Hepatitis E infection in a patient with transfusion-dependent β thalassemia
Authors: Farzana Sayani, David Goldberg, Linda Slaven, J. Eric Russell
Journal: American Journal of Hematology (2014)

To the Editor: The clinical course of transfusion-dependent β thalassemia is frequently complicated by liver disease resulting from infection with hepatitis C virus (HCV), biliary pigment stones, tissue iron overload, and/or iron chelator toxicity. We report an unusual case of acute hepatitis in a patient with β-thalassemia intermedia following infection with hepatitis E virus (HEV). Although HEV is endemic in many developing regions of the world and exhibits high seropositivity rates even in industrialized countries, it has not previously been associated with liver dysfunction in patients with thalassemic conditions. A 61-year-old man of Mediterranean descent was referred to our practice for the evaluation of anemia and splenomegaly, which had been noted prior to endoscopic retrograde cholangiopancreatography (ERCP) for acute choledocolithiasis. The patient stated a history of easy fatigue and splenic enlargement that dated to early adulthood, but had never been formally evaluated or empirically treated. Physical examination was remarkable for short stature, mild frontal bossing, and painless enlargement of the liver and spleen. Hematological studies revealed hemoglobin 7.5 g/dL, hematocrit 22%, MCV 75 fL, MCH 26 pg, white blood cell count 3.0 × 103/µL, and platelets 53 × 103/µL; a hemolysate comprising 88.1% HbA, 5.2% HbA2, and 6.7% HbF; and ferritin 1,361 ng/mL. Molecular studies demonstrated double heterozygosity for the c.17_18delCT and c.-151C→T β-globin gene mutations, confirming a diagnosis of β-thalassemia intermedia. Baseline (post-ERCP) liver function tests revealed total bilirubin 6.9 mg/dL, direct bilirubin 3.1 mg/dL, aspartate aminotransferase (AST) 82 U/L, and alanine aminotransferase (ALT) 119 U/L. Liver iron concentration (LIC) was estimated as 3.8 mg/g dry weight by liver R2 MRI (Ferriscan) analysis. Serological tests were positive for HCV antibody and antigen, but negative for surface antibodies against both hepatitis A virus (HAV) and hepatitis B virus (HBV). The patient initiated regular therapeutic red-cell transfusions and oral deferasirox (Exjade; 20 mg/kg/day) and reported rapid improvements in both fatigue and splenomegaly. Following 4 months of therapy, though, the patient developed non-focal abdominal discomfort, decreased appetite, and worsening jaundice; he denied any new medications (including acetaminophen) or alcohol consumption. Laboratory analyses revealed deteriorating liver function tests that continued to worsen even after deferasirox was discontinued (Fig. 1). Serological tests for HAV, HBV, and HCV were unchanged from baseline; the LIC was modestly elevated at 5.5 mg/g dry weight. Serological studies for HEV were positive for IgM and negative for IgG, consistent with acute infection. Course of acute Hepatitis E infection in thalassemia. Laboratory values are shown for ALT, AST, and alkaline phosphatase (left axis); and for total bilirubin (right axis). The dose of deferasirox (Exjade) is indicated in mg/kg/day. The results of serological studies for HEV IgM and IgG are illustrated. HEV infection typically manifests as a mild and self-limited liver inflammation that rarely progresses to either a fulminant or a chronic condition; contemporary studies cite seroprevalence rates of 6.25% in industrialized countries 1 and higher rates elsewhere 2. Although commonly transmitted by human fecal–oral contamination, HEV circulates in both domestic animals and in wild game and can be contracted by consuming raw or undercooked meat products 3, 4. HEV can also be transmitted through exposure to infected blood products 5, with donor viremia rates estimated between 0.03% and 1.5% in non-endemic and endemic populations, respectively 6-8. Importantly, nearly half of the recipients of HEV-infected blood will develop clinically relevant infection 7. The expectation that patients with transfusion-dependent β thalassemia will display high seropositivity rates for HEV, though, is not supported by the literature 9-11, possibly reflecting study groups that are both small in size and that are not stratified for the number of blood-product exposures. The present case emphasizes the importance of considering HEV as a cause of acute hepatic inflammation in patients with transfusion-dependent β thalassemia whose presentations are inconsistent with other, more common etiologies. The acuity of the inflammatory process in our patient was unlikely to reflect exacerbations in HCV- or iron-related processes; and our suspicions for deferasirox toxicity were proved false when the patient's liver function continued to deteriorate following its discontinuation. We subsequently considered the possibilities that the patient had contracted HEV either through leisure activities (he hunts and consumes wild game) or through HEV-contaminated donor red blood cells, and proved the diagnosis with IgM-positive, IgG-negative HEV serologies. The route of transmission, though, remains a mystery, as neither samples of game, nor blood segments from donor erythrocyte units, were available for post-transfusion viral analyses. Although there is no approved antiviral therapy for HEV infection, accurate diagnosis provided reassurance that the disease would likely be self-limited in this patient and would not require significant long-term changes to a transfusion and chelation strategy that was highly effective in treating his thalassemic condition. Farzana Sayani,1 David Goldberg,2 Linda Slaven,1 and J. Eric Russell1* 1Division of Hematology-Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 2Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania