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Year : 2021  |  Volume : 18  |  Issue : 1  |  Page : 34-36

A case of acute liver injury induced by methimazole

1 Department of Endocrinology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
2 Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
3 Department of Gastroenterology, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Submission13-Dec-2020
Date of Acceptance14-Dec-2020
Date of Web Publication19-Apr-2021

Correspondence Address:
Dr. Arun S Menon
Department of Endocrinology, Amrita Institute of Medical sciences, Kochi, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/trp.trp_73_20

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Antithyroid drugs, methimazole, and propylthiouracil have been reported to cause hepatotoxicity. We report the case of a patient with methimazole induced liver injury who presented within a few weeks of commencement of the drug. She presented with a cholestatic picture and responded well to discontinuation of the drug and administration of steroids.

Keywords: Cholestatic jaundice, hyperthyroidism, methimazole

How to cite this article:
Niveditha K, Menon AS, Kumar H, Eapen M, Gopalakrishna R. A case of acute liver injury induced by methimazole. Thyroid Res Pract 2021;18:34-6

How to cite this URL:
Niveditha K, Menon AS, Kumar H, Eapen M, Gopalakrishna R. A case of acute liver injury induced by methimazole. Thyroid Res Pract [serial online] 2021 [cited 2022 Dec 6];18:34-6. Available from: https://www.thetrp.net/text.asp?2021/18/1/34/314051

  Introduction Top
Antithyroid drugs, methimazole, and propylthiouracil have been reported to cause hepatotoxicity. Methimazole rarely causes cholestatic jaundice, which can be a management challenge when it occurs. We report a case of methimazole induced cholestatic jaundice which was successfully treated.
  Case Report Top
A 60-year-old female was referred with complaints of yellowish discoloration of sclera, dark urine, and pruritus of 2 weeks duration. She had been diagnosed to have hyperthyroidism 1 month prior and commenced on methimazole 20 mg twice daily. She had loss of appetite but no abdominal pain, distension, fever, bleeding diathesis, altered sensorium, or fever. Her body weight was 54 kg and height 164 cm was noted. She had a heart rate of 110 beats/min and blood pressure of 140/90 mmHg. Physical examination revealed scleral icterus and multiple pruritic scratch marks over the body. There was no palpable goiter. Her clinical activity score was 2/7. Her laboratory investigation showed that free thyroxine level was 1.36 ng/dl (1–1.6 ng/dl), thyroid-stimulating hormone was 0.02 IU/ml (0.25–4.00 IU/ml), anti-TPO was 387 (0–34 U/ml), and T3 was 4.18 (2.3–4.2 pg/ml). Her total bilirubin was elevated at (12.21 mg/dl), direct bilirubin (8.0 mg/dl), serum aspartate aminotransferase (45 IU/l), serum alanine aminotransferase (97 IU/L), serum alkaline phosphatase of 258 U/L, and GGT was 62 U/L. Serum albumin was 4.1 g/dl, and coagulation profile was normal. Viral hepatitis was excluded by serological analyses. To rule out autoimmune liver diseases, Anti mitochondrial antibody (AMA) and ANA were sent. AMA was negative but ANA was positive (speckled pattern, 2+) cANCA and pANCA were negative. Serum iron, ceruloplasmin, Alpha fetoprotein (AFP), and Carcinoembryonic antigen (CEA) were normal. Abdominal ultrasound showed normal liver span, no biliary obstruction, and no focal hepatic lesion.

She was suspected to have cholestatic liver disease due to methimazole. The drug was withheld and the patient was started on oral lithium 300 mg BD and propranalol 20 mg BD. Magnetic resonance cholangiopancreatography (MRCP) showed no Intrahepatic biliary radicle dilatation (IHBRD) and Common Bile duct (CBD) dilatation, no enhancing lesion in CBD or periampullary region. As the patient had ANA positivity, to rule out other autoimmune diseases involving liver biopsy was performed that showed canalicular cholestasis with focal lobular and portal inflammation with eosinophils, possibly drug-induced liver injury [Figure 1]. Dexamethasone 1 mg TID was started for the management of methimazole-induced hepatic injury. As the free T4 levels started to rise in spite of lithium treatment, the patient underwent low dose radioiodine ablation with 7.9 Mci dose of oral I131 sodium iodide solution with steroid cover. The liver function tests all normalized over the next 6 weeks. She developed hypothyroidism 6 months after administering radioiodine and currently is on thyroxine replacement.
Figure 1: (a and b) (X400) – Shows portal inflammation with a component of eosinophils and lobular changes with canalicular cholestasis and mixed inflammation respectively

