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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: Experiments demonstrated that BCBALys exhibited high efficacy for treating CCl4-induced liver injury in a targeted manner and the chemical mechanism of BCBalys nanoparticle formation and the pharmacological mechanism of mouse liver protection from CCl 4-induced injury were revealed.
Abstract: By use of carboxylbutyryl as a linker, adriamycin (ADR) and cholyl-l-Lys (an anti-inflammatory agent) were covalently conjugated and Nα-cholyl-Ne-(N-carbonylpropionoadriamycin)-l-Lys (BCBALys) was constructed as a liver-targeting nano-delivery system to release cholyl-l-Lys and protect the liver from CCl4-induced injury. In ultrapure water and rat plasma, 10-6 M BCBALys formed nanoparticles of 42-231 nm in diameter and ∼116 nm in height. In a CCl4-injured mouse model, however, only 2 µmol kg-1 of BCBALys effectively protected the liver of the mice from injury, and the mouse liver histology showed no hepatic architecture loss and inflammatory cell infiltration. BCBALys selectively accumulated in the liver of CCl4-injured mice, but not in other vital organs, and released cholyl-l-Lys. These data demonstrated that BCBALys exhibited high efficacy for treating CCl4-induced liver injury in a targeted manner. The chemical mechanism of BCBALys nanoparticle formation and the pharmacological mechanism of BCBALys mouse liver protection from CCl4-induced injury were also revealed by experiments.

2 citations

Journal ArticleDOI
TL;DR: A simple protocol for preparing donor faeces, which facilitates some practical aspects of faecal microbiota transplantation for recurrent Clostridium difficile infection (rCDI), and the route of administration, FMT via sigmoidoscopy, which was found to be safe.
Abstract: We thank Dr C.R. Kelly for her interest and comments on our work and her balanced view on the use of faecal microbiota transplantation (FMT) for recurrent Clostridium difficile infection (rCDI). We agree with Dr Kelly’s views in general and would like to discuss some specific issues further. In our paper, we describe a simple protocol for preparing donor faeces, which facilitates some practical aspects of FMT. In faecal preparation and storage, we used 80 °C freezer, which allows quick freezing. We have not tested standard freezers for this purpose and cannot exclude the possibility that the viability of microbiota is compromised by freezing and storing at 20 °C. Considering the route of administration, we used infusion into caecum in colonoscopy, because we had previously good experience of this method in treating rCDI patients. As pointed out by Dr Kelly, FMT via sigmoidoscopy would be easier and less costly as compared with colonoscopy. However, there are only few small scale studies comparing the treatment efficacy of FMT via different routes of administration and further studies are warranted. It is still difficult to conclude what would be the optimal route of administration considering all aspects of FMT. In our study, the follow-up period was 12 months, which is longer than in most other studies. The 1-year success rate of FMT treatment for rCDI was 88% and the treatment was found to be safe. Previously, Kelly et al. have demonstrated FMT to be a safe treatment for rCDI also in immunocompromised patients. Clearly, the short-term (up to 1 year) benefits of FMT outweigh the observed harms. However, we completely agree with Dr Kelly that further studies are needed to address the long-term health implications of FMT. In clinical work, experienced physicians should make the decision on using FMT by considering and balancing both the short-term benefits and possible long-term risks.

2 citations

Journal ArticleDOI
TL;DR: Although all types of hepatitis cause liver disease, their modes of transmission differ, and treatment may or may not be an option, treatment is complex and often associated with side effects, and it is costly to treat.
Abstract: Liver disease presents with classic symptoms: fatigue, anorexia that progresses to nausea and vomiting, muscle and joint pain, and jaundice. Its most common cause is viral infection (hepatitis) with one of the hepatotropic hepatitis viruses. Although all types of hepatitis cause liver disease, their modes of transmission differ, and treatment may or may not be an option. In all types of hepatitis, people older than 65 years of age tend to develop more severe disease than those who are younger. Hepatitis A is rare in the United States, usually resolves completely with rest and supportive care, and there is no drug treatment. The Food and Drug Administration has approved several medications for hepatitis B, although comorbidities in the elderly may preclude their use. Hepatitis C is generally treated with interferon alpha and ribavirin in patients who can tolerate these agents. Chronic hepatitis D infection is more aggressive than chronic hepatitis B infection, leading to cirrhosis within two years in 10% to 15% of patients. Treatment with interferon for at least one year is recommended, but may not help. Hepatitis E virus infection-typically associated with large waterborne epidemics and endemic in Asia, Africa, and Mexico-is poorly understood and reported only sporadically in the United States. Consultant pharmacists can provide invaluable input concerning management of patients with hepatitis since few guidelines are available. Treatment is complex and often associated with side effects, and it is costly to treat. Complete adherence is critical. Residents, their families, and long-term care staff will need education and support in treating these patients. Pharmacist involvement is especially important as newly approved agents become available; side effects can cause clinicians and patients to abandon treatment.

2 citations

11 Oct 2017
TL;DR: L’exposition au VHE chez les PVVIH au Pays basque est frequente et augmente avec l’âge, en particulier le VDRL et les IgG anti-VHE.
Abstract: Objectif : le but de l’etude etait d’evaluer la seroprevalence de l’hepatite E chez les PVVIH dans le Pays Basque ainsi que d’identifier les facteurs associes a l’infection et son retentissement sur le foie. Methodes : Un echantillon de 307 VIH âges de 19 a 84 ans, a ete examine par un test serologique Wantai avec recherche des anticorps IgG et IgM anti-VHE. Les serologies positives ont ete testees pour l’ARN VHE. Les facteurs de transmission du virus ont ete deceles par un auto-questionnaire. Le retentissement hepatique a ete apprecie par un fibrotest chez les co-infectes VIH/VHC. Une analyse uni- puis multivariee de l’association entre certains facteurs et l’exposition au virus a ete menee. Resultats : au total 307 patients ont ete inclus et avaient une mediane de 52 ans dont 220 hommes (71,6%). Le nombre median de T4 etait de 744 cellules/mm3 et de T8 de 819 cellules/mm3. 282 patients (91,9%) avaient une charge virale VIH 800 cellules/mm3 etaient considerees comme variables independantes, associees a l’absence d’anticorps anti VHE. Au niveau biologique les patients avec des IgG anti-VHE avaient des transaminases plus elevees, un taux de T4 et de T8 plus bas mais un ratio conserve. 7,5% des PVVIH etaient co-infectes VHB/VHE, 2,6% etaient VHC/VHE et 1,63% VHB/VHC/VHE. Parmi les patients co-infectes par le VHC, le fibrotest n’etait pas plus eleve chez les PVVIH seropositifs VHE. Conclusion : l’exposition au VHE chez les PVVIH au Pays basque est frequente et augmente avec l’âge. L’association entre la presence des marqueurs de la syphilis, en particulier le VDRL et les IgG anti-VHE peut laisser supposer un mode de transmission similaire notamment sexuel. D’autres etudes sont necessaires pour determiner le potentiel de transmission du VHE par voie sexuelle en particulier au sein d’une population a haut risque d’IST.

2 citations

References
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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

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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.

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Additional excerpts

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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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