CASE REPORT
Fatal Fulminant Hepatitis E Associated with Autoimmune Hepatitis and Excessive Paracetamol Intake in Southeastern France Barbara Doudier,a Hugues Vencatassin,d Sarah Aherfi,b,c Philippe Colsonb,c Hôpital Saint-Joseph, Service de Médecine Interne, Marseille, Francea; Fondation Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, Franceb; Aix-Marseille Université, URMITE UM 63 CNRS 7278 IRD 198 INSERM U1905, Facultés de Médecine et de Pharmacie, Marseille, Francec; Hôpital Saint-Joseph, Service de Réanimation Polyvalente, Marseille, Franced
CASE REPORT
A
77-year-old woman was admitted to an emergency unit for jaundice and fever in Marseille, France, in January 2013. She had a past medical history of autoimmune hepatitis without hepatocellular failure. She was receiving an oral anticoagulant for atrial fibrillation (fluindione, 35 mg/day), insulin for diabetes mellitus, and antihypertensive drugs (rilmenidine [2 mg/day], losartan [100 mg/day], and hydrochlorothiazide [25 mg/day]). Diclofenac/misoprostol (50/0.2 mg/day), tramadol chlorhydrate (225 mg/day), and paracetamol (or acetaminophen; 6.6 g/day) were taken from 1 week until 2 days prior to admission for recent dorsal pain. Physical examination revealed jaundice, drowsiness, and digestive tract hemorrhage, which led to admission of the patient into the intensive care unit. She then developed hepatic encephalopathy and hypovolemic shock within a few hours. Laboratory tests showed severe anemia (a hemoglobin level of 6.9 g/dl), acute renal failure (her creatinine level rose to 227 mol/ liter), and acute liver failure with an alanine aminotransferase activity level of 1,668 IU/liter and a prothrombin index of 10% (Table 1). The serum paracetamol level was 3.5 mg/liter (normal value, ⬍5 mg/liter), possibly because it was measured ⬎2 days after the last drug intake. Serological and/or molecular markers of hepatitis A, B, and C virus; Epstein-Barr virus; cytomegalovirus; and human immunodeficiency virus (HIV) infection were negative or indicated past infections. The diagnosis of hepatitis E virus (HEV) infection was based on HEV RNA detection in the patient’s serum with an in-house PCR assay (1). Subsequently, anti-HEV
IgM and IgG were detected (Adaltis, Rome, Italy). The patient was positive for antinuclear autoantibodies (ANA; titer, 1/640) and anti-smooth-muscle antibodies (ASMA; titer, 1/160) but negative for anti-liver kidney microsomal antibodies. Cerebral and abdominal computed tomography scans revealed no abnormalities. The patient’s condition deteriorated rapidly, with hemodynamic instability despite blood transfusions and hemodynamic support, which led to the patient’s death 5 days later. The patient’s family did not report any travel abroad or contact with travelers within the 10-week period prior to admission or a recent transfusion history. Consumption of cooked pork was reported, but consumption of uncooked pork, shellfish, or unsafe drinking water was not. The HEV strain was of genotype 3, as determined by phylogenetic analyses (1) (Fig. 1). The top BLAST hits against the NCBI GenBank nucleotide sequence database for fragments of HEV genome open reading frame 1 (ORF1) (accession no. KF921518) and ORF2 (KF921517) showed 92%
Received 13 December 2013 Returned for modification 9 January 2014 Accepted 27 January 2014 Published ahead of print 29 January 2014 Editor: Y.-W. Tang Address correspondence to Philippe Colson, [email protected]. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/JCM.03372-13
TABLE 1 Evolution of biochemical and hematological markers Value determined on (day/mo/yr): Parameter
Normal range
19/01/2013
20/01/2013
21/01/2013
22/01/2013
23/01/2013
24/01/2013
Serum bilirubin (mol/liter) Serum ALTa (IU/liter) Serum ALKPb (IU/liter) C-reactive protein (mg/liter) Prothrombin index (%) White blood cell count (109/liter) Polynuclear neutrophil count (109/liter) Lymphocyte count (109/liter) Hemoglobin (g/dl)
5–20 ⬍31 ⬍34 ⬍10 70–100 4–10 2–7.5 1.5–4 11.5–16.0
284 1,668 943 39.8 ⬍10 10.4 7.9 1.04 9.6
254 957 636 24 34 8.9 7.7 4.6 6.1
398 390 315 53 44 9.8 8.8 0.45 8.5
488 196 291 101 45 13.7 11.9 0.89 9.5
530 203 327 139 35 10.8 9 0.65 8.3
507 1,496 448 142 19 26 20.5 1.3 8.6
a b
ALT, alanine aminotransferase. ALKP, alkaline phosphatase.
