Hepatitis B
The disease
- Diagnosis
- Host immune response
- Prevalence
- Pathogenesis
- Transmission
- Risk groups
The course of hepatitis B may be extremely variable.31 Hepatitis B virus infection has different clinical manifestations depending on the patient’s age at infection and immune status, and the stage at which the disease is recognized.
During the incubation phase of the disease (6 to 24 weeks), patients may feel unwell with possible nausea, vomiting, diarrhea, anorexia and headaches. Patients may then become jaundiced although low grade fever and loss of appetite may improve. Sometimes HBV infection produces neither jaundice nor obvious symptoms.15, 31
The asymptomatic cases can be identified by detecting biochemical or virus-specific serologic alterations in their blood. They may become silent carriers of the virus and constitute a reservoir for further transmission to others.
Most adult patients recover completely from their HBV infection, but others, about 5 to 10%, will not clear the virus and will progress to become asymptomatic carriers or develop chronic hepatitis possibly resulting in cirrhosis and/or liver cancer.31 Rarely, some patients may develop fulminant hepatitis and die.
People who develop chronic hepatitis may develop significant and potentially fatal disease.31
In general, the frequency of clinical disease increases with age, whereas the percentage of carriers decreases.
Worldwide, about 1 million deaths occur each year due to chronic forms of the disease.39
Persistent or chronic HBV infection is among the most common persistent viral infections in humans. More than 350 million people in the world today are estimated to be persistently infected with HBV. A large fraction of these are in eastern Asia and sub-Saharan Africa, where the associated complications of chronic liver disease and liver cancer are the most important health problems.31
A small number of long-established chronic carriers apparently terminate their active infection and become HBsAg-negative (about 2%/year).
Survivors of fulminant hepatitis rarely become infected persistently, and HBsAg carriers frequently have no history of recognized acute hepatitis.
Click here for: Spectrum of liver disease after HBV infection
Click here for: Clinical phases of acute hepatitis B infection
Click here for: Clinical features of chronic hepatitis B
Click here for: HBV and hepatocellular carcinoma (HCC)
Click here for: Progression to fulminant hepatitis B
Click here for: Extrahepatic manifestations of hepatitis B
Click here for: Coinfection or superinfection with HDV
Click here for: Patterns of viral infection
Click here for: Serological markers of HBV infection
Diagnosis
Large-scale screening for HBV infection
Diagnosis of hepatitis is made by biochemical assessment of liver function. Initial laboratory evaluation should include: total and direct bilirubin, ALT, AST, alkaline phosphatase, prothrombin time, total protein, albumin, serum globulin, complete blood count, and coagulation studies.15, 31
Diagnosis is confirmed by demonstration in sera of specific antigens and/or antibodies. Three clinical useful antigen-antibody systems have been identified for hepatitis B:
- hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs)
- antibody (anti-HBc IgM and anti-HBc IgG) to hepatitis B core antigen (HBcAg)
- hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe)
Tests specific for complete virus particles or DNA and DNA polymerase-containing virions, and for hepatitis Delta antigen (HDAg) and hepatitis Delta virus (HDV) RNA in liver and serum are available only in research laboratories.31
HBsAg can be detected in the serum from several weeks before onset of symptoms to months after onset. HBsAg is present in serum during acute infections and persists in chronic infections. The presence of HBsAg indicates that the person is potentially infectious.15, 23, 31
Very early in the incubation period, pre-S1 and pre-S2 antigens are present. They are never detected in the absence of HBsAg. Hepatitis B virions, HBV DNA, DNA polymerase, and HBeAg are then also detected. The presence of HBeAg is associated with relatively high infectivity and severity of disease.15, 31
Anti-HBc is the first antibody to appear. Demonstration of anti-HBc in serum indicates HBV infection, current or past. IgM anti-HBc is present in high titre during acute infection and usually disappears within 6 months, although it can persist in some cases of chronic hepatitis. This test may therefore reliably diagnose acute HBV infection. IgG anti-HBc generally remains detectable for a lifetime.15, 23, 31
Anti-HBe appears after anti-HBc and its presence correlates to a decreased infectivity. Anti-HBe replaces HBeAg in the resolution of the disease.15, 23, 31
Anti-HBs replaces HBsAg as the acute HBV infection is resolving. Anti-HBs generally persists for a lifetime in over 80% of patients and indicates immunity.15, 23, 31
Acute hepatitis patients who maintain a constant serum HBsAg concentration, or whose serum HBeAg persists 8 to 10 weeks after symptoms have resolved, are likely to become carriers and at risk of developing chronic liver disease.15
A complication in the diagnosis of hepatitis B is the rare identification of cases in which viral mutations change the antigens so they are not detectable.
