AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1965, Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion. Since then, considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus.

Hepatitis B is a worldwide health care problem, especially in developing areas. An estimated one third of the global population has been infected with this virus. Approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of this disease.

HBV is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction resulting in either an acute symptomatic disease or an asymptomatic disease. Patients may become immune to HBV or may develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC). Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates, liver transplantation currently seems to be the only viable treatment for the latest stages of this disease.

Pathophysiology

HBV is a Hepadna virus. It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive when stored for 15 years at -20°C, for 24 months at -80°C, for 6 months at room temperatures, and for 7 days at 44°C. The viral genome consists of a partially double-stranded circular DNA of 3.2 kilobase pairs that encodes 4 overlapping open reading frames, as follows:

• S for the surface or envelope gene encoding the pre-S1, pre-S2, and the S protein
• C for the core gene, encoding for the core nucleocapsid protein and the e antigen
• X for the X gene encoding the X protein
• P for the polymerase gene encoding a large protein promoting priming, RNA-dependent and DNA-dependent DNA polymerase and RNase H activities

An upstream region for the S and C genes has been found, named pre-S and pre-C, respectively. The structure of this virion is a 42-nm spherical double-shelled particle consisting of small spheres and rods, with an average width of 22 nm.

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: a, common to all HBsAg, and d, y, w, and r, which are epidemiologically important. The core antigen, HBcAg, is the protein that encloses the viral DNA. It also can be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, comes from the core gene and is a marker of active viral replication. Usually, HBeAg can be detected in patients with circulating serum HBV DNA.

The best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum.

The role of the X gene is to encode proteins that act as transcriptional transactivators aiding viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to HBV. The immunoglobulin, immunoglobulin M (IgM) subtype, is indicative of acute infection or reactivation, while the immunoglobulin G (IgG) subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state, and the antigen has been cleared.

With the newest PCR techniques, scientists are able to identify variations in the HBV genome (variant strains). A mutation at the 1896 nucleotide (precore/core region) processing the production of the HBeAg was identified first. The prevalence of this mutant virus varies among different areas. Estimates indicate that 50-60% of the patients from southern Europe, the Middle East, Asia, and Africa and 10-30% of patients in the United States and Europe who have chronic HBV infection have been infected by this strain.

The pathogenesis and clinical manifestations are due to the interaction of the virus and the host immune system. The latter attacks the HBV and causes liver injury. Activated CD4⁺ and CD8⁺ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. Impaired immune reactions (eg, cytokine release, antibody production) or relatively tolerant immune status results in chronic hepatitis. In particular, a restricted T cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.

The final state of the disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop HCC. In the United States, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission). Four different stages have been identified in the viral life cycle.

The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period often is decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.

In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of HBV DNA is seen. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops.

In the third stage, the host can target the infected hepatocytes and the HBV. Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.

In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and co-infection with other viruses.

Eight different genotypes A through H representing a divergence of the viral DNA at around 8% have been identified. The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated, and the response to treatment with antivirals is less favorable for patients infected by genotype C compared with those infected by genotype B.

Frequency

United States

An estimated 200,000 new cases of HBV occur annually, and 1-1.25 million people are carriers. The prevalence of the disease is higher among African Americans and persons of Hispanic or Asian origin. In addition, a higher carrier rate exists among certain subpopulations such as the Alaskan Eskimos, Asian Pacific islanders, and Australian aborigines. HBV accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of HCC.

HBV is blamed for 5000 deaths annually. Prevalence is low in persons younger than 12 years, but it increases in those older than 12 years. The increased prevalence in persons older than 12 years is associated with the initiation of sexual contact (the major mode of transmission), the number of sexual partners, and an early age of first intercourse. Additional risk factors identified in the National Health and Nutrition Examination Survey III survey are non-Hispanic black ethnicity, cocaine use, high number of sexual partners, divorced or separated marital status, foreign birth, and low educational level.

Because of the implementation of routine vaccinations of infants in 1992 and adolescents in 1995, the prevalence of HBV is expected to decline further.

