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Journal ArticleDOI

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

01 Nov 2011-Gastroenterology (NIH Public Access)-Vol. 141, Iss: 5, pp 1665-1672

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.

AbstractBackground & Aims The diagnosis of drug-induced liver injury relies on exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States. Methods The Drug-Induced Liver Injury Network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig) G and IgM against HEV; selected samples were tested for HEV RNA. Results Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients who had anti-HEV IgM were mostly older men (89%; mean age, 67 years), and 2 were human immunodeficiency virus positive. Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2. Conclusions HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced. Serologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis.

Topics: Hepatitis E (62%), Viral hepatitis (61%), Liver disease (60%), Hepatitis E virus (57%), Cirrhosis (53%)

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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Acute Hepatitis E Infection Accounts for Some Cases of
Suspected Drug-Induced Liver Injury
Timothy J. Davern
1
, Naga Chalasani
2
, Robert J. Fontana
3
, Paul H. Hayashi
4
, Petr Protiva
5
,
David E. Kleiner
6
, Ronald E. Engle
7
, Hanh Nguyen
7
, Suzanne U. Emerson
7
, Robert H.
Purcell
7
, Hans L. Tillmann
8
, Jiezhun Gu
8
, Jose Serrano
9
, and Jay H. Hoofnagle
9
for the
Drug-Induced Liver Injury Network (DILIN)
Naga Chalasani: nchalasa@iupui.edu; Robert J. Fontana: rfontana@med.umich.edu; Paul H. Hayashi:
paul_hayashi@med.unc.edu; Petr Protiva: petr.protiva@yale.edu; David E. Kleiner: Kleinerd@mail.nih.gov; Ronald E.
Engle: rengle@niaid.nih.gov; Hanh Nguyen: htnguyen@niaid.nih.gov; Suzanne U. Emerson: semerson@niaid.nih.gov;
Robert H. Purcell: rpurcell@niaid.nih.gov; Hans L. Tillmann: hans.tillmann@duke.edu; Jiezhun Gu: jiezhun.gu@duke.edu;
Jose Serrano: SerranoJ@extra.niddk.nih.gov; Jay H. Hoofnagle: HoofnagleJ@extra.niddk.nih.gov
1
Department of Transplantation, California Pacific Medical Center, San Francisco, CA
2
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
3
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
4
Department of Internal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina
5
Department of Medicine, Yale University School of Medicine, New Haven, CT
6
Laboratory of Pathology, National Cancer Institute, National Institutes of Health (NIH), Bethesda,
MD
7
Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and
Infectious Diseases, NIH, Bethesda, MD
8
Duke Clinical Research Institute, Durham, NC
9
Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute
of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD
Abstract
Background & Aims—The diagnosis of drug-induced liver injury relies upon exclusion of
other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been
proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of
HEV infection among patients with drug-induced liver injury in the United States.
© 2011 The American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.
Corresponding Author: Timothy Davern, M.D., California Pacific Medical Center, San Francisco, CA. FAX: (415) 600-1200,
Telephone (415) 600-1020. DavernT@sutterhealth.org.
Conflicts of interest: Dr. Chalasani has received consulting fees regarding drug-induced liver injury in the past 12 months from the
following companies: Teva pharmaceuticals, KaroBio, J&J, Salix Pharmaceuticals, and Gilead Sciences and has received research
support from Eli Lilly for research on drug-induced liver disease. Dr. Fontana is on the Speaker‘s Bureau of Genentech and Gilead
Sciences and has received research support or consulting fees from Bristol-Myers Squibb, GlaxoSmithKline and Medtronic. Drs.
Davern, Hayashi, Kleiner, Engle, Nguyen, Emerson, Purcell, Gu, Serrano and Hoofnagle have no conflicts of interest to disclose.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
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discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
NIH Public Access
Author Manuscript
Gastroenterology
. Author manuscript; available in PMC 2013 May 15.
Published in final edited form as:
Gastroenterology
. 2011 November ; 141(5): 1665–72.e1-9. doi:10.1053/j.gastro.2011.07.051.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Methods—The drug-induced liver injury network (DILIN) is a prospective study of patients with
suspected drug-induced liver injury; clinical information and biological samples are collected to
investigate pathogenesis and disease progression. We analyzed serum samples, collected from
patients enrolled in DILIN, for immunoglobulin (Ig)G and IgM against HEV; selected samples
were tested for HEV RNA.
Results—Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive
for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM
(collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA,
genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were
negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients that had anti-
HEV IgM were mostly from older men (89%; mean age, 67 years) and 2 were HIV positive.
Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the
most likely diagnosis for 7 and might be the primary diagnosis for 2.
Conclusion—HEV infection contributes to a small but important proportion of cases of acute
liver injury that are suspected of being drug induced. Serologic testing for HEV infection should
be performed—particularly if clinical features are compatible with acute viral hepatitis.
Keywords
Viral hepatitis; jaundice; isoniazid; liver biopsy; causality assessment; liver disease; drug toxicity;
treatment; cirrhosis
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.
1
The diagnosis of drug-induced
liver injury is often difficult because of the lack of specific biomarkers and the diversity of
its clinical presentation.
2
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).
Hepatitis E virus (HEV) infection is another cause of acute liver injury but is rarely
considered in the differential diagnosis of drug-induced liver injury, largely because
hepatitis E is thought to be rare in the Western World and unlikely to occur unless there is a
history of recent travel to an endemic area such as Asia, Africa or Central or South
America.
3
Several recent findings have served to alter this opinion. First, indigenous cases
of acute hepatitis E have been reported in the United States as well as Europe, Japan, and
New Zealand caused by HEV genotype 3 strains which are endemic to domestic and wild
animals, particularly swine.
4-12
In addition, recent population-based surveys in the United
States have shown that at least 20% of adults are reactive for IgG anti-HEV, and thus have
serological evidence of previous HEV infection.
13,14
Finally, a publication from the United
Kingdom suggested that up to 12% of cases of acute liver injury initially attributed to
medications were actually due to unsuspected acute HEV infection.
15
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.
Davern et al.
Page 2
Gastroenterology
. Author manuscript; available in PMC 2013 May 15.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Material and Methods
Patient identification and causality analysis
The Drug Induced Liver Injury Network (DILIN) 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 (RUCAM) score
19
was determined and cases were graded for severity using a five-point scale developed by the
DILIN.
16
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. Cases were again judged for the likelihood that the implicated medication was
responsible for the liver injury as “definite” (>95% likelihood), “highly likely” (75-94%),
“probable” (50-74%), “possible” (25-49%) or “unlikely” (<25%).
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.
Davern et al.
Page 3
Gastroenterology
. Author manuscript; available in PMC 2013 May 15.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

