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Thyroid hormones and antithyroid drugs
J.A. Franklyn
41
Thyroid hormones and antithyroid drugs
THYROID HORMONES (SED-13, 1275; SEDA-20, 393; SEDA-21, 437; SEDA-22, 469) The routine use of sensitive assays for serum thyrotrophin (TSH) has led to the recognition that many patients taking standard doses of thyroxine (T4) are biochemically 'overtreated'. Most attention continues to be focused on the potential detrimental effect of such mild thyroid hormone excess on the bones and heart. There have been further cross-sectional studies examining the effect of thyroxine on bone mineral density. In one study bone mineral density was compared in 50 women taking T4 either for primary thyroid failure or for hypothyroidism secondary to radioiodine treatment for hyperthyroidism. These two groups did not differ in terms of bone density at the hip or spine and did not differ from the reference population. In addition, there was no correlation between bone density and circulating thyroid hormone concentrations or duration of T4 replacement (1c). These findings are reassuring for those taking and prescribing T4, although large studies of fracture risk in such patients are required, in view of previous evidence of an adverse effect of T4 on bone mineral density, especially in post-menopausal women (2c). Whether T4 therapy has an adverse effect on the cardiovascular system, and in particular on the risk of dysrhythmias, continues to be debated. Evidence from the Framingham population that suppression of serum TSH is a risk factor for atrialfibrillation has heightened concern that subclinical hyperthyroidism secondary to T4 therapy has a similar adverse effect (3c). Five women taking T4 who reported frequent bouts of palpitation were investigated while taking T4 and again after T4 withdrawal 9 2000 ElsevierScience B.V. All rights reserved. Side Effects of Drugs, Annual 23 J.K. Aronson,ed.
(4c). There was a clear increase in mean 24h heart rate during T4 treatment, as well as an increase in atrial extra beats and the number of episodes of re-entrant AV nodal tachycardia. Four of these patients had evidence of abnormal conduction pathways even when they were not taking T4 therapy, as evidenced by a short PR interval, but exacerbation of atrial dysrhythmias in these predisposed subjects is consistent with the view that thyroid hormones increase atrial excitability and may increase the risk of cardiac morbidity, especially if given in doses sufficient to suppress serum TSH. While biochemical evidence of mild thyroid hormone excess is common in subjects taking T4, it is uncommon to induce symptoms, signs, or biochemical changes of overt thyroid hormone excess by taking thyroid hormones. A report has described self-induced thyrotoxicosis associated with a marked rise in circulating free T4 and free tri-iodothyronine concentrations in a pregnant woman with an eating disorder who was abusing both T4 treatment and furosemide (5c). This case reminds us that if the cause for thyrotoxicosis remains obscure, T4 abuse should be explored and considered.
ANTITHYROID DRUGS (SED-13, 1279; SEDA-20, 394; SEDA-21, 437; SEDA-22, 469) Hematological The most feared complication of thionamide drugs is bone-marrow suppression. Agranulocytosis is the most common presentation of this idiosyncratic complication. Two further reports of agranulocytosis have appeared (6c). One unusually occurred after a second exposure to the drug, in this case propylthiouracil. Aplastic anemia is very rare and has been said to occur as an adverse effect of thionamide therapy with about one-tenth of the 451
452 frequency of agranulocytosis. A report has described the development of aplastic anemia in a 58-year-old woman taking methimazole for the third time; she responded well to drug withdrawal and treatment with human granulocyte colony stimulating factor (7c).
Immunological and hypersensitivity reactions Vasculitis is another important adverse effect that is often poorly recognized as being drug related, leading to a delay in diagnosis. Several recent reports have described propylthiouracil-induced ANCA-associated small vessel vasculitis (8 c, 9c), crescentic glomerulonephritis (10 c), and Wegener's granulomatosis (1 lC). More common, however, may be a condition termed 'antithyroid arthritis syndrome', which is a transient migratory polyarthritis occurring within 2 months of starting thionamides and resolving within 4 weeks of stopping therapy (12ca).
