Clinical presentation of hepatitis E

Virus Research 161 (2011) 15–22

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Review

Clinical presentation of hepatitis E Rakesh Aggarwal ∗ Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India

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Article history: Available online 31 March 2011 Keywords: Hepatitis E Clinical manifestations

a b s t r a c t Hepatitis E is a form of acute hepatitis, which is caused by infection with hepatitis E virus. The infection is transmitted primarily through fecal-oral route and the disease is highly endemic in several developing countries with opportunities for contamination of drinking water. In these areas with high endemicity, it occurs as outbreaks and as sporadic cases of acute hepatitis. The illness often resembles that associated with other hepatotropic viruses and is usually self-limiting; in some cases, the disease progresses to acute liver failure. The infection is particularly severe in pregnant women. Patients with chronic liver disease and superimposed HEV infection can present with severe liver injury, the so-called acute-on-chronic liver failure. In recent years, occasional sporadic cases with locally acquired hepatitis E have been reported from several developed countries in Europe, United States, and Asia. In these areas, in addition to acute hepatitis similar to that seen in highly endemic areas, chronic hepatitis E has been reported among immunosuppressed persons, in particular solid organ transplant recipients. HEV-infected mothers can transmit the infection to foetus, leading to premature birth, increased fetal loss and hypoglycaemia, hypothermia, and anicteric or icteric acute hepatitis in the newborns. Occasional cases with atypical non-hepatic manifestations, such as acute pancreatitis, hematological abnormalities, autoimmune phenomena, and neurological syndromes have been reported from both hyperendemic and non-endemic regions. The pathogenesis of these manifestations remains unclear. © 2011 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiologic patterns of HEV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical manifestations of hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Data from volunteer studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Hepatitis E in high-endemicity areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Hepatitis E outbreaks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Sporadic acute hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. HEV superinfection in chronic liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Hepatitis E in low-endemicity areas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Acute hepatitis E in low-endemicity regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Chronic HEV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis E in special settings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Hepatitis E in pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. HEV infection in neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-hepatic manifestations of hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Hemolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: HEV, hepatitis E virus; FHF, fulminant hepatic failure. ∗ Tel.: +91 522 249 4431; fax: +91 522 266 8017/266 8078. E-mail address: [email protected] 0168-1702/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.virusres.2011.03.017

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5.4. Autoimmune manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Neurological manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors influencing clinical severity of disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of hepatitis E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The term ‘hepatitis’ implies ‘inflammation of the liver’. Based on the duration of illness or associated laboratory abnormalities, it is subdivided, somewhat empirically, into acute hepatitis, i.e. lasting for up to 6 months, or chronic hepatitis, i.e. persisting for longer than 6 months. Liver inflammation may be caused by one of several etiologic agents, including viruses and other infectious agents, drugs, alcohol and other toxins, autoimmune disease, radiation injury, etc.; in some cases, no known cause can be found. Currently, at least five distinct hepatotropic or hepatitis viruses, named using consecutive letters from the English language, are recognized. These viruses vary widely in their size, structure, genomic organization, and mode of replication. HEV is a small 27–34 nm size virus with a nearly 7.2-kilobase, single-stranded RNA genome. Structure and molecular features of this virus are covered elsewhere in this supplement (Mitsuura et al., this issue; Jameel et al., this issue). At least four distinct genotypes of the virus (named as genotypes 1, 2, 3 and 4) are known. These four genotypes differ widely in geographical distribution and host species, as has been discussed in detail elsewhere in this supplement (Purdy et al., this issue). The virus is excreted in the stools of infected persons and is primarily transmitted through fecal-oral route (Aggarwal and Naik, 2009). The disease caused by HEV is termed as ‘hepatitis E’. This document reviews the clinical manifestations of hepatitis E, while recognizing that these often resemble those of acute hepatitis caused by other hepatotropic viruses. 2. Epidemiologic patterns of HEV infection HEV infection is associated with two distinct epidemiological patterns of disease, as has been reviewed in detail elsewhere recently (Aggarwal and Naik, 2009), as also in this review (Khuroo et al., this issue; Miyamura et al., this issue). Hepatitis E is highly endemic in the Indian subcontinent, China, Southeast and Central Asia, the Middle East, and northern and western parts of Africa (Aggarwal and Naik, 2009). In these areas, outbreaks of hepatitis E of variable sizes have been reported. In addition, a fairly large proportion of cases with sporadic acute hepatitis in these areas is caused by HEV infection. In these areas, water-borne transmission is the most common route for acquisition of infection. It is plausible that food-borne transmission also plays a role in the transmission of hepatitis E in these regions. However, this is difficult to prove because of the relatively long incubation period and the consequent difficulties in attributing disease to consumption of a particular food. Both outbreaks and sporadic cases of hepatitis E in such regions have been related to genotype 1 or 2 HEV; in some areas, a proportion of sporadic cases have been related to genotype 4 (Aggarwal and Naik, 2009). In comparison, in the developed parts of the world, e.g. western Europe, USA, Japan and Australia, hepatitis E is uncommon. Till nearly 10 years ago, cases of hepatitis E in these areas were all related to travel to areas where the disease is common. However, in recent years, several case reports and case-series of locally acquired (autochthonous) hepatitis E have been published from these areas. Autochthonous hepatitis E in these areas has differences in routes of transmission and in clinical features than those reported from the areas where hepatitis E is hyperendemic (Aggarwal and Naik,

