Accepted Manuscript Hepatitis E: Emerging Pathogen or Domestic Bystander? Erin K. Spengler, Robert J. Fontana
PII: DOI: Reference:
S1542-3565(15)00796-X 10.1016/j.cgh.2015.06.006 YJCGH 54330
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 9 June 2015 Please cite this article as: Spengler EK, Fontana RJ, Hepatitis E: Emerging Pathogen or Domestic Bystander?, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/j.cgh.2015.06.006. 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 the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT HEV in ALF 1 Hepatitis E: Emerging Pathogen or Domestic Bystander? ,
Erin K. Spengler Robert J. Fontana
Division of Gastroenterology, Department of Medicine, University of Michigan Health System, Ann Arbor, MI
RI PT
1
Please address correspondence to: Robert J. Fontana, MD
SC
Professor of Medicine Division of Gastroenterology
Ann Arbor, MI 48109 Ph: (734) 936-4780 Fax: (734)-936-7392
TE D
Email: [email protected]
M AN U
3912 Taubman Center
Key words: hepatitis E, acute liver failure, indeterminate ALF, DILI
Guarantor of the article: Robert J. Fontana
EP
Author contributions: Erin K. Spengler: Drafting of manuscript draft, and approved final submission; Robert J. Fontana: Editorial concept and design, critical revision of the manuscript, and approved final submission
AC C
Conflicts of interest: The authors disclose no conflicts.
Words = 1448
ACCEPTED MANUSCRIPT HEV in ALF 2 Acute liver failure (ALF) is a rare but potentially devastating illness that is characterized by the sudden onset of mental status changes and coagulopathy (i.e. elevated INR) in a subject without pre-existing liver disease. The leading causes of ALF vary significantly worldwide with viral hepatitis accounting for 40-80% of ALF cases in 1
RI PT
developing countries, but only 5 to 20% of ALF cases in western countries. In the U.S. and United Kingdom, nearly 50% of ALF cases are caused by acetaminophen (APAP) overdose with the remaining cases attributed to various other etiologies (Table 1).
2
SC
Prompt identification of the cause of ALF is critical, as it guides the initiation of potentially life-saving treatments and helps identify patients who are unlikely to survive in the absence of emergency liver transplantation (Table 2).
M AN U
Widely available serological and PCR testing for hepatitis A, B and C, Epstein Barr virus, and herpes simplex virus (HSV) infection currently allows for the rapid and accurate identification of viral causes of ALF. Similarly, the development of the highly sensitive and specific serum APAP-protein adduct assay holds the promise of more quickly and reliably identifying patients with APAP induced liver injury who can benefit from N-acetylcysteine 3
therapy. Despite these advances in diagnostic methods, 10 to 20% of western ALF patients have no identifiable 2
TE D
cause of liver injury and these patients do poorly, with a 3-week transplant-free survival rate of only 20-30%. The role of unsuspected HBV, hepatitis G, SEN-V, parvovirus and HSV infection have been investigated, but the results have been largely negative.
4,5
EP
Acute infection with the hepatitis E virus (HEV), a single stranded RNA virus, is a leading cause of icteric hepatitis and ALF in many developing countries including India, China and parts of the Middle East and North Africa.
1
6
AC C
Pregnant patients are especially susceptible to HEV infection and more likely to develop ALF. In endemic countries, most HEV infections are caused by the fecal-oral spread of contaminated water that harbors HEV 6
genotypes 1 and 2. In contrast, acute HEV in western countries is believed to be caused primarily by infection with 6
HEV genotype 3, which can be transmitted via ingestion of undercooked pork, wild game or shellfish. Both HEV genotypes 3 and 4 are swine viruses that can be detected in domestic and wild pigs and appear to infect humans as 7
an accidental host (i.e. zoonoses). As with HAV, the frequency of detectable anti-HEV IgG, indicative of prior HEV infection, increases with age and more than 20% of otherwise healthy Americans are anti-HEV IgG (+) despite
ACCEPTED MANUSCRIPT HEV in ALF 3 8
never having had an acute hepatic illness. Therefore, most experts believe that occult asymptomatic HEV infection is common in the US, but the source, route, and mechanism of transmission remain unknown.
