Misdiagnosed Antibiotic-Induced Liver Injury: Unveiling Acute Hepatitis E in a 65-Year-Old Patient

Introduction

Hepatic injury can be detected clinically and by routine laboratory testing and requires a thorough evaluation of potential differential diagnoses [1]. The major causes of severely elevated liver transaminases, namely, alanine transaminase (ALT) and aspartate aminotransferase (AST), are ischemic hepatitis, drug-induced liver injury (DILI), and viral hepatitis [1,2].

DILI is an adverse drug reaction [3]. As the liver is the primary site of metabolism and clearance of drugs, hepatocytes are frequently exposed to them and their metabolites, which can be directly hepatotoxic or trigger the host’s immune system, which in turn, can lead to liver damage. The most important drugs causing DILI are acetaminophen, antibiotics, tuberculo-static drugs, nonsteroidal anti-inflammatory drugs, and immunosuppressive drugs [4]. The incidence of DILI is estimated to be 15 to 20 per 100 000, but it is frequently underreported, which is why its number is still difficult to assess [5]. DILI is mainly a diagnosis of exclusion after other causes of severe liver injury have been ruled out. One differential diagnosis of DILI is viral hepatitis. In particular, hepatitis E and hepatitis A can present similarly as DILI – as an acute disease with highly elevated liver transaminases [1]. Most patients infected with hepatitis E develop no symptoms and present a self-limiting course of disease. The incidence of hepatitis E has been underestimated [6], as shown in studies in Swiss blood donors with a high seroprevalence of anti-hepatitis E virus (HEV) immunoglobulin G (IgG) of 20.4% [7]. The transmission of hepatitis E is fecal-oral and frequently associated with the consumption of raw pork, game, and shellfish [8]. The diagnosis is usually made by the detection of positive anti-HEV IgM and IgG in the serum [8,9].

In this case report, we aim to raise awareness of avoiding premature diagnostic closure in patients with suspected DILI. Markedly elevated liver transaminases require a broad differential diagnostic workup, including hepatitis E screening in particular. Making the correct diagnosis is crucial, as it affects the further treatment of the patient.

Case Report

A 65-year-old man was referred to the Emergency Department from the rehabilitation center due to elevated liver transaminases. His past medical history included a squamous cell carcinoma of the jaw and bronchial asthma, which was treated with inhalation medication. It was not significant for health issues that may have been associated with the abnormal laboratory values, including alcohol-related liver injury, chronic hepatitis B and C, hepatic steatosis, nonalcoholic steatohepatitis, hemochromatosis, and alpha1-antitrypsin deficiency. The patient reported no travel history and no consumption of raw pork, game, or shellfish within the last 2 to 6 weeks prior to admission. He was asymptomatic, alert, afebrile, normotensive, and presented a normal heart rate. He was 171 cm tall and weighed 63 kg (body mass index of 21.5 kg/m2). Physical examination revealed no jaundice or abdominal pain. He presented with slight pain at the left jaw, where he had undergone surgical removal of a squamous cell carcinoma 16 days earlier. Since then, he was treated with clindamycin for 5 days, which had been switched to imipenem/cilastatin due to evidence of a polymicrobial surgical site infection (Figure 1). Laboratory findings revealed severely elevated AST, ALT, and bilirubin levels (Table 1). The AST/ALT ratio (De Ritis ratio) was 0.6, indicating an acute hepatitis. The R value of 6 (R value=[ALT÷upper limit of normal (ULN) of ALT]/[AP ÷ ULN of AP], reference range: ≤5) on day of admission was in line with a hepatocellular injury pattern. Albumin concentration was 27 g/L (reference range 35–52 g/L), and the international normalized ratio was 1.0 (reference range <1.3). An ultrasound of the liver was unremarkable.

DILI was suspected due to the rise of the biochemical liver markers shortly after the initiation of antibiotic treatment. Consequently, treatment with imipenem/cilastatin and of all other potentially hepatotoxic drugs (acetaminophen, metamizole) were stopped. Furthermore, hepatitis B and C virus serology results were negative. The patient had previously been vaccinated against hepatitis A. The patient was also tested for Epstein-Barr virus, cytomegalovirus, and herpes simplex virus type 1 and 2. The serological test results indicated previous exposures to Epstein-Barr virus and cytomegalovirus. Polymerase chain reaction (PCR) results for herpes simplex virus type 1 and 2 in plasma were negative.

Due to the rare occurrence of severe DILI in case of clindamycin and imipenem/cilastatin treatment and the rapid and marked increase in liver transaminases rather untypical for DILI in rapidity and extent, we evaluated for other causes, including hepatitis E. Initially, hepatitis E was not suspected as a potential diagnosis, as the patient had been in the hospital for 17 days, and we were mainly assuming in hospital-acquired causes of hepatitis, although the known incubation period of hepatitis E is 2 to 10 weeks.

Additional serological tests were performed and revealed positive anti-HEV IgM and anti-HEV IgG. The serum HEV-ribonucleic acid-PCR was positive (5.02×106 RNA copies/mL), which confirmed the diagnosis of acute hepatitis E (Figure 1). Serum ALT and AST concentrations increased markedly, with a peak of 15 times the ULN on day 2 after admission. Liver transaminases decreased spontaneously during the subsequent course of the patient’s disease. Only supportive care was applied. The diagnosis of acute hepatitis E finally ruled out DILI due to imipenem/cilastatin or clindamycin.

