Update on the Management of Hyperthyroidism and Hypothyroidism

REVIEW ARTICLE Update on the Management of Hyperthyroidism and Hypothyroidism

Kenneth A. Woeber, MD, FRCPE

linical aspects, laboratory investigation, and treatment of hyperthyroidism and hypothyroidism are reviewed in light of recent information. Special circumstances, such as hyperthyroidism during pregnancy, Graves ophthalmopathy, iodine-induced hyperthyroidism, and subclinical hypothyroidism, are also considered. C Arch Intern Med. 2000;160:1067-1071

Hyperthyroidism and hypothyroidism are than 70 years, however, the classic clini- common disorders, especially in women. cal manifestations may be lacking and goi- In the 20-year follow-up of the original ter may be absent.3 Instead, anorexia with Whickham survey, which involved sev- wasting, atrial fibrillation, or congestive eral thousand randomly selected adults 18 heart failure may be the predominant years or older at enrollment, 0.8 per 1000 manifestations. Furthermore, the cause of surviving women per year developed hy- hyperthyroidism will differ between young perthyroidism and 3.5 per 1000 per year and elderly patients. In young patients developed spontaneous hypothyroid- Graves disease is almost always the cause, ism.1 In 1995, the American Thyroid As- whereas in elderly patients toxic nodular sociation published guidelines for the man- goiter is also a common cause. agement of these disorders.2 In this article, I provide an update of their management Laboratory Investigation in light of more recent information. Measurement of serum thyrotropin, HYPERTHYROIDISM using at least a second-generation assay (detection limit, approximately 0.05 Although the terms hyperthyroidism and thy- mIU/L), is the most sensitive test for rotoxicosis are frequently used interchange- screening for hyperthyroidism, a normal ably, in the strictest sense hyperthyroidism result virtually excluding hyperthyroid- refers to hyperfunction of the thyroid gland, ism, except in the rare instance where it whereas thyrotoxicosis refers to any state is due to thyrotropin hypersecretion. An characterized by thyroid hormone excess, undetectable value is the hallmark of including ingestion of excess thyroid hor- hyperthyroidism, but a low or sometimes mone and thyroiditis. This article, there- an undetectable value using a second- fore, will be principally concerned with the generation assay may occur in some management of hyperthyroidism caused by healthy elderly patients, in patients with Graves disease or associated with toxic nonthyroid illness, or in patients taking a nodular goiter. glucocorticoid or dopamine hydrochloride. In these circumstances, a third- Clinical Considerations generation assay (detection limit, approximately 0.005 mIU/L) will afford A diagnosis of hyperthyroidism is sug- the necessary distinction, because in gested by the presence of a constellation hyperthyroidism serum thyrotropin is of symptoms and signs. In patients older still undetectable, whereas in the other conditions thyrotropin is almost always From the Department of Medicine, University of California, San Francisco, detectable, albeit low.4 Confirmation is Mount Zion Medical Center. sought in measurement of serum free

