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Thionamides: Side effects and toxicities

Thionamides: Side effects and toxicities
Author:
Douglas S Ross, MD
Section Editor:
David S Cooper, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jan 2024.
This topic last updated: Jul 25, 2022.

INTRODUCTION — Thionamide compounds were found in 1943 to inhibit thyroid hormone synthesis. They are actively transported into the thyroid gland where they inhibit both the organification of iodine to tyrosine residues in thyroglobulin and the coupling of iodotyrosines (figure 1) [1]. Adverse effects of thionamides include common, minor side effects (eg, rash) and rare but serious adverse effects, such as agranulocytosis and hepatotoxicity. Patients should be made aware of side effects at the time of drug initiation, preferably in writing, and at subsequent visits.

The adverse effects of propylthiouracil (PTU) and methimazole and their management will be reviewed here. Specific issues related to their use in the treatment of Graves' disease are discussed separately. (See "Thionamides in the treatment of Graves' disease".)

PHARMACOKINETICS — Propylthiouracil (PTU) and methimazole are the thionamide drugs available in the United States. Carbimazole is a third option available in many countries, but not in North America. Methimazole and carbimazole are interchangeable because carbimazole is completely metabolized to methimazole. The carbimazole dose required to yield an equivalent dose of methimazole is approximately 40 percent higher.

PTU, but not methimazole, inhibits the 5'-monodeiodinase that converts thyroxine (T4) to triiodothyronine (T3) in extrathyroidal tissue. However, methimazole has several important pharmacokinetic advantages over PTU:

The serum half-life of methimazole is four to six hours, whereas that of PTU is 75 minutes.

The intrathyroidal methimazole concentration, which can reach a thyroid-to-serum ratio of 100:1, remains high for up to 20 hours, considerably longer than that of PTU.

Perchlorate discharge tests, which are a measure of inhibition of iodine organification, demonstrate the superiority of methimazole over PTU. In one study, perchlorate discharged 37 percent of the radioiodine tracer 24 hours after a single 15 mg dose of methimazole versus only 8.6 percent after a 300 mg dose of PTU [2].

COMMON, MINOR SIDE EFFECTS — Both methimazole and propylthiouracil (PTU) can cause pruritus, rash, urticaria, arthralgias, arthritis, fever, abnormal taste sensation, nausea, or vomiting in up to 13 percent of patients [3]. In one trial, the percentage of patients who discontinued antithyroid drugs due to adverse reactions was 17, 29, and 34 percent for 15 or 30 mg of methimazole or PTU, respectively [4].

Mild skin reactions can be treated with antihistamine therapy without stopping methimazole or PTU [5], with the caveat that some skin reactions from PTU may be indicative of vasculitis. If one drug is not tolerated, the other drug can be substituted, but up to 50 percent of patients have cross-sensitivity. For patients with serious allergic reactions, prescribing the alternative drug is not recommended and the patient should be managed with radioiodine or surgery.

The gastrointestinal side effects are dose dependent. Thus, we prefer to use divided doses in patients taking higher doses of methimazole (≥20 mg) and then change to single daily dosing if tolerated and as the dose is reduced. (See "Thionamides in the treatment of Graves' disease", section on 'Dosing'.)

RARE BUT SERIOUS ADVERSE EFFECTS

Potential teratogenicity — Thionamides have been associated with possible teratogenic effects, but teratogenic effects are more severe with methimazole and carbimazole compared with propylthiouracil (PTU). This topic is discussed in greater detail separately. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Choice of thionamide'.)

Agranulocytosis — Agranulocytosis is a rare but serious complication of thionamide therapy with a prevalence of 0.1 to 0.5 percent. The risk of agranulocytosis is higher for thionamides than for 20 other classes of drugs associated with this rare complication [6]. If a patient develops agranulocytosis with either PTU or methimazole, use of the other drug is contraindicated due to risk of cross-reactivity.

Agranulocytosis usually occurs within the first two to three months of treatment [7-10]. In one study from Japan, the average time to onset of agranulocytosis was 69 days (range 11 to 233 days) [8].

The risk of agranulocytosis from methimazole (but not PTU) appears to be dose related. Compared with low doses of methimazole, PTU (any dose) appears more likely to cause agranulocytosis [10]. In one study, agranulocytosis was more frequent in older patients taking methimazole in doses higher than 40 mg/day [11], while in two other studies, agranulocytosis was more common with doses >20 mg daily versus 5 to 15 mg daily [6,12], and in a third study, no cases were seen with methimazole doses under 30 mg and the prevalence of agranulocytosis with PTU was dose independent [11]. However, a Japanese study found that the development of agranulocytosis from methimazole was independent of dose, age, duration of treatment, or second exposure to the thionamide [13].

In the United Kingdom, reports of agranulocytosis are more common with PTU than carbimazole [14]. Most cases occur within three months after treatment is begun.

