Thyroid hormone resistance and its management Ana Marcella Rivas, MD, and Joaquin Lado-Abeal, MD, PhD
Table 1. Thyroid function panel from 2009 to 2014 The syndrome of impaired sensitivity to thyroid hormone, also known as syndrome of thyroid hormone Reference resistance, is an inherited condition that occurs in value 12/2009 10/2010 08/2011 04/2012 02/2013 07/2014 1 of 40,000 live births characterized by a reduced TSH (mcIntUnit/mL) 0.27–4.20 10.37 42.41 46.62 37.70 26.39 39.00 responsiveness of target tissues to thyroid horFT4 (ng/dL) 0.93–1.70 3.00 1.81 2.07 1.91 1.82 1.05 mone due to mutations on the thyroid hormone FT3 (pg/mL) 2.3–4.2 N/A N/A N/A N/A 8.86 3.64 receptor. Patients can present with symptoms of hyperthyroidism or hypothyroidism. They usually FT3 indicates free triiodothyronine; FT4, free thyroxine; NA, not available; TSH, thyroid-stimulating hormone. have elevated thyroid hormones and a normal or elevated thyroid-stimulating hormone level. Due to their nonspecific symptomatic presentation, these patients can be misdifor the patient. Her family history was relevant for a son with agnosed if the primary care physician is not familiar with the condition. “hypothyroidism.” The patient’s thyroid function panels from 2009 to 2014 This can result in frustration for the patient and sometimes unnecessary were reviewed and are presented in Table 1. During this peinvasive treatment such as radioactive iodine ablation, as in the case riod of time she was on different doses of thyroid replacement presented herein.
T
he syndrome of impaired sensitivity to thyroid hormone (ISTH) is a condition of decreased tissue sensitivity to thyroid hormone action usually caused by germline mutations of the thyroid hormone receptor beta (THRB) gene. The mutant receptor has lower binding affinity for thyroid hormone and, as a consequence, serum thyroid-stimulating hormone (TSH) levels remain nonsuppressed despite elevated thyroid hormones (1–3). We present the case of a 66-year-old woman who was referred for evaluation of an abnormal thyroid function panel that suggested ISTH. CASE REPORT A 66-year-old woman was referred for evaluation of thyroid dysfunction. Her complaints were memory loss and intermittent gastrointestinal symptoms with alternating diarrhea and constipation attributed to irritable bowel syndrome. In 1998, she had been diagnosed with “a thyroid condition that no one was able to fix.” At that time, she had a goiter and was treated with radioactive iodine (I-131) and was subsequently started on thyroid replacement therapy. For nearly 30 years, she was seen by multiple physicians who continuously modified her thyroid hormone replacement but had been unable to “normalize” her thyroid hormone levels, and this resulted in frustration Proc (Bayl Univ Med Cent) 2016;29(2):209–211
therapy, her TSH remained elevated despite normal or elevated free T4 levels. She also had magnetic resonance imaging of the head, which showed a possible right-sided pituitary microadenoma. A thyroid ultrasound showed a normal thyroid gland with some nonspecific nodules. PCR amplification of THRB gene exons 10, 9, and 8 followed by gene sequencing showed a heterozygous missense mutation C>A located at exon 10. The mutation caused a change in thyroid hormone receptor beta protein amino acid 453 proline to threonine, P453T (Figure 1). We recommended that the patient resume thyroid hormone replacement with liothyronine 10 mg twice a day and levothyroxine 75 mcg daily; unfortunately, she was lost to follow up thereafter. DISCUSSION We describe a case of ISTH caused by a common germline mutation located at THRB exon 10 hot spot (4). The patient went undiagnosed for many years. When reviewing her thyroid From the Department of Medicine, Division of Endocrinology and Metabolism, Mayo Clinic, Jacksonville, Florida (Rivas); and the Department of Medicine, Division of Endocrinology, Texas Tech University Health Science Center, Lubbock, Texas (Lado-Abeal). Corresponding author: Ana Marcella Rivas, MD, 4500 San Pablo Road, Jacksonville, FL 32224 (e-mail: [email protected]). 209
Figure 1. Sequence analysis of the thyroid hormone receptor beta (THRB) gene showing a heterozygous mutation C>A located in exon 10. The mutation results in a change of proline for threonine at amino acid position 453, P453T.
