This is a case of a woman who was diagnosed with resistance to thyroid hormone after total thyroidectomy for thyroid cancer. Preoperative laboratory examination revealed the syndrome of inappropriate secretion of TSH, however, the patient had no thyrotoxic symptoms and no family history. Based on the results of ultrasonography and fine needle aspiration, she was diagnosed with papillary thyroid carcinoma and underwent total thyroidectomy. After the surgery, she received L-T4 therapy, but her TSH levels remained elevated. MRI was performed on the brain, but no lesions were found in the pituitary gland. Therefore, she was tested for TRβ gene, and a previously defined mutation, P453S, was detected. Ultimately, she was diagnosed as RTH and treated with L-T4. In this case, the dose of L-T4 needed to be increased to suppress her TSH levels to the normal range or less, and to prevent stimulating malignant cells. Currently, her dose of L-T4 has been increased, and her TSH levels are still lower than normal, however, she has no thyrotoxic symptoms, recurrence or metastasis of thyroid cancer. The patient is currently under careful observation regarding her circulatory and physiological status. In addition, the results of treatment still need to be monitored and evaluated

Aoyama, Mariko

Tokushima University Institutional Repository

INTRODUCTIONResistance to thyroid hormone (RTH) is a syndrome involvingreduced responsiveness of target tissues to thyroid hormone (TH)(1). Patients with all RTH all have non-suppressed thyroid-stimu-lating hormone (TSH) levels despite elevated free thyroxine (FT4)and free triiodothyronine (FT3) levels, unless they have a co-ex-isting thyroid disease such as Graves’ disease or thyroid autonomy.This condition is known as the syndrome of inappropriate secre-tion of TSH (SITSH) (2). Patients with TSH-secreting pituitarytumors (TSHoma) and RTH often exhibit SITSH. In majority of pa-tients with RTH, this condition is caused by mutations in the thy-roid hormone receptor (TR) β gene (3).This rare case is an important addition to the literature becausethere have been few reports on hormone replacement therapy ina patient with RTH and thyroid cancer after total thyroidectomy.CASE PRESENTATIONA 54-year-old woman was admitted to our hospital because achest X-ray showed abnormal calcification in the bilateral lobes ofthe thyroid. She had no typical thyrotoxic signs or symptoms andthere was no relevant family history of thyroid disease.On palpation, her thyroid was mildly enlarged. Electrocardiog-raphy showed regular sinus rhythm. On the initial laboratory ex-amination before the operation, thyroid function tests demonstratedslightly elevated values of FT3 and FT4, and TSH was within thenormal range. (FT3 6.3 [range, 2.3 -4.1] pg/mL, FT4 3.0 [0.7 -1.7]ng/dL, TSH 4.03 [0.5 -4.3] μU/mL). Anti - thyroglobulin antibodyand anti - thyroid peroxidase antibody were negative, suggesting nochronic thyroiditis. Thyroglobulin was elevated (90 [0-32.7] ng/mL), thyroid-stimulating antibody and TSH-binding inhibitor im-munoglobulin levels were not measured (Table 1).Ultrasonography showed some masses in the bilateral lobes(one nodule in the right lobe and three nodules in the left lobe).They were hypoechoic and calcified masses, approximately 1 cmin size.Fine needle aspiration was performed for the nodule with fea-tures suggestive of malignancy in the left lobe (Figure 1), and thecytologic diagnosis was papillary carcinoma.CASE REPORTA case of resistance to thyroid hormone diagnosed after totalthyroidectomy for thyroid cancerMariko AoyamaDepartment of surgery, Tokushima Municipal HospitalAbstract : This is a case of a woman who was diagnosed with resistance to thyroid hormone after total thyroidec-tomy for thyroid cancer. Preoperative laboratory examination revealed the syndrome of inappropriate secretionof TSH, however, the patient had no thyrotoxic symptoms and no family history. Based on the results of ultra-sonography and fine needle aspiration, she was diagnosed with papillary thyroid carcinoma and underwent totalthyroidectomy. After the surgery, she received L-T4 therapy, but her TSH levels remained elevated. MRI wasperformed on the brain, but no lesions were found in the pituitary gland. Therefore, she was tested for TRβ gene,and a previously defined mutation, P453S, was detected. Ultimately, she was diagnosed as RTH and treated withL-T4. In this case, the dose of L-T4 needed to be increased to suppress her TSH levels to the normal range or less,and to prevent stimulating malignant cells. Currently, her dose of L-T4 has been increased, and her TSH levelsare still lower than normal, however, she has no thyrotoxic symptoms, recurrence or metastasis of thyroid cancer.The patient is currently under careful observation regarding her circulatory and physiological status. In addi-tion, the results of treatment still need to be monitored and evaluated. J. Med. Invest. 