Production and Regulation of Thyroid Hormones. Presentation : Nariman morai

Transcription

1 Production and Regulation of Thyroid Hormones Presentation : Nariman morai

2 The Thyroid Gland

3 Thyroid Hormones are produce in Follicles

4 Transport of Thyroid Hormones Thyroid hormones are not very soluble in water (but are lipid-soluble). Thus, they are found in the circulation associated with binding proteins: - Thyroid Hormone-Binding Globulin (~80% of hormone) - Pre-albumin (transthyretin), (~10%) - Albumin (~10%) Less than 1% of thyroid hormone is found free in the circulation. Only free thyroid hormone is biologically available to tissues.

5 Conversion of T4 to T3 The thyroid secretes about 80 µg of T4, but only 5 µg of T3 per day. However, T3 has a much greater biological activity (about 10 X) than T4. An additional 25 µg/day of T3 is produced by peripheral monodeiodination of T4. This conversion takes place mainly in the liver and kidneys. The T3 formed is then released to the blood stream. In addition to T3, an equal amount of reverse T3 may also be formed. This has no biological activity. thyroid T4 I - T3

6 Conversion of T4 to T3

7 Regulation of Thyroid Hormone Levels Thyroid hormone synthesis and secretion is regulated by two main mechanisms: an autoregulation mechanism, which reflects the available levels of iodine regulation by the hypothalamus and anterior pituitary

8 Thyroid function tests: Analytical Methods and Pre-analytical Errors Dr.Abasi

9 Patient Variables Diet Age Gender Body mass Medications Smoking Pregnancy Exercise Race Dehydration Preanalytical Errors

10 Preanalytical Errors Specimen Collection Variables Posture Diurnal variation Time of collection Fasting status Anticoagulants

11 Preanalytical Errors Specimen Handling Variables Hemolysis Lipemia Freezing and Tawing Processing time Temperature Transport conditions

12 Thyroid-Stimulating Hormone (TSH) Specimen Collection and Storage: Serum or plasma may be used for TSH measurements. TSH is stable for 5 days at 2 to 8 C, and for at least 1 month when stored frozen. For newborn screening, whole blood may be collected by heel puncture 48 to 72 hours after birth.

13 Thyroid-Stimulating Hormone

14 Thyroid-Stimulating Hormone (TSH) Comments on TSH Measurements: TSH has diuaral rhythm: peaks at AM and has lowest level at PM. The nocturnal increase in TSH is lost in critical illness and after surgery. TSH surges with birth, peaking at 30 min, declining back to cord blood levels by 3 days, and reaching adult values in the first week of life. In the first trimester of pregnancy, TSH concentrations decline as hcg stimulates the maternal thyroid gland to produce thyroid hormone, sometimes leading to a TSH concentration that is just below the lower limit of the reference interval.

15 Thyroxine [Tetraiodothyronine (T4)] Specimen Collection and Storage: Serum is the preferred specimen for the measurement of T4, but plasma with EDTA or heparin as anticoagulant has also been used. Plasma may form fibrin clots after freezing and thawing, however, and may produce spurious results in methods that are susceptible to changes in specimen viscosity. T4 is a stable analyte with no appreciable change in concentration for up to 7 days at room temperature, or 30 days when frozen.

16 Thyroxine [Tetraiodothyronine (T4)] Specimen Collection and Storage: Mild to moderate hemolysis and lipemia do not significantly affect most T4 immunoassays; Grossly hemolyzed specimens should be avoided because of dilutional effects. T4 autoantibodies interfere with some immunoassays and may produce erroneously low or high results, depending on the method.

17 Thyroxine [Tetraiodothyronine (T4)] Comments on Total T4 Measurements: Cord blood T4 concentrations are lower in preterm than in full-term neonates, and they correlate positively with birth weight in full-term infants. At birth, serum total T4 concentrations are higher in neonates because of the maternal estrogeninduced increase in serum TBG; free T4 concentrations are near adult concentrations. Total T4 rises abruptly in the first few hours after birth and declines gradually until adolescence. In males, T4 production declines as they mature sexually, but this phenomenon is not observed in females.