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. Each enrolled subject
signed an informed consent that allowed future testing on archived biosamples. 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.
Results
Serological Testing
Among 318 patients tested, 50 (16%) were reactive for IgG anti-HEV, 9 of whom (3%) were
also reactive for IgM anti-HEV. The demographical and clinical features of patients with
both IgG and IgM anti-HEV (Group 1, n=9), with IgG anti-HEV alone (Group 2, n=41), and
with no markers of HEV infection (Group 3, n= 268) are shown in Table 1. Comparing the
three groups, patients with anti-HEV reactivity were on average older (67 and 62 versus 47
years: both comparisons p = 0.001) and those with IgM anti-HEV were more often men
(90% versus 44% and 41%: p = 0.003). 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 cases included eight men and one woman; eight were non-
Hispanic whites and one was multiracial. The average age was 67 years (range 42 to 83
years). Initial serum bilirubin levels ranged from 0.4 to 15.1 mg/dL (mean = 7.0 mg/dL) and
peak levels were only slightly higher (mean = 10.8 mg/dL). Initial ALT levels ranged from
196 to 3838 U/L (mean = 1073 U/L) and alkaline phosphatase from 113 to 632 U/L (mean =
225 U/L). Based upon calculation of the R score (ALT divided by alkaline phosphatase both
expressed as multiple of the upper limit of the normal range
19
), the biochemical pattern of
serum enzyme elevations was hepatocellular (R > 5) in 5, cholestatic in 1 (R < 2) and
“mixed” in 3 (R 2-5). Three patients gave a history of fever and one of rash, but these
symptoms were not prominent and no patient had documented eosinophilia. Antinuclear
antibody was present in low titers in two patients (1:40 and 1:80) and smooth muscle
antibody in seven (titers ranging from 1:8-1:320) but other autoimmune features (arthritis,
rash, hyperglobulinemia) were not common. All patients were symptomatic, eight were
jaundiced, and seven were hospitalized for the liver injury. 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. Two of these patients had a
clinical syndrome resembling “acute on chronic” hepatitis, both having evidence of pre-
existing liver disease (alcoholic and nonalcoholic fatty liver disease).
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. One patient became
ill while travelling to Prague, Czech Republic, but symptoms arose upon his arrival, making
infection from exposure in the United States more likely. 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. The initially
implicated medications included nevirapine (as a part of antiretroviral therapy) in two
patients, and isoniazid, allopurinol, telithromycin, pravastatin, ezetimibe, azithromycin and
Davern et al.
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Gastroenterology
. Author manuscript; available in PMC 2013 May 15.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

