Emergencies preparedness, response

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

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

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

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

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

  • patients and employees in haemodialysis centres4, 41

  • 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, Philadelphia, Lippincott - Raven, 1997:745-778,6 with permission (http://lww.com).

The infecting dose of virus and the age of the person infected are important factors that correlate with the severity of acute or chronic hepatitis B.23, 31

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 icteric disease.51

Primary HBV infection may be associated with little or no liver disease or with acute hepatitis of severity ranging from mild to fulminant.31

HBV infection is transient in about 90% of adults and 10% of newborn, and persistent in the remainder.23

Most cases of acute hepatitis are subclinical, and less than 1% of symptomatic cases are fulminant.31

Worldwide, about 350 million people are estimated to be infected chronically with HBV.39

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 cirrhosis and HCC.31

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 carriers.6, 15, 23, 30, 31

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 virus in the inoculum, the mode of transmission and host factors.6, 15, 23, 31

The hallmark of acute viral hepatitis is the striking elevation in serum transaminase (aminotransferase) activity. The increase in aminotransferases, especially ALT, during acute hepatitis B varies from a mild/moderate increase of 3- to 10-fold to a striking increase of >100-fold. The latter does not necessarily imply a poor prognosis.

In patients with clinical illness, the onset is usually insidious with tiredness, anorexia, vague abdominal discomfort, nausea and vomiting, sometimes arthralgias and rash, often progressing to jaundice. Fever may be absent or mild.6, 15, 23, 31

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. Jaundice becomes apparent clinically when the total bilirubin level exceeds 20 to 40 mg/l.  It is accompanied by hepatomegaly and splenomegaly. About 4-12 weeks thereafter, the jaundice disappears and the illness resolves with the development of natural, protective antibodies (anti-HBs), in about 95% of adults.15

The larger the virus dose, the shorter the incubation period and the more likely that icteric hepatitis will result. The largest virus doses received by patients may occur in transfusions of infectious blood.31

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 anti-HBc IgM serum antibodies converting to IgG with convalescence and recovery, and the transient (<6 months) presence of HBsAg, HBeAg, and viral DNA, with clearance of these markers followed by seroconversion to anti-HBsAg and anti-HBeAg. More than 90% of adult-onset infection cases fall into this category. The remaining 5 to 10% of adult-onset infection and over 90% of cases of neonatal infection become chronic, and may continue for the life span of the patient.23

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 cirrhosis is high.

Low replicative phase. This phase is associated with the loss of HBeAg, or a decrease or loss of the HBV DNA concentrations, and with the appearance of anti-HBe. Histologically, a decrease in inflammatory activity is evident. Serologic changes like the loss of HBV DNA and HBeAg are referred to as seroconversion.

Nonreplicative phase. Markers of viral replication are either absent or below detection level, and the inflammation is diminished. However, if cirrhosis has already developed, it persists indefinitely. 

The laboratory abnormalities consist of elevation of the ALT, ranging from normal to 200 IU/l in up to 90% of patients. Transaminases, serum bilirubin, albumin, and gammaglobulin values are mild to markedly elevated, and autoimmune antibodies such as antinuclear antibody, anti-smooth muscle antibody and antimitochondrial antibody may be present.15

Sustained increases in the concentrations of the aminotransferases together with the presence of HBsAg for >6 months is regarded as indicative of chronic hepatitis.

Up to 20% of the chronic persistent hepatitis cases progress to cirrhosis. This a serious liver disease associated with chronic and often widespread destruction of liver substance occurring over a period of several years.

In cirrhosis, liver cells die and are progressively replaced with fibrotic tissue leading to nodule formation. The internal structure of the liver is deranged leading to the obstruction of blood flow and decrease in liver function. This damage is caused by recurrent immune responses stimulated by the presence of the virus. Because liver inflammation can be totally symptomless, progression of inflammation to cirrhosis can occur without the knowledge of the patient.

Therefore, most carriers are contagious but some are not. This is determined by the presence of HBV DNA.

Globally, HBV causes 60 - 80% of the world’s primary liver cancers.38

It is estimated that, in men, the lifetime risk of death from chronic disease which leads to cirrhosis and/or hepatocellular carcinoma is between 40 and 50%. In women the risk is about 15%, placing chronic hepatitis B infections among the 10 leading causes of death in men.

