A Review on: Antithyroid Drug Therapy
Rupali V Khankari, Kanchan R. Pagar, Sarika V. Khandbahale, Poonam S Sable
We assessed the effects of dose, regimen and duration of anti-thyroid drug therapy for Graves’ thyrotoxicosis on recurrence of hyperthyroidism, course of ophthalmopathy, adverse effects, health-related quality of life and economic outcomes. We undertook a systematic review and meta-analyses of randomised controlled trials (RCTs). We identified RCTs regardless of language or publication status by searching six databases, and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Trials included provided therapy for at least 6 months with follow-up at least 1 year after drug cessation. Fixed or random effects meta-analyses were used to combine study data. Twelve trials compared a Block-Replace regimen (requiring a higher dose of anti-thyroid drug treatment) with a Titration regimen. Overall, there was no significant difference between the regimens for relapse of hyperthyroidism. Participants were more likely to withdraw due to adverse events with a Block-Replace regimen. Prescribing replacement thyroxine, either with the anti-thyroid drug treatment, or after this was completed, had no significant effect on relapse. Limited evidence suggested 12–18 months of anti-thyroid drug treatment should be used. The titration regimen appeared as effective as the Block-Replace regimen, and was associated with fewer adverse effects. However, relapse rates over 50% and high participant drop-out rates in trials mean that the results should be interpreted with caution, and may suggest that other strategies for the management of Graves’ disease, such as radioiodine, should be considered more frequently as first-line therapy. There were no data on the course of ophthalmopathy, health-related quality of life and economic outcomes.
Hyperthyroidism is common, affecting approximately 2% of women and 0.2% of men (1). The most common cause of hyperthyroidism is Graves’ disease (1). Methimazole, carbimazole and propylthiouracil are the main drug treatments, blocking thyroid hormone synthesis. They may also help control thyrotoxicosis by immune suppression.
Propylthiouracil additionally inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine. Methimazole is the active metabolite of carbimazole, and since the conversion of carbimazole to methimazole is virtually complete, equivalent doses are thought to be comparable. Anti-thyroid drug therapy can be given either by the Block-Replace regimen (where a higher dose of antithyroid drug is used with a replacement dose of thyroid hormone) or by the Titration regimen (where the antithyroid drug dose is reduced by titrating treatment against thyroid hormone concentrations).
The preferred regimen and duration of therapy remain unresolved with varying duration from 6 to 24 months with either the Block-Replace or the Titration regimen. We undertook a substantial update to a Cochrane systematic review (2) assessing the effects of anti-thyroid drug regimen and duration in the treatment of Graves’ hyperthyroidism.
MECHANISM OF ACTION:
Inhibition of thyroid hormone synthesis:
The ‘thionamide’ antithyroid drugs are five- or six-membered ring structured sulfur-containing compounds that are thiourea derivatives. Contrary to popular belief, antithyroid drugs do not block thyroidal iodine uptake. Rather, their primary effect appears to inhibit an early step in thyroid hormone synthesis, which is the ‘organification’ of inorganic iodine. The process is catalyzed by thyroid peroxidase (TPO) and requires endogenously generated hydrogen peroxide. During the initial steps of organification, iodide is oxidized and bound to heme residues within TPO (TPO-Iox), prior to subsequent iodination of tyrosine residues in the thyroglobulin molecule. While antithyroid drugs can irreversibly inhibit TPO in vitro, in vivo (3), in the presence of iodine, the drugs appear to act as substrates for TPO-Iox (4) and are probably iodinated themselves to form unstable sulfenyl-iodide intermediates, thus diverting TPO-Iox moieties away from tyrosine iodination pathway (5). Others have suggested that methimazole, through its sulfur moiety (or after desulfuration) can interact directly with the iron (Fe (III)) atom at the center of the heme molecule (6). It has also been proposed that antithyroid drugs interfere with the coupling reaction, in which two iodotyrosine molecules form an ether link to yield the iodothyronines thyroxine (T4) and triiodothyronine (T3) (7). Other less well-documented proposed mechanisms to inhibit thyroid hormone synthesis include drug binding directly to thyroglobulin (8) or inhibition of thyroglobulin synthesis (9).
Propylthiouracil, but not methimazole or carbimazole, inhibits the selenoprotein type I iodothyronine deiodinase, thereby reducing T3 formation in peripheral tissues from T4. On the other hand, propylthiouracil does not inhibit the type 2 or type 3 deiodinases, which are also selenoproteins, suggesting that there are important steric considerations behind this disparity (10). The mechanism of inhibition of type I deiodinase appears to be formation of a stable selenyl-sulfide moiety, which prevents the formation of a key selenyl-iodide intermediate (11).
