Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

doi:10.1053/j.gastro.2005.05.006

Gastroenterology

Volume 129, Issue 2, August 2005, Pages 512-521

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https://doi.org/10.1053/j.gastro.2005.05.006 Get rights and content

Background & Aims: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. Methods: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. Results: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1–151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6–37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09–1.22; P < .0001). Conclusions: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.

Section snippets

Materials and Methods

The study population was all cases of toxic liver disease assembled in the Regional Registry of Hepatotoxicity in southern Spain since its foundation in April 1994. The registry is coordinated by 2 of the authors (R.J.A. and M.I.L.). The operational structure of the registry, data recording, and case ascertainment have been summarily reported elsewhere.⁶ In addition, several of the cases reported here have been published in peer-reviewed journals as case reports or case series.6, 7, 8

The

Demographic and Clinical Characteristics

From April 1994 to August 2004, 570 cases were submitted by 32 participant clinical units to the coordinating center belonging to 9 autonomous regions. One hundred nine were excluded: 36 because of unreliable chronologic criteria, 59 because an alternative cause of injury could be identified, including choledocholithiasis (13), viral hepatitis (11), underlying malignancy (10), autoimmune hepatitis (6), ischemic hepatitis (6), nonalcoholic steatohepatitis (4), alcoholic hepatitis (3), systemic

Discussion

Drug-induced idiosyncratic hepatotoxicity remains a challenge of modern hepatology. Hepatotoxicity is typically detected after marketing when several thousand patients are exposed to the drug, and regulatory authorities are often compelled to make decisions based on scanty, fragmentary, and incomplete epidemiologic data.¹⁵ In addition, whereas a major challenge is to be able to identify predisposed subjects before they receive the drug, genetic and environmental factors that appear to operate

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: Supported in part by a research grant from the Agencia Española del Medicamento.

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Clinical-liver, pancreas, and biliary tractDrug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

Section snippets

Materials and Methods

Demographic and Clinical Characteristics

Discussion

Hepatology

J Hepatol

Lancet

Hepatology

J Clin Epidemiol

Hepatology

An Esp Pediatr

J Hepatol

J Hepatol

J Hepatol

Gastroenterol Hepatol

Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993a regulatory perspective

Clin Pharmacol Ther

Epidemiology and individual susceptibility to adverse drug reactions affecting the liver

Semin Liver Dis

Accuracy of hepatic adverse drug reaction reporting in one English health region

BMJ

Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver. 2nd ed

Hepatic injury caused by acarbose

Ann Intern Med

Clinical-liver, pancreas, and biliary tract
Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period