Recently, some patients have inquired about thyroid hormone resistance syndrome, which is often overlooked in clinical practice and may be misinterpreted as a laboratory error that delays the best treatment opportunity and leads to lifelong abnormalities.
I. What is thyroid hormone (TH) resistance syndrome?
Thyroid hormone resistance syndrome (SRTH), also known as thyroid hormone insufficiency syndrome or thyroid hormone insensitivity syndrome (THIS), was first reported by Refetoff in 1967. The disease is an autosomal dominant disorder with familial onset, but there are a few disseminated cases, accounting for about 1/3 of cases.
The clinical presentation is characterized by persistent elevation of serum free T4 (FT4) and free T3 (FT3) with normal thyroid stimulating hormone (TSH) levels, in the absence of medications, non-thyroidal diseases and abnormal thyroid hormone transport. The most specific manifestation is the inability to bring elevated TSH down to normal levels after administration of supraphysiologic doses of thyroid hormone, as well as the absence of peripheral tissue response to excess thyroid hormone.
The etiology includes mutations in thyroid hormone receptors, impaired binding of thyroid hormone and receptors or abnormal action of thyroid hormone receptors after binding, which leads to reduced response of tissues and organs to thyroid hormone and causes manifestations such as abnormal metabolism and thyroid function. Thyroid hormone receptors are found in all organs, tissues and cells throughout the body, except for the testes and lymphoid organs. Partial resistance is mostly seen clinically; complete resistance is rare, and the degree of resistance to thyroid hormone varies among organs and tissues, and patients have different compensatory capacities, so there are different clinical manifestations and laboratory features.
There are several conditions of thyroid hormone resistance, the most common being pituitary resistance and systemic resistance, which can be clinically manifested as hyperthyroidism, normal thyroid function or hypothyroidism. If the pituitary and peripheral tissue resistance to thyroid hormone is similar, the patient presents with normal thyroid function; if pituitary resistance is lower than peripheral resistance, the patient presents with hypothyroidism; if pituitary resistance is higher than peripheral resistance, the patient presents with hyperthyroidism.
Because the clinical presentation of this syndrome is variable and can be hyperthyroid, hypothyroid or non-toxic goiter, it is often misdiagnosed and inappropriate therapeutic measures such as thyroidectomy, nuclear therapy or antithyroid medication are taken. The key to reducing misdiagnosis is to raise awareness and vigilance of the syndrome.
What are the causes of thyroid hormone resistance syndrome?
The causes of thyroid hormone resistance syndrome mainly include receptor defects and post-receptor factors. In addition, hypothalamic and pituitary level type II 5′-deiodinase deficiency or reduced activity, and increased anti-T3/T4 autoantibodies may also be influencing factors. The vast majority are due to mutations in thyroid hormone receptor genes, most commonly changes in nucleotides or deletions in the thyroid hormone receptor gene, resulting in changes in the amino acid sequence of the thyroid hormone receptor, leading to changes in receptor structure and function and resistance or insensitivity to thyroid hormones.
Secondly, a decrease in the number of thyroid hormone receptors, resulting in a weakening of the action of thyroid hormone, and a disorder in the post-receptor action of thyroid hormone, can also cause SRTH.
What types of thyroid hormone insensitivity syndrome can be classified? What are the common features?
There are three types of TH insensitivity syndrome: systemic insensitivity; pituitary insensitivity; and peripheral insensitivity. Their clinical manifestations are different, but the following four points are common.
① Diffuse enlargement of the thyroid gland;
②Serum TSH is significantly elevated;
③The clinical manifestations are not consistent with the laboratory findings;
④The number and/or affinity of TH receptors are abnormal.
IV. What are the clinical manifestations of systemic thyroid hormone resistance syndrome?
(1) Diffuse enlargement of the thyroid gland.
(2) Deafness, delayed bone development and point-color bone marrow on radiographs of bones.
(3) No clinical hyperthyroidism, but markedly elevated serum protein-bound iodine and normal or elevated TSH. there is a severe deletion of the T3R gene (complete absence of the gene encoding the T3 and DNA binding region), resulting in a complete absence of the T3Rβ gene, and both pituitary and peripheral target cells are insensitive to T3, but the clinical presentation is highly variable, ranging from asymptomatic to severe hypothyroidism. Individual patients have an increase in normal T3Rβ expression with age and may grow further in height. Some patients also have mental retardation, mainly in the form of dysarthria and a lower verbal IQ than working IQ.
