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Liver Diseases: Hepatitis B

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Hepatitis B is a viral infection that affects the liver. It is transmitted through blood or bodily fluids, and can range from a mild illness lasting only a few weeks to a lifelong condition. There's a vaccine for this disease, so most people won't suffer complications, which include cirrhosis or even liver cancer. However, having as much information as possible at hand won't hurt, so prepare an informative slideshow about hepatitis B with this editable template. Its palette revolves around dark red tones, and the text included in the different sections has been generated by AI. While it's not specificaly about hepatitis B, it will give you some tips when it comes to structuring a presentation.

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Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection

Hepatitis B (HBV) infection is a major public health problem and cause of chronic liver disease. 

The 2024 HBV guidelines provide updated evidence-informed recommendations  on key priority topics. These include expanded and simplified treatment criteria for adults but now  also for adolescents; expanded eligibility for antiviral prophylaxis for pregnant women to prevent  mother-to-child transmission of HBV; improving HBV diagnostics through use of point-of-care  HBV DNA viral load and reflex approaches to HBV DNA testing; who to test and how to test  for HDV infection;  and approaches to promote delivery of high-quality HBV services, including strategies to promote adherence to long-term antiviral therapy and retention in care.

The 2024 guidelines include 11 updated chapters with new recommendations and also update existing chapters without new recommendations, such as those on treatment monitoring and surveillance for liver cancer.

Policy brief

Policy brief – Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection

Web annexes

Web annex A1: summary of declarations of conflict of interest (‎guideline development group)‎: web annex A2: summary of declarations of conflict of interest (‎external review group)‎  (PDF, 330 KB)

Web annex B: evidence-to-decision making tables and GRADE tables  (PDF, 1.2 MB)

Web annex C : systematic reviews, modelling, and landscape reports (PDF, 4.5 MB)

Web annex D : values and preferences survey reports (PDF, 830 KB)

Recording: Hepatitis B – WHO's webinar on its 2024 guidelines 

Slides: technical briefing presentations (PDF, 7.5 MB)

WHO publishes new guidelines on hepatitis B – Departmental news, 29 March 2024

WHO 2024 hepatitis B guidelines: an opportunity to transform care  – The Lancet Gastroenterology & Hepatology, 10 April 2024

Global Hepatitis Programme

• Patient Care & Health Information
• Diseases & Conditions
• Hepatitis B

Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV). For most people, hepatitis B is short term, also called acute, and lasts less than six months. But for others, the infection becomes chronic, meaning it lasts more than six months. Having chronic hepatitis B increases your risk of developing liver failure, liver cancer or cirrhosis — a condition that permanently scars the liver.

Most adults with hepatitis B recover fully, even if their symptoms are severe. Infants and children are more likely to develop a long-lasting hepatitis B infection. This is known as a chronic infection.

A vaccine can prevent hepatitis B, but there's no cure if you have the condition. If you're infected, taking certain precautions can help prevent spreading the virus to others.

Symptoms of acute hepatitis B range from mild to severe. They usually appear about 1 to 4 months after you've been infected, although you could see them as early as two weeks after you're infected. Some people, usually young children, may not have any symptoms.

Hepatitis B signs and symptoms may include:

• Abdominal pain
• Loss of appetite
• Nausea and vomiting
• Weakness and fatigue
• Yellowing of the skin and the whites of the eyes, also called jaundice

When to see a doctor

If you know you've been exposed to hepatitis B, contact your health care provider immediately. A preventive treatment may reduce your risk of infection if you receive the treatment within 24 hours of exposure to the virus.

If you think you have symptoms of hepatitis B, contact your health care provider.

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Hepatitis B infection is caused by the hepatitis B virus (HBV). The virus is passed from person to person through blood, semen or other body fluids. It does not spread by sneezing or coughing.

Common ways that HBV can spread are:

• Sexual contact. You may get hepatitis B if you have unprotected sex with someone who is infected. The virus can pass to you if the person's blood, saliva, semen or vaginal secretions enter your body.
• Sharing of needles. HBV easily spreads through needles and syringes contaminated with infected blood. Sharing IV drug paraphernalia puts you at high risk of hepatitis B.
• Accidental needle sticks. Hepatitis B is a concern for health care workers and anyone else who comes in contact with human blood.
• Mother to child. Pregnant women infected with HBV can pass the virus to their babies during childbirth. However, the newborn can be vaccinated to avoid getting infected in almost all cases. Talk to your provider about being tested for hepatitis B if you are pregnant or want to become pregnant.

Acute vs. chronic hepatitis B

Hepatitis B infection may be short-lived, also called acute. Or it might last a long time, also known as chronic.

• Acute hepatitis B infection lasts less than six months. Your immune system likely can clear acute hepatitis B from your body, and you should recover completely within a few months. Most people who get hepatitis B as adults have an acute infection, but it can lead to chronic infection.
• Chronic hepatitis B infection lasts six months or longer. It lingers because your immune system can't fight off the infection. Chronic hepatitis B infection may last a lifetime, possibly leading to serious illnesses such as cirrhosis and liver cancer. Some people with chronic hepatitis B may have no symptoms at all. Some may have ongoing fatigue and mild symptoms of acute hepatitis.

The younger you are when you get hepatitis B — particularly newborns or children younger than 5 — the higher your risk of the infection becoming chronic. Chronic infection may go undetected for decades until a person becomes seriously ill from liver disease.

Risk factors

Hepatitis B spreads through contact with blood, semen or other body fluids from an infected person. Your risk of hepatitis B infection increases if you:

• Have unprotected sex with multiple sex partners or with someone who's infected with HBV
• Share needles during IV drug use
• Are a man who has sex with other men
• Live with someone who has a chronic HBV infection
• Are an infant born to an infected mother
• Have a job that exposes you to human blood
• Travel to regions with high infection rates of HBV , such as Asia, the Pacific Islands, Africa and Eastern Europe

Complications

Having a chronic HBV infection can lead to serious complications, such as:

• Scarring of the liver (cirrhosis). The inflammation associated with a hepatitis B infection can lead to extensive liver scarring (cirrhosis), which may impair the liver's ability to function.
• Liver cancer. People with chronic hepatitis B infection have an increased risk of liver cancer.
• Liver failure. Acute liver failure is a condition in which the vital functions of the liver shut down. When that occurs, a liver transplant is necessary to stay alive.
• Reactivation of the hepatitis B virus. People with chronic hepatitis B who have suppression of their immune system are prone to reactivation of the hepatitis B virus. This can lead to significant liver damage or even liver failure. This includes people on immunosuppressive medications, such as high-dose corticosteroids or chemotherapy. Before taking these medications, you should be tested for hepatitis B. If you test positive for hepatitis B, you should be seen by a liver specialist (hepatologist) before starting these therapies.
• Other conditions. People with chronic hepatitis B may develop kidney disease or inflammation of blood vessels.

The hepatitis B vaccine is typically given as two injections separated by a month or three or four injections over six months, depending on which vaccine is given. You can't get hepatitis B from the vaccine. The hepatitis B vaccine is recommended by the United States Advisory Committee on Immunization Practices for adults 19 to 59 years of age who do not have a contraindication to the vaccine.

The hepatitis B vaccine is also strongly recommended for:

• Children and adolescents not vaccinated at birth
• Those who work or live in a center for people who are developmentally disabled
• People who live with someone who has hepatitis B
• Health care workers, emergency workers and other people who come into contact with blood
• Anyone who has a sexually transmitted infection, including HIV
• Men who have sex with men
• People who have multiple sexual partners
• Sexual partners of someone who has hepatitis B
• People who inject illegal drugs or share needles and syringes
• People with chronic liver disease
• People with end-stage kidney disease
• Travelers planning to go to an area of the world with a high hepatitis B infection rate

Take precautions to avoid HBV

Other ways to reduce your risk of HBV include:

• Know the HBV status of any sexual partner. Don't engage in unprotected sex unless you're absolutely certain your partner isn't infected with HBV or any other sexually transmitted infection.
• Use a new latex or polyurethane condom every time you have sex if you don't know the health status of your partner. Remember that although condoms can reduce your risk of contracting HBV , they don't eliminate the risk.
• Don't use illegal drugs. If you use illicit drugs, get help to stop. If you can't stop, use a sterile needle each time you inject illicit drugs. Never share needles.
• Be cautious about body piercing and tattooing. If you get a piercing or tattoo, look for a reputable shop. Ask about how the equipment is cleaned. Make sure the employees use sterile needles. If you can't get answers, look for another shop.
• Ask about the hepatitis B vaccine before you travel. If you're traveling to a region where hepatitis B is common, ask your provider about the hepatitis B vaccine in advance. It's usually given in a series of three injections over a six-month period.
• Hepatitis B. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-b. Accessed Aug. 15, 2022.
• Feldman M, et al., eds. Hepatitis B. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Aug. 16, 2022.
• Kellerman RD, et al. Hepatitis A, B, D, and E. In: Conn's Current Therapy 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed Aug. 16, 2022.
• Lok AS. Hepatitis B virus: Clinical manifestations and natural history. https://www.uptodate.com/contents/search. Accessed Aug. 16, 2022.
• Eng-Kiong T, et al. Epidemiology, transmission, and prevention of hepatitis B virus infection. https://www.uptodate.com/contents/search. Accessed Aug. 16, 2022.
• Picco MF (expert opinion). Mayo Clinic. Aug. 22, 2022.
• Weng MK, et al. Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices — United States, 2022. MMWR [Morbidity and Mortality Weekly Report; Recommendations and Reports; Surveillance Summaries; or Supplements]. 2022; doi:10.15585/mmwr.mm7113a1.