8
Manka et al in this issue of Clinical Gastroenterology and Hepatology, investigated the prevalence of HEV
RI PT
seropositivity in 80 patients with indeterminate ALF from western Germany seen at a single center over a 7-year 9
period. The 15% anti-HEV IgG seroprevalence rate is consistent with prior population-based studies in Germany. However, the authors also reported that 8 patients (10%) were HEV RNA positive. The serologic patterns of these
SC
HEV RNA-positive patients varied substantially, with 3 being anti-HEV IgM negative. In addition, none of the HEV RNA (+ ) patients reported risk factors for HEV acquisition such as contact with farm animals, consumption of raw 9
M AN U
pork or travel to endemic areas. Unfortunately, the authors did not have convalescent serum samples to determine if anti-HEV IgG seroconversion developed during follow-up. After reviewing the clinical histories, the authors concluded that acute HEV infection had potentially contributed to the ALF episode in all 8 patients. However, at least one patient clearly had concomitant amanita mushroom toxicity, two were treated for autoimmune hepatitis with full recovery following steroids, and 1 patient had established GVHD on liver biopsy 9
injury episode remains unclear.
TE D
prior to presentation. Therefore, whether the HEV infection was causative or simply associated with the liver
Like all HEV investigations, this study is limited by the variability in the HEV assays used and the lack of
EP
standardized criteria for the diagnosis of acute and chronic HEV infection. Although several anti-HEV antibody test kits are commercially available, the sensitivity and specificity of these assays vary significantly and none are 10,
In addition, the concordance of test results between the various ELISA,
AC C
currently approved by the FDA.
Immunoblot, and in-house assays using an International reference standard has not been established. Therefore, the potential for false positive as well as false negative anti-HEV IgG and IgM levels remains of concern, particularly in patients with hypergammaglobulinemia or immunosuppressed state, respectively. There is also a lack of standardization in HEV RNA testing in reference laboratories worldwide. In the US, the CDC currently offers diagnostic testing for HEV infection as a reference lab for clinicians (see www.cdc.gov/hepatitis). A recent analysis of 154 cases of idiopathic hepatitis referred to the CDC between 2005 and 2012 identified 26 patients with acute HEV infection.
11
Acute HEV was defined as an acute hepatic illness in a person who was either anti-HEV IgM or
ACCEPTED MANUSCRIPT HEV in ALF 4 anti-HEV IgG positive on an immunoblot assay with detectable HEV RNA in their serum or stool or a patient who was initially anti-HEV IgM positive who developed anti-HEV IgG during follow-up. These 26 acute HEV cases included 11 international travelers to endemic countries who all had HEV genotype 1 or 4 infection and 15
RI PT
“domestic” patients without any recent travel history who all had HEV genotype 3. Interestingly, there was a predominance of older men (66%) in the patients with acute symptomatic HEV genotype 3 infection as was 12
recently reported by the Drug Induced Liver Injury Network in 9 DILI patients with acute HEV infection.
to previously unsuspected acute HEV genotype 3 infections.
13,14
SC
Prior studies from Europe have also suggested that some cases of unexplained severe acute hepatitis may be due For example, 4% of ALF patients in a multicenter
infection from stored sera.
13,14
M AN U
study in Germany had acute HEV genotype 3 infection and 5% of Scottish ALF patients had evidence of acute HEV Furthermore, 454 clinically apparent cases of acute HEV infection were recorded in
calendar year 2011 alone in England and Wales. In contrast, only a limited number of verified acute HEV genotype 14
3 cases have ever been reported in the US. The multicenter US Acute Liver Failure Study Group identified evidence of acute HEV infection in only 3 of 701( 6 months in 1.8% to 11.3% of solid organ transplant recipients and other immunosuppressed individuals.
