Hepatitis E: The Endemic Perspective

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1 REVIEW Hepatitis E: The Endemic Perspective Rakesh Aggarwal, M.D., D.M. Hepatitis E is the term used for disease caused by infection with hepatitis E virus (HEV). It is endemic in several parts of Africa and Asia, including the Indian subcontinent (Fig. 1), where it is often the most common cause of acute hepatitis. This review covers the key features of this disease from the perspective of a physician-hepatologist working in an area where the disease is endemic. Epidemiology of Hepatitis E in Endemic Areas In endemic regions, hepatitis E may present either as part of an outbreak or as isolated (sporadic) cases. The clinical characteristics of patients with epidemic hepatitis E and patients with sporadic hepatitis E are similar. Hepatitis E epidemics vary from small, unimodal outbreaks lasting a few weeks to large, multipeak epidemics lasting many months with several thousand cases. 1,2 The outbreaks are usually related to the contamination of drinking water supplies with human fecal matter that contains HEV. Several natural and manmade circumstances facilitate water contamination and hence the occurrence of such outbreaks. These include heavy rainfall and flooding, diminution of water flow in rivers during hot summers, disposal of sewage into rivers, leaky water pipes with intermittent water supplies passing through sewage-contaminated soil, and large-scale human displacements due to wars and internal conflicts. Occasional small, food-borne outbreaks have also been reported. In most outbreaks, person-to-person transmission has been insignificant. The outbreaks in these areas have invariably been due to HEV genotype 1 or 2. The zoonotic transmission of genotype 3 or 4 HEV from pigs or other animal reservoirs, the predominant mode of spread in nonendemic areas, has not been reported in endemic areas, and is either nonexistent or infrequent. Clinical Manifestations In endemic areas, hepatitis E, epidemic and sporadic, occurs most frequently in the age group of 10 to 40 years. Men tend to be affected somewhat more often; this may be related to greater exposure to contaminated water. The clinical outcomes of HEV infection vary widely 3,4 (Table 1). The most commonly observed illness is acute icteric hepatitis of variable severity. The illness often has two distinct phases. The initial pre-icteric phase consists of fever, malaise, anorexia, nausea, vomiting, bowel alterations, and abdominal pain lasting for a few days. This is followed by an icteric phase, which is characterized by dark urine and jaundice, lasts for a few weeks, and is usually followed by spontaneous resolution. Physical examination reveals jaundice, hepatomegaly, and sometimes a soft, palpable spleen. This illness in individual patients is usually indistinguishable from illness caused by other hepatotropic viruses (e.g., hepatitis A virus and hepatitis B virus) except for epidemiological features, such as occurrence as outbreaks, association with water contamination, young age, and a predilection to occur in pregnant women. Some patients experience a period of prolonged cholestatic symptoms with troublesome itching and jaundice persisting for several weeks; however, these usually resolve with time with no adverse outcome. A few patients develop severe liver injury, which manifests as fulminant liver failure (FHF) or subacute liver failure, either of which may be fatal. In contrast, many persons with HEV infection have mild liver injury with liver enzyme elevations but no icterus (anicteric hepatitis). A large proportion of persons with serological evidence of HEV infection have no past history of liver illness, and this suggests that asymptomatic infection is common. The overall mortality rate for those affected during an outbreak is usually low (<1/1000). Abbreviations: FHF, fulminant liver failure; HEV, hepatitis E virus; Ig, immunoglobulin From the Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Potential conflict of interest: Nothing to report. There is additional supporting information for this article. View this article online at wileyonlinelibrary.com VC 2013 by the American Association for the Study of Liver Diseases doi: /cld Clinical Liver Disease, Vol 2, No 6, December 2013 An Official Learning Resource of AASLD

