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.
In March 2013, a 62-year-old Bulgarian man was admitted with a provisional diagnosis of acute hepatitis based on a preexisting chronic HBV infection (inactive HBV carrier state: positive for HB surface antigen, core antibody, and envelope antibody; negative for HB envelope antigen and surface antibody with existing cirrhosis and ascites). One day prior to admission, the patient suffered from an acute onset of progressive, worsening upper abdominal discomfort, frequent episodes of diarrhea (2–3 times/day), loss of appetite, and fulminant jaundice without systemic symptoms. Laboratory results revealed elevated levels of aspartate aminotransferase (2,452 IU/L), ALT (1,161 IU/L), and GGT (301 IU/L), with high total bilirubin (392 μmol/L; direct bilirubin level: 345 μmol/L), and thrombocytopenia (119×106/L); C-reactive protein was markedly elevated (41.6 mg/L). HAV, HCV, and HIV were excluded. Serologic markers of previous CMV, EBV, and T. gondii infections were positive. Abdominal ultrasound showed known macronodular liver cirrhosis with manifest splenorenal shunting and splenomegaly. Anti-HEV IgM (165.9 IU/mL) and IgG (212.6 IU/mL) antibodies were positive. To exclude acute HBV-associated liver failure, polymerase chain reaction testing was performed using a commercially available kit (Abbott Laboratories, USA) to detect HBV-DNA (<12.5 IU/mL). HEV RNA was detected (9.76×105 copies/mL), and sequencing revealed HEV genotype 3f. Due to the severity of his condition, the patient was immediately transferred and underwent a high-urgency liver transplantation (CMV-positive transplant). The patient experienced the following complications: an ischemic cerebrovascular accident, acute renal failure, corticoid-induced diabetes mellitus, and CMV reactivation one month post-transplant (plasma viral load: 1,493 IU/L).\nIn September 2013, the patient died as a result of cardiac deterioration. A possible route of transmission could not be proven. However, there was a history of recent consumption of insufficiently heated pork sausage. Furthermore, the patient was at increased risk of developing severe complications due to the preexisting chronic liver disease.