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2009; Pavio and Mansuy, 2010). The locally acquired HEV infection in these areas has been found to be related to genotype 3 and 4 virus. 3. Clinical manifestations of hepatitis E Data on clinical manifestations of hepatitis E are available from (i) two case reports of volunteers who ingested preparations that contained the causative virus, (ii) from reports of hepatitis E outbreaks and sporadic disease from highly endemic areas, and (iii) case reports and case series from developed countries with low endemicity. Each of these is discussed separately, followed by clinical manifestations of hepatitis E in pregnant women and neonates, and some unusual non-hepatic manifestations of hepatitis E. 3.1. Data from volunteer studies The most reliable data on clinical disease caused by HEV infection are available from reports of two volunteers who ingested preparations derived from fecal specimens obtained from patients with enterically transmitted acute hepatitis (Balayan et al., 1983; Chauhan et al., 1993). In the first report (Balayan et al., 1983), the symptoms developed on day 36 post-inoculation, with asthenia, abdominal pain, nausea, vomiting and anorexia, followed by fever, dark urine and liver enlargement. This phase was followed a few days later by appearance of jaundice. The illness lasted till about day 60. ALT levels and AST levels were elevated during the illness, reaching peak levels of 3010 IU/L and 1165 IU/L, respectively, and returning to normal as symptoms improved. Laboratory testing showed fecal excretion of viral particles and appearance of specific antibodies in the serum. This report was notable in that it marked the first demonstration of HEV, then named as non-A, non-B hepatitis agent, as an entity distinct from the hepatitis A and B viruses. In the other volunteer (Chauhan et al., 1993), anorexia, epigastric pain, and discoloured urine appeared on day 30 post-inoculation; these were followed 8 days later by jaundice, which lasted until day 120. ALT levels rose on day 30, reached a peak on day 46 and gradually returned to normal by day 130 post-inoculation. The symptoms were particularly worse immediately following the ALT peak, resulting in severe nausea, vomiting, inability to take any food and absence of stools. He recovered completely and had no clinical or biochemical evidence of liver disease during a 2-year follow-up. The stools showed viral excretion during days 30–46, and were not tested thereafter. HEV viremia was detected from day 22 onwards till just prior to ALT peak. These disease descriptions among volunteers closely resemble those reported in studies of epidemic and sporadic disease in areas where the disease is highly endemic. 3.2. Hepatitis E in high-endemicity areas In these areas, HEV infection can lead to liver injury of variable severity (Table 1). The most characteristic and commonly observed clinical outcome in persons with HEV infection is as typical acute icteric hepatitis. This illness is often clinically and biochemically indistinguishable from that caused by other hepatotropic viruses, such as hepatitis A virus or hepatitis B virus, except for epidemiological features such as occurrence in outbreaks, association with

R. Aggarwal / Virus Research 161 (2011) 15–22 Table 1 Clinical manifestations of liver involvement in hepatitis E. Icteric hepatitis (similar to other forms of viral hepatitis) Severe hepatitis leading to fulminant hepatic failure Anicteric hepatitis (biochemical abnormalities but no jaundice) Inapparent or asymptomatic infection Acute on chronic liver disease