62 : 268-271, August, 2015Keywords : Resistance to thyroid hormone, papillary carcinoma, total thyroidectomy and levothyroxine therapyReceived for publication May 12, 2015 ; accepted July 27, 2015.Address correspondence and reprint requests to Mariko Aoyama, De-partment of surgery, Tokushima Municipal Hospital 2 -34, Kitajyosannjima,Tokushima-city, Tokushima, 770-0812, Japan and FAX : +81-88 -622-5313.Table 1. Blood chemistry resultsNormal rangeWBC 6.7 103/μl 4.0 -9.5RBC 4.92 106/μl 3.5 -5.0Hemoglobin 14.8 g/dl 11.0 -15.0Hematocrit 42.4 ％ 35.0 -45.1Platelets 20.9 104/μl 130 -400Ca 9.7 mg/dl 8.0 -11.0P 3.6 mg/dl 2.5 -4.5FT3 6.3 pg/ml 2.3 -4.1FT4 3 ng/dl 0.7 -1.7TSH 4.03 μU/ml 0.5 -4.3Anti -Tg Ab 10 mg/l 0 -40.6Anti -TPO Ab 1.7 mg/l 0 -5.2Tg 90 ng/ml 0-32.7WBC : white blood cells, RBC : red blood cells, FT3 : free triiodothy-ronine, FT4 : free thyroxine, TSH : thyroid-stimulating hormone, anti -Tg Ab : anti-thyroglobulin antibody, anti -TPO Ab : anti - thyroid peroxi-dase antibody, Tg : thyroglobulinThe Journal of Medical Investigation Vol. 62 2015268The patient underwent total thyroidectomy and cervical lymphnode dissection. Final postoperative pathology revealed four tu-mors of papillary carcinoma (10 mm7 mm in the right lobe and4 mm4 mm, 10 mm8 mm, and 4 mm3 mm in the left lobe),with no metastases to the cervical lymph nodes. On postoperativeday 7, she received L-T4 therapy at 100 μg/day. After 1 month ofL-T4 therapy, her TSH levels were markedly elevated (FT3 2.9pg/mL, FT4 1.5 ng/dL, and TSH 103.7 μU/mL). Two months aftersurgery, the TSH levels were still elevated (FT3 2.7 pg/mL, FT41.6 ng/dL, and TSH 102.09 μU/mL). Therefore, the dose of L-T4was increased from 100 μg to 125 μg daily. Three months post-surgery, the TSH levels were lower (FT3 3.4 pg/mL, FT4 1.8 ng/dL, and TSH 87.45 μU/mL), and the dose of L-T4 was decreasedto 100 μg/day. However, 4 months later, the TSH level was ele-vated again (FT3 2.6 pg/mL, FT4 1.5 ng/dL, and TSH 108.56 μU/mL). The dose of L-T4 was again increased to 125 μg/day, but theTSH levels were not suppressed despite the elevated FT4 (FT33.2 pg/mL, FT4 2.1 ng/dL, and TSH 112.59 μU/mL). TSHoma orRTH was then suspected, thus magnetic resonance imaging (MRI)of the brain was performed, but no tumors were found in the pi-tuitary gland (Figure 2), suggesting RTH. Written permission wasreceived from the patient for gene analysis of TRβ as approved bythe committee of Tokushima Municipal Hospital. Genomic DNAwas isolated from the peripheral blood, and the DNA sequenceanalysis of the TRβ gene revealed a heterozygous point mutation,CCT to TCT, resulting in substitution of proline by serine at codon453 (P453S), which has been found previously (Figure 3). Ulti-mately, she was diagnosed with RTH 7 months after surgery. Geneanalysis was recommended to her family, but they declined.The dose of L-T4 was increased to 350 μg/day. The latest thy-roid function tests showed that the TSH level was still slightly sup-pressed (FT3 6.0 pg/mL, FT4 4.5 ng/dL, and TSH 0.45 μU/mL),and she had no thyrotoxic symptoms (Figure 4). There has been norecurrence or metastasis of thyroid cancer 27 months post surgery.DISCUSSIONRTH is a syndrome that involves reduced tissue sensitivity to TH(1). Patients with RTH have non-suppressed TSH levels despite ele-vated FT4 and FT3 levels, unless they have a co-existing thyroiddisease such as Graves’ disease or thyroid autonomy, this condi-tion is known as SITSH (2). Approximately 85% of RTH kindredcases are caused by mutations in the TRβ gene, which is passeson by autosomal dominant inheritance (3). However, RTH cannotnecessarily be ruled out just because there are no mutations inthe TRβ gene (4).Figure 1. Ultrasonography of