Thyroid Hormone Resistance in Two Patients with Papillary Thyroid Microcarcinoma and Their Brafv600e Mutation Status

SUMMARY Resistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary disorder. Here in, we report two patients with RTH in whom differentiated thyroid cancer was diagnosed. Two patients were admitted to our clinic and their laboratory results were elevated thyroid hormone levels with unsuppressed TSH. We considered this situation thyroid hormone resistance in the light of laboratory and clinical datas. Thyroid nodule was palpated on physical examination. Thyroid ultrasonography showed multiple nodules in both lobes. Total thyroidectomy was performed. The pathological findings were consistent with papillary thyroid microcarcinoma. BRAFV600E mutation analysis results were negative. RTH is very rare and might be overlooked. There is no consensus on how to overcome the persistently high TSH in patients with RTH and differentiated thyroid cancer (DTC). Further studies are needed to explain the relationship between RTH and DTC which might be helpful for the treatment of these patients.


INTRODUCTION
R esistance to thyroid hormone (RTH) is a rare au- tosomal dominant hereditary disorder characterized by a reduced responsiveness of the pituitary and peripheral target tissues to thyroid hormone (1,2).RTH is caused by mutations in the thyroid hormone receptor beta (THRβ) gene (1,2).The incidence of RTH is unknown and both sexes affected equally by RTH (3).Patients with RTH have elevated serum free thyroxine (fT4) and free triiodothyronine (fT3) concentrations with nonsuppressed TSH secretion.Despite a variable clinical presentation, the common characteristic clinical features are goitre but absence of the usual symptoms and metabolic consequences of thyroid hormone excess.
Patients with RTH have an increased risk of developing autoimmune thyroid diseases (4).There are few case reports that describe RTH with papillary thyroid carcinoma (PTC) in the literature (5,6).PTC is the most common form of differentiated thyroid carcinoma (DTC) (7).Total thyroidectomy is applied in the treatment of these patients.However, adjuvant therapy in the form of radioactive iodine (RAI) is often administered as a means of reducing the risk of tumor recurrence (8).After than levothyroxine is used to suppress TSH release in order to prevent the relapse or progression of the residual thyroid cancer (9).TSH suppression may not be obtained despite increasing doses of levothyroxine in a patient with RTH.There is no consensus on how to overcome the persistently high TSH in patients with RTH and DTC.Herein we describe two patients with RTH in whom DTC was diagnosed.

CASE REPORTS Case 1
A 56-year-old Turkish women was referred to internal medicine because of the detection of multinodular goiter in physical examination.Subtotal thyroidectomy was performed because of multinodular goiter 20 years ago.She was admitted to our clinic and her laboratory results were detected as follows; TSH: 2.81 mUI/mL (range, 0.55-4.78),free T4 (fT4): 2.45 ng/dL (range, 0.74-1.52),free T3 (fT3): 6.2 pg/mL (range, 2.3-4.2),anti-thyroglobulin antibody (anti-TG) and anti-thyroperoxidase (anti-TPO) antibody were negative.She had no signs or symptoms of typical thyrotoxicosis.MRI scan did not detect the presence of a pituitary tumor.TSH showed exaggerated response to thyrotropin-releasing hormone and was suppressed following T3 administration.The a-subunit of TSH was normal (0.76 IU/L, range, 0-1.6).The patient also underwent testing for THRβ gene, which showed a missense mutation in exon 8 (A234D; c.701C>A).The patient was diagnosed as RTH in the light of laboratory and clinical datas.
Thyroid nodule was palpated on physical examination.Thyroid ultrasonography showed multiple nodules in both lobes.A fine-needle aspiration biopsy (FNAB) was performed and cytological examination showed 'atypical of undetermined significance'.Total thyroidectomy was performed.Pathologic examination revealed papillary thyroid microcarcinoma, tumor size was 0.2 cm (right lobe).Histologic sections of the tumor tissue are very small so that the BRAF mutation could not be analyzed.As the patient was considered at "very low risk" for an adverse clinical course of her thyroid cancer, ablative doses of radioactive iodine were not administered.Levothyroxine therapy was adjusted and the dose was gradually increased up to 200 mg/day.After two months, her TSH level was 84 mUI/L, whereas the fT4 level was 2.33 ng/dL and she complained for the symptoms of hyperthyroidism; therefore, we decreased the dose of levothyroxine to 175 mg/day.After two months her TSH level was 98.76 mUI/L, fT4 level was 1.06 ng/dL and her symptoms of hyperthyroidism was disappeared.
For to ensure the TSH suppression triiodotironin 50 mg/day was added to treatment and levothyroxine was reduced to 150 mg/day.After two months TSH level and fT4 level were 23.6 mUI/L and 1.11 ng/dL, respectively.

