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Journal ArticleDOI

Acute Hepatitis E Infection Accounts for Some Cases of Suspected Drug-Induced Liver Injury

TL;DR: HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced, andSerologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis.
About: This article is published in Gastroenterology.The article was published on 2011-11-01 and is currently open access. It has received 295 citations till now. The article focuses on the topics: Hepatitis E & Viral hepatitis.

Summary (4 min read)

Introduction

  • Drug-induced liver injury is the leading cause of acute liver failure and the primary reason for regulatory action leading to failed drug approval, market withdrawal, usage restrictions and warnings to practicing physicians in the United States.
  • The diagnosis is primarily one of exclusion and is made only after elimination of common causes of liver disease, such as alcoholic hepatitis, metabolic and genetic liver diseases, bile duct obstruction, and hepatitis A, B, and C virus infection (HAV, HBV, and HCV).
  • 3 Several recent findings have served to alter this opinion.
  • The aims of the current study were to assess whether acute hepatitis E accounts for some cases of suspected drug-induced liver injury in the United States and whether testing for HEV infection is warranted in the routine evaluation of patients with acute liver disease of unknown cause.

Patient identification and causality analysis

  • The Drug Induced Liver Injury Network consists of multiple (previously 5, and currently 8) U.S. clinical sites and a data coordinating center that have enrolled patients with suspected drug-induced liver injury into a prospective study since 2004.
  • The rationale, design and conduct of the DILIN, as well as a summary of the first 300 enrolled cases have been described.
  • 16, 17 All enrolled cases were subjected to formal causality assessment independently by three investigators, and a final causality score was obtained by consensus.
  • 18 At the same time, a Roussel Uclaf Causality Assessment score 19 was determined and cases were graded for severity using a five-point scale developed by the DILIN.

Serologic and Virologic Testing

  • Serum samples were obtained at the time of enrollment, which might be as long as 6 months after the onset of liver injury, and were stored at -80 degrees Celsius in a central repository.
  • For the current study, serum samples from the first 318 patients enrolled were tested for IgM and IgG anti-HEV using enzyme immunoassays of established sensitivity and specificity.
  • 20, 21 Samples with IgM anti-HEV and those with strongly positive reactions for IgG anti-HEV were further tested for HEV RNA using nested reverse transcription polymerase chain reaction (RT-PCR) 22 and the PCR products were separated by electrophoresis on ethidium bromide-stained agarose gels, extracted from the gel and directly sequenced to provide the consensus sequence.
  • A BLAST search of GenBank nucleotide sequences was performed to determine HEV genotype.
  • Details of the ELISA assays for anti-HEV and the PCR for HEV RNA are provided in Supplementary Material.

Histological Analysis

  • When available, liver biopsies (n=3) were reviewed by a hepatic pathologist (D.E.K.) who was unaware of the medications implicated and results of HEV testing.
  • Histological features of inflammation, fibrosis, steatosis, cholestasis, vascular injury and other findings were systematically recorded, along with a description of the overall pattern of injury.

Repeat Causality Analysis

  • Cases positive for HEV IgM were subjected to repeat causality analysis by three independent reviewers after the results of HEV serological and RT-PCR testing were available.
  • 18 Cases were also judged using the same scale as to the likelihood that the liver injury was due to acute hepatitis E based upon the clinical, biochemical and histological findings.

Data analysis

  • Pairwise comparisons were performed between the cases with no serological evidence of HEV infection versus patients with evidence of active or recent HEV infection (defined by presence of HEV IgM) and those with distant and resolved HEV infection (defined by presence of IgG without IgM anti-HEV).
  • The Wilcoxon test was used for continuous variables, Fisher's exact test for binary outcomes, and the Pearson chi-squared test for other categorical variables.

IRB approval

  • All details of the DILIN Prospective study were reviewed and approved by the institutional review boards of each clinical site and the data coordinating center.
  • In addition, the protocol for anti-HEV testing was specifically approved by the institutional review board of the National Institute of Allergy and Infectious Diseases of the intramural program of the National Institutes of Health.

