Background
Hepatitis E is an enterically transmitted infection that is typically self-limited. [1, 2] It is caused by the hepatitis E virus (HEV), which has eight known genotypes (of which four infect humans, G1-G4), [3, 4, 5] and is spread by fecally contaminated water within endemic areas or through the consumption of uncooked or undercooked meat. [6, 7, 8] Outbreaks can be epidemic and individual. Hepatitis E has many similarities with hepatitis A (HAV).
Hepatitis E has been associated with chronic hepatitis in solid-organ transplant recipients, patients infected by human immunodeficiency virus (HIV), and in an individual on rituximab treatment for non-Hodgkin lymphoma. [9, 10, 11, 12]
The course of infection has two phases, the prodromal phase and the icteric phase. The infection is self-limited. Whether protective immunoglobulins (Igs)develop against future reinfection remains unknown. The overall case fatality rate is 4%, although pregnant women and liver transplant recipients may be at substantially higher risk.
Therapy should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. A successful recombinant hepatitis E vaccine exists. [13, 14] More recently, a thiomersal-free recombinant HEV vaccine has been developed. [15]
Etiopathophysiology
The hepatitis E virus (HEV) genome contains three open reading frames (ORFs). [5] The largest, ORF-1, codes for the nonstructural proteins responsible for viral replication. ORF-2 contains genes encoding the capsid. The function of ORF-3 is encoding a protein that affects viral particle release from infected cells. [5]
Hepatitis E results from HEV infection and is spread by fecally contaminated water within endemic areas. [4] However, in nonendemic areas, the major mode of the spread of HEV is foodborne, especially consumption of undercooked pork, raw liver, and sausages. [16, 17] In Japan, it is estimated that a concentration of HEV over 5 × 104 IU/mL in donated blood may raise the risk of transmission by transfusion. [18]
HEV is an icosahedral and nonenveloped single-stranded RNA virus of the genus Hepevirus.{ref72 [5] Eight HEV genotypes have been identified. Genotypes 1 and 2 are considered human viruses, typically affecting Asia, Africa, and Mexico; genotypes 3 and 4 are zoonotic and have been isolated from humans and game animals (eg, pigs, boars, deer), with G3 having a global distribution and G4 mainly occurring in Southeast Asia. [4, 17, 19] G5 and G6 have been found in wild boar, and G7 and G8 have been identified in camels. [5]
Factors that affect the severity of HEV infection include older age and genetics, HEV viral load and genotype, nucleotide mutation, the presence of chronic liver disease and/or metabolic disease, as well as HAV coinfection. [18]
Epidemiology
United States statistics
Population-based surveys from 1988-1994 indicate that 21% of US adults had anti–hepatitis E virus (HEV) antibody, a rate lower than that of anti–hepatitis A virus (HAV) antibody (38.3%) but higher than that of antibodies against hepatitis B (5.7%) or hepatitis C (2%). [20]
Anti-HEV antibody rates increased markedly with age, from less than 10% among persons aged 6-19 years to more than 40% among those older than 60 years. Age-adjusted rates of anti-HEV antibody were lower among blacks (14.5%) than among non-Hispanic whites (22.1%); among men who had sex with men (23.1%) than among those who did not (23.9%); among cocaine users (16.8%) than among nonusers (23.6%); and among people living in the southern United States (14.7%) than among people living in the Northeast (20.8%), Midwest (26.6%), or West (25%). Rates of anti-HEV antibody were minimally higher among men than among women (21.6% vs 20.4%). Among men who had sex with men, the rates of anti-HEV antibody were lower among men with HIV infection (12.8%) than among men without HIV infection (19.2%). [21]
The route of exposure is unknown but is generally attributed to travel in endemic areas such as China, Nepal, India, Southwest France, North African countries, and Borneo. Exposure to pigs and consumption of undercooked pork are other methods of spread in autochthonous (nonendemic) areas, as testing of samples of pig liver and sausage from commercial groceries in the United States identified HEV RNA in a high percentage of samples. [22]
International statistics
The global disease burden of hepatitis E has been reported to be at least 20 million cases/year with about 44,000 fatalities. [3] However, this is considered an underestimate given the changing understanding of endemicity in high-income countries and the improving accuracy and sensitivity of serologic assays over time from earlier generation assays, on which many seroprevalence rates have been based. [4]
Hepatitis E has worldwide distribution, but predominating factors include tropical climates, inadequate sanitation, and poor personal hygiene. The traditional understanding was HEV is found most often in developing countries near the equator, in both the Eastern and Western hemispheres; regions with a prevalence rate of more than 25% include Central America, the Middle East, and large parts of Africa and Asia, [23] where outbreaks are associated with rainy seasons, floods, and overcrowding. More recently, HEV has been found to be endemic in most high-income nations and is predominantly a zoonotic infection involving pigs as the primary hosts. [4, 5]
Water supply contamination with human feces is a frequent source of epidemics. The largest outbreak was reported in Northeast China, with 100,000 people affected between 1986 and 1988. [24] The reservoir of HEV is unknown, but it is believed that the virus may be transmitted by animals. Waterborne epidemics of hepatitis E mainly affect young adults, the clinical attack rate being highest among those aged 15-35 years. [25] Men are clinically infected 2-5 times more commonly than women in most outbreaks. [24, 26] However, no sex difference exists in exposure to HEV. [27, 28]
Annually, an estimated 150,000 new cases of HEV infection occur in Japan, with a greater prevalence seen in eastern Japan (5.6%) than in western Japan (1.8%) and affecting men (3.9%) than women (2.9%) and adults more than children. [18]
The British Transplantation Society has estimated there is about a 13% seroprevalence of HEV G3 in England, comprising 200,000 infections annually and accounting for 600-800 cases. [4] Many of the infected are immunocompromised, such as recipients of solid organ transplants or hematopoietic stem cell transplants, those with hemato-oncologic conditions, and individuals with infected with human immunodeficiency virus.
A study that analyzed the seroprevalence of HAV and HEV among blood donor in Paraguay reported anti-HAV immunoglobulin (Ig) G was identified in 68.1% of donors, with more positive results in older age groups and significant variations across regions, whereas anti-HEV IgG was detected in 6.0% of donors, but no significant differences were seen in terms of age or regions. [29]
Prognosis
No chronic cases of acute hepatitis E have been reported. The infection is self-limited. Whether protective immunoglobulins develop against future reinfection remains unknown. The overall case fatality rate is 4%.
Among pregnant women, the case fatality rate is 20%, and this rate increases during the second and third trimesters. Reported causes of death include encephalopathy and disseminated intravascular coagulation. The rate of fulminant hepatic failure in infected pregnant women is high.
In a 3-year (2010-2013) prospective observational study of 55 symptomatic anti-HEV IgM-positive Indian women, the overall maternal mortality was 5%, including one antenatal death. The most common fetal complications were prematurity (80%) and premature rupture of membranes (11%), with a 28% rate of vertical transmission. [30]
Liver transplant recipients may be at a greater risk for HEV infection, which can lead to chronic hepatitis and rapid progression of liver fibrosis. [31, 32] The presence of anti-HEV-IgG titer in pretransplantation measurements do not lead to protection of hepatitis E in posttransplantation patients. [33]
Other potential complications of HEV infection include prolonged cholestasis, glomerulonephritis and cryoglobulinemia, hematologic anomalies, neurologic conditions, and other extrahepatic diseases. [18]
