A Family Showing Resistance to Thyroid Hormone Associated with Chronic Thyroiditis and Its Clinical Features: a Case Report

Endocrine Journal 2006, 53 (3), 421–425

A Family Showing Resistance to Thyroid Hormone Associated with Chronic Thyroiditis and its Clinical Features: A Case Report

HARUHIRO SATO AND HIDETO SAKAI

Department of Medicine, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1193, Japan

Abstract. Resistance to thyroid hormone (RTH) is characterized by decreased tissue responsiveness to thyroid hormone, due mainly to mutation of the thyroid hormone receptor (TR) β gene. It has been reported that serum of patients with RTH lacks autoantibodies against thyroglobulin (Tg) and thyroid peroxidase (TPO), except in rare cases where there is co- occurrence of coincidental autoimmune thyroiditis. Here we describe the five-year medical history of a Japanese woman and her father with RTH and coincidental chronic thyroiditis. The woman, aged 28 years, was referred to our hospital because of suspected hyperthyroidism. She showed a normal level of TSH and elevated levels of free triiodothyronine (FT3) and free thyroxine (FT4). Anti-Tg and anti-TPO antibodies were slightly positive. Since RTH was suspected, her parents were investigated with informed consent. Her father showed elevated levels of TSH, FT3 and FT4, and was positive for both anti-Tg antibody and anti-TPO antibody. Her mother had hypothyroidism caused by chronic thyroiditis. Sequencing of the TR β gene showed that the patient and her father had a codon 453 mutation resulting in a CCT (proline) to ACT (threonine) substitution. The patient gradually developed emotional disturbance, and was admitted to a psychiatry ward for two months, where she was treated with lorazepam and her condition improved. Her father, on the other hand, has been doing well for five years. The patient and the father showed different clinical courses, even though they carried the same mutation of the TR β gene. The fact that the father showed an elevated TSH level, whereas the patient did not, was thought to be due to decreased thyroid function caused by chronic thyroiditis.

Key words: Resistance to thyroid hormone, Chronic thyroiditis (Endocrine Journal 53: 421–425, 2006)

RESISTANCE to thyroid hormone (RTH) is a rare the majority of individuals are asymptomatic [3, 4]. It and usually dominantly inherited disorder character- has been reported that the serum of patients with RTH ized by high levels of circulating thyroid hormone is free of autoantibodies against thyroglobulin (Tg) and (TH), an inappropriately normal or elevated value of thyroid peroxidase (TPO), except in rare cases where TSH, and variable tissue hyposensitivity to TH. Muta- coincidental autoimmune thyroiditis is also present [5]. tions of the thyroid hormone receptor (TR) β gene We describe a 28-year-old Japanese woman with have been identified in the majority of patients with RTH and chronic thyroiditis. Her father also had RTH RTH [1, 2]. The clinical presentation of RTH is highly and chronic thyroiditis, whereas her mother carried a variable. Some patients may manifest symptoms sug- wild-type TR β gene but had hypothyroidism caused gestive of TH deprivation, such as growth retardation, by chronic thyroiditis. We followed the family for impaired cognitive ability, and hypercholesterolemia, five years, and here we describe the different clinical while others show signs of TH excess such as tachy- courses of the patient and her father. cardia, advanced bone age, or hyperactivity. However,

