Imported Hepatitis E Virus Genotype 1: A Rare Case of Acute Hepatitis Managed with Steroid Pulse Therapy

Abstract

A 26-year-old Indian man who had arrived in Japan 24 days prior presented to our hospital with abdominal pain and a fever. A blood test revealed marked hepatic dysfunction, and imaging tests confirmed a diagnosis of acute hepatitis. The patient's liver function and coagulability deteriorated, and his general condition was poor. Given the possibility of fulminant hepatic failure, we initiated steroid pulse therapy. Following the initiation of steroid therapy, the patient's liver function and subjective symptoms rapidly improved. Testing revealed positive findings for IgA-hepatitis E virus, and a genetic analysis of hepatitis E identified genotype 1, which is not endemic to Japan, leading to a definitive diagnosis of imported hepatitis E infection from India. The successful response to steroid therapy highlights the potential benefit of this approach in managing severe cases of acute hepatitis E, a rare occurrence in Japan. This case underscores the importance of considering hepatitis E infection in individuals with a recent travel history to regions with high prevalence and the potential benefits of steroid therapy in managing severe cases of acute hepatitis E.

Introduction

Hepatitis E virus (HEV), a single-stranded RNA virus, is a major causative agent of acute hepatitis in many developing countries in Asia, Africa, and Central America (1). Four major genotypes (genotypes 1, 2, 3, and 4) have been identified (1). HEV infection is particularly prevalent in areas with poor sanitation and weak public health infrastructure and is primarily transmitted through the fecal-oral route. HEV genotype 1 is prevalent in developing regions of Asia, Africa, and South America. In contrast, acute hepatitis E is rare in developed regions, including Japan, where only sporadic cases of HEV genotypes 3 or 4 are found (2). Most people are asymptomatic or develop flu-like symptoms, such as fatigue, a fever, and nausea, in response to acute HEV infection (3). Acute hepatitis E is cured in many cases without specific treatment, but some cases may progress to fulminant hepatitis (4).

A small percentage (0.5% to 4%) of HEV cases develop acute liver failure, resulting in an overall mortality rate of 0.5% to 3%. Furthermore, the rate of acute liver failure increases to 15% to 25% in pregnant women (3). Unlike the United States and Western Europe, where drug-induced liver injury is the most common cause, hepatitis A and E are the leading causes of acute liver failure worldwide, with high mortality rates reported in developing countries (5). Therefore, although the predominant causes of acute liver failure differ between developed and developing countries, viral infections, including hepatitis E, remain a significant public health concern worldwide.

We herein report a rare case of acute hepatitis due to HEV genotype 1 that was successfully treated with steroid pulse therapy, despite severe liver damage.

Case Report

A 26-year-old male presented to our hospital with a 3-day history of abdominal pain, a fever, and vomiting. The patient had arrived in Japan from India for work 24 days prior and had a history of dengue fever in 2018. There were no known allergies or recent consumption of raw food containing deer or boar. The patient had not been exposed to insect bites or new travelers within the past month.

A physical examination revealed a fever of 37.7°C, jaundice, abdominal pain, and positive Murphy's sign. The liver edge was palpable 4 cm below the costal margin. No evidence of hepatic encephalopathy was found. A blood test showed marked hepatic dysfunction and jaundice with aspartate aminotransferase (AST) 1,354 U/L, alanine aminotransferase (ALT) 1,617 U/L, total bilirubin (T-Bil) 5.1 mg/dL, and prothrombin time (PT) 56%.

Abdominal ultrasonography showed accentuated brightness of portal vein radicle walls in the liver, gallbladder wall thickening, and collapse of the lumen, consistent with acute hepatitis (Fig. 1). Abdominal computed tomography (CT) showed mild enlargement of the caudate lobe of the liver and a slight decrease in the CT value of the liver parenchyma (Fig. 2). The patient was hospitalized and treated with drip infusion and rest. Results of laboratory tests on admission are presented in Table. Hepatitis viral markers, including hepatitis B virus surface antigen, anti-hepatitis C virus antibody, and IgM anti-hepatitis A virus antibody, were all negative. Serological tests for Epstein-Barr virus indicated past infection, while IgM anti-cytomegalovirus antibody was negative. Anti-dengue virus IgM was also negative. In contrast, IgA-HEV was positive, and acute hepatitis due to HEV was diagnosed.

