Acute, serious drug-induced liver injury
2002; Elsevier BV; Volume: 37; Issue: 5 Linguagem: Inglês
10.1016/s0168-8278(02)00312-4
ISSN1600-0641
Autores Tópico(s)Drug Transport and Resistance Mechanisms
ResumoDrug-induced liver injury is a relatively common cause of acute liver disease and carries a mortality of around 10% [[1]Lewis J.H. Zimmerman H.J. Drug-induced liver disease.Med Clin North Am. 1989; 73: 775-792PubMed Google Scholar]. Linking liver disease to a drug is difficult; patients with suspected drug-induced liver injury often have multiple other risk factors for liver disease, may have taken many potential hepatotoxic drugs, and drug-induced liver injury may mimic virtually all forms of hepato-biliary diseases. The diagnosis of drug-induced liver injury is supported by: (a) temporal relationship between drug ingestion and liver injury; (b) exclusion of other diseases; (c) the presence of extrahepatic features of drug hypersensitivity; and (d) findings on liver biopsy [[2]Farrell G.C. Drug-induced hepatic injury.J Gastroenterol Hepatol. 1997; 12: S242-S250Crossref PubMed Scopus (76) Google Scholar]. In spite of the clinical importance, drug-induced liver injury has received less attention than many other forms of liver disease. Luisa Ibáñez and co-workers’ study in this issue of the Journal is therefore welcome [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar]. They present data from a prospective, observational epidemiologic study on acute, serious liver disease unrelated to infectious, obstructive, or metabolic ethiologies [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar]. The study originates from a collaborative network of 12 hospitals in Catalonia, Spain. During a 6-year period, the investigators identified 107 patients who fulfilled the inclusion criteria and none of the exclusion criteria. According to detailed questions about drug intake before onset of the liver disease, 103 of the 107 patients had been taking one or more drugs. This makes it likely that the hepatocellular, cholestatic, or mixed acute, serious liver affections were drug induced. The authors estimate the incidence to be 7.4 patients per million inhabitants per year, increasing with age. The fatality rate was 11.9%, and the risk of death did not significantly differ between hepatocellular and cholestatic patterns. The observed annual incidence of 7.4 patients per million is lower than the previously estimated 8.9–406 patients per million [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar]. As discussed by Ibáñez et al. [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar], the difference may be due to different study designs, different diagnostic criteria, unavailability of tests for hepatitis C virus at the time of some of the previous studies, and length of follow up. Further, pattern of drug use in the background population as well as referral patterns must be considered. It may seem surprising that this study does not report a higher incidence, considering the increased use of drugs and the high number of new chemical substances entering the market each year. Recent prospective population-based data from France demonstrate that more cases of drug-induced liver injury do occur [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar]. Sgro et al. [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar] studied drug-induced liver injury diagnosed in the primary health care sector (general practitioners and specialists), and observed a standardised annual global incidence of 81 patients per million. However, the French study [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar] supports the Spanish finding [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar]. Twelve percent of the French patients – corresponding to about ten patients per million – were hospitalised [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar]. This estimate is very close to the Spanish finding [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar]. In spite of the almost similar annual incidences reported in the Spanish [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] and French [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar] studies, the definitions of drug-induced liver injury differed. The French study [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar] used biochemical criteria (over two times upper normal limit of alanine aminotransferase or bilirubin; or combined increase of alanine aminotransferase, alkaline phosphatases, and bilirubin, provided that one of them were over two times the upper normal limits) proposed by an International Consensus Meeting [5AnonymousStandardisation of definitions and criteria of causality assessment of adverse drug reactions: drug-induced liver disorders: report of an international consensus meeting.Int J Clin Pharmacol Ther Toxicol. 1990; 28: 317-322PubMed Google Scholar, 6Benichou C. Criteria for drug-induced hepatic disorders. Report of an international consensus meeting.J Hepatol. 