Case 2
A 33-year-old Turkish man was admitted to our clinic because of her mother's RTH and MG disease (case 1).Serum thyroid function tests showed elevated fT4, fT3 and TSH (fT4:1.95ng/dL, fT3:7.2pg/mL, TSH: 5.52 mUI/L).Anti-TG and anti-TPO antibody were negative.He had no signs or symptoms of typical thyrotoxicosis.In such cases, a pituitary tumor (TSHoma) that secreting excess TSH should be excluded from RTH. TSH secreting pituitary adenoma was ruled out because the patient had a normal level of the a-subunit of TSH (0.36 IU/L, range, 0-1.6), a negative MRI of the pituitary gland, an exaggerated response of TSH to a thyrotropin-releasing hormone stimulation test and TSH was supressed following T3 administration.There was same mutation in the regions of the THRβ gene (exon 8; A234D; c.701C>A) that was detected in the first case.
Thyroid nodules were detected on physical examination.Ultrasonographic evaluation of the thyroid gland were detected multiple nodules in both lobes.The dominant nodule was 27 x 42 x 51 mm in size in the left lobe and had foci of macrocalcification with mixed echogenicity.Two FNAB was performed and cytological examination resulted as non-diagnostic.The patient underwent total thyroidectomy and papillary thyroid microcarcinoma were detected in two focus with diameters of 0.4 cm in the left lobe and 0.4 cm in isthmus.BRAFV600E mutation analysis results were negative from histopathological sections.I 131 radio remnant ablation was performed and after that levothyroxine therapy was initiated and the dose was gradually increased up to 100 mg/day.After two months her TSH level and fT4 level were 150 mUI/L and 1.26 ng/dL respectively.We increased the dose of levothyroxine to 150 mg/day and control appointment arranged for two months later.

DISCUSSION
RTH has been described by Refetoff in 1967 (10).The cause is mostly mutations in TRβ gene and inheritance of RTH is autosomal dominant (1,2).Those patients who present with goiter and elevated thyroid hormone levels with unsuppressed TSH must be investigated for RTH.The main differential diagnosis to be excluded is inappropriate TSH secretion from a pituitary tumour (TSHoma).The normal level of the TSH a-subunit, a normal MRI of the pituitary gland, an exaggerated response of TSH to a thyrotropin-releasing hormone stimulation test and TSH suppression after T3 administration favour the RTH.
The point mutations in the THRβ gene are found in about 90% of RTH cases.Our two cases have same mutations in the regions of the THRβ gene (exon 8; A234D; c.701C>A).This mutation had not been previously reported as being associated with RTH in the literature.This is a novel heterozygous missense mutation discovered by our clinic.Also Ünlütürk and cols.from Turkey reported a case of RTH with thyroid cancer which have a single nucleotide substitution (T>C) in codon 334 in THRβ gene (11).
PTC is the most common histological type of thyroid malignancy and the rising incidence of thyroid cancer is mainly attributed to the increased diagnosis of PTC, particularly the small micro PTC (12,13).BRA-FV600E mutation is the most common genetic alteration in thyroid cancer, and found in about 45% of papillary thyroid cancers (14).Our in the first case, we did not evaluate BRAFV600E mutation because of the small histopathologic cross-sections but in the second case BRAFV600E mutation was negative.High serum TSH levels, typically described in RTH, are associated with increased risk of thyroid malignancy (15).Whereas suppression of TSH levels are recommended as adjunctive treatment in differentiated thyroid cancer (16).
There are case reports related with the association of the RTH and PTC in the literature (5,6).In these cases, clinical euthyroidism with levothyroxine replacement has been achived but TSH suppression was not occured.When the dose of levothyroxine was increased, in those patients hyperthyroidism symptoms (tachycardia, anxiety) occurred, so levothroxine dose was decreased.In two cases, with the addition of T3 to the treatment TSH levels decreased to the normal range (17,18).There are also papers related with suppression of TSH with thyroid hormone analogs, such as triiodothyroacetic acid (TRIAC) in RTH (19,20).TRIAC might be an alternative drug in RTH with DTC to suppress TSH so much peripheral tissue effect.
In conclusion, there are two situation that need to be explained; one of them is whether patients with RTH are at an increased risk for thyroid cancer and the other one is whether thyroid cancer is more aggressive in patients with RTH because of the difficulty in suppressing serum TSH concentration.TSH suppression has been considered as the key step of DTC treatment after total thyroidectomy and radioactive iodine therapy.TSH suppression may not be obtained despite increasing doses of L-T4 in a patient with RTH.There is no consensus on how to overcome the persistently high TSH in patients with RTH and DTC.Further studies are needed to explain the relationship between RTH and DTC which might be helpful for the treatment of these patients.
Disclosure: no potential conflict of interest relevant to this article was reported.

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case of resistance to thyroid hormone Arch Endocrinol Metab.2015;59/4

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case of resistance to thyroid hormone Arch Endocrinol Metab.2015;59/4