Thyroid hormones used therapeutically include crude thyroid extracts as well as synthetic forms of L-thyroxine (levothyroxine, T4) and L-triiodothyronine (liothyronine, T3). Thyroid hormone plays an essential role in growth and development and regulates multiple metabolic processes that are responsible for functional homeostasis. When given in high doses, thyroid hormone preparations can cause mild serum enzyme elevations. In addition, standard doses of levothyroxine have been linked to rare instances of mild, immunoallergic liver injury.
Levothyroxine (lee" voe thye rox' een) is an orally available form of T4 that is commonly used to treat hypothyroidism and maintain the euthyroid state. Other forms of thyroid hormone include thyroid extract and triiodothyronine (T3) or liothyronine (lye" oh thye' roe neen). Thyroid hormone is essential for normal growth, particularly of the central nervous system. In adults, thyroid hormone maintains normal metabolism in virtually all organ systems. Thyroxine (T4) is released from the thyroid gland, but is converted in the liver and other tissues to the active form, which is triiodothyronine (T3) which engages thyroid hormone receptors in the nucleus of cells, which together bind to DNA, leading to transcription of thyroid responsive genes that have multiple actions in different cells affecting cell metabolism. Thyroid hormone is necessary for normal growth and development, and deficiency of thyroid hormone results in cretinism in children and hypothyroidism and myxedema in adults with a multitude of symptoms, signs and laboratory abnormalities, including fatigue, weight gain, drowsiness, mental torpor and confusion. Hypothyroidism is readily treated with oral forms of thyroid hormone which have been in clinical use for over 50 years, the most commonly used being desiccated thyroid (Armour Thyroid, 1950s), synthetic L-thyroxine or levothyroxine (T4, Synthroid, Levoxyl and others: 2002), and L-triiodothyronine or liothyronine (T3, Cytomel: 1956). Levothyroxine is currently one of the most commonly prescribed medications in the United States, with more than 100 million prescriptions filled yearly. The current indications are for maintenance of the euthyroid state. Levothyroxine is available in tablets at of 25 to 300 mcg for oral administration and as a lyophilized powder for parenteral use. Levothyroxine is typically started at a low daily dose (25 to 50 mcg) and increased based upon clinical effect and serum levels of thyroid stimulating hormone (TSH) and free T4. The usual adult replacement dose is 75 to 125 mcg daily. Side effects are uncommon at correct replacement doses, but high doses can cause symptoms of hyperthyroidism such as fatigue, weight loss, headache, anxiety, tremor, muscle weakness, tachycardia, cardiac arrhythmias, menstrual abnormalities, irritability, emotional labiality, sleep disturbance and changes in personality.
There is little information on serum aminotransferase levels during thyroxine therapy, but it is a very commonly prescribed medication and, at conventional doses, has not been linked to serum enzyme elevations. High doses of levothyroxine and other thyroid preparations, however, can cause serum enzyme elevations, typically in a hepatocellular or mixed pattern. Indeed, spontaneous hyperthyroidism can be accompanied by serum enzyme elevations and even jaundice. These abnormalities, however, resolve rapidly with control of the hyperthyroid state. High doses of thyroxine and hyperthyroidism also may exacerbate underlying liver disease including drug induced liver injury (acetaminophen, halothane). Thyroid hormones also have multiple drug-drug interactions and many drugs can cause hypothyroidism. Overdose of thyroxine, however, does not usually cause hepatic injury.
Finally, there have been rare reports of immunoallergic hepatitis or hypersensitivity reactions due to levothyroxine which can be associated with enzyme elevations and even mild jaundice. The time to onset is ranges from 1 to 8 weeks and symptoms are typically fever and fatigue. The enzyme pattern is usually hepatocellular or mixed. Autoantibodies are not detected, but eosinophilia is common. The fever resolves rapidly upon stopping, but the liver test abnormalities generally require one to two months to fall into the normal range. In at least one case, switching to another form of thyroid hormone was associated with persistence of fever and a worsening of liver tests. In contrast, waiting until recovery from the liver injury and starting triiodothyronine at a low dose with gradual increase to therapeutic levels is generally tolerated without recurrence. Strikingly, the case reports of liver injury due to levothyroxine and thyroid extract have all been reported from Japan, which suggests a racial and possibly genetic predisposition to this idiosyncratic hypersensitivity reaction.
