A 46-year-old Caucasian man who worked as a mechanic was transferred to the gastroenterology out-patient clinic by the department of hematology, where he was regularly treated for B-CLL. The reason for the visit was a continuous increase of transaminases over the previous 7 months (months 0 to 7). The patient reported persistent exhaustion and occasional right-side abdominal pain. B-CLL had been diagnosed 4 years earlier (initially Binet stage B; actual blood cell counts: leukocytes 13.6/nL, thrombocytes 224/nL, and hemoglobin 16.3g/dL). Owing to increasing night sweats and compression of the urinary bladder by lymphomas 2 years earlier (leukocyte count 61/nL), he was treated with rituximab, pentostatin, and cyclophosphamide for 3 months, resulting in partial remission. Maintenance therapy was performed by using rituximab and was finally abandoned in month 4 of increased transaminases because of severe fatigue and susceptibility to infections, after which the patient took no medication. At the time of referral to our department, the patient was in stable partial remission and B symptoms were absent. He had no history of recent travels to countries outside Germany, contact with animals, or consumption of venison, liver sausage, or offal. He had not received a blood transfusion prior to the infection.\nNormal alanine transaminase (ALT) was documented in our patient until 10 months prior to his admission to the gastroenterology department. No ALT results are available in the 3-month interval from 10 months until 7 months prior to his transfer to the department of gastroenterology. Therefore, there is a 3-month window during which the first increase of transaminases must have occurred. An elevated ALT concentration of 234U/L was first detected 7 months before referral to the department of gastroenterology (the month of referral is denoted as “month 0”). After the initial discovery of increased transaminases, moderate fluctuating transaminitis – month 1: aspartate transaminase (AST) 61U/L, ALT 139U/L; month 3: AST 108U/L, ALT 220U/L; month 5: AST 142U/L, ALT 337U/L; and month 6: AST 161U/L, ALT 408U/L – was observed. Bilirubin concentrations were repeatedly within the reference interval. A diagnostic workup ruled out autoimmune and metabolic liver disease, hepatitis A-C, and herpes virus infection. A physical examination revealed enlarged axillary lymph nodes. The results of an abdominal ultrasound examination were otherwise unremarkable. Finally, HEV was diagnosed in a blood sample by detection of anti-HEV antibodies and HEV RNA (month 7: 3.0×105 copies/mL). Retrospectively, the presence of HEV RNA in serum was confirmed in two earlier samples (month 0: 2.0×107 copies/mL and month 6: 1.0×107 copies/mL). Samples from earlier visits were not available for analysis. Figure shows ALT concentrations, HEV viral load, and phases of immunosuppressive therapy over time. Sequence determination and phylogenetic analysis revealed a novel HEV genotype 3 strain clustering with other European subgenotype 3c isolates (Figure ).\nLaboratory analyses ordered 10 days after referral to our department showed that transaminases had rapidly decreased to concentrations within the reference intervals without therapeutic intervention (Figure ). Four weeks later (month 8), our patient was seen again in the department of hematology; transaminase concentrations were still normal, and HEV-RNA was not detectable from blood. Thus, it may be concluded that HEV infection was spontaneously cleared 7 to 8 months after the first referral. Lymphocyte counts in our patient’s blood were 0.8/nL at month 0, 0.7/nL at month 6, 9.4/nL at month 7, and 1.4/nL at month 8.
A 69-year old male received seven cycles of R-CHOP plus two cycles of RTX in 2008 and 2009 for non-Hodgkin’s, lymphoma leading to long-term remission. A regular follow-up examination in July 2016 revealed elevated aminotransferases indicating hepatitis. An extended laboratory examination including HEV serology without HEV RNA testing failed to unravel the underlying cause. A liver biopsy obtained in September 2016 exhibited histological features of viral hepatitis, but laboratory results remained negative for hepatotropic viruses. The patient remained undiagnosed until HEV RNA quantitation was performed in March 2018, revealing a HEV load of 4.15 E6 copies/mL despite persistent HEV seronegativity until present (recomWell HEV IgG/IgM and for confirmation recomLine HEV IgG/IgM, both Mikrogen Neuried, Germany). Weight-based RBV was administered at a dose of 1000 mg/day for three months and the patient cleared HEV, which led to the termination of therapy. HEV relapsed after 4 weeks and RBV treatment was re-induced at a dose of 1000 mg/d for 4 additional months without achieving viral clearance. After a treatment pause of two months RBV was continued at a reduced dose of 800 mg/d due to increasing fatigue and insomnia of the patient, who shows persisting HEV replication and constantly elevated aminotransferases until present.