Case Report Received: December 9, 2005 Accepted: March 28, 2006 Correspondence to: Dr. Haruhiro SATO, Department of Medi- A 28-year-old woman was referred to our hospital cine, Tokai University School of Medicine, Boseidai, Isehara, because of suspected hyperthyroidism in August 2000. Kanagawa 259-1193, Japan She had been born at full term and showed normal 422 SATO and SAKAI weight gain during the neonatal period. No abnor- nary deoxypyridinoline level was within the normal mality of either TSH or thyroxine (T4) had been evi- range (Table 1 and Table 2). Electrocardiography dent at the time of routine neonatal screening. There showed a regular sinus rhythm. No pituitary tumor was no history of delayed speech development, hyper- was visualized by magnetic resonance imaging. activity, or learning disability, or any medical abnor- Thyroid function tests demonstrated elevated values mality. At school, the patient was within the average of free triiodothyronine (FT3) and free T4 (FT4), and range for general performance and intelligence. She the level of TSH was within the normal range. Anti-Tg graduated from a junior college at the age of 20, and antibody (14.6 IU/ml) and anti-TPO antibody (0.5 IU/ then worked as a clerk. At the age of 21, she visited ml) were slightly positive, suggesting mild chronic another hospital because of palpitation, and was diag- thyroiditis. Circulating antibodies against T3, T4, and nosed as having hyperthyroidism due to Graves’ dis- TSH, TSH receptor antibody (TSHRAb), and thyroid ease. Administration of methimazole was started, but stimulating antibody (TSAb) were not detected (Table she developed severe general malaise and became 3). A TRH administration test (500 µg iv) produced a overweight, and therefore the methimazole was with- normal response, and the maximum level of TSH was drawn. Thereafter, she gradually developed anxiety, 16.24 µU/ml, despite the elevated levels of FT3 and and had to resign from her job. She was then treated FT4 (Table 4). A liothyronine (L-T3) administration with a traditional Chinese medication for seven years at test was not performed because the patient was un- a local medical practice. However, as her level of thy- willing to undergo it. roxine continued to increase, she was referred to our It was suspected that the patient had RTH with hospital. chronic thyroiditis, because of the high level of TH, On presentation, the patient was 151 cm in height the inappropriately normal value of TSH, and positivity and weighed 38 kg. Her blood pressure was 112/68 for anti-Tg and anti-TPO antibodies. Therefore, her mmHg, pulse rate, 76/min and regular, and body tem- parents were also investigated with their informed con- perature 36.2°C. No finger tremor or proptosis was sent. Her younger sister was not examined. evident. Her thyroid was mildly enlarged. The relax- The patient’s father was 56 years old, 162 cm in ation phase of deep tendon reflexes was not prolonged. height and 49 kg in weight. His blood pressure was Neither her parents nor her younger sister had any 102/68 mmHg, and pulse rate 76/min and regular. He medical problems. had graduated from senior high school and had run a Results of a complete blood cell count (CBC) and blood chemistry examination were normal. The uri- Table 2. Blood chemistry