White blood cell (WBC) assessment – It is important to obtain a complete blood count (CBC) prior to starting a thionamide since 10 percent of patients with Graves' hyperthyroidism have neutropenia (average absolute neutrophil count [ANC] 1.4±0.3 x 109/L, which resolves with thionamide treatment [15].

We advise patients taking a thionamide to have an immediate white cell count with differential at the earliest sign of a fever, sore throat, or other infection and to discontinue the drug until the result is available.

Controversy exists as to the value of monitoring WBC counts. Most clinicians in the United States do not perform periodic monitoring, and the American Thyroid Association (ATA) guidelines do not recommend monitoring [5]. However, a study from Japan was able to identify 78 percent of cases of granulocytopenia before the development of agranulocytosis or the onset of symptoms by checking blood counts every two weeks for the first two months of therapy [16]. (See "Thionamides in the treatment of Graves' disease", section on 'Monitoring'.)

Prognosis – Recovery from agranulocytosis usually takes a few days but can be prolonged, and morbidity and death from serious infections can occur. In a Japanese registry, 30 of 754 cases (4 percent) were fatal [9]. Granulocyte colony-stimulating factor (G-CSF) has been used as adjunctive therapy in severe cases [17], but its efficacy was called into question in an older, randomized, prospective, controlled trial of 24 patients with a thionamide-induced neutrophil count of less than 500/microL, showing no difference in the time to neutrophil recovery between those who received G-CSF versus those who did not [18]. However, this study has been criticized because of its small sample size (n = 24) and the use of a likely inadequate dose of G-CSF (100 to 250 mcg/day). Subsequent nonrandomized studies have documented the effectiveness of hematopoietic growth factors to decrease the time to WBC normalization and the length of hospital stay [19]. However, there is no firm evidence that such therapy impacts mortality from antithyroid drug-induced agranulocytosis [20]. Glucocorticoid therapy is ineffective. (See "Drug-induced neutropenia and agranulocytosis".)

Hepatotoxicity — Hepatotoxicity is a rare complication of thionamide therapy. However, PTU can cause fulminant hepatic necrosis [21,22]. Over the past 20 years, 22 cases of severe hepatotoxicity in adults in the United States resulted in nine deaths and five liver transplants. Over the same period, 12 children developed liver failure, resulting in three deaths and six liver transplants. It was estimated that this complication occurs in 1 in 10,000 adults taking PTU, with an even greater risk in children (1 in 2000) [21,23,24]. PTU-related hepatotoxicity typically occurs within 90 days of starting the medication (although cases occurring up to one year have been reported), and it is not dose related. Accumulating evidence on PTU-associated hepatotoxicity, particularly in children [23], led to changes in recommendations for the use of thionamides. At a 2009 joint meeting of the ATA and US Food and Drug Administration (FDA), it was recommended that PTU not be prescribed as a first-line drug in children or adults [21,24]. PTU has a "boxed warning" because of the risk of liver failure. (See "Thionamides in the treatment of Graves' disease", section on 'Choice of drug'.)

It is important to measure liver function tests prior to starting a thionamide since hyperthyroidism per se can cause elevations in transaminases and alkaline phosphatase. In a meta-analysis, elevations in alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase were seen in 33, 23, and 44 percent of hyperthyroid patients, respectively, and became normal after thionamide therapy in 83, 87, and 57 percent of patients [25]. Importantly, elevations in alkaline phosphatase may originate from bone.

Patients taking PTU or methimazole who develop jaundice, dark urine, light stools, abdominal pain, anorexia, nausea, or other evidence of hepatic dysfunction should be told to discontinue the drug immediately and to contact the clinician for assessment of liver function (transaminases, bilirubin) [5]. PTU should not be used if transaminases reach three times the upper limit of normal and fail to improve on repeat testing one week later. After discontinuation, liver function tests should be monitored weekly until normalization. If they do not normalize, immediate referral to a hepatologist or gastroenterologist may be necessary.

Serum transaminase concentrations increase transiently in up to one-third of patients taking PTU; this abnormality may be associated with focal hepatic necrosis on liver biopsy [26]. A literature survey published in 1997 reported 49 cases of hepatotoxicity, 28 associated with PTU (including seven deaths) and 21 associated with methimazole (including three deaths) [27]. There was no relationship between a fatal outcome and either the dose or duration of thionamide treatment.

Although methimazole has been associated with liver disease, reports from the United States had suggested it is typically due to cholestatic dysfunction not hepatocellular inflammation [28]. In contrast, studies from Taiwan and China suggest similar [29] or higher rates of hepatitis with methimazole than PTU when the dose exceeded 13 mg/day [30], although the risk of liver failure was less [30]; almost all cases occurred within the first 180 days of treatment [30]. In Japan, among 18,558 patients with newly diagnosed Graves' disease, severe drug-induced liver injury (ALT higher than 20 times, or total bilirubin higher than 10 times the upper limit of normal) was 0.68 percent for PTU and 0.08 percent for methimazole, with no fatalities [31].

