Thyroid Function

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Thyroid Function

  1. 1. CLINICAL CHEMISTRY CHAPTER 20 THYROID FUNCTION
  2. 2. Introduction <ul><li>Have you been feeling lousy lately? </li></ul><ul><li>Always too hot or too cold? </li></ul><ul><li>Losing weight? Getting fat? </li></ul><ul><li>Sweating like a pig? Cold as a clam? </li></ul><ul><li>If you answered yes to any of these questions, then your thyroid gland may be talking to you. </li></ul>
  3. 3. KEY TERMS <ul><li>Free Thyroxine Index ( FTI ) </li></ul><ul><li>Graves’ Disease </li></ul><ul><li>Hashimoto’s Disease </li></ul><ul><li>Hyperthyroid </li></ul><ul><li>Hypothyroid </li></ul><ul><li>Euthyroid </li></ul><ul><li>Subclinical Thyroid disease </li></ul><ul><li>T3 Uptake ( T3U ) </li></ul><ul><li>Thyroid Binding Globulins </li></ul><ul><li>Thyroxine Binding Globulin (TBG) </li></ul><ul><li>Thyroxine Binding Albumin ( TBA) </li></ul><ul><li>Thyroxine ( T4 ) </li></ul><ul><li>Triiodothyronine ( T3 ) </li></ul><ul><li>Thyroid Stimulating Hormone (TSH) </li></ul><ul><li>Thyroxine Hormone Binding Ratio (THBR ) </li></ul><ul><li>Iodide </li></ul><ul><li>Hypothalamus Gland </li></ul><ul><li>Anterior Pituitary Gland </li></ul><ul><li>Thyroid Gland </li></ul><ul><li>Free T3 and T4 </li></ul><ul><li>Bound T3 and T4 </li></ul><ul><li>TSH Assay “Generation” </li></ul><ul><li>TSHR and TPO antibodies </li></ul>
  4. 4. Objectives <ul><li>Define each of the Key Terms </li></ul><ul><li>Discuss the synthesis, transport and effects of the thyroid hormones </li></ul><ul><li>Discuss the feedback systems that regulate thyroid concentrations </li></ul><ul><li>List common tests that are used to evaluate thyroid function </li></ul><ul><li>Discuss the common methodologies used to measure thyroid hormones </li></ul><ul><li>Interpret the results of thyroid testing and relate them to specific thyroid disease conditions </li></ul>
  5. 5. <ul><li>Thyroid Anatomy and Physiology </li></ul><ul><ul><li>2 lobes gland and the base of the neck </li></ul></ul><ul><ul><li>Produces Thyroxine ( T 4 ) and Triiodothyrine ( T 3 ) </li></ul></ul><ul><ul><li>Iodide is an essential component of T 4 and T 3 </li></ul></ul><ul><ul><li>Thyroid gland concentrates iodide from plasma </li></ul></ul><ul><ul><li>Iodide is oxidized to I 0 or I 1+ which combines with the glycoprotein thyroglobulin </li></ul></ul><ul><ul><li>Thyroglobulin contains tyrosyl groups, which react with iodide to form MIT or DIT </li></ul></ul>
  6. 7. <ul><li>Formation of T 3 and T 4 in the thyroid gland </li></ul><ul><ul><ul><li>MIT + DIT = T 3 </li></ul></ul></ul><ul><ul><ul><li>DIT + DIT = T 4 </li></ul></ul></ul><ul><ul><ul><li>T 4 - Iodide = rT 3 ( Reverse T 3 ) … Inactive form </li></ul></ul></ul><ul><ul><li>T 3 and T 4 are stored and released into the plasma by the enzymatic cleavage of thyroglobulin </li></ul></ul><ul><ul><li>T 4 concentrations are 50 times greater than T 3 </li></ul></ul><ul><ul><li>Peripheral de-iodination of T 4 to produce T 3 ( in liver & kidney ) </li></ul></ul><ul><ul><ul><li>T 4 – Iodide = T 3 ( 80% of T 3 ) </li></ul></ul></ul>
