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Liver Injury Associated With Drugs and Complementary and Alternative Medicines in India

2021; Elsevier BV; Volume: 11; Issue: 3 Linguagem: Inglês

10.1016/j.jceh.2021.04.004

ISSN

2213-3453

Autores

Einar S. Björnsson,

Tópico(s)

Pharmacogenetics and Drug Metabolism

Resumo

Idiosyncratic drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests.1Hoofnagle J.H. Björnsson E.S. Drug induced liver injury: types and phenotypes.N Engl J Med. 2019; 381: 264-273Crossref PubMed Scopus (132) Google Scholar The presentation is acute in the vast majority of cases, and the diagnosis is challenging. DILI is the most common cause of acute liver failure in the US2Ostapowicz G. Fontana R.J. Schiodt F.V. 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 (2002/12/18): 947-954Crossref PubMed Scopus (1616) Google Scholar and Europe,3Wei G. Bergquist A. Broome U. et al.Acute liver failure in Sweden: etiology and outcome.J Intern Med. 2007; 262: 392-401Crossref Scopus (118) Google Scholar but in India, viral hepatitis is the most common cause, followed by liver injury due to antituberculosis (anti-TB) therapy.4Anand A.C. Nandi B. Acharya S.K. et al.Indian national association for the study of the liver consensus statement on acute liver failure (Part 1):Epidemiology, pathogenesis, presentation and prognosis.J CLin Experiment Hepatol. 2020; 10: 339-376Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar During the last two decades, interest in the study of DILI has increased considerably. Results from several large cohorts of patients with DILI have been reported from Western countries mostly from Spain, Sweden, Iceland, and the US5Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 6Björnsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (458) Google Scholar, 7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 9Chalasani N. Bonkovsky H.L. Fontana R. et al.Featuresand outcomes of 899 patients with drug-induced liver injury.DILIN Prospect Stud Gastroentrol. 2015; 48: 1340-1352Abstract Full Text Full Text PDF Scopus (403) Google Scholar, 10Vega M. Verma M. Beswick D. et al.The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of Delaware.Drug Saf. 2017; 40: 783-787Crossref PubMed Scopus (54) Google Scholar but also from the East such as from Korea,11Suk K.T. Kim D.J. Kim C.H. et al.A prospective nationwide study of drugp-induced liver injury inKorea.Am J Gastroneterol. 2012; 107: 1380-1387Crossref PubMed Scopus (116) Google Scholar India,12Kumar R. Bhatia V. Khanal S. et al.Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome.Hepatology. 2010; 51: 1665-1674Crossref PubMed Scopus (115) Google Scholar, 13Devarbhavi H. Dierkhising R. Kremers W.K. Sandeep M.S. Karanth D. Adarsh C.K. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality.Am J Gastroenterol. 2010; 105: 2396-2404Crossref PubMed Scopus (152) Google Scholar, 14Devarbhavi H. Karanth D. Prasanna K.S. Adarsh C.K. Patil M. Drug-Induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents.Hepatology. 2011; 54: 1344-1350Crossref PubMed Scopus (51) Google Scholar and China.15Shen T. Liu Y. Shang J. et al.Incidence and etiology of drug-induced liver injury in mainland China.Gastroenterology. 2019; 107: 1380-1387Google Scholar Previous studies from India have been from single centers with a relatively limited number of patients.12Kumar R. Bhatia V. Khanal S. et al.Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome.Hepatology. 2010; 51: 1665-1674Crossref PubMed Scopus (115) Google Scholar, 13Devarbhavi H. Dierkhising R. Kremers W.K. Sandeep M.S. Karanth D. Adarsh C.K. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality.Am J Gastroenterol. 2010; 105: 2396-2404Crossref PubMed Scopus (152) Google Scholar, 14Devarbhavi H. Karanth D. Prasanna K.S. Adarsh C.K. Patil M. Drug-Induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents.Hepatology. 2011; 54: 1344-1350Crossref PubMed Scopus (51) Google Scholar,16Rathi C. Pipaliya N. Patel R. et al.Drug induced liver injury at a tertiary hospital in India.Ann Hepatol. 2017; 16: 442-450Crossref PubMed Google Scholar It is therefore of great importance for the DILI community and for research in liver disease that results from a prospective study of 1288 patients with well-characterized DILI are reported in the current issue of the journal from the great country of India.17Devarbhavi H. Joseph T. Kumar N.S. et al.The Indian network of Drug-induced liver injury: etiology, clinical features, outcomes and prognostic markers in 1288 patients.J CLin Experiment Hepatol. 2021; 11: 288-298Abstract Full Text Full Text PDF Scopus (8) Google Scholar This was a multicenter study over 5 years, with participating centers over large parts of India. It seems that the vast majority were teaching hospitals, using the same protocol, and the nodal center was St. John's Medical College Hospital in Bangalore. Criteria for the diagnosis of DILI and assessment of severity were based on and adopted from the criteria from the International DILI Expert Working Group.18Aithal G.P. Watkins P.B. Andrade R.J. et al.Case definition and phenotype standardization in drug-induced liver injury.Clin Pharmacol Ther. 2011; 89: 806-815Crossref PubMed Scopus (558) Google Scholar Causality was based on the RUCAM causality assessment method.19Danan 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 (1068) Google Scholar Patients had relatively severe liver injury as almost 70% presented with jaundice, as might be expected in patients seen in tertiary referral centers. In contrast, in the population-based