1. Mechanism of thyroid hormone action T3 that enters the cell can enter the nucleus and bind to thyroid hormone receptor. T3 has 15- fold higher binding affinity for TR than T4.

2. There are tissue – specific preferences in expression of various TRs: TRβ particularly TRβ2 is important in hypothalamus and pituitary, and is also expressed in the cochlea. Disruption of TRβ gene in mice causes deafness, reduction of feedback sensitivity of hypothalamus – pituitary-thyroid axis. Therefore they have high TSH and highT4; similar to ”resistance to thyroid hormone”.

3. TRα, is expressed in all tissues, especially kidney, liver, brain and heart. Disruption of its gene causes bradycardia and hypothermia.

4. Regulation of Thyroid Function

5. Hypothalamic – pituitary – Thyroid AXIS Close relationship between hypothalamus, ant.pituitary, thyroid Large intraglandular store of hormone buffers the effect of acute increases or decreases in hormone synthesis.

6. Thyrotropin – Releasing hormone TRH is derived from a large prepro-TRH molecule. TRH is expressed in hypothalamus, brain, C cells of thyroid, beta cells of pancreas, myocardium, prostate and testis, spinal cord. Parvocellular region of the paraventricular region of the hypothalamus is the source of TRH that regulates TSH secretion. TRH travels in the axons of the peptidergic neurons through the median eminence and is released close to the hypothalamic- pituitary portal plexus.

7. Normal feedback regulation of prepro- TRH MRNA synthesis by thyroid hormone requires a combination of T3 and T4 in circulation. Throid hormone also blocks the capacity of TRH to stimulate TSH release from thyrotroph.

8.  TSH is composed of an alpha-subunit, common to LH,FSH, and HCG and a specific beta-subunit.  TRH increases and thyroid hormone suppresses the transcription of both subunits

9. Thyrotropin  Glycosylation of TSH protects it from intracellular degradation and is required for its full biologic activity. TRH is required for this process.  The biologic activity of TSH in the serum of patients with pituitary tumors or hypothalamic disorders is inappropriately low compared with immunologic activity due to TRH deficiency.

10.  Circulating TSH displays both pulsatile and circadian variations, fluctuations at 1- to 2- hours intervals. Magnitude of TSH pulsations is decreased during fasting, illness, or after surgery.  There is a nocturnal surge that precedes the onset of sleep, independent of cortisol rhythm and T4 and T3 concentrations.

11.  Delayed onset of sleep enhances and prolonges TSH surge, early onset of sleep lessens and shortens TSH surge.  The degree of thyroid hypofunction after destruction of the hypothalamus is less severe than that which follows hypophysectomy.

12.  Somatostatin (SRIH) decreases TSH secretion, but prolonged treatment with a somatostatin analogue does not cause hypothyroidism.  Dopamine infusion and Bromocriptine administration decrease TSH secretion, but chronic administration of dopamine agonists do not cause hypothyroidism. Blockade of the dopamine receptors by metoclopramide increases TSH secretion.

13.  High dose glucocorticoids transiently suppress TSH secretion, although prolonged therapy does not cause hypothyroidism. Patients with Cushing's disease have subnormal TSH but minimal effects on T4.

14. Iodine Deficiency * Removal of iodine from the diet causes a rapid decrease in serum T4, increase in serum TSH, but no detectable decrease in T3. TSH increase leads to goiter. * If iodine deficiency is prolonged and severe, hypothyroidism will occur.

15. Iodine Excess * The usual source of excess iodine is pharmaceutical with radiographic dyes, amiodarone and povidone iodine. Increasing doses of iodide, firstly increase and then decrease the quantity of iodine organification. This decrease is termed wolf- chaikoff effect. * Chronic high iodine intake during pregnancy must be avoided because it will cause fetal hypothyroidism and compensatory potentially obstructive goiter.

16. Iodine Excess pharmacologic doses of iodine cause prompt inhibition of thyroid hormone release, especially in Graves' or toxic nodules, but the effect is mediated at the thyroid cell level, rather than through an action on TSH. * Iodine also diminishes the hypervascularity and hyperplasia of thyroid in Grave's disease and facilitates surgical therapy.

17. Thyroid Function in the Fetus and Newborn

18. Fetal Thyroid Function * Rates of production and degradation of T4 are 10- folds higher than adults. * Subnormal serum T3 and elevated serum rT3. * Fetal thyroid function begins at the end of the first trimester. Thereafter, steady increases in fetal TBG, T4 and T3. *Serum TSH is greater than mother, T3 is low, free T4 approximates the maternal circulation from age of 28 weeks.

19. Maternal – Fetal Interactions * Fetal pituitary- thyroid axis function is independent of the mother. * Transplacental passage of TSH from mother to fetus is negligible. * When the maternal- fetal concentration gradient is high, significant transfer of maternal T4 to the fetus can occus. * In infants with congenital hypothyroidism, T4 in cord bloods is one third to one half of normal.

20. Thyroid Function in the Newborn Cord blood: * Mean T4 level: 12 Mg/dl * TBG: elevated, but not as high as mother * Free T4: slightly lower than mother * T3: low (50 ng/dl) * r T3 and T3 So 4 : elevated

21. Thyroid Function in the Newborn After delivery: * TSH: increases rapidly to a peak (above 60 mu/L) at about 2-4 hours, returning to its initial value within 48 hours. * T4, T3 and Tg: increase rapidly during the first few hours, and are in the hyperthyroid range by 24 hr of life. * Enhancement of extrathyroidal conversion of T4 to T3. * Thyroid hormone production rates are higher per unit of body weight in infants and than in adults.