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations and jaundice during levothyroxine induced liver injury is likely due to hypersensitivity and is possibly genetically determined.
Outcome and Management
Cases of liver injury attributed to levothyroxine and thyroid extract have been mild-to-moderate in severity and self-limited in course, resolving within one to three months of stopping therapy. Rechallenge with levothyroxine has been reported to result in recurrence of fever and hepatic injury, but in several instances patients have later tolerated liothyronine (T3) as a means of treating the hypothyroidism. There have been no reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to levothyroxine therapy.
Case 1. Immunoallergic hepatitis due to levothyroxine.
[Modified from: Ohmori M, Harada K, Tsuruoka S, Sugimoto K, Kobayashi E, Fujimura A. Levothyroxine-induced liver dysfunction in a primary hypothyroid patient. Endocr J 1999; 46: 579-83. PubMed Citation].
A 13 year old girl was found to have hypothyroidism thought to be due to Hashimoto thyroiditis with serum TSH levels of 770 µU/mL, free T4 <0.1 ng/dL, thyroid peroxidase antibody 7.9 U/mL, and thyroglobulin antibody 11.8 U/mL. Her serum aminotransferase levels were mildly elevated (ALT 41 U/L, AST 35 U/L, Alk P 176 U/L) and an abdominal ultrasound showed mild fatty liver. She was started on oral levothyroxine in a dose of 50 µg daily which was increased to 150 µg daily. Thyroid test results improved, but she developed fever and mild serum enzyme elevations 3 weeks after starting levothyroxine (Table). The fever persisted despite a decrease in the dose of levothyroxine to 50 mcg daily and she developed fatigue and worsening liver test abnormalities, serum ALT rising to 365 U/L and Alk P to 833 U/L (Table). She had no history of liver disease or risk factors for viral hepatitis and was taking no other medications. Levothyroxine was stopped and her fever resolved within a few days and serum aminotransferase levels began to fall. Four weeks later, she was asymptomatic and liver tests were normal. Because thyroid test abnormalities had returned, low doses of triiodothyronine were started (5 µg daily). Liver tests remained normal and the dose was gradually increased to 50 µg daily.
||Levothyroxine (150 µg daily)
|Pattern:|| Mixed (R=4.7)|
||1+ (enzyme elevations without jaundice)
|Other medications:||None mentioned|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
|1 week||0||30||TSH 820|
|1 weeks||50 µg||42||TSH 81|
|3 weeks||150 µg||41||207||Fever, TSH 1.9|
|7 weeks||50 µg ||365||629||0.5||Levothyroxine stopped|
|9 weeks||0||61||833||TSH 100|
|14 weeks||0||28||566||Liothyronine started|
|17 weeks||0||21||553||TSH 6.7|
Although widely used, levothyroxine has not been mentioned as a cause of drug induced liver injury in large case series. Nevertheless, at least four cases of liver injury attributable to levothyroxine have been reported from Japan. As in the current case, the time to onset was generally within a few weeks of starting, and the presenting symptoms were fever and fatigue. Liver test abnormalities were mild, but transient jaundice occurred in at least two cases (one during rechallenge). Restarting thyroid replacement with triiodothyronine was generally tolerated, but abrupt switching to other forms of thyroid replacement did not always lead to resolution. The cause of the liver injury is unknown, but is likely to be part of a generalized hypersensitivity reaction. The clinical presentation, however, has been characterized as fever and eosinophilia and rarely drug rash.
REPRESENTATIVE TRADE NAMES
Levothyroxine – Synthroid®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
References updated: 8 April 2015
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Chitturi S, Farrell GC. Adverse effects of hormones and hormone antagonists on the liver. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 605-620. (Textbook on hepatotoxicity; antithyroid medications are discussed, but not thyroid hormones).
Brent GA, Koenig RJ. Thyroid and anti-thyroid drugs. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1131-61. (Textbook of pharmacology and therapeutics).
