Information of Hepatitis B

Viral Hepatitis
Hepatitis can be defined as the constellation of symptoms and signs resulting from hepatic inflammation and hepatic cell necrosis. If the insult is acute and occurs in a previously asymptomatic individual, the term acute hepatitis can be applied. The most common causes of acute hepatitis are viruses, toxins, and alcohol. Occasionally other disease entities such as Wilson's disease, leukemias, and lymphomas with acute infiltration of the liver may give rise to a clinical picture of acute hepatitis. Viruses, however, are the major etiologic agents of acute liver injury.
Systemic infection with several viruses results in hepatic inflammation and cell death. Viruses that cause hepatitis have been classified as hepatitis A (HAV), B (HBV), C (HCV), delta (HDV), and E (HEV). However, in some individuals, infection with the Epstein-Barr virus (EBV) or cytomegalovirus (CMV) also results in acute hepatitis.
In most patients, acute viral hepatitis presents as an acute illness characterized by the abrupt onset of malaise, fever, anorexia, nausea, headache, abdominal discomfort, and pain. Jaundice, itching, dark-colored urine, and light-colored stools often cause the patient to seek medical attention. At this stage, the disease caused by different viruses is usually indistinguishable, and serologic studies may provide the only means of identification. Pertinent factors regarding the five forms of acute and chronic viral hepatitis are summarized in Tables 1
Family Picornavirus Hepadnavirus Flavivirus Satellite Calicivirus
Size 27 nm 42 nm 30-60 nm 40 nm 32 nm
Genome ssRNA dsDNA ssRNA ssRNA ssRNA
Length 7.8 kb 3.2 kb 10.5 kb 1.7 kb 8.2 kb
0.2% 0.2%-1% 0.2% 2%-20% 0.2%
Chronicity None 2%-7% 50%-70% 2%-70% None
Spread Fecal-oral Parenteral
? Sexual
? Sexual
Antigens HAV Ag HBsAg
Antibodies Anti-HAV Anti-HBs
Anti-HCV Anti-HDV Anti-HEV
DNA polymerase
HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; ssRNA, single-stranded RNA; dsDNA, double-stranded DNA; kb, kilobase; Ag, antigen.

  • Hepatitis B. Infection with the hepatitis B virus (HBV) may result in three different clinical states: acute hepatitis, chronic hepatitis, and the asymptomatic carrier state. HBV causes much of the morbidity and mortality from acute and chronic liver disease worldwide. HBV is spread by the parenteral route and by intimate contact. In addition to chronic liver disease, it is also implicated in the pathogenesis of hepatocellular carcinoma.
    • HBV is a medium-sized DNA virus belonging to a new class of animal viruses called hepadna viruses. These viruses are hepatotropic, tend to cause persistent infections, and have been associated with the development of hepatocellular carcinoma. HBV is unique among human viruses in its genomic and antigenic structure and its replicative cycle.

It consists of an outer shell made up of a protein designated as the hepatitis B surface antigen (HBsAg) and a complex inner core called the hepatitis B core antigen (HBcAg). This core particle consists of a partially double-stranded circular DNA molecule and a DNA polymerase (DNAP). The genome is composed of circular DNA with a complete negative strand and an incomplete positive strand. The negative strand contains overlapping genes that encode structural proteins (surface proteins and their derivatives and core) and two replicative proteins (polymerase and X). HBV is unique among DNA viruses in that it replicates in a way similar to that of the RNA retroviruses such as the human immunodeficiency virus (HIV) via an RNA intermediate. Following entry of HBV into a hepatocyte, viral replication is initiated by the synthesis of an intermediary RNA molecule using host enzymes. Viral genomic DNA is produced by reverse transcription using DNA polymerase of the virus.