ARCH INTERN MED/ VOL 160, APR 24, 2000 WWW.ARCHINTERNMED.COM 1067

Downloaded From: https://jamanetwork.com/ on 09/29/2021 thyroxine (FT4). Occasionally, as a single daily dose, improving disorder has the potential to enter measurement of serum free triiodo- compliance.5 Moreover, in doses up a spontaneous remission. It is gen- thyronine (FT3) will be necessary to 30 mg/d, methimazole may carry erally considered the treatment of in a patient with clinical manifesta- a lower risk of agranulocytosis. choice for young patients with a tions of hyperthyroidism and an Treatment is usually initiated small goiter or patients with active undetectable serum thyrotropin with 30 mg of methimazole daily or ophthalmopathy (vide infra). Anti- and normal serum FT4 levels, 100 mg of propylthiouracil 3 times thyroid drugs are not indicated as defining the entity of triiodothyro- daily. The patient should be alerted long-term therapy in toxic nodular nine toxicosis. to the major, albeit rare (Ͻ1%), ad- goiter, since hyperthyroidism does In a patient with overt oph- verse effects of these drugs, includ- not remit. The likelihood of a long- thalmopathy, no additional testing ing agranulocytosis, liver disease, term remission is positively influ- is required, because the patient cer- and a lupuslike syndrome that tend enced by the duration of antithy- tainly has Graves disease. However, to occur within the first several roid drug therapy, and a duration of in a woman of child-bearing age, it months of therapy. Baseline labora- 1 to 2 years is recommended, with is essential to determine whether tory data should include a leuko- reported remission rates ranging she is pregnant, because this will cyte count and liver function tests, from 37% to 70%. Initial work had clearly influence the subsequent and monitoring of the leukocyte suggested that adding levothyrox- management (vide infra). In a count may predict agranulocytosis. ine sodium to long-term antithy- patient without ophthalmopathy, The patient should be instructed to roid drug therapy in patients with measurement of thyroid radioio- notify the physician immediately if Graves disease resulted in a greater dine (131I) uptake should be per- symptoms suggesting one of these likelihood of remission when the an- formed to establish the cause of adverse reactions appear. With- tithyroid drug was withdrawn. The thyrotoxicosis, ie, whether it is due drawal of the drug will result in reso- rationale for this approach was that to hyperthyroidism, in which case lution of the adverse reaction, but the antithyroid drugs might also ex- the uptake will be high, or to some both antithyroid drugs are contra- ert an immunosuppressive action, other condition where thyroid indicated thereafter, and the pa- and combination therapy permit- hyperfunction is lacking, such as tient will have to be treated with 131I ted the use of a higher dose of antithyroid hormone ingestion or thy- or surgery. With minor adverse re- thyroid drug. However, several more roiditis, in which case the uptake actions, such as pruritus, the patient recent studies6-9 have failed to con- will be low. A 131I scintiscan may be can be switched to the alternate firm these earlier findings. There are helpful in a patient with a nodular agent. no absolute predictors of outcome goiter, because it will serve to After treatment has been initi- following withdrawal of therapy, but define the functional characteristics ated, the patient should be fol- certain features, such as a small goi- of the gland. lowed up at approximately monthly ter, favor remission, whereas oth- intervals and the antithyroid drug ers, such as persistence of undetect- Treatment dose reduced to a maintenance dose able thyrotropin or high thyrotropin as a euthyroid state is approached. receptor antibody titer, favor re- Hyperthyroidism may be treated with The speed with which this is at- lapse.8 antithyroid drugs, 131I, or subtotal tained is determined by the sever- Following withdrawal of long- thyroidectomy, the type of treat- ity of disease, goiter size, and dose term therapy, the patient should ment being determined by the form of antithyroid drug. During this in- continue to be seen every 3 months of hyperthyroidism, the age of the pa- terim period, a ␤-adrenergic recep- for the first year, since relapse is most tient, the size of the goiter, and the tor blocking agent, such as pro- likely within this period. Thereaf- presence of coexisting conditions. pranolol hydrochloride, may be used ter, the patient should be seen an- to control the hyperadrenergic mani- nually, since relapse may occur in Antithyroid Drugs. Methimazole festations, such as tremor, anxiety, later years. Should relapse occur, the and propylthiouracil, the 2 drugs and palpitations, if these are trouble- patient should be treated with 131Ior available in the United States, are some, provided the patient does not subtotal thyroidectomy, although thioamides that are concentrated in have obstructive pulmonary dis- antithyroid drug therapy could be re- thyroid tissue and inhibit hormone ease or other contraindications to its instituted if the patient wishes to biosynthesis. In the United King- use. Measurement of serum FT4 avoid ablative therapy. dom and Europe, carbimazole is the rather than thyrotropin should be commonly used drug; it is virtually used to monitor treatment, since se- Radioiodine. 131I is the treatment of completely converted to methima- rum thyrotropin may remain unde- choice for patients with Graves hy- zole in vivo. In large doses, propyl- tectable for many months after a eu- perthyroidism who relapse after thiouracil also inhibits the periph- thyroid state is restored. Thereafter, long-term antithyroid drug therapy, eral tissue conversion of thyroxine the patient should be seen every 3 for patients with severe thyrocar- to triiodothyronine. Methimazole is months if long-term therapy is diac disease, for most patients with used in preference to propylthioura- planned. toxic multinodular or uninodular cil, because it has a longer inhibi- Long-term antithyroid drug goiter, and for patients with a ma- tory effect on glandular hormone therapy is only appropriate for jor adverse reaction to antithyroid synthesis and can therefore be taken Graves hyperthyroidism, since this drugs. 131I therapy is absolutely con-

