Hepatitis B

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Overview

Hepatitis Main Page
Hepatitis B
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Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Hepatitis B from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Ultrasound
Treatment
Medical Therapy
Surgery
Primary Prevention
Hepatitis B Vaccination
Hepatitis B Vertical transmission
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hepatitis B On the Web
Most recent articles
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Ongoing Trials at Clinical Trials.gov
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Hepatitis B in the news
Blogs on Hepatitis B
Directions to Hospitals Treating Hepatitis B
Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [2], João André Alves Silva, M.D. [3], Sara Mehrsefat, M.D. [4]

Overview

Chronic Hepatitis B virus (HBV) is a major global health problem, according to the World Health Organization (WHO). Hepatitis B virus (HBV) is a double-stranded DNA virus belonging to the family Hepadnaviridae. It is responsible for hepatitis B virus infection in humans, which attacks the liver and causes both acute and chronic disease. During HBV infection, the host's immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host's cell mechanisms to replicate its genome and proteins. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B. Hepatitis B must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, elevated ALT, and/or elevated AST, such as other viral hepatitis strains, alcoholic hepatitis, and autoimmune hepatitis. Generally, the highest risk for HBV infection is associated with certain lifestyles, occupations, or environments in which contact with blood from infected persons is frequent. The diagnosis of hepatitis B is made by biochemical assessment of liver function.

In the majority of patients with acute and chronic hepatitis B (HBV), symptoms may initially be non-specific and physical examination will be normal. The diagnosis of hepatitis B is made by biochemical assessment of liver function. Initial laboratory evaluation usually reveals increased bilirubin, ALT, AST, and alkaline phosphatase, as well as decreased protein. Prothrombin time may be prolonged in cases of hepatocellular necrosis. Serologic markers, such as Hepatitis B surface antigen (HBsAg); anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis Be antigen; and anti-HBeAg confirm the diagnosis of hepatitis B.

In the majority of adult patients, the body is able to eliminate the virus without treatment. Currently, there is no treatment available for acute hepatitis B infection. Early antiviral treatment may only be required in fewer than 1% of patients with fulminant hepatitis. Treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Treatment lasts between six months and a year, depending on the medication and genotype. Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. These include the antiviral drugs Lamivudine, Adefovir, Tenofovir, Telbivudine, and Entecavir, as well as immune system modulators such as interferon alpha-2a and pegylated interferon-alpha-2a.

Historical Perspective

The first descriptions of hepatitis (epidemic jaundice) are generally attributed to Hippocrates, who identified the disorder during the 5^th century BCE. In 1885, the earliest identifiable occurrence of hepatitis B virus was documented by Lurman. In 1947, the current nomenclature of hepatitis A (so-called "infectious hepatitis") and hepatitis B (so-called "serum hepatitis") was proposed by MacCallum and Bauer. Throughout the 20th century, advancements in the recognition, isolation, classification, and prevention of hepatitis B were achieved. Today, the focus around HBV remains on the spread of awareness and prevention across the world, especially in endemic areas that would benefit greatly from immunization programs.

Pathophysiology

The intracellular hepatitis B virus is a non-cytopathic virus that causes little or no damage to the cell. During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host cell's mechanisms to replicate its own genome and proteins. Different viral antigens and antibodies are detected in serum throughout the course of the disease, such as: HBsAg, HBcAg, HBeAg, anti-HBs, anti-HBC and anti-HBe. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B.

Causes

The hepatitis B virus is responsible for causing hepatitis B. HBV is a double-stranded DNA virus belonging to the family Hepadnaviridae. The viral particle consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA. HBV DNA polymerase has reverse transcriptase activity. It shows tropism for hepatocytes. Humans are the only natural reservoir of the virus. HBV is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins and ten genotypes (A-J) according to overall nucleotide sequence variation of the genome.

Differentiating Hepatitis B from other Diseases

Hepatitis B must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, and/or elevated ALT and AST, such as other forms of viral hepatitis, alcoholic hepatitis, and autoimmune hepatitis.

Epidemiology and Demographics

Chronic Hepatitis B (HBV) is a major global health problem. According to the World Health Organization (WHO), more than 2 billion people have been infected with HBV. It is a major cause of chronic liver disease worldwide, affecting an estimated 1.25 million people in the United States, and more than 240 million people worldwide.

Risk Factors

Generally, the highest risk for HBV infection is associated with lifestyles, occupations, or environments in which contact with blood from infected patients is frequent. High-risk populations include immigrants/refugees from areas of high HBV endemicity, clients in mental health institutions, injecting drug users, men who have sex with men (MSM), patients receiving hemodialysis, and household contacts of HBV carriers. Perinatal transmission from mother to infant at birth is very efficient. If the mother is positive for both HBsAg and HBeAg, 70%–90% of infants will become infected in the absence of post-exposure prophylaxis.

Screening

High-risk groups should be tested for HBV infection. These include immigrants/refugees from areas of intermediate or high endemicity, patients with chronically elevated aminotransferases, immunocompromised individuals, and people with a history of injection drug use (IDU). Additionally, screening for hepatocellular carcinoma should extend to any HBV carrier over 40 years of age with persistent or intermittent ALT elevation and/or high HBV DNA levels (>2,000 IU/mL).

Natural History, Complications and Prognosis

The course of hepatitis B is extremely variable. Hepatitis B has different clinical manifestations depending on the patient’s age at infection, immune status, and the stage at which the disease is recognized. During the incubation period, patients may experience flu-like symptoms such as nausea, vomiting, and headaches. A person infected with hepatitis B virus may recover completely, become an asymptomatic carrier of the virus, develop chronic disease, or develop fulminant hepatitis. In acute hepatitis B, the incubation period may range from 45 to 120 days, depending on the amount of virus in the inoculum, host factors, and the mode of transmission. These patients may experience the following symptoms: fatigue, nausea, vomiting, anorexia, abdominal pain, and jaundice. In most cases, no special diet or treatment are necessary. The risk of developing chronic hepatitis decreases with age, with infants having the highest risk. Chronic hepatitis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In most cases the prognosis of acute hepatitis is good, with symptoms lasting 2 to 3 weeks. However, in infants and immunocompromised patients, the risk of developing chronic disease is increased.

Diagnosis

Diagnostic criteria

The diagnosis of hepatitis is made by biochemical assessment of liver function. A diagnosis is confirmed by the presence of specific antigens and/or antibodies in sera. Three clinically useful antigen-antibody systems have been identified for hepatitis B. These include 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); and hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe).

Hepatitis B viral antigens and antibodies detectable in the blood following acute infection - CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=14144661

History and symptom

50% of adult patients and the majority of infants and children with acute HBV do not present with symptoms. Symptoms may initially be non-specific. It is critical to obtain an accurate and thorough history in cases of both acute and chronic HBV infections in order to determine modes of infection transmission, as well as to assess risk factors for the progression of HBV-related liver disease.

Physical examination

For the majority of patients with acute and chronic hepatitis B (HBV), the physical examination is normal.

