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To the Editor: Hepatitis E is a viral hepatitide that is endemic in many developing countries. In its classic form, it results from ingesting fecally contaminated water that carries hepatitis E virus (HEV), and it frequently resolves without treatment. When hepatitis E is imported to the United States, it originates mainly from persons who have acquired HEV genotype 1 infection from South Asia (1). We report imported HEV genotype 4 infection (Technical Appendix Figure, panel A) in a patient during which cirrhosis and fatal hepatic decompensation ensued. The patient was a 68-year-old man of Chinese ethnicity who had been a California resident since 1985. He sought treatment for mild jaundice in April 2013 in Hong Kong, where he had been staying for 7 weeks. Sixteen years before, he had undergone orthotopic liver transplantation at Stanford University Medical Center (Palo Alto, California, USA) for hepatitis B cirrhosis. Since then, he had received entecavir and tacrolimus for maintenance and had been vaccinated against hepatitis A virus. Until his current illness, routine liver function tests had not indicated hepatic dysfunction (values in November 2012: alanine aminotransferase 2 IU/L, aspartate aminotransferase 24 IU/L, alkaline phosphatase 67 IU/L, total bilirubin 0.5 mg/dL). When the patient returned to the United States, 3 weeks after onset of jaundice, the initial work-up showed the following values: alanine aminotransferase 149 IU/L, aspartate aminotransferase 59 IU/L, alkaline phosphatase 193 IU/L, total bilirubin 2.8 mg/dL (Technical Appendix Figure, panel B). Hepatitis B virus DNA and antinuclear antibodies were not detected, and the tacrolimus level was stable. Ultrasound revealed a normal transplanted liver. A liver biopsy specimen showed mild portal, biliary, and lobular inflammation and early biliary injury (Figure, panels A, B). The prednisone dosage was escalated, and mycophenolate mofetil was added. Liver enzyme activity showed some improvement, but the bilirubin level continued to rise (Technical Appendix Figure, panel B). Figure Serial histologic changes in liver of the patient who received a diagnosis of hepatitis E after a visit to Hong Kong in 2013 (A and B: at first biopsy; C and D: second biopsy; E and F: third biopsy. A) Mild mixed portal infiltration; minimal lobular inflammation; ... A biopsy specimen taken 3 months later showed grade 3 hepatitis with bile ductular reaction, bridging hepatocytic necrosis and fibrosis, and regenerative nodule formation (Figure, panels C, D). A blood sample taken about this time tested positive for HEV RNA. The patient was then given ribavirin (1,000 mg/d). Before hepatitis E was diagnosed, tacrolimus was given (1 mg 2×/d); when the diagnosis was confirmed, the tacrolimus dose was reduced to 0.5 mg every other day. Four months after the patient sought treatment, ascites was noted. Ribavirin was stopped because of pancytopenia. Blood samples subsequently tested negative for HEV RNA, but HEV IgM and IgG were found. Hepatic function did not improve. Eight months after onset of the patient’s condition, marked hepatic decompensation occurred (Technical Appendix Figure), culminating in esophageal variceal hemorrhage. The patient was placed on a waiting list and then underwent liver transplantation, but he died during the operation from complications of hemorrhage. Biopsy of the liver explant revealed intense lobular inflammation with the hepatocellular reactive changes persisting and stage IV fibrosis (Figure, panels E, F). The patient had lived and worked in Hong Kong before he became a resident of the United States. He had not visited Hong Kong in the 3 years preceding his most recent trip, nor had he traveled to Europe. Review of his medical records revealed no evidence of hepatic dysfunction after his previous travels. Considering that his most recent visit to Hong Kong coincided with the incubation period of hepatitis E (2), he most likely acquired HEV genotype 4 infection during that visit. In China over the past decade, national notifications of HEV infection have risen, with 28,232 cases reported in 2013 (3). In Hong Kong, where a rising trend in hepatitis E notifications also has been observed (150 cases reported in 2012 [4]), HEV infections are almost all associated with HEV genotype 4 (5). This patient’s HEV subgenomic sequence was closely related to human and porcine HEV genotype 4 sequences reported from mainland China and Hong Kong (Technical Appendix Figure, panel A). Porcine liver has been implicated as a possible HEV transmission vehicle in that region (6); although we do not know whether the patient ate food that carried HEV, the possibility underscores the importance of avoiding eating inadequately cooked animal-derived food products during international travel (2). Chronic hepatitis with accelerated cirrhosis has been reported in solid-organ transplant recipients infected with HEV genotype 3, but not with genotype 4 (7). Serial liver biopsy specimens from the patient showed persistent and worsening hepatitis and rapid onset of fibrosis that intensified (Technical Appendix Figure, panel B). Testing for HEV infection is recommended during initial assessments of posttransplant hepatic dysfunction because histologic appearances in liver biopsy specimens may not clearly distinguish between graft rejection and acute viral hepatitis (Figure, panels A, B). Early diagnosis of hepatitis E should lead to prompt administration of antiviral therapy and appropriate adjustments to the immunosuppressant drug regimen, particularly because some drugs can exert opposing effects on HEV replication (8). Technical Appendix. A) Phylogenetic tree comparing a 258-nt sequence within hepatitis E virus (HEV) open reading frame 1 (​(1)1) of the patient who visited Hong Kong in 2013 with corresponding, representative GenBank sequences. Included is a corresponding sequence from patient A, a 63-year-old Caucasian man, a resident of Alabama, in whom acute, self-resolving hepatitis developed 5 weeks after he returned from a 2-week visit to Shandong, China. Numerals beside each sequence denote year of sequence reporting; alphanumerics denote GenBank accession numbers. GT, genotype; CH, China; HK, Hong Kong; MX, Mexico; US, United States. B) Chronology of changes in liver function and hepatitis E markers in the patient. Click here to view.(215K, pdf)