contamination of water sources, young age of patients and predilection for pregnant women. A few patients develop severe liver injury that manifests as subacute or acute (or fulminant) liver failure, conditions that may be fatal. In several subjects with HEV infection, liver injury is milder with only non-specific symptoms resembling acute febrile viral illness without jaundice (anicteric hepatitis); liver involvement in these patients is recognized only if laboratory studies are done. In its most benign form, HEV infection is entirely asymptomatic and passes unnoticed. 3.2.1. Hepatitis E outbreaks Several large outbreaks of hepatitis E have been reported from developing countries in Asia and Africa. Descriptions of these outbreaks and clinical features in affected patients (Table 2) have generally been similar. Detailed description of clinical features of hepatitis E is available from a large outbreak in Delhi, India during 1955–1956 (Vishwanathan and Sidhu, 1957). Of the 958 cases admitted to various hospitals, 752 (78%) were in the age range of 15–34 years. The illness was described as having two distinct phases, namely preicteric phase and icteric phase. During the pre-icteric phase, the most common symptoms were fever, loss of appetite, distaste for food, anorexia, vomiting, constipation, diarrhea and loin pain. This phase lasted 1–27 (average 2.7) days. Onset of the icteric phase was marked by disappearance of fever and return of appetite. This phase lasted 10–24 days. Hepatomegaly was common. Some patients also had itching and painless lymphadenopathy. During this stage, some patients developed fulminant disease which often had a fatal outcome. Overall, 65 cases (22 male, 43 female including 30 pregnant women) were fatal; the phase of hepatic coma was preceded by mental changes in 45, restlessness in 41, hemorrhages in 21 and persistent vomiting in 12 patients. During an outbreak in Kashmir during 1978–1979 (Khuroo, 1980), a pre-icteric phase lasting 1–10 (mean 3.5) days was recorded in 61% of cases. Besides jaundice, the other common symptoms were anorexia (79%), dark urine (58%), nausea and vomiting (46%), fever (44%) and epigastric pain (41%); these symptoms generally lasted for less than one week. Cholestatic symptoms, i.e. clay stools and itching were reported in 20% of cases. Clinical examination revealed jaundice and mild hepatomegaly; liver size was reduced in 4.5% of cases. Outbreaks in Africa have also shown similar features. In an outbreak in Ghana with 136 cases, the commonest symptoms were: jaundice (100%), dark urine (100%), malaise (95%), anorexia and/or

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nausea (95%), feeling of fever (57%), and abdominal ache (37%). Examination findings included: jaundice, hepatomegaly (71%), splenomegaly (22%) and transient lymphadenopathy (14%). Laboratory abnormalities include predominantly conjugated hyperbilirubinemia, markedly elevated levels of alanine and aspartate aminotransferases, and, in some patients, a less marked elevation of alkaline phosphatase. These usually return to normal within 6 weeks. Disease attack rates are the highest among young persons, with those in the age group of 10–40 years being at the highest risk; children and elderly persons have relatively lower disease rates (Khuroo, 1980; Naik et al., 1992; Vishwanathan, 1957; Vishwanathan and Sidhu, 1957). The reason for this age distribution in the face of massive contamination of water supply systems is unclear. During hepatitis E outbreaks, the disease attack rates tend to be higher among men than in women. This is possibly related to the greater likelihood of exposure to contaminated water among men, who spend more time outside the household, and may consume more water because of greater physical activity, than to differential propensity of disease among the two gender groups. Case-fatality rates of 0.5–4% have been reported during outbreaks (Myint et al., 1985; Sanyal, 1957); these data are, however, based on hospitalized patients and may thus overestimate mortality. Studies based on data obtained from population surveys report lower mortality rates varying from 0.07% to 0.6% (Naik et al., 1992; Zhuang, 1992). In an epidemic among army personnel in Ethiopia, none of the 423 patients with icteric hepatitis developed fulminant hepatic failure or died (Tsega et al., 1991). Follow-up studies of persons who were affected during an outbreak did not reveal any evidence of chronic liver disease (Chuttani et al., 1966). 3.2.2. Sporadic acute hepatitis E In high-endemicity areas, HEV infection is the most common cause of sporadic acute viral hepatitis (Chadha et al., 2003; Kumar et al., 2007; Tan et al., 1995). Clinical features of these patients, the age distribution of cases, and specific predilection for severe disease among pregnant women in sporadic cases are similar to those reported during outbreaks of hepatitis E in these regions. A few patients with hepatitis E develop prolonged cholestasis, which is characterized by persistence of jaundice, marked itching and elevated alkaline phosphatase. These patients generally otherwise feel well and have no systemic complaints. The condition most often has a benign outcome with the symptoms gradually improving after several months. 3.2.3. HEV superinfection in chronic liver disease A specific manifestation reported in sporadic setting is hepatitis E virus infection superimposed on pre-existing chronic liver disease. The chronic liver disease can be of viral or non-viral etiology, and may be previously known or entirely asymptomatic and undiagnosed. These patients present with acute on chronic liver disease.

