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Thyroid hormones
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  • 1. THYROID HORMONES M.Prasad Naidu MSc Medical Biochemistry, Ph.D,.
  • 2.  Thyroid gland produces two principal hormones … thyroxine & tri iodo thyronine which regulate the metabolic rate of the body.  Iodine is essential for the synthesis of thyroid hormones  More than half of the body’s total content is found in the thyroid gland
  • 3. Hypothalamo pituitary axis The hypothalamo-pituitary axis is a classical negative feedback regulatory mechanism in which secretion of TSH is modulated by thyroid hormones. Release of TSH from the pituitary gland is stimulated by thyrotropin releasing hormone (TRH) from the hypothalamus.
  • 4. Hypothalamo pituitary axis  A small increase in T3 and T4 produces a diminished TSH response to TRH at the pituitary level.  T3 and T4 act at the hypothalamic level by inhibiting mRNA for TRH synthesis.  Only unbound fractions of hormone are metabolically active and only this free hormone has an inhibitory effect on the secretory activity of the thyroid.  dopamine physiologically inhibits TSH secretion  glucocorticoids have been shown to dull the response of the pituitary to TRH  oestrogens increase the sensitivity of thyrotrophs to TRH
  • 5. Mechanism of thyroid hormone receptor action
  • 6. Actions of thyroid hormones  Brain----growth&development of nervous system  Bone&tissue growth– linear growth & maturation of bones  CVS-- increased contractility,heart rate &cardiac output  GUT—increased absorption of nutrients, increased motility  Liver -increased gluconeogenesis&glyco genolysis  Adipose tissue –increased lipolysis  Muscle –increased protein catabolism in skeletal muscle  Kidney -increased erythropoietin synthesis  Respiration- increased central stimulation of respiration  Energy metabolism -increased BMR,increased oxygen consumption,increased heat production stimulation of Na-K- ATP ase
  • 7. Wolff-chaikoff effect  Iodine deficiency increases thyroid blood flow & upregulates the NIS , stimulating more efficient uptake.  Excess iodide transiently inhibits thyroid iodide organification ,a phenomenon known as the wolff-chaikoff effect
  • 8. The functional unit of thyroid is thyroid follicle. Normal follicle
  • 9. Thyroid follicle with out TSH Thyroid follicle with high TSH stimulation
  • 10. High T3 or T4 gives  decreased TSH subunit synthesis  inactive thyrotrophs may lose the capacity to respond to reduced T3 or T4 levels
  • 11.  inhibits TSH release  potentiates the effect of thyroid hormones on thyrotrophs, ie thyroid hormone has inhibitory effects on TSH release  derives from the median eminence of the hypothalamus  thyrotropin releasing hormone, ie stimulates TSH release somatostatin TRH
  • 12.  Iodine deficiency  Hasimoto’s thyroiditis  Thyroidectomy  Radiation therapy  Drugs-lithium,antithyroid drugs and PAS  Absent or ectopic thyroid gland  Dyshormonogenesis  TSH receptor mutation Hypopituitarism  Tumors,pituitary surgery, irradiation/infi ltration, sheehan’s syndrome & isolated TSH deficiency Hypothalamic disease  Trauma & infiltration Primary hypo thyroidism Secondary hypotyroidism
  • 13. cretinism - congential absence of T3 and T4 or chronic iodine deficiency during childhood - retarded growth - sluggish movements - mental deficiencies
  • 14. myxedema - low rate of metabolism and lethargy - decreased body temp - decreased heart rate - outer skin becomes scaley - myxodema – swelling of sub-cu connective tissues
  • 15.  Grave’ disease  Toxic multinodular goitre  Toxic adenoma  Functioning metastatic thyroid carcinoma  TSH receptor mutation  Struma ovarii  Iodine excess  TSH secreting pituitary adenoma  Thyroid hormone resistance syndrome  Chorionic gonadotropin secreting tumours  Gestational thyrotoxicosis Primary hyperthyroidism Secondary hyper thyroidism
  • 16. hyperthyroidism - Grave’s Disease - tall stature, hyperactivity - high rate of metabolism - high body temp - high heart rate
  • 17. Thyroid function in pregnancy Four factors alter thyroid function in pregnancy  Transient increase in hcG during first trimester which stimulates TSH-R  The estrogen induced rise in TBG during the first trimester which is sustained during pregnancy  Alterations in the immune system ,leading to onset, exacerbation ,or amelioration of an underlying auto immune thyroid disease  Increased urinary iodide excretion ,which can cause impaired thyroid hormone production