Laboratory tests

The diagnosis of hepatitis is made by the biochemical assessment of liver function. An initial laboratory evaluation usually reveals increased bilirubin levels; increased ALT, AST, and alkaline phosphatase; and decreased protein. Prothrombin time may be prolonged in cases of hepatocellular necrosis and hemoglobin may be low. Initial lymphopenia and neutropenia may be followed by lymphocytosis. Serologic markers, such as Hepatitis B surface antigen (HBsAg); anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis B e antigen and anti-HBeAg confirm the diagnosis of hepatitis B. These levels fluctuate throughout the course of the disease.

Hepatitis B assay results Adapted from World Health Organization

CT

CT scans may diagnose and/or monitor biliary obstruction, cirrhosis, and hepatocellular carcinoma in hepatitis B patients.:

MRI

An MRI may be used to diagnose/monitor biliary obstruction, cirrhosis, and hepatocellular carcinoma in hepatitis B patients. MRI findings in these patients may include nodular appearance and signs of portal hypertension, such as ascites and splenomegaly.

Ultrasound

Ultrasounds may be used as a screening tool in patients with chronic hepatitis for the early detection of hepatic cirrhosis. HBsAg carriers with cirrhosis should be echographically evaluated every 6 months.

Treatment

Medical therapy

The majority of adults are able to eliminate the virus without treatment. Currently, there is no treatment available for acute hepatitis B infection. Symptomatic treatment may be indicated. Early antiviral treatment may only be required in fewer than 1% of patients, whose hepatitis B takes a very aggressive course, such as in cases of fulminant hepatitis. Treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Chronically infected patients with persistently elevated serum alanine aminotransferase and HBV DNA levels are candidates for therapy. Treatment lasts from six months to a year, depending on the medication and genotype. Although none of the available drugs can clear the infection, they can stop the virus from replicating, thus minimizing liver damage. These include antiviral drugs (e.g., Lamivudine, Adefovir, Tenofovir, Telbivudine and Entecavir) and immune system modulators, including interferon alpha-2a and pegylated interferon-alpha-2a.

Surgery

Surgery is usually not indicated for the treatment of hepatitis B. However, for patients with advanced liver damage secondary to HBV infection or liver failure in fulminant hepatitis, liver transplantation may be beneficial.

Primary Prevention

The risk of transmission of hepatitis B may be diminished by following measures proposed by the WHO. These include vaccination of all infants within 24 hours of birth; vaccination of members of certain risk groups, such as travelers to endemic areas and healthcare workers (if they have not been vaccinated yet); avoidance of sexual contact with a person who has acute or chronic hepatitis B; and avoiding sharing personal items such as razors or toothbrushes. The HBV vaccine is effective in preventing HBV infections when it is administered either before or shortly after exposure.

Vaccination

The Hepatitis B vaccine is the most effective tool in preventing the transmission of HBV and HDV. Vaccines are composed of the surface antigen of HBV (HBsAg) and are produced by two different methods, including plasma-derived and recombinant DNA. The primary hepatitis B immunization series conventionally consists of three doses of vaccine. Vaccination of infants and, in particular, delivery of hepatitis B vaccine within 24 hours of birth is 90–95% effective in preventing infection with HBV, as well as decreasing HBV transmission if followed by at least two other doses. WHO recommends universal hepatitis B vaccination for all infants, and further advises that the first dose should be given as soon as possible after birth. This strategy has resulted in a dramatic decrease in the prevalence of CHB among young children in regions of the world where universal infant vaccination programs have been implemented. A small proportion of vaccinated children (5–10%) have a poor response to vaccination, and will remain susceptible as adults to acquisition of HBV infection.

Vertical transmission

Hepatitis B virus (HBV) infection in a pregnant woman poses a serious risk to the fetus. Without postexposure immunoprophylaxis, approximately 40% of infants born to HBV-infected mothers in the United States will develop chronic HBV infection, approximately one-fourth of whom will eventually die from chronic liver disease.

Secondary Prevention

Hepatitis B Immunoglobulin (HBIG) is a form of passive immunization when given shortly before or soon after exposure to hepatitis B virus. It is also administered in combination with HBV vaccines to newborns of HBsAg-positive mothers.

References

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Historical Perspective

Hepatitis Main Page
Hepatitis B
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Hepatitis B from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Ultrasound
Treatment
Medical Therapy
Surgery
Primary Prevention
Hepatitis B Vaccination
Hepatitis B Vertical transmission
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Cost-Effectiveness of Therapy
Future or Investigational Therapies
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Case #1
Hepatitis B On the Web
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Hepatitis B in the news
Blogs on Hepatitis B
Directions to Hospitals Treating Hepatitis B
Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [6], Sara Mehrsefat, M.D. [7]

Overview

The first descriptions of hepatitis (epidemic jaundice), recorded in the 5^th century BCE, are generally attributed to Hippocrates. In 1885, the earliest identifiable occurrence of hepatitis B virus was documented by Lurman. In 1947, the current nomenclature of hepatitis A (so-called infectious hepatitis) and hepatitis B (so-called serum hepatitis) was proposed by MacCallum and Bauer. Throughout the 20th century, advancements in the recognition, isolation, classification, and prevention of hepatitis B were achieved. Today, the focus around HBV remains on the spread of awareness and prevention across the world, especially in endemic areas that would benefit greatly from immunization programs.

Historical Perspective

Early History

• The first descriptions of hepatitis (epidemic jaundice), recorded in the 5^th century BCE, are generally attributed to Hippocrates.
• In 1885, the earliest identifiable occurrence of hepatitis B virus was documented by Lurman. Lurman's paper, which is regarded as a classic example of an epidemiological study, definitively identified contaminated lymph as the source of hepatitis outbreak. Lurman described a form of hepatitis that was transmitted by direct inoculation of blood or blood products during a smallpox outbreak in Bremen, Germany. Thousands of shipyard employees were vaccinated against smallpox with a preparation made from human lymph. Between several weeks and 8 months later, 15% of the workers became ill with jaundice, while unvaccinated workers remained healthy.
• During the early 20th century, similar outbreaks of jaundice occurring after longer incubation periods were documented in clinics treating patients with syphilis, diabetes, and tuberculosis.
• In the 1920s, reports from clinics in Germany and the United States referred to the treatment of syphilis with intravenous therapy. At the time, the so-called "salvarsan icterus" was thought to be a direct effect of the treatment for syphilis, rather than an artifact of the use of contaminated needles and syringes.
• In 1926, Flaum, Malmros, and Persson published a paper on the role of syringes and needles in the transmission of the disease, in which they documented the distinctive incubation period of the infection compared to the so-called spontaneous catarrhal jaundice (now known as Hepatitis A). In their paper, they introduced the possibility that two different viruses might cause hepatitis. Further evidence supporting the notion of the existence of at least two separate etiological agents causing hepatitis came during World War II, when jaundice epidemics were clearly distinguished among United States military personnel based on differences in transmission and incubation periods.
• In 1947, the current nomenclature of hepatitis A (so-called infectious hepatitis) and hepatitis B (so-called serum hepatitis) was proposed by MacCallum and Bauer. By this time, it was already known that in comparison with hepatitis A, hepatitis B:
  • Was transmitted by percutaneous exposure to blood products
  • Had a longer incubation period (2-6 months)
  • Occurred more often in adults
• In the 1960’s and 1970’s, Krugman et al. performed studies confirming these previously observed differences as well as the occurrence of homologous immunity after infection with hepatitis B.
• In 1965, the hepatitis B virus was discovered by Baruch Blumberg. He identified the Australia antigen (later known to be hepatitis B surface antigen or HBsAg) in blood collected from Australian aborigines. In 1970, the virus particle was identified with electron microscopy by D.S. Dane et al.
• In 1970, the virus particle was identified with electron microscopy by D.S. Dane et al.
• In 1972, hepatitis B virus was classified into four subtypes: adr, adw, ayr, and yaw. This initial classification was based on the envelope protein of the virus. The four subtypes were noted to have different geographical distributions, which helped trace the route of infections.

