Introduction
Hepatitis E is a self-limiting disease caused by the hepatitis E virus (HEV) (1,2). HEV is a single-stranded, uncoated RNA virus and the only member of the hepevirus species from the Hepeviridae family (3,4).
Similar to the hepatitis A virus (HAV), HEV (previously known as non-A or non-B hepatitis) is transmitted through water and feces (2). In this regard, water is considered to be a more important route for HEV transmission than food (2,3,5). According to the literature, HEV could also be transmitted through blood. Moreover, HEV could be transmitted from the mother to the fetus, sexual intercourse, and injection (2,6). Studies focusing on the incidence of HEV infection in animals, especially pigs and wild boars, have demonstrated that the dairy and meat products of these animals may contribute to HEV transmission (7). On the other hand, transmission of HAV is easier and more widespread compared to HEV, which is associated with a higher risk of infection.
Despite general beliefs, HEV infection has a higher prevalence rate in industrialized countries compared to underdeveloped regions (8,9). According to statistics, Asia, Africa, the Middle East, and Central America account for the highest incidence rate of HEV infection (1,10,11). Hepatitis E is endemic in Iran, and several cases of HEV infection outbreak have been reported to date. One of the major risk factors for acute HEV infection is the consumption of undercooked meat or other unhealthy meat products (12).
Hepatitis E virus is the first and second most frequent cause of acute hepatitis in adult populations in Asia and the Middle East, respectively (13-15). Detection of the hepatitis E virus in serum and feces specimens is based on identifying the RNA virus, immunoglobulin G (IgG) or IgM antibodies against HEV. Currently, the gold standard for HEV detection for diagnostic and epidemiological purposes is serological and nucleic acid tests, which involve the qualitative and quantitative measurement of HEV RNA (16-18).
Some studies have reported that chronic HEV infection could improve after the reduction or discontinuation of immunosuppressive therapy (19,20) and replacement therapy with the oral administration of ribavirin (21,22) and pegylated interferon (23,24). However, there are no definite treatments for acute or chronic HEV infection in transplant patients. In such cases, hepatitis E may not lead to chronic hepatitis, with the exception of the patients with solid organ transplant or suppressed immune system (25,26).
As the most common type of acute adult hepatitis in developing countries, the prevalence of hepatitis E has recently been investigated widely. Of note, the prevalence of HEV varies depending on the geographical location. The present study aimed to systematically review the prevalence of HEV in Iran. The findings could lay the groundwork for further studies regarding the methods of effective prevention, treatment, and management of HEV epidemics.

Methods
Literature Search methods
A comprehensive systematic review was conducted in May 2016 via searching in databases such as PubMed, Scopus, and IranMedex using keywords such as “hepatitis E” and “prevalence” to assess the prevalence of hepatitis E infection in Iran. To do so, all the appropriate articles were identified by the following approach: (((Hepatitis E OR HEV)) AND (epidemiology OR frequency OR prevalence)) AND Iran. In the next step, a customized search was used to limit the records to the studies conducted on the Iranian population.
To reduce the possibility of data loss, the reference lists of all the included documents were manually searched for the potentially relevant articles. Finally, we searched in the Google Scholar using the aforementioned keywords in order to enclose the eligible documents in the review. Literature search procedures and qualitative data analysis were performed by two independent researchers.

Article selection
To conduct a comprehensive literature search, no time or language limitations were defined in selecting the related documents, and all the relevant articles published in English and Persian were included in the literature review. Articles with irrelevant subjects and those published in other languages were excluded from further evaluation. In addition, we removed editorials, review articles, meta-analyses, abstracts, and conference proceedings from the review. Among the other excluded cases were duplicate documents, articles reporting the data of the same populations, and articles with inappropriate or incomplete data. Finally, only the articles with appropriate data and study design focusing on the prevalence of HEV in various geographical regions of Iran were reviewed, and the articles with the following criteria were excluded.

Data extraction
Extracted data for the present review included the name of the authors, date of publication, total number of the studied samples, study design, and demographic data of the study populations. In addition, other data on the geographical region, evaluation methods, target populations, and major findings of the studies were collected and categorized. The estimated prevalence of HEV in the selected studies was recorded and described qualitatively. All the required data were extracted and qualitatively described based on the results of the studies reporting the prevalence of HEV infection in various geographical regions of Iran.
All the research processes, including the literature search, article selection, and data extraction were performed in accordance with the recommended protocol of the PRISMA 2009 Checklist for systematic reviews (27). Moreover, possible discrepancies between the authors were resolved prior to additional data processing.