an herbal product in one case each. The latency to first documented laboratory abnormalities
ranged from 13 days to 12.7 years, being less than one month in two, 1 to 6 months in four
and greater than 6 months in three cases.
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. RUCAM scores of cases ranged
from 5 to 10, values of 3 to 5 (n=1) indicating a “possible”, values of 6 to 8 (n=5) a
‘probable” and those above 8 (n=3) a “highly probable” likelihood.
21
Thus, most cases were
considered compatible with drug-induced liver injury on initial assessment in the absence of
anti-HEV results.
On reassessment after the results of anti-HEV testing were available, the causality scores
changed in eight cases (remaining “possible” in one) and no case was considered more than
“probably” due to drug-induced liver injury (Table 2). 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. Case 2 developed serum enzyme
elevations without jaundice during antiretroviral therapy that persisted for 4 months and had
a liver histology (Figure 1) suggestive of chronic hepatitis with focal bridging necrosis and
hepatocyte rosette formation, minimal steatosis, a lymphocytic portal infiltrate with
scattered eosinophils and only rare plasma cells, and bridging fibrosis. 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). Hepatocyte rosetting was also present which is atypical of nonalcoholic fatty
liver disease and is consistent with regeneration following a more severe injury in the
immediate past. Case 7 developed jaundice and a hepatitis-like syndrome 1.5 years after
starting an antiretroviral regimen including nevirapine and on liver biopsy (Figure 2) 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
Davern et al.
Page 5
Gastroenterology
. Author manuscript; available in PMC 2013 May 15.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

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

  • ...Another published report from the DILIN showed that 3% of individuals with suspected DILI tested positive for anti–hepatitis E virus (HEV) immunoglobulin (Ig)M, and it was concluded that serological testing for acute hepatitis E infection should be performed in individuals with suspected DILI, especially if clinical features are compatible with acute viral hepatitis (46)....

    [...]


Journal ArticleDOI
Abstract: Background & Aims The Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. Methods In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. Results Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P 365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. Conclusions Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

457 citations


Journal ArticleDOI
TL;DR: In this comprehensive review, the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries are summarized.
Abstract: Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.

435 citations


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

  • ...In a more recent study from the United States, 3% of patients with “DILI” had been diagnosed erroneously, as they had hepatitis E on subsequent testing (25)....

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Journal ArticleDOI
TL;DR: The update of the well accepted original RUCAM scale is presented and its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI is recommended, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.
Abstract: RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.

329 citations


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

  • ...As Hawaii lacks FDA-approved HEV antibody tests [30,45], HEV infection was not validly excluded in the reported Hawaii cases [16,17,51,74,154]....

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  • ...Since individual weighing and scoring of key items are lacking and undiscussed [33,54], results published by the DILIN group using their method are not transparent [3,6,13,30,54] and not available for reassessment [53]....

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  • ...Problems of diagnosing infections by hepatitis E virus (HEV) are evident in the US with anti-HEV antibody tests that are not FDA approved [17,30,45]....

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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.
Abstract: Despite the great number of methods proposed, assessing the causal role of a drug in the occurrence of an adverse medical event remains one of the most controversial issues Qualifying terms for criteria, such as "compatible", "suggestive" of "inconclusive", have never been strictly defined, leading to low reproducibility Weights of the criteria are usually not adapted to the injured organ, decreasing the specificity of the method In this paper, a new method for drug causality assessment is described Contents and limits of the criteria have been defined by experts convened to organ-oriented international consensus meetings Additional criteria have been introduced and weights attributed The method was applied to reports of acute liver injuries The reproducibility was tested by an independent team The validity of this novel method is studied in the following paper, based on an original approach using reports with positive rechallenge as external standard

1,165 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.

1,039 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.

1,032 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.

785 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.
Abstract: Background & Aims Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled. Methods Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded. Results DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%. Conclusions DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related.

701 citations


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