1990; 11: 272-276Abstract Full Text PDF PubMed Scopus (1048) Google Scholar]. In contrast, the Spanish study [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] used more strict biochemical criteria (alanine aminotransferase over five times upper normal limit and/or alkaline phosphatases over two times upper normal limit provided that the bilirubin was three times upper normal limit). Ibáñez et al. [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] argue that they used the more strict biochemical criteria ‘because they imply clinical expression and make the patient look for medical attention in a hospital setting’ and ‘in order to limit selection bias’. I find this argumentation difficult to follow as all patients were hospitalised. I would rather have seen that both studies had used the internationally recommended biochemical criteria, as this would facilitate the comparison across studies. Both the Spanish [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] and the French [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar] studies seem to have used the same interval between drug exposure and hepato-biliary abnormality (of 15 days for hepatocellular pattern and 30 days for cholestatic and mixed patterns), according to international recommendations [5AnonymousStandardisation of definitions and criteria of causality assessment of adverse drug reactions: drug-induced liver disorders: report of an international consensus meeting.Int J Clin Pharmacol Ther Toxicol. 1990; 28: 317-322PubMed Google Scholar, 6Benichou C. Criteria for drug-induced hepatic disorders. Report of an international consensus meeting.J Hepatol. 1990; 11: 272-276Abstract Full Text PDF PubMed Scopus (1048) Google Scholar]. Ibáñez et al. [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] tried to exclude alcoholic liver disease (defined as aspartate aminotransferase/alanine aminotransferase >2, liver enlargement, and alcohol consumption >150 g/day). However, almost two out of three patients consented to some alcohol consumption in the year before the liver disease occurred. We do not know how many of the patients were suffering from alcohol abuse. Alcohol problems originate in the brain – and many patients with alcohol problems have difficulties admitting their problem [7Nielsen S.D. Storgaard H. Moesgaard F. Gluud C. Prevalence of alcohol problems among adult somatic in-patients of a Copenhagen hospital.Alcohol Alcohol. 1994; 29: 583-590PubMed Google Scholar, 8Rambaldi A. Gluud C. Belli A. Nielsen S.D. Storgaard H. Moesgaard F. Prevalence of alcohol problems among adult somatic in-patients of Naples.Alcohol Alcohol. 1995; 30: 441-448PubMed Google Scholar, 9Rambaldi A. Todisco N. Gluud C. Ambrosone L. Rambaldi M. Prevalence of alcohol problems in general practice: an experience from Southern Italy.Alcohol Alcohol. 1996; 31: 191-196Crossref PubMed Scopus (4) Google Scholar]. I therefore suspect that some of the patients included in the Spanish [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] study may have unrecognised alcohol-induced liver disease. This question is also applicable to the French study [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar]. The Spanish [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] study went at length in excluding viral, other infectious, autoimmune, and biliary causes of the liver disease. The investigators should have used questionnaires like cut down, annoyed by criticism, guilty about drinking, eye-opener drinks (CAGE), the Michigan Alcoholism Screening Test (MAST), or Alcohol Use Disorders Identification Test to examine for hidden alcohol problems [7Nielsen S.D. Storgaard H. Moesgaard F. Gluud C. Prevalence of alcohol problems among adult somatic in-patients of a Copenhagen hospital.Alcohol Alcohol. 1994; 29: 583-590PubMed Google Scholar, 8Rambaldi A. Gluud C. Belli A. Nielsen S.D. Storgaard H. Moesgaard F. Prevalence of alcohol problems among adult somatic in-patients of Naples.Alcohol Alcohol. 1995; 30: 441-448PubMed Google Scholar, 9Rambaldi A. Todisco N. Gluud C. Ambrosone L. Rambaldi M. Prevalence of alcohol problems in general practice: an experience from Southern Italy.Alcohol Alcohol. 1996; 31: 191-196Crossref PubMed Scopus (4) Google Scholar, 10Reinert D.F. Allen J.P. The Alcohol Use Disorders Identification Test (AUDIT): a review of recent research.Alcohol Clin Exp Res. 2002; 26: 272-279Crossref PubMed Scopus (793) Google Scholar]. Further, liver biopsies could also have assisted in the diagnostic work up of the patients [[2]Farrell G.C. Drug-induced hepatic injury.J Gastroenterol Hepatol. 1997; 12: S242-S250Crossref PubMed Scopus (76) Google Scholar]. Future studies need to address these questions. Several drug using patients with liver disease may harbour unrecognised alcohol induced liver disease – as well as other unrecognised causes of liver disease. Reaching a firm conclusion about the relationship between exposure to a drug and an adverse event can be difficult. In one study, clinical pharmacologists and treating physicians reached complete agreement less than half the time when determining whether medication, alcohol, or ‘recreational’ drug use had caused hospitalisation [[11]Karch F.E. Smith C.L. Kerzner B. Mazzullo J.M. Weintrab M. Lasagna L. Adverse drug reactions – a matter of opinion.Clin Pharmacol Ther. 1976; 19: 489-492PubMed Google Scholar]. Similar difficulties regarding causality assessment of hepatotoxicity have recently been reported in spite of using causality assessment methods [[12]Lucena M.I. Camargo R. Andrade R.J. Perez-Sanchez C.J. Sanchez I.F. Comparison of two clinical scales for causality assessment in hepatotoxicity.Hepatology. 2001; 33: 123-130Crossref PubMed Scopus (256) Google Scholar]. The Spanish research team [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] chose a novel approach to estimate the incidence of drug-induced liver injury. They ascertained potential cases without knowledge of drug exposure. This approach may be viewed as a strength of the study. It would also be interesting to see the results of assessing the Spanish patients according to recently developed causality assessment methods [6Benichou C. Criteria for drug-induced hepatic disorders. Report of an international consensus meeting.J Hepatol. 