resistance to thyroid hormone ( rth ) is an autosomal dominant disorder characterized by variable tissue hyposensitivity to triiodothyronine ( t3 ) , with persistent elevation of serum free t3 ( ft3 ) and free thyroxine ( ft4 ) levels , along with inappropriately non - suppressed thyroid stimulating hormone ( tsh ) . the majority of cases are associated with mutations in the thyroid hormone receptor beta ( tr ) gene ( 2,3 ) . heterozygous mutations in the tr gene , localized to restricted regions of the hormone - binding domain , cause a loss of receptor function . the mutant receptors are transcriptionally impaired , due to reduced ligand binding or attenuated interaction with co - activators , and inhibit wild - type tr and tr action in a dominant - negative manner ( 4 ) . heterozygous members of a family who had only one deleted tr allele revealed normal clinical and laboratory findings ( 5 ) . these findings suggest that a single copy of tr is sufficient for a normal function , and tr point mutations interfere with the normal functions of tr in human . the pathogenesis of variable tissue resistance is not fully understood , but may be related to the differing tissue distributions of tr and tr and variable dominant - negative activity of mutant receptors on different target genes . individuals with rth do not generally exhibit severe symptoms of hypothyroidism , because hormone resistance is believed to be compensated by increased thyroid hormone . the classic clinical features of rth include thyroid goiter , attention deficit disorders , delayed skeletal maturation , tachycardia , and an impaired metabolic response to thyroid hormone . other symptoms , such as frequent ear and throat infections , hearing loss , and a decreased bone mass have been recognized ( 6 - 8 ) . we herein describe a rth patient with a tr mutation who exhibited the symptoms of heart failure and an impaired glucose metabolism . a 60-year - old man was referred to our hospital because of abnormal thyroid function test results . he presented with episodic palpitations at 16 years of age , and was diagnosed with graves disease . he had no history of hyperactivity , learning problem or low performance . at 46 years of age , he was noted to have a high plasma glucose level ( 236 mg / dl ) and elevated hba1c ( 8.2% ) . he was diagnosed with diabetes mellitus and treated with 1 mg of glimepiride , a glucose - lowering agent . at 53 years of age , he was admitted to a hospital with symptoms of dizziness , and his electrocardiogram showed bradycardia with atrial fibrillation . the results of a thyroid function test at this time revealed that the serum level of ft4 was 3.0 ng / dl . he received a permanent pacemaker and was started on anti - thyroid therapy with methimazole ( mmi ) . the results of his thyroid function tests after stopping mmi treatment for two months revealed that the serum levels of ft4 and tsh were 3.5 ng / dl and 3.43 iu / ml , respectively , indicating syndrome of inappropriate tsh secretion ( sitsh ) . his physical examination revealed the following : height , 161 cm ; weight , 59 kg ( body mass index , 22.7 ) ; pulse rate , 63 beats / min ; blood pressure , 110/70 mmhg ; and body temperature , 37.3. the thyroid gland was normal , and there was no lid retraction . a systolic ejection murmur was detected in the cardiac apex area . he had simple diabetic retinopathy and moderate peripheral neuropathy . in laboratory tests on admission , the complete blood count was normal and , urinary albumin excretion was within the normal range . his c - reactive protein level was normal , creatinine was 0.84 mg / dl ( normal range : 0.6 to 1.1 mg / dl ) , blood urea nitrogen ( bun ) was 24.8 mg / dl ( normal range : 6 to 20 mg / dl ) , aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) were within the normal ranges , and alkaline phosphatase ( alp ) was 592 his lipid profiles were low - density lipoprotein ( ldl)-cholesterol 69 mg / dl , high - density lipoprotein ( hdl)-cholesterol 37 mg / dl , and triglyceride 54 mg / dl ( table 1 ) . his fasting plasma glucose was 114 mg / dl and hba1c was 8.1% under multiple injections of rapid - acting insulin . his ft4 level was 3.50 ng / dl ( normal range : 0.70 to 1.48 ng / dl ) , ft3 was 4.81 pg / ml ( normal range : 1.71 to 3.71 pg / ml ) , tsh was 3.43 iu / ml ( normal range : 0.35 to 4.94 iu / ml ) , anti - thyroglobulin and anti - thyroid peroxidase antibodies were negative , and anti - tsh receptor antibody level was below 1.0 ui / l ( normal range : 0.0 to 1.0 ui / l ) . other hormonal results were cortisol 8.7 g / dl ( normal range 3.7 