  • 18.  Iodine supplementation is considered to be important in women with precarious iodine intake  Maternal hypothyroidism occurs in 2 to 3% of women of child bearing age & is associated with increased risk of developmental delay in the offspring  Thyroid hormone requirements are increased by 25 to 50µg/day during pregnancy
  • 19. THYROID FUNCTION TESTS
  • 20. Thyroid function tests Estimation of thyroid hormones  Total T4  Total T3 Estimation of free hormone fraction  Free T4 fraction %FT4  Free T3 fraction %FT3  THBR Estimates of free hormone concentration  FT4E (T4 X %FT4)  FT3E (T3 X % FT3)  FT4I (T4 X THBR)  FT3I (T3 X THBR)  T4: TBG ratio
  • 21. Thyroid function tests Serum binding proteins  Thyroxine binding globulin  Thyroxine binding prealbumin Tests for auto immune thyroid disease  Anti thyroglobulin Abs  Anti TPO antibodies  TSH receptor anti bodies Other hormones & thyroid related proteins  TRH  Thyroglobulin  calcitonin
  • 22. Measurement of T4,T3 &rT3  METHOD  Immunoassay  Chemiluminiscence  The major clinical role for T3 measurements are in the diagnosis & monitoring of hyperthyroid pts with suppressed TSH &normal FT4  r T3 test is not always elevated with illness.It is seldom used in pts with euthyroid sick syndrome  Specifially,renal failure is associated with low r T3 conc.
  • 23. Sandwich ELISA
  • 24. Radioimmunoassay
  • 25. Determination of free thyroid hormones  Direct assays – currently serve as reference methods  Indirect assays - more widely available for general laboratory use
  • 26. Direct methods  Direct measurement of FT4&FT3 is a technical challenge as free hormone conc. are low in serum healthy individuals  Assays for free thyroid hormones must be capable of measuring sub picomole amounts  Only minimal dilution of serum specimens is allowed as dilution alters the binding of drugs, FFAs and other substances to serum proteins
  • 27. Methods  Equilibrium dialysis  Ultra filtration techniques these techniques physically separate free hormone from protein bound hormone (before direct measurement of the free fraction with a sensitive T4 or T3 immunoassay) These methods are unaffected by variations in SBPs or thyroid hormone auto antibodies
  • 28. Indirect methods  More convenient & less expensive than direct methods  Automated immuno assay instuments  Two step immunoassay  One step immunoassay  These methods estimate free hormone conc. by using antibody extraction techniques
  • 29.  FT4 is 0.03% of total serum T4  FT3 is 0.3% of total serum T3  Because T3 is less firmly bound by TBG than is T4 the dialyzable fraction of T3 is appreciably greater (by almost 10 times) than that of T4
  • 30. Free hormone estimates  FT4E = total T4 X %FT4  The free hormone fraction as measured dialysis or ultra filtration of diluted serum containing tracer T4 or t3 is multiplied by the respective total hormone concentration to obtain indirect estimates  THBR = %uptake(patient serum)/% uptake (reference serum)
  • 31. Invitro I –T3resin uptake by Resin  A known amount of I-T3 is added to a standard volume of serum from a patient  The amount of I-T3 which binds to the serum proteins varies inversely with the endogenous thyroid hormones already bound to serum proteins(TBG)  Residual free I-T3 then adsorbed by resin is removed from the sample and then adsorbed/bound I is measured
  • 32. FT4 index  Unlike direct free T4 methods , index methods measure both the serum total T4 & the free T4 fraction  They have an advtantage that they can define whether an abnormal FT4 estimate is due to abnormal hormone production or due to abnormal protein binding  An FT4 index is sometimes directly calculated using the percentage T-uptake  FT4I =total T4(µg/dl) x % thyroid uptake/ 100
  • 33. Plasma TSH Method- Immunoassay -chemiluminiscence Secretion of TSH occurs in a circadian fashion Primary Hypothyroidism-TSH increased Secondary hypothyroidism-TSH ,T3 ,T4 are low Primary hyper thyroidism –TSH decreased Secondary hyperthyroidism-TSH,T3,T4 high
  • 34. TSH stimulation test Measurement of serum T4 after TSH injection  No response - primary  Increase of T4- secondary  Useful for distinguishing primary from secondary hypothyroidism
