polymerase gene encodes a DNA polymerase enzyme needed for encapsidation of viral RNA into core particles, conversion of the pregenomic viral RNA into a negative strand of viral DNA (reverse transcription), and conversion of this first HBV DNA strand into a second DNA strand of positive polarity. In general, the HBV reverse transcriptase function of the polymerase gene is highly conserved because major mutations that impair the efficiency of viral replication lead to selection pressure against such variant forms. As indicated earlier, HBV has a high rate of replication (10¹¹ virions per day) and low replication fidelity, meaning that it has a propensity to mispair nucleotide bases when it reverse transcribes viral RNA to DNA. HBV DNA polymerase also lacks any proofreading activity, so it cannot repair its mistakes. Therefore, when a nucleotide base is misplaced, it remains in the growing viral DNA strand as a base mutation, and the new HBV DNA molecule has a different sequence from the original (wild-type) genome. The overall error rate of HBV DNA polymerase is estimated to be 1 per 10,000 nucleotides copied, which translates to the potential for 10 million base-pair errors per day in an infected person. All possible single-base mutations can be produced in a 24-hour period, although many such mutations will yield nonviable viruses.³⁴

Mutations in the sequence of HBV polymerase can lead to drug resistance to nucleoside analogs used to treat HBV infection because some HBV polymerase mutants have decreased susceptibility to these drugs and are selected during treatment. The mutations in the sequence of HBV DNA polymerase that confer drug resistance result in amino acid substitutions in the reverse transcriptase domain of the enzyme. The changes in the structure of the enzyme, in turn, are thought to sterically inhibit binding of the drugs to their active sites. The amino acids in the reverse transcriptase are numbered from 1 to 344, and an amino acid identity is given by the single letter amino acid code. By convention, substitutions in reverse transcriptase are designated by the wild-type amino acid, followed by the number of the amino acid, followed by the substituted amino acid. For example, for the nucleoside analog lamivudine (see later), two types of mutations occur at nucleotide position 204 of domain C (the catalytic site of the polymerase) that result in substitution of the amino acid methionine (M) for either isoleucine (I) or valine (V). These mutations are designated M204I and M204V, respectively, and are referred to collectively as YMDD mutants; the letters stand for the amino acids (Y = tyrosine, M = methionine, D = aspartate) in the C domain. The M204V mutation tends to occur in conjunction with a mutation in domain B that results in substitution of leucine (L) with methionine (L180M). The M204I mutation or the combined M204V-L180M mutations result in marked resistance to the effect of lamivudine (>10,000-fold reduction in susceptibility). After prolonged exposure to adefovir, drug resistant mutations in domains B and D are selected (A181V/T and N236T). Other nucleotide substitutions have been described that are instrumental for telbivudine and entecavir resistance (Fig. 78-3).

Figure 78-3. Common amino acid changes (top row) that result from nucleotide substitutions in the hepatitis B virus polymerase gene and confer drug resistance to oral antiviral agents (first column) used to treat hepatitis B (see text for description of nomenclature). Note that cross resistance exists among lamivudine, telbivudine, and entecavir, but entecavir requires the presence of one or more secondary substitutions at codons 184, 202, or 250 for clinically apparent drug resistance to appear. Note also that the potential for cross-resistance exists between adefovir and tenofovir, but the greater antiviral potency of tenofovir reduces the chances of resistance greatly. A, alanine; ADV, adefovir; ETV, entecavir; G, glycine; I, isoleucine; L, leucine; LAM, lamivudine; LdT, telbivudine; M, methionine; TDF, tenofovir; N, asparagine; S, serine; T, threonine; V, valine.

The inherent mutability of HBV indicates that single and even double polymerase mutants preexist as minor “quasispecies” even before treatment of HBV infection is begun. Because of the limitations in the sensitivities of current genotype assays, these mutants would not be detectable until they are selected and expanded under the pressure of drug treatment. Resistance to lamivudine is found in approximately 20% of patients after one year of treatment but in nearly 70% after five years (see Fig. 78-3).³⁵ Rates of resistance to adefovir, a nucleotide analog, are 0% at one year and 29% after five years.³⁶ The efficacy of both of these drugs against HBV is impaired by a single nucleotide substitution. The more mutations necessary for drug resistance (indicating a higher genetic barrier to resistance), the slower the emergence of and lower overall rate of resistance. For example, resistance to entecavir, another nucleoside analog, occurs in less than 1% of patients at five years because the preexistence of lamivudine-resistant mutations and one or more additional mutations in the viral polymerase gene are required for resistance.³⁷ Persistent infection with drug-resistant HBV ultimately is associated with progression of disease and blunting of hepatic histologic improvement with antiviral therapy.³⁸ Severe flares of hepatitis have also been reported after the emergence of drug-resistant mutants,³⁹ and acquisition of these mutants may lead to rapidly progressive liver disease after liver transplantation (Table 78-2).⁴⁰ Horizontal transmission of these mutants, which can complicate drug therapy in secondarily infected persons, is also possible.