ANCA-positive vasculitis — An antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis has been reported in association with PTU use [32]. There is also a possible association between methimazole and ANCA-positive vasculitis, but the number of cases is too small to establish a cause-and-effect relationship. This is one of several reasons why we strongly prefer the use of methimazole or carbimazole rather than PTU.

In a review of studies of patients with thionamide-induced ANCA-positive vasculitis, ANCA were present in 4 to 64 percent of patients taking PTU and 0 to 16 percent of patients taking methimazole; however, only approximately 15 percent (1 in 6) of ANCA-positive patients develop clinical evidence of vasculitis [32]. In a subsequent prospective study from Brazil, 21 percent of patients taking methimazole had ANCA, but none developed vasculitis [33]. Approximately one-third of the studies showed an association between duration of thionamide therapy and onset of ANCA positivity. In a retrospective report of 16 cases from China, median time of onset of PTU-induced ANCA-associated vasculitis was 36 months (range 1 to 193 months) [34]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

Clinical symptoms of ANCA-positive vasculitis may include fever; joint pain; weight loss; myalgia; ocular signs (eg, uveitis, scleritis); painful, necrotic, purpuric skin lesions, often affecting the ears and nose; hematuria, reflecting glomerular injury; hemoptysis; and central nervous system involvement. Since the majority of ANCA-positive patients have no clinical symptoms of vasculitis, we only assess ANCA levels in those patients who have symptoms consistent with possible vasculitis.

Treatment involves discontinuation of the offending drug and immunosuppressive therapy with glucocorticoids and other agents like cyclophosphamide. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Drug-induced ANCA-associated vasculitis'.)

Pancreatitis — In 2019, the European Medicines Agency (but not the FDA) added pancreatitis to the potential adverse reactions related to treatment with methimazole based on six case reports [35,36]. A registry-based study from Denmark identified 119,697 patients exposed to antithyroid drugs between 1995 and 2018. Excluding alcohol and gallstone-related pancreatitis, 459 were admitted to the hospital with a first case of pancreatitis (odds ratio [OR] 1.56 [95% CI 1.04-2.33]) for methimazole (n = 400) and 0.88 (95% CI 0.26-2.96) for PTU (n = 59) [37]. In another study (n = 23,807), the relative risk of pancreatitis was 3.4 (95% CI 2.12-5.48), 2.4 (95% CI 1.36-4.23), and 2.8 (95% CI 1.66-4.73), in the first, second, and third nine-month intervals after initiation of treatment, and fell to nonsignificant levels thereafter [38]. The absolute risk was 0.4 percent. Patients should be informed of this rare serious side effect of methimazole.

Other — Other rare but serious side effects of thionamides include aplastic anemia [39] and insulin autoimmune syndrome with hypoglycemia (methimazole) [40].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (The Basics)")

Beyond the Basics topics (see "Patient education: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient education: Antithyroid drugs (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

ThionamidesPropylthiouracil (PTU) and methimazole are the thionamide drugs available in the United States. Carbimazole is a third option available in many countries, but not in North America. Methimazole and carbimazole are interchangeable because carbimazole is completely metabolized to methimazole. The carbimazole dose required to yield an equivalent dose of methimazole is approximately 40 percent higher. (See 'Pharmacokinetics' above.)

Methimazole has clinical advantages and less severe toxicity when compared with PTU, and it is usually preferred to PTU (except during the first trimester of pregnancy or during the initial treatment of thyroid storm). (See "Thionamides in the treatment of Graves' disease", section on 'Choice of drug'.)

Common minor side effects – Both methimazole and PTU can cause pruritus, rash, urticaria, arthralgias, arthritis, fever, abnormal taste sensation, nausea, or vomiting in up to 13 percent of patients [3]. (See 'Common, minor side effects' above.)

Rare but serious side effects

Agranulocytosis – Agranulocytosis is a rare but serious complication of thionamide therapy, with a prevalence of 0.1 to 0.5 percent. (See 'Agranulocytosis' above.)

-It is important to obtain a complete blood count (CBC) prior to starting a thionamide since 10 percent of patients with Graves' hyperthyroidism have neutropenia, which resolves with thionamide treatment.

-We advise patients taking a thionamide to have a white blood cell (WBC) count with differential at the earliest sign of a fever, sore throat, or other infection and to discontinue the drug until the result is available.

Hepatotoxicity – Hepatotoxicity is a rare complication of thionamide therapy. PTU can cause fulminant hepatic necrosis. Although hepatocellular inflammation has also been reported with methimazole, severe drug-induced liver injury occurs less frequently than with PTU. (See 'Hepatotoxicity' above.)

-It is important to measure liver function tests prior to starting a thionamide since hyperthyroidism itself can cause elevations in transaminases and alkaline phosphatase, which normalize in the majority of patients with thionamide treatment.

-Patients taking PTU or methimazole who develop jaundice, dark urine, light stools, or other evidence of hepatic dysfunction should be told to discontinue the drug immediately and to contact the clinician for assessment of liver function.

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