Table 2 Clinical findings in hepatitis E outbreaks. Symptoms and signs

Delhi, India 1956 (%) (n = 958)

Accra, Ghana 1963 (%) (n = 136)

Kashmir, India 1978 (%) (n = 275)

Ethiopia 1989 (%) (n = 423)

Xinjing, China 1986–1988 (n = 85)

Jaundice Malaise Anorexia Abdominal pain Hepatomegaly Nausea, vomiting Fever Pruritus

100

100 95 95 37 67 48 57 47

100

100 100 100 82 10 100 97 14

91 95 69 55 80 91 53 59

66 63 62 29 23 14

79 41 85 46 44 20

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Men or non-pregnant women

Pregnant women

Fig. 1. A schematic diagram showing the relationship of clinical outcomes of hepatitis E virus (HEV) infection in a hypothetical population of pregnant women (blue rectangle) as compared to one of men and non-pregnant women (white rectangle). The pink circles represent proportion infected with HEV; no data are available on whether the risk of HEV infection differs between pregnant and non-pregnant persons. The yellow circles represent proportions developing icteric disease; this is more common in pregnant women than in the non-pregnant subjects. The innermost circle (black + red) inside the yellow circle represent the number of individuals that develop fulminant liver failure (FHF); this is more common among pregnant women with symptomatic hepatitis E than among similar non-pregnant women. The black pies in the innermost circles indicate proportions of persons with FHF who die; the available data indicate that these are similar among pregnant women and non-pregnant persons with HEV-induced FHF. However, since HEV-induced FHF is more common in pregnant women, the overall mortality rate due to HEV infection is higher among pregnant women than among men and non-pregnant women.

The clinical syndrome begins somewhat like acute viral hepatitis but is soon complicated by appearance of ascites, which suggests decompensation of chronic liver disease. In one study, evidence of recent HEV infection was found in nearly one-half of Indian patients with chronic liver disease and recent decompensation (Kumar et al., 2004). Such patients may be at a higher risk of a poor outcome (Kumar Acharya et al., 2007). 3.3. Hepatitis E in low-endemicity areas Till early 1990s, cases of hepatitis E in industrialized countries were found to be related to travel to areas where hepatitis E is hyperendemic. These cases had clinical manifestations similar to those recorded in the areas where the infection had been acquired. Beginning in mid-1990s, several cases of hepatitis E who had no history of travel to highly endemic areas have been described from western Europe (United Kingdom, France, Germany, Spain, the Netherlands, Denmark, Austria, Sweden), North America (United States of America), and developed countries of Asia-Pacific (Japan, Taiwan, Hong Kong, Australia, New Zealand). In these indigenously acquired cases in high-income, low-endemicity countries, the exact origin and route of transmission of hepatitis E remains unclear. A zoonotic transmission of genotype 3 and 4 HEV from animal reservoirs has been proposed based on detection of HEV genomic material in sera, feces and liver meat from several mammalian animal species, in particular pigs and deer, and close phylogenetic relationship between these animal isolates of HEV and those from human cases (Dalton et al., 2008b). In these countries, two clinical forms of hepatitis E have been described, namely acute hepatitis E, and chronic hepatitis E. 3.3.1. Acute hepatitis E in low-endemicity regions Clinical presentation of these patients has differences from those of patients with acute hepatitis E from areas where the disease is highly endemic (Dalton et al., 2008b; Pavio and Mansuy, 2010). These include: older age, a more marked male predominance, lack of severe disease among pregnant women, a higher frequency of underlying liver disease or alcohol use, a somewhat higher frequency of non-specific symptoms, and a higher mortality rate.