Interactions
Since thionamides block the organification of iodine and incorporation of iodine into iodotyrosines, administration of thionamides inhibits the uptake of iodine-131 used therapeutically in hyperthyroidism. For this reason, thionamides are generally withdrawn for a period of up to a week before radioiodine therapy is planned and re-introduction is similarly delayed until several days after radioiodine therapy. A recent retrospective study (13 C) has compared the effect of treatment with either methimazole or propylthiouracil before radioiodine, the thionamide being withdrawn 5-55 days before radioiodine administration. The findings confirmed the view that propylthiouracil, although not methimazole, significantly reduced the cure rate after radioiodine compared with that found in subjects not pretreated with propylthiouracil, and that discontinuation for 4 months was required for the cure rates to be similar. These findings highlight the relative 'radio-resistance' induced by thionamide therapy, determining that prolonged drug withdrawal or an increased dose of radioiodine may be required to produce an acceptable cure rate.
Chapter 41
J.A. Franklyn
IODINE AND THE IODIDES (SED-13, 1281; SEDA-21, 438; SEDA-22, 470) It has been estimated that in 1994 some 1.5 billion people in 118 countries were at risk of iodine deficiency, this being regarded as the world's most significant cause of preventable brain damage and mental retardation. Fortification of all salt for animal and human consumption has been chosen as the preferred method for the prevention of iodine deficiency disorders, and this approach is proving effective in reducing the incidence of such disorders. However, iodine supplementation is not Without risks, which have been discussed (14 R) and which include allergic reactions and iodineinduced hyperthyroidism. It has been clearly shown that the benefits of iodine deficiency outweigh the risks on a population basis, but it is nevertheless evident that introduction of iodine supplementation is associated with clinical problems in individual subjects. A summary of the occurrence and epidemiology of iodine-induced hyperthyroidism has been published (15R), based on the authors' experience in Tasmania, Zaire, Zimbabwe, and Brazil. Another review has more specifically examined the cardiac features of iodine-induced hyperthyroidism and has emphasized the importance of awareness, monitoring, and treatment of such hyperthyroidism in areas in which iodine supplementation has been recently introduced (16R). The complexity of the interaction between iodine intake and autoimmune thyroid disease has been highlighted by reports of evidence that iodide (compared with thyroxine) induces thyroid autoimmunity in patients with endemic (iodine deficient) goiter (17R), while in those with pre-existing thyroid autoimmunity, evidenced by the presence of antithyroid (thyroid peroxidase) antibodies, administration of iodine in an area of mild iodine deficiency led to subclinical or overt hypothyroidism (18R). More importantly, in a study from Italy the use of iodine-containing disinfectants was responsible for transient neonatal hypothyroidism in more than 50% of cases identified (another common cause being transfer of maternal antibodies) (19c). These findings led the authors to conclude that pregnant women should be advised of the adverse effects of using iodinecontaining products and that their use should be generally discouraged.
Thyroid hormones and antithyroid drugs
Chapter41
453
REFERENCES 1. Hanna FWF, Pettit RJ, Ammari F, Evans WD, Sandeman D, Lazarus JH. Effect of replacement doses of thyroxine on bone mineral density. Clin Endocrinol 1998;48:229-34. 2. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long-term treatment with thyroid hormones:a metaanalysis. J Clin Endocrinol Metab 1996;81:427889. 3. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PWF, Benjamin EJ, A'Agostino RB. Low serum thyrotropin concentration as a risk factor for atrial fibrillation in older persons. New Engl J Med 1994;331:1249-52. 4. Biondi B, Fazio S, Coltorti F, Palmieri EA, Carella C, Lombardi G, Sacca L. Clinical case seminar. Reentrant atrioventricular nodal tachycardia induced by levothyroxine. J Clin Endocrinol Metab 1998;83:2643-5. 5. Wark H, Wallace EM, Wigg S, Tippett C. Thyroxine abuse: an unusual case of thyrotoxicosis in pregnancy. Aust NZ J Obstet Gynaecol 1998;38:221-3. 6. Roeloffzen WWH, Verhaegh JJ, Van Poelgeest AE, Gansevoort RT. Fever or a sore throat after start of antithyroidal drugs? A medical emergency. Neth J Med 1998;53:113-17. 7. Mezquita P, Luna V, Mufioz-Torres M, TorresVela E, Lopez-Rodriguez F, Callejas JL, EscobarJimenez E Methimazole-induced aplastic anaemia in third exposure: successful treatment with recombinant human granulocyte colony-stimulating factor. Thyroid 1998;8/9:791~1. 8. Harper L, Cockwell E Savage COS. Case of propylthiouracil-induced ANCA associated small vessel vasculitis. Nephrol Dial Transplant 1998; 13:455-8. 9. Miller RM, Savige J, Nassis L, Cominos BI. Antineutrophil cytoplasmic antibody (ANCA)positive cutaneous leucocytoclastic vasculitis associated with antithyroid therapy in Graves' disease. Australas J Dermatol 1998;39:96-9. 10. Fujieda M, Nagata M, Akioka Y, Hattori M,