18 Triiodothyronine (T3) Specimen Collection and Storage Serum is the preferred specimen, but plasma with EDTA or heparin as anticoagulant may be used. Serum specimens should be tested within 24 hours of collection, or stored at 2 to 8 C if tested beyond 24 hours. Frozen specimens are stable for at least 30 days. Turbid samples may require centrifugation before testing

19 Measurement of Thyroxine-Binding Globulin (TBG) and Other Thyroid Hormone Binding Proteins Thyroxine-binding globulin (TBG): Estrogen-induced TBG excess and congenital TBG deficiency are the most significant TBG abnormalities that affect the interpretation of thyroid function test results.

20 Measurement of Thyroxine-Binding Globulin (TBG) Specimen Collection and Storage: Serum is the preferred specimen; plasma with EDTA or heparin as anticoagulant may also be used. Serum specimens are best stored at 2 to 8 C if they will not be tested within 24 hours. If longer periods of storage are necessary, freezing the specimens is recommended. Frozen specimens are stable for at least 30 days. Repeated freezing and thawing of the specimens should be avoided. Turbid samples should be centrifuged before testing.

21 Thyroglobulin Measurement The preferred specimen for Tg measurement is serum, but EDTA or heparinized plasma may also be used. If not tested within 24 hours, serum specimens are best stored at 2 to 8 C. If testing is delayed beyond a few days, the specimen should be frozen until it is analyzed. Frozen specimens are stable for at least 30 days. Repeated freeze-thaw cycles should be avoided. Turbid samples should be centrifuged before testing.

22 Drugs that influence thyroid function Drug that decrease TSH secretion Dopamine Glucocorticoids Ocreotide Drugs that decrease thyroid hormone secretion Lithium Iodide Amiodarone Drugs that increase thyroid hormone secretion Iodide Amiodarone

23 Drugs that influence thyroid function Drugs that decrease T4 absorption Colestipol Cholestyramine Aluminium hydroxide Ferrous sulphate Drugs that affect thyroid hormone transport Oestrogen Tamoxifen Heroin Methadone Androgens Glucocorticoids Salicylates Anabolic steroids

24 Drugs that influence thyroid function Drugs that increase hepatic metabolism of T4 and T3 Phenobarbitol Rifampicin Phenytoin Carbamazepine Decreased T4 5 -deiodinase activity Amiodarone Glucocorticoids Propylthoiuracil Beta-adrenergic antagonists

25 Interpretation of Thyroid Function Tests

26 GH

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28 BOUND FREE T % 60-75% TBG 10-25% TBPA 10%ALB T3 99.7% TBG 0.03% 0.3%

29 Hypothalamus TRH _ Pituitary TSH Inhibit responsiveness to TRH Thyroid Thyroxin

30 Thyroid Status Euthyroid Hyperthyroidism Hypothyroidism

31 Prevalence of Thyroid Dysfunction Condition Reported Prevalence in adult population % Hypothyroidism 2 Mild ( sub clinical ) Hypothyroidism 5 17 Hyperthyroidism 0.2 Mild ( sub clinical ) Hyperthyroidism

32 Common Symptoms & Signs Hypothyroidism Fatigue Weight gain Cold intolerance Skin dryness Depression Bradycardia Menstrual irregularity Infertility Hyperthyroidism Fatigue Weight loss Heat intolerance Hyperhydrosis Nervousness Tachicardia Menstrual irregularity

33 Diagnostic Criteria TT4 TT3 FT4 FT3 T-Uptake FTI THBR TSH TRH

34 FTI - THBR FTI T4 X Uptake % THBR Patient Uptake / Reference Uptake

35 Hyperthyroidism Decrease TSH Screening test Suppression level All patient diagnosed Exception : Thyroid neoplasm ( TSH secretion ) Ectopic secretion of TSH or TRH Thyroid Hormones Resistance Artifacts ( Autoantibody HAMA )

36 Which test should be used? In most situations use TSH as the sole test of thyroid function. It is the most sensitive test of thyroid function and adding other tests is only of value in specific circumstances. In normal patients, when the TSH is within the reference In normal patients, when the TSH is within the reference range, there is a 99% likelihood that the FT4 will also be within the reference range.