  7. 8. Chemical Structure of T3 and T4
  8. 9. <ul><ul><li>Greater than 99 % of circulating T 3 and T 4 are bound to plasma transport proteins </li></ul></ul><ul><ul><ul><li>Thyroxine Binding Globulin ( TBG ) </li></ul></ul></ul><ul><ul><ul><li>Transthyretin ( TTR ) </li></ul></ul></ul><ul><ul><ul><li>Thyroxine Binding Pealbumin ( TBPA ) </li></ul></ul></ul><ul><ul><ul><li>Thyroxine Binding Albumin ( TBA ) </li></ul></ul></ul><ul><ul><li>On average, ⅓ of protein binding sites are occupied by T 3 or T 4 </li></ul></ul><ul><ul><li>Percentages of T 3 and T4 in the free ( active ) forms </li></ul></ul><ul><ul><ul><li>0.4 % of T 3 </li></ul></ul></ul><ul><ul><ul><li>0.04 % of T 4 </li></ul></ul></ul><ul><ul><li>T 3 has the greatest hormonal effect </li></ul></ul>
  9. 10. <ul><ul><li> Binding Proteins  Bound T3 and T4 </li></ul></ul><ul><ul><li> Binding Proteins  Bound T3 and T4 </li></ul></ul><ul><ul><li>Free T3 and T4 remain stable, but Total T3 and T4 may vary </li></ul></ul><ul><ul><li>This is a problem because clinical conditions that effect the concentrations of the Thyroid Binding Proteins also effect the Total T3 and Total T4 hormones … But the Total T3 and T4 are not the physiologically active forms </li></ul></ul><ul><ul><li>This is why we have the T3U and THBR tests … to measure what effect the Thyroid Binding Proteins are having on the Total T3 and Total T4 values </li></ul></ul>
  10. 11. <ul><li>Causes of elevated Thyroxine Binding Globulins </li></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><ul><li>Estrogen therapy and oral contraceptives </li></ul></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><li>Causes of decreased Thyroxine Binding Globulins </li></ul><ul><ul><li>Protein malnutrition </li></ul></ul><ul><ul><li>Cirrhosis </li></ul></ul><ul><ul><li>Androgens </li></ul></ul><ul><ul><li>Acute and chronic illnesses </li></ul></ul><ul><ul><li>Hyperthyroidism </li></ul></ul>
  11. 12. <ul><li>Regulation of Thyroid Hormones </li></ul>HYPOTHALAMUS TRH ( Thyrotropin Releasing Hormone ) Y ANTERIOR PITUITARY GLAND Thyroid Stimulating Hormone ( TSH – Thyrotropin ) THYROID GLAND FT 3 AND FT 4 Negative Feedback loop
  12. 13. <ul><ul><li>TSH ( Thyroid Stimulating Hormone ) </li></ul></ul><ul><ul><ul><li>Glycoprotein hormone </li></ul></ul></ul><ul><ul><ul><li>Composed of Alpha and Beta subunits </li></ul></ul></ul><ul><ul><ul><li>Same subunits as LH, FSH and HCG - Possible cross-reactions </li></ul></ul></ul><ul><ul><ul><li>A 2 fold increase or decrease in T4 results in a 100 fold increase or decrease in TSH. For this reason … </li></ul></ul></ul><ul><ul><ul><li>TSH is the single best test to determine Primary Hypothyroidism or Hyperthyroidism </li></ul></ul></ul>
  13. 14. <ul><li>Roles of the Thyroid Hormones </li></ul><ul><ul><li>Brain and skeletal development in children </li></ul></ul><ul><ul><li>Regulates cellular oxygen consumption </li></ul></ul><ul><ul><li>Regulates heart rate </li></ul></ul><ul><ul><li>Regulates carbohydrate and lipid metabolism </li></ul></ul>