2 FIGURE 1 Geographical areas where hepatitis E is endemic (as evidenced by the occurrence of outbreaks or a large proportion of sporadic acute hepatitis cases being due to hepatitis E). Reprinted with permission from Journal of Gastroenterology and Hepatology. 1 Copyright 2009, John Wiley & Sons, Inc. TABLE 1 Clinical Manifestations of Liver Involvement in Hepatitis E Presentation Acute icteric hepatitis Fulminant hepatitis Anicteric hepatitis Unapparent infection Acute-on-chronic liver disease Details Illness resembling other forms of acute viral hepatitis Leads to acute liver failure (more common in pregnant women) Biochemical abnormalities but no jaundice Asymptomatic but leads to anti-hev antibodies With infection in persons with preexisting liver disease Importantly, no chronic sequelae of HEV infections or persistent HEV infections have been identified in endemic areas to date. Hepatitis E in Pregnant Women A characteristic feature of hepatitis E in endemic areas is its association with a high disease attack rate, a high rate of FHF development, and a high mortality rate in pregnant women. The mechanism of this predilection remains unclear. In an outbreak in Kashmir, India, 8.8%, 19.4%, and 18.6% of pregnant women in the first, second, and third trimesters, respectively, had symptomatic disease, whereas only 2.1% of nonpregnant women and 2.8% of men did so. 5 Furthermore, 22% of the affected pregnant cases developed FHF, whereas none of the affected nonpregnant women and only 3% of the affected men did so. Similar findings have been reported for other outbreaks 6-9 and for cases with sporadic endemic hepatitis E. 10 This predilection results in a much higher overall mortality rate for pregnant women versus nonpregnant women and men during hepatitis E outbreaks (Fig. 2). Some infants born to mothers with hepatitis E acquire an HEV infection through the transplacental route. Such infants are often born premature, may manifest hypothermia, hypoglycemia, or icteric or anicteric hepatitis, and have a mortality rate approaching 50%. 11 Acute Hepatitis E Superimposed on Chronic Liver Disease When HEV infects a person with preexisting liver disease, the manifestations may be somewhat different. Because of a lower functional hepatic reserve, acute liver injury due to hepatitis E may be expected to more often lead to symptomatic disease or liver failure (Fig. 3). These patients often present with a clinical syndrome of acute-on-chronic liver failure. In one study, 12 evidence of a recent HEV infection was found in nearly one-half of Indian patients with chronic liver disease and recent decompensation; in many of these patients, chronic liver disease had been asymptomatic until the infection with HEV. The underlying chronic liver disease may have been due to another hepatitis virus or a nonviral cause. Illness in these patients initially resembles typical acute viral hepatitis. However, within a few days to weeks, ascites, encephalopathy, or both appear, suggesting decompensated liver disease. Acute hepatitis E superimposed on chronic liver disease must be distinguished from severe acute hepatitis E. This may require additional investigation, including imaging or endoscopic findings characteristic of chronic liver damage or portal hypertension. The outcome of such 241 Clinical Liver Disease, Vol 2, No 6, December 2013 An Official Learning Resource of AASLD