Discovery and Vaccine

• By the early 1980s the genome of the hepatitis B virus had been sequenced.
• Since 1982, a vaccine against hepatitis B has been available.
• Recent discoveries have allowed hepatitis B virus to be classified not only according to serotype, but according to genotype. Today, HBV is classified into ten genotypes (A-J) according to the variation of the nucleotide sequence of the genome.

Global Health

• In 1992, the Global Advisory Group to the World Health Organization (WHO) recommended that hepatitis B vaccine be incorporated into national immunization programs in all countries by 1997.
• Since 2007, World Hepatitis Day has taken place on July 28. The intention of the day is to raise global awareness of hepatitis B and hepatitis C and encourage prevention, diagnosis, and treatment. It has been led by the World Hepatitis Alliance.
• On May 2010, the World Hepatitis Alliance received global endorsement from the World Health Organization.

References

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Pathophysiology

Hepatitis Main Page
Hepatitis B
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Hepatitis B from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Ultrasound
Treatment
Medical Therapy
Surgery
Primary Prevention
Hepatitis B Vaccination
Hepatitis B Vertical transmission
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
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Case #1
Hepatitis B On the Web
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American Roentgen Ray Society Images of Hepatitis B All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
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FDA on Hepatitis B
CDC on Hepatitis B
Hepatitis B in the news
Blogs on Hepatitis B
Directions to Hospitals Treating Hepatitis B
Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [8]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [9], Sara Mehrsefat, M.D. [10]

Overview

The intracellular hepatitis B virus is a non-cytopathic virus that causes little or no damage to the cell. During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host's cell mechanisms to replicate its genome and proteins. Different viral antigens and antibodies may be detected in serum throughout the course of the disease, including HBsAg, HBcAg, HBeAg, anti-HBs, anti-HBC, and anti-HBe. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B.

Pathogenesis

Immunopathogenesis

The host immune response is primarily responsible for both hepatocellular damage and viral clearance in patients with HBV infection. While the innate immune response does not play a significant role in these processes, the adaptive immune response (particularly virus-specific cytotoxic T lymphocytes) contributes to nearly all of the liver injury associated with HBV infection.

Life Cycle

• The HBV virion binds to a receptor at the surface of the hepatocyte.

• Several cellular receptors have been identified, including the transferrin receptor, the asialoglycoprotein receptor molecule, and the human liver endonexin. However, the mechanism by which HBsAg binds to a specific receptor to enter cells has not yet been established. Viral nucleocapsids enter the cell and reach the nucleus, where the viral genome is delivered.

• In the nucleus, second-strand DNA synthesis is completed and the gaps in both strands are repaired to yield a covalently closed circular (ccc) supercoiled DNA molecule that serves as a template for the transcription of four viral RNAs that are 3.5, 2.4, 2.1, and 0.7 kb long.

• These transcripts are polyadenylated and transported to the cytoplasm, where they are translated into the viral nucleocapsid and precore antigen (C, pre-C), polymerase (P), envelope L (large), M (medium), S (small)), and transcriptional transactivating proteins (X).

• The envelope proteins insert themselves as integral membrane proteins into the lipid membrane of the endoplasmic reticulum (ER). The 3.5 kb species, which spans the entire genome and is termed pregenomic RNA (pgRNA), is packaged together with HBV polymerase and a protein kinase into core particles, where it serves as a template for reverse transcription of negative-strand DNA. The RNA to DNA conversion takes place inside the particles.

• The new, mature, viral nucleocapsids can then follow either of two different intracellular pathways. One of these pathways leads to the formation and secretion of new virions, while the other leads to the amplification of the viral genome inside the cell nucleus. In the virion assembly pathway, the nucleocapsids reach the ER, where they associate with the envelope proteins and bud into the lumen of the ER, at which point they are secreted via the Golgi apparatus out of the cell.

HBV Antigens and Antibodies

Nomenclature	Full Name	Description
HBV	Hepatitis B Virus (complete infectious virion)	The 42 nm, double-shelled particle, that consists of a 7 nm thick outer shell and a 27 nm inner core. The core contains a small, circular, partially double-stranded DNA molecule and an endogenous DNA polymerase. This is the prototype agent for the family epadnaviridae.
HBsAg	Hepatitis B Surface Antigen (envelope antigen)	The complex of antigenic determinants found on the surface of HBV and of 22 nm particles and tubular forms.
HBcAg	Hepatitis B Core Antigen	The antigenic specificity.
HBeAg	Hepatitis B e Antigen	The antigenic determinant that is closely associated with the nucleocapsid of HBV. It also circulates as a soluble protein in serum.
Anti-HBs Anti-HBc Anti-HBe	Antibody to HBsAg Antibody to HBcAg Antibody to HBeAg	Specific antibodies that are produced in response to their respective antigenic determinants.

Transmission

• Transmission results from exposure to infectious blood or body fluids.
• Possible modes of transmission include:

• Unprotected sexual contact
• Blood transfusions
• Re-use of contaminated needles and syringes
• Vertical transmission from mother to child during childbirth (20% risk of transmission; the risk can be as high as 90% if the mother is also positive for the hepatitis B e antigen)
• Transmission between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV

Coinfections

Hepatitis D

• 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 on its own
• Superinfection - causes frequently chronic HDV infection and chronic active hepatitis

• Both types of infections may cause fulminant hepatitis.
• 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.

HIV

• About 10% of people living with HIV in the United States are coinfected with HBV.
• HIV-positive patients who are coinfected with HBV are at increased risk for serious, life-threatening health complications. HIV/HBV coinfection can also complicate the management of HIV infection.
• Hepatitis B is preventable through vaccination. HBV vaccination is recommended for people who are at risk for or living with HIV and who have tested negative for HBV.
• Persons infected with HIV are more likely to develop persistent infection with HBV.
• HIV infection is one of the factors that may reduce the immunogenicity of hepatitis vaccines, along with age (>40 years), gender, weight, genetics, hemodialysis, immunosuppression, and tobacco smoking.