  14. 15. <ul><ul><li>SYMPTOMS OF HYPERTHYROID </li></ul></ul><ul><ul><ul><li>MOIST WARM SKIN </li></ul></ul></ul><ul><ul><ul><li>WEIGHT LOSS </li></ul></ul></ul><ul><ul><ul><li>SWEATING </li></ul></ul></ul><ul><ul><ul><li>NERVOUSNESS </li></ul></ul></ul><ul><ul><ul><li>TREMORS </li></ul></ul></ul><ul><ul><ul><li>HEAT INTOLERANCE </li></ul></ul></ul><ul><ul><ul><li>TACHYCARDIA </li></ul></ul></ul>
  15. 16. <ul><ul><li>SYMPTOMS OF HYPOTHYROID </li></ul></ul><ul><ul><ul><li>WEAKNESS </li></ul></ul></ul><ul><ul><ul><li>LETHERGY </li></ul></ul></ul><ul><ul><ul><li>COLD DRY SKIN, </li></ul></ul></ul><ul><ul><ul><li>WEIGHT GAIN, SLOW SPEECH </li></ul></ul></ul><ul><ul><ul><li> CHOLESTEROL </li></ul></ul></ul><ul><ul><ul><li>COLD INTEROLANCE </li></ul></ul></ul><ul><ul><ul><li>HOARSENESS </li></ul></ul></ul><ul><ul><ul><li>BRADYCARDIA </li></ul></ul></ul>
  16. 17. Hyperthyroidism
  17. 18. <ul><li>COMMON TESTS FOR THYROID FUNCTION </li></ul><ul><ul><li>TSH </li></ul></ul><ul><ul><li>TOTAL T 3 AND T 4 (TT 3 AND TT 4 ) </li></ul></ul><ul><ul><li>FREE T 3 AND T 4 ( FT 3 AND FT 4 ) </li></ul></ul><ul><ul><li>T 3 U ( T 3 – UPTAKE ) …..MEASURES BINDING PROTEINS </li></ul></ul><ul><ul><li>FREE THYROXINE INDEX ( FT 4 I ) …. ESTIMATE OF FT 4 </li></ul></ul><ul><ul><li>SEROLOGICAL TESTS FOR ANTI-THYROID AUTOANTIBODIES </li></ul></ul>
  18. 19. <ul><li>CLASSIFICATION OF THYROID DISORDERS </li></ul><ul><ul><li>THYROID DISORDERS ( AND OTHER HORMONES TOO ) CAN BE CAUSED BY DIFFERENT GLANDS THAT FORM THE ENDOCRINE SYSTEM </li></ul></ul><ul><ul><ul><li>PRIMARY : THYROID GLAND DISORDER </li></ul></ul></ul><ul><ul><ul><li>SECONDARY : ANTERIOR PITUITARY GLAND DISORDER </li></ul></ul></ul><ul><ul><ul><li>TERTIARY : HYPOTHALAMUS GLAND DISORDER </li></ul></ul></ul><ul><ul><ul><li>EXAMPLE : A SECONDARY THYROID DISORDER IS ACTUALLY A DYSFUNCTION OF THE ANTERIOR PITUITARY </li></ul></ul></ul>
  19. 20. <ul><ul><li>MOST METHODOLOGIES FOR THYROID TESTING UTILIZE A VARIETY OF COMPETETIVE BINDING TECHNIQUES </li></ul></ul><ul><ul><ul><li>RIA, ELISA, FIA </li></ul></ul></ul><ul><ul><ul><li>KEEP IN MIND THAT TECHNIQUES THAT MEASURE TOTAL T 3 OR TOTAL T 4 WILL BE AFFECTED BY THE CONCENTRATIONS OF THE THYROID BINDING PROTEINS </li></ul></ul></ul><ul><ul><ul><li>FREE T 3 AND FREE T 4 TESTING REQUIRE SPECIAL TECHNIQUES THAT SEPARATE FREE FROM PROTEIN-BOUND HORMONES ( EQUILIBRIUM DIALYSIS TECHNIQUE ) </li></ul></ul></ul><ul><ul><ul><li>“ GENERATIONS” OF TSH TEST REFERS TO A 10-FOLD INCREASE IN SENSITIVITY </li></ul></ul></ul>
  20. 21. <ul><li>T 3 – UPTAKE ( T 3 U ) TEST </li></ul><ul><ul><li>MISNOMER !!! DOES NOT MEASURE T 3 !!! </li></ul></ul><ul><ul><li>Estimation of the Thyroid Binding proteins </li></ul></ul><ul><ul><li>VARIATIONS IN THYROID BINDING PROTEINS MAY BE UNRELATED TO THE THYROID GLAND </li></ul></ul><ul><ul><li>VARIATIONS IN THE BINDING PROTEINS STILL RESULT IN EUTHYROID PATIENTS BECAUSE THE THYROID ADJUSTS SECRETION OF HORMONES SO THAT THE CONCENTRATIONS OF THE FREE HORMONES REMAINS NORMAL </li></ul></ul>