to 19.4 g / dl ) , adrenocorticotropic hormone ( acth ) 63.0 pg / ml ( normal range 7.2 to 63.3 pg / ml ) , prolactin 20.0 ng / ml ( male normal range 3.46 to 19.4 ng / ml ) , luteinizing hormone 2.82 miu / ml , follicle stimulating hormone 3.5 miu / ml , insulin - like growth factor ( igf)-1 62 ng / ml ( normal range 79 to 232 ng / ml ) and brain natriuretic peptide ( bnp ) 2,182 pg / ml ( normal range 0.0 to 18.4 pg / ml ) . on a glucagon loading test , c peptide increment at 5 minutes after 1 mg of intravenous glucagon injection was 2.75 ng / ml . he also underwent thyrotropin - releasing hormone ( trh ) stimulation testing . after receiving 200 g of trh , the tsh showed a normal response ( tsh at baseline , 5.23 iu / ml ; tsh at 30 minutes , 18.20 iu / ml ; tsh at 60 minutes , 19.89 iu / ml ; and tsh at 120 minutes , 11.59 iu / ml ) ( table 2 ) . acr : albumin creatinine ratio , u- ' indicates urinary levels laboratory data and endocrinological test . bnp : brain natriuretic peptide , cpr : c peptide immunoreactivity , ft3 : free triiodothyronine , ft4 : free thyroxine , anti - gad ab : antiglutamic acid decarboxylase antibody , igf-1 : insulin like growth factor-1 , tbg : thyroxine binding globulin , tgab : anti - thyroglobulin antibody , tpo ab : anti - thyroid peroxidase antibody , trab : anti- tsh receptor antibody on chest radiography , the cardiothoracic ratio was 62% and bilateral increased lung markings were observed . an echocardiogram revealed a moderately dilated left ventricular cavity with diffuse hypokinesis ; left atrial diameter measured 54 mm , end - diastolic left ventricular diameter measured 55 mm , end - systolic left ventricular diameter measured 51 mm , left ventricular ejection fraction was 15.1% , and no valvular disease was detected . doppler recordings of transmitral filling velocities showed an e / a wave ratio of 4.3 and deceleration time ( dct ) of 114 milliseconds , indicating a restrictive filling pattern ( table 3 ) . e / a : early left ventricular filling velocity / late left ventricular filling velocity , dct : e wave deceleration time , ivs : interventricular septal thickness , lvedd : left ventricular end - diastolic diameter , lvesd : left ventricular end - systolic diameter , lvpw : left ventricular posterior wall thickness written informed consent was obtained , and a genetic study was conducted . a direct sequencing analysis of the full tr gene identified a heterozygous , missense mutation in exon 8 , with a replacement of alanine for aspartic acid at codon 268 ( a268d ) ( figure ) . the patient s activities of daily living ( adls ) were sufficient to allow him to be discharged . his serum tsh and ft4 levels were stable without anti - thyroid agents or thyroid hormone replacement . glycemic control was performed using a dipeptidyl peptidase-4 ( dpp-4 ) inhibitor and multiple - dosage insulin injections ( rapid acting insulin analogue : 20 units / day ) . a recent laboratory result of his hba1c level was 8.1% , which indicates poor glycemic control . he has been treated for heart failure with a -blocker , spironolactone , furosemide and a vasopressin receptor antagonist . he is comfortable at rest , but moderate physical activity currently results in fatigue and shortness of breath . thyroid hormones have diverse actions , which include regulation of skeletal growth ; maturation of the central nervous system , cardiac and gastrointestinal function ; and energy homeostasis . the receptors are encoded by two genes ( tr and tr ) , each of which undergoes alternate splicing to generate receptor subtypes ( tr1 , tr1 and tr2 ) with differing tissue distributions . tr1 is the predominant subtype in the bone , gastrointestinal tract , cardiac and skeletal muscle , and the central nervous system ; tr1 is most abundant in the liver and kidney ; and tr2 is discretely expressed in the hypothalamus , pituitary , cochlea , and retina ( 9 ) . rth is characterized by reduced responsiveness of target tissues to thyroid hormone , and 85% of patients with rth have a tr mutation ( 10 ) . novel mutations presenting reduced sensitivity to thyroid hormone were reported on monocarboxylate transporter8 ( mct8 ) and selenocysteine insertion sequence - binding protein ( secisbp2 ) ( 11,12 ) . reduced sensitivity to thyroid hormone syndrome ( rsth ) has been proposed to denote genetically determined reduced effectiveness of the hormone in this context ( 2,10 ) . in this case report , judging from his clinical course and the laboratory results , the initial diagnosis of graves disease was incorrect . the patient s mutation , a268d , was reported