Brief Reports
Brief reports of new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; not more than ten references and one figure or table can be used. See "Information for Readers and Authors" for form of references. Manuscripts should include an abstract of not over 150 words. Reports will be reviewed by consultants when, in the opinion of the Editors, such review is needed. The Editors reserve the right to shorten reports and to make changes in style.
Amiodarone-Induced Elevation of Thyroid Stimulating Hormone in Patients Receiving Levothyroxine for Primary Hypothyroidism James Figge, MD; and Robert G. Dluhy, MD Annals of Internal Medicine. 1190;113:553-555.
Amiodarone, an iodinated antiarrhythmic agent, has complex effects on thyroid hormone physiology. As a potent hepatic 5'-deiodinase inhibitor, the drug decreases thyroxine (T4) conversion to 3,5,3'-triiodothyronine (T3), and slows 3,3',5'-triiodothyronine (rT3) clearance (1-3). Amiodarone may inhibit both the cellular uptake of T3 and T4 (4, 5), and the binding of T3 to its receptor (5, 6). These effects modulate T3-mediated responses in vitro (5-7) and in animals (8). Finally, iodide released from metabolism of the drug may occasionally cause overt hypothyroidism or hyperthyroidism (9). Given the antagonistic effects of amiodarone on T3 action, we studied whether the drug could elevate thyroid stimulating hormone (TSH) levels in patients receiving exogenous levothyroxine for primary hypothyroidism. Patients and Methods Records of inpatients followed by the Lown Cardiovascular Group at Brigham and Women's Hospital, Boston, Massachusetts, were reviewed to identify patients who had concurrently received amiodarone and levothyroxine between 1 January 1987 and 1 June 1989. Of five identified patients, two had received levothyroxFrom Brigham and Women's Hospital, Boston, Massachusetts. For current author addresses, see end of text.
ine for primary hypothyroidism for at least 1 year before initiating amiodarone. The thyroid profile of each patient was assessed. Radioimmunoassay kits for total T4 (Diagnostic Products Corporation, Los Angeles, California) and total T3 (Baxter Travenol Diagnostics, Inc., Cambridge, Massachusetts) were used. The T3 uptake was measured by a radioassay kit (Diagnostic Products Corporation). The thyroid hormone binding ratio (THBR) was calculated as THBR = T3 uptake of sample/T3 uptake of an aliquot of pooled normal serum; the free T4 index (FT4I) as FT4I = total T4 x THBR; and the free T3 index (FT3I) as FT3I = total T3 x THBR. The TSH was measured by the Allegro Highly Sensitive TSH Immunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, California). Serum rT3 was measured at the Nichols Institute Reference Laboratory. Patient 1 A 73-year-old woman presented with myxedema at age 47, documented by a protein-bound iodine of 110 nmol/L (normal, 315 to 630 nmol/L). During a 5-year period before our study she was euthyroid while taking Synthroid (levothyroxine sodium, Boots-Flint, Inc., Lincolnshire, Illinois), 0.075 mg daily (Figure 1, left), but when the dose was lowered to 0.050 mg daily, her TSH levels rose to 26 mU/L, consistent with the diagnosis of primary hypothyroidism. The TSH levels decreased when her dose was restored to 0.075 mg daily. After a coronary artery bypass for three vessel disease, she developed paroxysmal atrial tachycardia and congestive heart failure. Amiodarone HCl was initiated at 800 mg daily and tapered to 200 mg daily. Levothyroxine was maintained at 0.075 mg daily, and other medications included isosorbide dinitrate, nifedipine, sublingual nitroglycerin, FeS0 4 , furosemide, potassium, aspirin, and dipyridamole. Within the first 2.5 months on amiodarone, the TSH increased to 20 to 30 mU/L, the FT4I remained within normal limits, but the FT3I dropped below the normal range (Figure 1, left), and the T3/T4 molar ratio declined by 33%. She developed fatigue, weakness, cold intolerance, and hyponatremia (Na + , 127 mmol/L). Adrenal insufficiency was excluded by a Cortrosyn stimulation test yielding a baseline Cortisol of 520 nmol/L (19 ^g/dL) and a 1-hour stimulated Cortisol of 1350 nmol/L (49 /xg/dL). An assay for antimicrosomal antibodies was negative. The rT3 was elevated in the range of 0.66 to 0.81 nmol/L (normal, 0.15 to 0.37 nmol/L). Levothyroxine was incrementally increased to 0.112 mg/d while amiodarone was maintained at 200 mg/d; the TSH level came down to 4.2 mU/L and the symptoms of hypothyroidism resolved (Figure 1, left). © 1990 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19713/ by a University of California San Diego User on 01/21/2017
553
Figure 1. Free T4 and free T3 indices and TSH levels in Patients 1 (left) and 2 (right) before and during amiodarone administration. Normal ranges are free T4 index, 55 to 156; free T3 index, 1.04 to 3.38; and TSH, 0.5 to 5.0 mU/L. Daily doses of amiodarone HCI and levothyroxine are given.