International

The HBV carrier rate variation is 1-20% worldwide. This variation is related to differences in the mode of transmission and age at infection. The prevalence of the disease in different geographical areas can be characterized as follows:

• Low-prevalence areas (rate of 0.1-2%) include Canada, western Europe, Australia, and New Zealand. In the areas of low prevalence, sexual transmission and percutaneous transmission during adulthood are the main modes of transmission.
• Intermediate-prevalence areas (rate of 3-5%) include eastern and northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and central Asia. In areas of intermediate prevalence, sexual and percutaneous transmission and transmission during delivery are the major routes.
• High-prevalence areas (rate of 10-20%) include China, Indonesia, sub-Saharan Africa, the Pacific islands, and Southeast Asia. In areas of high prevalence, the predominant mode of transmission is perinatal, and the disease is transmitted during early childhood vertically from the mother to the infant. Vaccination programs implemented in highly endemic areas such as Taiwan seem to change the prevalence of HBV infection. In Taiwan, seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 and the incidence of HCC declined from 0.52% to 0.13%.

Mortality/Morbidity

An estimated 250,000 persons per year globally and 5000 persons per year in the United States die from chronic HBV infection.

Race

African Americans have a higher prevalence of the disease than persons of Hispanic origin or white persons.

Sex

More cases occur in males than in females.

Age

The earlier the disease is acquired, the greater the chance of developing chronic infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and persons who are elderly have an approximately 20-30% chance of developing chronic disease.

CLINICAL

Section 3 of 11  

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History

The spectrum of the symptomatology varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC during the chronic phase.

• Acute phase
• • The incubation period is 1-6 months.
  • Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis.
  • Icteric hepatitis is associated with the prodromal period, during which a serum sickness–like syndrome can occur. The symptomatology is more constitutional and includes the following:
  • • Anorexia
    • Nausea
    • Vomiting
    • Low-grade fever
    • Myalgia
    • Fatigability
    • Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
    • Right upper quadrant and epigastric pain (intermittent, mild to moderate)
  • Patients with hyperacute, acute, and subacute hepatitis may present with the following:
  • • Hepatic encephalopathy
    • Somnolence
    • Disturbances in sleep pattern
    • Mental confusion
    • Coma
• Chronic phase
• • Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic.
  • Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:
  • • Symptoms similar to those of acute hepatitis
    • Fatigue
    • Anorexia
    • Nausea
    • Mild upper quadrant pain or discomfort
    • Hepatic decompensation

Physical

The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease.

• Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:
• • Low-grade fever
  • Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo)
  • Hepatomegaly (mildly enlarged soft liver)
  • Splenomegaly (5-15%)
  • Palmar erythema (rarely)
  • Spider nevi (rarely)
• The physical examination of patients with chronic hepatitis B can reveal stigmata of chronic liver disease such as the following:
• • Hepatomegaly
  • Palmar erythema
  • Spider angioma
• Patients with cirrhosis may have the following symptoms:
• • Ascites
  • Jaundice
  • History of variceal bleeding
  • Peripheral edema
  • Gynecomastia
  • Testicular atrophy
  • Abdominal collateral veins (caput medusa)

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Drug hepatotoxicity
Congestive heart failure

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• Acute hepatitis B
• • High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), at a range of 1000-2000 IU/mL, is the hallmark of the disease, although values 100 times more than the upper limit of normal can be identified. Higher values are found in patients with icteric hepatitis. ALT levels usually are higher than AST levels.
  • Alkaline phosphatase levels may be elevated, but usually they are not more than 3 times the upper limit of normal.
  • Albumin levels can be slightly low, and serum iron levels may be elevated. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the sedimentation rate.
  • Anemia due to a shortened red blood survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding.
  • Patients with severe hepatitis experience a prolongation of the prothrombin time.
  • Several viral markers can be identified in the serum and the liver. HBsAg (Australian antigen) and HBeAg (marker of infectivity) are the first markers that can be identified in the serum. HBcAb (IgM) follows.
  • For patients who recover, seroconversion to HBsAb and HBeAb is observed, and the HBcAb is of the IgG class. Patients with persistent HBsAg for longer than 6 months develop chronic hepatitis.
• Chronic inactive hepatitis B
• • Healthy carriers have normal AST and ALT levels, and the markers of infectivity (ie, HBeAg, HBV DNA) may be negative.
  • HBsAg, HBcAb of IgG type, and HBeAb also are present in the serum.
• Chronic active hepatitis B
• • Patients have mild-to-moderate elevation of the aminotransferases (less than or equal to 5 times the upper limit of normal). The ALT levels usually are higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease and can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time). HBV DNA levels are high during this phase. HBsAg and HBcAb of IgG or IgM type (in case of reactivation) are identified in the serum.
  • If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be excluded. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as antismooth muscle antibodies (20-25%) or antinuclear antibodies (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), also can be found. Mildly elevated levels of rheumatoid factor usually are present.
• Cirrhosis
• • In early stages, findings of chronic viral hepatitis can be found.
  • Later on as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged prothrombin time, low platelet count and white blood cell count, and AST levels higher than ALT levels can be identified.
  • Alkaline phosphatase levels and gamma-glutamyl transpeptidase can be slightly elevated.