In a report of 40 cases of hepatitis E from United Kingdom, median age was 65 years (Dalton et al., 2008b); at least 3 patients had underlying liver cirrhosis, and most patients consumed alcohol. In another report of 19 cases of hepatitis E from the Netherlands (Borgen et al., 2008), median age of patients was 50 years, and 11 patients had an underlying cardiac, respiratory, malignant or other disease; the latter was possibly related to the older age of these patients. A recent review (Pavio and Mansuy, 2010) of four case-series of hepatitis E reported from low-endemicity areas, i.e. the United Kingdom (Dalton et al., 2007b), south-west France (Mansuy et al., 2009), Germany (Wichmann et al., 2008) and the Netherlands (Borgen et al., 2008), found that jaundice was the most common symptom, being reported in 68–86% of patients in different series. The other common symptoms were asthenia, fever, joint and muscle pains, and abdominal pain. Some patients also complained of headache, nausea and vomiting, loss of appetite, loss of weight, bowel disturbances and purpuric skin rash. Some patients with hepatitis E in high-income countries had initially been diagnosed to have drug-induced livery injury (Dalton et al., 2007a); in many of these patients, HEV infection was detected only at retrospective serological testing. Fulminant liver failure due to indigenously acquired hepatitis E has been described occasionally from low-endemicity areas. In one report of seven such cases from France (Peron et al., 2007), five were men and mean age was 65 years; four patients were older than 70 years of age. Five of these patients consumed significant amounts of alcohol, six had underlying chronic liver disease and four had diabetes. None of the patients was pregnant. No specific clinical features distinct from fulminant disease in highendemicity areas were reported. Five of these 7 patients died; the underlying conditions possibly played a role in this high mortality. In a study from United Kingdom (Dalton et al., 2008a), patients with hepatitis E were generally similar to patients with proven hepatitis A in demographic and laboratory features except that they were older (mean age 61 vs. 45 years), less likely to present in winter. Complications were more frequent in patients with hepatitis E, but this could be related to their older age and higher frequency of underlying liver disease.

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3.3.2. Chronic HEV infection HEV infection was conventionally believed to be a self-limited infection with spontaneous clearance. However, in recent years, several cases of persistent HEV infection have been recognized in low-endemic areas. The first major report of chronic HEV infection was a case-series of 14 French solid-organ transplant (kidney 9, liver 3, both kidney and pancreas 2) recipients with liver function test abnormalities and HEV infection (Kamar et al., 2008). Of these patients, six cleared the virus within a few weeks, but eight developed a persistent HEV viremia that lasted longer than 6 months and was associated with persistent transaminase elevation and histological evidence of significant liver inflammation and fibrosis. The patients with chronic HEV infection had a significantly shorter time interval between organ transplantation and diagnosis of liver injury than in patients with self-limiting infection (6–63 months vs. 25–168 months); in addition, peripheral blood of patients with persistent infection had fewer lymphocytes and CD2, CD3, and CD4 T cells, suggesting a role for immunosuppression in the persistence of infection. Clinical illness in immunosuppressed patients with hepatitis E in this study was generally mild. In 7 of the 14 patients, initial acute hepatitis episode was asymptomatic and was diagnosed only through detection of liver-enzyme abnormalities during routine laboratory testing. The other seven patients presented with fatigue, diffuse arthralgias, and myalgias for 1–2 weeks; one patient also had marked weight loss and icterus. Clinical features among patients with persistent hepatitis E were not reported separately. Several other reports have confirmed the occurrence of chronic HEV infection in immunosuppressed transplant recipients (Gerolami et al., 2008; Haagsma et al., 2008; Kamar et al., 2010b; Pischke et al., 2010). In liver transplantation recipients, HEV infection may manifest as graft hepatitis (Pischke et al., 2010). Chronic HEV infection has since been shown to occur in patients with other conditions associated with immunosuppression, e.g. HIV infection (Dalton et al., 2009), hematological malignancies (le Coutre et al., 2009; Ollier et al., 2009), etc.; however, chronic HEV infection is much less common in these patients than in those with solid-organ transplantation. Chronic HEV infection in immunosuppressed persons has been shown to lead to chronic hepatitis and progressive liver fibrosis, culminating in liver cirrhosis (Gerolami et al., 2008; Haagsma et al., 2008). All patients with chronic HEV infection reported till date have been related to genotype 3 virus; no cases of chronic hepatitis E caused by infection with genotypes prevalent in high-endemicity countries, namely genotype 1 and 2, have been described.