Patient Father Mother Table 1. Complete blood cell counts Plasma glucose (mg/dl) 92 97 81 Creatinine kinase (IU/l) 63 176 75 Patient Father Mother Lactate dehydrogenase (IU/l) 286 202 350 WBC (×103/µl) 5.7 5.4 5.5 Aspartate aminotransferase (IU/l) 15 23 22 Neutrophils (%) 71.8 65.0 62.0 Alanine aminotransferase (IU/l) 13 16 22 Lymphocytes (%) 26.0 27.4 30.1 Total protein (g/dl) 7.3 8.3 7.1 Monocytes (%) 1.2 6.3 1.6 Albumin (g/dl) 4.7 4.6 4.6 Eosinophils (%) 0.5 1.1 5.8 Total cholesterol (mg/dl) 183 248 205 Basophils (%) 0.5 0.2 0.5 HDL-cholesterol (mg/dl) 55 50 73 RBC (×104/µl) 481 479 406 Triglyceride (mg/dl) 117 176 83 Hemoglobin (g/dl) 14.6 14.3 12.9 Urea nitrogen (mg/dl) 14 13 17 Hematocrit (%) 41.1 42.6 37.5 Creatinine (mg/dl) 0.6 0.6 0.6 MCV (fl) 86.9 88.9 92.4 Sodium (mEq/l) 139 142 144 MCH (pg) 30.4 29.9 31.8 Potassium (mEq/l) 4.1 4.2 4.2 MCHC (%) 34.9 33.6 34.4 Chloride (mEq/l) 105 104 106 Platelets (×104/µl) 29.3 21.4 24.1 Calcium (mg/dl) 9.1 9.3 9.3 Phosphate (mg/dl) 3.2 2.9 3.8 WBC: white blood cells, RBC: red blood cells, MCV: mean cor- Urinary deoxypyridinoline (nM/mMCr) 5.4 N.D. N.D. puscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration N.D.: not determined RESISTANCE TO THYROID HORMONE 423 car maintenance workshop, working well as a car had graduated from senior high school and done well as mechanic. He had been in good health and was com- a housewife. She had no significant medical history, pletely asymptomatic. His medical history included and had two sisters, both of whom were well. She had shigellosis at the age of six and appendicitis at the age felt mild fatigue over the last several years, but had not of 28. His parents died of old age, and he had five sought medical advice. She had a slight goiter, but her brothers and three sisters. One brother had died of a CBC and blood chemistry values were normal (Table 1 stroke and one sister had died due to gastric carcinoma, and Table 2). A thyroid function test showed an elevat- but there was no medical history of thyroid disease. He ed level of TSH (140.70 µU/ml), suppressed values of had never felt emotional disturbance, anxiety or ner- FT3 (2.32 pg/ml) and FT4 (0.34 ng/dl), and elevated vousness. He had a small goiter, but had no stigmata of titers of anti-Tg antibody (638.3 IU/ml) and anti-TPO either hyperthyroidism or hypothyroidism. His CBC antibody (>500.0 IU/ml) (Table 3). Hypothyroidism was normal (Table 1). Blood chemistry showed ele- caused by chronic thyroiditis was indicated. Replace- vated levels of triglyceride (176 mg/dl) and total cho- ment therapy with levothyroxine sodium (L-T4; 100 lesterol (248 mg/dl) (Table 2). Thyroid function tests µg per day) was started, and her symptoms were im- showed elevated levels of TSH (5.26 µU/ml), FT3 proved. (5.26 pg/ml) and FT4 (2.04 ng/dl). Anti-Tg antibody Blood samples were then obtained from the patient (176.9 IU/ml) and anti-TPO antibody (243.6 IU/ml) and her parents, and genomic DNA was isolated from were positive. TSHRAb and TSAb were negative. leukocytes by the standard protocol. Direct sequencing Anti-TSH antibody, anti-T3 antibody, and anti-T4 anti- of the amplified TR β gene was performed by the stan- body were negative (Table 3). A TRH administration dard cycle on an automated sequencer, as described test elicited a normal response (Table 4), the maximum elsewhere [6, 7]. All members gave their informed TSH level being 25.90 µU/ml at 60 min after TRH ad- consent to participate in this study, and the investiga- ministration. A L-T3 administration test was not per- tion was performed in accordance with the principles formed because he was unable to come to the hospital. of the Declaration of Helsinki. Genetic analysis re- The results suggested that he had RTH with chronic vealed a heterozygous point mutation, CCT to ACT, thyroiditis. Over the last five years, however, during resulting in substitution of proline by threonine at attendance as an outpatient, he has been feeling well. codon 453 (P453T) of the TR β gene in both the patient The patient’s mother was 55 years old, 144 cm in and her father (Fig. 1). The mother had the wild-type height and weighing 34 kg. Her blood pressure was TR β gene (data not shown). 102/60 mmHg, and pulse rate 62/min and regular. She The patient remained asymptomatic and within the average range of daily performance for three years. In 2003, however, she gradually developed severe pal- Table 3. Thyroid function tests pitation, emotional disturbance, anxiety, nervousness and appetite loss. The anti-anxiety drug lorazepam was Normal Patient Father Mother range prescribed at 0.5 mg three times daily, and this im- proved her anxiety slightly. However, the palpitation, TSH (µU/ml) 1.124 5.26 140.70 0.3–4.0 FT3 (pg/ml) 5.13 5.26 2.32 2.50–4.50 nervousness and appetite loss continued for two years, FT4 (ng/dl) 3.39 2.04 0.34 0.75–1.75 Tg (ng/ml) 10 77 15 <30 Table 4. TRH stimulating test TBG (µg/ml) 19.7 19.0 14 12–30 Patient TSH receptor Ab (%) –5.2 4.6 1.0 <10 Thyroid stimulating Ab (%) 160 135 151 <180 Basal 30 min 60 min 120 min Anti-Tg Ab (IU/ml) 14.6 176.9 638.3 <0.3 TSH (µU/ml) 1.584 16.24 14.46 9.235 Anti-TPO Ab (IU/ml) 0.5 243.6 >500.0 <0.3 PRL (ng/ml) 9.3 101.1 59.1 31.2 Anti-TSH Ab (%) 3.1 4.4 N.D. <6.5 Anti-T3 Ab (%) 2.8 2.9 N.D. <6.5 Father Anti-T4 Ab (%) 1.2 2.0 N.D. <5.0 Basal 30 min 60 min 120 min Tg: thyroglobulin, TBG; thyroxine binding globulin, TSH: thy- TSH (µU/ml) 5.127 25.37 25.90 22.01 roid stimulating hormone, Tg Ab: anti-thyroglobulin antibody, PRL (ng/ml) 6.7 50.5 26.4 14.7 TPO Ab: anti-thyroid peroxidase antibody, N.D.: not determined 424 SATO and SAKAI