37 When is it inappropriate to test only TSH? Central (secondary) hypothyroidism - This is the most significant condition in which an incorrect diagnosis of euthyroidism could be made, based on TSH alone. Non compliance with replacement therapy Early stages of therapy - During the first 2 months of treatment for hypo- or hyper-thyroidism, patients will have unstable thyroid status because TSH will not have reached equilibrium. Acutely ill patients - TSH is altered independent of thyroid status. As a result, testing should only be performed when it is likely to have an effect on acute management. Pregnant patients on replacement

38 When is it inappropriate to test only TSH? Non compliance with replacement therapy - In hypothyroid patients suspected of intermittent use or non-adherence with their thyroxine replacement regimen, both TSH and FT4 should be used for monitoring. Non-adherence patients may exhibit discordant serum TSH and FT4 values (e.g. high TSH/high FT4) because of disequilibrium between TSH and FT4.

39 Hyperthyroidism Increase Total T4 Free T4 TT4 > 16 confirmative 10 % cases normal Two time T4 = 100 time TSH Increase T3 & Uptake Increase T3 & Uptake 85 % cases T3 > T4 Increased Increase FTI 90 % CASES

40 Hyperthyroidism Normal TBG Positive Anti Microsomal Antibody 5 % T3 Thyrotixicosis Factitious Hyperthyroidism Thyroid storm ( self induced) ( surgery- pre surgery -fever )

41 Hypothyroidism Increase TSH Minimum 2 maximum 10 time normal Important when T4 FTI is normal Increase TSH Decrease FT4 Diagnostic Increase TSH FT4 normal = Early Stage Decrease TT4 FT4 T4 > 7 almost certainly exclude hypothyroidism Decrease T3 ( % ) Decrease T Uptake ( 50% ) Decrease FTI Normal TBG

42 Normal TSH Exclude Hypothyroidism

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44 Pregnancy & Thyroid Tests Increase TBG Increase TT4 From 12 weeks to 6 weeks after delivery µg / dl is normal TT4 from 4 to 8 may be Hypothyroidism Increase TT3 Normal FT4 FT3

45 Pregnancy & Thyroid Tests Decrease T UP Increase T UP at 8 10 weeks = Hyperthyroidism Decrease 3 6 weeks to end first trimester then platue Normal weeks after delivery

46 Euthyroid Sick Syndrome Infection Liver Disease Cancer Kidney Disease Heart Failure Trauma Surgery

47 Primary Changes in all cases : Decrease T3 Decrease T4 Increase rt3 Increase or normal in ESS Decrease in Hypothyroidism

48 Euthyroid Sick Syndrome Primary Hypothyroidism Primary Hypothyroidism with illness T4 N / D D D T3 D N / D D FT4 I / N / D D D TSH N I N / I UPTAKE I D -

49 Clinical Condition TT4 THBR FTI Euthyroid N N N Hyperthyroid I I I Hypothyroid D D D Increase TBG I D N Decrease TBG D I N

50 Increase TT4 Hyperthyroidism Pregnancy Estrogen OPC Amphetamine Increase TBG Infant( 1 2 month ) TT4 > 20 True Hyperthyroidism rather than increase of TBG

51 Decrease TT4 Hypothyroidism Nephritis Cirrhosis Testosterone ACTH Corticosteroid Decrease TBG Stress

52 Increase TSH Cold Sleeping Stress Norepinephrin Dopamine Antagonists Hashimoto Disease 2 3 month

53 Decrease TSH Pregnancy ( first trimester ) Graves Disease Thyroiditis Dopamine Levodopa Glucocorticoids

54 Treatment Monitoring Hypothyroidism TSH T4 Hyperthyroidism Hyperthyroidism T4 TSH

55 Monitoring patients on thyroxine TSH is the most appropriate test when monitoring patients receiving thyroxine for the treatment of hypothyroidism. It should be measured no sooner than 6-8 weeks after the start of treatment. In the unusual situation where thyroid function needs to be assessed before this time, FT4 should be used

56 Monitoring patients on anti-thyroid drugs Following initiation of anti-thyroid medication, the TSH may remain suppressed for 3-6 months. It is recommended that thyroid function be monitored every 4 weeks using FT4 and TSH to adjust the dose until the TSH normalises and clinical symptoms have improved. Then the patient can be monitored every 2 months using TSH only.

