Login Register Cart 0
Generic placeholder image

Current Drug Safety

Editor-in-Chief

ISSN (Print): 1574-8863
ISSN (Online): 2212-3911

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Case Report

Unmasking of Metamizole-induced Liver Injury by Simult aneous Development of Characteristic Agranulocytosis

Author(s): Mathias Lutz*, Inga Grünewald, Frank Lenze, Hauke Heinzow, Hansjörg Ullerich, Iyad Kabar, Hartmut H. Schmidt and Phil-Robin Tepasse

Volume 18, Issue 3, 2023

Published on: 29 August, 2022

Page: [404 - 412] Pages: 9

DOI: 10.2174/1574886317666220606150721

Price: $65

Abstract

Background: Metamizole is one of the most used analgesic, antipyretic, and spasmolytic agents in many countries worldwide. While metamizole-induced agranulocytosis is an, albeit seldom, well-known adverse event, metamizole-associated drug-induced liver injury has been reported rarely in the literature and hence often remains unconsidered. Here, we present a unique case where metamizole-induced hepatotoxicity got unmasked by the simultaneous development of characteristic agranulocytosis.

Case Report: A 22-year-old woman without known conditions presented with a new onset of fever, jaundice, and maculopapular rash and explicitly denied intake of any new substances. Laboratory tests showed liver injury, granulopenia, and positive anti-nuclear and anti-mitochondrial (AMA-M2) antibodies. Liver biopsy revealed a histological pattern characteristic of drug-induced liver injury and bone marrow biopsy, the classical picture of metamizole-induced agranulocytosis. Indeed the in-depth interview of the patient unveiled metamizole consumption over the last two months. Therefore, we could diagnose metamizole-induced hepato- and myelotoxicity. Accordingly, steroid therapy led to normalization of liver parameters and stimulation with granulocyte colony- stimulating factor to leukocyte recovery.

Conclusion: This case report is intended to increase the awareness of metamizole-associated druginduced liver injury which should always be kept in mind due to its occasionally life-threatening course. Diagnosis can be difficult particularly if anamnesis and written records are without hints for prior metamizole intake.

Keywords: Metamizole, dipyrone, liver, drug-induced liver injury, drug-induced hepatitis, agranulocytosis.

