A Case of Hyperthy Thyroid Hormone. roidism Due to Pituitary Resistance to

Transcription

1 Endocrine Journal 1994, 41(4), A Case of Hyperthy Thyroid Hormone roidism Due to Pituitary Resistance to YoH HIDAKA, HIsATO TADA, TAKU KASHIWAI, SHICEKAZU SASAKI*, SHINICHIRO ANDOH**, HIROTOSHI NAKAMURA** AND NOBUYUKI AMINO Department o f Laboratory Medicine, Osaka University Medical School, Suita 565, *Department o f Internal Medicine, Kyoto University School o f Medicine, Kyoto 606, and **Department o f Internal Medicine, Hamamatsu University School o f Medicine, Hamamatsu 43131, Japan Abstract. A fifteen-year-old male was admitted to our hospital because his thyroid function showed a lack of TSH suppression in the face of elevated thyroid hormone. This patient complained of heat intolerance, palpitation and hand tremor. Peripheral indices of thyroid hormone action indicated a hypermetabolic state. Serum TSH did not respond sufficiently to TRH stimulation, suggesting TSHsecreting pituitary adenoma. However, sellar CT scan and MRI images did not demonstrate any pituitary adenoma. Moreover, the serum TSH a-subunit concentration was not high and serum TSH was partially suppressed tion polymorphism by the administration of T3. Furthermore, the results of single stranded conforma- (SSCP) suggested the existence of mutation(s) in the exon 7 of T3 receptor f3 (TRI3) gene of this patient. These findings support the diagnosis of pituitary resistance to thyroid hormone. Key words: Inappropriate secretion of TSH, Thyroid hormone resistance, TSH-secreting pituitary adenoma, T3 receptor 13(TRfJ) gene. (Endocrine Journal 41: ,1994) INAPPROPRIATE secretion of TSH is characterized by an increase in serum thyroid hormones and a high or normal level of TSH. This syndrome is a rare disorder resulting from the syndromes of resistance to thyroid hormone or TSH-secreting pituitary adenoma. The syndromes of resistance to thyroid hormone are classified into two major types: generalized resistance to thyroid hormone (GRTH), and pituitary resistance to thyroid hormone (PRTH) [1, 2]. Two hundred and ninety-six cases of GRTH have been reported [3]. In GRTH, the responsiveness to thyroid hormone is reduced in all target tissues, including the pituitary. PRTH, which differs from GRTH in the apparent manifestations of thyroid hormone excess at the level of Received: September 14, 1993 Accepted: March 1, 1994 Correspondence to: Dr. Yoh HIDAKA, Department of Laboratory Medicine, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565, Japan peripheral tissues, has been reported in 50 cases [3]. Genetic analysis of the thyroid hormone receptor has provided the basis for further understanding of syndromes of thyroid hormone resistance [4, 5]. In most cases, mutations in the T3 receptor /3 (TR f3) gene are clustered in exons 7 and 8, and have been reported in 28 families with GRTH and in 2 subjects with PRTH [3, 6, 7], although another point mutation is reported in a family with GRTH [8]. In this paper we report a case of resistance to thyroid hormone and discuss the distinction between GRTH and PRTH. Methods Serum free T4 (FT4) and free T3 (FT3) were measured by analog RIA (FT4 kit, Eiken; Amerlex-M FT3, Amersham). The presence of autoantibodies to T4 or T3 was ruled out by showing the non-specific binding to be less than 10%. Serum TSH was