Effects on thyroid autoimmunity:
Given the decline in thyroid-stimulating antibody titers with antithyroid drug therapy (12) as well as the possibility that patients treated with antithyroid drugs may undergo a remission after a course of treatment, there has been interest in whether antithyroid drugs may have direct or indirect effects on the immune system (13). Unfortunately, space does not permit a thorough discussion of the extensive data on the subject (14). Suffice it to say that there is in vitro evidence that thionamide antithyroid drugs may have direct effects on intrathyroidal T cells (15,16) and HLA Class II expression by thyrocytes (17), as well as in vivo evidence for increased numbers of suppressor T cells and decreased intrathyroidal activated T cells (18).
On the other hand, others have argued that the putative direct effects of thionamides on thyroid autoimmunity are much less important than the indirect effects on the immune system that occur as a direct result of hyperthyroidism per se, and which are reversed after control of the hyperthyroidism by antithyroid drug therapy (19,20). The extent to which either the direct or indirect effects of antithyroid drugs on the immune system predominate to achieve the observed reduction in antiTSH receptor antibody titers and resultant remissions remains uncertain.
The increased basal metabolic rate associated with hyperthyroidism is believed to result in accelerated production of superoxide radicals as byproducts of electron transport (21,22). Reactive oxygen species have also been implicated in the pathogenesis of Graves’ orbitopathy (23,24,25). In vitro studies have shown that both MMI and PTU inhibit leukocyte production of oxygen radicals in a dose-dependent manner (26,27) and appear to accelerate hydrogen peroxide scavenging in cultured thyroid cells (28). A clinical study in patients with Graves’ disease found that plasma thiol levels and superoxide dismutase activity, both free radical scavengers, were reduced in patients presenting with thyrotoxicosis, but normalized following treatment with CBM (29). Another study found that indices of lipid peroxidation were elevated and the antioxidants vitamin E and coenzyme Q10 were reduced in untreated Graves’ disease patients but normalized after treatment with either MMI or PTU (30). Similar findings of enhanced lipid peroxidation were found in two additional studies of hyperthyroid Graves’ disease patients (31,32), but improvement following treatment with PTU occurred in only one of these studies (32). Each of these clinical studies is flawed by an inability to distinguish the effects of the ATDs from the effects of correcting hyperthyroidism per sec
PA was involved in protocol development, searching for trials, quality assessment of trials, data abstraction and data analysis. A A was involved in protocol development, quality assessment of trials, data abstraction and data analysis. W A W was involved in searching for trials, quality assessment of trials and data abstraction. C M P undertook quality assessment of trials and data abstraction. J S B provided clinical input, and resolution of differences of opinion. No Ethics approval was required.
Search strategy for identification of studies:
We identified relevant studies regardless of language or publication status by searching The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2004), MEDLINE (1966 to July 2004), EMBASE (1980 to July 2004), BIOSIS (1985 to July 2004), CINAHL (1982 to July 2004), HEALTHSTAR (1975 to June 2002) and trial registries. We contacted authors of published trials and thyroid researchers and checked the references of retrieved studies and reviews for additional trials. Three trialists provided additional data.
We included all published and unpublished, randomised and quasi-randomised controlled trials (RCTs) of patients of any age receiving anti-thyroid drug treatment for Graves’ hyperthyroidism, where Graves’ hyperthyroidism had been adequately defined. We pre-specified a minimum duration for drug treatment of 6 months and a minimum duration of follow-up of 1 year from completion of drug therapy to assess the pre-specified outcomes. We sought trials of carbimazole, propylthiouracil, methimazole, lithium or perchlorate. We pre-specified the comparisons of Block-Replace vs Titration regimen; short-term (6 months) vs long-term (over 6 months) regimens; high-dose drug therapy (equivalent to 40 mg carbimazole or more) vs low-dose (equivalent to 30 mg carbimazole or less); and continued thyroid hormone replacement with or without continued anti-thyroid medication. The main outcome measures were recurrence of hyperthyroidism, incidence of hypothyroidism and mortality. Additional outcome measures sought were the course of ophthalmopathy (need for corticosteroids, radiotherapy, visual compromise); adverse effects (agranulocytosis, drug rash, hepatitis, vasculitis); symptoms of hyperthyroidism (anxiety, tachycardia, heat intolerance, diarrhoea, oligomenorrhoea); thyroid antibody status; weight change; frequency of outpatient visits and thyroid function tests; health-related quality of life; economic outcomes; compliance; and necessity for surgery or radioiodine.