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We present, to our knowledge, the first case of fatal fulminant liver failure associated with hepatitis E virus infection, autoimmune hepatitis, and excessive paracetamol intake, which occurred in a 77-year-old woman. Hepatitis E testing should be performed in severe acute liver failure cases, even when another cause has been identified.
Downloaded from http://jcm.asm.org/ on January 28, 2015 by TULANE UNIV FIG 1 Phylogenetic tree based on a 232-nucleotide partial sequence corresponding to nucleotides 133 to 364 of ORF1 of the HEV genome (GenBank accession no. AB291961). The HEV sequences obtained in our laboratory are boxed. The sequences with the highest BLAST scores recovered from the NCBI GenBank nucleotide sequence database (in boldface, underlined, and identified by BBH [for best BLAST hit], GenBank accession number, host, country, and year of sample collection or sequence submission) as matches for sequences obtained in the present study (in boldface white font on a black background) have been incorporated into the phylogeny reconstruction in addition to sequences with known genotypes and subtypes (identified by genotype and subtype, GenBank accession number, host, country, and year of sample collection or sequence submission). Nucleotide sequence alignments were performed with the MUSCLE software (http://www.ebi.ac.uk/Tools/msa/muscle/). The tree was constructed with the MEGAv5.0 software (http://www.megasoftware.net/) by the neighborjoining method. Bootstrap values were obtained from 1,000 resamplings of the data, and values of ⬎40% are shown on branches of the tree. The avian HEV sequences with accession no. AY535004 and AM943646 were used as an outgroup. The scale bar indicates the number of nucleotide substitutions per site. Abbreviations: ARG, Argentina; AUS, Australia; BRA, Brazil; DEU, Germany; ESP, Spain; FRA, France; Hu, human; JPN, Japan; KGZ, Kyrgyzstan; MEX, Mexico; Mrs, Marseille; NLD, The Netherlands; NZL, New Zealand; Rb, rabbit; Sw, swine; UNK, unknown; USA, United States of America; Wb, wild boar.
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(JQ807482) and 89% (FJ998008) identity levels, respectively. These best matches had been obtained from two wild boars in Germany. In addition, the best matches corresponding to HEV RNA recovered from humans were obtained in Argentina (88% identity) and Japan (87% identity).
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ACKNOWLEDGMENT We have no potential-conflict-of-interest or financial disclosure to make.