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StatPearls [Internet].

Hepatitis b.

Nishant Tripathi ; Omar Y. Mousa .

Affiliations

Last Update: July 9, 2023 .

• Continuing Education Activity

Hepatitis B infection is a serious global healthcare problem. Often transmitted via body fluids like blood, semen, and vaginal secretions, the hepatitis B virus can cause liver injury. After infection with the hepatitis B virus, the majority of adults are able to clear the infection. Patients can present with acute symptomatic disease or have an asymptomatic disease that is identified during screening for the hepatitis B virus. This article focuses on identifying who is at risk of hepatitis B, and clinical evaluation and management of patients with hepatitis B by an interdisciplinary team. It also focuses on preventive measures.

• Describe the epidemiology of hepatitis B.
• Outline the common blood tests for the diagnosis of hepatitis B infection.
• Review the complications of hepatitis B infection.
• Explain the importance of collaboration and communication amongst the interdisciplinary teams to enhance the delivery of care for patients affected by hepatitis B.
• Introduction

Hepatitis B viral infection is a serious global healthcare problem. It is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV). It is often transmitted via body fluids like blood, semen, and vaginal secretions. The majority (more than 95%) of immunocompetent adults infected with HBV can clear the infection spontaneously. Patients can present with acute symptomatic disease or have an asymptomatic infection that is identified during screening for HBV. The clinical manifestations of HBV infection vary in both acute and chronic diseases. During the acute infection, patients can have subclinical or anicteric hepatitis, icteric hepatitis, or less commonly fulminant hepatitis. In chronic infection, patients can have an asymptomatic carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma.

Initial symptoms are nonspecific and may include anorexia, nausea, vomiting, abdominal pain, and jaundice. In cases of severe liver damage, patients can develop jaundice, hepatic encephalopathy, ascites, gastrointestinal bleeding secondary to esophageal varices, coagulopathy, or infections. Diagnosis is based on serologic blood tests in patients with suspected signs and symptoms and associated risk factors for viral hepatitis. This will be discussed in more detail below.

Transmission of hepatitis B involves the transfer of the virus from infected people to non-immune people in various ways. Major modes of transmission for hepatitis B are as follows:

1. Horizontal transmission: It involves the transmission of hepatitis B through sexual contact or mucosal surface contact. Unprotected sex and injection drug use are major modes of transmission in low to intermediate prevalence areas. [1]  

2. Vertical transmission: Vertical transmission involves the maternal-to-newborn perinatal transmission of the virus. [2]  It is the predominant mode of transmission in high-prevalence areas. 

Sexual contact includes unprotected intercourse (vaginal, oral, or anal) and mucosal contact involves any contact involving an infected patient’s saliva, vaginal secretion, semen, and blood.

Prevalence areas are based on the percentage of the population with hepatitis B surface antigen (HBsAg) positivity with greater than or equal to 8% representing high prevalence areas, 2-7% representing low to intermediate prevalence areas, and less than 2% representing low prevalence areas. [3]

• Epidemiology

HBV infection has the potential for progression to a chronic state and thus presents as a global public health threat for its associated morbidity and mortality. While hepatitis B vaccines are available, limited access to healthcare and lack of proper health education contributes to the increasing global prevalence of hepatitis B. Lower incidence of hepatitis B in the United States compared to Asia and Africa is due to better access to healthcare and better use of vaccinations and other preventive measures. 

 U.S. Statistics 

• Around 60,000 new cases of HBV infection annually [4]
• 2 million or more people with chronic hepatitis B infection [4]
• Prevalence is higher in black, Hispanic, and Asian populations compared to whites [5]  
• Prevalence is lower in people less than 12 years of age born in the U.S. 
• Accounts for 5% to 10% of chronic end-stage liver disease, and 10% to 15% of cases of hepatocellular cancer
• Causes 5000 deaths annually 

Worldwide Statistics

• 350-400 million of the world population has chronic hepatitis B. [6]
• The following population is known to have a higher prevalence: Asian Pacific Islanders, Alaskan Eskimos, and Australian aborigines. [6]
• The following geographic regions have higher prevalence: the Indian sub-continent, sub-Saharan Africa, and central Asia.
• The prevalence of hepatitis B is reduced after the initiation of the hepatitis B vaccination program.
• 10 genotypes (A-J) of hepatitis B have been identified. [7]

High-risk groups for HBV infection include intravenous drug users, infants born to infected mothers, males who have sexual intercourse with other males, hemodialysis patients (and workers), healthcare workers, household contacts of known patients with chronic HBV. A majority of the global HBV disease burden is primarily through vertical transmission.

• Pathophysiology

Hepatitis B virus is transmitted via percutaneous inoculation or through mucosal exposure with infectious bodily fluids. Oral-fecal transmission is possible but considerably rare. The incubation period of HBV infection is typically between 30 and 180 days, and while recovery is common in immunocompetent patients, a small percentage can progress to a chronic state, serologically defined as the presence of HBsAg for greater than six months. HBsAg is transmitted via blood contact or body secretions, and the risk of acquiring hepatitis B is considerably higher in individuals with close contact with HBsAg-positive patients.

The pathogenesis of liver disease in HBV infection is mainly immune-mediated, and in some circumstances, HBV can cause direct cytotoxic injury to the liver. HBsAg and other nucleocapsid proteins that are present on cell membranes promote T cells-induced cellular lysis of HBV-infected cells. Cytotoxic T cell response to HBV-infected hepatocytes is relatively ineffective; a significant majority of HBV DNA is cleared from the hepatic system prior to maximal T cell infiltration, suggesting that the immune response is likely more robust in the early stages of infection. The immune response may not be the sole etiology behind hepatic injury in hepatitis B patients. Hepatitis B-associated injury is also seen in post-liver transplant patients with hepatitis B that are on immunosuppressant therapy. The histological pattern that follows from this infection is termed fibrosing cholestatic hepatitis and is thought to be associated with an overwhelming exposure to HBsAg. This lends credence to the idea that hepatitis B may possess pathogenicity regardless of the immune system’s response. [8]

• Histopathology

Acute Hepatitis B Infection: Histologic findings include "lobular disarray, ballooning degeneration, multiple apoptotic bodies, Kupffer cell activation, and lymphocyte-predominant lobular and portal inflammation. [9]

Chronic Hepatitis B Infection:  Lymphocyte-predominant portal inflammation with interface hepatitis and spotty lobular inflammation. [9]

• History and Physical

Patients infected with HBV could be asymptomatic initially and, depending on the particular genotype, might not be symptomatic throughout the infected state. In these particular cases, careful history taking is important to establish a diagnosis. However, when symptomatic from acute HBV infection, patients can present with serum sickness-like syndrome manifested as fever, skin rash, arthralgia, and arthritis. This syndrome usually subsides with the onset of jaundice. Patients may also have fatigue, abdominal pain, nausea, and anorexia.

History taking should emphasize the social history, including sexual practices (e.g., unprotected, same-sex, etc.), illicit drug use, profession (e.g., healthcare worker, sex worker), and living arrangements (i.e., within the same household as a patient with HBV infection). Patients in high-risk groups (i.e., healthcare workers, IV substance abuse patients, etc.) or those from highly endemic areas may warrant testing. Those with certain mental illnesses like bipolar disorder, schizophrenia, or manic disorder are at an increased risk for contracting HBV infection during manic states within which one may participate in risky sexual behaviors, including unprotected sex.