Table 78-2 Hepatitis Flares in Patients with Chronic Hepatitis B

ALT, alanine aminotransferase; HIV, human immunodeficiency virus; HAART, highly active antiretroviral therapy; HBV, hepatitis B virus; YMDD, tyrosine-methionine-aspartate-aspartate.

* Has also been reported with adefovir and entecavir.

ALT as a Surrogate Marker for Disease Activity

The serum ALT level has been used conventionally as a measure of disease activity in patients with chronic hepatitis B. Use of the standard reference range (0 to 40 U/L), however, can be misleading for evaluating HBV-related disease activity. A serum ALT level within the normal range is an imperfect surrogate marker for the absence of disease activity because determination of standard reference ranges has not traditionally taken into account increased body mass index (BMI), diabetes mellitus, and other features, such as alcohol intake, that tend to inflate values in a “normal” reference population (see Chapter 73). An insurance record-based study in Korea that included more than 140,000 persons who were followed for eight years demonstrated that all-cause liver-related mortality is increased when the serum ALT level exceeds 20 U/L in women and 30 U/L in men.⁵² This finding is particularly relevant to the management of Asians with hepatitis B and viremia. Because these patients tend to have a small body mass, a normal serum ALT value according to the standard laboratory reference range may be misleading. Such patients often have been excluded from treatment and assumed to be immune tolerant (that is, without liver disease). Studies in Asia and the United States have shown that as many as 20% to 30% of HBV carriers with persistently normal serum ALT levels and serum HBV DNA levels >10⁴ copies/mL have stage 2 or greater (of 4) inflammation and stage 2 or greater (of 4) fibrosis on a liver biopsy specimen.⁵³ Moreover, Asian HBV carriers with high-normal serum ALT levels (>0.5 × upper limit of normal [ULN]) have been shown to have more fibrosis on liver biopsy specimens than do those with low-normal serum ALT levels (<0.5 × ULN) and often demonstrate higher serum ALT elevations on prolonged follow-up.^53–55 These data are consistent with the hypothesis that viremic HBV carriers who acquired HBV infection early in life and who have high-normal serum ALT levels may represent a subgroup of patients who have already entered the immune clearance phase and are not in the immune-tolerant phase. This occurrence should be suspected in particular in persons older than age 35 to 40 because immune tolerance often subsides after two to three decades of infection.⁵⁴ Liver biopsy can be a useful tool to distinguish persons in the immune clearance phase despite normal or near-normal ALT levels but with active liver disease from those in the immune tolerant phase and absence of active liver disease (see Fig. 78-4).

HBV DNA Level and Long-Term Complications

Population-based Asian cohort studies have established that the serum HBV DNA level is the single best predictor of future progression to cirrhosis and HCC in HBV-infected persons.^56,57 In a prospective cohort study, more than 3600 HBV carriers from Taiwan, of whom 60% were male, 70% were older than age 40, 85% were HBeAg negative, and 95% had normal serum ALT levels, were followed for a mean of 11 years. The calculated relative risks for cirrhosis and HCC were shown to correlate with the level of HBV DNA on entry into the study when compared with a reference population of HBV carriers in whom HBV DNA was undetectable in serum by a PCR assay.⁵⁷ Even serum HBV DNA levels as low as 10,000 copies/mL (equivalent to 2000 IU/mL) were associated with a higher relative risk of cirrhosis and HCC. The relative risk of HCC was highest in persons with a serum HBV DNA level of more than 1 million copies/mL and intermediate in those in whom follow-up serum samples indicated spontaneous reduction of the serum HBV DNA level from greater than 100,000 copies/mL to less than 10,000 copies/mL. These data can be interpreted to mean that both the duration and level of viremia are important risk factors for the development of HCC. The data also suggest that suppression of serum HBV DNA levels, whether spontaneously or as a result of antiviral therapy, lowers the risk of HCC. The serum HBV DNA level remained a significant predictor of cirrhosis and HCC even after adjustment for patient age, gender, serum ALT level, and HBeAg status. Other studies in Chinese HBV carriers have demonstrated that persons in whom liver decompensation and HCC develop often have modest serum ALT elevations that are frequently below the recommended threshold (2 × ULN) for antiviral treatment in current practice guidelines (see later).⁵⁸