Imaging Studies

• Acute hepatitis B
• • Performing abdominal ultrasonography, CT scan, or MRI is important to help exclude biliary obstruction.
  • Nonspecific findings include increased echogenicity of the liver parenchyma.
• Chronic hepatitis B: Nonspecific findings may include increased echogenicity of the liver parenchyma.
• Cirrhosis
• • Findings include coarse echogenicity of the liver, with a nodular appearance, and findings compatible with portal hypertension (eg, varices, splenomegaly, ascites, pleural effusion [ie, hepatic hydrothorax]).
  • Lesions can be detected and may be very difficult to evaluate because they can be mistaken for regenerating nodules. For these cases, highly sophisticated techniques, such as MRI with superparamagnetic iron oxide (ferumoxides), should be considered. Ferumoxides (negative contrast material) are phagocytosed by the reticuloendothelial cells of the normal liver, producing predominant T2 imaging on MRI. Therefore, a marked decrease of the signal in the normal liver parenchyma occurs, effectively permitting the identification of tumors.

Procedures

• Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease for patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of HBV DNA).

Histologic Findings

Although liver biopsy is not indicated for patients with acute hepatitis B, the findings are predominantly lobular, with degenerative and regenerative hepatocellular changes and accompanying inflammation. Necrosis may be predominantly centrilobular.

Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for HBsAg (see Media file 1). Immunohistochemical staining of the specimen can help identify the presence of HBsAg or HBcAg (ie, chronic infection).

Staging

• Liver damage grading according to the inflammatory component is described as follows:
• • Grade 0 - Portal inflammation only, no activity
  • Grade 1 - Minimal portal inflammation and patchy lymphocytic necrosis with minimal lobular inflammation and spotty necrosis
  • Grade 2 - Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage
  • Grade 3 - Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change
  • Grade 4 - Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent diffuse hepatocellular damage
• Liver damage staging (ie, fibrosis) is described as follows:
• • Stage 0 - No fibrosis
  • Stage 1 - Portal fibrosis
  • Stage 2 - Periportal fibrosis
  • Stage 3 - Septal, bridging fibrosis (see Media file 2)
  • Stage 4 - Cirrhosis (see Media file 3)

TREATMENT

Section 6 of 11  

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Medical Care

Therapy is currently recommended for patients with evidence of chronic active disease (ie, high aminotransferase levels, positive HBV DNA findings, HBeAg). See Medication. Currently, interferon alfa (IFN-a), lamivudine, adefovir dipivoxil, and entecavir are the main drugs approved globally, although ongoing trials are investigating new types of medications, such as tenofovir disoproxil in combination with emtricitabine, BL-thymidine (L-dT), DAPD, clevudine (l-FMAU), thymosin, and therapeutic vaccines. No clear-cut guidelines are available as to which medication should be chosen.

Patients who have lost HBeAg and in whom HBV DNA is undetectable have an improved clinical outcome (ie, slower rate of progression, prolonged survival without complications, reduced rate of HCC, and clinical and biochemical improvement after decompensation).

Special attention must be given to patients on transplantation lists. Initiation of treatment with adefovir or entecavir or in combination with lamivudine is of cardinal importance before and after liver transplantation to achieve viral suppression and to prevent recurrence of the disease after the procedure.

• Interferon alfa
• • Published reports indicate that after IFN-a treatment with 5 million U/d or 10 million U 3 times per week subcutaneously for 4 months, the HBV DNA levels and HBeAg become undetectable in 30-40% of patients. In addition, 10% of patients seroconvert from HBsAg to HBsAb. Unfortunately, 5-10% of patients relapse after completion of treatment. A transient "flare" (ie, increased aminotransferase levels during the beginning of treatment) can be identified, and this represents the impact of the activated cytolytic T cells on the infected hepatocytes.
  • High levels of aminotransferases, a low viral load, and infection with the wild type are good prognostic factors for response to IFN-a treatment.
  • Asian patients and patients with the precore mutant virus tend to not respond to IFN-a treatment.
  • Special attention must be given to patients with HBV-decompensated cirrhosis (eg, ascites, encephalopathy) who are taking IFN-a because of the fact that, although they occasionally may respond, they also can deteriorate further.
  • The adverse effects of IFN-a treatment sometimes can be severe, even devastating. Some patients cannot complete treatment. A flulike syndrome, myelosuppression (eg, leukopenia, thrombocytopenia), nausea, diarrhea, fatigue, irritability, depression, thyroid dysfunction, and alopecia are among the adverse effects that may occur.
  • Pegylated interferon has been used with or without the addition of nucleoside analogues with encouraging results.
• Lamivudine
• • A nucleoside analogue inhibiting the viral polymerase, lamivudine has been associated with a 4-log reduction of the viral load. Lamivudine treatment (100 mg/d) has been associated with a 16-18% seroconversion rate from HBeAg to HBeAb, a 30-33% rate of HBeAg loss, a 40-50% normalization of the value of the aminotransferases, and a 1-2% HBsAg seroconversion rate.
  • Histologic improvement (ie, reduction of histologic activity index of > 2 points) has been noticed in approximately 50% of patients taking this medication. The adverse effects are negligible.
  • Lamivudine appears to be effective for patients who do not respond to IFN-a treatment (eg, patients infected by the precore mutant virus). A transient elevation of aminotransferases can be noticed shortly after starting treatment.
  • The HBeAg seroconversion rate has been shown to possibly increase to 27% after 2 years, 40% after 3 years, and 47% after 4 years of treatment in patients with a viral load of less than 104 pg/mL.
  • Lamivudine treatment has also been shown to dramatically improve the condition of patients with decompensated disease due to HBV reactivation.
  • The emergence of viral variants is the major complication. Approximately 15-30% of patients develop a mutation of the viral polymerase gene (the YMDD variants) after 12 months of treatment, and approximately 50% develop a mutation after 3 years of treatment. However, continued treatment after the breakthrough with the variant type has been associated with lower HBV DNA levels, less aminotransferase activity, and histologic improvement. For these patients, discontinuation of treatment is accompanied by a reversion to a wild type of HBV and a flare of the disease.
• Adefovir dipivoxil
• • This agent is a nucleoside analogue, a potent inhibitor of the viral polymerase. The efficacy of this drug has been tested in HBeAg-positive, HBeAg-negative, and lamivudine-resistant patients with encouraging results.
  • The estimated rate of resistance to adefovir and the development of mutations (rtN236T and rtA181V) are approximately 4-6% after 3 years and approximately 30% after 5 years of treatment.
  • The optimal dose seems to be 10 mg/d. Higher doses are nephrotoxic.
  • The results of 2 multicenter trials using adefovir for 48 weeks were published.
  • In HBeAg-positive patients who received 10 mg of adefovir daily, a median 3.52 log reduction of the viral load (HBV DNA) level was noted. In 48% of the patients, normalized aminotransferase levels were reported. Histologic improvement was noticed in 53% of the patients who received this regimen. The HBeAg seroconversion rate was 12%.
  • Of the HBeAg-negative population, 64% experienced histologic improvement after receiving 10 mg of adefovir for 48 weeks, and 72% had normalized aminotransferase levels. The serum HBV DNA level was decreased in 51% of subjects (Hadziyannis, 2003; Marcellin, 2003). The outcomes are maintained if treatment is continued for 144 weeks, but the benefits are lost if treatment is discontinued at 44 weeks. The development of resistant mutations (rtN236T and rtA181V) has been estimated around 6% (Hadziyannis, 2005).
• Entecavir
• • Entecavir is a potent guanosine analogue inhibitor of the viral polymerase with no resistance developed so far after 2 years of use in patients who have no history of previous treatment with nucleoside analogues.
  • In regard to the HBeAg-positive population, administration of 0.5 mg of entecavir in patients who are naïve-to-nucleoside analogues versus patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 72% versus 62% of patients (p=0.009), respectively. Undetectable serum HBV DNA levels were reported in 67% versus 36% of patients (p <0.001), respectively. Normalized ALT levels were achieved in 68% versus 60% of patients (p=0.02), respectively. The mean reduction in serum HBV DNA from baseline to week 48 was 6.9 log versus 5.4 log (on a base-10 scale) copies per milliliter (p <0.001), respectively. HBeAg seroconversion occurred in 21% of patients treated with entecavir and 18% of patients treated with lamivudine (p=0.33).
  • In regard to the HBeAg-negative population, administration of 0.5 mg of entecavir in patients who are naïve-to-nucleoside analogues versus patients who received 100 mg of lamivudine for a duration of 48 weeks resulted in histologic improvement in 71% versus 61% of patients (p=0.01), respectively. Undetectable serum HBV DNA levels were found in 90% versus 72% of patients (p <0.001), respectively. Normalized ALT levels were achieved in 78% versus 71% of patients (p=0.045), respectively. The mean reduction in serum HBV DNA levels from baseline to week 48 was 5.0 log versus 4.5 log (on a base-10 scale) copies per milliliter (p <0.001), respectively.
• Telbivudine
• • Telbivudine, a newly FDA approved cytosine nucleoside analogue, is a potent inhibitor of the HBV DNA polymerase.
  • The results of the GLOBE Trial, a Phase III study, that tested the administration of 600 mg of telbivudine versus 100 mg of lamivudine over a 2-year period were announced. In regard to the HBeAg-positive population, therapeutic response (defined as HBV DNA <10,000 copies/mL, with either ALT normalization or HBeAg loss) was 75% for the patients treated with telbivudine compared with 67% for the patients treated with lamivudine. Of the patients receiving telbivudine, 26% lost the e antigen versus 23% of the patients receiving lamivudine. In addition, a 6.5 log reduction of the HBV DNA was noted for the patients receiving telbivudine versus a 5.5 log reduction for the patients receiving lamivudine.
• • In the HBeAg-negative patients, the respective response rates at 1 year were 75% and 77%, while 88% versus 71% were HBV DNA nondetectable. The HBV DNA log reduction was 5.2 versus 4.4, respectively.
  • Because resistance is a major issue, the reported rates at 1 year were 2.6% of patients on telbivudine and 8.2% of patients on lamivudine.