cohort of DILI patients, only approximately 30% presented with jaundice.8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar,20Sgro C. Clinard F. Ouazir K. et al.Incidence of drug-induced hepatic injuries: a French population-based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (573) Google Scholar The overall mortality in the Indian study was 12.3% and higher in those with jaundice. An unfavorable prognosis was independently associated with high INR and creatinine as well as ascites and hepatic encephalopathy. The most common drugs leading to DILI were the combination of anti-TB drugs in 46% of cases, complementary and alternative medicines(CAMs; 14%), antiepileptic drugs (8%), and non-TB antimicrobials (6.5%). The results of this large Indian study are very interesting and convincing. The authors are to be congratulated for their efforts. The methodology is sound and in accordance with the highest standard in the field. In many ways, the results are similar to those of other prospective studies of DILI published in the West.5Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 6Björnsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (458) Google Scholar, 7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar The prognosis was similar, although patients who fulfilled Hy's law had a somewhat higher mortality of approximately 17%, but in most of the other studies, this has been around 10–12%;5Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 6Björnsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (458) Google Scholar, 7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar but this is probably related to more severe liver disease at presentation. Interestingly, ascites was present in around 43% of nonsurvivors and in 12.5% of survivors, whereas this has rarely been reported in other DILI cohorts.5Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 6Björnsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (458) Google Scholar, 7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar Ascites in this context is most likely due to acute liver failure, although it is not entirely clear from the article how many had preexisting chronic liver disease as this could be a manifestation of decompensated chronic liver disease. The etiology was somewhat different in the Indian study owing to the predominance of the combination of anti-TB drugs in almost 50% of cases. This reflects that TB is still a major health issue in India and also the hepatotoxicity potential of current anti-TB drugs. In fact, anti-TB drugs have been the second most common cause of DILI in the Spanish hepatotoxicity registry,5Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar and isoniazid is also the second most common cause in the DILIN study,7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar although of much less magnitude than in India. In contrast to the West, where non-TB antimicrobials are the dominant etiology, this was relatively rare in the Indian cohort. Comparison between the results of the present study with those of prospective DILI studies undertaken in Spain, the US, and Iceland, in terms of demographics and the main etiologies of DILI, is shown in Table 1. CAMs were the second most common cause of liver injury as in previous studies from the US and Iceland.7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar,8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google ScholarTable 1The Most Common Implicated Agents Causing DILI in Four Prospective Studies on DILI.India (n = 1288)Mean age (years): 43Male (%): 51.4%Spain (n = 843)Age (years): 53Male (%): 51%USA (n = 899)Age (years): 49Male (%): 41%)Iceland (n = 96)Age (years): 55Male (%): 44%Antituberculosis drugs (46%)Amoxicillin-clavulanate (22%)Amoxicillin-clavulanate (10%)Amoxicillin-clavulanate (22%)Antiepileptics (8.1%)Antituberculosis (4.5%)Isoniazid (5.3%)Diclofenac (6.3%)Antibiotics (non-TB) (6.5%)Ibuprofen (3%)Nitrofurantoin (4.7%)Nitrofurantoin (4%)Antimetabolites (3.8%)Flutamide (2.6%)Sulfam-trimeth (3.4%)Azathioprine (4%)Antiretrovirals (3.5%)Atorvastatin (1.9%)Minocycline (3.1%)Infliximab (4%)NSAIDs (2.6%)Diclofenac (1.8%)Cefazolin (2.2%)Isotretinoin (3%)Hormones (2.5%)Ticlopidine (1.4%)Azithromycin (2%)Atorvastatin (2%)Statins (1.3%)Azathioprine (1.3%)Ciprofloxacin (1.8%)Doxycycline (2%)Others (11.3%)Fluvastatin (1.3%)Levofloxacin (1.4%)Imatinib (1%)Simvastatin (1.3%)Diclofenac (1.3%)Isoniazid (1%)CAM (13.9%)CAM (3.4%)CAM (16.1%)CAM (16%)DILI = drug-induced liver injury; Sulfam-trimeth = Sulfamethoxazole-trimethoprim; CAM = complementary and herbal supplements; TB = tuberculosis. Open table in a new tab DILI = drug-induced liver injury; Sulfam-trimeth = Sulfamethoxazole-trimethoprim; CAM = complementary and herbal supplements; TB = tuberculosis. Although CAMs are commonly used in India, the proportion of patients with CAM-induced liver injury was not higher than that in series from the West. A total of 14% patients had liver injury due to CAM in the Indian study, which was very similar to the 16% frequency in the US and Iceland.7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar,8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar As pointed out by the authors, there was a male predominance among patients with CAM-induced liver injury, in contrast with most previous studies from the West, showing more women having liver injury from CAMs. In the West, the indication of supplements found to have caused liver injury was frequently weight loss.21Navarro V. Khan I. Björnsson E. Seef L.B. Serrano J. Hoofnagle J.H. Liver injury from herbal and dietary supplements.Hepatology. 