3 patients is poorer than those of otherwise healthy persons with hepatitis E. 13 Diagnosis In endemic areas, patients suspected to have hepatitis E undergo biochemical liver function tests to confirm the diagnosis of acute hepatitis (conjugated hyperbilirubinemia, markedly elevated alanine and aspartate aminotransferase levels, and sometimes mildly elevated alkaline phosphatase levels) and serological tests to look for evidence of a recent HEV infection and to exclude an infection with another hepatitis virus. Some patients may need an ultrasound examination to exclude biliary obstruction or liver abscess. The most commonly used method to detect a recent HEV infection is one of the several available enzyme immunoassays for immunoglobulin M (IgM) anti-hev antibodies, which appear almost simultaneously with the onset of symptoms and persist for a few months. These assays vary widely in their performance characteristics, 14 but they generally appear to perform better in endemic areas than in nonendemic areas. None of the assays are approved for use in the United States. In patients with acute hepatitis E in endemic areas, IgM anti-hev is often accompanied by a high level of IgG anti- HEV, which may out-compete the IgM antibodies in conventional immunoassays. Hence, assays with an IgM capture format have been devised, and these appear to perform better. 15 The detection of HEV RNA is more specific for HEV infections; however, HEV RNA disappears early in the disease, and the results may be negative by the time the patient presents to a physician. Also, facilities for HEV RNA assays in disease-endemic areas are limited. Anti-HEV IgG has no role in the diagnosis of hepatitis E in endemic areas. Treatment In endemic areas, hepatitis E is generally self-limiting, so only supportive measures for the relief of fever, body aches, vomiting, and so forth are required; no specific treatment is deemed necessary. Whether specific treatment can benefit patients with hepatitis E related FHF, including pregnant women, or patients with chronic liver disease and HEV superinfections remains unclear because no clinical trials have been performed. The results of successful antiviral therapy using interferon or ribavirin for chronic infections with HEV genotype 3 in FIGURE 2. FIGURE 2 (A) This schematic diagram presents the clinical outcomes of HEV infections in groups of pregnant women (represented by the dark blue rectangle) and nonpregnant women (represented by the light blue rectangle). (B) The pink circles represent the proportions of women in each group who acquire HEV infections; no data are available to show that these proportions differ between pregnant and nonpregnant women. (C) The yellow circles represent the number of women with HEV infections who develop icteric disease; this number is greater for pregnant women versus nonpregnant women. (D) The red circles represent the number of women who develop fulminant hepatic failure (FHF); this number is greater for pregnant women with symptomatic hepatitis E versus similar nonpregnant women. (E) The black pies in the innermost circles indicate the proportions of FHF patients who die. The proportions are similar for pregnant and nonpregnant women with HEV-induced FHF. However, because HEVinduced FHF is more common in pregnant women, the overall mortality rate due to HEV infection is higher among pregnant women versus nonpregnant women. Adapted with permission from Virus Research. 3 Copyright 2011, Elsevier B.V. 242 Clinical Liver Disease, Vol 2, No 6, December 2013 An Official Learning Resource of AASLD

4 FIGURE 3 (A) This schematic diagram shows the clinical outcomes of HEV infections in otherwise healthy persons and persons with preexisting chronic liver disease. The x axis represents time, and the y axis represents the relative liver function in arbitrary units. The pink and blue dotted lines represent arbitrary thresholds of liver function below which jaundice and signs of liver failure may be expected to develop. In a previously healthy person with an HEV infection, progressively increasing degrees of liver injury may be expected to lead to (B) anicteric hepatitis (curve a), (C) acute uncomplicated icteric hepatitis (curve b), or (D) FHF (curve c). (E) Persons with preexisting chronic liver disease (curve d) have suboptimal liver function to begin with. Thus, HEV infections in these patients would be expected to more often cause reduction of liver function below the thresholds for jaundice and liver failure. They are thus likely to develop jaundice or liver failure more often. Also, these symptoms can be expected (F) to last for a longer duration than they would in otherwise healthy persons or (G) or to result in death (dotted red line). Adapted with permission from Seminars in Liver Disease. 4 Copyright 2013, Georg Thieme Verlag KG. nonendemic areas cannot be easily extrapolated to patients in endemic areas for several reasons. These include (1) the short survival duration of patients with FHF (within which the drug must act for it to influence the outcome), (2) the differences in prevalent viral genotypes in endemic areas, (3) the risks associated with the use of these drugs during pregnancy (including the risk to the fetus), and (4) the possibility of the worsening of liver disease with interferon treatment (as is known with other forms of viral hepatitis). Prevention In endemic areas, hepatitis E can be prevented through steps that ensure safe drinking water supplies. Steps directed against zoonotic transmission from pig or deer meat are not of much importance in these areas. Two subunit vaccines that contain recombinant partial HEV capsid proteins have been shown to prevent hepatitis E. 16,17 However, several additional pieces of information are needed before these vaccines can be applied for the prevention of hepatitis E in endemic areas: better estimates of the disease burden in various populations, the efficacy and safety of the vaccines in high-risk groups (e.g., pregnant women and patients with liver disease), the efficacy of the vaccines when they are administered after exposure (for outbreak control), the duration of the protection offered, the need for and frequency of boosters, and the cost-benefit ratio of vaccine use. CORRESPONDENCE Rakesh Aggarwal, M.D., D.M., Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow , India. aggarwal.ra@gmail.com. 243 Clinical Liver Disease, Vol 2, No 6, December 2013 An Official Learning Resource of AASLD

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