REFERENCES 1. Kaba M, Richet H, Ravaux I, Moreau J, Poizot-Martin I, Motte A, Nicolino-Brunet C, Dignat-George F, Menard A, Dhiver C, Brouqui P, Colson P. 2011. Hepatitis E virus infection in patients infected with the human immunodeficiency virus. J. Med. Virol. 83:1704 –1716. http://dx .doi.org/10.1002/jmv.22177. 2. Kaba M, Moal V, Gérolami R, Colson P. 2013. Epidemiology of mammalian hepatitis E virus infection. Intervirology 56:67– 83. http://dx.doi .org/10.1159/000342301. 3. Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J, Dalton HR. 2012. Hepatitis E. Lancet 379:2477–2488. http://dx.doi.org /10.1016/S0140-6736(11)61849-7. 4. Rein DB, Stevens GA, Theaker J, Wittenborn JS, Wiersma ST. 2012. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology 55:988 –997. http://dx.doi.org/10.1002/hep.25505. 5. Khuroo MS. 2011. Discovery of hepatitis E: the epidemic non-A, non-B hepatitis 30 years down the memory lane. Virus Res. 161:3–14. http://dx .doi.org/10.1016/j.virusres.2011.02.007. 6. Purcell RH, Emerson SU. 2008. Hepatitis E: an emerging awareness of an old disease. J. Hepatol. 48:494 –503. http://dx.doi.org/10.1016/j.jhep.2007 .12.008. 7. Teo CG. 2012. Fatal outbreaks of jaundice in pregnancy and the epidemic history of hepatitis E. Epidemiol. Infect. 140:767–787. http://dx.doi.org /10.1017/S0950268811002925. 8. Dalton HR, Bendall R, Ijaz S, Banks M. 2008. Hepatitis E: an emerging infection in developed countries. Lancet Infect. Dis. 8:698 –709. http://dx .doi.org/10.1016/S1473-3099(08)70255-X. 9. Dalton HR, Stableforth W, Thurairajah P, Hazeldine S, Remnarace R, Usama W, Farrington L, Hamad N, Sieberhagen C, Ellis V, Mitchell J, Hussaini SH, Banks M, Ijaz S, Bendall RP. 2008. Autochthonous hepatitis E in Southwest England: natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease. Eur. J. Gastroenterol. Hepatol. 20:784 – 790. http://dx.doi.org/10.1097/MEG.0b013e3282f5195a. 10. Okamoto H, Takahashi M, Nishizawa T. 2003. Features of hepatitis E virus infection in Japan. Intern. Med. 42:1065–1071. http://dx.doi.org/10 .2169/internalmedicine.42.1065. 11. Péron JM, Mansuy JM, Poirson H, Bureau C, Dupuis E, Alric L, Izopet J, Vinel JP. 2006. Hepatitis E is an autochthonous disease in industrialized countries. Analysis of 23 patients in South-West France over a 13-month period and comparison with hepatitis A. Gastroenterol. Clin. Biol. 30:757– 762. http://dx.doi.org/10.1016/S0399-8320(06)73310-3. 12. Aherfi S, Borentain P, Raissoun F, Le Goffic A, Guisset M, Renou C, Grimaud JC, Hardwigsen J, Garcia S, Botta-Fridlund D, Nafati C, Motte A, Le Treut YP, Colson P, Gérolami R. 22 January 2014. Liver transplantation for acute liver failure related to autochthonous genotype 3 hepatitis E virus infection. Clin. Res. Hepatol. Gastroenterol. http://dx.doi .org/10.1016/j.clinre.2013.05.013.
