Pathogenesis of acute hepatitis E virus infection in pregnancy DOI: 10.1111/j.1478-3231.2008.01893.x To the Editor: We thank Renou and colleagues for their valuable comments about the review. We also agree that hepa- titis E virus (HEV) virological characteristics along with the hormonal and immunological changes of pregnancy contribute to the varying geographic mor- tality of HEV in pregnancy. In fact in our study from South India (1), a region endemic for hepatitis E, we observed a low mortality rate of HEV in pregnancy similar to the Egyptian study (2). This was different from the reports from Northern India (3). This may be secondary to difference in subtypes or subgenotype shift as we had hypothesized in our study. Studies have shown that the subtype in Africa is different from Asia (4). However the distribu- tion of subtype differences in Northern and Southern India has not been found. Although genotype shift/ drift has not been shown yet to occur in HEV, we proposed that subtype shifts of a particular genotype can occur in epidemics accounting for the varying mortality in pregnancy (1). We also agree with Renou and colleagues’ observations that all the studies high- lighting the high mortality of HEV in pregnancy have been from endemic countries and fulminant hepatitis in non-endemic countries has been rarely reported. In fact all cases have been in patients with recent travel to endemic countries highlighting the importance of virological characteristics. But virological characteristics by themselves cannot produce fulminant liver failure as fulminant liver fail- ure is rare outside the setting of pregnancy with HEV. Reports of fulminant liver failure outside of pregnancy have been in children from endemic countries includ- ing India (5) or co-existing toxins in the form of herbal medications (6) or underlying chronic liver disease (7). Thus fulminant liver failure due to HEV requires the appropriate host where it can trigger the immuno- logical changes producing damage. Variations in the major histocompatibility complex (MHC) mediating antigen presentation to the lymphocytes have been proposed in other viruses to explain the varying immunological response (8). This phenomenon may also explain some of the difference in the mortality in different geographical areas in women infected with HEV and is a potential research area for the future. The host factors along with the immunological and hor- monal changes in pregnancy in addition to the virolo- gical factors account for the high mortality. We look forward to more studies to look for genotype shift/drift and also studies to identify specific host factors that prime the immune system to produce fulminant liver failure in certain geographic regions. Udayakumar Navaneethan, Mayar Al Mohajer and Mohamed T. Shata Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA References 1. Rasheeda CA, Navaneethan U, Jayanthi V. Liver disease in pregnancy and its influence on maternal and fetal mortality – A prospective study from Chennai, Southern India. Eur J Gastroenterol Hepatol 2008; 20: 362–4. 2. Stoszek SK, Abdel-Hamid M, Saleh DA, et al. High prevalence of hepatitis E antibodies in pregnant Egyptian women. Trans R Soc Trop Med Hyg 2006; 100: 95–101. Epub, 28 October 2005. 3. Navaneethan U, Mohajer M, Shata MT. Hepatitis E and pregnancy-Understanding the pathogenesis. Liver Int 2008; 1190–1199. Epub ahead of print, 23 July. 4. Lu L, Li C, Hagedorn CH. Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, sub types and zoonosis. Rev Med Virol 2006; 16: 5–36. 5. Samanta T, Ganguly S. Aetiology, clinical profile and prog- nostic indicators for children with acute liver failure admitted in a teaching hospital in Kolkata. Trop Gastroenterol 2007; 28: 135–9. 6. Navaneethan U, Venkatraman J. Herbal drugs in liver disease: how safe are they? Eur J Gastroenterol Hepatol 2008; 20: 224–6. 7. Ramachandran J, Eapen CE, Kang G, et al. Hepatitis E super- infection produces severe decompensation in patients with chronic liver disease. J Gastroenterol Hepatol 2004; 19: 134–8. 8. Hohler T, Reuss E, Evers N, et al. Differential genetic determi- nation of immune responsiveness to hepatitis B surface antigen and to hepatitis. A virus: a vaccination study in twins. Lancet 2002; 360: 991–5. Liver International (2008) 1466 c  2008 The Authors. Journal compilation c  2008 Blackwell Munksgaard Letters to the Editor