Surgical Care

Orthotopic liver transplantation (OLT) is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease. The implementation of hepatitis B immunoglobulin (HBIG) during and post-OLT period, and of lamivudine or adefovir in the pre-OLT period and post-OLT period, dramatically improves the recurrence rate of HBV infection.

Diet

• Acute and chronic hepatitis (patients without cirrhosis) - No restrictions
• Decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy) - Low-sodium diet (1.5 g/d), high-protein diet, ie, white-meat protein (eg, pork, turkey, fish), and, in cases of hyponatremia, fluid restriction (1.5 L/d)

MEDICATION

Section 7 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antivirals

Interfere with replication; weaken or abolish viral activity.

Drug Name	Lamivudine (Epivir)
Description	Thymidine analog that blocks viral replication by competitive inhibition of viral reverse transcriptase. Evidence that an indirect immunomodulatory effect can be observed.
Adult Dose	100 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	TMP-SMZ increases bioavailability; increases concentration of zidovudine when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal impairment; caution in history of pancreatitis

Drug Name	Adefovir dipivoxil (Hepsera)
Description	Used to treat chronic hepatitis B. This agent is a prodrug that is converted to the diphosphate salt. The active drug is classified as an antiviral nucleotide reverse transcriptase inhibitor. It inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate (dATP) and by causing DNA chain termination after its incorporation into viral DNA.
Adult Dose	CrCl >50 mL/min: 10 mg PO qd CrCl 20-49 mL/min: 10 mg PO q48h CrCl 10-19 mL/min: 10 mg PO q72h Hemodialysis: 10 mg PO qwk following hemodialysis
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Coadministration with ibuprofen increases bioavailability of adefovir; drugs that alter renal tubular secretion may affect adefovir renal elimination
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hepatitis exacerbation may occur following drug discontinuation; may increase risk of renal dysfunction; HIV resistance may emerge in patients with untreated or unrecognized HIV; lactic acidosis and hepatomegaly with steatosis have been reported with other nucleoside analogs

