Drug-Induced Liver Injury Caused by Metamizole: Identification of a Characteristic Injury Pattern

Abstract

Background and aims: Drug-induced liver injury (DILI) due to metamizole has gained increasing attention. Causality assessment remains a challenge, especially in patients with co-medications. We therefore aimed to further characterise metamizole DILI cases.

Methods: The data of patients with metamizole intake from our prospective study on acute liver injury with potential drug-related causes were analysed. Diagnosis and causality assessment were based on a thorough work-up and long-term follow-up.

Results: DILI was associated with metamizole in 61 of 324 DILI patients (prevalence 18.8%). A highly characteristic clinical pattern was observed in 43 of the 61 patients, characterised by marked elevation of transaminases peaking at the time of DILI recognition and a more pronounced increase of bilirubin within the first 3 days of clinical presentation. Patients fitting this picture had higher rates of jaundice, coagulopathy, and acute liver failure, however outcomes did not differ significantly when compared to non-metamizole DILI and autoimmune hepatitis (AIH) patients. Overall, fatal adverse outcomes defined by death or liver transplantation were observed in 13.1% of metamizole DILI patients. On multivariate analysis, only aspartate aminotransferase (AST) and INR were independently associated with a fatal adverse outcome. INR, in particular, performed better than Hy's law, bilirubin, transaminases, and the model for end-stage liver disease (MELD), with a c-statistic of 0.85 (95% CI: 0.70-1.0). At a cut-off of ≥ 2.1, sensitivity and specificity for a fatal adverse outcome were 75% and 96%, respectively.

Conclusions: Metamizole DILI can present with a characteristic pattern that can help clinicians to identify metamizole as the causative agent. Outcome, however, is not associated with this clinical picture and should rather be predicted by INR at onset.

Trial registration: ClinicalTrials.gov identifier: NCT02353455.

Keywords: drug adverse reactions; drug toxicity; hepatotoxicity; liver injury.

FIGURE 1

Evolution of liver parameters in patients with the characteristic metamizole DILI signature pattern versus non‐metamizole DILI. The graph demonstrates the mean values (with the 95% CI) for ALT, AST and TBIL of the patients with the characteristic metamizole DIIL signature pattern (n = 43; A) versus the patients with non‐metamizole DILI (n = 9; B). ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; DILI, drug‐induced liver injury; TBIL, total bilirubin.

FIGURE 2

ROC analysis for laboratory parameters at the time of clinical presentation and time‐dependent dynamic changes of liver parameters with regards diagnosis metamizole DILI with the characteristic signature pattern. Shown are the c‐statistics, sensitivity and specificity of (A) baseline parameters and scores at the time of clinical presentation, (B) the time‐dependent dynamic changes of AST, ALT and (C) the time‐dependent dynamic changes of TBIL regarding the diagnosis of metamizole DILI with the characteristic metamizole DILI signature pattern versus controls (as defined by non‐metamizole DILI and AIH). The cut‐offs were determined by ROC curve analysis and Youden's index. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; c‐statistics, concordance statistic; DILI, drug‐induced liver injury; INR, international normalised ratio; MELD, model for end‐stage liver disease; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver of the operator characteristic; TBIL, total bilirubin; ULN, upper limit of normal. * statistical significance (p < = 0.05).

FIGURE 3

Representative histological images of patients with metamizole DILI (H&E). The slides represent typical findings in metamizole DILI. (A, B) Hepatitis with predominant eosinophilic infiltration (arrowhead) and marked interface hepatitis (asterisk), single cell necrosis (arrow) and mild lipofuscinosis. (C) Eosinophilic hepatitis (arrowhead) with interface hepatitis, single as well as grouped cell necrosis and mild canalicular cholestasis. (D) Subacute confluent liver necrosis with lymphocytic infiltration (arrowhead) in a patient with acute liver failure, the necrosis is mostly localised in zone 1 and 2.

FIGURE 4

ROC analysis and predictive powers, sensitivity and specificity for laboratory parameters at the time of clinical presentation and for the time‐dependent dynamic changes of liver parameters regarding fatal adverse outcomes in metamizole DILI. Shown are the c‐statistics, sensitivity and specificity of (A) baseline parameters at the time of clinical presentation and scores, (B) the time‐dependent dynamic changes of AST, ALT and (C) the time‐dependent dynamic changes of TBIL regarding a fatal adverse outcome defined by death or liver transplantation. The cut‐offs were determined by ROC curve analysis and Youden's index. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug‐induced liver injury; INR, international normalised ratio; MELD, model for end‐stage liver disease; NPV, negative predictive value; PPV, positive predictive value; ROC, receiver of the operator characteristic; ROC, receiver operating characteristic; TBIL, total bilirubin. * statistical significance (p < = 0.05).