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Thyroid Disease : Thyroid Hormone Resistance Syndrome

Friday, October 18, 2013 5:21

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Home of Kyle J. Norton for The Better of Living & Living Health Thyroid is one of the largest endocrine glands found in the neck, below the Adam’s Apple with the function of regulating the body use of energy, make of proteins by producing its hormones as a result of the stimulation of thyroid-stimulating hormone (TSH) produced by the anterior pituitary.
Thyroid disease is defined as a condition of malfunction of thyroid. Hyperthyroidism is a condition in which the thyroid gland is over active and produces too much thyroid hormones. Hypothyroidism is a condition in which the thyroid gland is under active and produces very little thyroid hormones. Thyroid cancer is defined as condition in which the cells in the thyroid gland have become cancerous.
Thyroid hormone resistance syndrome
Thyroid hormone resistance syndrome is defined as a condition of which affected individuals have elevated serum thyroid hormone levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) but are usually clinically euthyroid and require no treatment. Selective pituitary resistance to thyroid hormone (PRTH) is characterized by resistance in the pituitary gland but not in peripheral tissues(a).

A. Symptoms
1. hyperactivity, emotional lability, a below average intelligence quotient, and short stature
Thyroid hormone resistance mutations are associated with a wide variety of phenotypes and subsequent treatment challenges. Among the more common symptoms are hyperactivity, emotional lability, a below average intelligence quotient, and short stature(1).

2. Hyperthyroid symptoms
There is a first case report of a resistance to thyroid hormone in a neonate presenting with hyperthyroid symptoms born to a mother with Graves’ disease and treated with methimazole and iodine(2). such as Sudden weight loss, rapid heartbeat (tachycardia), increased appetite, nervousness, anxiety and irritability, tremor, etc(3).

3. Psychiatric disorders
There is a report of six children from five unrelated families with esistance to thyroid hormone (RTH). All patients grew normally and presented variable symptoms that were treated according to need. Two patients developed psychiatric disorders. Only one of the four affected parents exhibited clinical signs of RTH (tachycardia and depression)(4).

4. Other symptoms
According to the study by the Northwestern University Medical School,, clinical effects of RTH can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as variable features of hyper- and hypothyroidism(5). Others indicated that RTH symptoms include failure to thrive, growth retardation and attention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic cardiac symptoms in adults(5a).

B. Causes
Genetic mutation
Thyroid hormone resistance occurs when a genetic mutation in the thyroid hormone receptor leads to reduced hormone binding affinity; the concentration of free thyroid hormone in the circulation is inversely correlated with the hormone binding affinity of the mutant receptor(6), such as mutation in the THRbeta gene, A317T(7) and E333D(8). According to the study of Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination by the University of Chicago, Mutations in MCT8 and SECISBP2 have also been associated with this condition(9) and a patient with the unusual coincidence of two rare congenital disorders, lingual ectopy of the thyroid gland and resistance to thyroid hormone (RTH), resulting in impaired thyroid hormone production and action, respectively(10). Thyroid hormone resistance syndrome affect approximately 1 in 40,000 live births and of of which over 100 different mutations have been identified.

B.2. Risk factors
1. Dominant inheritance
Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. To date, all individuals expressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor beta (TR beta) gene that impair T3-mediated function(11). Others reported a baby at age 70 days, an R243W mutation in thyroid hormone receptor β was detected in our patient; while absent in his mother, the mutation was present in his father, who never showed any symptoms(12).

2. Graves’ disease
Resistance to thyroid hormone is a syndrome caused by thyroid hormone receptor β mutations, which are usually inherited in an autosomal-dominant pattern. There is a report of a resistance to thyroid hormone in a neonate presenting with hyperthyroid symptoms born to a mother with Graves’ disease and treated with methimazole and iodine(12).

3. Minor alterations at the DNA level
Mutations in the thyroid hormone receptor (TR) beta gene are responsible for RTH and 122 different mutations have now been identified belonging to 300 families. With the exception of one family found to have complete deletion of the TRbeta gene, all others have been demonstrated to have minor alterations at the DNA level, according to the study by the Stoke Mandeville Hospital(13).

C. Complications and diseases associated to Thyroid hormone resistance
C.1. Complications
1. Growth retardation/short stature and skeletal dysplasia
There is a report of a first human cases (female, age 6 y; father and daughter, ages 47 and 11 y, respectively) with growth retardation/short stature, skeletal dysplasia, constipation, and defective thyroid receptor α (TRα)(14).