Drug Name	Entecavir (Baraclude)
Description	Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic HBV infection. Available as tab and as oral solution (0.05 mg/mL; 0.5 mg = 10 mL).
Adult Dose	Treatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc CrCl 30-49 mL/min: 0.25 mg PO qd CrCl 10-29 mL/min: 0.15 mg PO qd CrCl <10 mL/min: 0.05 mg PO qd Receiving lamivudine or lamivudine resistance: 1 mg PO qd 2 h ac or 2 h pc CrCl 30-49 mL/min: 0.5 mg PO qd CrCl 10-29 mL/min: 0.3 mg PO qd CrCl <10 mL/min: 0.1 mg PO qd
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Not a substrate, inhibitor, or inducer of cytochrome P450; coadministration with drugs that reduce renal function (eg, aminoglycosides, cidofovir, cyclosporine) or that compete for active tubular secretion (eg, probenecid, salicylates) may increase serum concentration of either entecavir or coadministered drug
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Reduce dose with renal impairment; if on hemodialysis, administer afterward; common adverse effects include headache, fatigue, dizziness, and nausea; may elevate liver enzyme levels; may cause lactic acidosis; severe acute exacerbations of HBV infection may occur in patients who discontinue anti-HBV therapy

Drug Name	Telbivudine (Tyzeka)
Description	Nucleoside analogue approved by FDA for chronic hepatitis B treatment. Inhibits hepatitis B viral DNA polymerase. Indicated for patients with evidence of ongoing hepatitis B viral replication and either persistent elevated aminotransferase activity or histologic evidence of active liver disease. Consider for patients who did not or are unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is major drawback of nucleoside analogue monotherapy.
Adult Dose	CrCl >50 mL/min: 600 mg PO qd CrCl 30-49 mL/min: 600 mg PO q48h or 400 mg PO qd CrCl <30 mL/min (not requiring dialysis): 600 mg PO q72h or 200 mg PO qd ESRD: 600 mg PO q96h Optimal treatment duration not established
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Toxicity may increase when administered concurrently with drugs that decrease renal excretion (eg, acyclovir, aminoglycosides, amphotericin B, cisplatin, cyclosporine, metformin, tacrolimus); may increase risk of myopathy when coadministered with HMG-CoA reductase inhibitors (statins)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with use of nucleoside analogs alone or in combination with antiretrovirals; severe acute hepatitis B exacerbations reported when anti?hepatitis B therapy (including telbivudine) is discontinued (closely monitor hepatic function with both clinical and laboratory follow-up for at least several months following discontinuation of anti?hepatitis B therapy, and resume therapy if necessary); myopathy has been reported; common adverse effects include upper respiratory tract infection, fatigue, malaise, abdominal pain, nasopharyngitis, headache, increased CK level, cough, nausea, vomiting, flulike symptoms, diarrhea, pyrexia, arthralgia, rash, back pain, dizziness, and dyspepsia

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Fulminant hepatic failure: Patients should be hospitalized in the intensive care unit and should be enrolled for liver transplantation in case they do not recover.
• Acute hepatitis: Patients should be monitored with blood tests in order to document biochemical improvement.

Further Outpatient Care

• Healthy carriers should have routine blood tests annually to check aminotransferase levels.
• Patients with chronic active hepatitis should have blood tests (ie, to evaluate aminotransferase levels, antigen-antibody HBV profile, and viral load), liver biopsy, and treatment.
• Patients with cirrhosis must be checked every 3-6 months with alpha-fetoprotein measurements and abdominal ultrasound for HCC surveillance.

Deterrence/Prevention

• Universal vaccination programs are ongoing in endemic areas, with encouraging results. This vaccine consists of recombinant HBsAg produced in yeast. A series of 3 injections may achieve HBsAb levels of greater than 10 million IU/mL in approximately 95% of people vaccinated.
• • Low response rates have been associated with obesity, smoking, immunosuppression, and advanced age.
  • The HBV vaccine seems to be safe, although some questions exist regarding neurological complications.
  • Approximately 25-50% of persons who initially do not respond to the vaccine will respond to one additional vaccine dose, and 50-75% of persons will respond to a second 3-dose series.
  • Vaccination with a single dose must be repeated every 5-10 years.
  • All newborns must be vaccinated. For infants born to mothers with active HBV infection, a passive-active (immunoglobulin and vaccination) approach is recommended.
  • A combined hepatitis A and B vaccine is licensed in many countries and offers the advantage of protection against both of these diseases at the same time.
  • Health care workers or people who have had a needle-stick accident from a patient with active HBV infection must receive the active-passive immunization approach (HBIG and the first dose of the vaccine at the same time) and must be monitored with blood tests.