16
Although chronically infected patients could serve as a reservoir of
AC C
infection, person to person spread of HEV is uncommon and confirmatory studies in the US and other western countries are lacking. In fact, one recent study of 166 HIV-positive liver and kidney transplant candidates in the US failed to demonstrate evidence of active HEV infection in any patient.
17
In summary, a growing body of evidence suggests that indigenous or native HEV genotype 3 infections from the local environment may be an important cause of acute and chronic liver disease in some western patients. However, the majority of these studies have come from single centers in Europe that have high local rates of HEV infection in their encatchment areas and local food sources. It is possible that transient HEV viremia from
ACCEPTED MANUSCRIPT HEV in ALF 5 transfusion of contaminated blood products or coincidental acute or chronic HEV infection may play a contributory rather than primary role in these cases. In contrast, studies from the US have only shown rare instances of acute 2
HEV genotype 3 infection in DILI, idiopathic hepatitis and ALF patients. Therefore, it is clear that the clinical
RI PT
relevance of HEV genotype 3 infection varies substantially by country and local geography and environment. To better define the impact of HEV infection in human health and liver disease, sensitive and specific serological assays that have been validated against an international standard are needed for use by clinicians, investigators, and public health officials. In addition, universally accepted evidence based diagnostic criteria for acute and
SC
chronic HEV infection are needed. In the interim, western clinicians are encouraged to consider locally-acquired HEV genotype 3 infection in their differential diagnosis of unexplained icteric hepatitis, regardless of travel history
M AN U
or risk factors. Although several commercial assays are available for anti-HEV serological testing, the potential for false positive and false negative results must be considered in the context of a given patient’s hepatic illness and
AC C
EP
TE D
after excluding more common causes of liver injury.
ACCEPTED MANUSCRIPT HEV in ALF 6
AC C
EP
TE D
M AN U
SC
RI PT
References 1. Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol 2013;59:74-80. 2. Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-54. 3. Davern TJ, James LP, Hinson JA, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006;130:687-94. 4. Lee WM, Brown KE, Young NS, et al. Brief report: no evidence for parvovirus B19 or hepatitis E virus as a cause of acute liver failure. Dig Dis Sci 2006;51:1712-5. 5. Levitsky J, Duddempudi AT, Lakeman FD, et al. Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure. Liver Transpl 2008;14:1498-504. 6. Wedemeyer H, Pischke S, Manns MP. Pathogenesis and treatment of hepatitis e virus infection. Gastroenterology 2012;142:1388-1397.e1. 7. Meng XJ. From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. Virus Res 2011;161:23-30. 8. Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994. J Infect Dis 2009;200:48-56. 9. Manka P, Bechmann LP, Coombes JD, et al. Hepatitis E Virus Infection as a Possible Cause of Acute Liver Failure in Europe. Clin Gastroenterol Hepatol 2015. 10. Rossi-Tamisier M, Moal V, Gerolami R, et al. Discrepancy between anti-hepatitis E virus immunoglobulin G prevalence assessed by two assays in kidney and liver transplant recipients. J Clin Virol 2013;56:62-4. 11. Drobeniuc J, Greene-Montfort T, Le NT, et al. Laboratory based surveillance for hepatitis E virus infeciton, United States, 2005-2012. Emer Inf Dis 2013: 19: 218-222. 12. Davern TJ, Chalasani N, Fontana RJ, et al. Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology 2011;141:1665-72.e1-9. 13. Hadem J, Tacke F, Bruns T, et al. Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol 2012;10:664-9.e2. 14. Crossan CL, Simpson KJ, Craig DG, et al. Hepatitis E virus in patients with acute severe liver injury. World J Hepatol 2014;6:426-34. 15. Fontana RJ, Engle RE, Trivedi S, et al. The role of hepatitis E virus infection in Adult Americans with acute Liver Failure (Abstract). Hepatology 2012: 56: 958A. 16. Pischke S, Suneetha PV, Baechlein C, et al. Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients. Liver Transpl 2010;16:74-82. 17. Sherman KE, Terrault N, Barin B, et al. Hepatitis E infection in HIV-infected liver and kidney transplant candidates. J Viral Hepat 2014;21:e74-7.