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We describe, to our knowledge, the first case of fatal fulminant hepatitis associated with HEV infection, autoimmune hepatitis, and excessive paracetamol intake. HEV is a leading cause of acute hepatitis in developing countries and an emerging causative agent of acute and chronic hepatitis in Europe (2–4). The mortality rate due to acute hepatitis E has been reported to be 0.2 to 4% during epidemics in developing countries (2, 5, 6), as high as 30% among pregnant women (5, 7), and 8 to 11% in a series of symptomatic cases in developed countries (8–11). In addition, HEV is a wellknown cause of liver decompensation in both developed and developing countries, and the case/fatality ratio is potentially quite high in cases of underlying chronic hepatitis and in elderly patients in Europe (12–17). The patient whose case is reported here was an elderly woman with autoimmune hepatitis, and excessive paracetamol intake was reported; she therefore presented several risk factors for HEVassociated acute liver failure, as observed in the majority of previously reported fatal HEV infections in Europe (12, 14, 17, 18). Paracetamol represents either the most or second most common identified cause of acute liver failure in developed countries and is associated with a spontaneous mortality rate of 32 to 50% (19– 21). Acute liver failure associated with both paracetamol intoxication and HEV infection, diagnosed on the basis of anti-HEV IgM positivity, was reported in Nepal in a 45-year-old male patient (22). In that case, the outcome was favorable. Nevertheless, viral hepatitis, such as hepatitis C, was described as a pejorative factor during paracetamol intoxication, whereas paracetamol-related hepatotoxicity was found to be more frequent in patients with underlying liver disease (23–26). Furthermore, HEV has been proposed to potentially trigger autoimmune hepatitis (27, 28), and a case of acute hepatitis E associated with autoimmunity signs (i.e., ANA [titer, 1/320] and ASMA positivity) was recently reported (28). Finally, viral features, including mutations and genotype (29–31), and host features, including some patterns of the immune response and a polymorphism in the promoter region of the gene for tumor necrosis factor alpha (31–33), were proposed to be factors associated with the occurrence of fulminant acute hepatitis E. Here, the full-length viral genome was not analyzed, but genotype 3 HEV substantially differed from those previously identified in fulminant hepatitis E cases in France, which were mostly of subtype 3f (12, 18, 34), and in another recent report from our center (12) (Table 1). A porcine reservoir of HEV exists, and hepatitis E is a zoonosis (2, 35–38). Nonetheless, no source or mode of transmission is documented in Europe in most HEV infections (2, 3). In the present case, the absence of travel abroad and an HEV strain of genotype 3 indicate an autochthonous infection (2, 37–39). The patient ate cooked pork, and no other potential risk factor for HEV infection was noted. HEV epidemiology must be studied more extensively to improve the prevention of this potentially life-threatening infection. In addition, hepatitis E is likely still underdiagnosed in developed Western countries because of the relatively recent
realization that it is mainly autochthonous and not systematically linked to travel abroad, as previously believed (2, 3). For instance, retrospective investigations of a series of acute liver disease cases attributed to drug-induced liver injury showed that 13 to 19% were associated with hepatitis E (40, 41). Suspicion of paracetamol intoxication and autoimmune hepatitis here may have prevented the detection of concurrent hepatitis E. Moreover, the diagnosis of hepatitis E can be jeopardized by concurrent infectious causes of liver cytolysis. Thus, HEV infection was previously detected concurrently with hepatitis B virus (HBV) reactivation (42), primary HBV infection (43), or acute hepatitis A virus infection (44, 45). Taken together, previous data support testing for HEV in cases of severe acute liver failure, even when another cause has already been identified. Notably, ribavirin therapy was reported in severe HEV-related acute liver failure cases (43, 46, 47) and was associated with rapid viral clearance and resolution, although it cannot be ascertained if or how it was influential.