Complications

• Hepatocellular carcinoma
• • Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with HBV infection and cirrhosis reported in Taiwan is 2.8%. The estimated US annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with HBV in Africa, the Far East, and Alaska.
  • The prevalence of hepatitis D virus (HDV) co-infection among patients infected with HBV worldwide is 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated. The prevalence of anti-delta among patients with cirrhosis with and without HCC was not significantly different. Therefore, delta superinfection does not appear to increase the rate of HCC.
  • The prevalence of HCC among patients with HBV and hepatitis C virus (HCV) co-infection is higher than in those with single infection alone. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and HBV infection, 3.7% in patients with HCV, and 6.4% in patients with dual infection. This points to a probable synergistic effect on the risk of HCC.
  • The mechanism by which chronic HBV infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors for nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk for HCC.
  • The fact that facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm. Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of alpha-fetoprotein. Although the cellular targets of carcinogenesis have not been identified, some evidence resulting from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC. Although cirrhosis is found in the majority of these patients, it is not obligatory because chronic carriers may develop HCC even without the evidence of cirrhosis.
  • HBV has been speculated to have intrinsic hepatocarcinogenic activity, interacting with host DNA in different ways. After entering the hepatocyte, viral DNA is integrated within the genome. The site of integration is not constant but usually involves the terminal repeat sequences. Chromosomal deletions, translocations, rearrangements, inversions, or even duplications of normal DNA sequencing accompany integration.
  • Transactivation of the function of genes controlling transcriptional factors (ie, insulinlike growth factor II, transforming growth factor-alpha (TGF-a), transforming growth factor-beta, cyclin-a [a protein that controls cell division], epidermal growth factor-r, retinoic acid receptor) and oncogenes such as c-myc, fos, ras (activating the internal signal transduction cascade up-regulating ras/mitogen–activated kinase, c-Jun N terminal kinase, nuclear factor – kB, Jak-1-STAT, src-dependent pathways) influence the normal hepatocyte differentiation or cell cycle progression.
  • Furthermore, the integrated part of the HBV controlling the production of the HBxAg is overexpressed. These observations suggest the site of viral genomic integration into the host's DNA alone is not the factor. Most likely, the HBxAg produced by these sequences is the transactivating factor because it has been found to bind to a variety of transcription factors such as CREB and ATF-2, which alters their DNA-binding specificity. Thus, the ability of pX to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.
  • Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53 and (1) sequester TP53 in the cytoplasm, resulting in the abrogation of TP53-induced apoptosis (although controversy exists regarding this concept); (2) reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD; (3) reduce p21WAF1 expression, which is a cell cycle regulator; and (4) bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with HBV infection, thus altering its function.
  • Tumor necrosis factor-alpha (TNF-alpha, a proinflammatory cytokine) levels also are up-regulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-alpha are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc, and this up-regulates the expression of TGF-a by transactivation.
• Glomerulonephritis
• • The most common type of glomerulonephritis (GN) described is membranous GN (MGN), mainly in children. However, membranoproliferative GN (MPGN) and, even more rarely, immunoglobulin A (IgA) nephropathy, have been identified. The prevalence rate of GN among patients with chronic HBV infection is not well known, although observations have been made in children that suggest a range of 11-56.2%. However, such a high prevalence is not recognized in the United States, and this may be because of the differences in epidemiology of HBV, which might be predominantly perinatal in other geographic areas of the world.
  • Previous history of chronic liver disease is not present in the majority of these patients at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. Serologic markers of an HBV replicative state often are evident, and complement activation is suggested by low levels of C3 and C4.
  • Generally, the most prominent finding among children is MGN, primarily with capillary wall deposits of HBeAg. In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy also has been described.
  • The mechanism by which patients with chronic HBV infection develop GN is not completely understood. One possible explanation is that HBV antigens (ie, HBsAg, HBeAg) act as triggering factors eliciting immunoglobulins and thus forming immune complexes, which are dense irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and epithelial cells of renal tubules.
  • INF-a therapy has been successful in treating HBV-related GN. A regimen of 5 million units of IFN-a subcutaneously daily for 4 months has achieved HBsAg seroconversion with improvement of GN. It also has been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative GN but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation.
  • The prognosis of the disease is related to several factors such as age and response to therapy. Children with MGN respond more favorably than adults. White persons respond better than Asians and African Americans. Approximately 30-60% of patients with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which HBV is endemic is not benign. Regardless of treatment, the disease has a slow but relentlessly progressive clinical course in approximately one third of patients who have progressive renal failure, necessitating maintenance dialysis therapy.
• Polyarteritis nodosa
• • An association between HBV and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN). This very serious complication presents early during the course of disease, and the incidence is high among certain populations such as Alaskan Eskimos. The pathogenesis of PAN is not clear. Circulating immune complexes containing HBsAg, immunoglobulins (IgG and IgM), and complement have been demonstrated by immunofluorescence in the walls of the affected vessels, which might trigger the onset of the disease. However, whether these represent the primary etiology of the disease remains unclear.
  • The clinical manifestations of the disease include cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure), renal (eg, hematuria, proteinuria, renal insufficiency), gastrointestinal (eg, abdominal pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis), neurological (eg, mononeuritis), and dermatological (eg, rashes) involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum creatinine >1.58 mg/dL), gastrointestinal involvement, cardiomyopathy, and CNS involvement are associated with increased mortality. The course of PAN is independent of the severity and the progression of liver disease. Of these patients, 20-45% die as a consequence of vasculitis in 5 years, despite treatment, and the mortality rate is similar for patients with PAN who are HBsAg seropositive and those with PAN who are seronegative.
  • Small and medium-sized arteries and arterioles are affected. Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they potentially may have a deleterious effect on the course of HBV liver disease because of viral reactivation, particularly after the withdrawal of treatment. Adenine arabinoside, an antiviral drug, and IFN-a, an immunomodulator and antiviral protein, have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results. Because of the fact that this is a rare complication, to date no reports have been published on the use of the newer therapies for HBV that include the nucleoside analogue, lamivudine.
• Skin manifestations
• • A variety of cutaneous manifestations already have been recognized, among which are hives and fleeting maculopapular rash, during the early course of viral hepatitis. Women are more prone to developing cutaneous manifestations.
  • The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities.
  • Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, more commonly with acute infection in children.
• Cardiopulmonary manifestations
• • Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis.
  • Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis.
• Joint and neurologic manifestations
• • Guillain-Barré syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis.
  • Arthralgias and arthritis (serum sickness) subcutaneous nodules also may occur but are rare.
• Hematologic and gastrointestinal tract manifestations
• • Patients may develop pancreatitis.
  • Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon.
  • Diffuse intravascular coagulation may occur in patients with fulminant hepatitis.