Serological Testing

  • Initial and peak serum bilirubin, alanine aminotransferase (ALT) and alkaline phosphatase levels were similar in the three groups of patients.
  • Furthermore, the three groups did not different in distribution of pattern of serum enzyme elevations, severity scores or causality scores.

Demographic and Clinical Features of IgM anti-HEV Positive Cases

  • Selective demographic and clinical features of the nine IgM anti-HEV positive cases are given in Table 2 , and detailed case summaries of each patient are provided as Supplementary Data.
  • The clinical course was considered severe in three patients who manifested signs of hepatic failure such as elevations in INR > 1.5, ascites or hepatic encephalopathy.
  • Information on exposures to farm animals or raw pork was not specifically sought but none offered such information or gave a history of travel to an endemic area.
  • The patients were geographically diverse and presented at 4 of the 5 DILIN centers including Indiana (n=5), San Francisco (n=2), Connecticut (n=1) and North Carolina (n=1) between 2004 and 2006.

HEV RNA results

  • Four patients with IgM anti-HEV were also reactive for HEV RNA, and all four harbored genotype 3.
  • Sequencing analyses showed that the four were not closely related phylogenetically (data not shown) and therefore were not likely due to a single source or contamination, presenting in different geographic areas (Indiana, San Francisco and North Carolina).
  • The four cases with viremia included both patients with HIV infection.
  • Follow-up serum samples, drawn approximately 6 months after enrollment, were available from four IgM anti-HEV-positive subjects: all had an increase in IgG anti-HEV titer, but IgM anti-HEV had diminished in titer or had become negative, consistent with seroconversion after acute infection.
  • All were also negative for HEV RNA (two were positive on the earlier specimen) (Table 3 ).

Causality Analysis/Re-analysis

  • The initial causality assessment for the nine cases concluded that 4 were highly likely, 3 probably and 2 possibly due to drug-induced liver injury.
  • 21 Thus, most cases were considered compatible with drug-induced liver injury on initial assessment in the absence of anti-HEV results.
  • Even with the information on HEV serology, two cases (implicated medications being allopurinol and telithromycin) were still considered probably due to drug-induced liver injury rather than hepatitis E. Both patients presented late during the course of illness and initial clinical features and laboratory results were not available.
  • The remaining seven cases were considered more likely to be acute hepatitis E than drug-induced liver injury, although four were still considered "possibly" due to the medication.
  • Three cases were considered "definite" acute hepatitis E.

Liver histology of IgM anti-HEV positive cases

  • Liver biopsy tissue was available from three patients.
  • The bile ducts showed mild injury with reactive changes, but without cholestasis.
  • Case 4 developed mild acute liver injury with jaundice after taking ezetimibe for one year and underwent liver biopsy during recovery when serum bilirubin (1.4 mg/dL) and ALT levels (60 U/L) were close to normal.
  • The biopsy (not shown) showed mild steatosis, ballooning and bridging fibrosis with focal copper accumulation consistent with nonalcoholic steatohepatitis which he was thought to have before onset of the acute injury (based upon chronic ALT elevations and obesity).
  • Case 7 developed jaundice and a hepatitis-like syndrome 1.5 years after starting an antiretroviral regimen including nevirapine and on liver biopsy had changes of lobular disarray, spotty hepatocyte necrosis without confluence, marked lobular but scant portal inflammation, mild intrahepatic cholestasis but no bile duct injury, steatosis or fibrosis.

Discussion

  • The accurate diagnosis of drug-induced liver injury is critically important not only for patient care, but also for drug development, as even a single episode of severe liver damage associated with a drug during pre-marketing clinical testing may undermine its subsequent approval and marketing.
  • These findings suggest that the recent acute HEV infection detected by IgM anti-HEV testing did not account for the acute liver injury in all cases and that co-incidental, subclinical hepatitis E may have preceded the acute liver injury caused by the implicated medication.
  • In the remaining five patients the absence of viremia may have been due to the delay between the onset of symptoms and blood sampling for the study, as patients were typically referred by local physicians to the DILIN investigators days or even weeks after initial presentation.
  • The presence of serological evidence of acute hepatitis E should also prompt a search for possible sources of infection, such as foreign travel, exposure to farm animals, consumption of undercooked pork or wild game, and close personal contact with chronically immunosuppressed persons.
  • Finally, these findings underscore the need for sensitive and reliable, commercially available assays for HEV infection in the United States and reexamination of the possible benefit of an HEV vaccine.