To the Editor: The Centers for Disease Control and Prevention and US Preventive Services Task Force recommend a one-time screening for hepatitis C virus (HCV) infection in adults born during 1945–1965 (birth cohort), a demographic group with a disproportionately high prevalence of HCV infection (1,2). However, some experts have warned against routine HCV screening of persons in the birth cohort, stating that this recommendation is based on unproven assumptions about the benefit of screening in reducing HCV-related mortality, given that only a minority of infected persons develop end-stage liver disease (ESLD) (3). To determine the relative effect of the birth cohort on HCV-related ESLD incidence in the United States, we analyzed trends in liver transplantation (LT) waitlist registrations and LT surgeries during 1995–2012. Using data from the United Network for Organ Sharing national registry, we evaluated birth cohort–specific (birth cohort vs. non–birth cohort) and etiology-specific (HCV vs. non-HCV) trends in LT waitlist registrations and LT surgeries performed in the United States during that 18-year period. The proportion of HCV-infected persons born during 1945–1965 among all persons with LT waitlist registrations in the United States increased from 17.8% in 1995 to 35.2% in 2012 (Table). The highest proportion of LT waitlist registrations for HCV-related ESLD was for persons in the birth cohort and increased incrementally from 61.2% in 1995 to 90.5% in 2012. The proportion of LT waitlist registrations for HCV-related ESLD among persons younger than the birth cohort was 1.0% in 1995 and 3.6% in 2012; among persons older than the birth cohort, the proportion was 37.8% in 1995 and 5.9% in 2012. Table Liver transplant waitlist additions and liver transplant recipients, United States* Similarly, among LT recipients, the proportion of HCV-infected persons born during 1945–1965 doubled from 17.4% in 1995 to 35.4% in 2012 (Table). The proportion of LT surgeries performed for HCV-related ESLD among persons in the birth cohort increased from 60.2% in 1995 to 90.7% in 2012. Among persons younger than the birth cohort, the proportion of LT surgeries performed for HCV-related ESLD was 0.7% in 1995 and 5.0% in 2012; among persons older than the birth cohort, the proportion was 39.1% in 1995 and 4.3% in 2012. During 1995–2012, the ratio of new LT waitlist registrations to LT surgeries performed for HCV-infected persons in the birth cohort remained unchanged at 1.9:2.0 despite the aging of this birth cohort. Overall trends in HCV-related LT waitlist registrations and LT surgeries stabilized during 2001–2012; the proportion of HCV-infected persons in the birth cohort increased, and the proportion of HCV-infected persons not in the birth cohort decreased. To exclude the possibility that HCV-related ESLD has always simply affected persons 50–70 years of age, we performed a subanalysis examining the proportion of LT waitlist registrations and LT surgeries for persons 50–70 years of age in each year from 1995 through 2012. During this 18-year period, among persons 50–70 years of age, new HCV-related LT waitlist registrations increased from 43.9% to 93.0%, and LT surgeries performed increased from 47.1% to 86.2%. This finding suggests that persons born during 1945–1965 are a distinct birth cohort that is increasingly affected by HCV-related ESLD. Although persons born during 1945–1965 make up an estimated 27% of the US population, they account for ≈75% of all HCV infections and 73% of HCV-associated deaths in the United (1). Our findings are consistent with those of an earlier modeling study by Davis et al. (4), which suggested that the age of persons with HCV-related cirrhosis and its complications will continue to increase. Limitations of our study include inherent limitations of retrospective design and registry data. The designation of HCV infection and birth cohort status is based entirely on data entered into the database, which are not necessarily subject to cross-checking confirmatory measures. However, any errors in data entry that may have occurred are probably nondifferential. Despite these limitations, our analysis demonstrates that >90% of HCV-infected persons registered for LT or undergoing LT surgeries in 2012 were in the birth cohort. Earlier diagnosis and preemptive cure of HCV infection with highly effective and safe direct-acting antiviral drugs may delay or reduce the need for LT among persons in the birth cohort (5). Testing and linkage to care for HCV-infected persons, particularly persons in the birth cohort, can be expected to reduce HCV-related illness and death (1,2). In response to the approval of higher efficacy antiviral drugs and rapidly rising liver failure–related death among this cohort (6,7), the use of HCV-infected donors has increased, resulting in truncated wait times for HCV-infected LT recipients in many regions (8), whereas HCV-uninfected persons are generally waiting considerably longer, often years, for HCV-uninfected donors (9). This phenomenon is another index of the extent of HCV-related ESLD in the United States.