Small-scale screening for HBV infection
Immunofluorescence studies, in situ hybridization, immunohistochemistry, and thin-section electron microscopy are used to examine pathological specimens for the presence of HBV-associated antigens or particles, providing information about the relationship between HBV DNA replication and HBV gene expression.15
Within the hepatocyte, HBsAg localizes in the cytoplasm, and HBcAg is seen in the nucleus and/or the cytoplasm. Detection of complete virions in the liver is uncommon.15
DNA hybridization techniques and RT-PCR assays have shown that almost all HBsAg/HBeAg-positive patients have detectable HBV DNA in their serum, whereas only about 65% of the HBsAg/anti-HBe-reactive patients are positive. All patients who recover from acute hepatitis B are negative for HBV DNA. On the other hand, some patients infected chronically who have lost their HBsAg remain HBV DNA positive.15, 31
Click here for: HBV serological markers in hepatitis patients
Host immune response
There is little evidence that humoral immunity plays a major role in the clearance of established infection. Cell-mediated immune responses, particularly those involving cytotoxic T-lymphocytes (CTLs), seem to be very important.30, 31
CD8-positive, class I major histocompatibility complex (MHC)-restricted CTLs directed against HBV nucleocapsid proteins are present in the peripheral blood of patients with acute, resolving hepatitis B. Such cells are barely detectable in the blood of patients with chronic HBV infection, suggesting that the inability to generate such cells may predispose to persistent infection, although their absence from the blood in chronic infection may be due to their sequestration elsewhere.
CTLs against envelope glycoprotein determinants, that are often CD4-positive, class II MHC-restricted, have also been detected.
Primary infection leads to an IgM and IgG response to HBcAg shortly after the appearance of HBsAg in serum, at onset of hepatitis. Anti-HBs and anti-HBe appear in serum only several weeks later, when HBsAg and HBeAg are no longer detected, although in many HBsAg-positive patients, HBsAg-anti-HBs complexes can be found in serum.23, 30, 31
Click here for: Serological markers of HBV infection
Click here for: Serological test findings at different stages of HBV infection and in convalescence
Click here for: Serological and clinical patterns of acute and chronic HBV infections
Click here for: Interpretation of hepatitis B markers
Click here for: Discordant or unusual hepatitis B serological profiles requiring further evaluation
Prevalence
HBV occurs worldwide.23, 31
The highest rates of HBsAg carrier rates are found in developing countries with primitive or limited medical facilities.23
In areas of Africa and Asia, widespread infection may occur in infancy and childhood. The overall HBsAg carrier rates may be 10 to 15%.
The prevalence is lowest in countries with the highest standards of living, such as Great Britain, Canada, United States, Scandinavia, and some other European Nations.
In North America infection is most common in young adults. In the USA and Canada, serological evidence of previous infection varies depending on age and socioeconomic class. Overall, 5% of the adult USA population has anti-HBc, and 0.5% are HBsAg positive.
In developed countries, exposure to HBV may be common in certain high-risk groups (see section on Risk groups).