22. Premature Infants * Immature hypothalamic- pituitary- thyroid axis with low T4, T3 and TSH. * Serum T4, Free T4 and TBG correlate with gestational age. * Attenuated TSH surge post delivery. * Increased prevalence of congenital hypothyroidism * RDS and nutritional problems cause; - decreased T4 and especially T3 - impairment of T4 to T3 conversion

23. Thyroid function during fasting or Illness

24. *pattern of changes in thyroid hormones and TSH are similar in fasting and illness During fasting: *Central reduction in TSH secretion * 50% reduction in serum T3 * Increased rT3 of serum * No initial changes in total or free T4 * Decreased peripheral T4 to T3 conversion The decrease in T3 during fasting is a beneficial energy and nitrogen sparing adaptation.

25. Chronic malnutrition such as anorexia nervosa: *Reduction of T3 and rarely free T4 *Normal TSH

26. Overfeeding: *Increased T3 * Reduced rT3

27. During illness: *Euthyroid sick syndrome, low T3 syndrome, nonthyroid illness; decreased T3, decreased pulsatile TSH release, increased rT3. *If illness progresses reduction in free T4

28. In illnesses such as mild MI, elective surgeries, infections such as pyelonephritis or pneumonia: * 50% reduction in free T3 * 2-3 fold increase in rT3 * Normal T4 and TSH

29. As illness becomes more severe: *Fall in T3 and increase in rT3 become more marked * Normal free T4 * TSH begins to fall * Release of FFA reduced binding of T4 to TBG increased free T4

30. Prolonged critical illness: * T3 is reduced * Free T4 and TSH are markedly reduced

31. * Acute medical illness in patients with primary hypothyroidism receiving levothyroxine: Over the first 3 days, T4, T3 and TSH fall about 50%.

32. Neither T3 nor T4 administration improves the outcomes in sick patients.

33. During recovery: * Increased TSH above the normal, persisting until free T4 and T3 return to normal. * They meet all lab. Criteria for primary hypothyroidism except for clinical context. T4 and TSH will normalize within 1 to 2 months.

34. TFT in neuropsychiatric illnesses * Bipolar disorders: Slight elevation in TSH and reduction in Free T4 * Severe depression: Slight elevation in T4 and reduction in TSH * Other acutely psychotic patients: Elevation in free T4, high or low TSH

35. Effect of Hormones on Thyroid Function *Glucocorticoids: Acute administration of pharmacologic doses of glucocorticoids reduced TRH, eliminated pulsatile release of TSH, reduced T3, increased rT3. With continued administration, there is an escape from this suppression. * primary adrenal insufficiency reduced T4 and elevated TSH Treatment of adrenal insufficiency leads to complete resolution. * prevalence of primary hypothyroidism is increased in patients with autoimmune hypoadrenalism.

36. Estrogen increases TBG increased total T4, normal free T4 Estrogen increases levothyroxine requirement in patients with primary hypothyroidism. Administration of androgens to women Decreased TBG, decreased T4, decreased levothyroxine requivements in patients with primary hypothyroidism *GH increases free T3 and decreases free T4. Gonadal steroids :

37. Physical Examination of the Thyroid

38. Physical Examination of the Thyro Evaluation begins with interview; Hoarseness : a sign of recurrent laryngeal nerve compression, associated with large benign goiters or malignant thyroid lesions and necessitate laryngoscope confirmation.

39. Physical Examination of the Thyroid * The patient seated in good light with the neck relaxed * A cup of water to facilitate swallowing *

40. Light from the side and slightly above enhances a shadowed border of thyroid and cricoid cartilages. normally,the extended neck from the cricoid to the sternal notch will form a straight line. Viewed from the side, anterior bowing suggests the presence of a goiter.

44. First inspect the neck, especially in swallowing, with the neck slightly extended: - Surgical scars - distended veins - redness or fixation of the overlying skin - position of the trachea

45. - If a mass is present: move with swallowing - Movement on swallowing is a characteristic of the thyroid gland, this feature distinguishes goiter from most other neck masses -If the thyroid is so large that it occupies all the available spaces in the neck, movement on swallowing may be lost. - A midline mass high in the neck, which rises further when the patient extends the tongue, is typical of thyroglossal cyst.

48. Erythema overlying a tender swelling : Acute suppurative thyroiditis Infected thyroglossal duct Branchial cleft cyst

49. Palpation Face the seated patient. Use gentle pressure with your thumb to locate the thyroid isthmus just caudal to the cricoid cartilage. Move your right thumb laterally without release of gentle pressure. Locate the right lobe by pressing it against the trachea as the patient swallows. Appreciate the size and texture of the gland as well as the presence or absence of nodules.

50. Note the shape of the gland, size, consistency which is slightly greater than adipose tissue but less than muscle. Consistency in graves is softer than normal but Hashimoto is firm. The normal thyroid lobe has the same size as the terminal phalanx of the patient’s thumb.

51. Irregularities of the surface, variations in consistency, and tender areas should be noted. Nodules : shape, size, position, translucency, consistency A firm nodule is more likely to be a cyst than a malignancy Vascular thrill in the absence of cardiac disease is suggestive of hyperthyroidism.

52. Examine the lymph nodes along the jugular vein, posterior to the sternocleidomastoids and in the supraclavicular region.

54. Auscultation A systolic or continuous bruit is sometimes heard over a hyperplastic gland. It should be differentiated from : Murmur transmitted from the base of the heart. Venous hum that is obliterated by gentle compression of the external jugular vein or by turning the head. It is found in younger patients with high cardiac output, such as graves ‘ or severe anemia.

55. Ultrasound device will become a common instrument in the endocrinologist’s office in the coming years.