    • Pathogenesis:- At the entry of HBV and its invasion of hepatocytes, viral proteins are expressed on the hepatitis membrane. These proteins are recognized by the host immune systems, both the humoral and the cellular arms. If the host immune response to the infected hepatocytes is strong enough to destroy all the involved cells, hepatits is results in clearance of the virus. However, if the immune response is inadequate to completely obliterate the infected hepatocytes, an ongoing viral infection ensues with varying degrees of hepatic inflammatory response.
    • Serology:- Infection with HBV results in an overproduction of HBsAg outnumbering the intact virus by 10 million to 1.

Hepatitis B e antigen (HBeAg) is an internal antigen of HBcAg particles that can be detected in the serum of patients with high levels of circulating HBV. HBeAg is found only in HBsAg-positive serum and signals active ongoing infection and infectivity. HBcAg is found only within the infected hepatocytes


and not in the serum. The hepatitis B antibody (Ab) is described in the following sections.

    • HBV infection. Infection with HBV can lead to several outcomes. Approximately two thirds of the individuals infected with HBV have a transient subclinical infection, followed by rapid clearance of the virus with a strong immune response, production of high titers of HBsAb, and permanent immunity. HBcAb is also produced in these individuals but does not confer or suggest immunity.
    • Acute hepatitis :- About one fourth of individuals with HBV infection develop clinically apparent acute hepatitis. The incubation period, or time between exposure and onset of symptoms, is 1 to 6 months. During this time, there is active viral replication, and the patient's serum becomes positive for HBsAg, DNA, and DNAP.
      • Clinical presentation. Before jaundice and typical clinical findings of hepatitis become apparent, these patients may present with rash, neuralgia, arthralgia, arthritis, glomerulonephritis, vasculitis, mixed cryoglobulinemia,


and aplastic anemia. These disease states are believed to result from circulating antigen-antibody complexes.

      • Laboratory tests
        • As the patient becomes symptomatic, there is a concomitant rise in serum ALT and AST (5-20 times normal) and a moderate elevation of the serum alkaline phosphatase (2-10 times normal). These enzymes represent hepatocellular damage. Serum bilirubin may reach very high levels (> 30 mg/dL).

Prothrombin time (PT) and partial thromboplastin time (PTT) levels may also become abnormal depending on the severity of the liver disease.

      • Serum DNA and DNAP become undetectable in these patients within 1 to 8 weeks after the onset of symptoms. HBcAg also disappears soon after the peak of serum transaminase. HBsAg usually remains detectable in the serum throughout the illness and may persist even into convalescence. This is because the initial HBsAg titers are very high, and because HBsAg has a long half-life of 8 days, it may take months to clear it to undetectable levels.
      • HBcAb is present in high titers in the serum of infected patients with HBV when jaundice appears. The initial antibody is of IgM type; with recovery, the IgM type disappears, and the IgG HBcAb titers reach high levels and persist for life.
      • HBeAb appears when HBeAg becomes negative and often disappears within a few months or years.
      • HBsAg arises during recovery after HBsAg has cleared. There is usually a window period between the disappearance of HBsAg and the appearance of HBsAb. The only way to make the diagnosis of acute


hepatitis in these individuals is to show the presence of HBcAb (IgM type). A minority of the patients (5%-15%) who clear HBV and recover normally never develop HBsAb. However, most of these individuals have positive IgM HBcAb.

        • In some patients (10%), HBV clearance is very rapid, and HBsAg levels may be absent at the onset of symptoms. These acutely ill patients have positive IgM HBcAb titers and may have detectable HBeAg levels. These variations are more common in both mild and fulminant disease.
        • HBV DNA can be detected and measured quantitatively with specific assays. The hybridization assay measures replicating HSV DNA whereas the amplication assay performed using the polymerase chain reaction (PCR) measures HBV DNA nonspecifically.
      • Prognosis:- In patients who can mount a vigorous immune response, the virus is cleared, and recovery is within a few months (1-6 months). A minority of the patients with acute hepatitis (1%-5%) develop fulminant hepatic failure (FHF) due to massive hepatic necrosis. The prognosis in these patients is poor and depends on hepatic regeneration.
    • Chronic HBsAg carrier state and chronic hepatitis
      • Clinical course and serology. About one tenth of patients infected with HBV do not clear the virus and remain HBsAg-positive. Some of these patients develop chronic progressive hepatitis, and others may remain in a


clinically quiescent carrier state.