On the basis of these data, some authorities have suggested that all persons who acquire HBV infection early in life and who are age 45 to 50 years or older and demonstrate serum HBV DNA levels of 100,000 or more copies/mL should receive long-term therapy with a nucleoside analog to prevent cirrhosis and HCC.^59,60 In a landmark study,⁶¹ more than 600 Asian patients with advanced fibrosis and a serum HBV DNA level greater than 100,000 copies/mL were randomized in a ratio of 2 : 1 to active treatment with lamivudine or placebo. Treatment was planned for 5 years, but the study was discontinued after a mean duration of only 32 months because disease progression and HCC occurred significantly more frequently in the group of patients randomized to placebo.⁶¹ Therapeutic benefit was independent of the serum ALT level at baseline. These data strongly suggest that continuing suppression of serum HBV DNA by antiviral therapy can alter the long-term outcome of active chronic hepatitis B.

Extrahepatic Manifestations

Extrahepatic syndromes seen in association with acute or chronic hepatitis B are important to recognize because they may occur without clinically apparent liver disease and can be mistaken for independent disease processes in other organ systems. The pathogenesis of these extrahepatic disorders has not been fully elucidated but likely involves an aberrant immunologic response to extrahepatic viral proteins.⁶⁷ Many of the extrahepatic manifestations (e.g., arthritis, dermatitis, glomerulonephritis, polyarteritis nodosa, cryoglobulinemia, papular acrodermatitis, and polymyalgia rheumatica) are observed in association with circulating immune complexes that activate serum complement. Antiviral therapy may be indicated for persistent symptoms.

Cryoglobulinemia

Type II cryoglobulins consist of a polyclonal IgG and monoclonal IgM, whereas type III cryoglobulins contain polyclonal IgG and rheumatoid factor. Type II and type III cryoglobulinemia have been associated with hepatitis B, but the association is uncommon. In a large patient cohort, the frequency of cryoglobulinemia was significantly higher in patients with chronic HCV infection (54%) than in patients with chronic HBV infection (15%) (see Chapter 79). Cryoglobulinemia may be associated with systemic vasculitis (purpura, arthralgias, peripheral neuropathy, and glomerulonephritis) but is often paucisymptomatic or asymptomatic. Interferon has been used successfully to treat symptomatic cryoglobulinemia in association with chronic hepatitis B. Experience with nucleoside analog therapy has not been reported.

Histopathologic Features

Chronic HBV infection is characterized by mononuclear cell infiltration in the portal tracts. Periportal inflammation often leads to the disruption of the limiting plate of hepatocytes (interface hepatitis), and inflammatory cells often can be seen at the interface between collagenous extensions from the portal tracts and liver parenchyma (referred to as active septa). During reactivated hepatitis B, lobular inflammation is more intense and reminiscent of that seen in acute viral hepatitis. Steatosis is not a feature of chronic hepatitis B, as it is in chronic hepatitis C.

The only histologic feature noted on routine light microscopy that is specific for chronic hepatitis B is the presence of ground-glass hepatocytes (Fig. 78-5). This morphologic finding results from accumulation of HBsAg particles (20 to 30 nm in diameter) in the dilated endoplasmic reticulum. Because of high levels of cysteine in HBsAg, ground-glass cells have a high affinity for certain dyes, such as orcein, Victoria blue, and aldehyde fuchsin. Ground-glass hepatocytes also may be seen in HBV carriers, in whom they may be detected in up to 5% of cells. When present in abundance, ground-glass hepatocytes often indicate active viral replication.⁷¹ Immunofluorescence and electron microscopic studies have shown HBcAg inside the hepatocyte nuclei of affected cells. During periods of intense hepatitis activity, cytoplasmic core antigen staining is generally observed. After successful treatment of HBV infection with a nucleoside analog, the cytoplasmic core antigen staining often disappears, but nuclear core antigen staining may remain, indicating persistence of the HBV cccDNA template.

Figure 78-5. A, Liver biopsy specimen showing ground-glass inclusions in hepatocytes. These inclusions represent large amounts of hepatitis B surface antigen (HBsAg) in the endoplasmic reticulum of infected hepatocytes (Hematoxylin and eosin, ×630.) B, Immunohistochemical stain for HBsAg. Note that the brownish inclusions correspond to the ground-glass inclusions seen in A (×630).

(Courtesy of Dr. Gist Farr, New Orleans, La.)