ACCEPTED MANUSCRIPT HEV in ALF 7 Table 1. Etiologies of ALF in western patients Multicenter US-ALFSG 2 N=309 39% 13% 11% (HAV, HBV) 4% 6% 1% 9% 17%
Multicenter Germany 13 N=109 9% 32% 21% (all viral) 3% 2% 3% 6% 24%
RI PT
Single center United Kingdom 1 N=350 % Acetaminophen 57% % DILI 9% % Viral 7% (all viral) % Autoimmune n/a % Ischemia n/a % Pregnancy 8% % Other etiologies 6% % Indeterminate 12% *Includes patients with ALI and ALF
SC
Cohort description
Table 2. Disease-specific treatments and short-term outcomes in ALF patients
Disease specific therapy
AC C
EP
TE D
M AN U
Diagnostic tests Favorable outcomes (50 -70% recovery) Acetaminophen overdose Medication history, serum APAP level, serum APAP-protein adducts Pregnancy 3rd trimester Ischemia History, echocardiogram, volume status Budd-Chiari Liver USN with Doppler, CT/ MRA Unfavorable etiologies ( < 30% recovery) Hepatitis B HBsAg, anti-HBc (IgM), HBV DNA Herpes simplex virus HSV-DNA Autoimmune hepatitis SmAb, ANA, IgG levels, biopsy Wilson’s disease 24 hr urine copper, slit lamp, liver biopsy Idiosyncratic DILI Medication history, temporal association, histology Indeterminate Negative diagnostic testing
N-acetylcysteine Emergent delivery Fluids, cardiopulmonary support Anti-coagulation Entecavir, tenofovir Acyclovir Corticosteroids Chelation ? N-acetylcysteine ? N-acetylcysteine
PII: DOI: Reference:
S1542-3565(15)00796-X 10.1016/j.cgh.2015.06.006 YJCGH 54330
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 9 June 2015 Please cite this article as: Spengler EK, Fontana RJ, Hepatitis E: Emerging Pathogen or Domestic Bystander?, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/j.cgh.2015.06.006. 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 the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT HEV in ALF 1 Hepatitis E: Emerging Pathogen or Domestic Bystander? ,
Erin K. Spengler Robert J. Fontana
Division of Gastroenterology, Department of Medicine, University of Michigan Health System, Ann Arbor, MI
RI PT
1
Please address correspondence to: Robert J. Fontana, MD
SC
Professor of Medicine Division of Gastroenterology
Ann Arbor, MI 48109 Ph: (734) 936-4780 Fax: (734)-936-7392
TE D
Email: [email protected]
M AN U
3912 Taubman Center
Key words: hepatitis E, acute liver failure, indeterminate ALF, DILI
Guarantor of the article: Robert J. Fontana
EP
Author contributions: Erin K. Spengler: Drafting of manuscript draft, and approved final submission; Robert J. Fontana: Editorial concept and design, critical revision of the manuscript, and approved final submission
AC C
Conflicts of interest: The authors disclose no conflicts.
Words = 1448
ACCEPTED MANUSCRIPT HEV in ALF 2 Acute liver failure (ALF) is a rare but potentially devastating illness that is characterized by the sudden onset of mental status changes and coagulopathy (i.e. elevated INR) in a subject without pre-existing liver disease. The leading causes of ALF vary significantly worldwide with viral hepatitis accounting for 40-80% of ALF cases in 1
RI PT
developing countries, but only 5 to 20% of ALF cases in western countries. In the U.S. and United Kingdom, nearly 50% of ALF cases are caused by acetaminophen (APAP) overdose with the remaining cases attributed to various other etiologies (Table 1).