Measured variables
The most important variables that were evaluated in the present review regarding the prevalence of HEV infection were anti-HEV IgG and IgM. Moreover, we assessed the prothrombin time and serum levels of other biochemical factors, including alanine transaminase, aspartate transaminase, alkaline phosphatase, albumin, direct and indirect bilirubin, and protein. It is also notable that the HEV RNA load was used in confirmatory testing in some of the selected studies, while biochemical tests and enzyme-linked immunosorbent assay (ELISA) were used in the evaluation of the required variables.
Results
Literature search results
In total, 46 potentially relevant articles were identified in the initial review search, 34 of which were in PubMed, nine were in Scopus, and three additional articles were found in IranMedex. According to the exclusion criteria of the study, 11 articles were eliminated after reviewing the titles and abstracts due to irrelevant subjects. Additionally, seven articles were excluded from further evaluation due to the inappropriate study design, and four documents were removed during data collection due to data inadequacy. Finally, the full texts of 24 articles, which focused on the prevalence of HEV in various geographical regions in Iran, were obtained and used for data extraction. Figure 1 depicts the procedures of literature search and article selection in the present study.

 General Features of the Selected Articles

Total number of the populations investigated in the selected articles focusing on the prevalence of HEV in Iran was 12,555 (range: 47-1,824). Studied populations included the patients with renal failure or end-stage renal disease (ESRD), pregnant women, blood donors, patients with HIV, patients undergoing chronic maintenance hemodialysis, renal transplant recipients, thalassemia patients, and general populations. Among these samples, 7,528 cases were male, and 5,027 cases were female. Age range of the studied populations in the selected studies was six months to 95 years.
The most recent reviewed article had been published in 2016, while the oldest article had been published in 2005. It is also noteworthy that all the selected studies that were used for qualitative data assessment were cross-sectional. The main features of the selected articles and their chronological date of publication are presented in Table 1.

Results of the Literature Review
After collecting the eligible articles, the extracted data were described qualitatively. According to the obtained results, the prevalence of the anti-HEV antibody is high in the Iranian population. The prevalence of HEV was observed to vary from 2.3% to more than 40% in the selected studies, with the highest and lowest rate reported in Ahvaz city located in Khuzestan province in the south-west of Iran (46.1%) and Sari city located in Mazandaran province in the north of Iran (2.3%), respectively (Table 2).
In the majority of the reviewed studies, sample populations consisted of patients with renal failure and those undergoing hemodialysis. Findings of the review indicated that male and female sample were susceptible to HEV infection since the anti-HEV IgG antibodies were detected in both genders with a similar prevalence (36,48). On the other hand, some studies reported the frequency of the anti-HEV IgG to be higher in male subjects compared to female subjects (44,49). Although the obtained results of some studies indicated that the prevalence of HEV increased with age (44,45,47,50), other research findings in this regard denoted no significant association between age and HEV prevalence since the rate of the infection was the same in earlier and older ages (46).
According to the results, the prevalence of HEV is higher in the rural areas of Iran compared to the urban areas (46). In addition, seroprevalence of HEV was observed to be high in the patients undergoing hemodialysis (33). While the qualitative assessment of the extracted data in the current review confirmed the relatively high prevalence of HEV in Iran, further comprehensive epidemiological studies are required in order to investigate the prevalence rate of this infection in the other geographical regions of Iran.
Figure 2 shows the prevalence of HEV in Iran. Studied variables, target populations, prevalence of HEV, and the main the findings of the reviewed studies are summarized in Table 2. According to this information and based on the IgG seroprevalence of HEV, the highest prevalence rate of HEV in Iran was observed in healthy populations (46.1%), kidney transplant patients (30.8%), and hemodialysis patients (28.3%), while the prevalence rate was found to be lower in pregnant women (3.6%).
Considering the high prevalence of HEV infection in various regions, it is recommended that diag hepatitis. Furthermore, performing other comprehensive studies across the country regarding the clinical manifestations and molecular features of this infection could yield detailed information on the epidemiology of HEV in Iran.

Conclusion
According to the results, the prevalence of HEV varies from 2.3% to more than 46% in the Iranian population. Additionally, data of the reviewed articles revealed that the prevalence of HEV is relatively low among pregnant women (3.6%), while the seroprevalence of HEV is estimated to be 2.3-46.1% in the healthy and general populations. In the patients with ESRD, the prevalence of HEV has been reported to be 10.6-26.9%. The reviewed studies denoted that the risk of HEV may increase with age. Moreover, the prevalence of HEV has been shown to be higher in hemodialysis patients.

Acknowledgment
The study was funded by the research committee at Mashhad University of Medical Sciences .We wish to thank Fahime Ahmadi, nurse in gastroenterology department for editing the article.

Conflict of Interest
The authors declare no conflict of interest.