Spontaneous Flares

Spontaneous exacerbations of chronic hepatitis B often result from reactivated infection, and an increase in serum HBV DNA levels often precedes an increase in serum aminotransferase levels. Histologic evidence of acute lobular hepatitis superimposed on the changes of chronic viral hepatitis is frequently observed during these flares.⁷² IgM anti-HBc, a marker that is often diagnostic of acute viral hepatitis, may also appear in serum at this time.⁷³

The reasons for reactivated infection are unknown but likely relate to subtle changes in the immunologic control of viral replication. Reactivation seems to occur more commonly in persons who are infected with HIV.⁷⁴ In persons who acquire HBV infection early in life, flares become more common during adulthood, presumably because of a breakdown in immune tolerance to HBV.⁷⁵

Fatigue may be reported during flares of chronic hepatitis B, but in many instances, patients remain asymptomatic. Occasionally symptoms and signs of frank liver failure become apparent, particularly when the flare is superimposed on advanced chronic hepatitis B.

Most clinically recognizable flares occur in patients who are in the nonreplicative phase of HBV infection (i.e., initially testing positive for anti-HBe and negative for serum HBV DNA on a molecular hybridization assay). During such flares, serum HBV DNA levels increase, and HBeAg often reappears in serum (seroreversion). HBV DNA and HBeAg are often detectable in serum when the patient is first seen, but if the flare has been ongoing for several weeks or longer, the accompanying enhancement of the immune response may make it difficult to detect a rise in serum HBV DNA levels. Frequently, subsidence of these flares of hepatitis is accompanied by loss of HBV DNA and HBeAg in serum.

Flares also can occur in patients who are in the replicative phase of infection (i.e., already positive for HBV DNA and HBeAg in serum). In these instances, HBV replication intensifies, serum HBV DNA levels rise, and liver biochemical deterioration occurs, often without the subsequent loss of HBeAg. Multiple episodes of reactivation and remission have been shown to accelerate the progression of chronic hepatitis B and are particularly likely to occur in patients infected with the precore mutant form of chronic hepatitis B (see earlier).⁴⁷

Immunosuppressive Therapy-Induced Flares

Reactivation of HBV replication is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy.⁷⁶ Suppression of the normal immunologic responses to HBV leads to enhanced viral replication and is thought to result in widespread infection of hepatocytes by HBV. On discontinuation of immunosuppressive medications, such as cancer chemotherapy, antirejection drugs, and glucocorticoid therapy, immune competence is restored and infected hepatocytes are rapidly destroyed. The more potent the immunosuppression, the higher the level of viral replication and, thus, the greater the potential for serious clinical consequences of sudden withdrawal of the therapy and restoration of immunologic competence. Postmortem studies of liver tissue from patients with severe liver injury have documented sparse staining of viral antigens, suggesting that the patients were in an active state of immune clearance.⁷⁷

The vast majority of patients who experience immunosuppressive therapy–induced flares have been positive for HBsAg in serum before treatment, but some studies have described the reappearance of HBsAg in patients who were initially positive for anti-HBs, anti-HBc, or both.⁷⁸ Reactivated hepatitis in patients who are negative for HBsAg and positive for either anti-HBc or anti-HBs is explainable by the possible latency of HBV in liver and mononuclear cells and the large extrahepatic reservoir of HBV. Chemotherapy given to patients with cancer who are HBV carriers is associated with an increased risk of liver-related morbidity and mortality.⁷⁹

Reactivated hepatitis B also occurs in patients who are given immunosuppressive medications to prevent organ transplant rejection. The frequency of reactivated hepatitis appears to be particularly high in patients who undergo bone marrow transplantation because of extensive immunologic conditioning before transplantation and treatment of graft-versus-host disease.⁸⁰ Rarely, fibrosing cholestatic hepatitis, a rapidly progressive form of liver injury associated with inordinately high levels of HBsAg and HBcAg in liver tissue, may develop in such patients.⁸¹

Acute flares of hepatitis B resulting from cancer chemotherapy and other immunosuppressive drugs are often detected after substantial increases in serum aminotransferase levels have been noted. Initiation of antiviral treatment after detection of such biochemical abnormalities has little effect on reducing liver injury because much of the immunologic response to HBV and viral elimination has already occurred. Instead, the key to management lies in anticipating the occurrence of a flare, initiating antiviral treatment preemptively (e.g., 4 to 6 weeks before the start of chemotherapy), and continuing the treatment for 6 to 12 months after completion of chemotherapy.⁸²

Antiviral Therapy–Induced Flares

Antiviral treatment of chronic hepatitis B can be associated with flares of hepatitis in several circumstances. Flares may occur during interferon therapy, after withdrawal of nucleoside analogs or glucocorticoid therapy, and in association with lamivudine-resistant mutants (see also later discussion of treatment).