  21. 22. <ul><li>T 3 U ( CONTINUED ) </li></ul><ul><ul><li>T 3 U METHODOLOGY </li></ul></ul><ul><ul><ul><li>PATIENT’S PLASMA INCUBATED WITH A TAGGED T 3 </li></ul></ul></ul><ul><ul><ul><li>EXCESS T 3 REMOVED ( BOUND ) TO BINDING AGENT ( RESIN, ANTIBODY, CHARCOAL ) </li></ul></ul></ul><ul><ul><ul><li>T 3 IS MEASURED IN BINDING AGENT AND RESIDUAL PLASMA </li></ul></ul></ul><ul><ul><ul><li> T 3 UPTAKE BY BINDING AGENT …  THYROID PROTEIN SITES </li></ul></ul></ul><ul><ul><ul><li> T 3 UPTAKE BY BINDING AGENT …  THYROID PROTEIN SITES </li></ul></ul></ul><ul><ul><ul><li>T 3 U IS REPORTED AS % OF NORMAL AVERAGE VALUE OR THBR </li></ul></ul></ul><ul><ul><ul><li>INCREASED T 3 U : 1  HYPERTHYROID, STEROIDS </li></ul></ul></ul><ul><ul><ul><li>DECREASED T 3 U : 1  HYPOTHYROID, PREGNANCY </li></ul></ul></ul>
  22. 23. Example T3 - Uptake Test ( T3U) Low TBG Normal TBG Increased TBG = Patient’s TBG = Excess tagged T3 from test Tagged T3 binds with available TBG or remains unattached Increased TBG binds more T3 Decreased TBG binds less T3
  23. 24. Bound and unbound T3 are separated from each other Added resin binds to unbound T3 Activity of the tag is measured in the separated resin and the residual plasma The T3U represents 3 / 1 = 3.0 2 / 2 = 1.0 1 / 3 = 0.3 The T3U is inversely proportional to the number of free thyroid binding hormone sites on the various thyroid binding globulins ( mostly TBG )
  24. 25. <ul><li>FT 4 I ( FREE T 4 INDEX ) </li></ul><ul><ul><li>CALCULATED ESTIMATE OF FREE T 4 </li></ul></ul><ul><ul><li>CORRECTS FOR ETHYROID PATIENTS WITH ABNORMAL THYROID BINDING HORMONES </li></ul></ul><ul><ul><li>CALCULATION </li></ul></ul><ul><ul><ul><li>FT 4 I = TT 4 X THBR (Thyroxine Hormone Binding Ratio) </li></ul></ul></ul><ul><ul><ul><li>THBR = </li></ul></ul></ul><ul><ul><li>The control T3U usually represents the T3U value from a pool of normal patients and by definition has a THBR of 1.0 </li></ul></ul><ul><ul><li>EXAMPLE: EUTHYROID PATIENTS WITH INCREASED THYROID BINDING PROTEINS WILL HAVE INCREASED TT 4 AND FALSELY LABELED AS HYPERTHYROID, BUT WILL HAVE A NORMAL FT 4 I </li></ul></ul>
  25. 26. <ul><li>Drug interference with T3U </li></ul><ul><ul><li>Different drugs can compete with T3 and T4 for binding sites on the TBGs, causing falsely increased T3U results </li></ul></ul><ul><ul><ul><li>Dilantin </li></ul></ul></ul><ul><ul><ul><li>Coumadins </li></ul></ul></ul><ul><ul><ul><li>Heparins </li></ul></ul></ul><ul><ul><ul><li>Aspirin </li></ul></ul></ul>
  26. 27. Example of the usefulness of the T3U Suppose a patient has the following results: TSH = 4.0 mU/ml ( Normal ) Total T4 = 14.3 ug/dl ( Increased ) Is the patient normal or hyperthyroid? We need the T3U to estimate TBGs T3U = 0.7 THBR = 0.7 / 1.0 = 0.7 T4 Index = 0.7 x 14.3 = 10.0 ( Normal ) Conclusion : The patient is normal. The increased TT4 is caused by an abnormal concentration of thyroid binding globulins. The weakness of the T4 Index is that it may not accurately reflect normal free hormone concentrations in patients with markedly abnormal binding proteins or anti-thyroid antibodies
  27. 28. Another Illustration of T3U Test Note : Although T3U testing originally used radioactive markers, enzymes are now commonly used due to costs and safety concerns.