2017; 65: 363-373Crossref PubMed Scopus (162) Google Scholar,22Hoofnagle J.H. Bonkovsky H.L. Phillips E.J. et al.HLA-B∗35:01 and green tea induced liver injury.Hepatology. 2020 Sep 5; (Online ahead of print)https://doi.org/10.1002/hep.31538Crossref PubMed Scopus (8) Google Scholar Apparently, it was difficult to tease out the indication for CAMs in India, and in very few instances was the prescription of the CAM traced. Therefore, the information was lacking on the indication, and it was very difficult to detect and characterize the ingredients. However, it is unlikely that CAMs were used to induce weight loss in the present study as the mean body mass index was normal in these patients, although this might be associated with severe liver injury. Anabolic steroids are also relatively a common cause of liver injury among nonprescription drugs in the West,21Navarro V. Khan I. Björnsson E. Seef L.B. Serrano J. Hoofnagle J.H. Liver injury from herbal and dietary supplements.Hepatology. 2017; 65: 363-373Crossref PubMed Scopus (162) Google Scholar but not a single case due to anabolic steroids was reported in the article from India. One of the interesting observations in the Indian study was the relatively low age of patients with DILI, who only had a mean age of 42 years, which is lower than that in studies from the West. It is acknowledged by the authors that this is probably reflecting the young population of India, with a median age of only approximately 28 years. Although direct toxicity was not a focus of the study and paracetamol hepatotoxicity was excluded, only 10 cases were found, and the authors suggested this as a marker of very low frequency of paracetamol intoxications in India, in contrast with studies from the West, wherein paracetamol is the most common cause of acute liver failure.2Ostapowicz G. Fontana R.J. Schiodt F.V. 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 (2002/12/18): 947-954Crossref PubMed Scopus (1616) Google Scholar,3Wei G. Bergquist A. Broome U. et al.Acute liver failure in Sweden: etiology and outcome.J Intern Med. 2007; 262: 392-401Crossref Scopus (118) Google Scholar However, it is not entirely clear if results would have been the same if the study aims had been to investigate the etiology of acute liver failure in India. Hypersensitivity skin reactions were observed in 19.4% of the Indian patients with DILI. This is a much higher frequency than that in previous DILI studies. In the DILIN study, only 9 of 899 (1%) presented with severe cutaneous reactions, Steven–Johnson syndrome, or toxic epidermal necrolysis.9Chalasani N. Bonkovsky H.L. Fontana R. et al.Featuresand outcomes of 899 patients with drug-induced liver injury.DILIN Prospect Stud Gastroentrol. 2015; 48: 1340-1352Abstract Full Text Full Text PDF Scopus (403) Google Scholar However, hypersensitivity reactions are not always severe, so it is difficult to compare these two studies in that respect. The reason for the high frequency of skin reactions in almost 20% of the patients is unclear. It is conceivable that Indian doctors were more thorough in their physical examination than their colleagues in the studies from the West.5Andrade R.J. Lucena M.I. Fernández M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Spanish Group for the Study of Drug-Induced Liver Disease.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar, 6Björnsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (458) Google Scholar, 7Chalasani N. Fontana R.J. Bonkovsky H.L. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Drug Induced Liver Injury Network (DILIN).Gastroenterology. 2008; 135: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 8Bjornsson E.S. Bergmann O.M. Bjornsson H.K. et al.Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.Gastroenterology. 2013; 144: 1419-1425Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 9Chalasani N. Bonkovsky H.L. Fontana R. et al.Featuresand outcomes of 899 patients with drug-induced liver injury.DILIN Prospect Stud Gastroentrol. 2015; 48: 1340-1352Abstract Full Text Full Text PDF Scopus (403) Google Scholar However, another reason might be the higher frequency of DILI due to antiepileptics than in other DILI studies, and these medications are commonly associated with cutaneous reactions.23Björnsson E. Hepatotoxicity associated with antiepileptic drugs.Acta Neurol Scand. 2008; 118: 281-290Crossref PubMed Scopus (113) Google Scholar Indeed, skin rash was observed in 61% of those who suffered from DILI owing to antiepileptic drugs. As pointed out previously, markers of severe liver disease were predictors of mortality such as a high INR and creatinine as well as ascites and encephalopathy. The Model for End-Stage Liver Disease (MELD) was shown to be a relatively good predictor of outcomes, yielded a C-statistics of 0.811. This is in agreement with a Korean study, showing the MELD to be a useful predictor of outcomes in patients with DILI.24Jeong R. Yoon-Seon Lee Y.S. Sohn C. et al.Model for end-stage liver disease score as a predictor of short-term outcome in patients with drug-induced liver injury.Scand J Gastroenterol. 2015; 50: 439-446Crossref PubMed Scopus (20) Google Scholar In summary, a large and impressive DILI study has come from the second largest country in the world, which is predicted to be the largest country within a few years. The results of the study do increase the knowledge of DILI in general and represent an important contribution to the study of DILI. The author has none to declare.

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