function tests, we noted a nonsuppressed serum TSH despite a normal or elevated free T4 level. These abnormal values led us to suspect THRB mutation and proceed with genetic studies, which confirmed the diagnosis. The diagnosis of ISTH requires a high degree of suspicion, and we therefore believe it is important for the general practitioner to be able to recognize the syndrome to avoid delay in diagnosis and unnecessary invasive treatments, such as thyroid surgery or radioactive iodine ablation. Thyroid hormone genomic actions are exerted by thyroid hormone binding mostly to nuclear receptors located in the nuclei and interaction with DNA to regulate the transcription of target genes. Most of the cases of ISTH are caused by mutations in the THRB gene located in chromosome 3, and these mutations most often clustered in three hot spots located in exons 8, 9, and 10. The mutant thyroid hormone receptor beta protein has either reduced affinity for T3 or abnormal interaction with cofactors involved in thyroid hormone action, making the target tissues refractory to thyroid hormones (5–7). In 15% of cases of ISTH, a gene mutation is not identified (6). Mutations affecting thyroid hormone cell membrane transporters and thyroid hormone metabolism have now been described, and the concept of syndrome of reduced sensitivity to thyroid hormone is used to encompass any defect causing reduced effectiveness of the thyroid hormone (3). The clinical presentation of patients with THRB mutations is variable. Patients may present with symptoms of hyperthyroidism, hypothyroidism, or a combination of symptoms of thyroid hormone deficiency and excess depending on the level of THRB and THRA gene expression in the target tissues (5, 6, 8). 210
Symptoms tend to decrease with age, and patients eventually become clinically euthyroid. Goiter is one of the most common findings for which patients seek medical attention. It’s usually refractory and recurs after surgery or treatment with radioactive iodine. Other common complaints include tachycardia, learning disabilities, and hyperactivity (8). The classic pattern of thyroid function test that these patients present with is elevated thyroid hormones with nonsuppressed TSH in serum. The response of TSH to thyrotropin-releasing hormone is normal or exaggerated, and thyroidal radioiodine uptake may be elevated (5). ISTH can be difficult to differentiate from TSH-producing pituitary tumors, which present with a similar thyroid function profile. A case of coexistence of both conditions has been reported (9). TSH-producing pituitary tumors present elevated serum levels of T4, T3, and nonsuppressed TSH. In contrast to patients with ISTH who may be clinically euthyroid, patients with TSHomas usually present with symptoms of mild to severe hyperthyroidism and compression symptoms resulting from tumor growth (7). When treating these patients, one should concentrate on the patient’s symptoms and clinical picture instead of aiming to normalize thyroid hormone levels (5, 8). Most patients, if left alone, adequately overcome the resistance by increased thyroid hormone secretion and therefore do not require treatment (8, 10). Treating patients who present with normal TSH is more challenging; in these patients, administration of supraphysiological doses of thyroid hormone might be required and, if so, should be closely monitored. Patients who present with symptoms of hyperthyroidism should be treated symptomatically with
Baylor University Medical Center Proceedings
Volume 29, Number 2
beta-blockers or antianxiety medications, among others, depending on their predominant symptoms (10). 1.
2. 3. 4.
Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosineguanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. J Clin Invest 1993;91(6):2408–2415. McDermott MT, Ridgway EC. Thyroid hormone resistance syndromes. Am J Med 1993;94(4):424–432. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830(7):3987–4003. Lado Abeal J, Albero Gamboa R, Araujo Vilar D, Barca Mallo O, Bernabeú Moron I, Calvo MT, Castro Piedras I, Martin Calamata J, Palos Paz F, Peinó R, Peteiro D, Victoria B. Clinical and molecular study of five families with resistance to thyroid hormones. Med Clin (Barc) 2011;137(12):551–554.
April 2016
5.
Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007;21(2):277–305. 6. Gonçalves AP, Aragüés JM, Nobre E, Barbosa AP, Mascarenhas M. A case of thyroid hormone resistance: a rare mutation. Arq Bras Endocrinol Metabol 2014;58(9):962–966. 7. Melmed S, Kleinberg D. Pituitary masses and tumors. In Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology, 12th ed. Philadelphia: Elsevier Saunders; 2011: chap 9. 8. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14(3):348–399. 9. Teng X, Jin T, Brent GA, Wu A, Teng W, Shan Z. A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). J Clin Endocrinol Metab 2015;100(7):2511–2514. 10. Weiss RE, Refetoff S. Treatment of resistance to thyroid hormone— primum non nocere. J Clin Endocrinol Metab 1999;84(2):401–404.