2 340 HIDAKA et ai. measured by an IRMA with monoclonal antibody (SPAC-S TSH kit; Daiichi). The presence of human anti-mouse antibody was ruled out by adding mouse IgG to the TSH assay [9]. Anti-thyroid microsomal (MCPA) and anti-thyroglobulin antibodies (TGPA) were tested by a passive particle agglutination method (Serodia-AMC and Serodia-ATG; Fujirebio). TSH-binding inhibitory immunoglobulin (TBII) was measured by radioreceptor assay with a commercial kit (Baxter). Thyroid stimulating antibody (TSAb) was measured as an increase in camp in FRTL-5 cells [10]. The TSH a-subunit was measured as described previously [11]. The normal value was less than 1.23 ng/ml. Single stranded conformation polymorphism (SSCP) analysis was performed according to the method previously described. Briefly, genomic DNA was prepared from the patient's periferal lymphocytes, and DNA fragments of exons 3-8 of the TR(3 gene were amplified by PCR using the oligonucleotide primers described in [6] with [a- 35S]deoxy-CTP under the temperature profiles in [12]. After adding formamide solution and heating at 80 C, the samples were loaded onto 5% polyacrylamide gel containing glycerol (0-10%) in 50 Table 1. Thyroid function test mm Tris borate buffer with 2 mm EDTA and electrophoresis was run for 3-4 h at 4 C. The gels were dried and put on a Kodak XAR5 film for 10 days. Case and Results A fifteen-year-old boy visited a family physician because of heat intolerance, palpitation and tremor which had been complained of for about five months. Thyroid function test showed a lack of appropriate TSH suppression despite high thyroid hormone levels. He was then referred to our hospital for further investigation. His personal history was uneventful and there was no family history of thyroid disease. His height was 181 cm and body weight was 69 kg. The pulse rate was 90/min and regular. His skin was moist and warm. He did not have a palpable goiter, ophthalmopathy or pretibial dermopathy. There was no relative who had ever had thyroid dysfunction pointed out. Thyroid function tests are summarized in Table 1, showing a lack of TSH suppression in the face of an increase in thyroid hormones. Moreover, TBII and TSAb were negative. These findings were quite atypical of Graves' disease and suggested the syndrome of inappropriate secretion of TSH. Thyroid function and peripheral indices of thyroid hormone action before and after administration of 75 µg of T3 for 14 days are summarized in Table 2. Before administration of T3, concentrations of serum sex hormone-binding globulin (SHBG), angiotensin-converting enzyme (ACE), alkaline phosphatase (ALP) and urine hydroxyproline increased and serum cholesterol level was decreased. These Table 2. Thyroid function and peripheral indices of thyroid hormone action, after administration of 75µg of T~ for 14 days before and

3 PITUITARY RESISTANCE TO THYROID HORMONE 341 findings demonstrate hyperthyroidism. Serum TSH and 123! uptake were partially suppressed by administration of T3 but serum FT4 was not. Elevation of urine hydroxyproline was found but SHBG, ACE, ferritin and total cholesterol did not show any obvious changes by T3 administration. TSH (Table 3), FT4 and FT3 did not respond sufficiently to TRH stimulation. The patient's serum TSH a- subunit concentration was 0.76 ng/ml, that was not elevated. Sellar CT scan and MRI images did not demonstrate any pituitary adenoma. To examine the possibility of point mutation of the patient's TR/3 gene, each DNA fragment of exon 3 to 8 was amplified by polymerase chain reaction (PCR) and analyzed by the single stranded conformation polymorphism (SSCP) method (Fig. 1). Exon 7 of the patient's TR/3 gene showed abnormal band ([1 ), suggesting the existence of mutation(s). not be taken as confirmation that there is no tumor as it may be missed because of small size. While TRH-stimulated TSH secretion is reported in 94% of subjects with PRTH, a significant response to TRH is found in only 39% of patients with TSHsecreting adenoma [3]. In the present case, however, the TSH response to TRH stimulation was low. The reason is unknown, but may due to the poor general condition of the patient in hypermetabolic state. Recently, a point mutation in exon 7 of the TR/3 gene was reported even in PRTH as well as in GRTH. The mutation lies at nucleotide 1297 (C to T) in exon 7, which alters the 333 amino acid, arginine, to tryptophan [6, 7]. In the present case, the result of SSCP, which is a simple and rapid method in detecting point mutations [14], suggested the existence of mutation(s) in exon 7 of the TRH gene of this patient. This finding supports the Discussion In the classification of syndrome of inappropriate secretion of TSH, the major disorders are resistance to thyroid hormone and TSH-secreting pituitary adenoma [13]. Patients with TSH-secreting adenoma are best distinguished from subjects with pituitary resistance to thyroid hormone (PRTH) by their disproportional secretion of a-subunit which was present in 88% of patients with TSH-secreting tumors [3]. In the present case, serum a-subunit concentration was not elevated. Patients with PRTH are more likely to respond to administration of T3 by a partial suppression of the basal serum TSH level. This was observed in 88% of subjects with PRTH as compared to only 25% of patients with TSH-secreting adenoma [3]. In the present case, TSH was partially suppressed by administration of T3. Sellar CT scan and MRI images failed to demonstrate any pituitary adenoma. These findings were compatible with PRTH. However, the absence of a tumor on MRI of the pituitary should Table 3. The TSH response in TRH test under no treatment Fig. 1. Single stranded conformation polymorphism (SSCP) in the DNA fragments from exon 7 and 8 of the patient's TRf3 gene. P, Patient; C, Healthy Control. An abnormal band (-') was observed in the patient's DNA fragments from exon 7.

