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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsOVERVIEW
Introduction
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.
Background
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.
Hepatotoxicity
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. Minor serum enzyme elevations may also accompany hypothyroidism or Hashimoto disease. The liver test abnormalities accompanying hyper- or hypo-thyroidism generally resolve promptly with establishment of the euthyroid state.
High doses of thyroxine and hyperthyroidism also may exacerbate underlying liver disease including drug-induced liver injury, as has been described with acetaminophen and halothane hepatotoxicity. Overdose of thyroxine, however, does not usually cause liver injury. Thyroid hormones also can have multiple drug-drug interactions and other drugs can cause changes in thyroid status, such as hypothyroidism.
Finally, there have been rare reports of immunoallergic hepatitis or hypersensitivity reactions due to levothyroxine which was associated with enzyme elevations and even mild jaundice. The time to onset ranged from 1 to 8 weeks and symptoms typically included fever and fatigue. The enzyme pattern was usually hepatocellular or mixed. Autoantibodies were not detected, but eosinophilia was common. The fever resolved rapidly upon stopping the thyroid preparation, but liver test abnormalities generally required 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 was generally tolerated without recurrence. Strikingly, the case reports of liver injury due to levothyroxine and thyroid extract were all reported from Asia and Japan, which suggests a racial and possibly genetic predisposition to this idiosyncratic hypersensitivity reaction. Another possibility, however, was that the cases were due to a locally contaminated commercial preparation of levothyroxine.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
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.
Drug Class: Thyroid Agents
CASE REPORT
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.
Key Points
| Medication: | Levothyroxine (150 µg daily) |
| Pattern: | Mixed (R=4.7) |
| Severity: | 1+ (enzyme elevations without jaundice) |
| Latency: | 3 weeks |
| Recovery: | 1 month |
| Other medications: | None mentioned |
Laboratory Values
| Time After Starting | Time After Stopping | ALT (U/L) | Alk P (U/L) | Bilirubin (mg/dL) | Other |
|---|---|---|---|---|---|
| 0 | 0 | 41 | 176 | 0.4 | Hypothyroidism |
| 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 | |
| Normal Values | <31 | <285 | <1.2 | ||
Comment
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.
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Levothyroxine – Synthroid®
DRUG CLASS
Thyroid Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
ANNOTATED BIBLIOGRAPHY
References updated: 15 April 2019
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- Thyroid Hormone - LiverToxThyroid Hormone - LiverTox
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