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  Discussion Top
Antithyroid drugs are thioamide derivatives that are in use for more than 60 years for managing hyperthyroid patients. Methimazole and propylthiouracil (PTU) are two frequently used antithyroid agents to treat hyperthyroidism. Despite being effective agents in controlling hyperthyroidism, rarely their administration is associated with hepatotoxicity.[1] Methimazole-induced hepatotoxicity usually develops in the first few weeks of drug consumption with an estimated incidence of 0.1%–0.2%,[2] compared to PTU where the toxicity develops in the first 3 months. Methimazole-induced hepatotoxicity is typically a cholestatic process. There are numerous factors that can contribute to differences among individuals in their sensitivity to xenobiotics.[3] Methimazole metabolism through CYP450 enzymes gives N-methylthiourea and glyoxal as two major metabolites. N-methylthiourea is further oxidized with flavin-containing monooxygenase (FMO) enzyme to give sulfinic and sulfenic acid species. N-methylthiourea is proposed to be the main methimazole reactive metabolite responsible for the hepatotoxicity induced by this drug.[4] Glyoxal is a reactive compound capable of interacting with different intracellular targets, such as proteins and sulfenic acids are high electrophilic species that form irreversible adduct with cellular nucleophilic sites[5] and may have a role in methimazole-induced hepatotoxicity. Polymorphism in drug-metabolizing enzymes also has a role in the idiosyncratic nature of the hepatic injury. The critical role of cellular defense mechanisms such as glutathione (GSH) in preventing antithyroid drugs-induced hepatotoxicity is also important,[6],[7] but the liver GSH content might be variable in different situations. Liver GSH reservoirs are lower in malnourished patients and/or in such as alcoholism,[8] so it seems that the risk of methimazole hepatotoxicity might be highest in these situations. Hence, particular attention should be given to the possibility that unexpected toxic reactions may be encountered under conditions of tissue GSH depletion. Physicians might advise their patient to avoiding alcohol consumption during anti-thyroid therapy. Next is the cytokines which are thought to play a role in immune-mediated liver injury caused by methimazole.

Another mechanism is that the activity of different enzymes which are involved in the antioxidant defense mechanism of the liver are changed in hyperthyroidism.[9] Studies have showed that glutathione reductase (GR) activity was lower in hyperthyroid patients, and they have impaired antioxidant defense mechanism.[10],[11],[12],[13] The hypothesis that GD itself has a role in antithyroid drugs-induced hepatic injury needs more controlled and in-depth investigations to be clarified. Patients should be aware of symptoms which might indicate anti-thyroid drugs-induced hepatic injury. Indeed, all anti-thyroid taking patients should be trained to report symptoms such as abdominal discomfort and pain, especially in the upper right quadrant and also other signs such as urine discoloration, which are connected to serious adverse reactions such as hepatotoxicity.

Intravascular glutathione was founded to be an effective treatment in the case of methimazole-induced hepatotoxicity and lowered transaminase levels in one patient.[10] In another study by Becker et al., it has been reported that corticosteroids might alleviate methimazole-induced hepatitis.[11] Prednisolone administration also has been shown to rapidly help recovery of patients from jaundice induced by anti-thyroid medications.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initial will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Vitug AC, Goldman JM. Hepatotoxicity from antithyroid drugs. Horm Res 1985;21:229-34.  Back to cited text no. 1
Woeber KA. Methimazole-induced hepatotoxicity. Endocr Pract 2002;8:222-4.  Back to cited text no. 2
Poulsen LL, Hyslop RM, Ziegler DM. S-oxidation of thioureylenes catalyzed by a microsomal flavoprotein mixed-function oxidase. Biochem Pharmacol 1974;23:3431-40.  Back to cited text no. 3
Mizutani T, Yoshida K, Murakami M, Shirai M, Kawazoe S. Evidence for the involvement of N-methylthiourea, a ring cleavage metabolite, in the hepatotoxicity of methimazole in glutathione-depleted mice: Structure-toxicity and metabolic studies. Chem Res Toxicol 2000;13:170-6.  Back to cited text no. 4
Mansuy D, Dansette PM. Sulfenic acids as reactive intermediates in xenobiotic metabolism. Arch Biochem Biophys 2011;507:174-85.  Back to cited text no. 5
Mizutani T, Murakami M, Shirai M, Tanaka M, Nakanishi K. Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione. J Appl Toxicol 1999;19:193-8.  Back to cited text no. 6
Heidari R, Babaei H, Roshangar L, Eghbal MA. Effects of enzyme induction and/or glutathione depletion on methimazole-induced hepatotoxicity in mice and the protective role of N-acetylcysteine. Adv Pharm Bull 2014;4:21-8.  Back to cited text no. 7
Shaw S, Rubin KP, Lieber CS. Depressed hepatic glutathione and increased diene conjugates in alcoholic liver disease. Evidence of lipid peroxidation. Dig Dis Sci 1983;28:585-9.  Back to cited text no. 8
Seven A, Seymen O, Hatemi S, Hatemi H, Yiğit G, Candan G. Antioxidant status in experimental hyperthyrodism: Effect of vitamin E supplementation. Clin Chim Acta 1996;256:65-74.  Back to cited text no. 9
Komosinska-Vassev K, Olczyk K, Kucharz EJ, Marcisz C, Winsz-Szczotka K, Kotulska A, et al. Free radical activity and antioxidant defense mechanisms in patients with hyperthyroidism due to graves' disease during therapy. Clin Chim Acta 2000;300:107-17.  Back to cited text no. 10
Venditti P, Balestrieri M, Di Meo S, De Leo T. Effect of thyroid state on lipid peroxidation, antioxidant defences, and susceptibility to oxidative stress in rat tissues. J Endocrinol 1997;155:151-7.  Back to cited text no. 11
Yang J, Zhong J, Zhou LZ, Hong T, Xiao XH, Wen GB, et al. Sudden onset agranulocytosis and hepatotoxicity after taking methimazole. Intern Med 2012;51:2189-92.  Back to cited text no. 12
Becker CE, Gorden P, Robbins J. Hepatitis from methimazole during adrenal steroid therapy for malignant exophthalmos. JAMA 1968;206:1787-9.   Back to cited text no. 13


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