Viral Hepatitis

Hepatitis, or inflammation of the liver, may be caused by viral infection. Hepatitis A, B, C, D, and E viruses (HAV, HBV, HCV, HDV, and HEV) infect hepatocytes and cause acute or chronic hepatitis. HBV and HCV can progress to chronic disease, but HDV and HEV may also present chronically in some circumstances. The symptoms of viral hepatitis are nonspecific and include jaundice, fever, and a lack of appetite. Diagnosis cannot be made by clinical evaluation alone. Chronic and sometimes acute viral infections can be asymptomatic or mildly symptomatic. However, even in the absence of symptoms, chronic viral hepatitis infections can result in cirrhosis, liver failure, or hepatocellular carcinoma if undiagnosed and untreated. Laboratory testing is useful for determining diagnosis, appropriate treatment, and vaccination status and for monitoring treatment. Hepatitis testing methods include serology and nucleic acid amplification testing (NAAT).

Quick Answers for Clinicians

Which testing strategy is appropriate when a patient presents with acute hepatitis symptoms?

Patients who present with classic hepatitis symptoms such as jaundice and fever should be tested for common hepatitis viruses to determine disease etiology and immunization status and inform potential management decisions. Refer to the Viral Hepatitis Screening and Diagnosis Algorithm for more information.

Which types of laboratory testing are recommended for prenatal hepatitis screening?

Prenatal screening should be performed for hepatitis B and C viruses (HBV and HCV).   For HBV screening, the appropriate ARUP test is Hepatitis B Virus Surface Antigen with Reflex to Confirmation, Prenatal (2007573). For HCV screening, the appropriate ARUP test is Hepatitis C Virus Antibody by CIA with Reflex to HCV by Quantitative NAAT (2010784).

For detailed information about these recommendations, see the U.S. Preventive Services Task Force (USPSTF) Screening for Hepatitis B Virus Infection in Pregnant Women: Recommendation Statement  and the CDC Recommendations for Hepatitis C Screening Among Adults. 

What other causes of hepatitis should be considered during diagnosis?

If common viral causes of hepatitis have been ruled out by clinical evaluation and laboratory testing, other etiologies may be considered. Other causes of hepatitis include autoimmune hepatitis, cytomegalovirus, yellow fever virus, Epstein-Barr virus, herpes simplex viruses, and measles, mumps, and chickenpox viruses.

Which laboratory tests can be used to determine immunization status for hepatitis A and B viruses?

Vaccines are available for both hepatitis A virus (HAV) and hepatitis B virus (HBV).

To determine HAV immunization status, testing should include total HAV antibodies. The appropriate ARUP test is Hepatitis A Virus Antibodies (Total) (0020591).

For HBV, immunization status testing should include antibodies against HBV surface antibodies (anti-HBs). The appropriate ARUP test is Hepatitis B Virus Surface Antibody (0020090).

The ARUP Consult Immunization Status topic contains more detailed information about laboratory testing to determine immunization status.

Indications for Testing

Laboratory testing for viral hepatitis is appropriate for screening (eg, prenatal screening for HBV and HCV) or at new onset of symptoms such as jaundice, anorexia, or dark urine, or after a known or suspected exposure to hepatitis virus.

Detailed information about the recommended laboratory testing strategy for acute viral hepatitis of an unknown etiology can be found in the Viral Hepatitis Screening and Diagnosis Algorithm.

Laboratory Testing

Hepatitis A

HAV is a vaccine-preventable disease transmitted through the fecal-oral route. HAV causes acute disease that may be asymptomatic or present with enteric symptoms. Populations at an increased risk for hepatitis A include travelers, persons experiencing homelessness, and persons who use illegal drugs (injection or noninjection).  A diagnosis must be made using both clinical and laboratory criteria. Detailed information about hepatitis A diagnosis may be found in the CDC’s acute hepatitis A case definition. 

HAV Testing

Diagnosis and Immune Response

For diagnosis of HAV, order immunoglobin M (IgM) HAV antibody testing.  Although serology is most often used for diagnosis, order a total anti-HAV assay to assess immunization status or previous infection. 

Hepatitis B

HBV is a vaccine-preventable disease that may occur acutely or chronically. Chronic infection is often asymptomatic until the onset of cirrhosis or end-stage liver disease. Transmission of HBV generally occurs through contact with the blood or body fluids of an infected person. Vertical transmission from mother to child is possible and may lead to chronic infection in children. Children are more likely to develop chronic, asymptomatic disease, whereas adults are more likely to develop acute, self-limiting disease.  Testing for HBV infection is appropriate in patients who were born in a region with high HBV prevalence (>2%), have an hepatitis B surface antigen (HBsAg)-positive sex partner, use drugs intravenously, are currently receiving or being considered for immunosuppressive medications, and persons with HIV. For more detailed information, see the CDC’s case definitions for acute and chronic HBV infections.  