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Citations
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Journal ArticleDOI
TL;DR: It is demonstrated that goats may be an important reservoir for HEV and can become a major source of HEV infection in humans via food chain.
Abstract: Background. Hepatitis E virus (HEV) is a significant pathogen of viral hepatitis and can be transmitted through fecal-oral route. Epidemiological data concerning HEV in goats, however, are relatively sparse to date. Here, the prevalence and characteristics of HEV isolated from goats at slaughterhouse were investigated in Tai’an region, China. Methods. Anti-HEV immunoglobulin G (IgG) in blood samples and HEV RNA in the liver samples were determined by using an enzyme-linked immunosorbent assay (ELISA) and a nested reverse transcription polymerase chain reaction (RT-PCR), respectively. In addition, partial nucleotide sequences of open reading frame 2 (ORF-2) of HEV isolates were analyzed. Results. Fifty goat blood samples (46.7%, 50/120) were masculine for anti-HEV IgG. HEV RNA was detected in 2 liver samples (4.0%, 2/50) and belonged to genotype 4 subtype 4 h, with high identity (91.2–93%) with cow HEV strains detected in the same province, China. Conclusions. These findings demonstrated that goats may be an important reservoir for HEV and can become a major source of HEV infection in humans via food chain.

24 citations

Journal ArticleDOI
TL;DR: Opinions are bolstered by evidence arguing against a significant incidence of severe hepatotoxicity from statins, including the report of an expert panel of hepatologists who concluded that abnormal liver-associated enzymes (LAEs) associated with statins are not evidence for hepatic dysfunction, and that no consistent histologic picture has emerged.
Abstract: The safety of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) remains very much in the news, with recent regulatory alerts issued about the potential for effects on memory loss, an increased risk of type 2 diabetes, myopathy, and possible drug interactions involving HIV and hepatitis C protease inhibitors [1–3]. Although the US Food and Drug Administration (FDA) currently considers serious statinrelated liver injury to be a rare and unpredictable event [1], it nevertheless remains an important concern among physicians and patients alike. Moreover, the risk of adverse hepatic events receives renewed emphasis with each new case series that appears in the literature. Indeed, the proportion of patients who are not being prescribed statins because of the potential for adverse hepatic events, but who might otherwise benefit from their cardioprotective effects, is substantial [4]. A reading of the recent published literature contains a not so subtle war of words over the risk and magnitude of statin-related hepatotoxicity [5–14]. It almost appears as if each new case series of statin-associated hepatic injury [5, 6, 15] can be matched with or accompanied by editorial comments to place the risk into perspective [11–13]. As a case in point, the authors of a recent Icelandic case series of statin-associated liver injury appearing in Digestive Diseases and Sciences suggest that the risk of jaundice seen with statins is substantially higher than has been previously estimated, and call for increased vigilance when statins are prescribed, while they chide the author of a number of editorials who has opined that statin-induced hepatotoxicity is no more than a ‘‘myth’’ [5]. In his editorial retorts [11–13], Bader’s choice of words regarding the safety of statins is based on the fact that asymptomatic aminotransferase elevations are not an accurate reflection of hepatic injury, as similar elevations have also been noted in placebo recipients. This is also echoed by a recent safety update by FDA which finds that the ‘‘routine periodic monitoring of serum ALT does not appear to detect or prevent serious liver injury in association with statins’’ [1]. Bader’s opinions are bolstered by evidence arguing against a significant incidence of severe hepatotoxicity from statins, including the report of an expert panel of hepatologists who concluded that abnormal liver-associated enzymes (LAEs) associated with statins are not evidence for hepatic dysfunction [14], and that no consistent histologic picture has emerged. Furthermore, Bader contends that given the extensive usage of statins worldwide for more than two decades, if there were one or more patterns of hepatotoxicity that could be definitively linked to statins, they would certainly have been identified long before now [11]. In an accompanying editorial to the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study [16], Bader reiterates his opinion that statins have only very rarely been implicated in causing liver injury, and he bemoans the fact that most clinicians still base their concern about statin-associated liver injury on the warnings in their prescribing information [12]. Indeed, as recently as 2005, many physicians were still reluctant to prescribe a statin to patients with only minimal ALT elevations [4]. Bader infers that a few isolated published reports are still capable of perpetuating the ‘‘myth of statin-induced hepatotoxicity.’’ To the casual reader, such contrasting views may be a source of confusion and even consternation. Is statin J. H. Lewis (&) Georgetown University Medical Center, Washington, DC, USA e-mail: LEWISJH@gunet.georgetown.edu