Patient 2 An 83-year-old man had had three myocardial infarctions in the distant past. Primary hypothyroidism was diagnosed 4 years before our study on the basis of elevated serial TSH values (8.8 to 10.0 mU/L) and an exaggerated TSH response to intravenous (500 /xg) thyrotropin-releasing hormone (TRH) (baseline TSH, 10.0 mU/L; 30-minute stimulated TSH, 38.2 mU/L). Synthroid treatment at 0.1 mg daily made him euthyroid. He subsequently developed symptomatic ventricular tachycardia, refractory to several agents. Amiodarone HCI was initiated at 600 mg daily and tapered to 400 mg alternating with 200 mg daily. Levothyroxine was maintained at 0.1 mg daily; other medications included nifedipine, isosorbide dinitrate, enteric-coated aspirin, and sublingual nitroglycerin. While he received amiodarone, the FT4I remained within the normal range, the FT3I and T3/T4 molar ratio each decreased by 35%, and the TSH progressively increased to 22 mU/L (Figure 1, right). There was no change in the THBR. The rT3 was elevated at 0.74 nmol/L at 9 months. Antimicrosomal antibodies were detected at a dilution of 1:6400. He had no intercurrent illnesses and remained clinically euthyroid. Discussion Our cases show that patients on physiologic levothyroxine replacement for primary hypothyroidism can develop elevated TSH levels or overt hypothyroidism, or both after starting amiodarone therapy. This contrasts with a previous study in which euthyroid subjects received supraphysiologic levothyroxine doses (0.3 mg daily) for 9 days and then levothyroxine plus amiodarone for 7 days (1). During this regimen of levothyroxine over-replacement, TRH-stimulated TSH levels remained suppressed even when subjects received amiodarone (1). Several mechanisms might explain the increased levels of TSH in our patients. Because the FT4I of both 554
patients remained normal, impaired absorption of levothyroxine or lack of compliance is unlikely. We suggest that impaired T4-to-T3 conversion, both in peripheral tissues and perhaps within the pituitary, is responsible. This interpretation, supported by the decrease in the FT3I and T3/T4 molar ratio and the increase in rT3 for each patient, is consistent with earlier reports (1-3). It is also in keeping with the findings of Lambert and colleagues (10) who treated hypothyroid patients with T3 instead of T4 before and during amiodarone administration, and thereby avoided the blockade of T4-to-T3 conversion. Those patients developed slightly increased T3 and decreased TSH levels (10). A second possibility is that amiodarone may block T3 and T4 entry into pituitary thyrotrophs or inhibit T3 binding to its receptor. These effects occur in cultured anterior pituitary cells (5, 6), but their importance in humans is unknown. The data of Lambert and colleagues (10) militates against an inhibition of T3 transport or receptor binding in vivo. A third possibility, which we regard as unlikely, is that iodide released from amiodarone suppressed residual thyroid function in our patients, resulting in lower T3 levels. Clinicians using amiodarone in levothyroxine-supplemented patients should periodically screen for hypothyroidism by monitoring TSH levels and doing clinical assessments. Clinically hypothyroid patients may be treated by carefully increasing the dose of levothyroxine. Treatment of patients who have arrhythmias with T3 is not recommended because of its potent cardiac effects. Acknowledgments: The authors thank Dr. Thomas Graboys for referral of patients, and Drs. Graboys and P. Reed Larsen for review of the manuscript. Grant Support: Dr. Figge was supported by a grant from the Lucille P. Markey Charitable Trust. The study was supported by Clinical Research Center and CLINFO facility grant RR-02635 from the National Institutes of Health. Requests for Reprints: James Figge, MD, Division of Endocrinology and Metabolism, Albany Medical College, A44, 47 New Scotland Avenue, Albany, NY 12208.