2. Thyroxine excess and inappropriate TSH secretion
Resistance to thyroid hormone (RTH) is an uncommon inherited cause of hyperthyroxinemia with inappropriate TSH secretion, according to the study by the University of Cambridge, Addenbrooke’s Hospital, United Kingdom(15).

3. Cardiovascular risk
RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk(16).

C.2. Diseases associated to Thyroid hormone resistance
1. Differentiated thyroid cancer (DTC)
There are reports of four unusual cases of DTC associated with TSHoma (2 cases), RTH (1 case), and an elevated TSH of unknown etiology (1 case)(17).

2. A pituitary tumor
There is a report of a woman in whom the standard evaluation for inappropriate TSH secretion was insufficient to distinguish these entities. The patient had a low-normal TRH stimulation test and an unmeasurable alpha-glycoprotein subunit level; however, a pituitary magnetic resonance imaging (MRI) revealed an adenoma. More testing using a T3 suppression test supported a RTH diagnosis and a R438H mutation was found in the TR-beta gene. To our knowledge, this represents the first report of an apparently incidental pituitary adenoma in the setting of documented resistance to thyroid hormone. As such, it raises the question of whether RTH predisposes to pituitary hyperplasia and adenoma. development(18).

3. Papillary thyroid carcinoma
There is an association of thyroid hormone resistance syndrome and papillary thyroid carcinoma(19).

4. Immune thrombocytopenic purpura (ITP)
There is a report of a 9-year-old girl presented with ITP and features of hypothyroidism in the form of goiter and growth retardation. She was subsequently found to have RTH. High-dose thyroid hormone replacement was required to overcome the resistance that not only ameliorated the features of hypothyroidism but also brought an apparent remission of ITP(20).

5. Postpartum thyroiditis
there is a repopt of a report of a unique case of a woman affected by RTH, due to a novel mutation V283A in THRB, who experienced PPT with a severe thyrotoxic phase after both her pregnancies. The association between RTH and PPT has never been reported in the literature. In particular, the marked suppression of TSH occurring when levels of TH are particularly elevated is not a frequent condition during RTH(21).

6. Chronic thyroiditis
There is a report of the five-year medical history of a Japanese woman and her father with RTH and coincidental chronic thyroiditis(22).

D. Misdiagnosis and Diagnosis
D.1. Misdiagnosis
1. Hyperthyroidism
There is a report of an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis(23).

2. Falsely diagnnosis
There is a report of a 63-year-old woman was referred because of suspected SITSH. Laboratory tests showed a normal TSH (0.52 μIU/L; normal range: 0.5-5.0) measured by sandwich Elecsys, and elevated FT4 (3.8 ng/dL; normal range: 0.9-1.6) and FT3 (7.6 pg/mL; normal range: 2.3-4.0), determined by competitive Elecsys. To exclude possible assay interference, aliquots of the original samples were retested using a different method (ADVIA Centaur), which showed normal FT4 and FT3 levels. Eight hormone levels, other than thyroid function tests measured by competitive or sandwich Elecsys, were higher or lower than levels determined by an alternative analysis. Subsequent examinations, including gel filtration chromatography, suggested interference by substances against ruthenium, which reduced the excitation of ruthenium, and resulted in erroneous results(24). Other suggested that patients with TSH-secreting pituitary tumors(TSHoma) also manifest SITSH. Thus, the differential diagnosis of RTH vs. TSHoma is sometimes difficult and challenging. In this review article, the etiology of RTH and diagnostic approach for SITSH are explained and an algorithm for differential diagnosis of RTH vs. TSHoma is proposed(25).

3. Coexistence of mutation genes
There is a report of the coexistence of THRB and TBG gene mutations in the same individual (mother of the proband), whereas other affected family members had only 1 of the 2 genes mutated. The case illustrates the difficulty that might be encountered in the interpretation of thyroid function tests when different genetic defects affecting thyroid function coexist(26).

4. Grave’s disease
RTH is often misdiagnosed as Graves’ disease. However, these disorders can coexist, and the concurrent presence of both disorders in a patient can present diagnostic challenges. A previous report of a patient with Graves’ disease associated with RTH was published before gene sequencing could be used to confirm diagnosis of RTH. There is a report of a patient with Graves’ disease and concurrent RTH that was confirmed by gene sequencing, showing a mutation in the thyroid hormone receptor beta gene(27).

