Acute Hepatitis E Infection during Chemotherapy for Lung Cancer: A Case Report

Acute hepatitis E, one of the causes of acute liver injury, is an infection caused by the hepatitis E virus (HEV) after an incubation period of 2–6 weeks. HEV infects humans mainly in developing countries via waterborne routes; recently, zoonotic HEV transmission has been increasingly reported in developed countries [1].

The causes of liver injury during chemotherapy are multifactorial and include liver metastasis, reactivation of viral hepatitis, immunologic effects, and hepatotoxicity of chemotherapeutic drugs [2]. When an acute liver injury occurs during chemotherapy for solid tumours, drug-induced liver injury (DILI) is usually suspected, and chemotherapy may be discontinued. However, previous reports have shown that HEV can mimic DILI in its clinical presentation [3], and diagnostic tests for HEV to rule out DILI are not as well-established as those for hepatitis B or C.

At present, there are no reports of acute hepatitis E diagnosed during chemotherapy for lung cancer in patients with initially suspected DILI. Here, we report a case of acute HEV-induced liver injury during chemotherapy for lung cancer.

A 78-year-old woman with left upper lobe lung adenocarcinoma (cT4N3M1c, stage IVB, International Association for the Study of Lung Cancer, 8th edition; programmed death ligand 1 tumour proportion score, 75%; driver gene mutation, KRAS G12C+) and multiple bone metastases had received chemotherapy with carboplatin + pemetrexed + pembrolizumab 16 months before admission. Subsequently, maintenance therapy with pemetrexed + pembrolizumab had been initiated 1 year before admission due to partial response during this course. Elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (77 and 89 U/L, respectively; Common Terminology Criteria for Adverse Events [CTCAE] version 5.0: grade 2) were observed 9 months before admission, indicating acute liver injury. Ursodeoxycholic acid was prescribed based on suspected DILI, and the levels of hepatic enzymes decreased. She continued to take ursodeoxycholic acid for 9 months. Other medications prescribed were tapentadol hydrochloride, oxycodone hydrochloride hydrate, precipitated calcium carbonate cholecalciferol, magnesium carbonate combination tablets, esomeprazole magnesium hydrate, magnesium oxide tablets, and metoclopramide tablets. There was no history of drug change within 3 months prior to admission. She had no history of malignancy before the diagnosis of lung cancer. She had neither travelled abroad nor received any blood transfusion in the past 12 months. She had smoked 20 cigarettes/day between the ages of 33 and 48 years and had a history of drinking 180 mL/day of canned beer. She had not consumed any raw shellfish in the 3 months prior to admission but grilled pork liver skewers at a street restaurant 3 months prior and pork shabu-shabu once a week for 2 months.

One week before admission, after 12 courses of maintenance therapy with pemetrexed + pembrolizumab, she felt malaise and nausea and had decreased appetite. Her serum AST and ALT levels were elevated (176 and 172 U/L, respectively; CTCAE version 5.0: grade 3) (Fig. 1), and glycyrrhizic acid was prescribed. She was admitted to the hospital 1 week later, as her liver enzymes were markedly elevated (serum AST, 381 U/L; serum ALT, 853 U/L; CTCAE version 5.0: grade 4). Physical examination showed no signs of jaundice of the bulbar conjunctiva or neurological abnormalities, including flapping tremors. The results of the blood test performed upon admission are presented in Table 1. The abdominal ultrasonography and contrast-enhanced computed tomography results were negative for liver metastases or biliary congestion.

On admission, chemotherapy was discontinued in anticipation of chemotherapy-induced liver injury as the differential diagnosis, and blood samples were collected to assess for hepatitis viral markers and antinuclear and antimitochondrial antibodies. The results of hepatitis A, B, and C and autoimmune screenings were negative. Cytomegalovirus and Epstein-Barr virus infections were in a preexisting infection pattern. On day 8 of hospitalisation, acute hepatitis E was diagnosed based on the detection of HEV immunoglobulin (Ig) A antibodies. The patient received liver support therapy, and the levels of hepatic enzymes improved. The patient was subsequently discharged on day 9 of hospitalisation. After confirming that the AST and ALT levels were normal, chemotherapy with pemetrexed + pembrolizumab was resumed on day 34 after discharge. The patient did not show elevated AST and ALT levels on days 62 and 90 after discharge.

Acute hepatitis E, a type of viral hepatitis that causes acute liver injury after an incubation period of 2–6 weeks, is usually a self-limiting disease. In developed countries, acute hepatitis E of zoonotic origin has been increasingly diagnosed [1], and recent studies have shown that the incidence of hepatitis E is higher than previously assumed. A study examining 1,998 blood donor samples in France reported a prevalence of 3.2% HEV-IgG positivity [4], and a survey of 22,027 donors in Japan reported a 5.3% HEV-IgG positivity [5], suggesting that a relatively high proportion of individuals, including asymptomatic cases, may be infected with HEV during their lifetime.

HEV infection in developed countries is caused by genotypes 3 and 4, and most infections are known to have zoonotic origins, such as wild boar, deer, and pig [1, 6]. However, a specific animal or dietary cause is often not identifiable. In this case, the patient had an episode of eating grilled pork liver skewers 3 months earlier and repeated consumption of pork shabu-shabu purchased at a supermarket 2 months earlier, which may be the source of the HEV infection. Thus, HEV should be suspected even when there is no clear history of suspected food intake.