4. Hepatitis E in special settings 4.1. Hepatitis E in pregnant women Hepatitis E is characteristically associated with a high disease attack rate among pregnant women. In addition, the affected pregnant women are at a higher risk of developing FHF and death. This association was first reported during outbreaks in India (Khuroo, 1980; Vishwanathan and Sidhu, 1957; Wahi and Arora, 1953), but has also been found in sporadic cases in endemic areas (Khuroo et al., 1983). In the Kashmir outbreak, 17.3%; 8.8%, 19.4% and 18.6% of pregnant women in the first, second and third trimesters, respectively, had clinical disease; in comparison, only 2.1% of non-pregnant women and 2.8% of men were affected (Khuroo et al., 1981). Further, 22.2% of the affected pregnant cases developed FHF, as compared to none of the non-pregnant women and 2.8% of the affected men. Similar findings have been reported in other outbreaks (Myint et al.,

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1985; Naik et al., 1992; Vishwanathan and Sidhu, 1957; Wahi and Arora, 1953). A recent study showed that once fulminant hepatitis appears, the mortality rate may be no different among pregnant women with hepatitis E than in those with other causes of severe liver injury (Bhatia et al., 2008). However, despite this finding, the higher incidence of symptomatic disease among pregnant women exposed to HEV and that of FHF among the affected pregnant women imply that the overall mortality rate among pregnant women is much higher than among non-pregnant women and men during outbreaks of hepatitis E(Fig. 1). Hepatitis E during pregnancy is also associated with prematurity, low birth weight and an increased risk of perinatal mortality (Patra et al., 2007). The exact cause for this specific predilection among pregnant women remains unknown; immunological or hormonal factors have been suspected (Kar et al., 2008; Navaneethan et al., 2008; Pal et al., 2005). Only occasional cases of hepatitis E during pregnancy have been reported with genotype 3 HEV or in low-endemicity areas (Andersson et al., 2008). Cases with fulminant hepatitis E have not been reported in these settings; however this may reflect a lack of sufficient data rather than a true difference in disease biology in these epidemiological settings.

4.2. HEV infection in neonates Vertical transmission of HEV from infected pregnant women to their newborn infants is well known. The first report on the subject included eight pregnant women with acute hepatitis E and their seven term infants and one pre-mature neonate (Khuroo et al., 1995). Six of the eight infants had evidence of HEV infection; of these, one had icterus at birth and elevated transaminase levels, and four other infants had anicteric hepatitis. Two infants died of hypothermia and hypoglycaemia. In another larger report from the same group, 15 of 19 infants born to HEV-infected mothers had detectable IgM anti-HEV or HEV RNA in cord blood indicating vertical transmission of infection (Khuroo and Kamili, 2009). Of these, seven had icteric hepatitis, five had anicteric hepatitis and three had high serum bilirubin but normal liver enzymes. In the infants with jaundice, the proportion of conjugated and unconjugated bilirubin was not reported, making it difficult to determine whether the jaundice was partly related to prematurity or hemolysis. Of these 15 HEV-infected infants, six died after a phase of unresponsiveness, hypoglycaemia and hypothermia. The remaining nine infants had a self-limiting illness with liver tests returning to normal within 8 weeks, and none of the infants had chronic HEV infection. In a report from Saudi Arabia that primarily included mothers of South Asian origin, 10 infants with vertically acquired HEV infection were included. Of these, two were born pre-term and the remaining eight were born at full-term. Of the 10 infants, two infants died of hypoglycaemia and hypothermia within 48 h of birth; both were full-term but had jaundice at birth. Of the remaining 8 infants, two had jaundice and three other had anicteric hepatitis; all these infants had eventual complete recovery of liver injury. In another study from India (Singh et al., 2003), 3 of 6 infants born to HEV-infected mothers had evidence of vertical transmission of HEV infection, but none had jaundice.

5. Non-hepatic manifestations of hepatitis E Several non-hepatic manifestations have been described in association with HEV infection (Table 3).

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Table 3 Non-hepatic manifestations of hepatitis E. Acute pancreatitis Hematological manifestations Thrombocytopenia Hemolysis Hemolysis secondary to G6PD deficiency Immune hemolysis Autoimmune phenomena Membranous glomerulonephritis Henoch-Schonlein purpura Neurological syndromes Guillian-Barre syndrome Meningoencephalitis, Pseudotumor cerebri Nerve palsies: oculomotor nerve, facial nerve Bilateral pyramidal syndrome Peripheral neuropathy Hematological manifestations