24 citations


Cites background from "Acute Hepatitis E Infection Account..."

  • ...Hepatitis E virus is increasingly being recognized in nonendemic areas, including the US [45], and recent series of suspected DILI cases have demonstrated positive hepatitis E serology in up to 20 % of those tested [46]....

    [...]

Journal ArticleDOI
TL;DR: The specific etiology of cases of hepatitis E infection can be diagnosed by serological testing and detecting viral RNA as discussed by the authors, and Ribavirin is currently the reference treatment for HEV infections in immunocompromised patients.
Abstract: Hepatitis E virus (HEV) is responsible for major outbreaks of acute hepatitis in developing countries where it was first described as a waterborne disease, transmitted by drinking water contaminated with feces. Attention was focused on HEV in developed countries and its associated diseases in recent years as a result of increasing reports of autochthonous infections. Hepatitis E is the zoonotic cause of these acute infections, and mainly in men over 50 years of age. The clinical manifestations and laboratory abnormalities of hepatitis E infections in immunocompetent patients cannot be distinguished from those caused by other hepatitis viruses. HEV is a major public health concern in immunocompromised patients because their infections can become chronic. The specific etiology of cases of hepatitis E infection can be diagnosed by serological testing and detecting viral RNA. Ribavirin is currently the reference treatment for HEV infections in immunocompromised patients. Several vaccines have proved safe and effective in clinical trials, but none have been approved for use in Europe yet.

24 citations

Journal ArticleDOI
TL;DR: Current tools used for DILI adjudication are imperfect and opportunities to improve current models, as well as the assessment process, in general, include provision of more precise clinical detail and to add new components to scoring systems.
Abstract: Purpose of reviewThere are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The

23 citations

Journal ArticleDOI
TL;DR: Hepatitis E virus infection is a known cause of acute‐on‐chronic liver failure in developing countries, but its implication in Western countries remains unknown.
Abstract: Background & Aims Hepatitis E virus (HEV) infection is a known cause of acute-on-chronic liver failure in developing countries, but its implication in Western countries remains unknown. HEV burden in the setting of severe acute alcoholic hepatitis (AAH) was assessed. Methods Patients admitted for severe AAH from 2007 to 2013, with available sera and histologically proven AAH, were included and managed according to current European guidelines. At admission, clinical and biological characteristics were collected; HEV serology and RNA detection were retrospectively performed. Results Eighty-four patients were included. Mean age was 50.8 ± 9.6 years, 65.5% were male, 91.7% were cirrhotic and 33.3% presented with encephalopathy. Mean MELD and Maddrey scores were respectively 32.4 ± 11.4 and 73.3 ± 37. Liver biopsy showed mild, moderate and severe hepatitis in 25 (29.8%), 23 (27.4%) and 32 (38.1%) patients respectively. Steroids were given to 61 patients (72.6%) of whom 35 (57.4%) presented corticoresistance (mean Lille score: 0.78 ± 0.21). During hospitalization, 24 patients (28.6%) died and 11 (13.1%) were transplanted. Three patients (3.6%) presented markers of acute HEV infection and 21 (25%) markers of past HEV infection. Patient with acute infection were men, cirrhotic, and 2/3 presented with encephalopathy. Steroids were given to two patients without any response. The third patient died. None were transplanted. Conclusions A substantial proportion of patients with severe AAH had markers of acute HEV infection, with similar clinical presentation and outcomes. Larger studies are needed to evaluate HEV impact on AAH management, resistance to steroids, and outcome.