References

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Epidemiology and Demographics

Hepatitis Main Page
Hepatitis B
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Hepatitis B from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Ultrasound
Treatment
Medical Therapy
Surgery
Primary Prevention
Hepatitis B Vaccination
Hepatitis B Vertical transmission
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hepatitis B On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis B All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis B
CDC on Hepatitis B
Hepatitis B in the news
Blogs on Hepatitis B
Directions to Hospitals Treating Hepatitis B
Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [11]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [12]

Overview

Chronic Hepatitis B (HBV) is a major global health problem. According to the World Health Organization (WHO), more than 2 billion people have been infected with HBV. It is a major cause of chronic liver disease worldwide, affecting an estimated 1.25 million people in the United States and more than 240 million people worldwide.

Epidemiology and Demographics

Prevalence

Worldwide, the prevalence rate of HBV ranges from <2% in developed countries to ≥8% in developing countries. Chronic HBV affects an estimated 800,000 - 1.4 million people in the United States.

Source: https://www.cdc.gov/

The prevalence of HBV is greater in certain high-risk groups:

• People who engage in high-risk sexual activity (79% of persons with newly aquired HBV infection engage in high-risk sexual activity or IDU)
• Injection-drug users
• People who might be exposed to infected blood or body fluids (e.g., occupational, household, travel, and healthcare-related)

16% of persons deny a specific risk factor for infection.

Source: https://www.cdc.gov/

Incidence

In the United States, the overall incidence rate in 2011 was 0.9 cases per 100,000 people. A total of 2,890 cases of acute HBV were reported. Between 1991 and 2010, the incidence of HBV has decreased by approximately 82%. The decrease was greatest among children, largely due to the implementation of routine vaccination in 1991. Since 2001, fewer than 30 cases of acute HBV have been reported annually among children born in 1991 or later, the majority of whom were international adoptees or children born outside of the United States who were not fully vaccinated.

Although the incidence of HBV is declining in the United States, it is important to note that reported cases underestimate the true incidence of HBV infection due to the asymptomatic nature of early infections and under-reporting of symptomatic cases.

Worldwide, there are over 4 million cases of acute HBV every year.

Source: https://www.cdc.gov/

Age

In many low-risk regions of the world, the highest incidence of HBV is observed in teenagers and young adults. In endemic regions of Africa and Asia, most infections occur in infants and children. In 2011, the highest rates of HBV were observed among people aged 30–39 years (2.00 cases/100,000 people), and the lowest rates of HBV were observed among adolescents and children aged <19 years (0.04 cases/100,000 people).

Gender

In 2011, the rate of HBV in the United States was 1.7 times higher among males than among females (1.18 cases and 0.69 cases per 100,000 people, respectively).

Race

The incidence of HBV infection in the United States differs significantly by race and ethnicity, with the highest rates observed among African-Americans. Rates are higher among Hispanics than non-Hispanics.

Developed Countries

Countries and regions with the highest standards of living, including North America, Western and Northern Europe, Australia, and parts of South America, have the lowest prevalence of HBV infection. The carrier rate in these regions is less than 2%, and less than 20% of the population is infected with HBV. In the United States, chronic HBV is responsible for approximately 3,000 annual deaths from associated chronic liver disease. 47 - 70% of United States residents with chronic HBV were born in other countries. While the prevalence of chronic HBV infection among younger, vaccinated, foreign-born United States residents is decreasing, the rate of liver cancer deaths continues to be high among certain foreign-born United States populations. The rate of liver cancer deaths is highest among Asians/Pacific Islanders, which reflects the high prevalence of chronic HBV in this population.

Developing Countries

Regions with the highest prevalence of HBV include Sub-Saharan Africa, Southeast Asia, and the Pacific Basin (excluding Japan, Australia, and New Zealand). Higher rates of chronic HBV are also found in southern parts of Eastern and Central Europe, the Amazon Basin, the Middle East, and India. In these areas, about 70 - 90% of the population becomes HBV-infected before the age of 40, and 8 - 20% of people are HBV carriers. In countries such as China, Senegal, and Thailand, infection rates are very high in infants, and continue through early childhood. In Panama, New Guinea, Solomon Islands, Greenland, and in populations such as Alaskan Indians, infection rates in infants are relatively low but increase rapidly during early childhood. The prevalence of HBV is decreasing in many regions including North Africa, the Middle East, Latin America, and Southeast Asia.

References

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Risk Factors

Hepatitis Main Page
Hepatitis B
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Overview
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History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
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Medical Therapy
Surgery
Primary Prevention
Hepatitis B Vaccination
Hepatitis B Vertical transmission
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
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Hepatitis B On the Web
Most recent articles
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Review articles
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Ongoing Trials at Clinical Trials.gov
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Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [13]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [14], Sara Mehrsefat, M.D. [15]

Overview

Common risk factors in the development of HBV infection include sexual contact with infected individuals, sharing a household with a carrier, intravenous drug use, travel to endemic regions, perinatal transmission from infected mothers to infants, and certain occupations.

Risk Factors

Individuals who are at increased risk of hepatitis B infection include:

• 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
• Patients and employees in hemodialysis centers
• Injection drug users sharing unsterilized needles
• People sharing unsterilized medical or dental equipment
• People providing or receiving acupuncture and/or tattooing with unsterilized medical devices
• Persons living in regions or travelling to regions with endemic hepatitis B
  • Country of origin is the major risk factor for HBV infection (prevalence threshold of 2% or greater to define countries with high risk for HBV infection)
• Sexually active heterosexuals
• Lack of vaccination in infancy
• Men who have sex with men
• Hemophilia patients
• Travel to areas where hepatitis B is common

Frequent and routine exposure to blood or serum is the common denominator of healthcare occupational exposure.

Source: https://www.cdc.gov/

Source: https://www.cdc.gov/

Hepatitis B Reactivation

Hepatitis B virus presents in all patients with infection. Patients who are either HBsAg-positive or anti HBc-positive are at the risk of hepatitis B reactivation.

Patients are at risk for HBV reactivation in the following conditions:

• Receive immunosuppressive therapy
  • Chemotherapy agents
  • Tumor necrosis factor (TNF) inhibitor (Infliximab)
  • Methotrexate (particularly following its withdrawal)
  • Abatacept
  • Ustekinumab
  • Anti-CD 20 agents (Rituximab and Ofatumumab)
  • High to moderate dose glucocorticoids
• Patients treated with direct-acting antivirals for hepatitis C
  • Daklinza
  • Epclusa
  • Exviera
  • Harvoni
  • Olysio
  • Sovaldi
  • Viekira Pak/ Viekira Pak XR
  • Technivie
  • Zepatier

References

Expand

Screening

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [16]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [17]

Overview

High-risk groups should be tested for HBV infection. These include immigrants/refugees from areas of intermediate or high endemicity, persons with chronically elevated aminotransferases, immunocompromised individuals, and persons with a history of injection drug use(IDU). Additionally, screening for hepatocellular carcinoma should extend to any HBV carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000 IU/mL.