1 October 1990 • Annals of Internal Medicine • Volume 113 • Number 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19713/ by a University of California San Diego User on 01/21/2017
Current Author Addresses: Dr. Figge: Division of Endocrinology and Metabolism, Albany Medical College, A44, 47 New Scotland Avenue, Albany, NY 12208. Dr. Dluhy: Department of Medicine, Endocrine-Hypertension Unit, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115.
References 1. Burger A, Dinichert D, Nicod P, Jenny M, Lemarchand-Beraud T, Vallotton MB. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. J Clin Invest. 1976;58:255-9. 2. Melmed S, Nademanee K, Reed AW, Hendrickson JA, Singh BN, Hershman JM. Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration. / Clin Endocrinol Metab. 1981;53:997-1001. 3. Nademanee K, Singh BN, Callahan B, Hendrickson JA, Hershman JM. Amiodarone, thyroid hormone indexes, and altered thyroid function: long-term serial effects in patients with cardiac arrhythmias. Am J Cardiol. 1986;58:981-6. 4. Krenning EP, Docter R, Bernard B, Visser T, Hennemann G. Decreased transport of thyroxine (T4), 3,3',5-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs. FEBS Lett. 1982;140:229-33. 5. Norman MF, Lavin TN. Antagonism of thyroid hormone action by amiodarone in rat pituitary tumor cells. J Clin Invest. 1989;83:30613. 6. Franklyn JA, Davis JR, Gammage MD, Littler WA, Ramsden DB, Sheppard MC. Amiodarone and thyroid hormone action. Clin Endocrinol. 1985;22:257-64. 7. Goldfine ID, Maddux B, Woeber KA. Effect of amiodarone on L-triiodothyronine stimulation of [3H]thymidine incorporation into GH 3 cells. J Endocrinol Invest. 1982;5:165-8. 8. Franklyn JA, Gammage MD, Sheppard MC. Amiodarone and thyroid hormone effects on anterior pituitary hormone gene expression. Clin Endocrinol. 1987;27:373-82. 9. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med. 1984;101:28-34. 10. Lambert M, Burger AG, De Nayer P, Beckers C. Decreased TSH response to TRH induced by amiodarone. Acta Endocrionologica. 1988;118:449-52.
1 October 1990 • Annals
of Internal
Medicine
• V o l u m e 113 • N u m b e r 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19713/ by a University of California San Diego User on 01/21/2017
555
Brief reports of new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; not more than ten references and one figure or table can be used. See "Information for Readers and Authors" for form of references. Manuscripts should include an abstract of not over 150 words. Reports will be reviewed by consultants when, in the opinion of the Editors, such review is needed. The Editors reserve the right to shorten reports and to make changes in style.
Amiodarone-Induced Elevation of Thyroid Stimulating Hormone in Patients Receiving Levothyroxine for Primary Hypothyroidism James Figge, MD; and Robert G. Dluhy, MD Annals of Internal Medicine. 1190;113:553-555.
Amiodarone, an iodinated antiarrhythmic agent, has complex effects on thyroid hormone physiology. As a potent hepatic 5'-deiodinase inhibitor, the drug decreases thyroxine (T4) conversion to 3,5,3'-triiodothyronine (T3), and slows 3,3',5'-triiodothyronine (rT3) clearance (1-3). Amiodarone may inhibit both the cellular uptake of T3 and T4 (4, 5), and the binding of T3 to its receptor (5, 6). These effects modulate T3-mediated responses in vitro (5-7) and in animals (8). Finally, iodide released from metabolism of the drug may occasionally cause overt hypothyroidism or hyperthyroidism (9). Given the antagonistic effects of amiodarone on T3 action, we studied whether the drug could elevate thyroid stimulating hormone (TSH) levels in patients receiving exogenous levothyroxine for primary hypothyroidism. Patients and Methods Records of inpatients followed by the Lown Cardiovascular Group at Brigham and Women's Hospital, Boston, Massachusetts, were reviewed to identify patients who had concurrently received amiodarone and levothyroxine between 1 January 1987 and 1 June 1989. Of five identified patients, two had received levothyroxFrom Brigham and Women's Hospital, Boston, Massachusetts. For current author addresses, see end of text.