Physical examination should also assess for stigmata of chronic liver disease, including jaundice, ascites, hepatomegaly, splenomegaly, palmar erythema, Dupuytren contractures, spider nevi, gynecomastia, caput medusa, and hepatic encephalopathy which suggests portal hypertension and cirrhosis.

Extrahepatic manifestations include polyarteritis nodosa and glomerular disease (membranous nephropathy and, less often, membranoproliferative glomerulonephritis). Aplastic anemia has also been described.

Diagnosis of Hepatitis B is based on proper history taking, physical examination, laboratory works, and imaging. 

Initial symptoms are nonspecific and can include anorexia, nausea, vomiting, abdominal pain, dark urine, clay-colored stool, and jaundice. In cases of severe liver damage, advanced findings specific to liver damage are common and can include hepatic encephalopathy, confusion, coma, ascites, gastrointestinal bleeding, coagulopathy, or infections. In cases of chronic hepatitis B, patients can have a chronic inactive infection, or they can develop findings of acute hepatitis known as chronic active hepatitis. 

The diagnosis of hepatitis B relies on the appropriate history/physical and evaluation of serum or viral biomarkers. Viral serology of hepatitis B is usually detectable 1-12 weeks after initial infection with the primary viral marker being hepatitis B surface antigen (HBsAg). The presence of HBsAg rarely persists beyond 6 months after infection and typically precedes detectable quantities of the corresponding antibody to surface antigen (Anti-HBsAg). The period of time between the disappearance of HBsAg and the appearance of Anti-HBsAg is termed “the window period” or “serological gap.” During the window period, other viral serology could also be undetectable. HBsAg is the first virological marker to be detected thanks to its exposure on the viral surface and is indicative of an acute infection. Immune-mediated destruction of the nucleocapsid allows exposure of core antigen (HBcAg) or e antigen (HBeAg) with subsequent antibody development. Liver enzymes are typically elevated within the latter part of the replicative phase on infection thanks to active inflammatory processes, otherwise, liver transaminases could also be within their reference ranges. Hence, liver transaminases should not be a sole guide to diagnosing suspected hepatitis B infection.

The presence of antibodies to HBsAg indicates immunized status while the presence of antibodies to HBeAg refers to a possible chronic infection state. Seroconversion refers to the transition between an acute, immune-active phase to an inactive carrier state and is marked by the spontaneous development of antibodies to HBeAg. Earlier seroconversion has been related to more favorable outcomes while later seroconversion, in conjunction with recurrent bouts of reactivation and remission, is more liable to complications like liver cirrhosis, thus resulting in poorer outcomes. [10] The persistence of serum HBsAg for a duration of 6 months or greater delineates acute hepatitis B infection from chronic hepatitis B infection. Following groups of people should be screened for hepatitis B: [3]

• Persons born in high or intermediate endemic areas (HBsAg prevalence of greater than or equal to 2%). African countries, countries from North, Southeast, and East Asia. All countries from Australia and South Pacific (except for Australia and New Zealand). All countries from the Middle East (except for Israel and Cyprus). All countries from Eastern Europe (except for Hungary), Western Europe (Spain, Malta, and the indigenous population of Greenland), North America (Alaskan natives and indigenous populations of Northern Canada), Mexico, Guatemala, and Honduras. South America (Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas). Caribbean (Antigua, Barbuda, Dominica, Grenada, Haiti, Jamaica, Saint Kitts and Nevis, Saint Lucia, and Turks and Caicos Islands).
• The unvaccinated U.S. citizens whose parents were born in high prevalence areas.
• History of illicit intravenous drug use.
• Men who have sex with men.
• Persons on immunosuppressive therapy.
• Persons with elevated ALT or AST of unknown origin.
• Blood, plasma, organ, tissues, or semen donors.
• Persons with end-stage renal disease.
• All pregnant women and infants born to HBsAg-positive mothers.
• Persons with chronic liver disease and HIV.
• Close contacts of HBsAg-positive persons, such as household, sexual, or needle-sharing.
• Persons with more than one sexual partner in the last six months.
• Persons requesting evaluation or treatment for sexually transmitted infections.
• Health care workers or public safety workers who are at risk for occupational exposure to blood or blood-contaminated body fluids.
• Residents and staff at facilities for developmentally disabled persons.
• Travelers to countries with an intermediate or high prevalence of Hepatitis B virus infection.
• Correctional facilities inmates.
• 19-59-year-old persons with diabetes who have not been vaccinated for Hepatitis B.
• Persons who are the source of blood or body fluid exposures that might require post-exposure prophylaxis.

Interpretation of Serologic Markers

Following serologic markers are often tested: Hepatitis B surface antigen (HBsAg), antibody to Hepatitis B surface antigen (anti-HBs), Hepatitis B core Ab (Anti-HBc) IgM, Hepatitis B core Ab (Anti-HBc) IgG, Hepatitis B e antigen (HBeAg), and Hepatitis B e antibody (anti-HBe). [10]

HBsAg: Acute infection (less than 6 months) or chronic infection (more than 6 months).

Anti-HBs: Recovery from acute infection or immunity from vaccination.

HBeAg: Mostly associated with high viral load.

Anti-HBe: Low replicative phase.

Anti-HBc IgM: Acute infection, an only marker present in the window period, can be present during exacerbation of chronic infection.

Anti-HBc IgG: Exposure to infection, chronic infection (if present along with HBsAg), recovery from acute infection (if present with anti-HBs), if isolated presence, may represent occult infection.

Other markers are: Hepatitis B viral DNA is for detection of viral load. Hepatitis B genotype provides input about disease progression and response to interferons. [11]

• Treatment / Management

Preventive measures constitute a major component of the management of hepatitis B. As of 2019, hepatitis B vaccines available in the United States are categorized into either single-antigen hepatitis B vaccines or combination vaccines.

Acute hepatitis B infection is self cleared in 95% of healthy adults. Management is supportive in a majority of patients. Patients with severe acute disease (2 of the 3: bilirubin more than 10 mg/dl, INR more than 1.6 and hepatic encephalopathy) and protracted acute severe disease (total bilirubin more than 3 mg/dl or direct bilirubin more than 1.5 mg/dl, INR more than 1.5, hepatic encephalopathy, or ascites) need antiviral treatment.

Management of chronic hepatitis B should include identification of HIV, hepatitis C, and hepatitis D coinfection, hepatitis B virus replication status, and severity of the disease. [10]  The severity of the disease is based on clinical assessment, blood counts, liver enzymes, and liver histology. [10]  While non-invasive tests are useful (blood test, imaging to measure liver stiffness) for chronic hepatitis B with normal alanine transferase, for patients with elevated or fluctuating alanine transferase, liver biopsy is necessary to identify if they need antiviral treatment. [10]

FDA-approved medications for chronic hepatitis B include interferons (peginterferon alfa-2a, interferon alfa-2b), nucleoside analogs (entecavir, lamivudine, telbivudine), and nucleotide analogs (adefovir, tenofovir). Entecavir and tenofovir are preferred for acute HBV infection if treatment is warranted, due to their relatively higher barrier to resistance. Entecavir combination drugs have been developed. However, a 2018 meta-analysis based on 24 studies involved with entecavir polytherapy vs entecavir monotherapy determined that entecavir combination drugs were no more effective than entecavir monotherapy. [12]  Vertical transmission of hepatitis B remains a significant cause of the global HBV burden. In a 2015 prospective, multicenter trial, administration of tenofovir in HBsAg-positive and/or HBeAg-positive mothers demonstrated a benefit in reducing ALT levels in mothers and decreasing infant HBsAg levels at 6 months postpartum. [13]  Major drawbacks for this study, however, include a relatively small sample size (n=118) and the lack of a placebo-based control group.  Oral nucleos(t)ide therapy has been shown to suppress viral replication and thus decrease the viral burden. Lamivudine was the first effective agent to successfully used to suppress viral counts but was associated with high drug resistance. [14]  A 2014 clinical trial comparing entecavir vs lamivudine in chronic B hepatitis reported better virological response in the entecavir group compared to the lamivudine group. [15]  The 2013 GAHB trial was a placebo-controlled, double-blind study that compared lamivudine with a placebo. HBsAg clearance was achieved in a majority of patients with lamivudine therapy but the overall strength of the study was weakened by low recruitment numbers (n = 35). [16] For patients in the immune-tolerant phase of hepatitis B infection, a stage marked by normal liver transaminases and HBV DNA, antiviral medications were not recommended. A randomized controlled study showed suboptimal control of viral burden, likely secondary to high circulating levels of HBV DNA. [17]  Regarding monotherapy versus combined therapy, there have been several limited studies addressing this issue. In the 2018 POTENT study, there was no demonstrated difference between monotherapy versus sequential therapy although there was insufficient data for statistical significance for HBsAg seroconversion. [18]

The counseling of patients on the prevention of transmission is extremely valuable. Lifestyle modifications include reducing intake of agents with potential for liver damage such as alcohol, hepatotoxic medications, herbal medications, and herbal supplements. 