to have reduced ligand - binding affinities and inhibit the wild - type tr action in a dominant - negative manner ( 13 ) . to the best of our knowledge , this is the first case report that evaluated glucose tolerance and the cardiac function in a patients with a tr(a268d ) mutation . patients with hypothyroidism have decreased cardiac contractility and cardiac output . on the other hand , patients with hyperthyroidism have increased cardiac contractility and cardiac output , with an increased left ventricular mass . however , patients with severe , sustained hyperthyroidism may have poor cardiac contractility , low cardiac output , and symptoms of congestive heart failure associated with dilated cardiomyopathy ( 14 - 16 ) . it is reported that approximately 6% of thyrotoxic patients develop heart failure and less than 1% develop dilated cardiomyopathy with an impaired left ventricular systolic function ( 17 ) . the persistence of hyperthyroidism may cause hypertrophic cardiomyopathy and progress to a dilated cardiomyopathy - like state . patients with atrial fibrillation may develop cardiac dilatation and irreversible damage of cardiomyocytes , progressing to congestive heart failure . the heart may be less resistant than other organs because tr is more predominant than tr. mutations in tr are associated with pituitary and liver resistance , whereas the tachycardia observed in patients with rth may reflect cardiac sensitivity to thyroid hormone through intact tr receptors . a study using dominant - negative mutant tr transgenic mice showed cardiac abnormalities similar to those present in hypothyroid animals , such as prolonged qrs in the electrocardiogram , reduced left ventricular ( lv)-developed pressure , and reduced dp / dt , which is a measure of the rate of change of contraction and relaxation indicating lv dysfunction ( 18 ) . these data in mice hearts indicated that a dominant - negative tr mutant can oppose and overwhelm the effects of the normally predominant tr1 . investigated 41 patients with rth by echocardiography and reported cardiac features of a higher heart rate and shorter diastolic relaxation in rth subjects ( 19 ) . for many parameters , rth patients had values that were between hyperthyroidism and healthy euthyroid control . from these findings , the authors concluded that an incomplete cardiac response to thyroid hormone is present in rth . the results of doppler echocardiography and coronary angiography for our case revealed a decreased left ventricular systolic function and impaired diastolic function with normal coronary artery . although the molecular mechanism was not tested , these results suggested that the cardiac functions of the current patient exhibited characteristics of dilated cardiomyopathy . it is possible that the cardiac manifestations in the current case may thus not be typical . pancreatic -cells , thyroid hormone rapidly induces akt activation via tr1 , with a non - genomic mechanism ( 20 ) . although the physiological function is not understood , tr1 is mainly expressed in -cells ( 21 ) . this is a result of increased glucose turnover with increased glucose absorption through the gastro - intestinal tract , post - absorptive hyperglycemia , and elevated hepatic glucose output , with elevated pro - insulin levels and elevated free fatty acid concentrations ( 22 ) . . in hyperthyroidism , dysregulation of this balance leads to glucose intolerance , mainly due to hepatic insulin resistance . on the other hand , in hypothyroidism , a previous study reported the glucose uptake in muscle and adipose tissue to be resistant to insulin partly due to a decreased blood flow in these tissues ( 23 ) . the influence of impaired tr signaling on the glucose metabolism was experimentally investigated in a mouse model . mice bearing the homozygous mutation 337 t on the tr gene ( tr ) are leaner and exhibit impaired hepatic glucose production , reduced gluconeogenesis and lower glycogen deposit ( 24 ) . heterozygous mice ( tr ) exhibited a similarly glucose metabolism to wild - type mice in this study . the discrepancy between transgenic models and patients may be due to species differences , various mutations and/or the heterogeneous distribution of tr subtypes . mitchell et al . showed that rth subjects exhibited insulin resistance ( 25 ) . in this study , rth patients undergoing oral glucose tolerant testing had significantly lower insulin sensitivity indices and significantly higher homeostasis model assessment - insulin resistance ( homa - ir ) than controls , indicating the presence of insulin resistance . moreover , a recent case