Prevalence and Clinical Correlates of Chronic Hepatitis E Infection in German Renal Transplant RecipientsWith Elevated Liver Enzymes

Abstract

Background

Elevated liver enzymes are frequently observed in renal transplant recipients and warrant further exploration. In immunosuppressed patients, hepatitis E virus (HEV) infection may cause chronic hepatitis, cirrhosis, and extrahepatic manifestations such as renal injury. Methods

We performed a retrospective cross-sectional study investigating the prevalence, clinical correlates, and outcome of chronic HEV infection in a cohort of renal transplant recipients with elevated liver enzymes. Results

Over a period of 30 months, 140 of 1469 renal transplant recipients had elevated liver enzymes, of which serum samples from 98 patients were available to determine HEV status. Seventeen patients were detected with HEV infection, of which 16 developed chronic HEV infection, while 1 patient controlled viremia (prevalence of chronic infection of 16.3%, with a minimum prevalence of 1.1% in the whole cohort). Increased liver stiffness was indicated by an average FibroScan result of 11.2 kPa in these patients. All 16 patients with chronic HEV infection were treated with ribavirin for a mean duration of 3 months. Five patients developed a viral rebound and received a second treatment course, of which 2 controlled HEV replication. Six months after the end of therapy, HEV clearance was achieved in 81.3% of the patients. One patient developed ribavirin resistance. Hemolytic anemia after ribavirin treatment was frequent, requiring blood transfusion in 3 patients. Four patients developed de novo glomerulonephritis, of which 2 were possibly associated with HEV infection. Conclusions

This retrospective study showed that prevalence of chronic HEV infection was high in our renal transplant patient cohort and was associated with significant liver impairment and the occurrence of renal injury. Ribavirin treatment was effective and should be initiated early to avoid complications, but the risk of severe hemolytic anemia makes strict monitoring essential.

Liver enzyme alteration without any preexisting liver disease is a frequent finding in renal transplant recipients. Thorough diagnostic evaluation is required to rule out multiple infectious and noninfectious causes. Among the most important being bacterial, fungal, and viral infections, but implicated are also drug toxicity and malignancies. Hepatitis E virus (HEV) infection, particularly genotype 3, is well recognized in industrialized countries. In Germany, a seroprevalence of 16.8% has been reported among healthy adults. Usually, HEV infection is self-limiting, although an acute infection can lead to chronic HEV infection in immunocompromised patients with increased risk of developing significant chronic liver disease and cirrhosis. Moreover, HEV-infected patients may develop various extrahepatic complications including glomerular injury. In fact, histopathologic findings, such as membranoproliferative, membranous, or mesangioproliferative glomerulonephritis, in transplant patients have been described. Because glomerulonephritis is a major cause of long-term renal graft failure, HEV infection is a potential risk factor for renal graft survival.In renal transplant patients with persisting HEV infection resistant to reduction of immunosuppression, treatment with ribavirin for a period of 3 to 6 months has been reported to be effective. Ribavirin therapy usually leads to rapid normalization of liver enzyme levels, HEV clearance, and a sustained virologic response (SVR) in up to 78% of patients.

Nevertheless, side effects are a limiting factor.

Diagnosing HEV infection in immunosuppressed patients is not trivial. As serology is of limited value due to compromised humoral immune responses, a quantitative HEV reverse transcription polymerase chain reaction (RT-PCR) is required to exclude active infection.

The HEV ribonucleinic acid (RNA) prevalence in patients with elevated liver enzymes has not been systematically addressed in kidney transplant recipients. Furthermore, additional data regarding clinical relevance and outcome of chronic HEV infection in renal transplant patients are warranted.

This study is the first systematic cross-sectional screening for HEV infection in a large cohort of renal transplant recipients with elevated liver enzymes. Over a period of 30 months, all renal and combined renal and other organ transplant recipients were screened for abnormal liver enzymes, HEV RNA, and IgG/IgM antibodies. The clinical correlates of renal transplant recipients with chronic HEV infection were also established in detail