The goals of antiviral therapy are: [10]

• Suppression of hepatitis B virus replication
• Reduction of liver inflammation
• Prevention of progression to liver cirrhosis and hepatocellular carcinoma

Appropriate treatment response is indicated by the following findings: [10]

• Blood tests: normalization of ALT
• Undetectable hepatitis B viral DNA
• Loss of HBsAg and HBeAg with seroconversion to anti-HBs and anti-HBe
• Reduced inflammation on liver biopsy with no worsening of fibrosis

Surgical intervention for hepatitis B is only indicated for fulminant liver disease requiring transplantation.

• Differential Diagnosis

The differential diagnosis for hepatitis B infection is broad due to the presence of non-specific symptoms such as fatigue, abdominal pain, nausea, and vomiting. Other etiologies of hepatitis (i.e., hepatitis A, hepatitis C, hepatitis E, alcoholic hepatitis, and autoimmune hepatitis) should be considered in conjunction with appropriate history taking and pertinent laboratory investigation.

Iron overload (hemochromatosis) can be associated with abdominal tenderness and abnormal liver transaminase levels. Pertinent findings that favor a diagnosis of hemochromatosis compared to hepatitis B include diffuse skin discoloration (bronze diabetes) and impaired glucose tolerance.

Wilson disease is a disease of excessive copper accumulation. It is associated with psychiatric disturbances due to copper accumulation in the basal ganglia. Kayser-Fleischer rings are pathognomonic for Wilson disease but are not completely sensitive (requires an expert ophthalmologist to confirm this finding). Laboratory evaluation that favors a diagnosis of Wilson disease includes low serum ceruloplasmin levels and elevated urinary copper, and if abnormal, requires further evaluation by a hepatologist.

• Alcoholic hepatitis
• Autoimmune hepatitis
• Drug-induced liver injury
• Hemochromatosis
• Hepatitis A
• Hepatitis C
• Hepatitis D
• Hepatitis E
• Hepatocellular carcinoma
• Human immunodeficiency virus
• Wilson disease

Acute HBV infection can be treated symptomatically and in immunocompetent patients, can spontaneously resolve. Those that progress to the chronic state, however, are at increased risk for the development of hepatocellular carcinoma, cirrhosis, or fulminant liver failure. The likelihood of risk is dependent on the particular genotype, and the method of transmission as vertical transmission has a higher risk of long-term complications compared to horizontal transmission cases.

• Complications

Unlike hepatitis A and hepatitis E, in which there is no chronic state, HBV infection has the potential for the development of a chronic state. Chronic hepatitis B predisposes a patient to the development of portal hypertension, cirrhosis, and its complications or hepatocellular carcinoma (HCC). As such, patients with HBV infection should be monitored closely, and a referral to a specialist is highly recommended.Fulminant liver failure from HBV infection requires an emergent liver transplant evaluation at a liver transplant center.

• Consultations

Hepatitis B management ideally involves interprofessional collaboration. Primary care, gastroenterology, hepatology, infectious disease, liver transplant, and palliative care services are among the different services involved.

• Deterrence and Patient Education

Patient education remains one of the most important components in preventative measures regarding HBV infection.

Education should be provided to expecting parents (particularly those from highly endemic regions) about the importance of vaccination and to clarify erroneous beliefs about vaccinations.Patient education should also include counseling about the avoidance of risky behaviors that predispose an individual to be infected, including promiscuous sexual activity or intravenous drug abuse. They should also be advised not to share items such as shaving razors, toothbrushes, or hair combs due to possible transmission via mucosal contact or through microtrauma to protective barriers.

• Pearls and Other Issues

Hepatitis D (a member of the delta virus family) has been long associated with HBV infections and cannot exert pathological influence without the presence of HBV infection. Two forms of infection exist; coinfection (acquired at the same time) and superinfection (hepatitis D infection in a patient with chronic hepatitis B infection). Superinfection tends to be more severe than coinfection. Due to the preexisting hepatitis B infection, anti-HBcAg IgM is undetectable in superinfection states but can be noted in coinfection.

• Enhancing Healthcare Team Outcomes

As hepatitis B infection is highly transmissible via accidental needlesticks, healthcare providers involved in taking care of a patient with HBV should exercise caution and practice proper preventative measures such as vaccination. Patient education should also include counseling about HBV transmission. The interprofessional team's role is crucial in ensuring the best patient outcomes.

The vaccination rate is low in many developing countries, and the majority of patients are undiagnosed. Educational programs and improved awareness among the general public and healthcare providers are necessary to improve the identification of the patients, reduce transmission of the disease, and reduce the complications of hepatitis B infection.

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Disclosure: Nishant Tripathi declares no relevant financial relationships with ineligible companies.

Disclosure: Omar Mousa declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Tripathi N, Mousa OY. Hepatitis B. [Updated 2023 Jul 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Hepatitis B

• Author: Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP(Edin); Chief Editor: BS Anand, MD  more...
• Sections Hepatitis B
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Approach Considerations
• Diagnostic Tests
• Radiologic Studies
• Liver Biopsy and Histologic Features
• Pharmacologic Management
• Surgical Intervention
• Hepatitis B and Pregnancy
• Vaccination
• Long-Term Monitoring
• 2016 and 2018 AASLD Guidelines
• 2017 and 2018 EASL Recommendations
• 2015 and 2020 WHO Guidelines Summary
• Medication Summary
• Interferons
• Antihepadnaviral, Reverse Transcriptase inhibitors
• Vaccines, Inactivated, Viral
• Questions & Answers
• Media Gallery

Hepatitis B infection is a worldwide healthcare problem, especially in developing areas. The hepatitis B virus (HBV) is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. [ 1 ]

The hematoxylin and eosin (H&E) stain below depicts "ground-glass" cells seen in approximately 50-75% of livers affected by chronic HBV infection.

Signs and symptoms

The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system, which leads to liver injury and, potentially, cirrhosis and hepatocellular carcinoma. Patients can have either an acute symptomatic disease or an asymptomatic disease.

Icteric hepatitis is associated with a prodromal period, during which a serum sickness–like syndrome can occur. The symptomatology is more constitutional and includes the following:

Low-grade fever

Fatigability

Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)

Right upper quadrant and epigastric pain (intermittent, mild to moderate)

Patients with fulminant and subfulminant hepatitis may present with the following:

Hepatic encephalopathy

Disturbances in sleep pattern

Mental confusion

Gastrointestinal bleeding

Coagulopathy

Patients with chronic hepatitis B infection can be immune tolerant or have an inactive chronic infection without any evidence of active disease, and they are also asymptomatic. Patients with chronic active hepatitis, especially during the replicative state, may have symptoms similar to those of acute hepatitis.

See Clinical Presentation for more detail.

The physical examination findings in hepatitis B disease vary from minimal to impressive (in patients with hepatic decompensation), according to the stage of the disease.

Examination in patients with acute hepatitis may demonstrate the following:

Jaundice (10 days after appearance of constitutional symptomatology; lasts 1-3 mo)

Hepatomegaly (mildly enlarged, soft liver)

Splenomegaly (5-15%)

Palmar erythema (rarely)

Spider nevi (rarely)

Signs of chronic liver disease include the following:

Hepatomegaly

Splenomegaly

Muscle wasting

Palmar erythema

Spider angiomas

Vasculitis (rarely)

Patients with cirrhosis may have the following findings:

History of variceal bleeding

Peripheral edema

Gynecomastia

Testicular atrophy

Abdominal collateral veins (caput medusa)

Laboratory studies

The following laboratory tests may be used to assess the various stages of hepatitis B disease:

Alanine aminotransferase and/or aspartate aminotransferase levels

Alkaline phosphatase levels

Gamma-glutamyl transpeptidase levels

Total and direct serum bilirubin levels

Albumin level

Hematologic and coagulation studies (eg, platelet count, complete blood count [CBC], international normalized ratio)

Ammonia levels

Erythrocyte sedimentation rate

Serologic tests

The serologic tests should include the following laboratory studies:

Hepatitis B surface antigen (HBsAg)

Hepatitis B e antigen (HBeAg)

Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM)

anti-HBc IgG

Hepatitis B e antibody (anti-HBe)

hepatitis B virus (HBV) deoxyribonucleic acid (DNA)

Imaging studies

The following radiologic studies may be used to evaluate patients with hepatitis B disease:

Abdominal ultrasonography

Abdominal computed tomography (CT) scanning

Abdominal magnetic resonance imaging (MRI)

Liver biopsy, percutaneous or laparoscopic, is the standard procedure to assess the severity of disease in patients with features of chronic active liver disease (ie, abnormal aminotransferase levels and detectable levels of HBV DNA).