report of a rth patient complicated with diabetes suggested the potential interactions between diabetes mellitus and thyroid hormone resistance ( 26 ) . we did not perform the glucose clamp technique or minimal model approach in order to quantify insulin resistance in this patient . however , we speculate that our patient exhibited insulin resistance , because his basal and glucagon stimulated insulin secretion were not impaired . these findings may support the possibility that glucose intolerance is present in patients with thyroid hormone resistance . type 2 diabetes is a major common disease and cardiomyopathy is caused by many conditions such as hypertension , coronary ischemia , diabetes , alcohol drinking , metabolic diseases , viral infections , pregnancy , sarcoidosis , amyloidosis , and toxins . although these two diseases can incidentally co - exist in rth patients , a further accumulation of clinical data may be necessary to determine whether diabetes mellitus and cardiomyopathy are induced by a tr mutation in humans . in conclusion , our findings suggested that the cardiac function and glucose metabolism should be investigated in all rth patients . thyroid hormones have diverse actions , which include regulation of skeletal growth ; maturation of the central nervous system , cardiac and gastrointestinal function ; and energy homeostasis . the receptors are encoded by two genes ( tr and tr ) , each of which undergoes alternate splicing to generate receptor subtypes ( tr1 , tr1 and tr2 ) with differing tissue distributions . tr1 is the predominant subtype in the bone , gastrointestinal tract , cardiac and skeletal muscle , and the central nervous system ; tr1 is most abundant in the liver and kidney ; and tr2 is discretely expressed in the hypothalamus , pituitary , cochlea , and retina ( 9 ) . rth is characterized by reduced responsiveness of target tissues to thyroid hormone , and 85% of patients with rth have a tr mutation ( 10 ) . novel mutations presenting reduced sensitivity to thyroid hormone were reported on monocarboxylate transporter8 ( mct8 ) and selenocysteine insertion sequence - binding protein ( secisbp2 ) ( 11,12 ) . reduced sensitivity to thyroid hormone syndrome ( rsth ) has been proposed to denote genetically determined reduced effectiveness of the hormone in this context ( 2,10 ) . in this case report , judging from his clinical course and the laboratory results , the initial diagnosis of graves disease was incorrect . the patient s mutation , a268d , was reported to have reduced ligand - binding affinities and inhibit the wild - type tr action in a dominant - negative manner ( 13 ) . to the best of our knowledge , this is the first case report that evaluated glucose tolerance and the cardiac function in a patients with a tr(a268d ) mutation . patients with hypothyroidism have decreased cardiac contractility and cardiac output . on the other hand , patients with hyperthyroidism have increased cardiac contractility and cardiac output , with an increased left ventricular mass . however , patients with severe , sustained hyperthyroidism may have poor cardiac contractility , low cardiac output , and symptoms of congestive heart failure associated with dilated cardiomyopathy ( 14 - 16 ) . it is reported that approximately 6% of thyrotoxic patients develop heart failure and less than 1% develop dilated cardiomyopathy with an impaired left ventricular systolic function ( 17 ) . the persistence of hyperthyroidism may cause hypertrophic cardiomyopathy and progress to a dilated cardiomyopathy - like state . patients with atrial fibrillation may develop cardiac dilatation and irreversible damage of cardiomyocytes , progressing to congestive heart failure . the heart may be less resistant than other organs because tr is more predominant than tr. mutations in tr are associated with pituitary and liver resistance , whereas the tachycardia observed in patients with rth may reflect cardiac sensitivity to thyroid hormone through intact tr receptors . a study using dominant - negative mutant tr transgenic mice showed cardiac abnormalities similar to those present in hypothyroid animals , such as prolonged qrs in the electrocardiogram , reduced left ventricular ( lv)-developed pressure , and reduced dp / dt , which is a measure of the rate of change of contraction and relaxation indicating lv dysfunction ( 18 ) . these data in mice hearts indicated that a dominant - negative tr mutant can oppose and overwhelm the effects of the normally predominant tr1 . investigated 41 patients with rth by echocardiography and reported cardiac features of a higher