ARCH INTERN MED/ VOL 160, APR 24, 2000 WWW.ARCHINTERNMED.COM 1068

Downloaded From: https://jamanetwork.com/ on 09/29/2021 traindicated during pregnancy or pothyroidism emerges or persists for Special Circumstances breastfeeding. In addition, 131I more than 6 months after 131I therapy should be avoided or post- therapy, it is likely to be perma- Hyperthyroidism During Preg- poned in patients with active Graves nent, and levothyroxine treatment nancy. Hyperthyroidism that com- ophthalmopathy, especially if they should be instituted. Other adverse plicates pregnancy may lead to in- are cigarette smokers, since a re- effects of therapeutic doses of 131I for creased fetal loss and should cent prospective study10,11 has dem- hyperthyroidism are minimal. Data therefore be treated with antithy- onstrated worsening in such pa- from the Swedish Cancer Registry roid drugs, using the smallest dose tients treated with 131I compared with suggest a slight overall increase in that maintains a euthyroid state. Pro- those treated with antithyroid drugs cancer risk but no increase in risk pylthiouracil is usually given in pref- or subtotal thyroidectomy. for leukemia or lymphoma.14 Ac- erence to methimazole because of its The dose of 131I used to treat cordingly, since young tissue is more reported lower transplacental pas- Graves hyperthyroidism ranges from sensitive to ionizing radiation, 131I sage, although recent work15 does 185 to 555 MBq (5-15 mCi), de- therapy is generally not considered not corroborate this difference. Since pending on the size of the goiter and as the initial treatment for chil- pregnancy attenuates the course of the magnitude of uptake of an an- dren. There is no evidence for in- Graves hyperthyroidism, probably as tecedent tracer dose of 131I. With creased rates of teratogenesis with a result of the increased immune tol- toxic nodular goiter, larger doses are the doses of 131I used for hyperthy- erance, the antithyroid drug can of- required to achieve a euthyroid state. roidism. ten be withdrawn in the third tri- Pretreatment with propylthioura- mester but will usually have to be cil, but perhaps not methimazole, Subtotal Thyroidectomy. Subtotal reinstituted in the early postpar- may reduce the one-dose cure rate thyroidectomy is indicated in tum period. Breastfeeding can be of 131I through a putative radiopro- pregnant patients and children continued, since propylthiouracil is tective effect.12,13 Accordingly, meth- who have a major adverse reaction poorly transferred into breast milk. imazole should only be used before to propylthiouracil or methima- Although methimazole is readily 131I treatment in patients with se- zole. It is also appropriate therapy transferred into breast milk, a re- vere hyperthyroidism or a very large for patients with large goiters that cent study16 suggests that thyroid goiter to forestall exacerbation of hy- extend retrosternally and lead to function remains normal in breast- perthyroidism as a result of the tran- compressive manifestations and fed infants of lactating mothers tak- sient radiation thyroiditis. In these for patients with thyroid carci- ing a maintenance dose of methima- circumstances, the antithyroid drug noma complicating a toxic goiter. zole. If subtotal thyroidectomy is is given to restore euthyroidism and The patient must be restored to a indicated, it should be undertaken then stopped 3 to 5 days before the euthyroid state before surgery to in the middle of the second trimes- administration of 131I. forestall postoperative thyrotoxic ter. In more than 80% of patients, crisis. This is accomplished with hyperthyroidism will be cured and propylthiouracil or methimazole Ophthalmopathy. Clinically overt the goiter will decrease with a single as described earlier, and in the 7 ophthalmopathy is seen in approxi- dose of 131I. Since it may take sev- to 10 days before surgery for mately 50% of patients with Graves eral months for euthyroidism to be Graves hyperthyroidism, inor- disease and runs a course that may restored, patients with severe hy- ganic iodide is added to further be independent of the hyperthy- perthyroidism may require treat- reduce thyroid vascularity. Inor- roid component. In patients with ac- ment with an antithyroid drug or a ganic iodide should not be given tive ophthalmopathy, 131I therapy ␤-adrenergic receptor blocking agent to patients with toxic nodular goi- should be postponed or avoided, es- during this interim period. Women ter, because it may lead to exacer- pecially if they are cigarette smok- of child-bearing age should be ad- bation of hyperthyroidism. If the ers, because it may lead to worsen- vised to postpone conception for at patient is unable to take propyl- ing of the eye disease.10,11 If, for other least 6 months after treatment with thiouracil or methimazole, a reasons, 131I is the only reasonable 131I. ␤-adrenergic receptor blocking therapeutic option, it should be ad- Permanent hypothyroidism is agent may be given in the 7 to 10 ministered as a fully ablative dose the major complication of 131I days before surgery along with and followed by a 3-month course therapy, its prevalence at 1 year be- inorganic iodide. The early com- of glucocorticoid therapy, which will ing determined by the dose given. plications of subtotal thyroidec- forestall aggravation of the eye dis- Thereafter, the prevalence rises at a tomy, which include hypoparathy- ease.10 rate of 2% to 3% per year. Accord- roidism and recurrent laryngeal ingly, the patient should be fol- nerve damage, are rare, but per- Iodine-Induced Hyperthyroidism lowed up at monthly intervals ini- manent hypothyroidism will even- (Jod-Basedow Disease). Excess io- tially and at increasing intervals once tually occur in a significant per- dine has the potential to lead to hy- euthyroidism is restored, with moni- centage of patients. Accordingly, perthyroidism in some patients with toring of serum FT4 and thyrotro- the patient should be followed up multinodular goiter or other states pin levels. Transient hypothyroid- in 1 month and then at increasing of relative thyroid autonomy. The io- ism may occur during the first 6 intervals thereafter, with monitor- dine excess usually results from use 131 months after I therapy. When hy- ing of serum FT4 and thyrotropin. of a radiographic contrast agent or