2
SC
Prompt identification of the cause of ALF is critical, as it guides the initiation of potentially life-saving treatments and helps identify patients who are unlikely to survive in the absence of emergency liver transplantation (Table 2).
M AN U
Widely available serological and PCR testing for hepatitis A, B and C, Epstein Barr virus, and herpes simplex virus (HSV) infection currently allows for the rapid and accurate identification of viral causes of ALF. Similarly, the development of the highly sensitive and specific serum APAP-protein adduct assay holds the promise of more quickly and reliably identifying patients with APAP induced liver injury who can benefit from N-acetylcysteine 3
therapy. Despite these advances in diagnostic methods, 10 to 20% of western ALF patients have no identifiable 2
TE D
cause of liver injury and these patients do poorly, with a 3-week transplant-free survival rate of only 20-30%. The role of unsuspected HBV, hepatitis G, SEN-V, parvovirus and HSV infection have been investigated, but the results have been largely negative.
4,5
EP
Acute infection with the hepatitis E virus (HEV), a single stranded RNA virus, is a leading cause of icteric hepatitis and ALF in many developing countries including India, China and parts of the Middle East and North Africa.
1
6
AC C
Pregnant patients are especially susceptible to HEV infection and more likely to develop ALF. In endemic countries, most HEV infections are caused by the fecal-oral spread of contaminated water that harbors HEV 6
genotypes 1 and 2. In contrast, acute HEV in western countries is believed to be caused primarily by infection with 6
HEV genotype 3, which can be transmitted via ingestion of undercooked pork, wild game or shellfish. Both HEV genotypes 3 and 4 are swine viruses that can be detected in domestic and wild pigs and appear to infect humans as 7
an accidental host (i.e. zoonoses). As with HAV, the frequency of detectable anti-HEV IgG, indicative of prior HEV infection, increases with age and more than 20% of otherwise healthy Americans are anti-HEV IgG (+) despite
ACCEPTED MANUSCRIPT HEV in ALF 3 8
never having had an acute hepatic illness. Therefore, most experts believe that occult asymptomatic HEV infection is common in the US, but the source, route, and mechanism of transmission remain unknown.
8
Manka et al in this issue of Clinical Gastroenterology and Hepatology, investigated the prevalence of HEV
RI PT
seropositivity in 80 patients with indeterminate ALF from western Germany seen at a single center over a 7-year 9
period. The 15% anti-HEV IgG seroprevalence rate is consistent with prior population-based studies in Germany. However, the authors also reported that 8 patients (10%) were HEV RNA positive. The serologic patterns of these
SC
HEV RNA-positive patients varied substantially, with 3 being anti-HEV IgM negative. In addition, none of the HEV RNA (+ ) patients reported risk factors for HEV acquisition such as contact with farm animals, consumption of raw 9
M AN U
pork or travel to endemic areas. Unfortunately, the authors did not have convalescent serum samples to determine if anti-HEV IgG seroconversion developed during follow-up. After reviewing the clinical histories, the authors concluded that acute HEV infection had potentially contributed to the ALF episode in all 8 patients. However, at least one patient clearly had concomitant amanita mushroom toxicity, two were treated for autoimmune hepatitis with full recovery following steroids, and 1 patient had established GVHD on liver biopsy 9
injury episode remains unclear.
TE D
prior to presentation. Therefore, whether the HEV infection was causative or simply associated with the liver
Like all HEV investigations, this study is limited by the variability in the HEV assays used and the lack of
EP
standardized criteria for the diagnosis of acute and chronic HEV infection. Although several anti-HEV antibody test kits are commercially available, the sensitivity and specificity of these assays vary significantly and none are 10,
In addition, the concordance of test results between the various ELISA,
AC C
currently approved by the FDA.