HBV Testing

Several markers are useful for the diagnosis of HBV infection. No single test is sufficient to definitively diagnose HBV. The table below details common HBV markers and their significance.

HBV Markers
Marker Indication

HBsAg

Presence of HBsAg indicates current HBV infection (acute or chronic)

HBsAg-positive individuals are infectious

Anti-HBs

Presence of anti-HBs indicates either recovery from past HBV infection or previous HBV vaccination

IgM anti-HBc

Presence of IgM anti-HBc generally indicates acute or recently acquired HBV infection

Total anti-HBc (IgG and IgM)

A positive total anti-HBc result indicates previous or ongoing HBV infection or previous HBV vaccination

HBeAg and HBe Ab

Presence of HBeAg is generally associated with a high HB viral load

Seroconversion from HBeAg to HBeAb generally indicates recovery; serology may be useful to monitor treatment

HBV DNA

Presence of HBV DNA indicates current HBV infection

HBV DNA-positive individuals are infectious; HBV DNA testing may be useful to monitor treatment

anti-HBs, antibodies against hepatitis B surface antibody; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; IgM anti-HBc, IgM antibodies against HBV core antigen

Sources: CDC, 2022 ; CDC, 2020 

Screening

The table below describes the CDC screening recommendations for HBV in asymptomatic patients.

Population/Clinical Situation Screening Recommendation

Prenatal screening

Pregnant individuals should be screened for HBsAg at their first prenatal visit for each pregnancy and again at delivery if at high risk

Individuals requiring immunosuppressive therapy

Total anti-HBc and HBsAg testing should be performed before immunosuppressive treatment

MSM

All MSM should be tested for HBsAg, total anti-HBc, and anti-HBs

Persons with HIV

Testing for HBsAg and anti-HBc and/or anti-HBs is recommended

Individuals at increased risk (eg, born in a region with high HBV prevalence [>2%], those with an HBsAG-positive sex partner)

Screening for HBsAg is recommended for individuals at increased risk

MSM, men who have sex with men

Sources: CDC, 2022 ; U.S. Preventive Services Task Force, 2009 

Diagnosis and Immune Response

Several laboratory tests should be ordered for the diagnosis and evaluation of HBV. Detailed recommendations on testing strategy can be found in the Viral Hepatitis Screening and Diagnosis Algorithm and the Chronic Hepatitis B Virus Testing Algorithm.

The table below details the expected HBV test results for HBV markers in various clinical situations.

Interpretation HBsAg IgM Anti-HBc IgG Anti-HBc Total Anti-HBc Anti-HBs

No past or current infection or immunization

Negative

Negative

Negative

Negative

Negative

Acute HBV

Positive

Positive

Negative

Positive

Negative

Chronic HBV

Positive

Negative

Positive

Positive

Negative

Resolving HBV infection

Negative

Positive

Positive

Positive

Negative

Immune due to vaccination

Negative

Negative

Negative

Negative

Positive

Source: CDC, 2022 

Treatment Determination and/or Monitoring

Resistance testing (NAAT) should be used to guide drug therapy. Quantitative NAAT is also used to monitor treatment. Serology testing (HBsAg, HBeAg, HBeAb, and anti-HBs) may be performed to monitor treatment.

Hepatitis C

HCV may occur acutely, but the majority of cases (75-80%) become chronic.  Acute and chronic disease are commonly asymptomatic. Transmission of HCV is parenteral. Factors that increase the risk of HCV infection include past or present injection or intranasal drug use, HIV, receipt of blood transfusion before 1992, long-term hemodialysis, and being born to a mother infected with HCV.  Detailed information about acute and chronic HCV infections can be found in the CDC’s case definitions.  

HCV Testing

Screening

Serology to detect HCV antibodies (anti-HCV) is the recommended screening test. The table below describes the screening recommendations for hepatitis C in asymptomatic patients. More detailed information on recommended HCV screening can be found in the CDC’s Recommendations for Hepatitis C Screening Among Adults. 