5.1. Pancreatitis Several single case reports and small case series of acute pancreatitis associated with acute non-fulminant hepatitis E have been published (Bhagat et al., 2008; Jain et al., 2007; Jaroszewicz et al., 2005; Maity and Ray, 2002; Majumder et al., 1999; Makharia et al., 2003; Mishra et al., 1999; Thapa et al., 2009a). Most of these patients were young men. Acute pancreatitis in them usually appeared in the 2nd or 3rd week after the onset of jaundice, and was characterized by upper abdominal pain and serum amylase elevation. Severity of pancreatitis varied from mild to severe, and it resolved spontaneously in most patients. Interestingly, most of these reports have been from India or among persons who have recently been in India, a highly endemic area. No cases of pancreatitis associated with hepatitis E have been reported from the developed world. The mechanism of pancreatic inflammation in these cases has not been studied. 5.2. Thrombocytopenia Some individual case reports (Ali et al., 2001; Colson et al., 2008; Singh and Gangappa, 2007; Thapa et al., 2009c) and a short series of three persons (Fourquet et al., 2010) with thrombocytopenia of variable severity during the course of acute hepatitis have been published. These cases with thrombocytopenia varied widely in age from 8 to 72 years, and have been reported from regions where hepatitis E is highly endemic as well as those areas where the disease is infrequent. One of the patients also had associated glomerulonephritis (Ali et al., 2001). All patients improved, mostly spontaneously though some had received intravenous immunoglobulins and one was treated with corticosteroids. Mechanism of thrombocytopenia in these cases remains unclear. In some of these cases, anti-platelet antibodies were detected in the patient serum (Singh and Gangappa, 2007; Thapa et al., 2009c); this test was not done in most of the other cases. Thrombocytopenia has been reported during several other viral infections, including hepatitis A virus infection, and is believed to be related to immune mechanisms. 5.3. Hemolysis Patients with hepatitis E may present with hemolysis. In some cases, hemolysis has been related to underlying inherited glucose6-phosphate dehydrogenase deficiency (Abid and Khan, 2002). Hemolysis in these patients leads to anemia and marked hyperbilitubinemia, and may be complicated by renal failure. The illness in

these patients has a more prolonged and protracted clinical course. In these patients, HEV infection In addition, occasional cases of immune hemolysis associated with acute hepatitis E have been reported. In these cases, hemolysis appeared a few days to weeks after the liver disease had started improving (Mishra et al., 2007; Thapa et al., 2009c); detection of antibodies reactive against red blood cells on Coomb’s test indicate that the hemolysis was immune-mediated. 5.4. Autoimmune manifestations In addition to thrombocytopenia and hemolysis discussed above, other manifestations with an immunological basis have occasionally been described among patients with hepatitis E. A patient with acute hepatitis E who had proteinuria and hematuria, in addition to thrombocytopenia, has been described; his kidney biopsy showed evidence of membranous glomerulonephritis and presence of immune complexes on electron microscopy (Ali et al., 2001). Occurrence of Henoch-Schonlein purpura during acute phase of hepatitis E in a child has also been reported (Thapa et al., 2010). 5.5. Neurological manifestations Several neurological manifestations have been described, though only occasionally, in patients with hepatitis E virus infection. These include Guillian-Barre syndrome (Kamani et al., 2005; Loly et al., 2009; Sood et al., 2000), meningoencephalitis (Kejariwal et al., 2001), pseudotumor cerebri (Thapa et al., 2009b) and palsy of the facial (Dixit et al., 2006) and oculomotor nerves (Yadav et al., 2002); however, in all these reports, the diagnosis of hepatitis E was based on presence of anti-HEV antibodies and viral RNA was not looked for. Recently, a French renal transplant recipient receiving immunosuppressive drugs and chronic HEV infection with involvement of both central (bilateral pyramidal syndrome) and peripheral (peripheral neuropathy) nervous system was reported; in this patient, genotype 3 HEV was isolated from the cerebrospinal fluid implicating the virus more strongly in causation of the neurological syndrome (Kamar et al., 2010c). Interestingly, HEV RNA sequences in serum and cerebrospinal fluid showed differences, suggesting that neurological symptoms may have been related to emergence of neurotropic variants. 6. Factors influencing clinical severity of disease Factors determining the severity of illness caused by HEV infection are not fully understood. These could include host factors or viral factors. Of these, host factors, in particular pregnancy, age and pre-existing liver disease clearly appear to be important, as has been discussed earlier. In addition, host immune response may also play a role. Whether viral factors play a role remains unclear, particularly since subjects infected with the same strain of HEV during a waterborne outbreak show different severity of clinical manifestations. However, the dose of viral inoculum may play a role. In a study in primates, a larger viral inoculum dose was associated with more marked liver injury (Aggarwal et al., 2001). In a report from Japan, patients with genotype 4 HEV infection were found to have more severe illness than those who had infection with genotype 3 virus (Ohnishi et al., 2006). The patients with genotype 4 HEV infection had significantly higher peak ALT level and significantly lower prothrombin activity. Fulminant hepatitis has not been described with genotype 2 HEV; however, this may merely represent the fact that data on infection with this genotype are limited.

