Thyroid Disorders & Thyroid Function Test 2024 PDF

Thyroid Disorders & Thyroid Function Test MED 402 Oksana Ryabinina, PhD 2024 Objectives Describe the structure and function of the thyroid gland Explain the function of thyroid hormones Outline the action of thyroid hormones Outline the control of thyroid hormo...

Thyroid Disorders & Thyroid Function Test MED 402 Oksana Ryabinina, PhD 2024 Objectives Describe the structure and function of the thyroid gland Explain the function of thyroid hormones Outline the action of thyroid hormones Outline the control of thyroid hormones secretion from the thyroid gland Describe the conditions which lead to abnormal thyroid hormone production: hyperthyroidism & hypothyroidism Discuss the investigation of suspected thyroid dysfunction 2 Thyroid gland Thyroid gland is a butterfly shaped endocrine gland Located in the lower front of the neck Normal thyroid gland weighs approximately 30 g Its highly vascularized, receiving 80–120 mL of blood per minute 3 4 Thyroid gland Microscopic examination of thyroid tissues shows small spherical sacs called thyroid follicles that make up most of the thyroid gland The wall of each follicle is composed mainly of follicular cells Follicular cells produce two hormones: thyroxine (T4) & tri-iodothyronine (T3) Together T4 and T3 are known as thyroid hormones The parafollicular cells or C-cells lie in between the follicles and produce a hormone called calcitonin, which regulates calcium homeostasis. 5 6 7 Thyroid hormones TH synthesized in the thyroid gland by iodination & coupling of 2 tyrosine molecules whilst attached to a complex protein, thyroglobulin T4 contains four iodine atoms & T3 contains three iodine atoms Thyroxine is the major hormone secreted by the thyroid gland, which is converted by specific de-iodinase enzymes, particularly in the liver and kidney, to form T3, the biologically active hormone The peripheral deiodination of T4 provides approximately 80% of plasma T3, the remainder being derived from thyroid gland secretion 8 Thyroid hormones TH (T4 & T3) are produced by the incorporation of iodine into tyrosyl residues in thyroglobulin in a series of steps: Active transport of iodide into the cell Iodination of the tyrosyl residues on thyroglobulin (Tg) coupling of iodotyrosine molecules within Tg to form T4 & T3 Proteolysis of Tg with release of free iodotyrosine: T4 & T3 secretion of thyroid hormones transport of thyroid hormones in the blood 9 10 11 Bunding in plasma T4 & T3: lipid soluble > 99% of T4 & T3 in plasma bound to specific proteins In order to render them water-soluble, reduce renal loss and to provide a large pool of hormones, whiles protecting the cells from the physiological effect of the hormones 12 Bunding in plasma The plasma concentrations and proportions of thyroid hormones which are bound : 13 Bunding in plasma The unbound or free T4 (0.03%) and T3 (0.3%) are the biologically active fraction The approximate reference ranges for serum concentrations of total and free thyroid hormones are: 14 Peripheral conversion of thyroid hormone T3 production: 20%: secreted by the thyroid gland 80%: produced enzymatically in non-thyroidal tissue by the removal of an iodine atom from the outer ring T3 binds more avidly to thyroid receptors than T4 T3 is the main active form 15 Peripheral conversion of thyroid hormone Conversion of T4 to T3 may be reduced: Systemic illness Prolonged fasting Drugs (beta-blockers) Conversion of T4 to T3 may be increased: Drugs that induce hepatic enzyme activity (phenytoin) 16 Physiological effects of thyroid hormones TH has 2 major effects: increases metabolism necessary for growth & development in children (mental development & attainment of sexual maturity) 17 Physiological effects of thyroid hormones Metabolic rate: Increases the basal metabolic rate: 60-100% Depending on the metabolic status, it can induce lipolysis or lipid synthesis. Stimulate the metabolism of carbohydrates Anabolism of proteins. Permissive effect on catecholamines In children: thyroid hormones act synergistically with growth hormone to stimulate bone growth; induces chondrocytes, osteoblasts, and osteoclasts; helps with brain maturation by axonal growth and the formation of the myelin sheath. Affects fertility, ovulation, and menstruation. 18 Organ Systems Involved Thyroid hormone affects virtually every organ system in the body: heart, CNS, autonomic nervous system, bone, GI, and metabolism. Heart: thyroid hormones have a permissive effect on catecholamines. It increases the expression of beta-receptors to increase heart rate, stroke volume, cardiac output, and contractility. Lungs: thyroid hormones stimulate the respiratory centers and lead to increased oxygenation because of increased perfusion. 