Hepatitis B Virus : Clinical Features, Laboratory Diagnosis, and
Medical Management
HBV is a small, double-shelled virus in the family Hepadnaviridae. Other
Hepadnaviridae include duck hepatitis virus, ground squirrel hepatitis
virus, and woodchuck hepatitis virus. The virus has a small circular DNA
genome that is partially double-stranded. HBV contains numerous antigenic
components, including HBsAg, hepatitis B core antigen (HBcAg), and
hepatitis B e antigen (HBeAg). Humans are the only known host for HBV,
although some nonhuman primates have been infected in laboratory
conditions. HBV is relatively resilient and, in some instances, has been
shown to remain infectious on environmental surfaces for more than 7 days
at room temperature.
An estimated 2 billion persons worldwide have been infected with HBV, and
more than 350 million persons have chronic, lifelong infections. HBV
infection is an established cause of acute and chronic hepatitis and
cirrhosis. It is the cause of up to 50% of hepatocellular carcinomas (HCC).
The World Health Organization estimated that more than 600,000 persons died
worldwide in 2002 of hepatitis B-associated acute and chronic liver
disease. Several well-defined antigen–antibody systems are associated with
HBV infection. HBsAg, formerly called Australia antigen or
hepatitis-associated antigen, is an antigenic determinant found on the
surface of the virus. It also makes up subviral 22-nm spherical and tubular
particles. HBsAg can be identified in serum 30 to 60 days after exposure to
HBV and persists for variable periods. HBsAg is not infectious. Only the
complete virus (Dane particle) is infectious.
During replication, HBV
produces HBsAg in excess of that needed for production of Dane particles.
HBsAg is antigenically heterogeneous, with a common antigen (designated a)
and 2 pairs of mutually exclusive antigens (d, y, w [including several
subdeterminants] and r), resulting in 4 major subtypes: adw, ayw, adr and
ayr. The distribution of subtypes varies geographically; because of the
common “a” determinant, protection against one subtype appears to confer
protection against the other subtypes, and no differences in clinical
features have been related to subtype.
HBcAg is the nucleocapsid protein core of HBV. HBcAg is not detectable in
serum by conventional techniques, but it can be detected in liver tissue of
persons with acute or chronic HBV infection. HBeAg, a soluble protein, is
also contained in the core of HBV. HBeAg is detected in the serum of
persons with high virus titers and indicates high infectivity. Antibody to
HBsAg (anti-HBs) develops during convalescence after acute HBV infection or
following hepatitis B vaccination. The presence of anti-HBs indicates
immunity to HBV. (Anti-HBs is sometimes referred to as HBsAb, but use of
this term is discouraged because of potential confusion with HBsAg.)
Antibody to HBcAg (anti-HBc) indicates infection with HBV at an undefined
time in the past. IgM class antibody to HBcAg (IgM anti-HBc) indicates
recent infection with HBV. Antibody to HBeAg (anti-HBe) becomes detectable
when HBeAg is lost and is associated with low infectivity of serum.
Genotype classification based on sequencing of genetic material has been
introduced and is becoming the standard: HBV is currently classified into 8
main genotypes (A–H). HBV genotypes are associated with the modes of HBV
transmission (vertical vs. horizontal) and with the risk of certain
outcomes of chronic infection, such as cirrhosis and HCC. In Alaska, HBV
genotype F is associated with HCC in young children as well as adults
younger than 30 years of age. In Asia as well as Alaska, HBV genotype C has
been associated with a significantly higher risk of HCC than other
genotypes.
Clinical Features
The clinical course of acute hepatitis B is indistinguishable from that of other types of acute viral hepatitis. The incubation period ranges from 45 to 160 days (average,120days). Clinical signs and symptoms occur more often in adults than in infants or children, who usually have an asymptomatic acute course. However, approximately 50% of adults who have acute infections are asymptomatic.
The preicteric, or prodromal phase from initial symptoms to onset of jaundice usually lasts from 3 to l0 days. It is nonspecific and is characterized by insidious onset of malaise, anorexia, nausea, vomiting, right upper quadrant abdominal pain, fever, headache, myalgia, skin rashes, arthralgia and arthritis, and dark urine, beginning 1 to 2 days before the onset of jaundice. The icteric phase is variable but usually lasts from l to 3 weeks and is characterized by jaundice, light or gray stools, hepatic tenderness and hepatomegaly (splenomegaly is less common). During convalescence, malaise and fatigue may persist for weeks or months, while jaundice, anorexia, and other symptoms disappear.
Most acute HBV infections in adults result in complete recovery with elimination of HBsAg from the blood and the production of anti-HBs, creating immunity to future infection.