See Workup for more detail.

The primary treatment goals for patients with hepatitis B infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, or hepatocellular carcinoma (HCC). [ 2 ] Pegylated interferon alfa (PEG-IFN-a), entecavir, and tenofovir disoproxil fumarate are the FDA-approved agents in the treatment of hepatitis B disease.

Pharmacotherapy

The following medications are used in the treatment of hepatitis B:

Nucleos(t)ide reverse transcriptase inhibitors (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine)

Hepatitis B/hepatitis C agents (eg, adefovir dipivoxil, entecavir, PEG-IFN-a 2a, interferon alfa-2b)

Dietary changes

For individuals with decompensated cirrhosis (prominent signs of portal hypertension or encephalopathy), the following dietary limitations are indicated:

A low-sodium diet (1.5 g/day)

High-protein diet (ie, white-meat protein [eg, chicken, turkey, fish])

Fluid restriction (1.5 L/day) in cases of hyponatremia

Liver transplantation

Orthotopic liver transplantation is the treatment of choice for patients with fulminant hepatic failure who do not recover and for patients with end-stage liver disease due to hepatitis B disease.

See Treatment and Medication for more detail.

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population is infected with the hepatitis B virus (HBV). Approximately 250-350 million people have lifelong chronic infection, [ 3 ] with approximately 1.5 million new cases every year. [ 4 ] Approximately 0.5% of patients spontaneously seroconvert annually from having the hepatitis B surface antigen (HBsAg) to having the hepatitis B surface antibody (anti-HBs). [ 5 ] (See Pathophysiology , Etiology , and Epidemiology .)

Complications from hepatitis B include progression to hepatocellular carcinoma (HCC) and, rarely, cirrhosis. Extrahepatic disease can involve glomerulonephritis and polyarteritis nodosa, as well as various dermatologic, cardiopulmonary, joint, neurologic, hematologic, and gastrointestinal (GI) manifestations. (See Pathophysiology .)

Since the 1970s, considerable progress has also been made regarding the knowledge of the epidemiology, virology, natural history, and treatment of the hepatitis B virion, a hepatotropic virus particle (see the image below). In addition, ongoing vaccination programs have been successful in many countries and territories in decreasing the prevalence of HBV disease (eg, Taiwan). [ 6 ] (See Etiology , Epidemiology , Workup , Treatment , and Medication .)

HBV is transmitted vertically from mother to fetus, hematogenously, and sexually. The outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease or an asymptomatic disease. Some patients clear HBV and develop anti-HBs; however, as long as the individual has antibody to hepatitis B core antigen (HBcAg), he or she is at risk for reactivation because HBV infection remains an incurable disease, similar to Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Herpes simplex virus (HSV) infections. Alternatively, a patient may develop a chronic infection state with positivity for HBsAg. Late consequences are cirrhosis and the development of HCC in 15-30% of individuals. [ 6 , 7 , 8 , 9 ]

In immunocompetent adults, less than approximately 4% of HBV infections become chronic, whereas up to 90% of perinatally infected infants will have chronic disease. [ 10 ] Among children who acquire HBV infection between ages 1 and 5 years, 30-50% become chronically infected.

Taiwan launched a nationwide HBV vaccination program in 1984. The prevalence of HCC in children younger than 20 years has been reported to be 0.5% or less. [ 6 ]

According to the World Health Organization (WHO), by the end of 2010, the HBV vaccine had been routinely introduced in 179 countries, with a global coverage of 75%. Coverage in the Americas was at 89%; in Europe, 78%; in Africa, 76%; and in Southeast Asia, 52%. [ 11 ]

Antiviral treatment may be effective in approximately 95% of the patients who are treated with first-line oral therapy, as defined by undetectable HBV DNA. For those who are treated with interferon, about 17% have persistent HBV DNA suppression. For selected candidates, liver transplantation currently seems to be the only viable treatment for the later stages of hepatitis B infection, with a posttransplantation viral suppression of greater than 90-95%. (See Treatment and Medication .)

See also Liver Disease in Pregnancy , Hepatitis A , Hepatitis C , Hepatitis D , and Hepatitis E .

Hepatitis B virus (HBV) is a hepadnavirus (see the following image), with the virion consisting of a 42-nm spherical, double-shelled particle composed of small spheres and rods and with an average width of 22 nm. [ 12 , 13 , 14 , 15 , 16 ] It is an exceedingly resistant virus, capable of withstanding extreme temperatures and humidity. HBV can survive when stored for 15 years at –20°C, for 24 months at –80°C, for 6 months at room temperature, and for 7 days at 44°C. Indeed, the approximately 400-year-old mummified remains of a child found on a mountain top in Korea had HBV in the liver that could be sequenced, and a viral genotype C was identified. [ 17 ]

Viral genome

The viral genome of hepatitis B consists of a partially double-stranded, circular DNA molecule of 3.2 kilobase (kb) pairs that encodes the following 4 overlapping open reading frames:

S (the surface, or envelope, gene): Encodes the pre-S1, pre-S2, and S proteins

C (the core gene): Encodes the core nucleocapsid protein and the e antigen; an upstream region for the S (pre-S) and C (pre-C) genes has been found

X (the X gene): Encodes the X protein

P (the polymerase gene): Encodes a large protein promoting priming ribonucleic acid (RNA) ̶ dependent and DNA-dependent DNA polymerase and ribonuclease H (RNase H) activities

Surface gene

The S gene encodes the viral envelope. There are five main antigenic determinants: (1) a, common to all hepatitis B surface antigens (HBsAg), and (2-5) d, y, w, and r, which are all epidemiologically important and identify the serotypes.

The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response.

The e antigen, HBeAg, which is also produced from the region in and near the core gene, is a marker of active viral replication. It serves as an immune decoy and directly manipulates the immune system; it is thus involved in maintaining viral persistence. HBeAg can be detected in patients with circulating serum HBV DNA who have “wild type” infection. As the virus evolves over time under immune pressure, core promotor and precore mutations emerge, and HBeAg levels fall until the level is not measurable by standard assays.

Individuals who are infected with the wild type virus often have mixed infections, with core and precore mutants in up to 50% of individuals. They often relapse with HBeAg-negative disease after treatment.

The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

Antibody production

The production of antibodies against HBsAg (anti-HBs) confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated.

Antibody to HBcAg (anti-HBc) is detected in almost every patient with previous exposure to HBV and indicates that there is a minute level of persistent virus, as demonstrated by the risk of reactivation in individuals who undergo immune suppression regardless of their anti-HBs status.

The immunoglobulin M (IgM) subtype of anti-HBc is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. The activity of the disease cannot be understood using this marker alone, however.

Antibody to HBeAg may be suggestive of a nonreplicative state if there is undetectable HBV DNA or the emergence of the core/precore variants and of chronic HBV HBeAg-negative disease.

Variants of HBV

With the newest polymerase chain reaction (PCR) assay techniques, scientists are able to identify variations in the HBV genome (variants) as far back as 1995, even in patients who are positive for HBeAg. Mutations of various nucleotides such as the 1896, 1764, and 1768 (precore/core region) processing the production of the HBeAg have been identified (HBeAg-negative strain). [ 18 ]

These variants are generally less efficient at viral replication without HBeAg and tend to have lower viral loads, although with a suspected higher risk of development of cirrhosis and hepatocellular carcinoma (HCC). [ 19 ]

The prevalence of the HBeAg-negative virus varies from one region to another. Estimates indicate that among patients with chronic HBV infection, 50-60% of those from Southern Europe, the Middle East, Asia, and Africa, as well as 10-30% of patients in the United States and Europe, have been infected with this strain.

Immune response

The pathogenesis and clinical manifestations of hepatitis B infection are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury, the result of an immunologic reaction when activated CD4 + and CD8 + lymphocytes recognize various HBV-derived peptides on the surface of the hepatocytes. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T-cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes. [ 20 , 21 ]

The final state of HBV disease is cirrhosis. With or without cirrhosis, however, patients with HBV infection are at risk of developing HCC. [ 6 , 7 , 8 ] In the United States, hepatitis B–associated HCC cases most often occur in the setting of vertical transmission (mother to fetus) in patients of Asian descent.