Quality assessment of RCTs included allocation concealment, whether intention-to-treat analysis was undertaken, comparability of groups at baseline, and blinding of outcome assessors. The summary risk of bias was based on the concealment of allocation.
Two reviewers independently abstracted the data and assessed the methodological quality of the studies. Any differences were resolved by discussion between the reviewers. Quantitative data synthesis Where appropriate, the results of comparable groups of trials were combined for relative risks (RRs) using fixedeffects models, and results are presented with 95% confidence intervals (CIs). Heterogeneity between comparable trials was assessed by the I2 statistic (33). Random effects models were used where I2 was 50% or more. Pre-specified subgroup and sensitivity analyses were undertaken.
Six decades after their introduction, antithyroid drugs continue to be important in the management of hyperthyroidism. Patients with Graves’ disease, who have an approximately 40 to 50 percent chance of remission after 12 to 18 months of therapy, are the best candidates. Antithyroid drugs are deceptively easy to use, but because of the variability in the response of patients and the potentially serious side effects, all practitioners who prescribe the drugs need to have a working knowledge of their complex pharmacology.
1. Franklyn JA. The management of hyperthyroidism. New England Journal of Medicine 2002 330 1731–1738.
2. Abraham P, Avenell A, Watson WA, Park CM and Bevan JS. Antithyroid drug regimen for treating Graves’ hyperthyroidism. The Cochrane Database of Systematic Reviews 2005 2.
3. Taurog A. The mechanism of action of the thioureylene antithyroid drugs. Endocrinology 1976981031–1046. (https://doi.org/10.1210/endo-98-4-1031)
4. Davidson B Soodak MNeary JT Strout HV Kieffer JD Mover HMaloofF. The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings. Endocrinology 1978103871–882. (https://doi.org/10.1210/endo-103-3-871)
5. CooperDS.Antithyroid drugs. New England Journal of Medicine2005352905–917. (https://doi.org/10.1056/NEJMra042972)
6. Manna D Roy G Mugesh G. Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action. Accounts of Chemical Research 2013462706–2715. (https://doi.org/10.1021/ar4001229)
7. Engler H T aurog A Dorris M L. Preferential inhibition of thyroxine and 3,5,3′-triiodothyronine formation by propylthiouracil and methylmercaptoimidazole in thyroid peroxidase-catalyzed iodination of thyroglobulin. Endocrinology1982110190–197. (https://doi.org/10.1210/endo-110-1-190)
8. Papapetrou P D Mothon S Alexander W D. Binding of the 35-s of 35-s-propylthiouracil by follicular thyroglobulin in vivo and in vitro. Acta Endocrinology197579248–258.
9. MonacoF Santolamazza CDe RosI Andreoli A. Effects of propylthiouracil and methylmercaptoimidazole on thyroglobulin synthesis. Acta Endocrinology19809332–36. (https://doi.org/10.1530/acta.0.0930032)
10. Visser T J. Mechanism of inhibition of iodothyronine-5′-deiodinase by thioureylenes and sulfite. Biochimica et Biophysica Acta1980611371–378. (https://doi.org/10.1016/0005-2744(80)90074-1)
11. Kuiper G G Kester M H Peeters R P Visser T J. Biochemical mechanisms of thyroid hormone deiodination. Thyroid 200515787–798. (https://doi.org/10.1089/thy.2005.15.787)
12. Fenzi G HashizumeKRoudebushCPDeGrootLJ.Changes in thyroid-stimulating immunoglobulins during antithyroid therapy. Journal of Clinical Endocrinology and Metabolism197948572–576. (https://doi.org/10.1210/jcem-48-4-572)
