Extra-hepatic manifestations associated with hepatitis E virus infection:a comprehensive review of the literature

Background and aims:Hepatitis E virus(HEV)infection is a significant public health problem that afflicts almost 20 million individuals annually and causes acute liver injury in 3.5 million,with approximately 56000 deaths.As with other viral hepatitides,extra-hepatic manifestations could represent an important aspect of this infection.The spectrum of these manifestations is still emerging.Acute pancreatitis and neurological,musculoskeletal,hematological,renal,and other immune-mediated manifestations have been described.The aim of this article is to comprehensively review the published literature of extra-hepatic manifestations associated with HEV infection.Data sources:We searched the PubMed database using the MeSH term“hepatitis E”and each of the extra-hepaticmanifestations associated with HEV infection.No language or date restrictions were set in these searches.Searches retrieving articles with non-A,non-B hepatitis were excluded.Additional articles were identified through the reference lists of included articles.Results:Several extra-hepatic manifestations associated with HEV infection have been published.The temporal association between some extra-hepatic manifestations and HEV infection and the exclusion of other possible etiologies suggests that HEV infection could have caused some of them.According to the available data,HEV infection appears to be strongly associated with acute pancreatitis,neurological disorders(with primarily dominant peripheral nerve involvement,most commonly manifested as Guillain-Barre´syndrome,followed by neuralgic amyotrophy),hematological diseases(hemolytic anemia due to glucose phosphate dehydrogenase deficiency,and severe thrombocytopenia),glomerulonephritis,and mixed cryoglobulinemia.More data are needed to clarify whether an association exists with musculoskeletal or other immunemediated manifestations.Conclusions:HEV infection should be considered in patients with acute pancreatitis,Guillain-Barre´syndrome,neuralgic amyotrophy,hemolytic anemia due to glucose phosphate dehydrogenase deficiency,severe thrombocytopenia,glomerulonephritis,and mixed cryoglobulinemia.Alternatively,signs and symptoms of these conditions should be sought in patients with acute or chronic HEV infection.More data are needed to confirm the role of HEV in other extra-hepatic disorders.