ARCH INTERN MED/ VOL 160, APR 24, 2000 WWW.ARCHINTERNMED.COM 1069

Downloaded From: https://jamanetwork.com/ on 09/29/2021 a medication such as amiodarone, tration. Measurement of serum without preexisting angina, treat- which is composed by weight of 37% thyrotropin is the most sensitive test ment will provoke the onset of an- iodine.17 (Amiodarone may also for detecting early thyroid failure, gina, and some patients with coro- cause thyrotoxicosis by producing since an increase will antedate a de- nary heart disease will experience a thyroiditis.) Treatment involves the cline of serum FT4 to subnormal by myocardial infarction at some time use of potassium perchlorate, a drug many months and sometimes years after initiation of therapy. Accord- that blocks thyroid iodide trans- (subclinical hypothyroidism). Con- ingly, for patients with angina pec- port, and propylthiouracil or meth- firmation of clinical hypothyroid- toris, treatment should be initiated imazole to inhibit hormone biosyn- ism is sought in a decreased serum with 25 µg/d or less of levothyrox- thesis. FT4 level. In patients with no prior ine sodium and the dose gradually in- history of thyroid ablative therapy, creased at approximately 6-week in- HYPOTHYROIDISM the presence in serum of thyro- tervals. Angina should be managed peroxidase antibody will confirm in the usual manner with a ␤-adren- Hypothyroidism refers to any state chronic autoimmune thyroiditis as ergic blocking agent, but smaller- that results in a deficiency of thy- the cause. Because of its clinical or than-usual doses will be required be- roid hormone, including hypotha- immunologic overlap with other au- cause of its reduced clearance in the lamic or pituitary disease and gen- toimmune diseases, such as perni- hypothyroid state. If angina cannot eralized tissue resistance to thyroid cious anemia and adrenal insuffi- be controlled despite careful dosing hormone, and disorders that affect ciency, the physician should be on with levothyroxine, percutaneous the thyroid gland directly. Since the the alert for these in a patient with transluminal coronary angioplasty or former 2 forms of hypothyroidism chronic autoimmune thyroiditis.18 coronary artery bypass grafting are rare (Ͻ5%), this article will ad- should be undertaken, since mortal- dress the management of primary Treatment ity and major morbidity do not ap- thyroid failure. pear to be greater than in persons in With the exception of certain con- the euthyroid state. Clinical Considerations ditions that lead to self-limited Ideally, levothyroxine should hypothyroidism, treatment of be taken on awakening at least 30 The clinical manifestations of hy- hypothyroidism will be lifelong. minutes before eating, because some pothyroidism emerge insidiously, are Levothyroxine is the drug of fiber or bran products may impair nonspecific, and often are attrib- choice, because its conversion to absorption.20 Moreover, if the pa- uted to aging. They include a gen- L-triiodothyronine will be appropri- tient is taking other medications, eral slowing down, mental depres- ately regulated by the tissues. The such as iron, antacids, sucralfate, or sion, modest weight gain, intolerance mean dose of levothyroxine sodium bile acid sequestrants, ingestion of of cold, constipation, vague aches required to restore euthyroidism these drugs and levothyroxine and pains, dryness of the skin, and (replacement dose) in adults is should be separated by hours.21 Fi- brittleness of the scalp hair. As the approximately 1.6 µg/kg daily. nally, the dose of levothyroxine may disorder becomes more fully estab- Neonates and children require have to be increased when its meta- lished, the classic features of non- larger replacement doses. In bolic disposition is accelerated by pitting edema (myxedema) of the patients without evidence of preex- pregnancy or by drugs that induce skin, periorbital edema, hoarse- isting coronary heart disease, treat- hepatic microsomal mixed func- ness, sinus bradycardia, decrease in ment is initiated with 50 µg/d of tion oxygenases, such as rifampin, body temperature, and delayed re- levothyroxine sodium and in young phenytoin, or carbamazepine.21 Once laxation of the deep tendon re- patients can be initiated with a full the patient has been restored to a eu- flexes appear. Laboratory investiga- replacement dose. Serum thyrotro- thyroid state, follow-up is required tion may reveal a mild anemia, pin, not FT4, is used to monitor only at 6- to 12-month intervals with increased creatine phosphokinase replacement. Since it takes at least measurement of serum thyrotropin concentrations, and an abnormal 4 weeks for thyrotropin to stabilize and FT4 levels. Overtreatment must lipid profile with increased total and in response to levothyroxine, dose be avoided, because thyroid hor- low-density lipoprotein choles- increases should not occur more mone excess may lead to a decrease terol and decreased high-density li- frequently. Accordingly, the patient in bone mineral density in post- poprotein cholesterol concentra- should be followed up at 1- to menopausal women and to adverse tions. In the United States, primary 2-month intervals initially, and the cardiac consequences.22,23 thyroid failure is most often caused dose of levothyroxine should be by chronic autoimmune thyroid- increased gradually until the Special Circumstances: itis, with or without goiter, or by patient is clinically euthyroid, with Subclinical Hypothyroidism prior surgical or 131I ablative therapy. the serum thyrotropin level in the normal range. Subclinical hypothyroidism refers to Laboratory Investigation In patients with preexisting an- the state in which an increased se- gina pectoris, treatment will aggra- rum thyrotropin level is accompa- The laboratory hallmark of pri- vate angina in about one fifth and re- nied by a normal serum FT4 level in mary hypothyroidism is an in- sult in no change or improvement in an asymptomatic patient.24 Progres- creased serum thyrotropin concen- the remainder.19 In some patients sion to overt hypothyroidism is likely