4 342 HIDAKA et al. diagnosis of PRTH, although it is necessary for the definitive diagnosis to detect the mutation(s) in DNA sequence which we shall show in another chance together with other cases. The patient demonstrated heat intolerance, palpitation and tremor. Moreover, the base-line values of tests that measure peripheral effects of thyroid hormone, including SHBG, ACE, ALP and urine hydroxyproline elevated. We, therefore, concluded that this patient was both chemically and clinically hyperthyroid. Serum ferritin and ACE were reported to be increased by short term administration of T3 [15, 16]. In the present case, however, ferritin and ACE did not show any obvious changes by T3 administration. The above findings suggested that the present case, conventionally diagnosed as PRTH, has some degree of resistance to thyroid hormone in the peripheral tissues besides the pituitary. This observation, together with the fact that mild hypermetabolic symptoms in some organs are sometimes seen in GRTH, supports the idea that thyroid hormone resistance arises from some common genetic conditions and that PRTH and GRTH are the typical extremes in their representations [6]. Acknowledgments We are indebted to Dr. Junta Takamatsu for valuable advice on thyroid hormone resistance. This work is supported by grants from Grant-in Aid for Scientific Research (to N. Amino; No ) from the Ministry of Education, Science, and Culture of Japan; the Intractable Disease Division of the Public Health Bureau, Ministry of Health and Welfare and the Foundation for Total Health Promotion. References 1. Refetoff S, Dewind LT, DeGroot LJ (1967) Familial syndrome combining deafmutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. I Clin Endocrinol Metab 27: Gershengorn MC, Weitraub BD (1975) Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone. J Clin Invest 56: Refetoff S, Weiss RE, Usala SJ (1993) The syndromes of resistance to thyroid hormone. Endocr Rev 14: Sakurai A, Takeda K, Amn K, Ceccarelli P, Nakai A, Seino S, Bell GI, Refetoff S, DeGroot LJ (1989) Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor f. Proc Natl Acad Sci USA 86: Takeda K, Balzano S, Sakurai A, DeGroot LJ, Refetoff S (1991) Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor fj gene and the detection of a new mutation. J Clin Invest 87: Sasaki S, Nakamura H, Tagami T, Miyoshi Y, Nogimori T, Mitsuma T, Imura H (1993) Pituitary resistance to thyroid hormone associated with a base mutation in the hormone-binding domain of the human 3,5,3'-triiodothyronine receptor-13. J Clin Endocrinol Metab 76: Mixson AJ, Renault JC, Ransom S, Bodenner DL, Weitraub BD (1993) Identification of a novel mutation in the gene encoding the f3-triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone. Clin Endocrinol (Ox f.) 38: Behr M, Loos U (1992) A point mutation (Ala229 to Thr) in the Hinge Domain of the c-erba13 thyroid hormone receptor gene in a family with generalized thyroid hormone resistance. Mol Endocrinol 7: Iitaka M, Ishii J, Ishikawa N, Yoshimura H, Momotani N, Saitou H, Ito K (1991) A case of Graves' disease with false hyperthyrotropinemia who developed silent thyroiditis. Endocrinol Japon 38: Tamaki H, Amino N, Kaneda T, Mitsuda N, Tanizawa 0, Miyai K (1993) Crucial role of serum human chorionic gonadotropin in the aggravation of thyrotoxicosis in early pregnancy in Graves' disease. Thyroid (In press). 11. Kashiwai T, Ichihara K, Tamaki H, Endo Y, Kimura M, Takeoka K, Amino N, Miyai K (1991) The stability of immunological and biological activity of human thyrotropin in buffer: its temperature dependent dissociation into subunits during freezing. Scand J Clin Lab Invest 51: Sasaki S, Nakamura H, Tagami T, Miyoshi Y, Tanaka K, Imura H (1992) A point mutation of the T3 receptor 31 gene in a kindred of generalized re-

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