In addition, patients with this type may have other somatic malformations such as pterygoid shoulder, spinal deformity, pigeon chest, bird face, navicular head, bull’s eye, shortened 4th metacarpal, congenital ichthyosis, Besiner’s itchy rash, and nystagmus. Laboratory findings depend on the relative severity and compensatory degree of TH insensitivity in pituitary and peripheral target cells, and all of the abnormal laboratory findings seen in the pituitary and peripheral cell insensitive phenotype can be present. Some patients have normal basal serum TSH, but are relatively elevated for elevated blood T3 and T4.
The above laboratory tests only demonstrate that the pituitary or peripheral target cells are insensitive to TH. Further tests include the number and affinity of T3R and the determination of T3R gene defects.
V. How is pituitary selective thyroid hormone resistance syndrome typed?
(1) Autonomic type: In this type, TSH is elevated, and pituitary TSH does not respond significantly to TRH. High levels of T3 and T4 only slightly inhibit TSH secretion, and dexamethasone only slightly reduces TSH secretion, so it is called autonomous type, but no pituitary tumor exists. Patients have clinical manifestations of goiter and hyperthyroidism, but no neurological deafness, delayed epiphyseal healing, short stature, poor intelligence, poor calculation power and other bone development abnormalities.
(2) Partial type: The clinical manifestations may be the same as the autonomic type, but not as obvious as the autonomic type, and may have hyperthyroidism and elevated TSH. This type may also have cystinuria.
What are the clinical manifestations of peripheral tissue-selective thyroid hormone resistance syndrome?
In peripheral tissue-selective thyroid hormone resistance syndrome, only peripheral target cells are insensitive to the effects of TH, while pituitary TSH cells respond normally to TH. Most patients have a family history of normal response to thyroid hormones, clinical manifestations of goiter (multinodular goiter), no deafness or epiphyseal changes, and increased blood TH, but clinical manifestations of hypothyroidism, such as easy fatigue, dryness and loss of hair, fear of cold, slow pulse, delayed mental development, or mental retardation.
The clinical manifestations vary from systemic TH insensitivity (e.g., point-color bone marrow, delayed bone age and delayed mental development) to only goiter. The most characteristic clinical manifestation of this type of patients is that even though the blood T3 and T4 are significantly elevated with a large pharmacological dose of TH (T4 or T3), there is no clinical manifestation of hyperthyroidism.
VII. What are the early diagnostic clues of thyroid hormone resistance syndrome?
Clinically, the possibility of this syndrome should be considered in all cases where one of the following conditions is encountered, and further additional laboratory tests should be performed.
(1) An enlarged thyroid gland, mostly Ⅰ° or Ⅱ°, with no clinical manifestations of abnormal thyroid function but multiple significant increases in serum total T3, T4 and free T3, T4.
(2) Enlarged thyroid gland with clinical manifestations of hypothyroidism and elevated serum total T3, T4 and free T3 and T4.
(3) Goiter with clinical manifestations of hyperthyroidism, but with elevated serum TH and plasma TSH to exclude pituitary tumors.
(4) Patients with hypothyroidism who are not effective even with higher pharmacological doses of TH preparations.
(5) Patients with hyperthyroidism who are prone to relapse with multiple treatments and can be excluded from pituitary TSH tumors.
(6) Patients with this syndrome in the family, with elevated or normal TSH levels, mental retardation, delayed epiphyseal maturation, dotted skeleton, negative perchlorate test for congenital deafness and negative TG and TM, etc.
What are the treatment measures for thyroid hormone insensitivity syndrome?
There is no cure for thyroid hormone insensitivity syndrome. Treatment options should be made according to the severity of the disease and the different types, and should be maintained for life. Mild forms can be left untreated if they are clinically asymptomatic. Symptomatic individuals should be treated with L-T3 at individualized doses, but at pharmacological doses. In some peripheral hypothyroidism, it takes a T3 dose of 500 μg/d to normalize some of the indicators of TH peripheral effects. In systemic hypothyroidism, serum TSH levels can be reduced and hypothyroidism symptoms can be improved after T3 treatment. Treatment of infants and children with the onset of hypothyroidism should be done as early as possible, otherwise there may be a delay in growth and development.