Viral life cycle

The five stages that have been identified in the viral life cycle of hepatitis B infection are briefly discussed below. Different factors have been postulated to influence the development of these stages, including age, sex, immunosuppression, and coinfection with other viruses.

Stage 1: Immune tolerance

This stage, which lasts approximately 2-4 weeks in healthy adults, represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.

Stage 2: Immune active/immune clearance

In the immune active stage, also known as the immune clearance stage, an inflammatory reaction with a cytopathic effect occurs. Serum HBeAg can be identified, and a decline in the levels of HBV DNA is seen in some patients who are clearing the infection. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops, immune clearance takes place, HCC develops, or the chronic HBeAg-negative variant emerges.

Stage 3: Inactive chronic infection

In the third stage, the inactive chronic infection stage, the host can target the infected hepatocytes and HBV. Viral replication is low or no longer measurable in the serum, and anti-HBe can be detected. Aminotransferase levels are within the reference range. It is likely that at this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present in the serum.

Stage 4: Chronic disease

The emergence of chronic HBeAg-negative disease can occur from the inactive chronic infection stage (stage 3) or directly from the immune active/clearance stage (stage 2).

Stage 5: Recovery

In the fifth stage, the virus cannot be detected in the blood by DNA or HBsAg assays, and antibodies to various viral antigens have been produced. The image below depicts the serologic course of HBV infection.

Genotypes and disease progression

Ten different genotypes (A through J), representing a divergence of the viral DNA of about 8%, have been identified. [ 22 ] The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated and the response to treatment with antiviral agents is less favorable for patients infected by genotype C, compared with those infected by genotype B. However, much of this can be explained by the presence of core and precore mutations found in multivariate analysis. [ 23 , 24 ]

It has been confirmed that the risk of HCC is related to higher serum HBV DNA levels and the duration of HBV DNA presence, with an even higher risk if there is an increasing level of hepatitis B viral load, the presence of genotype C, and the presence of mutations in the precore and basal core promoter regions.

Hepatocellular carcinoma

Even the presence of hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC, although surveillance for HCC is not recommended in the affected group unless cirrhosis is present. In the United States, the estimated annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. In Taiwan, the annual incidence of this malignancy in patients with hepatitis B and cirrhosis is 2.8%. Familial clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska.

HBV and HCV coinfection

The prevalence of HCC among patients with HBV and hepatitis C virus (HCV) coinfection is higher than in those with a single infection. The rate of development of HCC per 100 person years of follow-up is 2% in patients with cirrhosis and HBV infection, 3.7% in patients with HCV infection, and 6.4% in patients with dual HBV and HCV infection. These findings point to a probable synergistic effect on the risk of HCC.

HBV and HDV coinfection

Individuals coinfected with hepatitis D (delta) virus (HDV) are thought to have a higher rate of HCC and cirrhosis, with the virus reportedly increasing the risk of HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis. [ 25 ]

Worldwide, the prevalence of HDV coinfection among patients infected with HBV is 0-30%, with the highest prevalence in Mongolia, Southeast Turkey, and the Orinoco River in South America. The speculation that HDV may promote hepatocarcinogenesis in these patients has been investigated with varying results. The prevalence of anti-delta antibody among patients with cirrhosis with and without HCC was not significantly different in one study, whereas most other investigations show the delta virus to be more aggressive, with higher rates of cirrhosis and cancer. [ 25 , 26 , 27 ]

Possible pathogenic mechanisms

The mechanism by which chronic hepatitis B infection predisposes to the development of HCC is not clear. Cirrhosis is a cardinal factor in carcinogenesis. Hepatocyte inflammation, necrosis, mitosis, and features of chronic hepatitis are major factors in nodular regeneration, fibrosis, and carcinoma. Liver cell dysplasia, defined as cellular enlargement, nuclear pleomorphism, and multinucleated cells affecting groups or whole nodules, may be an intermediate step. The high cell-proliferation rate increases the risk of HCC.

The fact that the facultative liver stem cells are capable of bipotent differentiation into hepatocytes or biliary epithelium, termed oval cells, may play an important role in the pathogenesis. These cells are small, with oval nuclei and scant pale cytoplasm.

Oval cells are prominent in actively regenerating nodules and in liver tissue surrounding the cancer. They appear to be the principal producers of alpha-fetoprotein (AFP). Although the cellular targets of carcinogenesis have not been identified, some evidence from experimental animal models suggests that oval cell proliferation is associated with an increased risk for the development of HCC.

Although cirrhosis is found in the majority of patients with HCC, it is not obligatory, because individuals with chronic infection may develop HCC even without the evidence of cirrhosis.

HBV has been speculated to have intrinsic hepatocarcinogenic activity, interacting with host DNA in different ways. After entering the hepatocyte, viral DNA is integrated within the genome. The site of integration is not constant but usually involves the terminal repeat sequences. Chromosomal deletions, translocations, rearrangements, inversions, or even duplications of normal DNA sequencing accompany integration.

Transactivation of the function of genes controlling transcriptional factors (ie, insulinlike growth factor II [IGF-2], transforming growth factor-alpha [TGF-a], TGF-beta, cyclin-a [a protein that controls cell division], epidermal growth factor-r [EGFR], retinoic acid receptor [RAR]), and oncogenes such as c- myc, fos, ras (activating the internal signal transduction cascade upregulating ras /mitogen–activated kinase, c-Jun N terminal kinase, nuclear factor–kB [NF-kB], Jak-1-STAT, src- dependent pathways) influence normal hepatocyte differentiation or cell cycle progression.

Furthermore, the integrated part of HBV controlling the production of the HBxAg (antigen for the X gene of HBV) is overexpressed. These observations suggest that the site of viral genomic integration into the host's DNA is not the only factor.

Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB (cyclic adenosine monophosphate [cAMP]–response element-binding protein) and ATF-2 (activating transcription factor 2), altering their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.

Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53 , as well as to do the following:

Sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept)

Reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD

Reduce p21WAF1 expression, which is a cell cycle regulator

Bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B, thus altering its function

The levels of tumor necrosis factor-alpha (TNF-a), a proinflammatory cytokine, are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-a are responsible for the high levels of NO found in these patients. NO is a putative mutagen that develops through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c- fos and c- myc ; this upregulates the expression of TGF-a by transactivation.

Glomerulonephritis

The most common type of glomerulonephritis described in association with hepatitis B is membranous glomerulonephritis (MGN) , found mainly in children. However, membranoproliferative glomerulonephritis (MPGN) and, even more rarely, immunoglobulin (Ig) A nephropathy, have also been identified.

The prevalence rate of glomerulonephritis among patients with chronic hepatitis B is not well known, although observations have been made in children that suggest a range of 11-56.2%. However, such a high prevalence is not recognized in the United States; this may be because of the differences in epidemiology of HBV, which may be predominantly perinatal in other geographic areas of the world (see Epidemiology ).

A previous history of chronic liver disease is not present in the majority of patients with chronic hepatitis B at presentation, and most of them have no clinical or biochemical findings to suggest acute or chronic liver disease. However, liver biopsies often demonstrate features of chronic hepatitis. In addition, serologic markers of an HBV replicative state are often evident, and complement activation is suggested by low levels of C3 and C4.

Generally, the most prominent finding among affected children is MGN, primarily with capillary wall deposits of hepatitis B e antigen (HBeAg). In contrast, adults present with features of MPGN with mesangial and capillary wall deposits of HBsAg. A rare overlap between membranous nephropathy and IgA nephropathy has also been described.

The mechanism by which patients with chronic hepatitis B develop glomerulonephritis is not completely understood. One possible explanation is that HBV antigens (ie, HBsAg, HBeAg) act as triggering factors, eliciting immunoglobulins and thus forming immune complexes, which are dense, irregular deposits in the glomerular capillary basement membranes. HBV DNA has been identified by in situ hybridization in kidney specimens, distributed generally in the nucleus and cytoplasm of epithelial cells and mesangial cells of glomeruli and in the epithelial cells of renal tubules.

Polyarteritis nodosa

An association between hepatitis B and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN) . This very serious complication presents early during the course of hepatitis B, and the incidence is high among certain populations, such as Alaskan Eskimos.

The pathogenesis of PAN is not clear. Circulating immune complexes containing HBsAg, immunoglobulins (IgG and IgM), and complement have been demonstrated by immunofluorescence in the walls of the affected vessels and may trigger the onset of PAN. However, whether these represent the primary etiology of the disease remains unclear.