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7. Treatment of hepatitis E Since hepatitis E is generally a self-limiting disease, drug treatment has not been considered in patients with acute hepatitis E, either uncomplicated or associated with acute liver failure. The treatment therefore is supportive, and directed primarily at relief of symptoms such as fever, body aches, vomiting, etc. Patients with liver failure need measures to control cerebral edema and consideration of liver transplantation. In pregnant women, termination of pregnancy has not proven benefit to terminating the pregnancy has been documented; postpartum hemorrhage resulting from deranged coagulation requires treatment with fresh-frozen plasma. However, recent recognition of chronic HEV infection among immunosuppressed individuals has led to attempts to treat such infection with either pegylated interferon (both alpha-2a and alpha-2b have been tried) (Alric et al., 2010; Haagsma et al., 2010; Kamar et al., 2010a; Kamar et al., 2010d) or ribavirin (Kamar et al., 2010e; Mallet et al., 2010). The treatment duration has varied from 3 to 12 months. Most published reports till date have been in the form of case reports or small case series. In these reports, a fair proportion of patients have achieved sustained virological response, which has been tentatively defined as absence of detectable viral RNA 3–6 months after stopping treatment). No large controlled trial of such treatment has yet been reported. Also, before embarking on anti-viral treatment, either withdrawal or reduction in dose of immunosuppressive drugs should be considered since these have been shown to lead to disappearance or reduction of HEV viremia (Kamar et al., 2010b). No data are yet available on the role of such treatment in pregnant women with acute hepatitis E, non-pregnant patients with acute liver failure, or during neonatal HEV infection. These conditions that occur in areas where hepatitis E is hyperendemic, differ from patients with chronic hepatitis E in that the time window available for the drugs to act may be much shorter. In addition, the experience with anti-viral drugs in hepatitis E is limited to genotype 3 HEV. It is possible that the inhibitory effect of drugs on HEV varies with viral genotype, as is well known in hepatitis C virus infection. In addition, in pregnant women, possible adverse effects of drugs on foetus will also need consideration. Also, no data are available on the role of anti-viral therapy in patients with chronic liver disease and HEV superinfection. References Abid, S., Khan, A.H., 2002. Severe hemolysis and renal failure in glucose-6-phosphate dehydrogenase deficient patients with hepatitis E. Am. J. Gastroenterol. 97 (6), 1544–1547. Aggarwal, R., Kamili, S., Spelbring, J., Krawczynski, K., 2001. Experimental studies on subclinical hepatitis E virus infection in cynomolgus macaques. J. Infect. Dis. 184 (11), 1380–1385. Aggarwal, R., Naik, S., 2009. Epidemiology of hepatitis E: current status. J. Gastroenterol. Hepatol. 24 (9), 1484–1493. Ali, G., Kumar, M., Bali, S.K., Wadhwa, W.B., 2001. Hepatitis E associated immune thrombocytopenia and membranous glomerulonephritis. Indian J. Nephrol. 11 (2), 70–72. Alric, L., Bonnet, D., Laurent, G., Kamar, N., Izopet, J., 2010. Chronic hepatitis E virus infection: successful virologic response to pegylated interferon-alpha therapy. Ann. Intern. Med. 153 (2), 135–136. Andersson, M.I., Hughes, J., Gordon, F.H., Ijaz, S., Donati, M., 2008. Of pigs and pregnancy. Lancet 372 (9644), 1192. Balayan, M.S., Andjaparidze, A.G., Savinskaya, S.S., Ketiladze, E.S., Braginsky, D.M., Savinov, A.P., Poleschuk, V.F., 1983. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 20, 23–31. Bhagat, S., Wadhawan, M., Sud, R., Arora, A., 2008. Hepatitis viruses causing pancreatitis and hepatitis: a case series and review of literature. Pancreas 36 (4), 424–427. Bhatia, V., Singhal, A., Panda, S.K., Acharya, S.K., 2008. A 20-year single-center experience with acute liver failure during pregnancy: is the prognosis really worse? Hepatology 48 (5), 1577–1585. Borgen, K., Herremans, T., Duizer, E., Vennema, H., Rutjes, S., Bosman, A., de Roda Husman, A.M., Koopmans, M., 2008. Non-travel related Hepatitis E virus genotype 3 infections in the Netherlands; a case series 2004–2006. BMC Infect. Dis. 8, 61.

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