19 Organ Systems Involved Skeletal muscles: thyroid hormones cause increased development of type II muscle fibers. These are fast-twitch muscle fibers capable of fast and powerful contractions. CNS: During the prenatal period, it is needed for the maturation of the brain. In adults, it can affect mood. Hyperthyroidism can lead to hyperexcitability and irritability. Hypothyroidism can cause impaired memory, slowed speech, and sleepiness. 20  Function of thyroid hormones Effects of thyroid hormones on metabolic indices 21 22 23 Control of thyroid hormone secretion Thyroid hormone production is under both positive and negative feedback control Thyrotrophin releasing hormone (TRH) from the hypothalamus acts on the anterior pituitary causing release of TSH, which in turn acts on the thyroid gland and stimulates the synthesis and release of thyroid hormones. Briefly, a low blood concentration of free T4 or T3 stimulates the hypothalamus to secrete TRH, which enters the hypothalamic portal veins and flows to the anterior pituitary where it stimulates thyrotrophs to secrete TSH. TSH then acts on the follicular cells to stimulate T4 and T3 production & their subsequent release A rise in the concentration of unbound T4 and T3 in the blood inhibits further release of TRH and TSH from the hypothalamus and anterior pituitary respectively, via a negative feedback effect 24 25  26 Thyroid Function Test Thyroid Function Test Thyroid function test (TFT): collective term for blood tests used to check the function of the thyroid TSH T4 or Free T4 T3 or Free T3 Thyroid peroxidase antibodies Thyroglobulin antibodies Thyroid stimulating hormone receptor antibodies 27 Thyroid Function Test TSH: 0.5 - 5.0 mU/L Free T4 9.0 – 25.0 pmol/L Free T3: 3.5 – 7.8 pmol/L Reference ranges for TFTs often vary between labs 28 Thyroid Function Test: TSH Third generation sensitivity: 0.010 - 0.20 mU/L Fourth generation sensitivity: < 0.004 mU/L TSH –centered strategy limitation: Is assumed that hypothalamus-pituitary function is intact & normal Is assumed that then patient is stable 29 Thyroid Function Test: TSH Hyperthyroidism Primary: [TSH] ↓ Secondary: [TSH] ↑ Hypothyroidism Primary: [TSH] ↑ Secondary: [TSH] ↓ Not meet → TSH result is misleading → add total T4 or fT4 30 Thyroid Function Test: T3 Not for routine measurement Useful in diagnosis of T3-toxicosis (normal serum fT4) Not useful in the evaluation of hypothyroidism 31 Interpretation of TFT Interpretation of thyroid function tests: changes in the hormone pairs TSH and free T4 32 33 Interpretation of TFT Pregnancy can have a significant effect on the result of thyroid hormone testing Normal pregnancy: [TBG] increases due to the action of estrogen →[total thyroid hormone] increase 1,5 times by 16 w of gestation to the weak thyroid stimulating effect of high concentrations of human chorionic gonadotrophin (hCG) in early pregnancy → slight increase [free thyroid hormone] → [TSH] ↓ first trimester Hyperemesis gravidarum or a state of severe vomiting during the first trimester: very high [free T4] & [free T3] → syndrome ‘gestational transient thyrotoxicosis” 34 Thyroid Function Test: Thyroxine-binding globulin RR [TBG] 13 – 39 ug/dl Serum [T4] ↓ & [T3] ↓ → no agreement with other lab parameters of thyroid function or no compatible with clinical fundings Euthyroid state: 1/3 of the binding sites on TBG are occupied by T4 & remainder are unoccupied (irrespective of the concentration of the binding proteins) Hyperthyroidism: number of unoccupied binding cites on TBG ↓ Hypothyroidism: number of unoccupied binding cites on TBG ↑ 35 36 Thyroid Function Test: Thyroxine-binding globulin ↑ Plasma TBG → ↑bound T4 & ↑ unoccupied binding sites BUT no change in [fT4] Cause: High [estrogen] during pregnancy or in newborn infant Estrogen therapy Inherited TBG excess (rare) 37 Thyroid Function Test: Thyroxine-binding globulin ↓Plasma TBG → ↓ bound T4 & ↓ unoccupied binding sites BUT no change in [fT4] Causes: Severe illness (usually temporary) Loss of LWwt proteins (usually in the urine) Androgens or danazol treatment Inherited TBG deficiency (rare) 38 Thyroid Function Test: Thyroglobulin RR [Tg] up to 30 ng/ml Tg: glycoprotein, M wt: 660 kDa Function: a propeptide for the intrathyroidal synthesis of T4 & T3 Serum [Tg] reflects thyroid mass, thyroid injury & TSH receptor stimulation High level: pregnancy, nontoxic goiter, thyroid adenomas, subacute thyroiditis, well differentiated cancer (papillary & follicular types). Graver’s disease Not for routine measurement Monitoring of thyroid cancer postoperatively 39 Thyroid Function Test: Thyroid peroxidase antibodies TPO Ab are involved in