The clinical manifestations of PAN include the following:

Cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure)

Renal (eg, hematuria, proteinuria, renal insufficiency)

Gastrointestinal (GI) (eg, abdominal pain, mesenteric vasculitis)

Musculoskeletal (eg, arthralgias, arthritis)

Neurologic (eg, mononeuritis)

Dermatologic (eg, rashes)

Significant proteinuria (>1 g/day), renal insufficiency (serum creatinine >1.58 mg/dL), GI and central nervous system involvement, and cardiomyopathy are associated with increased mortality.

The course of PAN is independent of the severity and progression of the liver disease. Among patients with PAN, 20-45% die as a consequence of vasculitis in 5 years, despite treatment, with the mortality rate being similar whether patients are HBsAg seropositive or seronegative.

Hepatitis B infection, caused by the hepatitis B virus (HBV), is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. [ 1 ] Consequently, sexual contact, accidental needle sticks or sharing of needles, blood transfusions, and organ transplantation are routes for HBV infection. Infected mothers can also pass the infection to their newborns during the delivery period (vertical transmission). [ 1 ]

Genetics of infection with hepatitis B

Several genes, many having to do with the host immune response, have been implicated in the susceptibility to chronic hepatitis B infection. The TNFSF9 gene encodes the CD137L protein, and its expression was found to be significantly higher in patients with chronic hepatitis B infection than in healthy controls. Its expression was also found to be higher in patients who had chronic hepatitis B with cirrhosis, in contrast to those without cirrhosis. [ 28 ]

Research done in West Africa, where 90% of the population is infected with hepatitis B, shows that certain human leukocyte antigen (HLA) class II haplotypes influence the likelihood of chronic infection. For reasons that are not completely clear, patients in the study who were heterozygous for the HLA-DRA and HLA-DQA1 genes were found to be less likely to develop a chronic infection. [ 29 ]

IFNGR1 gene

Several additional genes are associated with susceptibility to hepatitis B infection. The IFNGR1 gene is located at 6q23.3 and encodes the interferon gamma (IFN-γ) receptor 1, which has an important role in cell-to-cell communications and can be activated in response to infection, but it is not specific to hepatitis B. [ 30 ] Patients with significant dysfunction in this gene have a particular immune deficiency that leaves them extremely susceptible to mycobacterial infections. [ 30 ]

A more subtle change in the promoter region at location -56 in this gene has shown significant association with the natural history of hepatitis B infection. Individuals with the C allele at this location were found in a study to be more likely to clear the virus, whereas individuals with the T allele at this location were more likely to have persistent viral infection. [ 31 ]

IFNAR2 gene

The IFNAR2 gene is located at 21q22.1 and encodes the IFN-alpha, -beta, and -omega receptor 2. Although it presumably is like the previous gene, with multiple functions in the immune system, at the present time it is known only to be associated with susceptibility to hepatitis B.

A study looking at this gene found that a single nucleotide polymorphism, resulting in a phenylalanine-to-serine substitution at position 8, was associated with an increased risk for chronic hepatitis B infection. [ 32 ]

IL1OR2 gene

The same study also found that a polymorphism in the IL10R2 gene (or the CRFB4 gene), also located at 21q22.11, is associated with an increased risk of chronic hepatitis B infection. This particular polymorphism results in a lysine-to-glutamic acid substitution at position 47. [ 32 ]

Variations in vaccine response

It is also known that certain patients have different responses to the hepatitis B vaccine. One study found that 14% of patients who received the vaccine were low responders. [ 33 ] A greater-than-expected number of these patients were homozygotes for the HLA-B8, -SC01, and -DR3 haplotypes. It was hypothesized that because HLA II binds antigens, different haplotypes may alter the way in which vaccine peptides activate the immune system. [ 33 ]

Another study, which looked at 914 immune candidates in over 1600 patients who were given the HBV vaccine, found numerous single-nucleotide polymorphisms (SNPs) that were associated with inadequate levels of antibody response after vaccination, [ 34 ] with most found in the HLA genes.

However, one SNP was found in the 3 prime (3’) downstream region of the FOXP1 gene. This gene is a transcriptional repressor that plays a role in the differentiation of monocytes and the function of macrophages. [ 34 ]

US statistics

Because of the implementation of routine vaccination of infants in 1992 and of adolescents in 1995, the prevalence of HBV infection has significantly declined in individuals born in the United States.

It is estimated that there are around 60,000 new cases annually. Two million or more people in the United States have chronic HBV infection; it is estimated that foreign-born persons from high endemic areas represent more than half of the total cases. [ 35 ] The prevalence of the disease is higher among Black individuals and persons of Hispanic or Asian origin.

HBV disease not only accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of hepatocellular carcinoma (HCC) in the United States, it is also the dominant cause of cirrhosis and HCC worldwide.

HBV is responsible for at least 5000 US deaths annually. The prevalence is low in persons younger than 12 years born in the United States, with the subsequent increase being associated with the initiation of sexual contact (the major mode of transmission in adults, along with intravenous drug abuse [IVDA]). It is also associated with the occurrence of first intercourse at an early age. Additional risk factors, as identified in the National Health and Nutrition Examination Survey (NHANES) III, are as follows:

Non-Hispanic Black ethnicity

Cocaine use

High number of sexual partners

Divorced or separated marital status

Foreign birth

Low educational level

International statistics

Globally, chronic HBV infection affects 250-350 million people, [ 34 , 36 ] with disease prevalence varying among geographic regions, from 1-20%. A higher rate exists, for example, among Alaskan Eskimos, Asian Pacific islanders, Australian aborigines, and populations from the Indian subcontinent, sub-Saharan Africa, and Central Asia. In some locations, such as Vietnam, the rate is as high as 30%. Such variation is related to differences in the mode of transmission, including iatrogenic transmission, and the patient's age at infection.

Occult hepatitis B infection appears to have an overall prevalence of 4% in Asia (3% each in East and South Asia; 9% each in West and Souteast Asia) and is associated with disease progression. [ 37 ]  There is a 1% prevalence of occult infection in the general population but a 5% prevalence in high-risk groups, 9% in HIV patients; and 18% in hepatopathy patients.

The lifetime risk of HBV infection is less than 20% in low prevalence areas (generally 0.1-2%), [ 10 ] and sexual transmission and percutaneous transmission during adulthood are the main modes through which it spreads. About 12% of HBV-infected individuals live in low-prevalence areas, which include the United States, Canada, western Europe, Australia, and New Zealand. [ 10 ]

Sexual and percutaneous transmission and transmission during delivery are the major transmission routes in areas of intermediate prevalence (rate of 3-5%). These regions include Eastern and Northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and Central Asia. One study reported approximately 43% of HBV-infected individuals live in South Central and West Asia, Eastern Europe, Russia, and Central and South America, with a prevalence rate of 2-7% and a lifetime HBV risk of 20-60%. [ 10 ]

In areas of high prevalence (≥8%, generally 10-20%), the predominant mode of transmission is perinatal, and the disease is transmitted vertically during early childhood from the mother to the infant. Approximately 45% of individuals infected with HBV live in high-prevalence areas, with a lifetime infection risk of over 60%, as demonstrated by the presence of hepatitis B core antibodies (anti-HBc) to hepatitis B core antigen (HBcAg) in serum. [ 10 ] Such regions include China, Southeast Asia, Indonesia, sub-Saharan Africa, Pacific Islands, parts of the Middle East, and the Amazon Basin.

Vaccination programs implemented in highly endemic areas seem to have reduced the prevalence of HBV infection. In Taiwan, for example, HBV seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 after the implementation of vaccination programs, and the incidence of HCC declined from 0.52% to 0.13% during the same period. [ 6 ]

The 10 genotypes of HBV (A-J) also correspond to specific geographic distributions. [ 22 ] Genotype A is more frequently found in North America, northwestern Europe, India, and Africa, whereas genotypes B and C are endemic to Asia, and genotype D predominates in Eastern Europe and the Mediterranean. Type E is found in western Africa; type F, in South America; and type G, in France, Germany, Central America, Mexico, and the United States. Type H is prevalent in Central America [ 10 ] ; type I, in Vietnam; and type J, in Japan. [ 22 ]

Race-, sex-, and age-related demographics

In the United States, Black persons have a higher prevalence of HBV disease than do Hispanics or whites. In addition, more cases of chronic HBV disease occur in males than in females.