Although symptoms, such as fatigue in this case, may be present, HEV infection is often asymptomatic. In an HEV infection outbreak on a cruise ship, 67% of the HEV cases were asymptomatic [7]. Thus, HEV-IgM/IgG levels, as well as polymerase chain reaction tests, are necessary tools to diagnose HEV infection [8]. In this case, the viral marker HEV-IgA was used because of its superior sensitivity (98.8%) and specificity (99.9%) compared to those of HEV-IgM; thus, using HEV-IgA in diagnosing acute HEV infection is comparable with the identification of HEV-IgM or HEV-RNA [9]. However, according to the guideline of the European Association for the Study of the Liver, HEV-RNA in blood or stool and elevated anti-IgM and anti-IgG are practical indicators of acute HEV infection, and testing for anti-IgA antibody is useful albeit not widely available [8]. Among patients with acute HEV infection diagnosed based on HEV-RNA positivity, positive anti-HEV-IgA and anti-HEV-IgM results were maintained in 30% and 5% of cases, respectively, at 5 months after onset [10]. Based on these findings, the duration of maintained antibody positivity may be longer for HEV-IgA than for HEV-IgM. In this case, HEV-IgA antibody positivity was the basis of the diagnosis of acute type E infection, mainly because both anti-IgM antibody and HEV-RNA detection are not clinically available in Japan, and the anti-IgA antibody test is the only test that is reimbursed by medical insurance. In this case, blood samples were obtained once a month for 8 months before the episode, and elevated liver enzyme levels were not observed. Considering that the incubation period of acute hepatitis E is 2–6 weeks [1], there was no clinical evidence that acute HEV infection had occurred before the episode. We considered that the elevation in IgA antibody levels was caused by the current episode of acute HEV infection.

The diagnosis of DILI is clinically critical, and once a DILI diagnosis is confirmed, it is difficult to use the drug again without inducing any complications. Many complex factors are known to cause liver injury during chemotherapy, including comorbidities such as malnutrition, polypharmacy, liver metastasis of tumours, immunologic effects caused by immune checkpoint inhibitors, and reactivation of viral hepatitis [2]. There are several criteria for the diagnosis of DILI, such as the Roussel Uclaf Causality Assessment Method [11], which specifies that the exclusion of viral hepatitis is mandatory. Furthermore, the diagnosis of hepatitis E should be considered, especially if there is a history of travel to areas with endemic HEV infection, after organ transplantation, or in immunosuppressed states [1, 3]. Retrospective studies on patients with DILI found that 6 (12.8%) of 47 patients in the United Kingdom [12] and 9 (2.8%) of 318 patients in the USA [13] had acute hepatitis E. A recent clinical study in Spain reported similar results, suggesting that 8.3% of patients (8/144) diagnosed with DILI actually had hepatitis E, not DILI [14].

Case reports of HEV-induced hepatitis in patients undergoing chemotherapy for breast and uterine cancers [15], organ transplant recipients [16], and haematopoietic stem cell transplant recipients [17] have been published. However, there are no case reports of initially suspected DILI during chemotherapy including immune checkpoint inhibitors for lung cancer, where the liver injury was later diagnosed as acute hepatitis E. Similar to other DILIs, there are no clear diagnostic criteria for immune checkpoint inhibitor-induced liver injury, and exclusion is an essential aspect of the diagnosis. The diagnosis of DILI in a patient responding to chemotherapy is highly disadvantageous because the treatment must be discontinued; therefore, DILI should be diagnosed with caution. We suggest that even in developed countries and areas where hepatitis E outbreaks have been reported, a detailed interview and viral marker measurements should be routinely performed to ensure the appropriate DILI diagnosis.

This case report has some limitations. Only the serum anti-HEV-IgA test is clinically available in Japan, and this diagnostic approach may not meet universal approval. However, some evidence supports the validity of using serum anti-HEV-IgA for diagnosing acute HEV infection. In addition, reactivation of other viral infections, such as cytomegalovirus or Epstein-Barr virus, was not confirmed by polymerase chain reaction but was confirmed by serum IgM and IgG levels (Table 1).

We herein reported the first case of acute hepatitis E infection during chemotherapy for lung cancer. HEV infection often mimics DILI in its clinical presentation. Therefore, when a liver injury occurs during chemotherapy, the patient’s history of food intake and viral markers should be thoroughly examined for the differential diagnosis of DILI.

This case report was conducted ethically in accordance with the World Medical Association’s Declaration of Helsinki and was approved by the local Ethics Committee of Toranomon Hospital (Branch), approval number 2404B (November 16, 2022). The patient has provided written informed consent for the publication of this case report.

The authors have no conflicts of interest to declare.

No funding was used to acquire the information/data described in this case report.

H.O., A.M., and H.T. conceived and designed this study. H.O., A.M., F.S., and H.T. contributed to the analysis and interpretation of data. H.O. and A.M. wrote the manuscript. F.S. and H.T. supervised this study and critically reviewed the manuscript for important intellectual content. All authors have read and approved the final manuscript.

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.