      • In patients who develop chronic type B hepatitis, the initial pattern of HBV markers is similar to that in patients with acute, self-limited hepatitis. However, in patients with ongoing active disease, HBeAg, DNA, and DNAP persist and accompany elevated serum transaminases even after 6 months of symptomatic disease.
      • In most patients the initial disease is mild, and some patients may be anicteric and symptomatic. These patients may present with only nonspecific symptoms of anorexia and fatigue and mild-to-moderate elevation of liver tests.
      • IgM HBcAb levels remain elevated in chronic active type B hepatitis. As the disease wanes, the titers diminish with an increase in IgG HBcAb.
      • Patients who remain HBsAg-positive do not produce specific HBsAb. However, in 20% to 40% of HBsAg carriers, there may be low levels of HBsAb directed toward HBsAg subdeterminants not present in the serum.
      • The course of chronic HBV infection varies. The activity of the liver disease and the serologic markers change over time. In approximately one half of these patients, HBeAg disappears and is replaced by HBeAb. Concomitantly, there is a flare of the hepatitis with elevated ALT and AST levels and loss of DNA and DNAP from serum. This is followed by marked improvement of liver histology and a decrease in serum transaminases. The transition from the viral replicative phase, suggested by the presence of HBeAb, to the nonreplicative phase, suggested by the presence of HBeAb, is marked by an increased immune response of the patient to clear viral replication.


        • HBsAg persists in the serum of most of these patients even though there may be no evidence of viral replication. These individuals are referred to as the healthy HBsAg carriers. Integration of HBV DNA into the hepatocyte DNA occurs during chronic HBV infection and persistent viral replication. This may be a necessary step in the development of hepatocellular carcinoma in patients with previous HBV infection.
        • If the HBV infection has occurred in adulthood, approximately 1% of the patients also clears the HBsAg and becomes HBsAb-positive. Because previous liver damage has occurred in these patients, they are usually left with some degree of cirrhosis. These individuals account for some of the patients with cryptogenic cirrhosis.
        • In some patients, chronic HBV infection remains in the viral replicative stage. This may be continuous, with positive HBeAg titers; or intermittent or low grade, with undetectable HBeAg. The latter pattern is more common in the Far East and with HBV infection early in life.
        • In 10% to 30% of the patients with chronic HBV hepatitis, cirrhosis develops accompanied by its complications of portal hypertension, esophageal varices, ascites, and encephalopathy. The level of IgM HBcAb correlates with the activity of the chronic hepatitis. High titers are found in severe exacerbations, moderate titers in moderately active disease, and low titers in mild cases. Patients who are healthy HBsAg carriers with no evidence of active liver disease have no detectable IgM HBcAb titers.
      • The determining factors for development of chronic hepatitis after HBV infection are (a) the age of the individual when initially infected, (b) the immune status of the host, (c) gender, and (d) the severity of the acute infection.

Ninety to ninety-five percent of infected neonates and about 30% of children but only 1% to 10% of adults develop chronic disease. Women are less affected than men, and the disease becomes chronic much more frequently in patients undergoing hemodialysis and in other intrinsically or iatrogenically immunocompromised patients. The severity of the initial disease appears to have little predictive value when the age of onset and the host immune status are taken into account.