HBV and hepatocellular carcinoma (HCC)

A number of HBV patients with chronic hepatitis will develop hepatocellular carcinoma 15, 31. Persons at increased risk of developing HCC, who contracted hepatitis B in early childhood 23. Only about 5% of patients with cirrhosis develop HCC. On the other hand, between 60 and 90% of HCC patients have underlying cirrhosis.15, 30, 31

The incidence of HCC varies with geography, race, age, and sex. HCC is responsible for 90% of the primary malignant tumours of the liver observed in adults. Worldwide, it is the seventh most frequent cancer in males and ninth most common in females. Liver cancer is the cause of more than 500 000 deaths annually throughout the world, with a male:female ratio of 4:1. The frequency of HCC follows the same general geographic distribution pattern as that of persistent HBV infection. The age distribution of patients with clinically recognized tumours suggests that these tumours appear after a mean duration of about 35 years of HBV infection.15, 31

Patients who develop HCC as a result of malignant transformation of hepatocytes have a mean 5-year survival rate of 25 to 60%.15 This variation depends on the symptoms, the size of the tumour, its resectability, and the presence or absence of α-fetoprotein (AFP). Non-resectable tumours have a mean survival rate of 5 months for AFP-positive tumours and of 10.5 months for AFP-negative tumours.15

When serum α-fetoprotein (AFP) followed serially in HBsAg carriers rises significantly above the patient’s own baseline (>100 μg/ml), HCC can often be detected by liver scanning or ultrasound procedures at a stage when the tumour can be cured by surgical resection.31 This suggests that HBsAg carriers should have regular serial serum AFP determinations and ultrasound examinations (at 6 months intervals for those above 40 years). Both these tests are recommended to be repeated regularly for all HBsAg carriers with cirrhosis.31

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 South-east Asia, the Pacific Basin, and sub-Saharan Africa.31

Primary liver cancer is the eighth most common cancer in the world.31 Up to 80% of liver cancers are due to HBV. When HCC presents clinically, the disease is fatal. The median survival frequency of HCC patients is less than 3 months. However, if the cancer is detected early, there is a 85% chance of a cure. Treatment involves surgery, hepatic irradiation, and anticancer drugs. 

Progression to fulminant hepatitis B

Fulminant hepatitis B is a rare condition that develops in about 1% of cases. It is caused by massive necrosis of liver substance and is usually fatal.15, 23 

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.15, 31

Patients infected with precore mutants often manifest severe chronic hepatitis, early progression with cirrhosis, and a variable response to interferon therapy. It may have an association with fulminant hepatic failure.52

Genetic heterogeneity of HBV, coinfection or superinfection with other viral hepatitis agents, or host immunological factors, may be associated with the development of fulminant hepatitis B.15, 31

A rapid fall in ALT and AST in patients with fulminant hepatic failure may be erroneously interpreted as a resolving hepatic infection, when in fact hepatocytes are being lost and the outcome is fatal.11

Extrahepatic manifestations of hepatitis B

Extrahepatic manifestations of hepatitis B are seen in 10-20% of patients as

- transient serum sickness-like syndrome15, 23, 31

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 jaundice by a few days to 4 weeks and subside after onset of jaundice and may persist throughout the course of the disease. No recurrent or chronic arthritis occurs after recovery.

Immune complexes (e.g. surface antigen-antibody) are important in the pathogenesis of other disease syndromes characterized by severe damage of blood vessels:31

- acute necrotizing vasculitis (polyarteritis nodosa)15, 31

with high fever, anemia, leucocytosis, arthralgia, arthritis, renal disease, hypertension, heart disease, gastrointestinal disease, skin manifestations, neurologic disorders. Highly variable disease with mortality rate of 40% within 3 years unless treated. The diagnosis is established by angiography.

- membranous glomerulonephritis15, 31      

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 HBeAg from serum.

- papular acrodermatitis of childhood (Gianotti-Crosti syndrome)15  

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 sera of all patients with fulminant hepatitis, but are seen only infrequently in nonfulminant infections. Perhaps complexes are critical factors only if they are of a particular size or of a certain antigen-to-antibody ratio.52

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 virus (HDV) is a defective virus that is only infectious in the presence of active HBV infection. HDV infection occurs as either coinfection with HBV or superinfection of an HBV carrier. Coinfection usually resolves. Superinfection, however, causes frequently chronic HDV infection and chronic active hepatitis. Both types of infections may cause fulminant hepatitis.3, 31

Routes of transmission are similar to those of HBV.3

Preventing acute and chronic HBV infection of susceptible persons by vaccination will also prevent HDV infection.3, 23

Lamivudine, an inhibitor of HBV-DNA replication, is not beneficial for the treatment of chronic hepatitis D.22

Patterns of viral infection

Several patterns of infection define the spectrum of responses to HBV.31

Self-limited HBsAg-positive primary HBV infection

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, 1995:1406-1439,31 with permission.

