Resistance to Thyroid Hormone in Hashimoto's Thyroiditis
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《新英格兰医药杂志》
To the Editor: The diagnosis of resistance to thyroid hormone requires careful analysis of clinical and laboratory data. The presence of Hashimoto's thyroiditis in a patient with resistance to thyroid hormone makes hypothyroidism and its treatment more difficult. We present such a case.
A 41-year-old woman underwent subtotal thyroidectomy in 1993 and consulted us in 1998 for further evaluation of the possibility of relapsing thyrotoxicosis. She was already receiving methimazole therapy and had mild fatigue, with a diffuse goiter of 64 cc, as estimated by ultrasonography. Thyroid-function tests showed a normal serum free thyroxine level, at 1.1 ng per deciliter (normal range, 0.75 to 1.8), and an elevated serum thyrotropin level, at more than 100 μU per milliliter (normal range, 0.40 to 4.50).
Thyroid-function tests performed two months after the discontinuation of methimazole therapy showed a normal serum thyrotropin level, at 3.2 μU per milliliter, and an elevated serum free thyroxine level, at 2.6 ng per deciliter, with a positive test for antimicrosomal antibody, at 1:400. The results of a thyrotropin stimulation test and a magnetic resonance imaging study of the pituitary gland were normal. Her serum thyrotropin levels were inadequately suppressed by daily administration of levotriiodothyronine. Analysis of the thyroid hormone receptor beta gene from DNA in lymphocytes showed a heterozygous replacement of arginine with histidine at amino acid position 438 (Figure 1). The patient's family members did not have abnormal results on thyroid-function tests. Thus, this was a sporadic case of resistance to thyroid hormone associated with Hashimoto's thyroiditis, and the patient was observed without receiving any medication.
Figure 1. Sequence Analysis of the Thyroid Hormone Receptor Beta Gene from Genomic DNA from the Patient.
The G1303A substitution results in the replacement of arginine with histidine at amino acid position 438.
Two years later, mild fatigue developed along with an increased goiter (63.9 cc). The patient's serum thyrotropin level was increased, at 73 μU per milliliter, with a normal free thyroxine level, and she had a strongly positive test for antimicrosomal antibody, at 1:102,400. The cytologic findings on aspiration biopsy were consistent with Hashimoto's thyroiditis. After treatment with 100 μg of levothyroxine daily, her clinical condition improved, with an elevated free thyroxine level and a normal serum thyrotropin level. None of the thyroid hormone action markers described by Ferretti et al.1 were closely correlated with her hypothyroid symptoms. Thus, the thyroid status in this disorder should be judged primarily on a clinical basis.2 The coexistence of resistance to thyroid hormone and Hashimoto's thyroiditis is fortuitous.3,4 However, resistance to thyroid hormone can easily be overlooked or missed in the presence of Hashimoto's thyroiditis, because patients with Hashimoto's thyroiditis frequently have elevated serum thyrotropin levels and normal free thyroxine levels — a condition known as subclinical hypothyroidism. As the case of our patient shows, unusually high serum thyrotropin levels with normal serum free thyroxine levels in patients with Hashimoto's thyroiditis should raise the question of resistance to thyroid hormone, with or without hypothyroidism.
Shuji Fukata, M.D.
Kuma Hospital
Kobe 650-0011, Japan
fukata@kuma-h.or.jp
Gregory A. Brent, M.D.
Masahiro Sugawara, M.D.
Greater Los Angeles Veterans Affairs Medical Center
Los Angeles, CA 90074
References
Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, Tamburrano G, Beck-Peccoz P. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999;84:924-929.
Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771-776.
Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid. 8th ed. Philadelphia: J.B. Lippincott, 2000:1028.
Reinhardt W, Jockenhovel F, Deuble J, Chatterjee VK, Reinwein D, Mann K. Thyroid hormone resistance: variable clinical manifestations in five patients. Nuklearmedizin 1997;36:250-255.
A 41-year-old woman underwent subtotal thyroidectomy in 1993 and consulted us in 1998 for further evaluation of the possibility of relapsing thyrotoxicosis. She was already receiving methimazole therapy and had mild fatigue, with a diffuse goiter of 64 cc, as estimated by ultrasonography. Thyroid-function tests showed a normal serum free thyroxine level, at 1.1 ng per deciliter (normal range, 0.75 to 1.8), and an elevated serum thyrotropin level, at more than 100 μU per milliliter (normal range, 0.40 to 4.50).
Thyroid-function tests performed two months after the discontinuation of methimazole therapy showed a normal serum thyrotropin level, at 3.2 μU per milliliter, and an elevated serum free thyroxine level, at 2.6 ng per deciliter, with a positive test for antimicrosomal antibody, at 1:400. The results of a thyrotropin stimulation test and a magnetic resonance imaging study of the pituitary gland were normal. Her serum thyrotropin levels were inadequately suppressed by daily administration of levotriiodothyronine. Analysis of the thyroid hormone receptor beta gene from DNA in lymphocytes showed a heterozygous replacement of arginine with histidine at amino acid position 438 (Figure 1). The patient's family members did not have abnormal results on thyroid-function tests. Thus, this was a sporadic case of resistance to thyroid hormone associated with Hashimoto's thyroiditis, and the patient was observed without receiving any medication.
Figure 1. Sequence Analysis of the Thyroid Hormone Receptor Beta Gene from Genomic DNA from the Patient.
The G1303A substitution results in the replacement of arginine with histidine at amino acid position 438.
Two years later, mild fatigue developed along with an increased goiter (63.9 cc). The patient's serum thyrotropin level was increased, at 73 μU per milliliter, with a normal free thyroxine level, and she had a strongly positive test for antimicrosomal antibody, at 1:102,400. The cytologic findings on aspiration biopsy were consistent with Hashimoto's thyroiditis. After treatment with 100 μg of levothyroxine daily, her clinical condition improved, with an elevated free thyroxine level and a normal serum thyrotropin level. None of the thyroid hormone action markers described by Ferretti et al.1 were closely correlated with her hypothyroid symptoms. Thus, the thyroid status in this disorder should be judged primarily on a clinical basis.2 The coexistence of resistance to thyroid hormone and Hashimoto's thyroiditis is fortuitous.3,4 However, resistance to thyroid hormone can easily be overlooked or missed in the presence of Hashimoto's thyroiditis, because patients with Hashimoto's thyroiditis frequently have elevated serum thyrotropin levels and normal free thyroxine levels — a condition known as subclinical hypothyroidism. As the case of our patient shows, unusually high serum thyrotropin levels with normal serum free thyroxine levels in patients with Hashimoto's thyroiditis should raise the question of resistance to thyroid hormone, with or without hypothyroidism.
Shuji Fukata, M.D.
Kuma Hospital
Kobe 650-0011, Japan
fukata@kuma-h.or.jp
Gregory A. Brent, M.D.
Masahiro Sugawara, M.D.
Greater Los Angeles Veterans Affairs Medical Center
Los Angeles, CA 90074
References
Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, Tamburrano G, Beck-Peccoz P. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999;84:924-929.
Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771-776.
Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid. 8th ed. Philadelphia: J.B. Lippincott, 2000:1028.
Reinhardt W, Jockenhovel F, Deuble J, Chatterjee VK, Reinwein D, Mann K. Thyroid hormone resistance: variable clinical manifestations in five patients. Nuklearmedizin 1997;36:250-255.