Liver injury associated with the analgetic drug metamizole

Idiosyncratic drug-induced liver injury (DILI) is a rare but clinically important liver disorder. DILI is often a differential diagnosis in patients with acute liver injury without obvious etiology.1 The diagnosis is challenging and is one of the most challenging diagnosis of all liver disorders. It is a common myth that “almost all drugs can lead to liver injury.” Some drugs been on the market for decades have never been associated with liver injury. A recent analysis of drugs described in Liver Tox (http://livertox.nih.gov) demonstrated that only 53% of drugs marketed in the United States had convincing published case report.2 Among the most commonly implicated drugs in the DILIN study were drugs that had been on the market for many years or even decades.3 It is well known that for most drugs, DILI is detected in the post marketing phase. As DILI is generally a very rare adverse effect, it is not recognized during clinical trials. The most common drug leading to DILI in most studies has been amoxicillin-clavulanate.1, 3, 4 Data on numbers needed to harm in terms of idiosyncratic DILI are limited. Amoxicillin-clavulanate was found to occur in 1 out of 2350 treated, but higher risk was associated with infliximab (1/148 treated) and azathioprine in 1/133 patients treated with the drug in a prospective population-based study.4 In the current issue of the journal, Sebode et al. reported a total of 23 cases of liver injury due to metamizole.5 According to the authors, 23/154 (15%) cases were considered to be metamizole-induced DILI, which was the second most common cause of DILI, after phenprocoumon in this large university medical center in Hamburg, Germany.5 Hepatic adverse reactions are not in the European Medical Agency (EMA) drug label of metamizole. It has been documented that metamizole can be purchased through the internet without prescription.6 A few case reports on metamizole suspected liver injury were reported from 1988 to 2019.7-10 A case–control study for the quantification of DILI, from several clinics in Berlin, identified 13 cases considered to be metamizole-induced DILI, with an odds ratio of 5.2 for liver injury after treatment with metamizole.9 Last year, acute liver failure associated with metamizole was reported leading to acute liver transplantation.10 So far with the cases reported in the current issue of BJCP, approximately 40 cases have been published.5, 7-10 Thus, according to categorization of drugs leading to DILI in LiverTox (http://livertox.nih.gov) and recently published,2 metamizole would qualify in Category B, which after Category A (>50 cases reported) is the second category of drugs associated with DILI, with <50 but >12 cases reported.2 DILI lacks a gold standard for diagnosis, but there is no doubt that drugs in Category A are hepatotoxic and drugs in Category B have also most likely a hepatotoxic potential. In Category A, 88% have a published case with a positive rechallenge and 39% in Category B.2 A positive rechallenge is considered to be a strong indicator of hepatotoxicity and means a new onset liver injury with the same drug in the same patient who has recovered from the injury. In the current report, 4 cases with positive rechallenge are described. The hepatotoxicity of metamizole has in my opinion been convincingly demonstrated with the current paper and other reports.5, 7-10 How is it possible that this appears so long after marketing of this drug, that has been on the market for approximately 100 years? Before attempting to answer that difficult question, what is the history of this drug, type, and metabolism? Metamizole (or dipyrone) is a nonaddictive analgesic with analgesic, antipyretic, and spasmolytic effects. According to a recent report from EMA (https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-chmp-assessment-report_en.pdf), it is indicated for severe acute and chronic pain and also for fever, which is not responding to other treatments. According to German drug label, the indication for metamizole is for severe pain after trauma or surgery and cancer pain, but only pain nonresponsive to other analgetics. It is authorized in several member states in European Union (EU). It is mainly prescribed for its analgetic effects. Metamizole (dipyrone) was patented 1922 in Germany. It was removed from the market in Canada (1963) and the United States (1977) and from the United Kingdom and the Scandinavian market later due to side effects, mainly agranulocytosis.5 Apparently apart from Germany, the drug is still used in countries such as Spain, Poland, Russia, and