Screening

Recommendations for Persons Who Should Be Screened for HBV Infection

The following groups should be tested for HBV infection:

• Persons born in high or intermediate endemic areas
• United States–born people who were not vaccinated as infants and whose parents were born in regions with high HBV endemicity
• Persons with chronically elevated aminotransferases
• Persons who require immunosuppressive therapy
• Men who have sex with men
• People with multiple sexual partners or history of sexually transmitted disease
• Incarcerated people
• Persons who have ever used injecting drugs, dialysis patients, HIV- or HCV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected people
• Testing for HBsAg and anti-HBs should be performed, and seronegative persons should be vaccinated. (Grade I Recommendation)

Group	Screening Recommendations
Pregnant women	All pregnant women should screen (HBsAg testing) at the first prenatal visit Re-screen women with unknown HBsAg status or new or continuing risk factors Refer women who test positive for counseling and medical management Administer hepatitis B vaccine and hepatitis B immune globulin to exposed infants within 12 hours of birth
Asymptomatic/Nonpregnant adolescents and adults at high risk (HBV)	Risk Assessment: Persons born in countries and regions with a high prevalence of HBV infection (≥2%) U.S.-born persons not vaccinated as infants whose parents were born in regions with a very high prevalence of HBV infection (≥8%), HIV-positive persons Injection drug users Men who have sex with men Household contacts or sexual partners of persons with HBV infection Screening Tests: (HBsAg) test followed by a licensed, neutralizing confirmatory test Testing for antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc) (distinguish between infection and immunity)

Recommendations for HCC Screening: AASLD Practice Guidelines

The following groups should be screened with US examination every 6-12 months: (Grade II-2)

• HBV carriers at high risk for HCC such as Asian men over 40 years and Asian women over 50 years of age
• People with cirrhosis
• People with a family history of HCC
• Individuals of African descent over 20 years of age
• Any carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000 IU/mL

For HBV carriers at high risk for HCC who are living in areas where US is not readily available, periodic screening with AFP should be considered. (Grade II-2)

References

Expand

Causes

Hepatitis B virus
Micrograph showing hepatitis B virions - Author: GrahamColm na projektu Wikipedie v jazyce angličtina, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=6032684
Virus classification
Group: Group VII (dsDNA-RT) Family: Hepadnaviridae Genus: Orthohepadnavirus Species: Hepatitis B virus

This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Hepatitis B.

Hepatitis Main Page
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Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
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Surgery
Primary Prevention
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Hepatitis B Vertical transmission
Secondary Prevention
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Future or Investigational Therapies
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American Roentgen Ray Society Images of Hepatitis B All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
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Hepatitis B in the news
Blogs on Hepatitis B
Directions to Hospitals Treating Hepatitis B
Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [18]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [19]

Overview

The hepatitis B virus is responsible for causing hepatitis B. HBV is a double stranded DNA virus belonging to the family Hepadnaviridae. The viral particle consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA. HBV DNA polymerase has reverse transcriptase activity. It shows tropism for hepatocytes. Humans are the only natural reservoir. The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins and ten genotypes (A-J) according to overall nucleotide sequence variation of the genome.

History

The earliest record of an epidemic caused by Hepatitis B virus was made by Lurman in 1885. An outbreak of smallpox occurred in Bremen in 1883 and 1,289 shipyard employees were vaccinated with lymph from other people. After several weeks, and up to eight months later, 191 of the vaccinated workers became ill with jaundice and were diagnosed as suffering from serum hepatitis. Other employees who had been inoculated with different batches of lymph remained healthy. Lurman's paper, now regarded as a classical example of an epidemiological study, proved that contaminated lymph was the source of the outbreak. Later, numerous similar outbreaks were reported following the introduction, in 1909, of hypodermic needles that were used, and more importantly reused, for administering Salvarsan for the treatment of syphilis. The virus was not discovered until 1965 when Baruch Blumberg, then working at the National Institutes of Health (NIH), discovered the Australia antigen (later known to be Hepatitis B surface antigen, or HBsAg) in the blood of Australian aboriginal people. Although a virus had been suspected since the research published by MacCallum in 1947. In 1970, D.S. Dane and others discovered the virus particle by electron microscopy. By the early 1980s the genome of the virus had been sequenced, and the first vaccines were being tested.

Microbiology

Structure

A simplified drawing of the HBV particle and surface antigen - Public Domain, https://en.wikipedia.org/w/index.php?curid=14175845

Hepatitis B virus (HBV) is a member of the Hepadnavirus family.

The viral particle (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA and a DNA polymerase, that has reverse transcriptase activity.

The outer envelope contains embedded proteins that are involved in viral binding of, and entry into, susceptible cells. The virus is one of the smallest enveloped animal viruses, with a virion diameter of 42nm, but pleomorphic forms exist, including filamentous and spherical bodies lacking a core. These particles are not infectious and are composed of the lipid and protein that form part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus.

The protein of the virion coat is termed "surface antigen" or HBsAg. It is sometimes extended as a tubular tail on one side of the virus particle. The surface antigen is generally produced in vast excess, and is found in the blood of infected individuals in the form of filamentous and spherical particles. Filamentous particles are identical to the virion "tails" - they vary in length and have a mean diameter of about 22nm. They sometimes display regular, non-helical transverse striations.

Genome

The genome organisation of HBV. The genes overlap - By TimVickers at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=3288245

• HBV virion DNA is a relaxed circular, partially duplex molecule of 3.2 kb, whose circularity is maintained by 5' cohesive ends.

• A virion-associated polymerase can repair gaps and generate a fully duplex genome. Negative strand DNA is the template for the synthesis of the viral mRNA transcripts. HBV DNA has a very compact coding organization with four partially overlapping open reading frames (ORFs) that are translated into seven known proteins.

• Noncoding regions are not present.

• Four separate viral promoters have been identified, driving expression of:

• Genomic, P, and pre-C and C RNAs
• L protein mRNA
• M and S protein mRNAs
• X protein mRNA

They are referred to as the genomic, pre-S1, S, and X promoters, respectively.

• Two major classes of transcripts exist:

• The subgenomic RNAs function exclusively as messenger RNAs (mRNAs) for translation of envelope and X proteins.
• The genomic RNAs are bifunctional, serving as both the templates for viral DNA synthesis and as messages for ORF pre-C, C, and P translation.

• ORF P encodes the viral polymerase and the terminal protein found on minus strand DNA. ORF C encodes the structural protein of the nucleocapsid and the HBeAg, and ORF S/pre-S encodes the viral surface glycoproteins. The product of ORF X is a poorly understood regulatory protein that enhances the expression of heterologous and homologous cellular genes in trans.

• The three envelope glycoproteins are not distributed uniformly among the various HBV particle types. Subviral 22 nm particles are composed predominantly of S proteins, with variable amounts of M proteins and few or no L proteins. Virus particles are enriched for L proteins. L proteins carry the receptor recognition domain, which allows efficient binding to cell surface receptors.

• HBcAg is the most conserved polypeptide among the mammalian hepadnaviruses with 68% homology between HBV and GSHV and 92% between GSHV and WHV. Furthermore, it plays important roles in the encapsidation of the viral pregenomic RNA. The polymerase protein is quite immunogenic during both acute and chronic infection.