ine for primary hypothyroidism for at least 1 year before initiating amiodarone. The thyroid profile of each patient was assessed. Radioimmunoassay kits for total T4 (Diagnostic Products Corporation, Los Angeles, California) and total T3 (Baxter Travenol Diagnostics, Inc., Cambridge, Massachusetts) were used. The T3 uptake was measured by a radioassay kit (Diagnostic Products Corporation). The thyroid hormone binding ratio (THBR) was calculated as THBR = T3 uptake of sample/T3 uptake of an aliquot of pooled normal serum; the free T4 index (FT4I) as FT4I = total T4 x THBR; and the free T3 index (FT3I) as FT3I = total T3 x THBR. The TSH was measured by the Allegro Highly Sensitive TSH Immunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, California). Serum rT3 was measured at the Nichols Institute Reference Laboratory. Patient 1 A 73-year-old woman presented with myxedema at age 47, documented by a protein-bound iodine of 110 nmol/L (normal, 315 to 630 nmol/L). During a 5-year period before our study she was euthyroid while taking Synthroid (levothyroxine sodium, Boots-Flint, Inc., Lincolnshire, Illinois), 0.075 mg daily (Figure 1, left), but when the dose was lowered to 0.050 mg daily, her TSH levels rose to 26 mU/L, consistent with the diagnosis of primary hypothyroidism. The TSH levels decreased when her dose was restored to 0.075 mg daily. After a coronary artery bypass for three vessel disease, she developed paroxysmal atrial tachycardia and congestive heart failure. Amiodarone HCl was initiated at 800 mg daily and tapered to 200 mg daily. Levothyroxine was maintained at 0.075 mg daily, and other medications included isosorbide dinitrate, nifedipine, sublingual nitroglycerin, FeS0 4 , furosemide, potassium, aspirin, and dipyridamole. Within the first 2.5 months on amiodarone, the TSH increased to 20 to 30 mU/L, the FT4I remained within normal limits, but the FT3I dropped below the normal range (Figure 1, left), and the T3/T4 molar ratio declined by 33%. She developed fatigue, weakness, cold intolerance, and hyponatremia (Na + , 127 mmol/L). Adrenal insufficiency was excluded by a Cortrosyn stimulation test yielding a baseline Cortisol of 520 nmol/L (19 ^g/dL) and a 1-hour stimulated Cortisol of 1350 nmol/L (49 /xg/dL). An assay for antimicrosomal antibodies was negative. The rT3 was elevated in the range of 0.66 to 0.81 nmol/L (normal, 0.15 to 0.37 nmol/L). Levothyroxine was incrementally increased to 0.112 mg/d while amiodarone was maintained at 200 mg/d; the TSH level came down to 4.2 mU/L and the symptoms of hypothyroidism resolved (Figure 1, left). © 1990 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19713/ by a University of California San Diego User on 01/21/2017
553
Figure 1. Free T4 and free T3 indices and TSH levels in Patients 1 (left) and 2 (right) before and during amiodarone administration. Normal ranges are free T4 index, 55 to 156; free T3 index, 1.04 to 3.38; and TSH, 0.5 to 5.0 mU/L. Daily doses of amiodarone HCI and levothyroxine are given.
Patient 2 An 83-year-old man had had three myocardial infarctions in the distant past. Primary hypothyroidism was diagnosed 4 years before our study on the basis of elevated serial TSH values (8.8 to 10.0 mU/L) and an exaggerated TSH response to intravenous (500 /xg) thyrotropin-releasing hormone (TRH) (baseline TSH, 10.0 mU/L; 30-minute stimulated TSH, 38.2 mU/L). Synthroid treatment at 0.1 mg daily made him euthyroid. He subsequently developed symptomatic ventricular tachycardia, refractory to several agents. Amiodarone HCI was initiated at 600 mg daily and tapered to 400 mg alternating with 200 mg daily. Levothyroxine was maintained at 0.1 mg daily; other medications included nifedipine, isosorbide dinitrate, enteric-coated aspirin, and sublingual nitroglycerin. While he received amiodarone, the FT4I remained within the normal range, the FT3I and T3/T4 molar ratio each decreased by 35%, and the TSH progressively increased to 22 mU/L (Figure 1, right). There was no change in the THBR. The rT3 was elevated at 0.74 nmol/L at 9 months. Antimicrosomal antibodies were detected at a dilution of 1:6400. He had no intercurrent illnesses and remained clinically euthyroid. Discussion Our cases show that patients on physiologic levothyroxine replacement for primary hypothyroidism can develop elevated TSH levels or overt hypothyroidism, or both after starting amiodarone therapy. This contrasts with a previous study in which euthyroid subjects received supraphysiologic levothyroxine doses (0.3 mg daily) for 9 days and then levothyroxine plus amiodarone for 7 days (1). During this regimen of levothyroxine over-replacement, TRH-stimulated TSH levels remained suppressed even when subjects received amiodarone (1). Several mechanisms might explain the increased levels of TSH in our patients. Because the FT4I of both 554