Inui A, Ishikawa K, Mizuno N, Oimomi M, Baba S. [Case of Hashimoto's disease with thyroxine induced allergic hepatitis]. Nihon Naika Gakkai Zasshi 1983; 72: 1407-13. Japanese. PubMed Citation (63 year old Japanese woman developed fever and fatigue 2 weeks after starting L-thyroxine [bilirubin normal, ALT 2097 U/L, Alk P ~225 U/L, eosinophilia], resolving rapidly on stopping and recurring with restarting L-thyroxine [bilirubin 6.5 mg/dL, ALT ~1000 U/L, Alk P ~200 U/L with rash and fever], but not after subsequent use of triiodothyronine).
Shibata H, Hayakawa H, Hirukawa M, Tadokoro K, Ogata E. Hypersensitivity caused by synthetic thyroid hormones in a hypothyroid patient with Hashimoto's thyroiditis. Arch Intern Med 1986; 146: 1624-5. PubMed Citation (63 year old Japanese woman with hypothyroidism developed fatigue 4 months after starting triiodothyronine [T3] [ALT 1044 U/L, bilirubin and Alk P not given], resolving within 1 month of stopping and recurring with fever within 4 days of starting levothyroxine [bilirubin 1.1 mg/dL, ALT 610 U/L, Alk P 717 U/L, 9% eosinophils], fever resolving in 1 day and liver tests in 2 months; she later tolerated slow introduction of triiodothronine).
Mandel SH, Magnusson AR, Burton BT, Swanson JR, LaFranchi SH. Massive levothyroxine ingestion. Conservative management. Clin Pediatr (Phila) 1989; 28: 374-6. PubMed Citation (29 month old girl ingested 90 levothyroxine tablets [200 µg each] and had high serum T4 levels, but only mild irritability, vomiting and tremor starting around day 4 and resolving within 2 weeks; no mention of ALT elevations or hepatotoxicity).
Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993; 119: 492-502. PubMed Citation (Review of the mechanism of action, clinical efficacy, use and safety of levothyroxine; no mention of hepatotoxicity).
Ohmori M, Harada K, Tsuruoka S, Sugimoto K, Kobayashi E, Fujimura A. Levothyroxine-induced liver dysfunction in a primary hypothyroid patient. Endocr J 1999; 46: 579-83. PubMed Citation (13 year old Japanese female with hypothyroidism developed fever and malaise within 3 weeks and rising ALT levels within 6 weeks of starting levothyroxine [bilirubin 0.4 mg/dL, ALT 41 rising to 365 U/L, Alk P 207 rising to 853 U/L], fever resolving within days and liver tests within 2 months of stopping, and not recurring with triiodothyronine: Case 1).
Kawakami T, Tanaka A, Negoro S, Morisawa Y, Mikami M, Hojo M, Yamamoto T, et al. Liver injury induced by levothyroxine in a patient with primary hypothyroidism. Intern Med 2007; 46: 1105-8. PubMed Citation (63 year old Japanese man with hypothyroidism developed liver test abnormalities 2 months after starting levothyroxine [bilirubin 1.5 rising to 11.5 mg/dL, ALT 884 U/L, Alk P 458 U/L], not improving on switching to thyroid extract or triiodothyronine, but resolving when all thyroid was stopped, later tolerating triiodothyronine).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to thyroid hormone).
Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to thyroid hormone).
Warner JV, Morton AP, Hall AJ, Henman MG, Pool LF. Internet slimming, thyrotoxicosis and the liver. Med J Aust 2014; 200: 419-20. PubMed Citation (34 year old woman developed thyrotoxicosis and mild serum enzyme elevations 8 weeks after starting a Chinese herbal preparation for weight loss [bilirubin not given, ALT 49 U/L, Alk P 121 U/L], improving but with persistence of liver enzyme abnormalities once the herbal preparation [which was shown to contain free thyroxine] was stopped).
Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR,
et al.; United States Drug Induced Liver Injury Network. Features and outcomes
of 899 patients with drug-induced liver injury: The DILIN Prospective Study.
Gastroenterology 2015; 148: 1340-1352. PubMed Citation (Among 899 cases of drug induced liver injury enrolled in a US prospective
study between 2004 and 2013, none were attributed to thyroid hormone or levothyroxine).
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