Replication

Hepatitis B virus replication. - By GrahamColm at English Wikipedia - Transferred from en.wikipedia to Commons by Berichard using CommonsHelper., Public Domain, https://commons.wikimedia.org/w/index.php?curid=6030623

The life cycle of Hepatitis B virus is complex. Hepatitis B is one of a few known non-retroviral viruses which use reverse transcription as a part of its replication process. The virus gains entry into the cell by binding to a receptor on the surface of the cell and enters it by endocytosis. Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host proteins called chaperones. The partially double stranded viral DNA is then made fully double stranded and transformed into closed circular supercoiled DNA (cccDNA) that serves as a template for transcription of four viral mRNAs. The largest mRNA, (which is longer than the viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral DNA polymerase. These four viral transcripts undergo additional processing and go on to form progeny virions which are released from the cell or returned to the nucleus and re-cycled to produce even more copies. The long mRNA is then transported back to the cytoplasm where the virion P protein synthesizes DNA via its reverse transcriptase activity.

Serotypes and Genotypes

The virus is divided into:

• Four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins
• Ten genotypes (A-J) according to overall nucleotide sequence variation of the genome
• The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus.
• Differences between genotypes affect:
• Outcome (worst in genotype C)
• Seroconversion (lower in genotype C)
• Tendency to chronicity (higher in genotype A)
• Likelihood of complications (higher in genotype C)
• Response to treatment and possibly vaccination (better response to IFN therapy in genotypes A and B. No association was found between genotypes and response to nucleosides or nucleotides)

Transmission

Prevalence of Hepatitis B virus as of 2005 - By below - CDC Travelers' Health: Yellow Book Chapter 4 – Prevention of Specific Infectious Diseases: Hepatitis, Viral, Type Bmap based on http://i33.tinypic.com/mh37sx.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2127055

Transmission results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include (but are not limited to) unprotected sexual contact, blood transfusions, re-use of contaminated needles & syringes, and vertical transmission from mother to child during childbirth. Without intervention, a mother who is positive for the hepatitis B surface antigen confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for the hepatitis B e antigen. HBV can be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV. However, at least 30% of reported hepatitis B among adults cannot be associated with an identifiable risk factor.

The primary method of transmission reflects the prevalence of chronic HBV infection in a given area. In low prevalence areas such as the continental United States and Western Europe, where less than 2% of the population is chronically infected, injection drug abuse and unprotected sex are the primary methods, although other factors may be important. In moderate prevalence areas, which include Eastern Europe, Russia, and Japan, where 2-7% of the population is chronically infected, the disease is predominantly spread among children. In high prevalence areas such as China and South East Asia, transmission during childbirth is most common, although in other areas of high endemicity such as Africa, transmission during childhood is a significant factor. The prevalence of chronic HBV infection in areas of high endemicity is at least 8%.

Tropism

Hepatitis B virus shows tropism for hepatocytes.

Natural Reservoir

The natural reservoir for hepatitis B virus is man. Closely related hepadnaviruses have been found in woodchucks and ducks, but they are not infectious for humans.

Pathogenesis

The hepatitis B virus primarily interferes with the functions of the liver by replicating in liver cells, known as hepatocytes. During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to most of the liver injury associated with HBV infection. By killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, CTLs eliminate the virus. Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs into the liver.

See also

• Hepatitis A
• Hepatitis B in China
• Hepatitis C
• Hepatitis D
• Hepatitis E
• Hepatitis F
• Hepatitis G
• Jade Ribbon Campaign
• Maurice Hilleman
• Baruch S. Blumberg

References

External links

• NIH collection of links to relevant articles on Hepatitis B
• Hepatitis B Foundation, non-profit organization dedicated to the global problem of hepatitis B
• CDC webpage on Hepatitis B
• ThinkB: Hepatitis B information for Asians. Multiple language content available.
• Pediatric Hepatitis Report compiled by Parents of Kids with Infectious Diseases
• Advances in Hepatitis B Research: From Virology to Clinical Management
• An illustration of subunit vaccine development for Hepatitis B - Nova Online
• American Liver Foundation: Comprehensive information about Hepatitis B, including links to chapters for finding local resources
• Children's Liver Disease Foundation

Expand

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [20]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [21], Sara Mehrsefat, M.D. [22]

Overview

Hepatitis B must be differentiated from other diseases that cause fever, nausea, vomiting, jaundice, hepatomegaly, icteric sclera, elevated ALT, and elevated AST, such as other types of viral hepatitis, alcoholic hepatitis, and autoimmune hepatitis.

Differentiating Hepatitis B from other Diseases

The table below summarizes the findings that differentiate hepatitis B from other conditions that cause fever, nausea, vomiting, jaundice, hepatomegaly, and icteric sclera.

Disease	Findings
Viral Hepatitis A	Abrupt onset of prodromal symptoms Detectable serum immunoglobulin M (IgM) anti-HAV antibodies Hepatitis, caused by the hepatitis A virus, produces a self-limited disease
Viral Hepatitis C	Acute hepatitis with possible recent exposure to HCV (needle-stick) Symptoms are similar to the ones of hepatitis B, however, hepatitis C can cause acute and/or chronic hepatitis Serologic testing will help differentiate these two conditions Detectable HCV RNA by PCR and anti-HCV antibody testing by enzyme-linked immunosorbent assay (ELISA)
Viral Hepatitis D	Symptoms are similar to the ones of hepatitis B, however, hepatitis D is a serious liver disease caused by infection with the Hepatitis D virus Only occurs among people who are infected with the hepatitis B virus (HBV) May complicate into cirrhosis and hepatocellular carcinoma. Serologic testing will help differentiate these two conditions Detectable IgM anti-HBc with Serum HDAg (enzyme-linked (EIA) or radioimmunoassays (RIA))
Viral Hepatitis E	Symptoms are similar to the ones of hepatitis B, however, hepatitis E may complicate into chronic hepatitis and liver failure in rare cases Detectable IgM antibodies to HEV or HEV in serum or stool by polymerase chain reaction (PCR)
Alcoholic Hepatitis	Symptoms are similar to the ones of hepatitis B, however, alcoholic hepatitis is related to the excessive use of alcohol Often leads to cirrhosis and liver failure Moderately elevated aminotransferases (typically <300 int. unit/mL) ALT<AST in alcoholic hepatitis (inverse from viral hepatitis, which is ALT>AST) Elevated serum bilirubin (>5 mg/dL), elevated INR, and possible leukocytosis
Autoimmune Hepatitis	Autoimmune hepatitis occurs when the body's immune system attacks the hepatocytes It often affects young females and may present with signs of acute hepatitis or chronic liver disease Autoimmune hepatitis has a fluctuating nature It may be asymptomatic or at the far end of the spectrum, may present with acute liver failure with jaundice, elevated PT, and aminotransferase values >1000 U/L