  28. 29. <ul><li>COMMON THYROID DISORDERS </li></ul><ul><ul><li>GRAVES DISEASE </li></ul></ul><ul><ul><ul><li>AUTOIMMUNE, COMMON CAUSE ( 80% ) OF HYPERTHYROID CASES, ANTI-THYROID ANTIBODIES </li></ul></ul></ul><ul><ul><li>HASHIMOTO’S DISEASE </li></ul></ul><ul><ul><ul><li>COMMON HYPOTHYROIDISM, INFILITRATION OF THYROID GLAND BY LYMPHOCYTES AND ANTI-THYROID ANTIBODIES </li></ul></ul></ul><ul><ul><li>MYXEDEMA </li></ul></ul><ul><ul><ul><li>SEVERE HYPOTHYROIDISM </li></ul></ul></ul><ul><ul><li>NEWBORN SCREENING </li></ul></ul><ul><ul><ul><li>1 IN 4,000 BIRTHS HAVE CONGENITAL HYPOTHYROIDISM </li></ul></ul></ul>
  29. 30. Retracted eyelids in Graves’ disease
  30. 31.             YES GRAVE’S DISEASE NONE NORMAL NORMAL NORMAL NORMAL EUTHYROID 1  HYPO- THYROID 1  HYPER- THYROID ANTIBODY T 3 U FT 4 TT 4 TSH
  31. 32. TOP 10 <ul><li>T4 = Thyroxin and T3 = Triiodothyrine </li></ul><ul><li>Iodide is required for thyroid hormone synthesis ( look at your salt ) </li></ul><ul><li>Hyperthyroid “speeding metabolism / Hypothyroid “ slow metabolism” </li></ul><ul><li>> 99% of thyroid hormones are bound to proteins </li></ul><ul><li>Only free thyroid hormones are physiologically active </li></ul><ul><li>TSH is synthesized by the Anterior Pituitary </li></ul><ul><li>Primary Hypothyroid Increased TSH ( and visa versa ) </li></ul><ul><li>T3U test measures thyroid binding proteins </li></ul><ul><li>FT4I = TT4 x THBR </li></ul><ul><li>Graves’ Disease : Autoimmune hyperthyroid condition </li></ul>
  32. 33. <ul><li>REFERENCE RANGES: </li></ul><ul><ul><li>TSH 0.5 - 5.0  U / ml </li></ul></ul><ul><ul><li>T 4 4.5 - 13.0  g / dl </li></ul></ul><ul><ul><li>T 3 60 - 220 ng / dl </li></ul></ul><ul><ul><li>T 3 U 25 - 30% </li></ul></ul><ul><ul><li>TBHR 0.8 - 1.4 </li></ul></ul>
  33. 34. Links http://www.nlm.nih.gov/medlineplus/thyroiddiseases.html http://www.endocrineweb.com http://www.muhealth.org/~pharm204/hormones.html

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