      • Reactivation of quiescent chronic HBV infection occurs spontaneously or, more frequently, in individuals following the withdrawal of immunosuppressive drugs (e.g., chemotherapy, steroids, organ transplantation). In some patients, reactivation may precipitate fulminant hepatic necrosis. Most individuals with reactivation have positive HBsAg titers without positive HBeAg titers. In some patients, if the prior presence of HBsAg was not known due to subclinical acute disease, reactivation may be regarded as the initial acute infection. In these individuals, HBeAg, DNA, DNAP, and IgM HBcAb all may become positive. The initial loss of HBeAg in the carrier does not necessarily represent resolution of the infection, which suggests that HBV infection may become latent as the herpesvirus infections do. Recent data suggest that HBV may infect and reside quietly in the lymphocytes in the spleen of previously infected individuals.
      • HBV mutants. HBV polymerase is an RNA/DNA transcriptase that lacks a proofreading function. During viral replication, it frequently transcribes its template incorrectly, creating mutant viruses. Many of these mutants are incapable of forming infectious virions. However, several infectious HBV mutants have been identified by PCR. One of these mutants contains a point mutation in the gene coding the surface protein in the highly antigenic a determinant of HBsAg. This mutation alters the antigenic properties of the HBV, allowing it to escape the protective effects of the HBV vaccine.

Another mutant of HBV has been identified in patients who have active hepatitis B but lack HBcAg. These hepatitis B virions have a point mutation


in the precore gene. This mutation prevents the synthesis of the precore-core protein and abolishes the formation of HBcAg, which modulates viral infection. Lack of HBcAg expression on the infected hepatocytes prevents immunologic recognition and destruction of these infected cells, resulting in chronic active hepatitis.

      • Superinfection. HBV carriers may develop hepatic superinfections with other hepatotropic viruses. Sudden increases in the serum transaminases may represent superinfection with HAV, HCV, or HDV.
        • HAV infection may be a superinfection or simultaneous coinfection and is usually associated with more severe and fulminant hepatitis.
        • HCV superinfections may be difficult to document accurately due to the delay of detectability of HCAb in acute HCV infections. However, the diagnosis can be made in the face of increased serum transaminases with reduction of HBsAg titers due to viral interference, and negative tests for IgM HBcAb, IgM HAV, and anti-HDV. HCAb titers should be measured again in ongoing hepatitis.
        • HDV superinfection is discussed in section V.
        • Nonviral causes. It should always be kept in mind that sudden increases in the serum transaminases may result from nonviral causes, such as drug and alcohol hepatotoxicity, shock, congestive heart failure, right ventricular failure, and extrahepatic biliary obstruction.
      • Primary hepatocellular carcinoma (PHC). In the parts of the world where HBV infection is endemic (e.g., Far East, sub-Saharan Africa), PHC is the leading cause of death from cancer. It appears that persistent HBV infection is the leading cause of PHC. This suggests that HBV is an oncogenic virus.
        • Predisposing factors. Some of the predisposing factors for development of PHC are race (e.g., Asians, Inuits), age at infection (especially infancy and early childhood), chronic-persistent infection, and the presence of environmental cocarcinogenic factors, such as ingestion of ethanol, cigarette smoking, and possibly exposure to aflatoxin.
        • Pathogenesis. It is thought that the integration of HBV DNA into the DNA of the hepatocyte leads to alterations in cellular gene expression and cellular transformation. The resulting clones of transformed cells may become autonomous and form PHC.
        • Diagnosis. Early clinical detection of PHC is difficult. However, determination of elevation of serum alpha-fetoprotein (AFP) levels and


demonstration of a mass in the liver by ultrasonography (US), computed tomography (CT) scanning, or magnetic resonance imaging (MRI) are currently used with reasonable success. Tissue diagnosis can be made by needle biopsy of the liver under US or CT guidance.



Suggestive Features

Acute hepatitis B

IgM anti-HBc

Acute delta hepatitis (coinfection)

IgM anti-HBc and anti-HDV

Chronic hepatitis B with

Acute hepatitis A

IgM anti-HAV

Delta hepatitis (superinfection)


Acute hepatitis C



Change in HBV markers

Other acute liver injury

Drug or alcohol history


Evidence of other liver disease

HBc, hepatitis B core; HDV, hepatitis delta virus; HAV, hepatitis A virus; HCV, hepatitis C virus; HBV, hepatitis B virus.