Adults infected with HBV usually acquire acute hepatitis B and recover, but 5 to 10% develop the chronic carrier state. Infected children rarely develop acute disease, but 25 to 90% become chronic carriers. About 25% of carriers will die from cirrhosis or primary liver cancer as adults.3, 23
In the past, recipients of blood and blood products were at high risk (for HBV infection). Over the last 25 years, testing blood donations for HBsAg has became a universal requirement. Testing procedures have made major progress in sensitivity in the last 15-20 years. However 19% of countries reported that they were not testing all blood donations for HBsAg (WHO Global Database on Blood Safety, unpublished data). In the many countries where pretransfusion screening of blood donations for HBsAg is carried out systematically, the residual risk of HBV transmission is minimal. Moreover, plasma derived medicinal products (including antihaemophilic factors) undergo additional viral inactivation and removal procedures resulting in greatly reduced or no transmission of HBV by these products.
However, the risk is still present in many developing countries. Contaminated and inadequately sterilized syringes and needles have resulted in outbreaks of hepatitis B among patients in clinics and physicians’ offices. Occasionally, outbreaks have been traced to tattoo parlors and acupuncturists. Rarely, transmission to patients from HBsAg positive health care workers has been documented.41
Reductions in the age-related prevalence of HBsAg in countries where hepatitis B is highly endemic and universal immunization of infants has been adopted suggest that it may be possible to eradicate HBV from humans.
Hepatitis B vaccines have been available since 1982 and have been used in hundreds of millions of individuals with an outstanding record of safety and impact on the disease. Carriage of HBV has already been reduced from high prevalence to low prevalence in immunized cohorts of children in many countries.
Click here for: Prevalence of hepatitis B in various areas
Pathogenesis
HBV infection contracted early in life may lead to chronic hepatitis, then to cirrhosis, and finally to HCC, usually after a period of 30 to 50 years. Once infected with HBV, males are more likely to remain persistently infected than women, who are more likely to be infected transiently and to develop anti-HBs.
It is possible that in man HBV is not carcinogenic by a direct viral mechanism. Instead, the role of HBV may be to cause chronic liver cell damage with associated host responses of inflammation and liver regeneration that continues for many years. This pathological process, especially when leading to cirrhosis, may be carcinogenic without involving a direct oncogenic action of the virus. No viral oncogene, insertional mutagenesis, or viral activation of oncogenic cellular genes has been demonstrated.30
The expression of HBV proteins and the release of virions precedes biochemical evidence of liver disease. Moreover, large quantities of surface antigen can persist in liver cells of many apparently healthy persons who are carriers. HBV is therefore not directly cytopathic.6
Three mechanisms seem to be involved in liver cell injury during HBV infections.
The first is an HLA class I restricted cytotoxic T-cell (CTL) response directed at HBcAg/HBeAg on HBV-infected hepatocytes.23, 30, 31
A second possible mechanism is a direct cytopathic effect of HBcAg expression in infected hepatocytes.23, 30, 31
A third possible mechanism is high-level expression and inefficient secretion of HBsAg.31
Click here for: Hypothetical course of hepatitis virus (HBV) immunopathogenesis
Transmission
Currently, there are four recognized modes of transmission:15, 39
1. From mother to child at birth (perinatal)
2. By contact with an infected person (horizontal)
3. By sexual contact
4. By parenteral (blood-to-blood) exposure to blood or other infected fluids.
There is considerable variation between areas, countries and continents as to the age at which most transmission takes place.
There can be carriers with or without hepatitis.31
There is no convincing evidence that airborne infections occur and faeces are not a source of infection, since the virus is inactivated by enzymes of the intestinal mucosa or derived from the bacterial flora. HBV is not transmitted by contaminated food or water, insects or other vectors.15, 31
HBsAg has been found in all body secretions and excretions. However, only blood, vaginal and menstrual fluids, and semen have been shown to be infectious.15, 23, 30, 31
Transmission occurs by percutaneous and permucosal exposure to infective body fluids. Percutaneous exposures that have resulted in HBV transmission include transfusion of unscreened blood or blood products, sharing unsterilized injection needles for iv drug use, haemodialysis, acupuncture, tattooing and injuries from contaminated sharp instruments sustained by hospital personnel.15, 23, 31
Sexual and perinatal HBV transmission usually result from mucous membrane exposures to infectious blood and body fluids. Perinatal transmission is common in hyperendemic areas of south-east Asia and the far East, especially when HBsAg carrier mothers are also HBeAg positive.15, 23, 31
Infection may also be transmitted between household contacts and between sexual partners, either homosexual or heterosexual, and in toddler-aged children in groups with high HBsAg carrier rates.15, 23
Immune globulins, heat-treated plasma protein fraction, albumin and fibrinolysin are considered safe when manufactured appropriately.
