Hepatitis E virus (HEV) is a single-stranded RNA virus in the Hepeviridae family with four major genotypes. Genotypes 1 and 2 are restricted to humans with genotype 1 predominant in Asia and genotype 2 in Africa and Mexico. HEV genotypes 3 and 4 infect humans as well as other mammalian species in a worldwide distribution.[2, 3] The prevalence of HEV in the U.S. population is 21.0% based on HEV immunoglobulin G (IgG) antibody seropositivity in population-based surveys from 1988 to 1994.3
Reports of chronic HEV infection have been limited to immunosuppressed patients who are human immunodeficiency virus (HIV)-positive, have hematological malignancies, or are solid-organ transplant recipients. Reduction of immunosuppression and/or monotherapy with pegylated interferon or ribavirin has shown efficacy in the treatment of chronic HEV infection. A study in France of six kidney transplant recipients with chronic HEV genotype 3 infection demonstrated that ribavirin therapy for 3 months led to sustained virilogical response in four patients.
Here we describe a unique case of chronic hepatitis E, anti-HEV IgG-positive, anti-HEV IgM-negative, HEV RNA-positive in an immunocompetent patient. The patient is a 62-year-old woman who presented in 2005 with persistently elevated alanine aminotransferase and aspartate aminotransferase levels. She had been treated for systemic lupus erythematosus in her 20s with prednisone and plaquenil and remained in remission thereafter. She drank socially and ran 3-4 miles every day. Work-up for viral, autoimmune, and genetic liver diseases was negative. She had a weakly positive antinuclear antibody (ANA) but her immunoglobulin levels were normal.
Her initial liver biopsy in 2005 showed a mild nonspecific hepatitis. A trial of prednisone and azathioprine for possible autoimmune hepatitis was discontinued after 7 months due to lack of efficacy. In 2007 her biopsy showed grade 2, stage 2 chronic hepatitis. This progression prompted a second unsuccessful course of oral steroids and azathioprine. A final biopsy in 2009 showed stable hepatitis and fibrosis (Fig. 1A,B). Ursodiol was started. Transient elastography (FibroScan) in 2011 reported a value of 11.2 kPa, correlating with Metavir stage 3 fibrosis.
Amid reports of chronic HEV infections in solid organ transplant recipients, the patient was tested for HEV serological markers in December 2011, and while anti-HEV IgG was positive, anti-HEV IgM was negative. Frozen serum was sent to the Centers for Disease Control and Prevention in January of 2012 for IgM and IgG anti-HEV serology and real-time polymerase chain reaction (PCR) for HEV RNA. (http://www.cdc.gov/hepatitis/HEV/LabTestingRequests.htm). The sample tested anti-HEV-IgG-positive and anti-HEV IgM-negative. HEV RNA was detected in serum with a titer of 6.2 × 105 IU/L. Sequencing studies determined HEV genotype 3.
Based on chronicity of HEV supported by HEV RNA and anti-HEV IgG positivity for ∼5 months and negative anti-IgM along with persistently elevated transaminases, therapy with ribavirin 400 mg twice daily was initiated in April of 2012 with normalization of liver enzymes at 2 months. HEV RNA was undetectable at 4 months. Treatment was discontinued after 6 months and liver enzymes have remained normal to date.
The patient denies receiving blood products. She does eat pork, oysters, and mussels. She drinks well water in her rural vacation home. She made several trips to Mexico and experienced an episode of fever and gastrointestinal disturbance upon returning from a trip in 2002. HEV genotype 3 has been isolated in those who consumed pork products, mussels, and game meat.[1, 3, 4] Swine-associated HEV strains have been identified in sewage water and can lead to shellfish contamination. It is tempting to speculate that this patient may have acquired HEV infection by consuming pork or shellfish.
Recent studies in solid organ transplant recipients have shown that acute HEV genotype 3 infection or reactivation in anti-HEV IgG-positive transplant recipients can lead to chronic hepatitis with progression to cirrhosis. Our patient also had HEV genotype 3 infection; the distant history of lupus may have predisposed her to the development of chronic HEV infection. This case highlights the importance of suspecting chronic HEV infection in patients with unexplained chronic hepatitis. However, the lack of a standardized commercial nucleic acid-based assay in the U.S. to detect HEV RNA in stool or serum limits testing, although two commercially available RT-PCR RNA assays for HEV genotype 3 are reported in Europe. Chronic HEV infections related to genotypes 1 and 2 have not been reported so far. An effective HEV vaccine has been approved in China following a controlled trial in 100,000 volunteers. HEV vaccination would be very useful to prevent chronic HEV in immunosuppressed patients and those with chronic liver disease.