Metamizole: an underrated agent causing drug-induced liver injury (DILI) in Germany

Background:

Drug-induced liver injury (DILI) is a heterogenous entity leading to acute liver damage. Large DILI registries like in the United States have identified the most frequent agents causing DILI, among those mainly antibiotics such as amoxicillin-clavulanate and analgetics such as diclofenac. The RUCAM score has been established to assess causality for DILI. We have analysed the most frequent drugs causing DILI at our tertiary centre.

Methods:

Consecutive cases of DILI presented to the I. Department of Medicine at the University Medical Centre Hamburg-Eppendorf were analysed retrospectively. Causality was assessed by the RUCAM score. Cases of acute hepatitis other than DILI were excluded, especially acute hepatitis E viral infection. Autoimmune hepatitis was ruled out by clinical follow-up of DILI cases to assure that liver enzymes did not rise again after the drug had been stopped.

Results:

154 DILI cases with acute icteric hepatitis were admitted to our centre from 2008 to 2017. After phenprocoumon, metamizole was identified as the second most frequent drug causing DILI (14,9% of all DILI cases). Median RUCAM score for metamizole cases was 8 (“probable”). In 14 cases, metamizole was the sole drug causing DILI, in the other 9 cases concomitant drugs like statins or NSAIDs were also probable causative agents. In 4 of the 21 cases, patients were accidently re-exposed to metamizole resulting in another episode of acute icteric hepatitis, stressing the lack of awareness of metamizole being a DILI-causing drug. The biochemical pattern on admission of all metamizole cases was hepatitic with median levels of ALT (823 U/l) exceeding median ALP levels (131 U/l). Median MELD score on admission was 12. 61% of metamizole-induced DILI cases showed the presence of autoantibodies such as ANA and/or SMA. 15 of 23 patients with metamizole-induced DILI received liver biopsy. The histological pattern of an acute hepatitis with infiltrating immune cells was present in all metamizole cases and 8 of 15 patients showed centrilobular liver parenchyma damage. 68% of cases were treated with steroids. 21 of the 23 metamizole DILI cases did not progress to acute liver failure and liver damage resolved. Two patients developed acute liver failure, received liver transplantation and are still alive.

Conclusions:

Elevation of liver enzymes, acute icteric hepatitis or acute liver failure are not labelled on metamizole as side effects. Our study reveals that metamizole is a frequent and underrated agent causing DILI and can even result in acute liver failure.