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13. Dalton HR. 2012. Hepatitis: hepatitis E and decompensated chronic liver disease. Nat. Rev. Gastroenterol. Hepatol. 9:430 – 432. http://dx.doi.org /10.1038/nrgastro.2012.121. 14. Dalton HR, Hazeldine S, Banks M, Ijaz S, Bendall R. 2007. Locally acquired hepatitis E in chronic liver disease. Lancet 369:1260. http://dx .doi.org/10.1016/S0140-6736(07)60595-9. 15. De Silva S, Hassan-Ibrahim MO, Austin M, Newport M, Verma S. 2012. Hepatitis E infection is an under recognized cause of acute decompensation in patients with chronic liver disease. Dig. Liver Dis. 44:930 –934. http://dx.doi.org/10.1016/j.dld.2012.04.011. 16. Kumar Acharya S, Kumar Sharma P, Singh R, Kumar Mohanty S, Madan K, Kumar Jha J, Kumar Panda S. 2007. Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death. J. Hepatol. 46:387–394. http://dx.doi.org/10.1016/j.jhep .2006.09.016. 17. Péron JM, Bureau C, Poirson H, Mansuy JM, Alric L, Selves J, Dupuis E, Izopet J, Vinel JP. 2007. Fulminant liver failure from acute autochthonous hepatitis E in France: description of seven patients with acute hepatitis E and encephalopathy. J. Viral Hepat. 14:298 –303. http://dx.doi.org /10.1111/j.1365-2893.2007.00858.x. 18. Marion-Audibert AM, Tesse S, Graillot E, Phelip G, Radenne S, Duperret S, Durieux M, Rode A, Mabrut JY, Souquet JC, Nicand E. 2010. Lethal acute HEV superinfection on hepatitis B cirrhosis. Gastroenterol. Clin. Biol. 34:334 –336. http://dx.doi.org/10.1016/j.gcb.2010.02.003. 19. Bernal W, Auzinger G, Dhawan A, Wendon J. 2010. Acute liver failure. Lancet 376:190 –201. http://dx.doi.org/10.1016/S0140-6736(10)60274-7. 20. Bunchorntavakul C, Reddy KR. 2013. Acetaminophen-related hepatotoxicity. Clin. Liver Dis. 17:587– 607. http://dx.doi.org/10.1016/j.cld.2013 .07.005. 21. Larrey D, Pageaux GP. 2005. Drug-induced acute liver failure. Eur. J. Gastroenterol. Hepatol. 17:141–143. http://dx.doi.org/10.1097/00042737 -200502000-00002. 22. Kc S. 2007. Acute liver failure caused by hepatitis E virus and paracetamol. JNMA J. Nepal. Med. Assoc. 46:74 –76. http://www.jnma.com.np/jnma /index.php/jnma/article/view/334/592. 23. Myers RP, Shaheen AA, Li B, Dean S, Quan H. 2008. Impact of liver disease, alcohol abuse, and unintentional ingestions on the outcomes of acetaminophen overdose. Clin. Gastroenterol. Hepatol. 6:918 –925. http: //dx.doi.org/10.1016/j.cgh.2008.02.053. 24. Nguyen GC, Sam J, Thuluvath PJ. 2008. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis. Hepatology 48:1336 –1341. http: //dx.doi.org/10.1002/hep.22536. 25. Uehara T, Kosyk O, Jeannot E, Bradford BU, Tech K, Macdonald JM, Boorman GA, Chatterjee S, Mason RP, Melnyk SB, Tryndyak VP, Pogribny IP, Rusyn I. 2013. Acetaminophen-induced acute liver injury in HCV transgenic mice. Toxicol. Appl. Pharmacol. 266:224 –232. http://dx .doi.org/10.1016/j.taap.2012.11.019. 26. Yaghi C, Honein K, Boujaoude J, Slim R, Moucari R, Sayegh R. 2006. Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis. Gastroenterol. Clin. Biol. 30:763–768. http://dx.doi.org/10.1016/S0399-8320(06)73311-5. 27. Pischke S, Agisa Witte T, Suneetha PV, Bremer B, Raupach R, Lehman P, Darnedde M, Bantel H, Taubert R, Jaeckel E, Rifai K, Cornberg M, Schmidt RE, Manns MP, Wedemeyer H. 2013. Increased HEV seroprevalence in patients with autoimmune hepatitis. J. Hepatol. 508:S409 – S566. http://dx.doi.org/10.1371/journal.pone.0085330. 28. Vieira CL, Baldaia C, Fatela N, Ramalho F, Cardoso C. 2013. Case of acute hepatitis E with concomitant signs of autoimmunity. World J. Hepatol. 5:152–155. http://dx.doi.org/10.4254/wjh.v5.i3.152. 