HBV is stable on environmental surfaces for at least 7 days, and indirect inoculation of HBV can occur via inanimate objects like toothbrushes, baby bottles, toys, razors, eating utensils, hospital equipment and other objects, by contact with mucous membranes or open skin breaks.31
Infectious HBV can be present in blood without detectable HBsAg, so that the failure to detect antigen does not exclude the presence of infectious virus.32
The source of infection cannot be identified in about 35% of cases.
The natural reservoir for HBV is man.38 Closely related hepadnaviruses have been found in woodchucks and ducks, but they are not infectious for humans.10
The reuse of the same, unsterilized needle and syringe for vaccination of many different children accounts for many unnecessary HBV infections.31, 41
People depending on repeated transfusion should be vaccinated against HBV.
HBV is about 100 times more infectious than HIV.38
Risk groups
Here is a list of groups of people who are at risk of contracting HBV:15, 31
-
infants born to infected mothers
-
young children in day-care or residential settings with other children in endemic areas
-
sexual/household contacts of infected persons
-
health care workers
-
injection drug users sharing unsterile needles41
-
people sharing unsterile medical or dental equipment
-
people providing or receiving acupuncture and/or tattooing with unsterile medical devices
-
persons living in regions or travelling to regions with endemic hepatitis B50
-
sexually active heterosexuals
-
men who have sex with men
Frequent and routine exposure to blood or serum is the common denominator of healthcare occupational exposure. Surgeons, dentists, oral surgeons, pathologists, operating room and emergency room staff, and clinical laboratory workers who handle blood are at the highest risk.31
HBV infection is the major residual posttransfusion risk in developed countries because of the long window period, HBV mutants, the low viraemia (difficulties for PCR on pooled samples) and the very high infectivity.
Over one-third of patients with acute hepatitis B do not have readily identifiable risk factors.3
Efforts to vaccinate persons in the major risk groups have had limited success because of the difficulties in identifying candidates belonging to high risk groups. Moreover, regulations have to be developed to ensure implementation of vaccination programs.3, 37
High risk persons should be post-tested within 1-2 months of receipt of the third dose of HBV vaccine, to identify good responders to vaccination. This policy is cost-saving since adequate responders do not need to be retested or given HBIG whenever they later are exposed to HBV. They also do not need to be offered booster doses of vaccine periodically.
Spectrum of liver disease after HBV infection
From: Chisari FV, Ferrari C. Viral Hepatitis. In: Nathanson N et al., eds. Viral Pathogenesis,
The infecting dose of
Only a small proportion of acute HBV infections are recognized clinically. Less than 10% of children and 30-50% of adults with acute HBV infection will have
Primary HBV infection may be associated with little or no liver disease or with acute hepatitis of severity ranging from mild to
HBV infection is transient in about 90% of adults and 10% of newborn, and persistent in the remainder.
Most cases of acute hepatitis are subclinical, and less than 1% of symptomatic cases are
Worldwide, about 350 million people are estimated to be infected chronically with HBV.
Persistent HBV infection is sometimes associated with histologically normal liver and normal liver function, but about one third of chronic HBV infections are associated with
Clinical phases of acute hepatitis B infection
The acute form of the disease often resolves spontaneously after a 4-8 week illness. Most patients recover without significant consequences and without recurrence. However, a favourable prognosis is not certain, especially in the elderly who can develop fulminating, fatal cases of acute hepatic necrosis. Young children rarely develop acute clinical disease, but many of those infected before the age of seven will become chronic
The incubation period varies usually between 45 and 120 days, with an average of 60 to 90 days. The variation is related to the amount of
The hallmark of acute viral hepatitis is the striking elevation in
In patients with clinical illness, the onset is usually insidious with tiredness, anorexia, vague abdominal discomfort, nausea and vomiting, sometimes
The icteric phase of acute viral hepatitis begins usually within 10 days of the initial symptoms with the appearance of dark urine followed by pale stools and yellowish discoloration of the mucous membranes, conjunctivae, sclerae, and skin.
