Hepatitis E virus (HEV) is a single-stranded RNA virus and was first discovered in 1983 [1], but the viral genome was cloned in 1990 [2]. It is estimated that HEV causes 20.1 million infections annually, leading to 3.4 million symptomatic cases with acute hepatitis and 70,000 deaths related to acute liver failure [3].

HEV has eight genotypes. Genotypes 1 and 2 only infect humans, are detected mainly in Asia and Mexico, respectively and they spread through fecal-oral route. Genotypes 3 and 4 are detected mainly in Europe and North America, circulate in animal species such as pigs, wild boars and deer and occasionally infect humans via consumption of contaminated meat or direct contact [4]. Also, genotype 3 has been detected in shellfishes in Scotland and in southern Italy [5,6]. Genotypes 5 and 6 have been only reported in wild boar and genotypes 7 and 8 have been identified in camels [7].

The diagnostic tests for HEV infection include detection of antibodies against HEV (IgM anti-HEV and IgG anti-HEV) and detection of HEV RNA. IgM anti-HEV is positive during the first month after HEV infection, while IgG anti-HEV represents current or past infection [8]. Detection of HEV RNA in blood or stool characterizes chronic or acute HEV infection. Chronic hepatitis E is defined as HEV RNA being detectable for at least 3 months. In immunosuppresed patients with chronic HEV infection, antibodies are often undetectable [9]. HEV infection is usually self-limiting and causes acute mild illness. However, HEV infection during pregnancy, especially in the third trimester may lead to acute liver failure [10]. Chronic HEV infection is rare and may develop in immunocompromised patients, such as organ transplant recipients [11].

In addition, HEV has been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms and diseases, hematological disorders, renal diseases, acute pancreatitis, myocarditis, arthritis and autoimmune thyroiditis (Table 1) [12]. However, the pathophysiologic mechanism of extrahepatic manifestations remains unclear. It seems that viral infections trigger a variety of host-defense mechanisms, which may not be restricted to the primary location of infection and can cause crossreactions between viral epitopes and self-antigens, leading to multisystemic manifestations. Another possible explanation is that HEV replicates not only in liver, but also in other tissues. HEV has been detected in neuronal cells [13], human placenta [14], breast milk [15], and urine [16].

Several neurological manifestations have been associated with HEV infection and include Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculoneuropathy), neuralgic amyotrophy, encephalitis, myelitis, myositis, vestibular neuritis, peripheral neuropathy, Bell’s palsy and mononeuritis multiplex [17]. In a prospective multicenter study from United Kingdom, France and Netherlands it was found that 2.4% (11/464) of patients with non-traumatic neurologic injury had evidence of HEV infection [18]. Also, a study from France demonstrated the neurologic disorders in patients infected with HEV and found that 16.5% of HEV-infected patients reported neurologic symptoms and neurological manifestations were more frequent in immunocompetent patients compared to immunosuppressed patients (22.6% vs. 3.2%, P<0.001) [19]. However, a study from China compared the prevalence of acute hepatitis E between 1,117 patients diagnosed with neurological illness and 1,475 healthy controls and found that there was no difference (0.54% vs. 0.68%) [20]. A possible explanation is the geographical distribution of HEV. The study from China was conducted in an area endemic for HEV genotype 4, while the European studies reported cases associated with HEV genotype 3. Therefore, HEV genotype 4 seems not to contribute to neurological disorders [21].

Renal disorders have been reported during HEV infection, including membranoproliferative glomerulonephritis and cryoglobulinemia. A retrospective study assessed kidney function and histology in 51 cases of solid-organ transplant patients during genotype 3 HEV infection and they observed statistically but not clinically significant decrease in estimated glomerular filtration rate (-5 mL/min, P =0.04) during HEV infection. In renal biopsies, glomerular diseases were identified. They included relapse of IgA nephropathy and membranoproliferative glomerulonephritis. The majority of these patients had cryoglobulinemia. After HEV clearance, cryoglobulinemia resolved and proteinuria and renal function improved [45]. Additional cases of HEV-related membranoproliferative glomerulonephritis and membranous nephropathy have been reported [46,47]. In one case, HEV infection triggered monoclonal gammopathy of renal significance [48].

The association between cryoglobulinemia and HEV infection has not been fully investigated. In a study with solid organ recipients, who suffered from HEV infection, the prevalence of cryoglobulinemia was increased during chronic phase of infection (52.9%) compared to acute phase of infection (36.4%) and HEV-negative solid organ recipients (23.6%) (P<0.01). Also, HEV infection was identified as an independent predictive factor for cryoglobulinemia (odds ratio, 2.3) [49]. Another retrospective study from Germany compared the prevalence of IgG anti-HEV between patients with cryoglobulinemia and healthy controls. They found that the anti-HEV seroprevalence rate was significantly higher in patients with essential cryoglobulinemia than in non-essential cryoglobulinemia patients (P =0.043), suggesting that previous HEV contact might play a role in some cases of cryoglobulinemia that are currently classified as essential [50].

A wide variety of infectious agents has been associated with acute pancreatitis and these include viruses, bacteria and parasites. The association between acute pancreatitis and viral hepatitis is well known and HAV, HBV, and hepatitis C virus have been implicated most often [75,76]. A proposed pathogenetic mechanism is the development of edema of the ambulla of Vater, causing obstruction of pancreatic fluid flow [77]. Several cases of HEV-induced acute pancreatitis have been reported [78,79]. In a single-center study from France, 2.1% (16/790) of patients with acute pancreatitis had serological evidence of recent HEV infection with no other discernible cause of pancreatitis [80]. The typical profile of a patient is a young male from an endemic area or having recently travelled to that area, who develops mild to moderate acute pancreatitis [81]. However, life-threatening complications, such as, acute necrotizing pancreatitis, pseudocyst bleeding and multiorgan failure, have been reported [82-84].

Development of many other diseases has been reported during HEV infection, but further studies are needed to establish the association. In previous literatures, three cases of HEV-associated myocarditis have been reported [85]. Furthermore, HEV infection has been correlated with thyroid diseases. These include autoimmune thyroiditis, subacute thyroiditis and Grave’s thyrotoxicosis [86-88]. In addition, a case of Henoch-Schönlein purpura triggered by acute HEV infection [89] and another case of HEV-induced myasthenia Gravis have been described [90]. Lastly, HEV infection may cause acute polyarthritis [91,92].

Several extrahepatic manifestations and diseases have been documented during acute and chronic HEV infection. Neurologic diseases are demonstrated to be the most common extrahepatic manifestations of HEV infection, followed by hematological disorders and kidney injury. However, the pathophysiology of these manifestations and the causal relation with HEV infection remain ambiguous. Therefore, further studies are needed to estimate the epidemiological characteristics of HEV-related extrahepatic manifestations and to elucidate their underlying pathogenetic mechanisms.