Hepatitis B must be differentiated from other causes of rash and arthritis

Disease	Findings
Nongonococcal septic arthritis	Presents with an acute onset of joint swelling and pain (usually monoarticular) Culture of joint fluid reveals organisms
Acute rheumatic fever	Presents with polyarthritis and rash (rare presentation) in young adults. Microbiologic or serologic evidence of a recent streptococcal infection confirm the diagnosis. Poststreptococcal arthritis have a rapid response to salicylates or other antiinflammatory drugs.
Syphilis	Presents with acute secondary syphilis usually presents with generalized, pustular lesions at the palms and soles with generalized lymphadenopathy Rapid plasma reagin (RPR), Venereal Disease Research Laboratory (VDRL) and Fluorescent treponemal antibody absorption (FTA-ABS) tests confirm the presence of the causative agent.
Reactive arthritis (Reiter syndrome)	Musculoskeletal manifestation include arthritis, tenosynovitis, dactylitis, and low back pain. Extraarticular manifestation include conjunctivitis, urethritis, and genital and oral lesions. Reactive arthritis is a clinical diagnosis based upon the pattern of findings and there is no definitive diagnostic test
Hepatitis B virus (HBV) infection	Presents with fever, chills, polyarthritis, tenosynovitis, and urticarial rash Synovial fluid analysis usually shows noninflammatory fluid Elevated serum aminotransaminases and evidence of acute HBV infection on serologic testing confirm the presence of the HBV.
Herpes simplex virus (HSV)	Genital and extragenital lesions can mimic the skin lesions that occur in disseminated gonococcal infection Viral culture, polymerase chain reaction (PCR), and direct fluorescence antibody confirm the presence of the causative agent.
HIV infection	Present with generalized rash with mucus membrane involvement, fever, chills, and arthralgia. Joint effusions are uncommon
Gout and other crystal-induced arthritis	Presents with acute monoarthritis with fever and chills Synovial fluid analysis confirm the diagnosis.
Lyme disease	Present with erythema chronicum migrans rash and monoarthritis as a later presentation. Clinical characteristics of the rash and and serologic testing confirm the diagnosis.

Differential diagnosis of jaundice are:

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALK BLR Indirect BLR Direct Viral serology Jaundice Hepatocellular Jaundice Liver infiltration: Hemochromatosis, amyloidosis + - -/+ - ↑ ↑ ↑/N ↑/N N - Ferritin ↑ in hemochromatosis Liver biopsy Wilson's disease + - -/+ - ↑ ↑ N ↑/N N - Serum cerulloplasmin ↑ Liver biopsy Viral hepatitis - -/+ - - ↑ ↑ N ↑/N N + Specific viral antibody for each type - Alcoholic hepatitis - -/+ -/+ - ↑↑ ↑ N ↑/N N - - - Drug induced hepatitis - -/+ - - ↑ ↑ N ↑/N N - - - Autoimmune hepatitis -/+ - - -/+ ↑ ↑ N ↑/N N - Anti-LKM antibody Liver biopsy Cirrhosis -/+ -/+ -/+ - ↑ ↑ ↑/N ↑/N ↑/N -/+ Low platate Small liver on ultrasond Nonalcoholic steatohepatitis -/+ - - - ↑ ↑ N ↑/N N - High lipids liver biopsy Ischemic hepatopathy -/+ - -/+ - ↑ ↑ N ↑/N N - Cardiovascular risk factors Clinical setting Cholestatic Jaundice Common bile duct stone -/+ - + + N N ↑ N ↑ - Dilated ducts on sono CT/ERCP Hepatitis A cholestatic type - -/+ + + N N ↑ N ↑ + HAV- AB Abdominal ultrasound EBV / CMV hepatitis - -/+ + + N N ↑ N ↑ + Positive serology - Primary biliary cirrhosis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - AMA positive Liver biopsy Primary sclerosing cholangitis -/+ - -/+ + N/↑ N/↑ ↑ N ↑ - Pos. autoantibodies Beading on MRCP, Liver biopsy Sickle cell disease + - - +/- N/↑ N/↑ ↑ N ↑ - Genetic testing Pancreatic carcinoma + - -/+ -/+ N/↑ N/↑ ↑ N ↑ - - CT scan for diagnosis AIDS cholangiopathy - - -/+ -/+ N/↑ N/↑ ↑ N ↑ - Pos. HIV Sono or ERCP for diagnosis Parasites induces cholestasis - - -/+ -/+ N/↑ N/↑ ↑ N ↑ - Ab or parasite serology Sono or ERCP for diagnosis Intrahepatic cholestasis of pregnancy -/+ - -/+ + ↑ ↑ ↑ N ↑ - Low PLT, Neg viral serology Diagnosed clinically Isolated Jaundice Crigler-Najjar type 2 + - - - N N N ↑ ↑ - Genetic testing Gilbert + - - - N N N ↑ ↑ - Genetic testing Rotor syndrome + - - - N N N N ↑ - Genetic testing Liver biopsy Dubin-Johnson syndrome + - - - N N N N ↑ - Genetic testing Liver biopsy Hereditory spherocytosis + - -/+ - N N N ↑ N - Genetic testing Osmotic fragility G6PD deficiency + - - - N N N ↑ N - Genetic testing Thalassemia + - - - N N N ↑ N - Genetic testing Paroxismal nocturnal hemoglobinoria - - - - N N N ↑ N - Flocytometery Immune hemolysis - -/+ - - N N N ↑ N - Autoantibodies Hematoma - -/+ - - N N N ↑ N - Anemia Truma or surgery in history

References

Template:WH Template:WS

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Natural History, Complications & Prognosis

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Natural History

Hepatitis Main Page
Hepatitis B
Home
Patient Information
Overview
Historical Perspective
Pathophysiology
Causes
Differentiating Hepatitis B from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Laboratory Findings
CT
MRI
Ultrasound
Treatment
Medical Therapy
Surgery
Primary Prevention
Hepatitis B Vaccination
Hepatitis B Vertical transmission
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Hepatitis B On the Web
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Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Hepatitis B All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Hepatitis B
CDC on Hepatitis B
Hepatitis B in the news
Blogs on Hepatitis B
Directions to Hospitals Treating Hepatitis B
Risk calculators and risk factors for Hepatitis B

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [23]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [24]

Overview

The course of hepatitis B may be extremely variable. Hepatitis B has different clinical manifestations depending on the patient’s age at infection, immune status, and the stage at which the disease is recognized. During the incubation period patients may experience flu-like symptoms, such as nausea, vomiting, and headaches. A person infected with hepatitis B virus may recover completely, become an asymptomatic carrier of the virus, develop chronic disease, or develop fulminant hepatitis. In acute hepatitis B, the incubation period may range from 45 to 120 days, depending on the amount of virus in the inoculum, host factors, and mode of transmission. These patients may experience the following symptoms: fatigue, nausea, vomiting, anorexia, abdominal discomfort, and jaundice. In most cases, no special diet or treatment are necessary. The risk of developing chronic hepatitis decreases with age, with infants having the highest risk. Chronic hepatitis may progress to: cirrhosis, liver failure, or hepatocellular carcinoma. In most cases the prognosis of acute hepatitis is good, with symptoms lasting 2 to 3 weeks. However, in infants and immunocompromised persons, the risk of developing chronic disease is increased.

Natural History

During the incubation phase of the disease, 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 other obvious symptoms.

