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.

Objectives:

• 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.

Etiology

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.

Evaluation

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]

1. 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).
2. The unvaccinated U.S. citizens whose parents were born in high prevalence areas.
3. History of illicit intravenous drug use.
4. Men who have sex with men.
5. Persons on immunosuppressive therapy.
6. Persons with elevated ALT or AST of unknown origin.
7. Blood, plasma, organ, tissues, or semen donors.
8. Persons with end-stage renal disease.
9. All pregnant women and infants born to HBsAg-positive mothers.
10. Persons with chronic liver disease and HIV.
11. Close contacts of HBsAg-positive persons, such as household, sexual, or needle-sharing.
12. Persons with more than one sexual partner in the last six months.
13. Persons requesting evaluation or treatment for sexually transmitted infections.
14. Health care workers or public safety workers who are at risk for occupational exposure to blood or blood-contaminated body fluids.
15. Residents and staff at facilities for developmentally disabled persons.
16. Travelers to countries with an intermediate or high prevalence of Hepatitis B virus infection.
17. Correctional facilities inmates.
18. 19-59-year-old persons with diabetes who have not been vaccinated for Hepatitis B.
19. 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

Prevention

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.

Management

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]

1. Suppression of hepatitis B virus replication
2. Reduction of liver inflammation
3. Prevention of progression to liver cirrhosis and hepatocellular carcinoma

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

1. Blood tests: normalization of ALT
2. Undetectable hepatitis B viral DNA
3. Loss of HBsAg and HBeAg with seroconversion to anti-HBs and anti-HBe
4. 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
• Cirrhosis
• Drug-induced liver injury
• Hemochromatosis
• Hepatitis A
• Hepatitis C
• Hepatitis D
• Hepatitis E
• Hepatocellular carcinoma
• Human immunodeficiency virus
• Wilson disease

Prognosis

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.