57 When is it inappropriate to test only TSH? Early stages of therapy - During the first 2 months of treatment for hypo- or hyper-thyroidism, patients will have unstable thyroid status because TSH will not have reached equilibrium.

58 Range of tests available TSH - In most situations TSH analysed using a high sensitivity assay is now accepted as the first line test for assessment of thyroid function. A TSH between 0.4 and 4.0 miu/l gives 99% exclusion of hypo- or hyperthyroidism,12 while the TSH is considered more sensitive than FT4 to alterations of thyroid status in patients with primary thyroid disease. FT4 - This test measures the metabolically active, unbound portion of T4. Measurement of FT4 eliminates the majority of protein binding errors associated with measurement of the outdated total T4, in particular the effects of oestrogen. FT3 - FT3 has little specificity or sensitivity for diagnosing hypothyroidism and adds little diagnostic information. The main value of FT3 is in the evaluation of the 2 to 5% of patients who are clinically hyperthyroid, but have normal FT4. In this situation, an elevated FT3 would be suggestive of T3 toxicosis, in which the thyroid secretes increased amount of T3 or there is excessive conversion of T4 to T3. Thyroglobulin Levels are increased in all types of thyrotoxicosis, except thyrotoxicosis factita caused by self-administration of thyroid hormone. The main role for thyroglobulin is in the follow-up of thyroid cancer patients. After total thyroidectomy and radioablation, thyroglobulin levels should be undetectable; measurable levels (>1 to 2ng/mL) suggest incomplete ablation or recurrent cancer.

59 Sensitive TSH Undetectable Subnormal Normal Elevated Hyperthyroidism Borderline Thyroid Status Non Thyriod Dysfunction Hypothyroidism Free T4 T3 if FT4 Normal Free T4 FreeT3 No further Tests Free T4

60 Possible explanations for various result combinations High T4 Normal T4 Low T4 High TSH Irregular use of thyroxine Amiodarone Pituitary hyperthyroidism (TSHproducing pituitary tumour - rare) Thyroid hormone resistance (very rare) Subclinical hypothyroidism T4 under replacement Primary hypothyroidism Normal TSH As above Some drugs (steroids, betablockers, NSAIDS) Non-thyroidal illness T4 replacement (sometimes stablises with normal TSH and FT4) Normal Some drugs (anticonvulsants,anti-t3, anti-t4) Pituitary or hypothalamic hypothyroidism, Severe non-thyroidal illness Low TSH Primary hyperthyroidism Subclinical hyperthyroidism Subtle T4 over replacement Non-thyroidal illness Pituitary or hypothalamic hypothyroidism, Severe non-thyroidal illness

61 Limitations of thyroid function tests Thyroid function tests are measured by immunoassays that use specific antibodies and are subject to occasional interference. Results should be interpreted in the context of the clinical picture. If the laboratory results appear inconsistent with the clinical picture, communicate this to the laboratory and request the following checks: Confirm the specimen identity. Reanalyse the specimen using an alternative manufacturer s assay. Analyse the specimen for the presence of a heterophilic antibody. When you are unsure of the relevance of a particular result, a phone call to the pathologist can be extremely helpful.

62 GP and laboratory communication To provide a better outcome for the patient it is important there is open and clear communication between the GP and the laboratory. It is important the laboratory is aware of the following: - The clinical indication for testing - Any relevant drug treatments the patient may be taking Providing the laboratory with as much clinical information as possible allows the laboratory to provide a better service. Reflex tests can be added more appropriately, and abnormal or unexpected results can be investigated and interpreted more effectively.

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