ARCH INTERN MED/ VOL 160, APR 24, 2000 WWW.ARCHINTERNMED.COM 1070

Downloaded From: https://jamanetwork.com/ on 09/29/2021 if the serum thyrotropin level ex- illness.JClinEndocrinolMetab.1994;78:1368-1371. therapeutic efficacy of iodine-131 in hyperthy- ceeds 10 mIU/L or if thyroid antibod- 5. Okamura K, Ikenoue H, Shiroozu A, Sato K, Yoshi- roidism. J Clin Endocrinol Metab. 1998;83:685- nari M, Fujishima M. Reevaluation of the effects 687. ies are present in high titer. Accord- of methylmercaptoimidazole and propylthioura- 14. Holm L-E, Hall P, Wiklund K, et al. Cancer risk af- ingly, if either of these findings is cil in patients with Graves’ hyperthyroidism. J Clin ter iodine-131 therapy for hyperthyroidism. J Natl present, a case can be made for levo- Endocrinol Metab. 1987;65:719-723. Cancer Inst. 1991;83:1072-1077. thyroxine replacement. Moreover, 6. Tamai H, Hayaki I, Kawai K, et al. Lack of effect of 15. Mortimer RH, Cannell GR, Addison RS, Johnson thyroxine administration on elevated thyroid stimu- LP, Roberts MS, Bernus I. Methimazole and pro- some of these patients will have an ab- lating hormone receptor antibody levels in treated plythiouracil equally cross the perfused human normal serum lipid profile that may Graves’ disease patients. J Clin Endocrinol Metab. term placental lobule. J Clin Endocrinol Metab. be corrected by replacement therapy. 1995;80:1481-1484. 1997;82:3099-3102. 7. McIver B, Rae P, Beckett G, Wilkinson E, Gold A, 16. Azizi F. Effect of methimazole treatment of ma- Toft A. Lack of effect of thyroxine in patients with ternal thyrotoxicosis on thyroid function in breast- Accepted for publication July 12, 1999. Graves’ hyperthyroidism who are treated with an an- feeding infants. J Pediatr. 1996;128:855-858. Reprints: Kenneth A. Woeber, tithyroid drug. N Engl J Med. 1996;334:220-224. 17. Harjai KJ, Licata AA. Effects of amiodarone on MD, FRCPE, UCSF/Mount Zion, 8. Lucas A, Salinas I, Rius F, et al. Medical therapy thyroid function. Ann Intern Med. 1997;126:63- Campus Box 1640, San Francisco, CA of Graves’ disease: does thyroxine prevent recur- 73. 94143-1640. rence of hyperthyroidism? J Clin Endocrinol Metab. 18. Baker JR Jr. Autoimmune endocrine disease. 1997;82:2410-2413. JAMA. 1997;278:1931-1937. 9. Rittmaster RS, Abbott EC, Douglas R, et al. Ef- 19. Bernstein R, Muller C, Midtbo K, Smith G, Haug REFERENCES fect of methimazole, with or without L-thyroxine, E, Hertzenberg L. Silent myocardial ischemia in on remission rates in Graves’ disease. J Clin En- hypothyroidism. Thyroid. 