patients remained normal, impaired absorption of levothyroxine or lack of compliance is unlikely. We suggest that impaired T4-to-T3 conversion, both in peripheral tissues and perhaps within the pituitary, is responsible. This interpretation, supported by the decrease in the FT3I and T3/T4 molar ratio and the increase in rT3 for each patient, is consistent with earlier reports (1-3). It is also in keeping with the findings of Lambert and colleagues (10) who treated hypothyroid patients with T3 instead of T4 before and during amiodarone administration, and thereby avoided the blockade of T4-to-T3 conversion. Those patients developed slightly increased T3 and decreased TSH levels (10). A second possibility is that amiodarone may block T3 and T4 entry into pituitary thyrotrophs or inhibit T3 binding to its receptor. These effects occur in cultured anterior pituitary cells (5, 6), but their importance in humans is unknown. The data of Lambert and colleagues (10) militates against an inhibition of T3 transport or receptor binding in vivo. A third possibility, which we regard as unlikely, is that iodide released from amiodarone suppressed residual thyroid function in our patients, resulting in lower T3 levels. Clinicians using amiodarone in levothyroxine-supplemented patients should periodically screen for hypothyroidism by monitoring TSH levels and doing clinical assessments. Clinically hypothyroid patients may be treated by carefully increasing the dose of levothyroxine. Treatment of patients who have arrhythmias with T3 is not recommended because of its potent cardiac effects. Acknowledgments: The authors thank Dr. Thomas Graboys for referral of patients, and Drs. Graboys and P. Reed Larsen for review of the manuscript. Grant Support: Dr. Figge was supported by a grant from the Lucille P. Markey Charitable Trust. The study was supported by Clinical Research Center and CLINFO facility grant RR-02635 from the National Institutes of Health. Requests for Reprints: James Figge, MD, Division of Endocrinology and Metabolism, Albany Medical College, A44, 47 New Scotland Avenue, Albany, NY 12208.
1 October 1990 • Annals of Internal Medicine • Volume 113 • Number 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19713/ by a University of California San Diego User on 01/21/2017
Current Author Addresses: Dr. Figge: Division of Endocrinology and Metabolism, Albany Medical College, A44, 47 New Scotland Avenue, Albany, NY 12208. Dr. Dluhy: Department of Medicine, Endocrine-Hypertension Unit, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115.
References 1. Burger A, Dinichert D, Nicod P, Jenny M, Lemarchand-Beraud T, Vallotton MB. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. J Clin Invest. 1976;58:255-9. 2. Melmed S, Nademanee K, Reed AW, Hendrickson JA, Singh BN, Hershman JM. Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration. / Clin Endocrinol Metab. 1981;53:997-1001. 3. Nademanee K, Singh BN, Callahan B, Hendrickson JA, Hershman JM. Amiodarone, thyroid hormone indexes, and altered thyroid function: long-term serial effects in patients with cardiac arrhythmias. Am J Cardiol. 1986;58:981-6. 4. Krenning EP, Docter R, Bernard B, Visser T, Hennemann G. Decreased transport of thyroxine (T4), 3,3',5-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs. FEBS Lett. 1982;140:229-33. 5. Norman MF, Lavin TN. Antagonism of thyroid hormone action by amiodarone in rat pituitary tumor cells. J Clin Invest. 1989;83:30613. 6. Franklyn JA, Davis JR, Gammage MD, Littler WA, Ramsden DB, Sheppard MC. Amiodarone and thyroid hormone action. Clin Endocrinol. 1985;22:257-64. 7. Goldfine ID, Maddux B, Woeber KA. Effect of amiodarone on L-triiodothyronine stimulation of [3H]thymidine incorporation into GH 3 cells. J Endocrinol Invest. 1982;5:165-8. 8. Franklyn JA, Gammage MD, Sheppard MC. Amiodarone and thyroid hormone effects on anterior pituitary hormone gene expression. Clin Endocrinol. 1987;27:373-82. 9. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med. 1984;101:28-34. 10. Lambert M, Burger AG, De Nayer P, Beckers C. Decreased TSH response to TRH induced by amiodarone. Acta Endocrionologica. 1988;118:449-52.
1 October 1990 • Annals
of Internal
Medicine
• V o l u m e 113 • N u m b e r 7
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19713/ by a University of California San Diego User on 01/21/2017
555