Figure 1. Schematic representation of viral markers in the blood through a typical course of self-limited HBsAg-positive primary HBV infection.31

This is the most common pattern of primary infection in adults.

Self-limited primary infection without detectable serum HBsAg


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, 1995:1406-1439,31 with permission.

Figure 2. Schematic representation of the serologic response through a typical course of HBsAg-negative primary HBV infection.31

A significant number of patients with acute self-limited primary HBV infection never have detectable HBsAg in the blood.

HBsAg-positive persistent HBV infection


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, 1995:1406-1439,31 with permission.

Figure 3. Schematic representation of viral markers in the blood through a typical course of HBV infection that becomes persistent.31

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 carriers.31

Serological markers of HBV infection

During HBV infection, the serological markers vary depending on whether the infection is acute or chronic.11, 23, 31





Hepatitis B surface antigen is the earliest indicator of acute infection and is also indicative of chronic infection if its presence persists for more than 6 months. It is useful for the diagnosis of HBV infection and for screening of blood.

Its specific antibody is anti-HBs.




This is the specific antibody to hepatitis B surface antigen. Its appearance 1 to 4  months after onset of symptoms indicates clinical recovery and subsequent immunity to HBV. Anti-HBs can neutralize HBV and provide protection against HBV infection.




Hepatitis B core antigen is derived from the protein envelope that encloses the viral DNA, and it is not detectable in the bloodstream. When HBcAg peptides are expressed on the surface of hepatocytes, they induce an immune response that is crucial for killing infected cells. The HBcAg is a marker of the infectious viral material and it is the most accurate index of viral replication.

Its specific antibody is anti-HBc.



This is the specific antibody to hepatitis B core antigen. Antibodies to HBc are of class IgM and IgG. They do not neutralize the virus. The presence of IgM identifies an early acute infection. In the absence of HBsAg and anti-HBs, it shows recent infection. IgG with no IgM may be present in chronic and resolved infections. Anti-HBc testing identifies all previously infected persons, including HBV carriers, but does not differentiate carriers and non-carriers.




Hepatitis B e antigen appearing during weeks 3 to 6 indicates an acute active infection at its most infectious period, and means that the patient is infectious.

Persistence of this virological marker beyond 10 weeks shows progression to chronic infection and infectiousness. Continuous presence of anti-HBe indicates chronic or chronic active liver disease. HBeAg is not incorporated into virions, but is instead secreted into the serum. Mutant strains of HBV exist that replicate without producing HBeAg. HBeAg’s function is uncertain.

Its specific antibody is anti-HBe.




This is the specific antibody to hepatitis B e antigen. During the acute stage of infection the seroconversion from e antigen to e antibody is prognostic for resolution of infection. Its presence in the patient’s blood along with anti-HBc and in the absence of HBsAg, anti-HBs and core HBV mutants indicates low contagiousness and convalescence. 31




Hepatitis B x antigen is detected in HBeAg positive blood in patients with both acute and chronic hepatitis. HBxAg is a transcriptional activator. It does not bind to DNA.

Its specific antibody is anti-HBx.            




This is the specific antibody to hepatitis B x antigen. It appears when other virological markers are becoming undetectable.





HBV DNA is detectable by hybridization assays or PCR as soon as 1 week after initial infection. The tests are generally performed for monitoring of antiviral treatment or to detect mutants that escape detection by current methods.




HBV DNA polymerase

Tests for the presence of HBV DNA polymerase, detectable within 1 week of initial infection, are only performed for research purposes.



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 carrier, or is susceptible to HBV infection.15, 23, 31

Assay results
















Early acute HBV infection









Acute or chronic HBV infection. Differentiate with IgM-anti-HBc

. Determine level of infectivity with HBeAg or HBV DNA.










Indicates previous HBV infection and immunity to hepatitis B.








Possibilities include: past HBV infection; low-level HBV carrier; time span between disappearance of HBsAg and appearance of anti-HBs; or false-positive or nonspecific reaction. Investigate with IgM anti-HBc, and/or challenge with HBsAg vaccine. When present, anti-HBe helps validate the anti-HBc reactivity.