Figure 1.

Abdominal ultrasonography showing accentuated brightness of portal vein radicle walls in the liver (arrowheads) and gallbladder wall thickening (circle).

Figure 2.

Abdominal computed tomography (CT) showing mild enlargement of the caudate lobe of the liver and a slight decrease in the CT value of the liver parenchyma.

Table.

Laboratory Data on Admission.

(Peripheral blood)

(Biochemistry)

(Viral marker)

WBC

6,100

/μL

TP

6.9

g/dL

HBs-Ag

(-)

RBC

544

×104/μL

ALB

4

g/dL

HBs-Ab

(+)

Hb

14.3

g/dL

AST

1,354

U/L

HBc-Ab

(-)

Plt

16.5

×104/μL

ALT

1,617

U/L

HCV-Ab

(-)

ALP

860

U/L

IgM anti-VCA-Ab

(-)

(Coagulation)

T-Bil

5.1

mg/dL

IgG anti-VCA-Ab

(+)

PT-%

56

%

D-Bil

3.4

mg/dL

anti-EBNA-Ab

(+)

PT-INR

1.42

LDH

613

U/L

IgM anti-CMV-Ab

(-)

APTT

26.8

s

γ-GTP

170

U/L

IgG anti-CMV-Ab

(±)

D-dimer

1.5

μg/mL

BUN

7

mg/dL

Dengue IgM

(-)

Cr

0.74

mg/dL

IgM anti-HAV

(-)

eGFR

105.9

mL/min

IgA anti-HEV

(+)

Na

138

mmol/L

K

4.2

mmol/L

Cl

102

mmol/L

CRP

1.48

mg/dL

NH3

35

μg/dL

WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Ht: hematocrit, Plt: platelet, PT: prothrombin time, APTT: activated partial thromboplastin time, TP: total protein, ALB: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, T-Bil: total bilirubin, D-Bil: direct bilirubin, LDH: lactate dehydrogenase, γ-GTP: γ-glutamyl transpeptidase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, Na: sodium, K: potassium, Cl: chloride, CRP: C-reactive protein, NH₃: ammonia, HBs-Ag: hepatitis B surface antigen, HBs-Ab: hepatitis B surface antibody, HBc-Ab: hepatitis B core antibody, HCV-Ab: hepatitis C virus antibody, IgM anti-VCA-Ab: immunoglobulin M anti-viral capsid antigen antibody of Epstein-Barr virus, IgG anti-VCA-Ab: immunoglobulin G anti-viral capsid antigen antibody of Epstein-Barr virus, anti-EBNA-Ab: antibody against Epstein-Barr nuclear antigen, IgM anti-CMV-Ab: immunoglobulin M anti-cytomegalovirus antibody, IgG anti-CMV-Ab: immunoglobulin G anti-cytomegalovirus antibody, Dengue IgM: dengue fever immunoglobulin M antibody, IgM anti-HAV: immunoglobulin M anti-hepatitis A virus antibody, IgA anti-HEV: immunoglobulin A anti-hepatitis E virus antibody

Despite medical treatment, the patient continued to experience fatigue and abdominal pain, and his condition worsened. On day 4 of hospitalization, AST 2,399 U/L, ALT 2,094 U/L, T-Bil 9.5 mg/dL, and PT 50% indicated further deterioration of liver function and coagulability, and the patient's general condition remained poor. Steroid pulse therapy was initiated due to concern for fulminant hepatic failure. After starting steroid therapy, his liver function and subjective symptoms rapidly improved (Fig. 3). The steroid treatment was tapered, and the patient was discharged on day 27 of hospitalization. A genetic analysis of hepatitis E by reverse transcription-polymerase chain reaction (RT-PCR) for a phylogenetic tree analysis revealed genotype 1, confirming an imported infection with HEV from India. The patient's liver function improved after the steroid dosage was reduced, and there were no exacerbations of symptoms. Treatment was discontinued three months after the start of treatment.

Figure 3.

Clinical course during hospitalization. mPSL: methylprednisolone, PSL: prednisolone, AST: aspartate aminotransferase, ALT: alanine aminotransferase, PT: prothrombin time (%), T-Bil: total bilirubin (mg/dL)

Discussion

HEV is a major etiology of acute viral hepatitis worldwide, with HEV genotypes 1 and 2 primarily responsible for epidemics in developing countries, whereas genotypes 3 and 4 have a zoonotic transmission cycle and are prevalent in both developing and developed countries (6).