« Previous Next »
Graphical Abstract

[1]
Kötter T, da Costa BR, Fässler M, et al. Metamizole-associated adverse events: A systematic review and meta-analysis. PLoS One 2015; 10(4): e0122918.
[http://dx.doi.org/10.1371/journal.pone.0122918] [PMID: 25875821]
[2]
Lutz M. Metamizole (Dipyrone) and the liver: A review of the literature. J Clin Pharmacol 2019; 59(11): 1433-42.
[http://dx.doi.org/10.1002/jcph.1512] [PMID: 31433499]
[3]
Cismaru AL, Rudin D, Ibañez L, et al. Genome-wide association study of metamizole-induced agranulocytosis in European populations. Genes 2020; 11(11): 1275.
[http://dx.doi.org/10.3390/genes11111275] [PMID: 33138277]
[4]
Blaser L, Hassna H, Hofmann S, et al. Leucopenia associated with metamizole: A case-control study. Swiss Med Wkly 2017; 147: w14438.
[http://dx.doi.org/10.4414/smw.2017.14438]
[5]
Preissner S, Siramshetty VB, Dunkel M, Steinborn P, Luft FC, Preissner R. Pain-prescription differences - An analysis of 500,000 discharge summaries. Curr Drug Res Rev 2019; 11(1): 58-66.
[http://dx.doi.org/10.2174/1874473711666180911091846] [PMID: 30207223]
[6]
Curtis BR. Drug-induced immune neutropenia/agranulocytosis. Immunohematology 2014; 30(2): 95-101.
[http://dx.doi.org/10.21307/immunohematology-2019-103] [PMID: 25247619]
[7]
Klose S, Pflock R, König IR, Linder R, Schwaninger M. Metamizole and the risk of drug-induced agranulocytosis and neutropenia in statutory health insurance data. Naunyn Schmiedebergs Arch Pharmacol 2020; 393(4): 681-90.
[http://dx.doi.org/10.1007/s00210-019-01774-4] [PMID: 31811328]
[8]
Sabaté M, Ibáñez L, Pérez E, et al. Risk of acute liver injury associated with the use of drugs: A multicentre population survey. Aliment Pharmacol Ther 2007; 25(12): 1401-9.
[http://dx.doi.org/10.1111/j.1365-2036.2007.03338.x] [PMID: 17539979]
[9]
Andrade S, Bartels DB, Lange R, Sandford L, Gurwitz J. Safety of metamizole: A systematic review of the literature. J Clin Pharm Ther 2016; 41(5): 459-77.
[http://dx.doi.org/10.1111/jcpt.12422] [PMID: 27422768]
[10]
Krisai P, Rudin D, Grünig D, et al. Acute liver failure in a patient treated with metamizole. Front Pharmacol 2019; 10: 996.
[http://dx.doi.org/10.3389/fphar.2019.00996] [PMID: 31572180]
[11]
Sebode M, Reike-Kunze M, Weidemann S, et al. Metamizole: An underrated agent causing severe idiosyncratic drug-induced liver injury. Br J Clin Pharmacol 2020; 86(7): 1406-15.
[http://dx.doi.org/10.1111/bcp.14254] [PMID: 32080881]
[12]
Weber S, Benesic A, Neumann J, Gerbes AL. Liver injury associated with metamizole exposure: Features of an underestimated adverse event. Drug Saf 2021; 44(6): 669-80.
[http://dx.doi.org/10.1007/s40264-021-01049-z] [PMID: 33638811]
[13]
Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR. ACG clinical guideline: Diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2021; 116(5): 878-98.
[http://dx.doi.org/10.14309/ajg.0000000000001259] [PMID: 33929376]
[14]
Danan 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(11): 1323-30.
[http://dx.doi.org/10.1016/0895-4356(93)90101-6] [PMID: 8229110]
[15]
Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge. J Clin Epidemiol 1993; 46(11): 1331-6.
[http://dx.doi.org/10.1016/0895-4356(93)90102-7] [PMID: 8229111]
[16]
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 2007; 156(3): 609-11.
[http://dx.doi.org/10.1111/j.1365-2133.2006.07704.x] [PMID: 17300272]
[17]
Shiohara T, Iijima M, Ikezawa Z, Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol 2007; 156(5): 1083-4.
[http://dx.doi.org/10.1111/j.1365-2133.2007.07807.x] [PMID: 17381452]
[18]
Herdeg C, Hilt F, Büchtemann A, Bianchi L, Klein R. Allergic cholestatic hepatitis and exanthema induced by metamizole: Verification by lymphocyte transformation test. Liver 2002; 22(6): 507-13.
[http://dx.doi.org/10.1034/j.1600-0676.2002.01718.x] [PMID: 12445177]
[19]
Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: Summary of a clinical research workshop. Hepatology 2010; 52(2): 730-42.
[http://dx.doi.org/10.1002/hep.23696] [PMID: 20564754]
[20]
Benjamin JE, Biederman JB. Agranulocytic leukopenia induced by a drug related to aminopyrine. J Am Med Assoc 1936; 107(7): 493-4.
[http://dx.doi.org/10.1001/jama.1936.92770330003007b]
[21]
Risks of agranulocytosis and aplastic anemia. A first report of their relation to drug use with special reference to analgesics. The international agranulocytosis and aplastic anemia study. JAMA 1986; 256(13): 1749-57.
[http://dx.doi.org/10.1001/jama.1986.03380130077032] [PMID: 3747087]
[22]
Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol 2002; 58(4): 265-74.
[http://dx.doi.org/10.1007/s00228-002-0465-2] [PMID: 12136373]
[23]
Shah RR. Metamizole (dipyrone)-induced agranulocytosis: Does the risk vary according to ethnicity? J Clin Pharm Ther 2019; 44(1): 129-33.
[http://dx.doi.org/10.1111/jcpt.12768] [PMID: 30311250]
[24]
Hoffmann F, Bantel C, Jobski K. Agranulocytosis attributed to metamizole: An analysis of spontaneous reports in EudraVigilance 1985-2017. Basic Clin Pharmacol Toxicol 2020; 126(2): 116-25.
[http://dx.doi.org/10.1111/bcpt.13310] [PMID: 31449718]
[25]
Björnsson ES. Liver injury associated with the analgetic drug metamizole. Br J Clin Pharmacol 2020; 86(7): 1248-50.
[http://dx.doi.org/10.1111/bcp.14294] [PMID: 32400058]
[26]
Reike-Kunze M, Zenouzi R, Hartel J, et al. Drug-induced liver injury at a tertiary care centre in Germany: Model for end-stage liver disease is the best predictor of outcome. Liver Int 2021; 41(10): 2383-95.
[http://dx.doi.org/10.1111/liv.14985] [PMID: 34152686]
[27]
Sebode M, Lohse AW, Schramm C. Metamizole has been overlooked as a trigger for acute liver injury and acute liver failure. Dtsch Arztebl Int 2020; 117(37): 610.
[http://dx.doi.org/10.3238/arztebl.2020.0610a] [PMID: 33263530]
[28]
Hedenmalm K, Pacurariu A, Slattery J, Kurz X, Candore G, Flynn R. Is there an increased risk of hepatotoxicity with metamizole? A comparative cohort study in incident users. Drug Saf 2021; 44(9): 973-85.
[http://dx.doi.org/10.1007/s40264-021-01087-7] [PMID: 34273099]
[29]
Björnsson ES, Hoofnagle JH. Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports. Hepatology 2016; 63(2): 590-603.
[http://dx.doi.org/10.1002/hep.28323] [PMID: 26517184]
[30]
Weber S, Benesic A, Gerbes AL. Further evidence for the hepatotoxic potential of metamizole. Br J Clin Pharmacol 2021; 87(3): 1587-8.
[http://dx.doi.org/10.1111/bcp.14473] [PMID: 32696537]
[31]
Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011; 56(4): 958-76.
[http://dx.doi.org/10.1007/s10620-011-1611-4] [PMID: 21327704]
[32]
Andrès E, Villalba NL, Zulfiqar AA, Serraj K, Mourot-Cottet R, Gottenberg AJ. State of art of idiosyncratic drug-induced neutropenia or agranulocytosis, with a focus on biotherapies. J Clin Med 2019; 8(9): 1351.
[http://dx.doi.org/10.3390/jcm8091351] [PMID: 31480527]
[33]
Germani G, Battistella S, Ulinici D, et al. Drug induced liver injury: From pathogenesis to liver transplantation. Minerva Gastroenterol 2021; 67(1): 50-64.
[http://dx.doi.org/10.23736/S2724-5985.20.02795-6] [PMID: 33222432]

Rights & Permissions Print Cite
Article Metrics
4
© 2024 Bentham Science Publishers | Privacy Policy