Another infectious agent, toxic injury to the liver, disorder of immunity, hereditary disease of the liver, or disease of the biliary tract.










vaccine-type response.

From: Hollinger FB, Liang TJ. Hepatitis B Virus. In: Knipe DM et al., eds. Fields Virology, 4th ed., Philadelphia, Lippincott Williams &Wilkins, 2001:2971-3036,15 with permission (http://lww.com).

Interpretation of HBV serologic markers in patients with hepatitis.15

Serological test findings at different stages of HBV infection and in convalescence






Stage of infection








late incubation period









+ or -




acute hepatitis B or persistent carrier state















HBsAg-negative acute hepatitis B infection















recovery with loss of detectable anti-HBs















healthy HBsAg carrier









+ or -






chronic hepatitis B, persistent carrier state









+ or -






HBV infection in recent past, convalescence









+ or -






HBV infection in distant past, recovery





+ or -


+ or -








recent HBV vaccination, repeated exposure to antigen without infection, or recovery from infection with loss of detectable anti-HBc














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, 1995:1406-1439,31 with permission.

Hepatitis B virus serological markers in different stages of infection and convalescence.23, 31, 52

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, 1999:158-182,15 with permission .

Titre of hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), IgM anti-HBc, and antibody to hepatitis B surface antigen (anti-HBs) in patients with acute hepatitis B with recovery.23

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, 1999:158-182,15 with permission.

Titre of hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and IgM anti-HBc during progression to chronic hepatitis B virus infection.23

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.15


HBsAg positive /
anti-HBc negative


An HBsAg-positive response is accompanied by an anti-HBc negative reaction only during the incubation period of acute hepatitis B, before the onset of clinical symptoms and liver abnormalities.



HBsAg positive /
anti-HBs positive /
anti-HBc positive



Uncommon, may occur during resolution of acute hepatitis B, in chronic carriers who have serious liver disease, or in carriers exposed to heterologous subtypes of HBsAg.



Past infection not resolved completely


HBeAg positive /
HBsAg negative





HBeAg positive /
anti-HBe positive




anti-HBs positive only in a nonimmunized person



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 IG administration, or in newborn children of mothers with recent or past HBV infection.

Passively acquired antibodies disappear gradually over 3 to 6 months, whereas actively produced antibodies are stable over many years.

Apparently quite common when person has forgotten his/her immunization status!


Mutant proteins from mutant HBV strains may escape diagnostic detection. The presence of different serological markers should therefore be tested for a correct diagnosis. Diagnostic kits should contain antibodies against a variety of mutant proteins, if perfection is the goal.

Prevalence of hepatitis B in various areas


% of population positive for















Northern, Western, and Central Europe, North America, Australia















Eastern Europe, the Mediterranean, Russia and the Russian Federation, Southwest Asia, Central and South America



















Parts of China, Southeast Asia, tropical Africa










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, 1996:849-863,52 with permission.

Hypothetical course of immunopathogenesis of hepatitis B virus (HBV)

From: Chisari FV, Ferrari C. Viral Hepatitis. In: Nathanson N et al., eds. Viral Pathogenesis, Philadelphia, Lippincott - Raven, 1997:745-778,6 with permission (http://lww.com).

Eradication of HBV infection depends on the coordinate and efficient development of humoral and cell-mediated immune responses against HBV proteins. Antibodies secreted by plasma cells (PC) derived from antigen-specific B cells (which usually recognize viral antigens in their native conformation) are mostly responsible for the neutralization of free circulating viral particles, Cytotoxic T cells (CTL) that recognize endogenous viral antigens in the form of short peptides associated with human leukocyte antigen (HLA) class I molecules on the surface of the infected hepatocytes (HC) are the main effectors for the elimination of intracellular virus. They can do this by at least two different mechanisms: direct attachment to the cell membrane, causing the infected cell to undergo apoptosis; and the release of soluble cytokines that can downregulate viral gene expression, leading to the elimination of intracellular virus without destruction of the infected cell. Both humoral and cytotoxic functions are more or less stringently regulated by the helper effect of the CD4+ T cells (TH) that recognize exogenous viral antigens, released or secreted by liver cells, in the form of short peptides that associate with HLA class II molecules in the endosomal compartment of professional antigen-presenting cells such as B cells, macrophages (), and dendritic cells.