Hepatitis E virus infection in a single center in Japan

Introduction

The hepatitis E virus (HEV) was estimated to cause approximately 19.47 million cases of acute hepatitis and 3,450 deaths globally in 2021 [1]. A meta-analysis further estimated that 12.47% of the global population has been exposed to HEV [2], underscoring its significant public health burden. While HEV epidemics were traditionally thought to be confined to areas with poor sanitation, since the 2000s, increasing numbers of autochthonous infections – particularly genotypes 3 and 4 transmitted from animal reservoirs such as pigs – have been reported even in high-income countries, including Japan [3].
In Japan, HEV infection has become increasingly recognized as a significant public health concern since anti-HEV immunoglobulin A (IgA) antibody testing was included under national health insurance coverage in October 2011, leading to a significant increase in officially diagnosed cases – from approximately 50 cases annually before 2011 to 126 cases in 2013 [4]. Additionally, nationwide implementation of nucleic acid amplification tests (NAT) for HEV screening in blood products since August 2020 has further emphasized the importance of managing transfusion-related HEV infections, particularly among immunocompromised populations [5, 6].
Epidemiological data indicate a clear demographic pattern, particularly affecting elderly males. A nationwide serological survey among 12,600 Japanese blood donors demonstrated an overall anti-HEV IgG seroprevalence of approximately 3.4%, with significantly higher rates in males (3.9%) compared to females (2.9%, p = 0.002), and notably higher prevalence in eastern Japan (5.6%) compared to western Japan (1.8%, p < 0.001) [7]. Furthermore, severe HEV infections, including fulminant hepatitis, occur more frequently in individuals aged 60 years or older, highlighting age-related vulnerability in the Japanese population [8, 9].
Regionally, clinical HEV cases in Japan show significant geographic disparities, predominantly reported from the Kanto region northward, especially Hokkaido and the northern areas of Honshu, contrasting with lower incidence in western and southern regions [10]. Despite these findings, limited domestic data exist regarding specific patient backgrounds in which HEV should be prioritized in differential diagnoses. Moreover, the clinical implications of hepatic fibrosis markers such as the FIB-4 index in elderly HEV patients remain unclear. Because the FIB-4 index was primarily developed for chronic liver diseases and may overestimate fibrosis in older adults, we used it 3-6 months after recovery as a descriptive, exploratory indicator rather than a diagnostic test in the acute setting. This study retrospectively analyzed HEV cases at our institution to identify potential risk factors.

Material and methods

This single-center retrospective observational study analyzed electronic medical records of patients diagnosed with acute HEV infection at our center between January 1, 2016, and March 31, 2025. Patients were included if they tested positive for anti-HEV IgA antibodies or HEV RNA. No specific exclusion criteria were set, as we aimed to capture all acute HEV cases during the study period to avoid selection bias and ensure a comprehensive analysis of acute HEV infections in real-world clinical practice.
Data collected included age, sex, clinical symptoms, underlying conditions, alcohol consumption, history of consuming raw pork liver or game meat, travel history, treatment, duration of hospitalization, and initial laboratory findings (albumin, total bilirubin, AST, ALT, prothrombin time [%], and platelet count). In this study, we calculated the FIB-4 index 3-6 months after clinical recovery using the standard formula (age × AST) / (platelet count × √ALT) and used it as an exploratory, noninvasive indicator to contextualize the possibility of underlying liver fibrosis after acute hepatitis E. Because the FIB-4 index was primarily developed and validated in chronic liver disease cohorts and should not be used in acutely ill patients, our use and interpretation were descriptive rather than inferential. For contextualization only, commonly used chronic disease thresholds are < 1.3 (low risk/rule out), 1.3-2.67 (indeterminate), and ≥ 2.67 (high risk/consider referral); in individuals ≥ 65 years, a higher threshold (> 2.0) has been proposed to reduce false positives. In this study, these cutoffs were not used to classify participants, and FIB-4 values were analyzed as continuous variables. Previous studies indicate that biochemical abnormalities and markers of liver fibrosis can persist for several months after the initial acute hepatitis E infection, potentially reflecting residual hepatic injury or pre-existing liver fibrosis in affected individuals [11]. Furthermore, large-scale population analyses have established normative, age-adjusted values for the FIB-4 index, providing critical reference points to contextualize findings in patients recovering from acute liver injuries, including hepatitis E virus infections [12]. Therefore, measuring the FIB-4 index during the recovery phase (3-6 months after infection) is clinically justified to evaluate residual hepatic injury and to detect underlying chronic liver conditions that could influence long-term outcomes. Continuous variables were expressed as medians with interquartile ranges (IQRs). This study was approved by the Ethics Committee of Eastern Chiba Medical Center (approval number 306) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Due to the retrospective nature of the study, an opt-out consent model was employed.