29. Inoue J, Nishizawa T, Takahashi M, Aikawa T, Mizuo H, Suzuki K, Shimosegawa T, Okamoto H. 2006. Analysis of the full-length genome of genotype 4 hepatitis E virus isolates from patients with fulminant or acute self-limited hepatitis E. J. Med. Virol. 78:476 – 484. http://dx.doi.org/10 .1002/jmv.20565. 30. Inoue J, Takahashi M, Mizuo H, Suzuki K, Aikawa T, Shimosegawa T, Okamoto H. 2009. Nucleotide substitutions of hepatitis E virus genomes associated with fulminant hepatitis and disease severity. Tohoku J. Exp. Med. 218:279 –284. http://dx.doi.org/10.1620/tjem.218.279. 31. Mishra N, Walimbe AM, Arankalle VA. 2013. Hepatitis E virus from
Fatal Fulminant Hepatitis E Associated with Autoimmune Hepatitis and Excessive Paracetamol Intake in Southeastern France Barbara Doudier,a Hugues Vencatassin,d Sarah Aherfi,b,c Philippe Colsonb,c Hôpital Saint-Joseph, Service de Médecine Interne, Marseille, Francea; Fondation Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie, Centre Hospitalo-Universitaire Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, Franceb; Aix-Marseille Université, URMITE UM 63 CNRS 7278 IRD 198 INSERM U1905, Facultés de Médecine et de Pharmacie, Marseille, Francec; Hôpital Saint-Joseph, Service de Réanimation Polyvalente, Marseille, Franced
CASE REPORT
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77-year-old woman was admitted to an emergency unit for jaundice and fever in Marseille, France, in January 2013. She had a past medical history of autoimmune hepatitis without hepatocellular failure. She was receiving an oral anticoagulant for atrial fibrillation (fluindione, 35 mg/day), insulin for diabetes mellitus, and antihypertensive drugs (rilmenidine [2 mg/day], losartan [100 mg/day], and hydrochlorothiazide [25 mg/day]). Diclofenac/misoprostol (50/0.2 mg/day), tramadol chlorhydrate (225 mg/day), and paracetamol (or acetaminophen; 6.6 g/day) were taken from 1 week until 2 days prior to admission for recent dorsal pain. Physical examination revealed jaundice, drowsiness, and digestive tract hemorrhage, which led to admission of the patient into the intensive care unit. She then developed hepatic encephalopathy and hypovolemic shock within a few hours. Laboratory tests showed severe anemia (a hemoglobin level of 6.9 g/dl), acute renal failure (her creatinine level rose to 227 mol/ liter), and acute liver failure with an alanine aminotransferase activity level of 1,668 IU/liter and a prothrombin index of 10% (Table 1). The serum paracetamol level was 3.5 mg/liter (normal value, ⬍5 mg/liter), possibly because it was measured ⬎2 days after the last drug intake. Serological and/or molecular markers of hepatitis A, B, and C virus; Epstein-Barr virus; cytomegalovirus; and human immunodeficiency virus (HIV) infection were negative or indicated past infections. The diagnosis of hepatitis E virus (HEV) infection was based on HEV RNA detection in the patient’s serum with an in-house PCR assay (1). Subsequently, anti-HEV
IgM and IgG were detected (Adaltis, Rome, Italy). The patient was positive for antinuclear autoantibodies (ANA; titer, 1/640) and anti-smooth-muscle antibodies (ASMA; titer, 1/160) but negative for anti-liver kidney microsomal antibodies. Cerebral and abdominal computed tomography scans revealed no abnormalities. The patient’s condition deteriorated rapidly, with hemodynamic instability despite blood transfusions and hemodynamic support, which led to the patient’s death 5 days later. The patient’s family did not report any travel abroad or contact with travelers within the 10-week period prior to admission or a recent transfusion history. Consumption of cooked pork was reported, but consumption of uncooked pork, shellfish, or unsafe drinking water was not. The HEV strain was of genotype 3, as determined by phylogenetic analyses (1) (Fig. 1). The top BLAST hits against the NCBI GenBank nucleotide sequence database for fragments of HEV genome open reading frame 1 (ORF1) (accession no. KF921518) and ORF2 (KF921517) showed 92%