1995;5:443-447. docrinol Metab. 1998;83:814-818. 20. Liel Y, Harman-Boehm I, Shany S. Evidence for a 1. Vanderpump MPJ, Tunbridge WMG, French JM, 10. Bartalena L, Marcocci C, Bogazzi F, et al. Rela- clinically important adverse effect of fiber- et al. The incidence of thyroid disorders in the com- tion between therapy for hyperthyroidism and the enriched diet on the bioavailability of levothyrox- munity: a twenty-year follow-up of the Whick- course of Graves’ ophthalmopathy. N Engl J Med. ine in adult hypothyroid patients. J Clin Endocri- ham survey. Clin Endocrinol. 1995;43:55-68. 1998;338:73-78. nol Metab. 1996;80:857-859. 2. Singer PA, Cooper DS, Levy EG, et al. Treatment 11. Bartalena L, Marcocci C, Tanda ML, et al. Ciga- 21. Mandel S, Brent GA, Larsen PR. Levothyroxine guidelines for patients with hyperthyroidism and rette smoking and treatment outcomes in Graves’ therapy in patients with thyroid disease. Ann In- hypothyroidism. JAMA. 1995;273:808-812. ophthalmopathy. Ann Intern Med. 1998;129:632- tern Med. 1993;119:492-502. 3. Trivalle C, Doucet J, Chassagne P, et al. Differ- 635. 22. Greenspan SL, Greenspan FS. The effect of thy- ences in the signs and symptoms of hyperthy- 12. Tuttle RM, Patience T, Budd S. Treatment with pro- roid hormone on skeletal integrity. Ann Intern Med. roidism in older and younger patients. JAm pylthiouracil before radioactive iodine therapy is 1999;130:750-758. Geriatr Soc. 1996;44:50-53. associated with a higher treatment failure rate than 23. Ching GW, Franklyn JA, Stallard TJ, Daykin J, 4. Franklyn JA, Black EG, Betteridge J, Sheppard MC. therapy with radioactive iodine alone in Graves’ Sheppard MC, Gammage MD. Cardiac hypertro- Comparison of second and third generation meth- disease. Thyroid. 1995;5:243-247. phy as a result of long-term thyroxine therapy and ods for measurement of serum thyrotropin in pa- 13. Imseis RE, Vanmiddlesworth L, Massie JD, Bush thyrotoxicosis. Heart. 1996;75:363-368. tients with overt hyperthyroidism, patients receiv- AJ, Vanmiddlesworth NR. Pretreatment with pro- 24. Woeber KA. Subclinical thyroid dysfunction. Arch ing thyroxine therapy, and those with nonthyroidal pylthiouracil but not methimazole reduces the Intern Med. 1997;157:1065-1068.

ARCH INTERN MED/ VOL 160, APR 24, 2000 WWW.ARCHINTERNMED.COM 1071

Downloaded From: https://jamanetwork.com/ on 09/29/2021