Immunoblot, and in-house assays using an International reference standard has not been established. Therefore, the potential for false positive as well as false negative anti-HEV IgG and IgM levels remains of concern, particularly in patients with hypergammaglobulinemia or immunosuppressed state, respectively. There is also a lack of standardization in HEV RNA testing in reference laboratories worldwide. In the US, the CDC currently offers diagnostic testing for HEV infection as a reference lab for clinicians (see www.cdc.gov/hepatitis). A recent analysis of 154 cases of idiopathic hepatitis referred to the CDC between 2005 and 2012 identified 26 patients with acute HEV infection.
11
Acute HEV was defined as an acute hepatic illness in a person who was either anti-HEV IgM or
ACCEPTED MANUSCRIPT HEV in ALF 4 anti-HEV IgG positive on an immunoblot assay with detectable HEV RNA in their serum or stool or a patient who was initially anti-HEV IgM positive who developed anti-HEV IgG during follow-up. These 26 acute HEV cases included 11 international travelers to endemic countries who all had HEV genotype 1 or 4 infection and 15
RI PT
“domestic” patients without any recent travel history who all had HEV genotype 3. Interestingly, there was a predominance of older men (66%) in the patients with acute symptomatic HEV genotype 3 infection as was 12
recently reported by the Drug Induced Liver Injury Network in 9 DILI patients with acute HEV infection.
to previously unsuspected acute HEV genotype 3 infections.
13,14
SC
Prior studies from Europe have also suggested that some cases of unexplained severe acute hepatitis may be due For example, 4% of ALF patients in a multicenter
infection from stored sera.
13,14
M AN U
study in Germany had acute HEV genotype 3 infection and 5% of Scottish ALF patients had evidence of acute HEV Furthermore, 454 clinically apparent cases of acute HEV infection were recorded in
calendar year 2011 alone in England and Wales. In contrast, only a limited number of verified acute HEV genotype 14
3 cases have ever been reported in the US. The multicenter US Acute Liver Failure Study Group identified evidence of acute HEV infection in only 3 of 701( 6 months in 1.8% to 11.3% of solid organ transplant recipients and other immunosuppressed individuals.
16
Although chronically infected patients could serve as a reservoir of
AC C
infection, person to person spread of HEV is uncommon and confirmatory studies in the US and other western countries are lacking. In fact, one recent study of 166 HIV-positive liver and kidney transplant candidates in the US failed to demonstrate evidence of active HEV infection in any patient.
17
In summary, a growing body of evidence suggests that indigenous or native HEV genotype 3 infections from the local environment may be an important cause of acute and chronic liver disease in some western patients. However, the majority of these studies have come from single centers in Europe that have high local rates of HEV infection in their encatchment areas and local food sources. It is possible that transient HEV viremia from
ACCEPTED MANUSCRIPT HEV in ALF 5 transfusion of contaminated blood products or coincidental acute or chronic HEV infection may play a contributory rather than primary role in these cases. In contrast, studies from the US have only shown rare instances of acute 2
HEV genotype 3 infection in DILI, idiopathic hepatitis and ALF patients. Therefore, it is clear that the clinical
RI PT
relevance of HEV genotype 3 infection varies substantially by country and local geography and environment. To better define the impact of HEV infection in human health and liver disease, sensitive and specific serological assays that have been validated against an international standard are needed for use by clinicians, investigators, and public health officials. In addition, universally accepted evidence based diagnostic criteria for acute and
SC
chronic HEV infection are needed. In the interim, western clinicians are encouraged to consider locally-acquired HEV genotype 3 infection in their differential diagnosis of unexplained icteric hepatitis, regardless of travel history
M AN U
or risk factors. Although several commercial assays are available for anti-HEV serological testing, the potential for false positive and false negative results must be considered in the context of a given patient’s hepatic illness and
AC C
EP
TE D
after excluding more common causes of liver injury.