the thyroid.Thyroid ultrasonography showed some masses in the bilateral lobes(one nodule in the right lobe and three nodules in the left lobe) suggest-ing malignancy. Fine needle aspiration was performed for the nodulewith features suggestive of a malignancy in the left lobe (arrow).Figure 2. MRI of the brain.No tumors were found in the pituitary gland.Figure 3. Sequence analysis of the TRβ gene.Sequence analysis of the TRβ gene revealed a heterozygous point mu-tation, CCT to TCT, resulting in substitution of proline by serine at co-don 453 (P453S).The Journal of Medical Investigation Vol. 62 August 2015 269In most patients with RTH, TSH is inappropriately secreted andstimulates the thyroid gland continuously. Thus, such patients’ thy-roid glands appear mildly enlarged, and iodine123 scintigraphy showsdiffuse enlargement of the thyroid gland with increased uptake.Some patients with RTH have thyrotoxic signs and symptoms, suchas tachycardia, atrial fibrillation, attention deficit disorder, and hy-peractivity (4-7). On laboratory examination, thyroid function testsshow unsuppressed TSH levels despite elevated FT4 and FT3 levels(2). In particular, FT4 is elevated in most cases (4, 5).If thyroid function tests suggest SITSH, assay interference shouldbe excluded, it is occasionally necessary to change the measure-ment method. If laboratory dates still suggest SITSH, then RTH orTSHoma are suspected, and the patient’s family history shouldfirst be confirmed. If the patient has no family history of RTH, thenext step is to check for a pituitary tumor using MRI to rule outthe possibility of TSHoma. In patients with a family history of RTHor those with no lesions in the pituitary gland, analysis of the TRβgene should be performed to confirm a diagnosis of RTH. A diag-nosis of RTH can be made if there is a mutation of the TRβ gene.In the present case, the patient’s thyroid function tests on initiallaboratory examination showed slightly elevated values of FT3 andFT4, with TSH in the normal range. RTH was not suspected at thatpoint, because there was no significant family history or symptomsof hyperthyroidism or hypothyroidism. However, her thyroid func-tion should have been assessed again before the operation. Al-though the treatment policy was not changed as a result, she mayhave been able to receive suitable hormone replacement therapysoon after surgery.Treatment of RTH is unnecessary if the patient has no symptoms.In patients with hypothyroidism, a trial of TH therapy can be consid-ered. If hyperthyroidism is present, β adrenergic blocking agentsand other appropriate agents should be given (4, 6). In the presentcase, the patient underwent total thyroidectomy for thyroid cancer,and thus required hormone replacement therapy. Two experts(Yoshitaka Hayashi, Associate Professor, and Yoshiharu Murata,former Professor of the Research Institute of Environmental Medi-cine of Nagoya University) were consulted on how to control thedose of L-T4 in the present case, and they suggested that the pa-tient should have received the appropriate L-T4 dose to achievethe preoperative TSH level. A few cases of RTH with total thyroi-dectomy have been reported (8, 9), and the TH levels as were con-trolled in the present case. Moreover, another case report sug-gested that the family’s mean THS level should be used as thetarget for L-T4 replacement therapy (10). However, this is notavailable in sporadic RTH patients. Furthermore, the authors ofthe above study did not evaluate the effect of L-T4 therapy afterthe operation on the patient’s long-term circulatory and physiologi-cal status, as well as the prognosis and treatment results of thyroidcancer in such cases.The method used in the present case appears to be physiologicand suitable as an improved approach to the patient’s preoperativecondition, although there is no clear evidence to support this. Ad-ditionally, I think that estimation of other clinical data, for exam-ple, change in body weight, heart rate, creatine kinase, and alka-line phosphatase, would have been useful for evaluating TH levelin the patient.In the present case, it was necessary to increase the dose of L-T4 to suppress the TSH levels to the normal range or less and toprevent stimulating malignant cells based on the general guidelinesfor thyroid cancer. The patient currently