Patients with asymptomatic HBV may become silent carriers of the virus, and constitute a reservoir for further transmission to others.

Patients infected with hepatitis B may:

• Recover completely from their acute HBV infection
• Not clear the virus (5-10%), becoming asymptomatic carriers
• Develop chronic hepatitis, which may become complicated by cirrhosis and/or liver cancer
• Develop fulminant hepatitis and die

In general, the frequency of clinical disease increases with age, whereas the likelihood of being a carrier decreases.

Acute Hepatitis B

• 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 favorable 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.

Incubation Period

• Usually ranges from 45 to 120 days (average of 60 to 90 days), based on:

• Amount of virus in the inoculum (a larger initial dose of virus is associated with a shorter incubation period)
• Mode of transmission
• Host factors

Preicteric or Prodromal Phase

• Period between initial symptoms and onset of jaundice
• Usually lasts from 3 to 10 days
• Nonspecific; characterized by insidious onset of:

• Fatigue
• Anorexia
• Abdominal discomfort
• Nausea
• Vomiting
• Arthralgias
• Rash
• Fever may be absent or mild

Icteric Phase

• The icteric phase is variable, but usually begins within 10 days of symptom onset and lasts from l to 3 weeks.
• The icteric phase is characterized by:

• Jaundice (clinically apparent when the total bilirubin level exceeds 20 to 40 mg/l)
• Yellowish discoloration of the mucous membranes, conjunctivae, and sclerae
• Dark urine
• Acholic stools
• Hepatic tenderness
• Hepatomegaly
• Splenomegaly (less common)

Convalescence Phase

• About 4-12 weeks thereafter, jaundice disappears and the illness resolves with the development of natural and protective antibodies (anti-HBs) in about 95% of adults.
• Malaise and fatigue may persist for weeks or months, while jaundice, anorexia, and other symptoms disappear.
• In most cases, no special treatment or diet is required, and patients need not be confined to bed. However, a small percentage of patients die from acute HBV infection.

Chronic Hepatitis B

• Although most adult patients recover completely from an acute episode of hepatitis B, in a significant proportion—5 to 10%—the virus persists in the body. This figure is much higher in children: 70 to 90% of infants infected in their first few years of life become chronic carriers of HBV.

• Chronic hepatitis generally develops over many years.

• The risk of chronic HBV infection decreases with age. As many as 90% of infants who acquire HBV infection from their mothers at birth 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%.

• Three phases of viral replication occur during the course of HBV infection, especially in patients with chronic hepatitis B:

• High replicative phase - In this phase, HBsAg, HBeAg, and HBV DNA are present and detectable in the sera. Aminotransferase levels may 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 and a decrease or loss of the HBV DNA concentrations, 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 inflammation is diminished. However, if cirrhosis has already developed, it persists indefinitely.

• Chronic infection is responsible for most HBV-related morbidity and mortality, including:

• Cirrhosis
• Liver failure
• Hepatocellular carcinoma

• Up to 20% of the chronic persistent hepatitis cases progress to cirrhosis. 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 a 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 asymptomatic, progression of inflammation to cirrhosis can occur without the knowledge of the patient.

Complications

While most acute HBV infections in adults result in complete recovery, fulminant hepatitis occurs in between 1 and 2% of acutely infected patients. Approximately 200 to 300 Americans die of fulminant disease each year. Although the consequences of acute HBV infection can be severe, most of the serious complications associated with HBV infection are the result of chronic disease. Approximately 25% of carriers develop serious liver disease such as chronic hepatitis, cirrhosis, or primary hepatocellular carcinoma.

Common complications of hepatitis include:

• Fulminant hepatitis
• Chronic hepatitis
• Cirrhosis
• Hepatocellular carcinoma

Hepatocellular Carcinoma

• Hepatitis B is often associated with hepatocellular carcinoma.
• More than 85% of examined hepatocellular tumours harbor integrated HBV DNA, often multiple copies per cell. The viral DNA integrants are usually highly rearranged, with deletions, inversions, and sequence reiterations all commonly observed. Most of these rearrangements ablate viral gene expression, but the integrations alter the host DNA.

• Every cell in the tumor contains an identical complement of HBV insertions. This implies that the integration event(s) preceded the clonal expansion of the cells.
• There is no similarity in the pattern of integration between different tumors, and variation is seen in both the integration site(s) and in the number of copies or partial copies of the viral genome.

Associated Disorders

Hepatitis B infection is associated with several disorders characterized by immune complex deposition. These include polyarteritis nodosa, membranous nephropathy, and Gianotti-Crosti syndrome.

Polyarthritis Nodosa

• One form of polyarthritis nodosa (PAN) is the hepatitis B virus-associated polyarthritis nodosa (HBV-PAN). Its occurence is attributed to the deposition of auto-immune complexes with excess antigen in tissues such as the kidneys, joints, and GI tract. It can be characterized by:

• Renal involvement
• Renal vasculitis
• Rare relapses, never occurring after viral replication has stopped and seroconversion has occurred.

• Clinically, it may present with high fever, anemia, leucocytosis, arthralgia, arthritis, renal disease, hypertension, heart disease, gastrointestinal disease, skin manifestations, and neurologic abnormalities. The disorder has a highly variable prognosis with mortality rates reaching 40% within 3 years without appropriate therapy. The diagnosis may be established by angiography.
• GI tract involvement represents the greatest cause of death
• Vaccination and blood safety have decreased the incidence of HBV-PAN

Membranous glomerulonephritis

HBV-associated membranous glomerulonephritis is more common in children than in adults, where spontaneous remission is seen in up to 60% of patients within 1 year. Spontaneous resolution of HBV-related membranous nephropathy is not a common finding among adults, especially in patients living in endemic regions. These patients often develop complications related to overt nephrotic syndrome. Remission of membranous nephropathy is associated with clearance of the HBeAg from the serum.

Papular acrodermatitis of childhood (Gianotti-Crosti syndrome)

Gianotti-Crosti syndrome is a distinctive disease of childhood. Patients present with skin lesions, lentil-sized, flat, erythematous, and papular eruptions localized to the face and extremities and lasting 15 to 20 days. The disease is accompanied by generalized lymphadenopathy and hepatomegaly. It is associated with acute anicteric hepatitis B of ayw subtype.

Prognosis

• Acute hepatitis often lasts for 2-3 weeks. The liver usually returns to normal within 4-6 months in most infected patients.

• Almost all newborns and about 50% of children who are infected with hepatitis B develop chronic hepatitis. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus. 30% for younger children, and about 5% of newborns that acquire the infection from their mother at birth will clear the infection.
• This population has a 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma.

• People who have chronic hepatitis B can transmit the infection. They are considered carriers of the disease, even if they do not have any symptoms.

• In developing countries, most people with liver cancer die within months of diagnosis. In high-income countries, surgery and chemotherapy can prolong life for up to a few years.

• Hepatitis D (HDV) can occur only with a concomitant hepatitis B infection. Co-infection with hepatitis D increases the risk of liver cirrhosis and HCC.

References

Diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [25]; Associate Editor In Chief: Cafer Zorkun, M.D., Ph.D. [26]