The larger the
In most cases, no special treatment or diet is required, and patients need not be confined to bed.
Acute hepatitis B is characterized by the presence of
A small percentage of persons die from acute HBV.
Clinical features of chronic hepatitis B
increase, and moderate inflammatory activity is histologically apparent. The risk of evolving to
Low replicative phase. This phase is associated with the loss of
Nonreplicative phase. Markers of viral replication are either absent or below detection level, and the inflammation is diminished. However, if
The laboratory abnormalities consist of elevation of the
Sustained increases in the concentrations of the aminotransferases together with the presence of
Up to 20% of the chronic persistent hepatitis cases progress to
In
Therefore, most
Globally, HBV causes 60 - 80% of the world’s primary liver cancers.
It is estimated that, in men, the lifetime risk of death from chronic disease which leads to
HBV and hepatocellular carcinoma (HCC)
A number of HBV patients with chronic hepatitis will develop hepatocellular
The
Patients who develop HCC as a result of malignant transformation of
When
HBV causes 60-80% of the world’s primary liver cancer, and primary liver cancer is one of the three most common causes of cancer deaths in males in East and
Primary liver cancer is the eighth most common cancer in the world.
Progression to fulminant hepatitis B
Survival in adults is uncommon, prognosis for children is rather better. Remarkably, the few survivors usually recover completely without permanent liver damage and no chronic infection.
Patients infected with precore mutants often manifest severe chronic hepatitis, early progression with
Genetic heterogeneity of HBV, coinfection or superinfection with other viral hepatitis agents, or host immunological factors, may be associated with the development of
A rapid fall in
Extrahepatic manifestations of hepatitis B
Extrahepatic manifestations of hepatitis B are seen in 10-20% of patients as
- transient
with fever (<39°C), skin rash (erythematous, macular, macopapular, urticarial, nodular, or petechial lesions), polyarthritis (acute articular symmetrical inflammation, painful, fusiform swelling of joints of hand and knee, morning stiffness. Symptoms usually precede the onset of
Immune complexes (e.g. surface
- acute necrotizing vasculitis (polyarteritis nodosa)
with high fever, anemia, leucocytosis,
- membranous glomerulonephritis
is present in both adults and children. Remission of nephropathy occurs in 85 to 90% of cases over a period of 9 years and is associated with clearance of
- papular acrodermatitis of childhood (Gianotti-Crosti syndrome)
a distinctive disease of childhood. Skin lesions, lentil-sized, flat, erythematous, and papular eruptions localized to the face and extremities, last 15 to 20 days. The disease is accompanied by generalized lymphadenopathy, hepatomegaly, and acute anicteric hepatitis B of ayw subtype.
Immune complexes have been found in the
Why only a small proportion of patients with circulating complexes develop vasculitis or polyarteritis is still not clear.
Coinfection or superinfection with HDV
Hepatitis Delta
Routes of transmission are similar to those of HBV.
Preventing acute and chronic HBV infection of susceptible persons by vaccination will also prevent HDV infection.
Lamivudine, an inhibitor of HBV-DNA replication, is not beneficial for the treatment of chronic hepatitis D.
Several patterns of infection define the spectrum of responses to HBV.
Self-limited
From: Robinson WS. Hepatitis B virus and hepatitis D virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill Livingstone, 1995:1406-1439,
Figure 1. Schematic representation of viral markers in the blood through a typical course of self-limited
This is the most common pattern of primary infection in adults.
Self-limited primary infection without detectable
From: Robinson WS. Hepatitis B virus and hepatitis D virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill Livingstone, 1995:1406-1439,
Figure 2. Schematic representation of the serologic response through a typical course of
A significant number of patients with acute self-limited primary HBV infection never have detectable
From: Robinson WS. Hepatitis B virus and hepatitis D virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill Livingstone, 1995:1406-1439,
Figure 3. Schematic representation of viral markers in the blood through a typical course of HBV infection that becomes persistent.