Received 13 December 2013 Returned for modification 9 January 2014 Accepted 27 January 2014 Published ahead of print 29 January 2014 Editor: Y.-W. Tang Address correspondence to Philippe Colson, [email protected]. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/JCM.03372-13
TABLE 1 Evolution of biochemical and hematological markers Value determined on (day/mo/yr): Parameter
Normal range
19/01/2013
20/01/2013
21/01/2013
22/01/2013
23/01/2013
24/01/2013
Serum bilirubin (mol/liter) Serum ALTa (IU/liter) Serum ALKPb (IU/liter) C-reactive protein (mg/liter) Prothrombin index (%) White blood cell count (109/liter) Polynuclear neutrophil count (109/liter) Lymphocyte count (109/liter) Hemoglobin (g/dl)
5–20 ⬍31 ⬍34 ⬍10 70–100 4–10 2–7.5 1.5–4 11.5–16.0
284 1,668 943 39.8 ⬍10 10.4 7.9 1.04 9.6
254 957 636 24 34 8.9 7.7 4.6 6.1
398 390 315 53 44 9.8 8.8 0.45 8.5
488 196 291 101 45 13.7 11.9 0.89 9.5
530 203 327 139 35 10.8 9 0.65 8.3
507 1,496 448 142 19 26 20.5 1.3 8.6
a b
ALT, alanine aminotransferase. ALKP, alkaline phosphatase.
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We present, to our knowledge, the first case of fatal fulminant liver failure associated with hepatitis E virus infection, autoimmune hepatitis, and excessive paracetamol intake, which occurred in a 77-year-old woman. Hepatitis E testing should be performed in severe acute liver failure cases, even when another cause has been identified.
Downloaded from http://jcm.asm.org/ on January 28, 2015 by TULANE UNIV FIG 1 Phylogenetic tree based on a 232-nucleotide partial sequence corresponding to nucleotides 133 to 364 of ORF1 of the HEV genome (GenBank accession no. AB291961). The HEV sequences obtained in our laboratory are boxed. The sequences with the highest BLAST scores recovered from the NCBI GenBank nucleotide sequence database (in boldface, underlined, and identified by BBH [for best BLAST hit], GenBank accession number, host, country, and year of sample collection or sequence submission) as matches for sequences obtained in the present study (in boldface white font on a black background) have been incorporated into the phylogeny reconstruction in addition to sequences with known genotypes and subtypes (identified by genotype and subtype, GenBank accession number, host, country, and year of sample collection or sequence submission). Nucleotide sequence alignments were performed with the MUSCLE software (http://www.ebi.ac.uk/Tools/msa/muscle/). The tree was constructed with the MEGAv5.0 software (http://www.megasoftware.net/) by the neighborjoining method. Bootstrap values were obtained from 1,000 resamplings of the data, and values of ⬎40% are shown on branches of the tree. The avian HEV sequences with accession no. AY535004 and AM943646 were used as an outgroup. The scale bar indicates the number of nucleotide substitutions per site. Abbreviations: ARG, Argentina; AUS, Australia; BRA, Brazil; DEU, Germany; ESP, Spain; FRA, France; Hu, human; JPN, Japan; KGZ, Kyrgyzstan; MEX, Mexico; Mrs, Marseille; NLD, The Netherlands; NZL, New Zealand; Rb, rabbit; Sw, swine; UNK, unknown; USA, United States of America; Wb, wild boar.
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(JQ807482) and 89% (FJ998008) identity levels, respectively. These best matches had been obtained from two wild boars in Germany. In addition, the best matches corresponding to HEV RNA recovered from humans were obtained in Argentina (88% identity) and Japan (87% identity).