the tissue destructive process associated with hypothyroidism in Hashimoto’s disease TPO Ab are present in about 95% of patients with autoimmune hypothyroidism secondary to Hashimoto’s thyroiditis TPO Ab may also be found in a small number of healthy individuals, but their appearance usually precedes the development of thyroid disorders 40 Thyroid Function Test: Thyroglobulin antibodies Tg Ab are directed against the Tg protein; a major constituent of thyroid colloid Tg Ab found in many patients with autoimmune thyroid disease; Tg Ab measurement can be used in iodide-deficient areas to detect autoimmune thyroid disease in patients with a goiter and for monitoring iodide therapy in endemic areas 41 Thyroid Function Test: Thyroid stimulating hormone receptor antibodies TR Ab measurement is not essential for diagnostic purposes in most patients Gravers’ disease (is an autoimmune condition in which goiter and hyperthyroidism are induced by TR Ab that mimic the action of TSH The target of the autoimmune response is the TSH receptor TR Ab positive in 85% in patients with Gravers’ disease 42 Disorders of thyroid function Clinical perspective: Disorders of thyroid function can be classified into two broad categories: hyperfunction states (thyroid hormones are produced in excess) referred to as hyperthyroidism hypofunction states (deficiency of thyroid hormones) referred to as hypothyroidism 43 44 Investigation & Diagnosis Routine biochemical assessment: measurement of [TSH] & [free T4] As the concentration of thyroid hormones declines, the concentration of TSH increases [T3] is preferentially maintained & measurement of T3 is not recommended as this could be misleading [T4] correlates better with thyroid activity than that of [T3] for diagnosis of hypothyroidism 45 Investigation & Diagnosis Primary hypothyroidism due to Hashimoto’s thyroiditis: increased [TSH], low [free T4] thyroid peroxidase antibodies may also be detected Secondary hypothyroidism: low serum [TSH] & low [free T4] distinguishing feature: [TSH] is inappropriately low 46 Hypothyroidism Estimation of thyroxine binding proteins Definitive test of primary hypothyroidism Test of pituitary function Thyroid antibodies Nonspecific lab investigation, e.g. plasma lipids 47 48 Case study A 57-year-old female consulted her general practitioner because of weight gain, constipation and weakness. The following thyroid function test results were returned. Plasma TSH 54.6 mU/L (0.20-5.0) Free T4 5.7 pmol/L (12-25) 49 Discussion The results show primary hypothyroidism with high plasma TSH and low fT4 concentrations. The symptoms are typical or hypothyroidism. The patient was also shown to have positive thyroid antibodies (anti- TPO). The thyroid function tests normalized on treatment with 100 ug/day of T4. 50 51 Investigation & Diagnosis [T4] & [T3] high, [TSH] is suppressed [TSH] ↓, [T4] ↑, [T3] ↓ or N: T4 thyrotoxicosis [TSH] ↓, [T3] ↑, [T4] ↓ or N: T3 thyrotoxicosis [fT4] raised, [TSH] normal: euthyroid hyperthyroxaemia Thyroid-stimulating antibodies: diagnosis of Graves’ disease 52 53 Case study A 45-year-old male was on the coronary care unit the day after an acute myocardial infection. One of his doctors thought that he looked hypothyroid and requested thyroid function tests, the results of which were as follows. Plasma TSH < 0.05 mU/L (0.20-5.0) Free T4 10.1 pmol/L (12-25) Free T3 1.4 pmol/L (3-7) On repeating the tests 3 months later at a follow-up appointment in medical out-patients, the following results were obtained. Plasma TSH < 2.3 mU/L (0.20-5.0) Free T4 18.1 pmol/L (12-25) Free T3 4.5 pmol/L (3-7) 54 Discussion The first set of result could indicate hypothyroidism due to pituitary or hypothalamic defects (secondary hypothyroidism), i.e. low TSH and “normal” fT4 and fT3 concentrations. However, the normalization of the results when the patient was not acutely ill suggested sick euthyroidism or non-thyroidal illness. NB: Beware of requesting thyroid function tests in acutely ill patients. 55 56 Euthyroid Goitre Plasma T4 raised, Enlargement of the thyroid gland (goitre): cause TSH stimulation resulting in cellular hyperplasia Thyroxine synthesis may be impaired by iodine deficiency Under the influence of prolonged stimulation by TSH, the number of thyroid cells increases & plasma thyroid hormone concentrations are maintained at the expense of the development of a goitre 57 Nonthyroidal illness Severe ill patients can have abnormal TFT (no underling thyroid pathology) Rapid ↓ total T3/ free T3 (myocardial infarction, sepsis) Acute stage: low or low-normal TSH; low or low-normal T4, very low T3 More severe: ↓ total T4/ free T4 Conversion of T4 to T3 may be impaired with low plasma [t3] 58