International Journal of Gerontology | December 2009 | Vol 3 | No 4248

■CASE REPORT

© 2009 Elsevier.

Introduction

Abnormal liver function is usually found in thyrotoxi-cosis. Hyperthyroidism may cause an elevation of serumhepatic enzymes and bilirubin levels1. Hepatotoxicityis also one major side effect of antithyroid agents, includ-ing carbimazole, methimazole and propylthiouracil.Cholestasis is an adverse effect of methimazole andcarbimazole2. We report an elderly male patient withthyrotoxicosis who developed cholestasis followingtreatment with methimazole.

Case Report

A 69-year-old male, a farmer, was admitted to ourinstitution because of fever and chills lasting for 1 day.He had a history of thyrotoxicosis and received subtotalthyroidectomy about 30 years previously. No recurrenceof thyrotoxicosis was noted after the management. In6 months, his body weight decreased from 58kg to 39kg.

Poor appetite, nausea and weakness were also present.He also had dyspnea on exertion and hand tremor.Poor sleep, loose stool and heat intolerance were alsofound. No other symptoms were noted. He had nothad any recent change in his medication, and he de-nied chronic viral hepatitis, alcohol consumption, bloodtransfusion, recent travel or animal contact. He hadno family history of thyroid or liver disease.

He visited our outpatient department because ofshortness of breath, malaise, and body weight loss. Hehad a free thyroxine of 9.07 ng/dL (reference range,0.80–2.00 ng/dL) and thyroid-stimulating hormone of0.05 μIU/mL (reference range, 0.25–4.00 μIU/mL). Mildelevation of serum alanine aminotransferase (ALT) at42 IU/L (reference range, 15–41 IU/L) and serum alkalinephosphatases at 135 IU/L (reference range, 38–126 IU/L)was found, but a normal concentration of serum aspar-tate aminotransferase (AST) at 40 IU/L (reference range,14–40 IU/L) was noted. Abdominal ultrasound revealedliver calcification and a gallbladder polyp.

He was thin and chronically ill-looking. His bodyheight of 163 cm and body weight of 39 kg were noted.Heart rate was 87 beats/min. Blood pressure was 124/87 mmHg. There was no exophthalmos. The thyroidwas palpable. Physical examination did not reveal anyicteric sclera, ascites, hepatomegaly, splenomegaly orother signs related to chronic liver disease. No otherpositive signs were found by physical examination.

CHOLESTASIS AND ACUTE CHOLECYSTITIS IN

HYPERTHYROIDISM TREATED WITH METHIMAZOLE

Wei-Che Chen1*, Zheng-Xin Zhu2,3, Chao-Hung Wang1, Ming-Nan Chien1,3

1Division of Endocrinology and Metabolism, Department of Internal Medicine, and 2Division ofGastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, and

3Mackay Medicine, Nursing and Management College, Taipei, Taiwan.

SUMMARY

Hepatic dysfunction and jaundice are usually present in patients with hyperthyroidism. It may be the clinicalmanifestation of the disease or the adverse effect of antithyroid therapy. We report a 69-year-old male withhyperthyroidism who developed cholestasis and acute cholecystitis after a 4-day course of methimazole. Afterwithdrawal of methimazole, his cholestasis subsided. [International Journal of Gerontology 2009; 3(4): 248–250]

Key Words: acute cholecystitis, cholestasis, hyperthyroidism, methimazole

*Correspondence to: Dr Wei-Che Chen, Division ofEndocrinology and Metabolism, Department ofInternal Medicine, Mackay Memorial Hospital, 92,Section 2, Chung-Shan North Road, Taipei, Taiwan.E-mail: cerebrum22@gmail.comAccepted: March 11, 2009

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■ ■Hyperthyroidism Treated With Methimazole

Thyrotoxicosis due to Graves disease was diagnosed.During the outpatient department visit, methimazole30 mg daily in divided doses was prescribed as well asβ-adrenergic blockade with propranolol 10 mg threetimes a day.

Four days later, he presented at our emergencydepartment with fever and fatigue. He exhibited abody temperature of 39.2°C, a pulse rate of 87/minand a respiratory rate of 20/min. The blood pressurewas 132/63 mmHg. Icteric sclera accompanied by acuteill demeanor was found. Breathing sounds were clear.No tenderness, Murphy’s sign, knocking pain or otherrelated signs were found. Laboratory data revealedleukocytosis with leukocytes at 20,300/μL and left shiftin differential count. Elevated serum AST (134 IU/L)and ALT (124 IU/L) and total bilirubin (5.5 mg/dL) werefound. No pyuria was present in the urinalysis. Thechest X-ray showed emphysema changes but no con-solidation or filtration as in pneumonia. Abdominalultrasound found contracted gallbladder with gallblad-der wall thickening without dilatation of the commonbile duct. He was hospitalized with the suspicion of acutecholecystitis. Thyroid ultrasound revealed multinodu-lar goiter and heterogeneous parenchyma, suggestiveof autoimmune thyroid disorder.