Patients who remain HBsAg-positive for 20 weeks or longer after primary infection are very likely to remain positive indefinitely and be designated chronic HBsAg
Serological markers of HBV infection
During HBV infection, the serological markers vary depending on whether the infection is acute or chronic.
Hepatitis B surface Its specific This is the specific Hepatitis B core Its specific This is the specific Hepatitis B e Persistence of this virological marker beyond 10 weeks shows progression to chronic infection and infectiousness. Continuous presence of Its specific This is the specific HBxAg Hepatitis B x Its specific anti-HBx This is the specific HBV DNA HBV DNA is detectable by hybridization assays or HBV DNA Tests for the presence of HBV DNA
HBV serological markers in hepatitis patients
The three standard blood tests for hepatitis B can determine if a person is currently infected with HBV, has recovered, is a chronic
Assay results Interpretation anti-HBs anti-HBc + - - Early acute HBV infection + +/- + Acute or chronic HBV infection. Differentiate with - + + Indicates previous HBV infection and immunity to hepatitis B. - - + Possibilities include: past HBV infection; low-level HBV - - - Another infectious agent, toxic injury to the liver, disorder of immunity, hereditary disease of the liver, or disease of the biliary tract. - + - v
HBsAg
From: Hollinger FB, Liang TJ. Hepatitis B Virus. In: Knipe DM et al., eds. Fields Virology, 4th ed., Philadelphia, Lippincott Williams &Wilkins, 2001:2971-3036,
Interpretation of HBV serologic markers in patients with hepatitis.
Serological test findings at different stages of HBV infection and in convalescence
Stage of infection late incubation period + - - + or - - acute hepatitis B or persistent + - + + + - - - - + - - recovery with loss of detectable - - + - - - healthy + - +++ + or - - + chronic hepatitis B, persistent + - +++ + or - + - HBV infection in recent past, convalescence - ++ ++ + or - - + HBV infection in distant past, recovery - + or - + or - - - - recent HBV vaccination, repeated exposure to - ++ - - - -
From: Robinson WS. Hepatitis B virus and hepatitis D virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill Livingstone, 1995:1406-1439,
Hepatitis B virus serological markers in different stages of infection and convalescence.
Serological and clinical patterns of acute or chronic HBV infections
acute HBV infection
From: Mahoney FJ, Kane M. Hepatitis B vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia, W.B. Saunders Company, 1999:158-182,
chronic HBV infection
From: Mahoney FJ, Kane M. Hepatitis B vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia, W.B. Saunders Company, 1999:158-182,
Discordant or unusual hepatitis B serological profiles requiring further evaluation
Repeat testing of the same sample or possibly of an additional sample is advisable when tests yield discordant or unusual results.
An Uncommon, may occur during resolution of acute hepatitis B, in chronic Past infection not resolved completely Unusual It may be a result of passive transfer of anti-HBs after transfusion of blood from a vaccinated donor, in patients receiving clotting factors, after Passively acquired Apparently quite common when person has forgotten his/her immunization status!
Mutant
Prevalence of hepatitis B in various areas
% of population positive for infection Area neonatal childhood Northern, Western, and Central 0.2-0.5 4-6 rare infrequent 2-7 20-55 frequent frequent Parts of China, Southeast Asia, tropical Africa 8-20 70-95 very frequent very frequent
From: Zuckerman AJ. Hepatitis Viruses. In: Baron S, eds. Medical Microbiology, 4th ed. Galveston, TX, The University of Texas Medical Branch at Galveston, 1996:849-863,
Hypothetical course of immunopathogenesis of hepatitis B virus (HBV)
From: Chisari FV, Ferrari C. Viral Hepatitis. In: Nathanson N et al., eds. Viral Pathogenesis,
Eradication of HBV infection depends on the coordinate and efficient development of