13. AstwoodEB.Thyrotoxicosis. Baltimore: Williams and Wilkins1967.
14. DalanRLeowMK.Immune manipulation for Graves’ disease: re-exploring an unfulfilled promise with modern translational research. European Journal of Internal Medicine201223682–691. (https://doi.org/10.1016/j.ejim.2012.07.007)
15. MitsiadesNPoulakiVTseleni-BalafoutaSChrousosGPKoutrasDA.Fas ligand expression in thyroid follicular cells from patients with thionamide-treated Graves’ disease. Thyroid200010527–532. (https://doi.org/10.1089/thy.2000.10.527)
16. HumarMDohrmannHSteinPAndriopoulosNGoebelURoessleinMSchmidtRSchwerCILoopTGeigerKKThionamides inhibit the transcription factor nuclear factor-kappaB by suppression of Rac1 and inhibitor of kappaB kinase alpha. Journal of Pharmacology and Experimental Therapeutics20083241037–1044. (https://doi.org/10.1124/jpet.107.132407)
17. Zantut-WittmannDETambasciaMAda Silva TrevisanMAPintoGAVassalloJ.Antithyroid drugs inhibit in vivo HLA-DR expression in thyroid follicular cells in Graves’ disease. Thyroid200111575–580. (https://doi.org/10.1089/105072501750302886)
18. TottermanTHKarlssonFABengtssonMMendel-HartvigI.Induction of circulating activated suppressor-like T cells by methimazole therapy for Graves’ disease. New England Journal of Medicine198731615–22. (https://doi.org/10.1056/NEJM198701013160104)
19. VolpeR.The immunomodulatory effects of anti-thyroid drugs are mediated via actions on thyroid cells, affecting thyrocyte-immunocyte signalling: a review. Current Pharmaceutical Design20017451–460. (https://doi.org/10.2174/1381612013397898)
20. LaurbergP.Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism?European Journal of Endocrinology2006155783–786. (https://doi.org/10.1530/eje.1.02295)
21. AbalovichMLlesuySGutierrezSRepettoM.Peripheral parameters of oxidative stress in Graves’ disease: the effects of methimazole and 131 iodine treatments. Clinical Endocrinology200359321–327. (https://doi.org/10.1046/j.1365-2265.2003.01850.x)
22. AdemogluEOzbeyNErbilYTanrikuluSBarbarosUYanikBTBozboraAOzarmağanS.Determination of oxidative stress in thyroid tissue and plasma of patients with Graves’ disease. European Journal of Internal Medicine200617545–550. (https://doi.org/10.1016/j.ejim.2006.04.013)
23. BurchHBLahiriSBahnRSBarnesS.Superoxide radical production stimulates retroocular fibroblast proliferation in Graves’ ophthalmopathy. Experimental Eye Research199765311–316. (https://doi.org/10.1006/exer.1997.0353)
24. HeufelderAEWenzelBEBahnRS.Methimazole and propylthiouracil inhibit the oxygen free radical-induced expression of a 72 kilodalton heat shock protein in Graves’ retroocular fibroblasts. Journal of Clinical Endocrinology and Metabolism199274737–742. (https://doi.org/10.1210/jcem.74.4.1532179)
25. MarcocciCKahalyGJKrassasGEBartalenaLPrummelMStahlMAlteaMANardiMPitzSBoboridisKSelenium and the course of mild Graves’ orbitopathy. New England Journal of Medicine20113641920–1931. (https://doi.org/10.1056/NEJMoa1012985)
26. ImamuraMAokiNSaitoTOhnoYMaruyamaYYamaguchiJYamamotoT.Inhibitory effects of antithyroid drugs on oxygen radical formation in human neutrophils. Acta Endocrinology1986112210–216. (https://doi.org/10.1530/acta.0.1120210)
27. WeetmanAPHoltMECampbellAKHallRMcGregorAM.Methimazole and generation of oxygen radicals by monocytes: potential role in immunosuppression. BMJ1984288518–520. (https://doi.org/10.1136/bmj.288.6416.518)
28. KimHLeeTHHwangYSBangMAKimKHSuhJMChungHKYuDYLeeKKKwonOYMethimazole as an antioxidant and immunomodulator in thyroid cells: mechanisms involving interferon-gamma signaling and H(2)O(2) Scavenging. Molecular Pharmacology200160972–980. (https://doi.org/10.1124/mol.60.5.972)
29. WilsonRBuchananLFraserWDJenkinsCSmithWEReglinskiJThomsonJAMcKillopJH.Evidence for carbimazole as an antioxidant?Autoimmunity199827149–153. (https://doi.org/10.3109/08916939809003862)
30. BianchiGSolaroliEZaccheroniVGrossiGBargossiAMMelchiondaNMarchesiniG.Oxidative stress and anti-oxidant metabolites in patients with hyperthyroidism: effect of treatment. Hormone and Metabolic Research199931620–624. (https://doi.org/10.1055/s-2007-978808)
31. AdaliMInal-ErdenMAkalinAEfeB.Effects of propylthiouracil, propranolol, and vitamin E on lipid peroxidation and antioxidant status in hyperthyroid patients. Clinical Biochemistry199932363–367. (https://doi.org/10.1016/S0009-9120(99)00024-7)
32. ErdamarHDemirciHYamanHErbilMKYakarTSancakBElbegSBiberoğluGYetkinI.The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clinical Chemistry and Laboratory Medicine2008461004–1010. (https://doi.org/10.1515/CCLM.2008.183)
33. HigginsJPTThompson SG Deeks JJ and Altman DG. Measuring inconsistency in meta- analyses. British Medical Journal2003327557–560.
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