After admission, empiric antibiotic therapy withflomoxef (3 g daily) in divided doses was started.Methimazole (20 mg daily) and propranolol (30 mgdaily) were maintained because of his thyrotoxicosis.Blood culture isolated Escherichia coli with sensitivityto cephalosporin. Duodenal ulcer and esophagealulcer with anemia were also found after admission.

With the initiation of antibiotic therapy, his feverand leukocytosis improved. No black stool or tarrystool was kept. At that time, the total bilirubin was4.1mg/dL, with an AST of 51 IU/L and an ALT of 61 IU/L.Antinuclear factor and anti-double-stranded DNA wereinvestigated for the suspicion of autoimmune hepatitis,but no positive finding was found.

Cholestasis and acute cholecystitis caused by methi-mazole were suspected. So methimazole was held andLugol’s solution administered. Then, the patient under-went subtotal thyroidectomy. Three days after the sur-gery, the serum total bilirubin level was lowered to1.4 mg/dL with an AST of 37 IU/L and an ALT of 47 IU/L.One month later, the total bilirubin normalized to1.1 mg/dL, while AST and ALT remained at the samelevels. Levothyroxine (50 μg) was supplied for his post-surgical hypothyroidism.

Discussion

Hepatic dysfunctions, including elevated serum AST andALT levels, hepatitis and cholestasis, are usually notedin patients with hyperthyroidism. This relationship wasreported more than 100 years ago3. Hyperthyroidismcauses hepatic dysfunction or cholestasis. Abnormalliver function tests occur in 15–76% of the cases4. Thehepatic dysfunction can also be secondary to othercomplications of hyperthyroidism4,5. With medication,the antithyroid agents have an adverse effect on hepaticdysfunction.

The liver plays a major role in the metabolism of thyroxine6. Hyperthyroidism causes liver damagedirectly. Autopsies in patients with hyperthyroidismdemonstrate hepatic inflammation, fibrosis, and cen-trilobular necrosis7. Organ oxygen consumption but notblood flow augments with the increase of the metabolicrate. The arteriovenous oxygen difference across thesplanchnic bed increases, and hypoxia causes hepaticdifferences. A reduction in heart rate and cardiac output by β-adrenergic blockade may encourage theprogress1,4,8.

Autoimmune liver disease is related to autoim-mune thyroid disease, which causes most cases ofhyperthyroidism. Tests for antinuclear factor and anti-double-stranded DNA, and even liver biopsy, can beperformed to differentiate autoimmune hepatitis fromother hepatic injury conditions in hyperthyroidism8,9.Hashimoto thyroiditis is thought to be related to primarybiliary cirrhosis8.

Cholestasis may occur in patients with hyperthy-roidism. Bile transport is interfered with due to theincrease of hepatic oxygen consumption but withoutan increase of hepatic blood flow thus lowering theoxygen tension in the centrilobular zone. Thyroxine alsocan cause cholestasis directly4. Jaundice from congestiveliver may be secondary to thyrotoxic heart failure10.

Antithyroid agents, including methimazole andpropylthiouracil, have an adverse effect on hepaticdysfunction. The injury is likely to be mediated byimmune mechanisms. The estimated incidence ofantithyroid agents associated with hepatotoxicity isabout 0.5%11. The estimated frequency of immunoal-lergic hepatitis is 0.1–0.2%. Immunoallergic hepatitisis seen exclusively in patients treated with propylth-iouracil. A transient increase in AST and ALT levels isobserved in 30% of patients taking propylthiouracil12.It happens at all ages and more often in females4.

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■ ■W.C. Chen et al

The propylthiouracil-induced hepatic injury is usuallysubclinical and difficult to diagnose. It can, however,rarely cause submassive hepatic necrosis and hepaticfailure. Cholestasis is a rare pattern of hepatotoxicityassociated with the antithyroid agents and has beenreported exclusively with Tapazole (methimazole)12.Hepatotoxicity by Tapazole is thought to be related tocell-mediated immunity4.

In the present case, serum AST and ALT levels werenormal prior to medical management. Hyperbiliru-binemia and elevated serum AST and ALT levelsappeared after only a 4-day course of methimazoletherapy. These abnormalities persisted with the remis-sion of leukocytosis due to acute cholecystitis and sub-sided after the withdrawal of methimazole. The timingsuggests a causal association between methimazole andhepatic dysfunction. Acute cholecystitis had not beenpreviously reported as an adverse effect of antithyroidagents, but it can be secondary to cholestasis.

Hepatic dysfunction is usual in patients with hyper-thyroidism. It may be due to the disease or the medica-tion. Hepatic test function should be closely monitoredin patients with hyperthyroidism. The possible etiologiesof hepatic dysfunction in patients with hyperthyroidismshould be kept in mind to adjust the management ofhyperthyroidism.

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