heart rate and shorter diastolic relaxation in rth subjects ( 19 ) . for many parameters , rth patients had values that were between hyperthyroidism and healthy euthyroid control . from these findings , the authors concluded that an incomplete cardiac response to thyroid hormone is present in rth . the results of doppler echocardiography and coronary angiography for our case revealed a decreased left ventricular systolic function and impaired diastolic function with normal coronary artery . although the molecular mechanism was not tested , these results suggested that the cardiac functions of the current patient exhibited characteristics of dilated cardiomyopathy . it is possible that the cardiac manifestations in the current case may thus not be typical . pancreatic -cells , thyroid hormone rapidly induces akt activation via tr1 , with a non - genomic mechanism ( 20 ) . although the physiological function is not understood , tr1 is mainly expressed in -cells ( 21 ) . thyrotoxic subjects frequently show impaired glucose tolerance . this is a result of increased glucose turnover with increased glucose absorption through the gastro - intestinal tract , post - absorptive hyperglycemia , and elevated hepatic glucose output , with elevated pro - insulin levels and elevated free fatty acid concentrations ( 22 ) . thyroid hormone effects can be either insulin agonistic in muscle or antagonistic in the liver . in hyperthyroidism , dysregulation of this balance leads to glucose intolerance , mainly due to hepatic insulin resistance . on the other hand , in hypothyroidism , a previous study reported the glucose uptake in muscle and adipose tissue to be resistant to insulin partly due to a decreased blood flow in these tissues ( 23 ) . the influence of impaired tr signaling on the glucose metabolism was experimentally investigated in a mouse model . mice bearing the homozygous mutation 337 t on the tr gene ( tr ) are leaner and exhibit impaired hepatic glucose production , reduced gluconeogenesis and lower glycogen deposit ( 24 ) . heterozygous mice ( tr ) exhibited a similarly glucose metabolism to wild - type mice in this study . the discrepancy between transgenic models and patients may be due to species differences , various mutations and/or the heterogeneous distribution of tr subtypes . mitchell et al . showed that rth subjects exhibited insulin resistance ( 25 ) . in this study , rth patients undergoing oral glucose tolerant testing had significantly lower insulin sensitivity indices and significantly higher homeostasis model assessment - insulin resistance ( homa - ir ) than controls , indicating the presence of insulin resistance . moreover , a recent case report of a rth patient complicated with diabetes suggested the potential interactions between diabetes mellitus and thyroid hormone resistance ( 26 ) . we did not perform the glucose clamp technique or minimal model approach in order to quantify insulin resistance in this patient . however , we speculate that our patient exhibited insulin resistance , because his basal and glucagon stimulated insulin secretion were not impaired . these findings may support the possibility that glucose intolerance is present in patients with thyroid hormone resistance . type 2 diabetes is a major common disease and cardiomyopathy is caused by many conditions such as hypertension , coronary ischemia , diabetes , alcohol drinking , metabolic diseases , viral infections , pregnancy , sarcoidosis , amyloidosis , and toxins . although these two diseases can incidentally co - exist in rth patients , a further accumulation of clinical data may be necessary to determine whether diabetes mellitus and cardiomyopathy are induced by a tr mutation in humans . in conclusion , our findings suggested that the cardiac function and glucose metabolism should be investigated in all rth patients .
resistance to thyroid hormone ( rth ) is a genetic disorder characterized by reduced tissue responsiveness to thyroid hormone . 
 we herein describe a 60-year old man who presented with the clinical features of cardiomyopathy , diabetes mellitus and elevated thyroid hormones with unsuppressed thyroid stimulating hormone . 
 a genetic analysis of thyroid hormone receptor ( tr ) revealed a missense mutation ( a268d ) in the tr gene . 
 clinical manifestations of rth may be variable due to different tissue distributions of tr subtypes and different actions of mutant receptors . 
 the current case demonstrates that patients with a tr mutation may have impaired his glucose metabolism and a reduced cardiac function , although patients appear clinically euthyroid .