Kawaguchi H, Ito K. Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with propylthiouracil therapy. Acta Paediatr Jap Overs Ed 1998;40:286-9. 11. Pillinger M, Stand R. Wegener's granulomatosis in a patient receiving propylthiouracil for Graves' disease. Sem Arthritis Rheum 1998; 28:124-9. 12. Bajaj S, Bell MJ, Shumak S, Briones-Urbina R. Antithyroid arthritis syndrome. J Rheumatol 1998;25:1235-9. 13. Imseis RE, Van Middlesworth L, Massie JD, Bush AJ, Van Middlesworth NR. Pretreatment with propylthiouracil but not methimazole reduces the therapeutic efficacy of iodine- 131 in hyperthyroidism. J Clin Endocrinol Metab 1998;83:685-7. 14. Delange E Risks and benefits of iodine supplementation. Lancet 1998;351:9234. 15. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, Vidor G, Braverman LE, Medeiros-Neto G. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998;8:83-100. 16. Dunn JT, Semigran MJ, Delange E The prevention and management of iodine-induced hyperthyroidism and its cardiac features. Thyroid 1998;8:101-6. 17. Kahaly GJ, Dienes HP, Beyer J, Hommel G. Iodine induces thyroid autoimmunity in patients with endemic goitre: a randomised, doubleblind, placebo-controlled trial. Eur J Endocrinol 1998; 139:290-7. 18. Reinhardt W, Luster M, Rudorff KH, Heckmann C, Petrasch S, Lederbogen S, Haase R, Sailer B, Reiners C, Reinwein D, Mann K. Effect of small doses of iodine on thyroid function in patients with Hashimoto's thyroiditis residing in an area of mild iodine deficiency. Eur J Endocrinol 1998;139: 23-8. 19. Weber G, Vigone MC, Rapa A, Bona G, Chiumello G. Neonatal transient hypothyroidism: aetiological study. Arch Dis Child Fetal Neonat Ed 1998;79:F70-2.
41
Thyroid hormones and antithyroid drugs
THYROID HORMONES (SED-13, 1275; SEDA-20, 393; SEDA-21, 437; SEDA-22, 469) The routine use of sensitive assays for serum thyrotrophin (TSH) has led to the recognition that many patients taking standard doses of thyroxine (T4) are biochemically 'overtreated'. Most attention continues to be focused on the potential detrimental effect of such mild thyroid hormone excess on the bones and heart. There have been further cross-sectional studies examining the effect of thyroxine on bone mineral density. In one study bone mineral density was compared in 50 women taking T4 either for primary thyroid failure or for hypothyroidism secondary to radioiodine treatment for hyperthyroidism. These two groups did not differ in terms of bone density at the hip or spine and did not differ from the reference population. In addition, there was no correlation between bone density and circulating thyroid hormone concentrations or duration of T4 replacement (1c). These findings are reassuring for those taking and prescribing T4, although large studies of fracture risk in such patients are required, in view of previous evidence of an adverse effect of T4 on bone mineral density, especially in post-menopausal women (2c). Whether T4 therapy has an adverse effect on the cardiovascular system, and in particular on the risk of dysrhythmias, continues to be debated. Evidence from the Framingham population that suppression of serum TSH is a risk factor for atrialfibrillation has heightened concern that subclinical hyperthyroidism secondary to T4 therapy has a similar adverse effect (3c). Five women taking T4 who reported frequent bouts of palpitation were investigated while taking T4 and again after T4 withdrawal 9 2000 ElsevierScience B.V. All rights reserved. Side Effects of Drugs, Annual 23 J.K. Aronson,ed.
(4c). There was a clear increase in mean 24h heart rate during T4 treatment, as well as an increase in atrial extra beats and the number of episodes of re-entrant AV nodal tachycardia. Four of these patients had evidence of abnormal conduction pathways even when they were not taking T4 therapy, as evidenced by a short PR interval, but exacerbation of atrial dysrhythmias in these predisposed subjects is consistent with the view that thyroid hormones increase atrial excitability and may increase the risk of cardiac morbidity, especially if given in doses sufficient to suppress serum TSH. While biochemical evidence of mild thyroid hormone excess is common in subjects taking T4, it is uncommon to induce symptoms, signs, or biochemical changes of overt thyroid hormone excess by taking thyroid hormones. A report has described self-induced thyrotoxicosis associated with a marked rise in circulating free T4 and free tri-iodothyronine concentrations in a pregnant woman with an eating disorder who was abusing both T4 treatment and furosemide (5c). This case reminds us that if the cause for thyrotoxicosis remains obscure, T4 abuse should be explored and considered.