  • 35. TRH response test  TRH administration will stimulate the production of TSH  Useful for differentiating hypothalamic from a pituitary hypotyroidism  There is increase of TSH after TRH in hypothalamic disorder
  • 36. If the hypothalamo pituitary axis is normal .the T3 and T4 secretions will be increased An abnormal response is seen in Hyperthyroidism – T4 elevated  Hypopituitarism- T4 Levels subnormal  Primary hypothyroidism-exaggerated response
  • 37. Determination of thyroid binding globulin  TBG is the thyroid binding globulin with the greatest affinity for T4  TBG is very important for regulating the conc. And availability of the FT4 hormone.  Method - immunoassay - commercial kit methods available - chemiluminiscence  Estrogen induced TBG excess and congenital TBG deficiency are important abnormalities that affect the test results
  • 38. Calculation of T4:TBG & T3:TBG ratios  These ratios correlate with FT4 or FT3 conc. And are particularly useful in sera with altered TBG conc.  failures:They may fail however to compensate for TBG variants with reduced T4 affinity & for abnormal albumin binding  Ref . Interval is 3.8 to 4.5
  • 39. Determination of thyroglobulin  Method –immunometric assay method  These assays are based on the use of two or more monoclonal antibodies directed to different portions of the Tg molecule  Difficulty: interference with anti-Tg antibodies as seen in pts with thyroid cancer Heterophilic antibody interference(HAMA)  Ref interval is 3 to 42 μg/dl
  • 40.  Thyroglobulin is used primarily as tumor marker in pts carrying a diagnosis of differentiated thyroid carcinoma Tg levels are elevated in Thyroid follicular &papillary carcinoma Certain non neoplastic conditions like..,  Thyroid adenoma  Subacute thyroiditis  hashimoto’s thyroiditis  Grave’s disease
  • 41.  Serum Tg conc. are not increased in pts with medullary thyroid carcinoma  Serial measurements of Tg is most useful in detecting recurrence of diff. thyroid carcinoma following surgical resection  Tg determination is used as an adjunct to ultrasound and radio iodine scanning  Assessment of serum Tg also aids in management of infants with congenital hypo thyroidism  In hyperthyroidism-Tg Low conc.- thyrotoxicosis factita
  • 42. Determination of antithyroid antibodies Anti thyroid antiodies are found in autoimmune diseases and certain malignancies These autoantibodies are directed against several thyroid and thyroid hormone antigens  Tg (Tg Ab)  Thyroid peroxidase(TPO Ab)  Thyroid receptor(TR Ab)  TSH,T4,T3
  • 43.  The presence of TPO antibodies is a risk factor for autoimmune thyroid dysfunction  However there is a high prevalence of anti- TPO antibodies in the elderly  With sensitive assays,low conc of TPO antibodies may be detected in some healthy individuals—they may have occult or subclinical thyroid dysfunction
  • 44. Method  RIA  CHEMILUMINISCENCE based immunometry  Radioimmunometric technique Reference value is ≤2U/ml(with sensitive chemiluminiscence assay) Detectable conc. Of TPO Ab are seen in hashimoto’s thyroiditis,idiopathic myxedema, grave’s disease, Type 1 IDDM
  • 45. Determination of thyrotropin receptor antibodies Thyrotropin receptor antibodies are a group of related immunoglobulins that bind to TSH receptors Seen in pts with Graves disease & other auto immune thyroid disorders These Ab s demonstrate substantial heterogeneity Some cause thyroid stimulation , where as others have no effect or decrease thyroid secretion by blocking the action of TSH
  • 46.  Invitro bioassays assess the capacity of immunoglobulins to stimulate functional activity of thyroid gland such as.., 1.adenylatecyclase stimulation 2. c AMP formation 3.colloid mobilization 4.iodothyronine release TSI s are present in 95% of pts with untreated Grave’s disease TSI measurement is also used for following the course of therapy & predicting relapse & remission
  • 47. Radio active iodine uptake(RAIU)  Radioactive iodine uptake by thyroid gland and thyroid scanning with Tc 99 are of diagnostic value.
  • 48. calcitonin  Calcitonin is secreted by the para follicular or C cells ,which arise from the neural crest & are distributed through out the thyroid gland  A marker for medullary thyroid carcinoma (tumor of C cells)  Ref range ≤ 25pg/m L in men and ≤20 pg/m L
  • 49. Normal ranges  T3 :120-190 ng/dl  r T3 : 10-25 ng/dl  T4 : 5-12 µg/dl  Thyroglobulin:3-5 µg/dl  TRH :5-60 ng/L  TSH :0.5-5 µU/ L  Thyroxine binding globulin :1-2 mg/dl
  • 50. THANK YOU