1990; 11: 272-276Abstract Full Text PDF PubMed Scopus (1048) Google Scholar, 12Lucena M.I. Camargo R. Andrade R.J. Perez-Sanchez C.J. Sanchez I.F. Comparison of two clinical scales for causality assessment in hepatotoxicity.Hepatology. 2001; 33: 123-130Crossref PubMed Scopus (256) Google Scholar, 13Danan G. Benichou C. Causality assessment of adverse reactions to drugs – I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.J Clin Epidemiol. 1993; 46: 1323-1330Abstract Full Text PDF PubMed Scopus (1218) Google Scholar, 14Benichou C. Danan G. Flahault A. Causality assessment of adverse reactions to drugs – II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.J Clin Epidemiol. 1993; 46: 1331-1336Abstract Full Text PDF PubMed Scopus (458) Google Scholar, 15Maria V.A. Victorino R.M. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis.Hepatology. 1997; 26: 664-669Crossref PubMed Scopus (431) Google Scholar, 16Lee W.M. Assessing causality in drug-induced liver injury.J Hepatol. 2000; 33: 1003-1005Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. Some of the drugs listed as potential causes of the liver injury are somewhat surprising to me, e.g. heparins, insulins, and corticosteroids. I am not disregarding these drugs as potential causative agents, but a rechallenge experience in some of these patients may have been worth-while to consider. However, my surprise to find these drugs on the list could also be due to ignorance. The problem with knowledge about rare adverse drug events is that we mainly have to rely on reporting after a drug is marketed. And the health-care profession is not very good at identifying and reporting such adverse events. Studies show that rarely more than 10% of serious adverse drug events and 2–4% of non-serious adverse drug events are reported [[17]Rawlins M.D. Pharmacovigilance: paradise lost, regained or postponed. The William Withering Lecture 1994.J R Coll Physicians Lond. 1995; 29: 41-49PubMed Google Scholar]. These observations have recently been confirmed by the French study [[4]Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar]; drug-induced liver injury was at least 16 times more frequent than notified by spontaneous reporting. At least 11 of the 107 Spanish patients had been taking medical herbs, but we are not informed about which type of herbs [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar]. In western countries, we have, during the last 30 years, observed an increased use of such herbs, mostly originating from ’the far East’. It is well known that some herbs may cause liver injury [[18]Seef L.B. Lindsay K.L. Bacon B.R. Kresina T.F. Hoofnagle J.H. Complementary and alternative medicine in chronic liver disease.Hepatology. 2001 Sep; 34: 595-603Crossref PubMed Scopus (233) Google Scholar]. Therefore, their use must await convincing randomised clinical trials demonstrating that they do more good than harm. E.g. convincing trials regarding medical herbs for viral hepatitis are still lacking [19Liu J.P. Manheimer E. Tsutani K. Gluud C. Medicinal herbs for hepatitis C virus infection.Cochrane Database Syst Rev. 2001; : CD003183PubMed Google Scholar, 20Liu J.P. McIntosh H. Lin H. Chinese medicinal herbs for asymptomatic carriers of hepatitis B virus infection.Cochrane Database Syst Rev. 2001; : CD002231PubMed Google Scholar, 21Liu J.P. McIntosh H. Lin H. Chinese medicinal herbs for chronic hepatitis B.Cochrane Database Syst Rev. 2001; : CD001940PubMed Google Scholar]. The Spanish authors are to be congratulated with the collaborative spirit that has resulted in a well-performed study. As any good study, it raises more questions than it can answer. The authors have demonstrated the amount of work required identifying 107 patients with presumed drug-induced liver injury. This raises the question why Ibáñez et al. [[3]Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar] did not combine the epidemiologic search for patients with a randomised clinical trial evaluating an intervention for suspected drug-induced acute, serious liver injury? I hope such combined approaches may speed up the development of medical interventions for drug-induced liver injury as well as other diseases in the future. Apart from finding better treatments for patients with drug-induced liver injury, we also need to know more about why such drug reactions occur. Are they related to improper use of the drugs? Are they related to the use of other drugs or substances? Are they related to other life style factors? Are they related to the genes of the patient? The two epidemiologic studies from Europe [3Ibáñez L, Pérez E, Vidal X, Laporte J-R, the Grup d'Estudi Multicèntric d'Hepatotoxicitat Aguda de Barcelona. Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs. J Hepatol 2002;37:572–580.Google Scholar, 4Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (652) Google Scholar] together with other initiatives in Europe [[22]Peire M.A. Lucena M.I. Ruiz-Extremera A. Jara P. Romero-Gonzalez J. Andrade R.J. Drug-induced hepatotoxicity in children. Where we are and where were are going (in Spanish).An Esp Pediatr. 2002; 56: 434-442Crossref PubMed Google Scholar] and USA [[23]This Month from The NIHHepatotoxicity clinical research network.Hepatology. 2002; 36: 277Abstract Full Text PDF PubMed Google Scholar] herald that we are going to know more about drug-induced liver injury in the future.
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