Prognosis

• Approximately 9% of patients in western Europe who have cirrhosis develop HCC due to HBV infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis is established is 6%, and the probability of decompensation is 23%.
• Significant risk factors for carcinogenesis include older age, liver firmness, and thrombocytopenia. Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with HBV infection and cirrhosis reported in Taiwan is 2.8%. The US estimates for the annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with HBV in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% and 68% at 5 years and 10 years, respectively.
• Cox's regression analysis identified 6 variables that independently correlate with survival. These include age, albumin level, platelet count, splenomegaly, bilirubin level, and HBeAg positivity at the time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index has been constructed that allows calculation of the estimated survival probability. No difference in survival is observed in patients with HDV infection compared to those who are not infected.
• The prevalence of HDV co-infection among patients infected with HBV varies worldwide from 0-20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated, with controversial results. The prevalence of anti-delta among patients with cirrhosis with and without HCC is not significantly different, although HDV infection has been reported to increase the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis.

Patient Education

• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education article Hepatitis B.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to identify hyperacute fulminant hepatic failure cases and list the patient as a liver transplant candidate
• Failure to monitor healthy carriers for probable reactivation
• Failure to inform the spouses and sexual partners about the infectivity of the disease and their possible need for vaccination
• Failure to monitor patients with cirrhosis and perform HCC surveillance studies (ie, alpha-fetoprotein level and liver ultrasound) every 3-6 months
• Failure to put patients with cirrhosis in liver transplant lists when needed
• Failure to identify HDV superinfection

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Hepatitis B. Liver biopsy specimen showing ground-glass appearance of hepatocytes.
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Media file 2:  Hepatitis B. Liver biopsy with trichrome stain showing stage 3 fibrosis.
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Media file 3:  Hepatitis B. Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis).
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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