The earlier the disease is acquired, the greater the chance a patient has of developing chronic hepatitis B infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and elderly persons have an approximately 20-30% chance of developing chronic disease.

The prognosis of patients who contract hepatitis B depends on several factors. Those with an acute hepatitis B virus (HBV) infection may spontaneously clear the virus, while others may progress to chronic infection, ultimately leading to cirrhosis and to hepatocellular carcinoma (HCC), the risk of which depends on the mode of infection, viral genotype, and presence of coinfection, among other factors. An estimated 1 million persons per year globally, including at least 5000 persons annually in the United States, die from chronic hepatitis B disease. [ 35 ]

Positive prognostic factors

Patients who have lost the hepatitis B e antigen (HBeAg) and in whom hepatitis B virus (HBV) DNA is undetectable have an improved clinical outcome, as characterized by the following:

Slower rate of disease progression

Prolonged survival without complications

Reduced rate of HCC and cirrhosis

Clinical and biochemical improvement after decompensation

Chronic hepatitis B infection is the major contributor to the development of approximately 50% of cases of hepatocellular carcinoma (HCC) worldwide. [ 38 ] Studies indicate that the level of hepatitis B virus (HBV) DNA, which indicates viral replication, is a strong predictor for cirrhosis and HCC regardless of other viral factors. [ 38 ] Approximately 9% of patients in western Europe who have cirrhosis develop HCC due to hepatitis B infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis has been established at 6%, and the probability of decompensation is 23%.

Significant risk factors for carcinogenesis include the following:

Exposure to aflatoxins

Coinfection with HCV and HDV

Immune status

Core and precore mutations

Thrombocytopenia

High serum viral load (ie, viral replication) that is persistently elevated over time is the most reliable indicator in predicting the development of HCC. [ 39 ]

Even the presence of hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) or HBV DNA is significantly related to an increased risk for HCC, although there are no recommendations for HCC surveillance in such cases unless cirrhosis is present.

The annual incidence of HCC reported in Taiwan in patients with hepatitis B infection and cirrhosis is 2.8%. The US estimates for the annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons.

Distinct mutations associated with different HBV genotypes have been linked to an increased risk of developing advanced fibrosis and HCC. Genotype C is closely associated with HCC; this appears to be related to a higher incidence of core and precore mutations in patients older than 50 years with cirrhosis and genotype C, [ 22 ] whereas genotype B is associated with HCC development in young, noncirrhotic patients and in postsurgical relapse. [ 39 ] Various international studies additionally demonstrated a greater association of genotypes C, D, and F with cirrhosis and HCC compared to genotypes A and B.

Familial clustering of HCC has been described among families with hepatitis B infection in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% at 5 years and 68% at 10 years.

Cox regression analysis has identified 6 variables that independently correlate with overall survival for individuals with cirrhosis or HCC. These include age, albumin level, platelet count, splenomegaly, bilirubin level, and positivity for hepatitis B e antigen (HBeAg) at the time of the hepatitis B diagnosis. Based on the contribution of each of these factors to the final model, a prognostic index has been constructed that allows calculation of the estimated survival probability.

Expression of inflammatory molecules in HBV-related HCC tissues is associated with poor prognosis. [ 39 ] Imbalance between intratumoral CD8* T cells and regulatory T cells or type 1 helper T cells (Th1), and type 2 helper T-cell (Th2) cytokines in peritumoral tissues can predict the prognosis of HBV-related HCC. These molecules are also important for developing active prevention and surveillance of HBV-infected patients. [ 39 ]

The prognosis of renal disease in hepatitis B is related to several factors, such as age and the response to therapy. Children with membranous glomerulonephritis (MGN) have a more favorable response than adults. White persons have a better response than Asian and Black patients.

Approximately 30-60% of cases with MGN undergo spontaneous remission. However, the course of HBV-related membranous nephropathy in adults in areas in which the virus is endemic is not benign. Regardless of treatment, hepatitis B disease has a slow, but relentlessly progressive, clinical course in approximately one third of patients, resulting in progressive renal failure and necessitating maintenance dialysis therapy.

Patients with acute and chronic hepatitis B virus (HBV) infections should be advised that this is a blood-borne disease that can be transmitted during sexual intercourse or at the time of childbirth. Prophylaxis is strongly advised. Family members borne by the same parents should also be checked for HBV infection. The best preventative measurement is vaccination. [ 1 ]

For patient education information, see Hepatitis A (HAV, Hep A) ; Hepatitis B (HBV, Hep B) ; Hepatitis C (HCV, Hep C) ; Cirrhosis of the Liver ; Liver Cancer ; Immunization Schedule, Adults ; and Childhood Immunization Schedule and Chart .

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• Hepatitis B. Under higher-power magnification, ground-glass cells may be visible in chronic hepatitis B virus (HBV) infection. Ground-glass cells are present in 50% to 75% of livers with chronic HBV infection. Immunohistochemical staining is positive for hepatitis B surface antigen (HBsAg.)
• Hepatitis B. Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.
• Hepatitis B. Hepatitis B virus (HBV) is a hepadnavirus, highly resistant to extremes of temperature and humidity, that invades the hepatocytes. The viral genome is a partially double-stranded, circular DNA linked to a DNA polymerase that is surrounded by an icosahedral nucleocapsid and then by a lipid envelope. Embedded within these layers are numerous antigens that are important in disease identification and progression. Within the nucleocapsid are the hepatitis B core antigen (HBcAg) and precore hepatitis B e antigen (HBeAg), and on the envelope is the hepatitis B surface antigen (HBsAg). Transmission electron micrograph (TEM) from Graham Colm and Wikipedia, licensed under the Creative Commons Attribution 3.0 Unported license.
• Hepatitis B. Serologic course of hepatitis B virus (HBV) infection. The flat bars show the duration of seropositivity in self-limited acute HBV infection. The pointed bars show that HBV DNA and e antigen (HBeAg) can become undetectable during chronic infection. Only immunoglobulin G (IgG) antibodies to the HBV core antigen (anti-HBc) are predictably detectable after resolution of acute hepatitis or during chronic infection. Antibody to hepatitis B surface antigen (anti-HBs) is generally detectable after resolution of acute HBV infection but may disappear with time. It is only rarely found in patients with chronic infection and does not indicate that immunologic recovery will occur or that the patient has a better prognosis. ALT = alanine transaminase. (Adapted from Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373(9663):582-92.)
• Hepatitis B. Radiologic studies may be useful in all stages of hepatitis B infection. Ultrasonography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) may exclude biliary obstruction in acute infection. In chronic disease, ultrasonograms may show nonspecific increased echogenicity of the liver parenchyma. In patients with long-standing disease, CT imaging may be used to detect cirrhosis or hepatocellular carcinoma (as shown).
• Hepatitis B. Long-standing cirrhosis leads to progressive replacement of liver parenchyma with fibrotic tissue. Over time, the liver contracts and develops a lobulated contour. These changes are readily apparent on cross-sectional imaging. This contrast-enhanced computed tomography (CT) scan demonstrates extensive cirrhosis, as well as malignant hepatocellular lesions (arrow).

Contributor Information and Disclosures

Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP(Edin) Professor and Chief, Division of Gastroenterology and Hepatology, Professor of Physiology, Pharmacology, and Neuroscience, Medical Director of Liver Transplantation, Rutgers New Jersey Medical School Nikolaos T Pyrsopoulos, MD, PhD, MBA, FACP, AGAF, FAASLD, FRCP(Edin) is a member of the following medical societies: American Association for the Study of Liver Diseases , American College of Gastroenterology , American College of Physicians , American Gastroenterological Association , American Liver Foundation , American Medical Association , American Society for Gastrointestinal Endoscopy , American Society of Transplantation , International Liver Transplantation Society , Transplantation Society Disclosure: Received research grant from: GRIFOLS. BAYER, DURECT, INTERCEPT, BEIGENE, BMS.

Ranya Selim, MD Gastroenterologist/Transplant Hepatologist Ranya Selim, MD is a member of the following medical societies: American College of Gastroenterology Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Received salary from Medscape for employment. for: Medscape.

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases , American College of Gastroenterology , American Gastroenterological Association , American Society for Gastrointestinal Endoscopy Disclosure: Nothing to disclose.

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases , American Gastroenterological Association , American Medical Association , American Society for Clinical Investigation , and Association of American Physicians

Disclosure: Springer Consulting fee Consulting; Gilead Consulting fee Review panel membership; Gilead Honoraria Speaking and teaching; Bristol-Myers Squibb Honoraria Speaking and teaching; Springer Royalty Review panel membership

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