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ACKNOWLEDGMENT We have no potential-conflict-of-interest or financial disclosure to make.
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We describe, to our knowledge, the first case of fatal fulminant hepatitis associated with HEV infection, autoimmune hepatitis, and excessive paracetamol intake. HEV is a leading cause of acute hepatitis in developing countries and an emerging causative agent of acute and chronic hepatitis in Europe (2–4). The mortality rate due to acute hepatitis E has been reported to be 0.2 to 4% during epidemics in developing countries (2, 5, 6), as high as 30% among pregnant women (5, 7), and 8 to 11% in a series of symptomatic cases in developed countries (8–11). In addition, HEV is a wellknown cause of liver decompensation in both developed and developing countries, and the case/fatality ratio is potentially quite high in cases of underlying chronic hepatitis and in elderly patients in Europe (12–17). The patient whose case is reported here was an elderly woman with autoimmune hepatitis, and excessive paracetamol intake was reported; she therefore presented several risk factors for HEVassociated acute liver failure, as observed in the majority of previously reported fatal HEV infections in Europe (12, 14, 17, 18). Paracetamol represents either the most or second most common identified cause of acute liver failure in developed countries and is associated with a spontaneous mortality rate of 32 to 50% (19– 21). Acute liver failure associated with both paracetamol intoxication and HEV infection, diagnosed on the basis of anti-HEV IgM positivity, was reported in Nepal in a 45-year-old male patient (22). In that case, the outcome was favorable. Nevertheless, viral hepatitis, such as hepatitis C, was described as a pejorative factor during paracetamol intoxication, whereas paracetamol-related hepatotoxicity was found to be more frequent in patients with underlying liver disease (23–26). Furthermore, HEV has been proposed to potentially trigger autoimmune hepatitis (27, 28), and a case of acute hepatitis E associated with autoimmunity signs (i.e., ANA [titer, 1/320] and ASMA positivity) was recently reported (28). Finally, viral features, including mutations and genotype (29–31), and host features, including some patterns of the immune response and a polymorphism in the promoter region of the gene for tumor necrosis factor alpha (31–33), were proposed to be factors associated with the occurrence of fulminant acute hepatitis E. Here, the full-length viral genome was not analyzed, but genotype 3 HEV substantially differed from those previously identified in fulminant hepatitis E cases in France, which were mostly of subtype 3f (12, 18, 34), and in another recent report from our center (12) (Table 1). A porcine reservoir of HEV exists, and hepatitis E is a zoonosis (2, 35–38). Nonetheless, no source or mode of transmission is documented in Europe in most HEV infections (2, 3). In the present case, the absence of travel abroad and an HEV strain of genotype 3 indicate an autochthonous infection (2, 37–39). The patient ate cooked pork, and no other potential risk factor for HEV infection was noted. HEV epidemiology must be studied more extensively to improve the prevention of this potentially life-threatening infection. In addition, hepatitis E is likely still underdiagnosed in developed Western countries because of the relatively recent
realization that it is mainly autochthonous and not systematically linked to travel abroad, as previously believed (2, 3). For instance, retrospective investigations of a series of acute liver disease cases attributed to drug-induced liver injury showed that 13 to 19% were associated with hepatitis E (40, 41). Suspicion of paracetamol intoxication and autoimmune hepatitis here may have prevented the detection of concurrent hepatitis E. Moreover, the diagnosis of hepatitis E can be jeopardized by concurrent infectious causes of liver cytolysis. Thus, HEV infection was previously detected concurrently with hepatitis B virus (HBV) reactivation (42), primary HBV infection (43), or acute hepatitis A virus infection (44, 45). Taken together, previous data support testing for HEV in cases of severe acute liver failure, even when another cause has already been identified. Notably, ribavirin therapy was reported in severe HEV-related acute liver failure cases (43, 46, 47) and was associated with rapid viral clearance and resolution, although it cannot be ascertained if or how it was influential.
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