Thyroid hormone resistance and its management
211
Table 1. Thyroid function panel from 2009 to 2014 The syndrome of impaired sensitivity to thyroid hormone, also known as syndrome of thyroid hormone Reference resistance, is an inherited condition that occurs in value 12/2009 10/2010 08/2011 04/2012 02/2013 07/2014 1 of 40,000 live births characterized by a reduced TSH (mcIntUnit/mL) 0.27–4.20 10.37 42.41 46.62 37.70 26.39 39.00 responsiveness of target tissues to thyroid horFT4 (ng/dL) 0.93–1.70 3.00 1.81 2.07 1.91 1.82 1.05 mone due to mutations on the thyroid hormone FT3 (pg/mL) 2.3–4.2 N/A N/A N/A N/A 8.86 3.64 receptor. Patients can present with symptoms of hyperthyroidism or hypothyroidism. They usually FT3 indicates free triiodothyronine; FT4, free thyroxine; NA, not available; TSH, thyroid-stimulating hormone. have elevated thyroid hormones and a normal or elevated thyroid-stimulating hormone level. Due to their nonspecific symptomatic presentation, these patients can be misdifor the patient. Her family history was relevant for a son with agnosed if the primary care physician is not familiar with the condition. “hypothyroidism.” The patient’s thyroid function panels from 2009 to 2014 This can result in frustration for the patient and sometimes unnecessary were reviewed and are presented in Table 1. During this peinvasive treatment such as radioactive iodine ablation, as in the case riod of time she was on different doses of thyroid replacement presented herein.
T
he syndrome of impaired sensitivity to thyroid hormone (ISTH) is a condition of decreased tissue sensitivity to thyroid hormone action usually caused by germline mutations of the thyroid hormone receptor beta (THRB) gene. The mutant receptor has lower binding affinity for thyroid hormone and, as a consequence, serum thyroid-stimulating hormone (TSH) levels remain nonsuppressed despite elevated thyroid hormones (1–3). We present the case of a 66-year-old woman who was referred for evaluation of an abnormal thyroid function panel that suggested ISTH. CASE REPORT A 66-year-old woman was referred for evaluation of thyroid dysfunction. Her complaints were memory loss and intermittent gastrointestinal symptoms with alternating diarrhea and constipation attributed to irritable bowel syndrome. In 1998, she had been diagnosed with “a thyroid condition that no one was able to fix.” At that time, she had a goiter and was treated with radioactive iodine (I-131) and was subsequently started on thyroid replacement therapy. For nearly 30 years, she was seen by multiple physicians who continuously modified her thyroid hormone replacement but had been unable to “normalize” her thyroid hormone levels, and this resulted in frustration Proc (Bayl Univ Med Cent) 2016;29(2):209–211
therapy, her TSH remained elevated despite normal or elevated free T4 levels. She also had magnetic resonance imaging of the head, which showed a possible right-sided pituitary microadenoma. A thyroid ultrasound showed a normal thyroid gland with some nonspecific nodules. PCR amplification of THRB gene exons 10, 9, and 8 followed by gene sequencing showed a heterozygous missense mutation C>A located at exon 10. The mutation caused a change in thyroid hormone receptor beta protein amino acid 453 proline to threonine, P453T (Figure 1). We recommended that the patient resume thyroid hormone replacement with liothyronine 10 mg twice a day and levothyroxine 75 mcg daily; unfortunately, she was lost to follow up thereafter. DISCUSSION We describe a case of ISTH caused by a common germline mutation located at THRB exon 10 hot spot (4). The patient went undiagnosed for many years. When reviewing her thyroid From the Department of Medicine, Division of Endocrinology and Metabolism, Mayo Clinic, Jacksonville, Florida (Rivas); and the Department of Medicine, Division of Endocrinology, Texas Tech University Health Science Center, Lubbock, Texas (Lado-Abeal). Corresponding author: Ana Marcella Rivas, MD, 4500 San Pablo Road, Jacksonville, FL 32224 (e-mail: [email protected]). 209
Figure 1. Sequence analysis of the thyroid hormone receptor beta (THRB) gene showing a heterozygous mutation C>A located in exon 10. The mutation results in a change of proline for threonine at amino acid position 453, P453T.