receives 350 μg/day L-T4and has no thyrotoxic symptoms. There has been no recurrenceor metastasis of thyroid cancer 27 months after the surgery.Figure 4. Clinical course of the patient.L -T4 : levothyroxineThe figure shows the thyroid function tests and the dose of L-T4 after the surgery.M. Aoyama A case of resistance to thyroid hormone in a thyroid cancer patient270In patients with RTH, TSH is unsuppressed. Therefore, the nec-essary dose of L-T4 will increase if the patient needs hormone re-placement therapy, which could cause thyrotoxic symptoms in suchpatient (4, 5). In addition, there have been a few reports on thelong term treatment results of thyroid cancer in such cases. In thepresent case, the patient will be observed, and the effect of L-T4therapy will be followed up. Although long- term observation is notpossible, I have considered and addressed these issues, and I thinkthat this report provides useful information.Moreover, my patient had papillary carcinoma. Approximately95% of RTH patients have diffuse goiter, and continuous stimula-tion of the thyroid by excess TSH may be related to the formationof thyroid nodules and growth of thyroid cancer (8). However, thecontribution of RTH to thyroid tumorigenesis is not fully under-stood, and there is no confirmatory evidence. Further studies onthe association between thyroid cancer and RTH are warrantedand I must carefully observe and evaluate my patient for recur-rence and metastasis.CONCLUSIONSIn conclusion, a patient diagnosed with RTH after total thyroidec-tomy for thyroid cancer was described. It is difficult to decide onthe most appropriate dose of TH in these situations and furtherinvestigation is required.LIST OF ABBREVIATIONSRTH : resistance to thyroid hormoneTSH : thyroid-stimulating hormoneSITSH : syndrome of inappropriate secretion of TSHFT3 : free triiodothyronineFT4 : free thyroxineL-T4 : levothyroxineMRI : magnetic resonance imagingTR : thyroid hormone receptorTH : thyroid hormoneTSHoma : TSH-secreting pituitary tumorsCOMPETING INTERESTSThe author declares that he have no competing interests.ACKNOWLEDGMENTSThe author would like to express his gratitude to AssociateProfessor Yoshitaka Hayashi and Professor Emeritus YoshiharuMurata, of the Research Institute of Environmental Medicine ofNagoya University.REFERENCES1. Refetoff S, De Wind LT, DeGroot LJ : Familial syndrome com-bining deaf -mutism, stippled epiphyses, goiter, and abnor-mally high PBI : possible target organ refractoriness to thy-roid hormone. J Clin Endocrinol Metab 27 : 279-294, 19672. Gershengorn MC, Weintraub BD : Thyrotropin- induced hy-perthyroidism caused by selective pituitary resistance to thy-roid hormone. A new syndrome of “inappropriate secretion ofTSH”. J Clin Invest 56 : 633-642, 19753. Weiss RE, Refetoff S : Resistance to thyroid hormone. Rev En-docr Metab Disord 1 : 97-108, 20004. Murata Y : The pathology and diagnosis of resistance to thy-roid hormone. Current Therapy JPN : 81-87, 20135. Murata Y : Syndromes of resistance to thyroid hormone andinappropriate secretion of TSH (SITSH). Nihon Rinsho 70:1951-1957, 20126. Beck-Peccoz P, Chatterjee VKK : The variable clinical phe-notype in thyroid hormone resistance syndrome. Thyroid 4 :225-232, 19447. Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, HauserP, Wiggs E, Weintraub BD : Genetic and clinical features of42 kindreds with resistance to thyroid hormone. Ann InternMed 123 : 573-583, 19958. Kim HK, Kim D, Yoo EH, Lee JI, Jang HW, Tan AHK, HurKY, Kim JH, Kim KW, Chung JH, Kin SW : A case of resis-tance to Thyroid Hormone with Thyroid Cancer. J KoreanMed Sci 25 : 1368-1371, 20109. Sugita M, Harada H, Yamamoto T : Perioperative managementof a patient with thyroid hormone resistance who underwenttotal thyroidectomy for thyroid cancer. J Anesth 26 : 595-597,201210. Tran HA : Difficult in diagnosing and managing coexisting pri-mary hypothyroidism and resistance to thyroid hormone. En-docr Pract 12 : 288-293, 2006The Journal of Medical Investigation Vol. 62 August 2015 271

A case of resistance to thyroid hormone diagnosed after total thyroidectomy for thyroid cancer

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A case of resistance to thyroid hormone diagnosed after total thyroidectomy for thyroid cancer

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