ANTITHYROID DRUGS (SED-13, 1279; SEDA-20, 394; SEDA-21, 437; SEDA-22, 469) Hematological The most feared complication of thionamide drugs is bone-marrow suppression. Agranulocytosis is the most common presentation of this idiosyncratic complication. Two further reports of agranulocytosis have appeared (6c). One unusually occurred after a second exposure to the drug, in this case propylthiouracil. Aplastic anemia is very rare and has been said to occur as an adverse effect of thionamide therapy with about one-tenth of the 451
452 frequency of agranulocytosis. A report has described the development of aplastic anemia in a 58-year-old woman taking methimazole for the third time; she responded well to drug withdrawal and treatment with human granulocyte colony stimulating factor (7c).
Immunological and hypersensitivity reactions Vasculitis is another important adverse effect that is often poorly recognized as being drug related, leading to a delay in diagnosis. Several recent reports have described propylthiouracil-induced ANCA-associated small vessel vasculitis (8 c, 9c), crescentic glomerulonephritis (10 c), and Wegener's granulomatosis (1 lC). More common, however, may be a condition termed 'antithyroid arthritis syndrome', which is a transient migratory polyarthritis occurring within 2 months of starting thionamides and resolving within 4 weeks of stopping therapy (12ca).
Interactions
Since thionamides block the organification of iodine and incorporation of iodine into iodotyrosines, administration of thionamides inhibits the uptake of iodine-131 used therapeutically in hyperthyroidism. For this reason, thionamides are generally withdrawn for a period of up to a week before radioiodine therapy is planned and re-introduction is similarly delayed until several days after radioiodine therapy. A recent retrospective study (13 C) has compared the effect of treatment with either methimazole or propylthiouracil before radioiodine, the thionamide being withdrawn 5-55 days before radioiodine administration. The findings confirmed the view that propylthiouracil, although not methimazole, significantly reduced the cure rate after radioiodine compared with that found in subjects not pretreated with propylthiouracil, and that discontinuation for 4 months was required for the cure rates to be similar. These findings highlight the relative 'radio-resistance' induced by thionamide therapy, determining that prolonged drug withdrawal or an increased dose of radioiodine may be required to produce an acceptable cure rate.
Chapter 41
J.A. Franklyn
IODINE AND THE IODIDES (SED-13, 1281; SEDA-21, 438; SEDA-22, 470) It has been estimated that in 1994 some 1.5 billion people in 118 countries were at risk of iodine deficiency, this being regarded as the world's most significant cause of preventable brain damage and mental retardation. Fortification of all salt for animal and human consumption has been chosen as the preferred method for the prevention of iodine deficiency disorders, and this approach is proving effective in reducing the incidence of such disorders. However, iodine supplementation is not Without risks, which have been discussed (14 R) and which include allergic reactions and iodineinduced hyperthyroidism. It has been clearly shown that the benefits of iodine deficiency outweigh the risks on a population basis, but it is nevertheless evident that introduction of iodine supplementation is associated with clinical problems in individual subjects. A summary of the occurrence and epidemiology of iodine-induced hyperthyroidism has been published (15R), based on the authors' experience in Tasmania, Zaire, Zimbabwe, and Brazil. Another review has more specifically examined the cardiac features of iodine-induced hyperthyroidism and has emphasized the importance of awareness, monitoring, and treatment of such hyperthyroidism in areas in which iodine supplementation has been recently introduced (16R). The complexity of the interaction between iodine intake and autoimmune thyroid disease has been highlighted by reports of evidence that iodide (compared with thyroxine) induces thyroid autoimmunity in patients with endemic (iodine deficient) goiter (17R), while in those with pre-existing thyroid autoimmunity, evidenced by the presence of antithyroid (thyroid peroxidase) antibodies, administration of iodine in an area of mild iodine deficiency led to subclinical or overt hypothyroidism (18R). More importantly, in a study from Italy the use of iodine-containing disinfectants was responsible for transient neonatal hypothyroidism in more than 50% of cases identified (another common cause being transfer of maternal antibodies) (19c). These findings led the authors to conclude that pregnant women should be advised of the adverse effects of using iodinecontaining products and that their use should be generally discouraged.
