Clinical Review & Education

JAMA Diagnostic Test Interpretation

Diagnostic Testing for Acute Hepatitis

Adam E. Mikolajczyk, MD; Nakia L. Chung, MD, PhD

An 18-year-old man from India who emigrated to the United States 4 weeks earlier pre-
sented with fever, malaise, and anorexia for 4 days. The patient reported ingesting no pre- WHAT WOULD YOU DO NEXT?
scription, over-the-counter, or herbal medications; alcohol; or illicit drugs. On physical exami-
nation, he was afebrile and had scleral icterus and a palpable liver edge. Initial laboratory test A. α1-Antitrypsin phenotype testing
results showed a white blood cell count of 3.9 × 103/μL and elevations in total bilirubin
(5.6 mg/dL), direct bilirubin (3.6 mg/dL), alkaline phosphatase (240 U/L), aspartate amino-
B. Anti–hepatitis E virus (HEV)
transferase (3322 U/L), and alanine aminotransferase (6114 U/L). His platelet count was
IgM testing
126 000 × 109/μL and prothrombin time was 17 seconds. Testing for viral hepatitis was per-
formed (Table). Antinuclear, antismooth muscle, and liver/kidney microsomal antibodies were
not detected. Immunoglobulin G (1294 mg/dL) and ceruloplasmin (22 mg/dL) levels were nor- C. Antimitochondrial antibody testing
mal. Right upper quadrant ultrasonography demonstrated a liver span of 16 cm, a common
bile duct measuring 0.3 cm, and patent hepatic vasculature. D. Repeat hepatitis D virus antibody
testing with polymerase chain
Table. Patient’s Laboratory Values reaction testing
Laboratory Test Patient’s Value Reference Value
Hepatitis A IgM Negative Negative
Hepatitis B
Surface antigen Positive Negative
E antigen Negative Negative
E antibody Positive Negative
Core IgM Negative Negative
Core IgG Positive Negative
Polymerase chain reaction, IU/mL 76 Not detected
Surface antibody, mIU/mL <2.0 <8.0 (no immunity)
Hepatitis C
Antibody Negative Negative
Polymerase chain reaction, IU/mL Not detected Not detected
Hepatitis D antibody Negative Negative
Epstein-Barr virus polymerase chain reaction Not detected Not detected
Cytomegalovirus polymerase chain reaction Not detected Not detected

Answer (when symptoms begin to occur), remains elevated for 8 weeks

B. Anti–hepatitis E virus (HEV) IgM testing
Test Characteristics
Annually, an estimated 20 million cases of hepatitis E virus (HEV)
occur worldwide.1 HEV is endemic in resource-limited countries and
is typically caused by transmission of genotypes 1 or 2 via fecal-
contaminated water.1 HEV accounts for many acute hepatitis cases
in India.2 However, in resource-rich countries, HEV is rare; typically
caused by genotypes 3 and 4; and results from ingestion of under-
cooked pig, boar, or deer meat.1 The annual estimated incidence in
the United States from 1998 to 1994 was 0.7% per 1000 persons.3
HEV is typically self-limited and asymptomatic, but has a mortality
rate of up to 20% in pregnant women and can lead to chronic in-
fections in immunosuppressed individuals (eg, solid organ or bone
marrow transplant recipients, individuals with HIV).1,3
During an acute HEV infection, anti-HEV IgM is typically
detected 2 weeks after the initial exposure, peaks at 4 weeks
after the exposure, and becomes undetectable by 3 to 4
months.4 Multiple enzyme immunoassays for detecting anti-HEV
IgM are commercially available in the United States, including
through the Centers for Disease Control and Prevention, but none
are currently approved by the US Food and Drug Administration.
The sensitivities of 6 indirect enzyme-linked immunosorbent
assays (ELISAs) range from 72% to 98% and the specificities
range from 78% to 96%.4,5 In a nonendemic area with a preva-
lence of 11%, the positive predictive values of several ELISAs were
17% to 40% and the negative predictive values were 98% to
100%.6 Conversely, in an endemic area with a prevalence of 29%
to 43%, 1 ELISA had a positive predictive value of 99% and nega-
tive predictive value of 95%.2,7 Discordant results between the
assays are caused by different diagnostic antigens, genomic vari-
ability across genotypes, and cross-reactivity with other viruses.4
The 2019 Medicare reimbursement rate for anti-HEV IgM testing
was $14.31.

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 Clinical Review & Education JAMA Diagnostic Test Interpretation

Application to This Patient
Measurement of anti-HEV IgM is the most appropriate next diag-
nostic step for this patient given his acute liver injury and recent emi-
gration from an area where HEV is endemic. Although this patient
has serologic evidence of a concomitant hepatitis B virus (HBV), the
minimally detectable viral load for HBV is consistent with suppres-
sion of HBV replication by a more robust viral superinfection
(eg, hepatitis D virus, HEV). Because testing results showed an ab-
sence of hepatitis D virus antibody, HEV testing was indicated next.
The prevalence of HEV-HBV coinfection is 0.7% in North America
and 2.8% in India.8,9 α1-Antitrypsin deficiency and primary biliary
cholangitis (screened for with antimitochondrial antibodies) would
not cause the marked, acute elevations in aminotransferases.
laboratory testing results.10 However, anti-HEV IgM is the pre-
ferred initial test to diagnose acute HEV in an immunocompetent
patient given its lower cost and wider availability.3
Patient Outcome
The patient’s test results were positive for anti-HEV IgM and anti-
HEV IgG. An acute HEV infection was confirmed by a viral load
of 71 500 IU/L. The viral load decreased to 5280 IU/mL 5 weeks
later. With close monitoring, his liver test results, prothrombin
time (13 seconds), and platelet count (268 000 × 103/μL) normal-
ized after 8 weeks. The patient was then lost to follow-up.

Clinical Bottom Line

What Are Alternative Diagnostic Testing Approaches?
Direct detection of HEV viral RNA in the serum or stool through
reverse transcriptase polymerase chain reaction indicates an
active HEV infection.4,10 Because anti-HEV IgM testing is only
modestly sensitive and specific, HEV RNA polymerase chain reac-
tion testing can be used to diagnose acute HEV when anti-HEV
IgM is normal in a patient suspected to have an acute HEV infec-
tion. HEV RNA polymerase chain reaction testing should also be
used to confirm the diagnosis when anti-HEV IgM is detected via
• Hepatitis E virus (HEV) infection should be considered in patients
with acute liver injury/failure of unclear etiology, especially those
with recent exposure to highly endemic areas.
• Testing for anti-HEV IgM is the appropriate first step for
diagnosing acute HEV, but can be limited by modest sensitivity
and specificity in areas where HEV is rare.
• Confirmation of acute HEV can be established with
measurement of serum or fecal HEV RNA.

ARTICLE INFORMATION
Author Affiliations: Division of Gastroenterology
and Hepatology, University of Illinois at Chicago,
Chicago, Illinois (Mikolajczyk); Department of
Internal Medicine, University of Illinois at Chicago,
Chicago, Illinois (Chung).
Corresponding Author: Adam E. Mikolajczyk, MD,
Division of Gastroenterology and Hepatology,
University of Illinois at Chicago, 840 S Wood St,
1034 CSB, MC 716, Chicago, IL 60612 (amikolaj@
uic.edu).
Section Editor: Mary McGrae McDermott, MD,
Deputy Editor.
Published Online: February 13, 2020.
doi:10.1001/jama.2019.21895
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for
providing permission to share his information.
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