Results

Eight patients were analyzed. The median age was 68 years (IQR: 63.5-70.5), and six patients (75%) were male. Seven presented with symptoms such as fatigue, anorexia, and jaundice, while one asymptomatic case was detected through blood donor screening.
Comorbidities included hypertension in three patients and diabetes in one. Only two had a history of regular alcohol consumption. No clear history of consuming raw pork liver or game meat was confirmed; all records listed this as “unknown” or “no consumption”. None had a history of overseas travel.
FIB-4 index values were higher in symptomatic patients (median 2.00, IQR: 1.65-3.08) relative to the asymptomatic patient (1.61); this observation is descriptive only, as no inferential analysis was undertaken.
All patients received supportive therapy. One patient was treated with high-dose methylprednisolone (1 g/day for 3 days) due to a high risk of severe liver dysfunction. Six patients were hospitalized, with a median hospital stay of 17.5 days (IQR: 12-27). In all patients, transaminase levels normalized within nine weeks. No cases progressed to chronic hepatitis.

Discussio

Most HEV cases in this study were in males aged 60 or older. This aligns with UK cohort data reporting a male-to-female ratio of 3 : 1 and a median age of 63 years [11]. The FIB-4 index for symptomatic patients (median 2.00) was numerically higher than that of the general Japanese population (1.20 ±0.63) [12]. This population-based reference also reported a mean FIB-4 index of 1.60 ±0.75 for Japanese individuals aged 60-69 years. In this context, our symptomatic HEV cases (median age 68 years) showed numerically higher FIB-4 values; no formal statistical testing was performed. Although FIB-4 indices naturally increase with age, symptomatic HEV cases consistently showed higher FIB-4 index values, suggesting not only age-related physiological changes but also possible underlying chronic liver conditions or hepatic vulnerability in elderly patients, which may predispose them to symptomatic HEV infection. Prior studies have also reported higher FIB-4 index values in men compared to women in health checkup data from Sapporo, Japan [13]. Thus, the elevated FIB-4 index in our patients likely reflects underlying liver fibrosis or subtle hepatic impairment that predisposes older individuals, particularly males, to symptomatic HEV infection. These findings underscore the importance of evaluating liver fibrosis in elderly patients presenting with acute HEV infection.
Although transmission routes could not be definitively identified, genotypes 3 and 4 of HEV are molecularly linked to pigs as the main reservoir [14]. Given local dietary habits, oral transmission through pork consumption is likely. The typical HEV incubation period is 3-8 weeks [15], and the prolonged asymptomatic phase hinders source tracking. Japanese clinical guidelines now recommend HEV screening in elderly or immunocompromised patients [16], and our findings support this guidance.
Limitations of this study include its small sample size, single-center and retrospective design, and lack of HEV genotype analysis. Moreover, our application of the FIB-4 index outside its original validation domain (chronic liver disease) and the older age of many participants may inflate scores; thus, interpretations are descriptive and require confirmation with elastography or other noninvasive tests where indicated. Future prospective, multicenter studies incorporating viral genome sequencing are warranted. Additionally, future research should evaluate genotype-specific clinical presentations to refine diagnostic and therapeutic approaches for HEV infection, particularly in elderly populations.

Conclusions

Most HEV patients at Eastern Chiba Medical Center were elderly males, and symptomatic cases had elevated FIB-4 index values, suggesting a potential association between age-related liver fibrosis and symptomatic HEV infection. Among elderly men presenting with acute liver dysfunction, clinicians should consider evaluation for underlying chronic liver disease where clinically indicated, preferably using elastography-based or multi-tier noninvasive strategies. The FIB-4 index, if used outside the acute phase, may provide contextual information but should not be used as a standalone or routine test in this setting.

Disclosures

This research received no external funding.
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Eastern Chiba Medical Center (approval number: 306). Given the retrospective nature of this study, the requirement for informed consent was waived, and an opt-out consent approach was employed.
The authors declare no conflict of interest.

References