function tests, we noted a nonsuppressed serum TSH despite a normal or elevated free T4 level. These abnormal values led us to suspect THRB mutation and proceed with genetic studies, which confirmed the diagnosis. The diagnosis of ISTH requires a high degree of suspicion, and we therefore believe it is important for the general practitioner to be able to recognize the syndrome to avoid delay in diagnosis and unnecessary invasive treatments, such as thyroid surgery or radioactive iodine ablation. Thyroid hormone genomic actions are exerted by thyroid hormone binding mostly to nuclear receptors located in the nuclei and interaction with DNA to regulate the transcription of target genes. Most of the cases of ISTH are caused by mutations in the THRB gene located in chromosome 3, and these mutations most often clustered in three hot spots located in exons 8, 9, and 10. The mutant thyroid hormone receptor beta protein has either reduced affinity for T3 or abnormal interaction with cofactors involved in thyroid hormone action, making the target tissues refractory to thyroid hormones (5–7). In 15% of cases of ISTH, a gene mutation is not identified (6). Mutations affecting thyroid hormone cell membrane transporters and thyroid hormone metabolism have now been described, and the concept of syndrome of reduced sensitivity to thyroid hormone is used to encompass any defect causing reduced effectiveness of the thyroid hormone (3). The clinical presentation of patients with THRB mutations is variable. Patients may present with symptoms of hyperthyroidism, hypothyroidism, or a combination of symptoms of thyroid hormone deficiency and excess depending on the level of THRB and THRA gene expression in the target tissues (5, 6, 8). 210
Symptoms tend to decrease with age, and patients eventually become clinically euthyroid. Goiter is one of the most common findings for which patients seek medical attention. It’s usually refractory and recurs after surgery or treatment with radioactive iodine. Other common complaints include tachycardia, learning disabilities, and hyperactivity (8). The classic pattern of thyroid function test that these patients present with is elevated thyroid hormones with nonsuppressed TSH in serum. The response of TSH to thyrotropin-releasing hormone is normal or exaggerated, and thyroidal radioiodine uptake may be elevated (5). ISTH can be difficult to differentiate from TSH-producing pituitary tumors, which present with a similar thyroid function profile. A case of coexistence of both conditions has been reported (9). TSH-producing pituitary tumors present elevated serum levels of T4, T3, and nonsuppressed TSH. In contrast to patients with ISTH who may be clinically euthyroid, patients with TSHomas usually present with symptoms of mild to severe hyperthyroidism and compression symptoms resulting from tumor growth (7). When treating these patients, one should concentrate on the patient’s symptoms and clinical picture instead of aiming to normalize thyroid hormone levels (5, 8). Most patients, if left alone, adequately overcome the resistance by increased thyroid hormone secretion and therefore do not require treatment (8, 10). Treating patients who present with normal TSH is more challenging; in these patients, administration of supraphysiological doses of thyroid hormone might be required and, if so, should be closely monitored. Patients who present with symptoms of hyperthyroidism should be treated symptomatically with
Baylor University Medical Center Proceedings
Volume 29, Number 2
beta-blockers or antianxiety medications, among others, depending on their predominant symptoms (10). 1.
2. 3. 4.
Weiss RE, Weinberg M, Refetoff S. Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosineguanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families. J Clin Invest 1993;91(6):2408–2415. McDermott MT, Ridgway EC. Thyroid hormone resistance syndromes. Am J Med 1993;94(4):424–432. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830(7):3987–4003. Lado Abeal J, Albero Gamboa R, Araujo Vilar D, Barca Mallo O, Bernabeú Moron I, Calvo MT, Castro Piedras I, Martin Calamata J, Palos Paz F, Peinó R, Peteiro D, Victoria B. Clinical and molecular study of five families with resistance to thyroid hormones. Med Clin (Barc) 2011;137(12):551–554.
April 2016
5.
Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007;21(2):277–305. 6. Gonçalves AP, Aragüés JM, Nobre E, Barbosa AP, Mascarenhas M. A case of thyroid hormone resistance: a rare mutation. Arq Bras Endocrinol Metabol 2014;58(9):962–966. 7. Melmed S, Kleinberg D. Pituitary masses and tumors. In Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology, 12th ed. Philadelphia: Elsevier Saunders; 2011: chap 9. 8. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993;14(3):348–399. 9. Teng X, Jin T, Brent GA, Wu A, Teng W, Shan Z. A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). J Clin Endocrinol Metab 2015;100(7):2511–2514. 10. Weiss RE, Refetoff S. Treatment of resistance to thyroid hormone— primum non nocere. J Clin Endocrinol Metab 1999;84(2):401–404.
Thyroid hormone resistance and its management
211