ACCEPTED MANUSCRIPT HEV in ALF 6
AC C
EP
TE D
M AN U
SC
RI PT
References 1. Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol 2013;59:74-80. 2. Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-54. 3. Davern TJ, James LP, Hinson JA, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 2006;130:687-94. 4. Lee WM, Brown KE, Young NS, et al. Brief report: no evidence for parvovirus B19 or hepatitis E virus as a cause of acute liver failure. Dig Dis Sci 2006;51:1712-5. 5. Levitsky J, Duddempudi AT, Lakeman FD, et al. Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure. Liver Transpl 2008;14:1498-504. 6. Wedemeyer H, Pischke S, Manns MP. Pathogenesis and treatment of hepatitis e virus infection. Gastroenterology 2012;142:1388-1397.e1. 7. Meng XJ. From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. Virus Res 2011;161:23-30. 8. Kuniholm MH, Purcell RH, McQuillan GM, et al. Epidemiology of hepatitis E virus in the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994. J Infect Dis 2009;200:48-56. 9. Manka P, Bechmann LP, Coombes JD, et al. Hepatitis E Virus Infection as a Possible Cause of Acute Liver Failure in Europe. Clin Gastroenterol Hepatol 2015. 10. Rossi-Tamisier M, Moal V, Gerolami R, et al. Discrepancy between anti-hepatitis E virus immunoglobulin G prevalence assessed by two assays in kidney and liver transplant recipients. J Clin Virol 2013;56:62-4. 11. Drobeniuc J, Greene-Montfort T, Le NT, et al. Laboratory based surveillance for hepatitis E virus infeciton, United States, 2005-2012. Emer Inf Dis 2013: 19: 218-222. 12. Davern TJ, Chalasani N, Fontana RJ, et al. Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology 2011;141:1665-72.e1-9. 13. Hadem J, Tacke F, Bruns T, et al. Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol 2012;10:664-9.e2. 14. Crossan CL, Simpson KJ, Craig DG, et al. Hepatitis E virus in patients with acute severe liver injury. World J Hepatol 2014;6:426-34. 15. Fontana RJ, Engle RE, Trivedi S, et al. The role of hepatitis E virus infection in Adult Americans with acute Liver Failure (Abstract). Hepatology 2012: 56: 958A. 16. Pischke S, Suneetha PV, Baechlein C, et al. Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients. Liver Transpl 2010;16:74-82. 17. Sherman KE, Terrault N, Barin B, et al. Hepatitis E infection in HIV-infected liver and kidney transplant candidates. J Viral Hepat 2014;21:e74-7.
ACCEPTED MANUSCRIPT HEV in ALF 7 Table 1. Etiologies of ALF in western patients Multicenter US-ALFSG 2 N=309 39% 13% 11% (HAV, HBV) 4% 6% 1% 9% 17%
Multicenter Germany 13 N=109 9% 32% 21% (all viral) 3% 2% 3% 6% 24%
RI PT
Single center United Kingdom 1 N=350 % Acetaminophen 57% % DILI 9% % Viral 7% (all viral) % Autoimmune n/a % Ischemia n/a % Pregnancy 8% % Other etiologies 6% % Indeterminate 12% *Includes patients with ALI and ALF
SC
Cohort description
Table 2. Disease-specific treatments and short-term outcomes in ALF patients
Disease specific therapy
AC C
EP
TE D
M AN U
Diagnostic tests Favorable outcomes (50 -70% recovery) Acetaminophen overdose Medication history, serum APAP level, serum APAP-protein adducts Pregnancy 3rd trimester Ischemia History, echocardiogram, volume status Budd-Chiari Liver USN with Doppler, CT/ MRA Unfavorable etiologies ( < 30% recovery) Hepatitis B HBsAg, anti-HBc (IgM), HBV DNA Herpes simplex virus HSV-DNA Autoimmune hepatitis SmAb, ANA, IgG levels, biopsy Wilson’s disease 24 hr urine copper, slit lamp, liver biopsy Idiosyncratic DILI Medication history, temporal association, histology Indeterminate Negative diagnostic testing
N-acetylcysteine Emergent delivery Fluids, cardiopulmonary support Anti-coagulation Entecavir, tenofovir Acyclovir Corticosteroids Chelation ? N-acetylcysteine ? N-acetylcysteine