23 citations


Cites background from "Acute Hepatitis E Infection Account..."

  • ...Hepatitis E is still not commonly diagnosed in the first line of ACLF in most centres, and is often an exclusion diagnosis (13, 14)....

    [...]

  • ...Hepatitis E Virus diagnosis is challenging because it is commonly performed after exclusion of other causes of hepatitis, including viral infections (hepatitis A, B, C, CMV, EBV) (13), though autochthonous HEV infections are increasingly reported in developed countries (28)....

    [...]

References
More filters
Journal ArticleDOI
TL;DR: In this paper, a new method for drug causality assessment is described and applied to reports of acute liver injuries, using reports with positive rechallenge as external standard.

1,291 citations

Journal ArticleDOI
TL;DR: The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.
Abstract: Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.

1,139 citations

Journal ArticleDOI
TL;DR: The discovery of swine HEV not only has implications for HEV vaccine development, diagnosis, and biology, but also raises a potential public health concern for zoonosis or xenozoonosis following xenotransplantation with pig organs.
Abstract: A novel virus, designated swine hepatitis E virus (swine HEV), was identified in pigs. Swine HEV crossreacts with antibody to the human HEV capsid antigen. Swine HEV is a ubiquitous agent and the majority of swine ≥3 months of age in herds from the midwestern United States were seropositive. Young pigs naturally infected by swine HEV were clinically normal but had microscopic evidence of hepatitis, and developed viremia prior to seroconversion. The entire ORFs 2 and 3 were amplified by reverse transcription–PCR from sera of naturally infected pigs. The putative capsid gene (ORF2) of swine HEV shared about 79–80% sequence identity at the nucleotide level and 90–92% identity at the amino acid level with human HEV strains. The small ORF3 of swine HEV had 83–85% nucleotide sequence identity and 77–82% amino acid identity with human HEV strains. Phylogenetic analyses showed that swine HEV is closely related to, but distinct from, human HEV strains. The discovery of swine HEV not only has implications for HEV vaccine development, diagnosis, and biology, but also raises a potential public health concern for zoonosis or xenozoonosis following xenotransplantation with pig organs.

1,088 citations

Journal ArticleDOI
TL;DR: Hepatitis E virus is an enterically transmitted virus that causes both epidemics and sporadic cases of acute hepatitis in many countries of Asia and Africa but only rarely causes disease in more industrialised countries.
Abstract: Hepatitis E virus (HEV) is a positive-stranded RNA virus with a 7.2 kb genome that is capped and polyadenylated. The virus is currently unclassified: the organisation of the genome resembles that of the Caliciviridae but sequence analyses suggest it is more closely related to the Togaviridae. Hepatitis E virus is an enterically transmitted virus that causes both epidemics and sporadic cases of acute hepatitis in many countries of Asia and Africa but only rarely causes disease in more industrialised countries. Initially the virus was believed to have a limited geographical distribution. However, serological studies suggest that HEV may be endemic also in the United States and Europe even though it infrequently causes overt disease in these countries. Many different animal species worldwide recently have been shown to have antibodies to HEV suggesting that hepatitis E may be zoonotic. Although two related strains have been experimentally transmitted between species, direct transmission from an animal to a human has not been documented. There are four currently recognised genotypes and two of the four contain viruses isolated from swine as well as from humans. Regardless of country of origin or genotype of the virus, most, if not all, strains belong to a single serotype. A promising recombinant vaccine candidate comprised of a truncated capsid protein is currently under evaluation in Nepal.

799 citations


Additional excerpts

  • ...31 4 (10) 40 (15) 5 (12) 25 (10) 4 (10) 9 (3)...

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Journal ArticleDOI
TL;DR: This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled in a prospective study to recruit patients with suspected idiosyncratic drug-induced liver injury and create a repository of biological samples for analysis.

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