Hepatitis E virus as an emerging cause of chronic liver disease in organ transplant recipients
Authors: René Gérolami, Valérie Moal, Christophe Picard, Philippe Colson
Journal: Journal of Hepatology (2008)

We read with great interest the very complete and up-to-date review by R.H. Purcell and S.U. Emerson on hepatitis E virus (HEV) [[1]Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar]. It highlights that this virus is the leading or the second leading cause of acute hepatitis in adults in many parts of the developing world, and that an increasing number of sporadic autochthonous acute hepatitis E cases have been recently reported in industrialized countries [[1]Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar]. Unexpectedly, a new clinical feature has just been described in association with autochthonous hepatitis E virus (HEV) infections in developed countries [2Kamar N. Selves J. Mansuy J.M. Ouezzani L. Péron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1063) Google Scholar, 3Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (299) Google Scholar, 4Haagsma E.B. Van Den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (279) Google Scholar]. Indeed, since February 2008, cases of HEV-related chronic hepatitis have been reported in organ transplant recipients by three different teams, including ours. This finding still adds significant interest to hepatitis E, and questions the extent and clinical presentation and outcome of chronic HEV infections. We describe herein a new case of chronic hepatitis E in an organ transplant recipient, which was associated with very mild elevation of liver biological tests in contrast with previous reports. A 45-year-old patient who had undergone kidney transplantation in 1991 and in 2004 presented in September 2006 with increased liver biological tests. Gamma-glutamyltransferases (GGT) level had risen from 42 to 170 IU/L between June 2006 and September 2006, concurrently with a fourfold increase in alanine amino transferases (ALT) level, from 6 to 35 IU/L (Fig. 1A). During the following months, GGT levels progressively decreased while ALT level plateaued at a significantly higher level than before September 2006 (Fig. 1A). Hepatitis C virus (HCV) serology and serum HCV RNA (Cobas TaqMan assay, Roche Diagnostics, Meylan, France) were negative. Hepatitis B virus (HBV) serology showed past immunization and HBV DNA (Cobas TaqMan assay) was undetectable in serum. No evidence for auto-immune hepatitis could be found. Ferritinemia and transferrin saturation were normal. Alcohol consumption was lower than 10 g/day. No modification of the patient's therapy could be noted. Diagnosis of hepatitis E virus (HEV) infection was established in March 2007 on the basis of IgG and IgM anti-HEV antibodies positivity (Optical Density Ratio, 5.4 and 4.3, respectively; Adaltis EIAGen kits, Adaltis Italia S.p.A., Casalecchio di Reno, Italy) and HEV RNA detection and sequencing in serum using in-house assays [[5]Colson P. Borentain P. Motte A. Lagrange X. Kaba M. Henry M. et al.First human cases of hepatitis E infection with genotype 3c strains.J Clin Virol. 2007; 40: 318-320Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Retrospective HEV RNA and anti-HEV antibody testings that could be performed on five available sera collected between November 2002 and October 2005 were negative. Liver biopsy performed in August 2007 showed evidence for chronic hepatitis with periportal inflammation, piece-meal necrosis, and fibrosis (Fig. 1B and C). Ursodeoxycholic acid (UDCA) was introduced in September 2007. Subsequently, liver biological tests slightly improved. However, HEV RNA remained detectable at stable titres in serum from March 2007 until March 2008. The patient did not report any recent travel abroad or contacts with travellers. HEV RNA ORF-2 sequence clustered into genotype 3f, which is found in autochthonous hepatitis E and in swine in Europe [[1]Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar]. Thus, HEV sequences corresponding to the ten BLAST hits with the highest scores on sequence from the case reported here were from French and Spanish humans or Spanish swine (http://www.ncbi.nlm.nih.gov/BLAST/). The present observation fulfils the criteria for chronic hepatitis, consisting in elevation of liver biological tests and HEV RNA detection lasting more than 6 months, in association with histological evidence for liver inflammation and fibrosis. Eleven cases of chronic HEV infection have been reported since the review by Purcell and Emerson on hepatitis E was published in a recent issue of the Journal of Hepatology. All cases occurred in solid-organ transplant recipients. Transplanted organs were liver, kidney, and kidney/ pancreas in 5, 4, and two cases, respectively. This clearly suggests that the atypical clinical and virological outcome for HEV infection in these cases could be related to the immunosuppressive treatment, which might have resulted in sub-optimal anti-HEV specific immune responses and subsequent viral persistence. Such a hypothesis has been evocated by Kamar et al. who found significantly reduced CD2-, CD3-, and CD4-lymphocytes counts in patients in whom chronic disease developed, and it has been recently debated by Schildgen et al. [[6]Schildgen O. Müller A. Simon A. Chronic hepatitis E and organ transplants.N Engl J Med. 2008; 358: 2521-2522Crossref PubMed Scopus (8) Google Scholar] However, the present case distinguishes itself from previously reported chronic hepatitis E. Indeed, the patient did not present clinical signs for acute hepatitis and ALT level never exceeded 1.5-fold the upper normal limit (Fig. 1A). Noteworthy, ALT level returned to normal ranges following UDCA initiation despite stable HEV RNA titers in serum. In contrast, in previously reported chronic hepatitis E, ALT levels were nearly ten-fold the upper normal limit (mean highest ALT level = 276 IU/mL; range, 69–874 IU/mL) [2Kamar N. Selves J. Mansuy J.M. Ouezzani L. Péron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1063) Google Scholar, 3Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (299) Google Scholar, 4Haagsma E.B. Van Den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (279) Google Scholar]. Furthermore, HEV-related cirrhosis could be found in five patients, including one in whom cirrhosis occurred as early as one year following infection, and two other cases that necessitated liver transplantation [3Gerolami R. Moal V. Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.N Engl J Med. 2008; 358: 859-860Crossref PubMed Scopus (299) Google Scholar, 4Haagsma E.B. Van Den Berg A.P. Porte R.J. Benne C.A. Vennema H. Reimerink J.H. et al.Chronic hepatitis E virus infection in liver transplant recipients.Liver Transpl. 2008; 14: 547-553Crossref PubMed Scopus (279) Google Scholar]. With regards to these severe clinical outcomes, it should be outlined that, in the present case, liver histology showed only mild hepatitis with very early fibrosis. Therefore, although a longer follow-up is mandatory to confirm this issue, the present observation suggests that chronic HEV infection may also result in mild chronic hepatitis with low activity and almost normal biological liver tests. Altogether, these data deserve further studies to assess the actual incidence, prevalence and outcome of chronic HEV infection in organ transplant recipients and warrants for including HEV testing in diagnosis investigation in transplanted patients presenting with mild chronic elevation of liver biological tests.