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).