Population/Clinical Situation Screening Recommendation

Prenatal screening

Screening is recommended during each pregnancy except in settings where prevalence is <0.1%

MSM

Screening is recommended in all adults older than 18 yrs except in settings where prevalence is <0.1%

Annual HCV testing is recommended in MSM with HIV

Persons with HIV

Serologic testing is recommended at initial HIV evaluation

Annual HCV testing is recommended in MSM with HIV

All individuals

Screening recommended for all adults older than 18 yrs except in settings where prevalence is <0.1%

Sources: CDC, 2020 ; CDC, 2022 

Diagnosis

Serology to detect HCV antibodies should be ordered as a first-line test to diagnose HCV infection. If serology returns a positive result, reflex NAAT should be performed to confirm active HCV infection. NAAT is also recommended for diagnosing HCV infection in immunocompromised individuals who may be seronegative due to low antibody response. More detailed information about the recommended testing strategy for acute or chronic HCV, including test interpretation guidance, can be found in the Viral Hepatitis Screening and Diagnosis Algorithm.

Treatment Determination and/or Monitoring

Quantitative NAAT is useful to determine the viral load of HCV. For confirmed cases of HCV infection, viral genotyping can inform antiviral therapy selection. Resistance-associated variant testing should be considered before treatment with nonstructural protein 5A (NS5A) inhibitors. Quantitative NAAT may be used before treatment to determine a baseline viral load measurement and throughout treatment to monitor disease progression.

Hepatitis Delta

Hepatitis D, also known as delta hepatitis, only occurs in patients who are also infected with HBV. Because HDV infection only occurs with HBV infection, HBV vaccines also provide protection against HDV. HDV infection may occur concurrently with HBV (coinfection) or in patients already infected with HBV (superinfection). Acute HBV/HDV coinfections may resolve on their own, but HDV superinfection may dramatically increase the rate of HBV disease progression to cirrhosis and liver failure.  HDV infection may present acutely or chronically. Transmission is most commonly parenteral, sexual, or through contact with the blood or body fluids of an infected person. Factors that increase the risk of HDV infection include being chronically infected with HBV, sexual contact with persons infected with HDV, and injection drug use. Testing for HDV should be considered in any person who is positive for HBsAg and has severe symptoms of hepatitis or acute exacerbations. The CDC provides more detailed information about HDV infection. 

HDV Testing

Screening

HDV testing is recommended only in patients who are HBsAg positive. 

Diagnosis

For diagnosis, serology testing to detect total HDV antibodies (IgG and IgM) is recommended. NAAT can be used to confirm an active HDV infection. HDV antigen and IgM antibody testing are not recommended for HDV diagnosis. More detailed information about the recommended laboratory testing strategy for HDV can be found in the Viral Hepatitis Screening and Diagnosis Algorithm.

Monitoring

Quantitative NAAT is useful to monitor drug therapy.

Hepatitis E

HEV infection is generally asymptomatic, acute, and self-limiting. HEV is rare in the United States but common in areas such as Asia and Africa. When symptomatic, HEV infection presents enterically. In rare cases, persons who have undergone solid-organ transplantation and are being treated with immunosuppressants may contract a chronic HEV infection. HEV transmission is through the fecal-oral route. In endemic areas, factors that increase the risk of HEV infection include travel, crowded living conditions, and consumption of unpurified water or contaminated food. Testing for HEV should be informed by patient history (eg, past travel to endemic areas).  In areas with low HEV prevalence, testing should be considered in persons who exhibit symptoms of viral hepatitis but have tested negative for other hepatitis viruses. Detailed information about the recommended laboratory testing strategy for HEV can be found in the Viral Hepatitis Screening and Diagnosis Algorithm.

HEV Testing

Diagnosis

Serology is indicated for the diagnosis of HEV. The presence of IgG antibodies against HEV indicates past exposure, whereas IgM antibodies indicate current or recent infection. NAAT to detect HEV RNA may be useful for diagnosis in certain situations, such as in cases of suspected chronic infection after solid organ transplantation or in immunosuppressed patients.

ARUP Laboratory Tests

Diagnosis for Patients With Acute Hepatitis
Prenatal Screening for HBV and HCV
HAV and HBV Immunization Status
HAV Diagnosis
HBV Screening
HBV Diagnosis
HBV Treatment Determination
HBV Treatment Monitoring
HCV Screening
HCV Diagnosis and Treatment Determination
HCV Treatment Monitoring
HDV Screening and Diagnosis
HDV Monitoring
HEV Diagnosis

Medical Experts

Contributor

Hillyard

David R. Hillyard, MD
Adjunct Associate Professor of Pathology, University of Utah
Medical Director, Molecular Infectious Diseases, ARUP Laboratories
Contributor

Slev

Patricia R. Slev, PhD, D(ABCC)
Associate Professor of Pathology (Clinical), University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories

References