some countries in Latin America.5 Data on its use in most countries are difficult to obtain, but for some reason, it seems very popular in Germany. The used defined daily dose (DDD) of metamizole increased in Germany from 32 million DDD in the year 2000 to 225 million DDD in 2018.5 It is not entirely clear how much it has been used in different countries, but according to a recent report, well over 8 billion gram metamizole (as a single ingredient) have been sold in the EU: Austria, Belgium, Croatia, Czech republic, Germany, Hungary, Italy, Luxembourg, Netherlands, Norway, Portugal, Romania, Slovakia, and Spain (https://www.ema.europa.eu/en/documents/referral/metamizole-article-31-referral-chmp-assessment-report_en.pdf). Despite this, the vast majority of the DILI cases reported are from Germany.5, 7-10 The mechanism of action of metamizole is not completely understood. Some studies suggest that metamizole and its main metabolite 4-methyl-amino-antipyrine (MAA) may have a combined central and peripheral mechanism of action. An inhibition of prostaglandin synthesis has been recognized, based on interaction with different cyclooxygenases, modifying the arachidonic acid metabolism. Some data suggest central action. However, the mode of action remains incompletely understood. The recommended oral single dose in adults is 500 to 1000 mg up to 4 times a day at intervals of 6–8 h leading to a maximum daily dose of 4000 mg. Metamizole is a prodrug, converted in the stomach by gastric acid to 4-MAA, which is metabolized by a saturable liver oxidation pathway to 4-formyl-amino-antipyrine and by liver demethylation to the active 4-amino-antipyrine (4-AA). Metamizole has extensive hepatic metabolism. The prodrug has a low lipophilicity, but the metabolites such as 4-MMA and 4-AA have higher lipophilicity and have been detected in cerebrospinal fluid due to their lipid solubility. The cases reported by Sebode et al.5 had a peculiar phenotype with a clear hepatocellular pattern with a median ALT of 779 U/L, whereas median ALP was only 131 U/L and 61% had a hepatocellular pattern. Presence of ANA was observed in approximately 50% of cases. A total of 17/23 (74%) had a liver biopsy, which revealed moderate to severe inflammatory activity with severe centrilobular necrosis in more than 30% of cases. Overall, 9 (39%) patients presented with jaundice, and two (8.7%) out of the 23 patients developed acute liver failure and required a liver transplantation. Thus, majority of patients had hepatocellular pattern with “hepatitis-like” liver histology, often with ANA positivity and were therefore treated with corticosteroids. The prognosis was in line with drug-induced jaundice in other DILI cohorts.1 The signature pattern of liver injury associated with Metamizole was similar, with hepatocellular type in the majority of cases etc. Furthermore, 4 cases had a positive rechallenge after inadvertent rechallenge, which further strengthens the relationship. The drug seems also have prerequisites for a DILI potential: it is given in a relatively high daily dose, it has extensive hepatic metabolism, and its metabolites have relatively high lipophilicity. All three features, high daily dose, extensive hepatic metabolism, and high lipophilicity, are drug-related risk factors for DILI.1 Coming back to the question raised above. How is it possible that this appears so long after marketing of this drug, that has been on the market for approximately 100 years? The drug has in many countries been forgotten as it is off the market. However, it is still used in many other countries, and its popularity seems to have increased. Particularly in Germany where the current report comes from the use has increased quite remarkably. As mentioned above, the use of metamizole increased in Germany from 32 million DDD in the year 2000 to 225 million DDD in 2018.5 The liver injury due to metamizole might be very rare and with increased use might lead to cases of hepatotoxicity. However, this is speculative. The underreporting of adverse effects of drugs is also well recognized and has been well documented in many studies. Last but not least, the impact of the current paper by Sebode et al. should lead to correct labeling of the drug with adding liver injury as a potential adverse effect. Moreover, it should guide physicians in clinical practice of the risk of DILI with the use of this analgetic drug and immediately discontinue the drug in patients with unclear liver test abnormalities to reduce the risk of further damage. There are no competing interests to declare.

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