D.2. Diagnosis
If you are experience certain symptoms of the above and your doctor suspects that you have developed acute thyroiditis, after recording the past and present history and completing a physical exam, the tests which your doctor orders may include
1. Urinary test
Urinary cortisol metabolites are altered both quantitatively and qualitatively in thyroid dysfunction. According to the study by the Showa University, the ratio of the urinary concentrations of cortisol metabolites, THE/THF, appears to be a good marker for peripheral thyroid hormone resistance(28).

2. Blood test
Unfortunately, the blood test results of the disorder can also be found in other disorders such as TSH-oma (pituitary adenoma), or other pituitary disorders. According to the study by the Nagoya University, almost all patients with RTH manifest unsuppressed thyrotropin (TSH) despite elevated free-T4 and free-T3 levels. This abnormal finding in the thyroid function test is termed “syndrome of inappropriate secretion of TSH” (SITSH) or “central hyperthyroidism”. Patients with TSH-secreting pituitary tumors(TSHoma) also manifest SITSH. Thus, the differential diagnosis of RTH vs. TSH-oma is sometimes difficult and challenging(29)

3. Identifying a mutation of the thyroid receptor
Resistance to thyroid hormone (RTH) is a rare condition usually diagnosed in patients with classic thyroid function tests (TFTs) of elevated thyroid hormone levels with nonsuppressed TSH. According to the study by the, At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor β gene and has been given the acronym RTH(30).

E. Treatments
E.1. In conventional medicine perspective
1. The table
Table. Suggested therapeutic approaches for resistance to thyroid hormone (RTH) patients.

___________________________________________________________________
Drugs	Untoward effects and limitations
___________________________________________________________________
TRIAC	Effective in almost all patients
D-T4	Effective in almost all patients
T3	Production of daily peaks of very high T3 concentrations, which
	contribute to maintain clinical hyperthyroidism
Bromocriptine	Transient effect owing to TSH escape from inhibition
Sms analog	Transient effect owing to TSH escape from inhibition
Corticosteroid	Cause of severe inhibition of hypothalamic-pituitary-adrenal axis function and cushingoid features
Antithyroid drugs	Cause of further increase in TSH circulating level with consequent increase of goiter size and to hyperplasia at pituitary thyrotroph level
b-blockers	Effects limited to b-adrenergic blockade. Propranolol inhibits peripheral conversion of T4 to T3, causing a worsening of tissue hypometabolic state. Cardiac selective compounds, such as atenolol devoid of effect on peripheral T4 conversion, appear to be more useful(31).

2. Limitation
According to the study by the Fitzsimons Army Medical Center, the thyroid hormone resistance syndromes are disorders in which the body’s tissues are resistant to the effects of thyroid hormone. Generalized resistance to thyroid hormone (GRTH) is characterized by resistance in the pituitary gland and in most or all of the peripheral tissues. Affected individuals have elevated serum thyroid hormone levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) but are usually clinically euthyroid and require no treatment. Selective pituitary resistance to thyroid hormone (PRTH) is characterized by resistance in the pituitary gland but not in peripheral tissues. Patients have elevated serum thyroid hormone levels and normal or elevated TSH levels and are clinically thyrotoxic. Therapy is usually necessary, but current choices are not completely satisfactory. Selective peripheral resistance to thyroid hormone (PerRTH) is characterized by resistance in peripheral tissues but not in the pituitary. The only patient thus far described had normal serum thyroid hormone and TSH levels but was clinically hypothyroid and improved with thyroid hormone administration. All of these disorders are probably more common than is generally recognized and are often misdiagnosed and inappropriately treated. GRTH, in most cases studied, results from a mutation in the thyroid hormone receptor beta gene causing an amino acid substitution in or a partial or complete deletion of the thyroid hormone-binding domain of the receptor. The causes of PRTH and PerRTH remain to be determined(32). Other studies indicated that in this age of rapidly advancing knowledge, it is reasonable to expect that the not too distant future will bring specific treatments for RTH. This will probably not be in the form of gene therapy as the dominant expression would require excision of the defective gene. The most simple genetic approach, one within the realm of current technology, is the selection of an oocyte from the affected mother that does not harbor the abnormal allele for in vitro fertilization followed by implantation into the donor. This insures a fetus without RTH but does not guarantee a normal pregnancy and fetal development. The development of TH agonists and antagonists that are TR-isoform specific would allow the stimulation or blockade of specific tissue effects that are perturbed in a given individual with RTH(33).

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