Thyroid hormones and antithyroid drugs
Chapter41
453
REFERENCES 1. Hanna FWF, Pettit RJ, Ammari F, Evans WD, Sandeman D, Lazarus JH. Effect of replacement doses of thyroxine on bone mineral density. Clin Endocrinol 1998;48:229-34. 2. Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long-term treatment with thyroid hormones:a metaanalysis. J Clin Endocrinol Metab 1996;81:427889. 3. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PWF, Benjamin EJ, A'Agostino RB. Low serum thyrotropin concentration as a risk factor for atrial fibrillation in older persons. New Engl J Med 1994;331:1249-52. 4. Biondi B, Fazio S, Coltorti F, Palmieri EA, Carella C, Lombardi G, Sacca L. Clinical case seminar. Reentrant atrioventricular nodal tachycardia induced by levothyroxine. J Clin Endocrinol Metab 1998;83:2643-5. 5. Wark H, Wallace EM, Wigg S, Tippett C. Thyroxine abuse: an unusual case of thyrotoxicosis in pregnancy. Aust NZ J Obstet Gynaecol 1998;38:221-3. 6. Roeloffzen WWH, Verhaegh JJ, Van Poelgeest AE, Gansevoort RT. Fever or a sore throat after start of antithyroidal drugs? A medical emergency. Neth J Med 1998;53:113-17. 7. Mezquita P, Luna V, Mufioz-Torres M, TorresVela E, Lopez-Rodriguez F, Callejas JL, EscobarJimenez E Methimazole-induced aplastic anaemia in third exposure: successful treatment with recombinant human granulocyte colony-stimulating factor. Thyroid 1998;8/9:791~1. 8. Harper L, Cockwell E Savage COS. Case of propylthiouracil-induced ANCA associated small vessel vasculitis. Nephrol Dial Transplant 1998; 13:455-8. 9. Miller RM, Savige J, Nassis L, Cominos BI. Antineutrophil cytoplasmic antibody (ANCA)positive cutaneous leucocytoclastic vasculitis associated with antithyroid therapy in Graves' disease. Australas J Dermatol 1998;39:96-9. 10. Fujieda M, Nagata M, Akioka Y, Hattori M,
Kawaguchi H, Ito K. Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with propylthiouracil therapy. Acta Paediatr Jap Overs Ed 1998;40:286-9. 11. Pillinger M, Stand R. Wegener's granulomatosis in a patient receiving propylthiouracil for Graves' disease. Sem Arthritis Rheum 1998; 28:124-9. 12. Bajaj S, Bell MJ, Shumak S, Briones-Urbina R. Antithyroid arthritis syndrome. J Rheumatol 1998;25:1235-9. 13. Imseis RE, Van Middlesworth L, Massie JD, Bush AJ, Van Middlesworth NR. Pretreatment with propylthiouracil but not methimazole reduces the therapeutic efficacy of iodine- 131 in hyperthyroidism. J Clin Endocrinol Metab 1998;83:685-7. 14. Delange E Risks and benefits of iodine supplementation. Lancet 1998;351:9234. 15. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, Vidor G, Braverman LE, Medeiros-Neto G. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998;8:83-100. 16. Dunn JT, Semigran MJ, Delange E The prevention and management of iodine-induced hyperthyroidism and its cardiac features. Thyroid 1998;8:101-6. 17. Kahaly GJ, Dienes HP, Beyer J, Hommel G. Iodine induces thyroid autoimmunity in patients with endemic goitre: a randomised, doubleblind, placebo-controlled trial. Eur J Endocrinol 1998; 139:290-7. 18. Reinhardt W, Luster M, Rudorff KH, Heckmann C, Petrasch S, Lederbogen S, Haase R, Sailer B, Reiners C, Reinwein D, Mann K. Effect of small doses of iodine on thyroid function in patients with Hashimoto's thyroiditis residing in an area of mild iodine deficiency. Eur J Endocrinol 1998;139: 23-8. 19. Weber G, Vigone MC, Rapa A, Bona G, Chiumello G. Neonatal transient hypothyroidism: aetiological study. Arch Dis Child Fetal Neonat Ed 1998;79:F70-2.