In Japan, HEV causes hepatitis in humans through the consumption of raw or undercooked meat, including game meat (7). HEV genotypes 3 and 4 are predominantly found in human and animal populations in Japan, while HEV genotype 1 infections are rare (7). Abe et al. conducted a study in Japan, which revealed that among 228 cases of acute hepatitis E, 138 were genotype 3, 82 were genotype 4, and only 8 were genotype 1. Interestingly, 7 of the 8 patients with genotype 1 had a travel history to India (n=4), Bangladesh (n=2), and Nepal (n=1) (8). Therefore, most cases of acute hepatitis E due to HEV genotype 1 in Japan are imported infections.

In the present case, the patient was an Indian national who had traveled to Japan from India 24 days earlier. In India, HEV infection is highly endemic, with almost 60% of blood donors having circulating anti-HEV IgG antibodies, indicating prior exposure to the virus. Notably, in India, hepatitis E, whether in epidemic form or sporadic cases, is solely caused by HEV genotype 1 (9). HEV genotype 1, which is almost never transmitted in Japan, in this case can be considered an imported infection that was contracted in India, an endemic area, and subsequently developed into acute hepatitis in Japan. This underscores the importance of considering hepatitis E infection in patients with a recent travel history to areas with a high incidence of the disease.

Clinical manifestations of HEV infection vary across genotypes. Infections with genotypes 1 and 2 are generally subclinical and may eventually progress to acute hepatitis (10,11). In contrast, infections with genotypes 3 and 4 are typically self-limiting, with less than 2% of infected individuals showing symptoms (10). However, genotypes 3 and 4 may cause persistent or chronic disease (10). Acute liver failure is known to occur in some cases of genotype 1 and 2 infections (11). Pregnancy is a high-risk factor for symptomatic disease, severe liver injury, and mortality in genotype 1 infection, while genotype 3 and 4 infections are less severe in pregnant women (10). Some cases of genotype 1 and 2 have associated extrahepatic manifestations, such as acute pancreatitis and neurologic symptoms (11). Genotype 3 is also associated with extrahepatic manifestations, including neuropathy and nephropathy (10). Therefore, determining the HEV genotype causing the infection is crucial for prognostic purposes and identifying the source of infection.

There is no specific treatment for acute hepatitis E, and symptomatic treatment is the mainstay of therapy. Approximately 0.5-4% of cases of acute hepatitis E progress to acute liver failure, with an overall mortality rate of 0.5-3%. Thus, the development of acute liver failure should be closely monitored (3). Liver transplantation is the only proven effective treatment for acute liver failure, but in Japan, alternative treatments are mostly employed due to the scarcity of donors (12). In the early management of acute liver failure, it is crucial to effectively suppress hepatocyte damage and prevent failure of liver regeneration. Steroids have been shown to be effective in rapidly and strongly inhibiting liver microcirculatory disturbance caused by inflammatory cytokines and hepatocyte destruction triggered by apoptosis (12,13). Steroid therapy has been shown to improve the prognosis of patients with acute liver failure, particularly when initiated within 14 days of the symptom onset (14). However, the indication for this therapy remains controversial, with some reports suggesting no improvement in mortality in patients with advanced liver failure (15). Despite this controversy, several studies have suggested the efficacy of steroid therapy in treating liver damage in acute hepatitis E (2,16). In the present case, due to the patient's rapidly deteriorating liver function and coagulation capacity, we deemed aggressive treatment necessary and initiated steroid therapy at an early stage. This approach proved to be successful, as the patient's liver function, coagulability, and subjective symptoms improved rapidly following the initiation of steroid therapy. Given these results, steroid therapy may be a viable treatment option for patients with acute hepatitis E who are at risk of developing acute liver failure.

Conclusion

Acute hepatitis E virus infection is rare in developed countries, such as Japan, but it should be considered in individuals with a recent travel history to high-prevalence areas. Steroid pulse therapy may be beneficial in managing severe cases of acute hepatitis E. Our case report provides valuable insight into the management of this rare disease.

The authors state that they have no Conflict of Interest (COI).