Discussion

We present a case of a patient with suspected DILI that turned out to be acute hepatitis E. Premature diagnostic closure in patients with markedly elevated liver transaminases pointing toward DILI should be avoided as to not miss other diagnoses, such as hepatitis E, which can affect the further treatment of the patient. In this case, given the patient’s history, DILI was highly suspected due to the antibiotic treatment that had previously been initiated. Furthermore, the patient reported no travel history and no consumption of raw pork, game, or shell-fish as a potential source of transmission of hepatitis E [8].

DILI can present with the pattern of acute hepatocellular and/or cholestatic injury and can mimic all forms of acute and chronic liver disorder. The clinical manifestation of hepatocellular injury ranges from acute hepatitis with mild liver enzyme elevation to severe liver injury and acute liver failure [3]. The DILI prevalence at admission was found to be 0.7%, and the overall incidence during hospitalization was 1.4% in a cohort study of 4209 Swiss patients at risk for DILI [10]. An increased number of drugs prescribed increases the risk of developing DILI [11]. This can be caused by possible drug-drug interactions, which are a reason behind many adverse drug reactions [12]. The management of DILI depends on the severity of disease and the causative agent. The most important first treatment is the discontinuation of the suspected hepatotoxic medication. The treatment of DILI is mainly supportive, except for DILI caused by acetaminophen and valproic acid, which should be treated immediately with N-acetylcysteine and L-carnitine, respectively [6]. Close monitoring of ALT and AST concentrations is important, especially in patients with underlying liver diseases [4,12]. Once the drug is identified and stopped, the clinical and laboratory values usually improve over the next few days or weeks. In addition, corticosteroids are a recognized option in cases of immune-mediated DILI, such as checkpoint inhibitor-induced liver injury or drug-induced autoimmune hepatitis, for example, caused by tumor necrosis factor inhibitors [4]. Nevertheless, DILI can progress to acute liver failure with a fatal outcome or the need for a liver transplantation [12]. Acute liver failure due to idiosyncratic hepatotoxicity has an especially poor prognosis, with only 20% to 50% of patients surviving without a liver transplant. Depending on the causative active agent, DILI with jaundice is associated with a 10% to 50% risk of mortality [11].

Hepatitis E is one of the most common causes of acute viral hepatitis, and the frequency of HEV as a cause of acute hepatitis might be underestimated in central Europe, where most hepatitis E cases are caused by HEV genotype 3 [13]. Most infections are acquired locally rather than being associated with travel [14]. The incubation period ranges from 2 to 10 weeks [15]. The diagnostic workup in patients with high liver transaminases and suspected DILI should include the testing for hepatitis E in addition to testing for hepatitis A and B virus and acetaminophen overdose [16]. The De Ritis ratio (AST/ALT ratio) can be used as an indicator of the cause of the elevated liver transaminases. Acute viral hepatitis is characterized by a ratio <1, whereas ischemic or toxic hepatitis shows mainly a ratio >1 [17,18]. Our patient presented highly elevated liver transaminases and bilirubin and a De Ritis ratio of <1, demonstrating acute hepatocellular injury. However, no hemostatic disorders could be observed. Moderate hypoalbuminemia was present, which was probably not associated with hepatic dysfunction but related to the pervious hospitalization, including surgery, infection, and inflammation, factors known to be associated with hypoalbuminemia [19]. Accordingly, a marker of inflammation, C-reactive protein, was markedly elevated at day −15, when the surgical site infection was treated, but was almost within the normal range when the diagnosis of hepatitis E was made (day 2: 11.1 mg/L).

For the diagnosis of HEV infection, serology and PCR can be used in combination. It can take 3 weeks after the infection for HEV RNA to be detectable in serum, plasma, and stool by PCR. Anti-HEV antibodies can be detected in the acute phase of infection by enzyme immunoassays. Anti-HEV IgM is measurable in the first 2 weeks after onset of illness in most patients, and anti-HEV IgG appears shortly after. Anti-HEV IgM usually remains detectable for no longer than 3 to 4 months; anti-HEV IgG persists for longer [9]. In more than 90% of cases in immunocompetent hosts, hepatitis E is a self-limiting disease [20]. However, older age is a risk factor for severe hepatitis, and acute liver failure can occur in <1% of cases [21,22]. There is no recommended treatment for acute HEV infection in immunocompetent patients. [6] However, HEV infection, especially with HEV genotype 3, has been reported to bear a high risk of developing into chronic hepatitis in immunocompromised patients [23]. It has been observed that two-thirds of solid organ transplant recipients can develop chronic infection [23], which may be treated with a 12-week course of ribavirin [24].

In a cohort of 158 Swiss patients, HEV RNA was found to be present in 2% of liver biopsies in patients with suspected DILI. The high prevalence even led the authors to recommend performing HEV testing in all patients with suspected DILI [25]. This approach might be supported by a risk assessment carried out in Switzerland, which estimated the total annual number of food-borne hepatitis E cases in Switzerland to be 1481 [26]. Additionally, other studies that were conducted in the United States showed that a small but important proportion of patients (approximately 1%) with suspicion of DILI finally had acute hepatitis E [27,28].

Conclusions

This case underlines the importance of reviewing all potential differential diagnoses, including hepatitis E testing, when a patient presents with markedly elevated liver enzymes initially suggestive of DILI. Premature diagnostic closure in these patients should be avoided as to not miss other diagnoses, such as hepatitis E, which can affect further treatment of the patient.