Complications
While most acute HBV infections in adults result in complete recovery, fulminant hepatitis occurs in about 1% to 2% of acutely infected persons. About 200 to 300 Americans die of fulminant disease each year (case-fatality rate 63% to 93%). Although the consequences of acute HBV infection can be severe, most of the serious complications associated with HBV infection are due to chronic infection.
Chronic HBV Infection
The proportion of patients with acute HBV Infection who progress to chronic infection varies with age and immune status. As many as 90% of infants who acquire HBV infection from their mothers at birth or in infancy become chronically infected. Of children who become infected with HBV between 1 year and 5 years of age, 30% to 50% become chronically infected. By adulthood, the risk of acquiring chronic HBV infection is approximately 5%. Acute HBV progresses to chronic HBV in approximately 40% of hemodialysis patients and up to 20% of patients with immune deficiencies.
Persons with chronic infection are often asymptomatic and may not be aware that they are infected; however, they are capable of infecting others and have been referred to as carriers.
Chronic infection is responsible for most HBV-related morbidity and mortality, including chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Approximately 25% of persons with chronic HBV infection die prematurely from cirrhosis or liver cancer. Chronic active hepatitis develops in more than 25% of carriers and often results in cirrhosis. An estimated 3,000 to 4,000 persons die of hepatitis B-related cirrhosis each year in the United States. Persons with chronic HBV infection are at 12 to 300 times higher risk of hepatocellular carcinoma than noncarriers. An estimated 1,000 to 1,500 persons die each year in the United States of hepatitis B-related liver cancer.
Laboratory Diagnosis
Diagnosis is based on clinical, laboratory, and epidemiologic findings. HBV infection cannot be differentiated on the basis of clinical symptoms alone, and definitive diagnosis depends on the results of serologic testing. Serologic markers of HBV infection vary depending on whether the infection is acute or chronic.
HBsAg is the most commonly used test for diagnosing acute HBV infections or detecting carriers. HBsAg can be detected as early as 1 or 2 weeks and as late as 11 or 12 weeks after exposure to HBV when sensitive assays are used. The presence of HBsAg indicates that a person is infectious, regardless of whether the infection is acute or chronic.
Anti-HBc (core antibody) develops in all HBV infections, appears shortly after HBsAg in acute disease, and indicates HBV infection at some undefined time in the past. Anti-HBc only occurs after HBV infection and does not develop in persons whose immunity to HBV is from vaccine. Anti-HBc generally persists for life and is not a serologic marker for acute infection.
IgM anti-HBc appears in persons with acute disease about the time of illness onset and indicates recent infection with HBV. IgM anti-HBc is generally detectable 4 to 6 months after onset of illness and is the best serologic marker of acute HBV infection. A negative test for IgM-anti-HBc together with a positive test for HBsAg in a single blood sample identifies a chronic HBV infection. HBV DNA assays are used to monitor response to treatment, assess the likelihood of maternal-to-child transmission of HBV, and to detect the presence of occult HBV infection (i.e. infection in someone who tests HBsAg negative).
HBeAg is a useful marker associated strongly with the number of infective HBV particles in the serum and a higher risk of infectivity.
Medical Management
There is no specific therapy for acute HBV infection. Treatment is supportive.
Two major groups of antiviral treatment have been licensed for the treatment of chronic HBV infection in many countries. These include interferon alpha (IFNa, or PEG-IFNa) and nucleoside or nucleotide analogues such as lamivudine, adefovir, entecavir telbivudine, and tenofovir. Many other drugs are being evaluated. Although the decision to treat and choosing the appropriate therapy remain challenging, considerable progress has been made in the treatment of persons with chronic HBV infection.
Patients generally are considered for treatment when they have HBV DNA levels above 2000 IU/ml, serum alanine aminotransferase levels above the upper limit of normal, and severity of liver disease assessed by liver biopsy (or non-invasive markers once validated in HBV-infected patients) showing moderate to severe active necroinflammation and/or at least moderate fibrosis using a standardized scoring system. The majority of patients will require prolonged treatment in order to maintain suppression of viral replication. Consequently, treatment costs in both developing and developed countries are currently prohibitively high. The efficacy of combination therapy will have to be studied further, but it is likely to diminish the occurrence of virus mutants resistant to treatment. Medications have significant side effects that require careful monitoring.
Persons with acute or chronic HBV infections should prevent their blood and other potentially infective body fluids from contacting other persons. They should not donate blood or share toothbrushes or razors with household members.
In the hospital setting, patients with HBV infection should be managed with standard precautions.
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