Graves’ disease, and this had aggravated her symp- toms. Thus, the diagnosis of RTH requires awareness of its possible presence. The co-occurrence of coincidental autoimmune thy- roiditis in patients with RTH is reportedly rare [5]. As the patient and her father were positive for anti-Tg and anti-TPO antibodies, we diagnosed them as having RTH with coincidental autoimmune thyroiditis. The level of TSH in the father was slightly higher than that in the patient, and his elevated total cholesterol level was consistent with a hypothyroid state. It appeared that his decreased thyroid function due to chronic thyroiditis had resulted in an increase of TSH to com- pensate for the RTH. However, he showed no evi- dent signs or symptoms of hypothyroidism during five years of observation. If he develops stigmata of hypo- thyroidism due to aggravation of the chronic thyroiditis, replacement therapy with TH will be needed. The present patient sometimes suffered palpitation Fig. 1. Sequence analysis of the TR β gene revealed a hetero- and emotional disturbance, which are common clinical zygous point mutation, CCT to ACT, resulting in sub- features of RTH [1, 3, 4]. Findings of electrocardio- stitution of proline by threonine at codon 453 (P453T) graphy, Holter electrocardiography, and echocardio- of the TR β gene in both the patient and her father. graphy were within normal limits and indicated no severe cardiac complications. Her cardiac symptoms and her body weight decreased to 32 kg. Because of and emotional status differed from her family members her emotional disturbance, she had to be admitted to with the same mutation of TR β, which is apparently a the psychiatry ward of our hospital from March 11 to monogenic condition. Variations in phenotype within May 2, 2005. Intravenous hyperalimentation was start- the same family suggest the importance of other ge- ed to improved her malnutrition. Findings of Holter netically determined co-factors [9, 10]. Thus, the electrocardiography and echocardiography were within most likely explanation for the variable clinical manifes- normal limits. The palpitation and emotional distur- tations of this condition is the genetic heterogeneity bance gradually improved with supportive therapy, and of the many co-factors that modulate the receptor- the patient was discharged. Thereafter, her emotional dependent action of TH. state and daily performance were adequately main- In conclusion, we have described the five-year histo- tained by the lorazepam medication. ry of a Japanese woman and her father with RTH and chronic thyroiditis. The two individuals showed clini- cal courses different from each other, despite the fact Discussion that they carried the same mutation (P453T) of the TR β gene. If their thyroid function deteriorates as a result This report has described a Japanese woman and her of chronic thyroiditis, replacement therapy with TH father who showed high levels of circulating TH and will be needed. no suppression of TSH. Analysis of the TR β gene showed that both individuals carried a heterozygous missense mutation of P453T. Routine neonatal screen- Acknowledgements ing of both TSH and T4 when the patient was an infant had not revealed any abnormality. However, it has The authors thank Dr. Yoshifumi Abe at Tana been reported that routine neonatal screening rarely Hospital for his valuable comments. This work was identifies RTH [8]. Furthermore, the patient had re- supported in part by Tokai University School of ceived anti-thyroidal drug therapy under a diagnosis of Medicine Research Aid. RESISTANCE TO THYROID HORMONE 425

References

1. Refetoff S, Weiss RE, Usala SJ (1993) The syndromes Weintraub BD (1991) Characterization of seven novel of resistance to thyroid hormone. Endocr Rev 14: 348– mutations of the c-erbA β gene in unrelated kindreds 399. with generalized thyroid hormone resistance. J Clin 2. Weiss RE (1996) Dominant inheritance of resistance to Invest 88: 2123–2130. thyroid hormone not linked to defects in the thyroid 7. Sasaki S, Nakamura H, Tagami T, Miyoshi Y, hormone receptor α or β genes may be due to a defec- Nogimori T, Mitsuma T, Imura H (1993) Pituitary tive cofactor. J Clin Endocrinol Metab 81: 4196–4203. resistance to thyroid hormone associated with a base 3. Beck-Peccoz P, Chatterjee VKK (1994) The variable mutation in the hormone-binding domain of the human clinical phenotype in thyroid hormone resistance syn- 3,5,3'-triiodothyronine receptor-β. J Clin Endocrinol drome. Thyroid 4: 225–232. Metab 76: 1254–1258. 4. Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, 8. Weiss RE, Balzano S, Scherberg NH, Refetoff S Hauser P, Wiggs E, Weintraub BD (1995) Genetic and (1990) Neonatal detection of generalized resistance to clinical features of 42 kindreds with resistance to thy- thyroid hormone. JAMA 264: 2245–2250. roid hormone. Ann Intern Med 123: 573–583. 9. Franklin HE (1994) The molecular basis of thyroid 5. Lamberg BA, Rosengard S, Liwendahl K (1978) Fa- hormone action. New Engl J Med 331: 847–853. milial partial peripheral resistance to thyroid hormones. 10. Nagaya T, Seo H (1998) Molecular basis of resistance Acta Endocrinol 87: 303–312. to thyroid hormone (RTH). Endocr J 45: 709–718. 6. Parrilla R, Mixson AJ, McPherson JA, McClaskey JH,