1. Hypothyroidism Diagnosis and Management dr Pandji M,SpPD, KEMD,FINASIM

2. Definition : Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid hormone which in turn results in generalized slowing down of metabolic processes.

3. Etiology of Hypothyroidism Primary : 1. Hashimoto’s thyroiditis : a.With goiter b.“Idiopathic” thyroid atrophy, presumably end-stage auto- immune thyroid disease, following either Hashimoto’s thyroiditis or Graves’ disease c.Neonatal hypothyroidism due to placental transmision of TSH-R blocking antibodies. 2. Radioactive iodine therapy for Graves’ disease 3. Subtotal thyroidectomy for Graves’ disease or nodular goiter 4. Excessive iodide intake (kelp, radiocontrast dyes) 5. Subacute thyroiditis 6. Rare causes in the USA a.Iodide deficiency b.Other goitrogens (Adapted : Greenspan FS, 2001)

4. Secondary: Hypopituitarism due to Pituitary Adenoma Pituitary Ablative Therapy or Pituitary Destruction Tertiary : Hypothalamic Dysfunction ( rare ) Peripheral resistance to the action of thyroid hormone

5. Pharmacologic Hypothyroidism I.Thyroid Hormone Synthesis Inhibitor –Tionamide : MTU, PTU, Carbimazol –Perchlorat, Sulfonamid –Yodide (Expectoran, Amiodaron) –Lithium II.Thyroid Hormone Destruction –Phenitoin & Phenobarbital –Enterohepatic pathway inhibitor of thyroid hormone  Colestipol, Colestyramin

6. The Hypothalamic-Hypophysial-Thyroid Axis Hypothalamus TSH Thyroid T3T3T3T3 T3T3T3T3 T4T4T4T4 T3T3T3T3 T4T4T4T4 T4T4T4T4 Anteriorpituitary Tissue “Free” + + TRH Portal system

7. Grades of Hypothyroidism Individual and median values of thyroid function tests in patients with various grades of hypothyroidism. Discontinuous horizontal lines represent upper limit (TSH) and lower limit (FT4, T3) of the normal reference ranges. (Adapted : Greenspan FS, 2001) 20010040104.0 TSH mU/L FT 4 pmol/L 15129630 T 3 nmol/L 2.52.01.51.00.50 Subclinical Hypothyroldism Mild Hypothyroldism Overt Hypothyroldism

8. Pathogenesis Thyroid Hormones Synthesis of hyaluronate fibronectin and collagen by fibroblast Accumulation of glucosaminoglycans mostly hyaluronic acid in interstitial tissues Hydrophilic substance increase capillary permeability to albumin Interstitial edema Skin Many organs (heart muscle, striated muscle) (Wiersinga, 2004: The thyroid and its disease)

9. Hypothyroidism in adult (myxedema)

10. Physiologic Effect of Thyroid Hormone Tissue growth Brain maturity Heat production & Oxygen consumption Cardiovascular Sympathetic PulmonaryHematopoitic Gastrointestinal neuromuscular Skeletal Lipid & carbohydrate metabolism Endocrine THYROID

11. DIAGNOSIS HYPOTHYROIDISM

12. SubclinicalHypothyroidismSubclinicalHypothyroidismSecondaryHypothyroidismSecondaryHypothyroidism Clinical Hypothyroidism FT4TSHFT4TSH FT4 N TSH  FT4 N TSH  TRH Test PrimaryHypothyroidism FT4  TSH  FT4  TSH  FT4 N TSH N FT4 N TSH N FT4  TSH N/  FT4  TSH N/  PrimaryHypothyroidismPrimaryHypothyroidismNormalNormal FT4  TSH  FT4  TSH  FT4  TSH  FT4  TSH  NoResponseNoResponse TertiaryHypothyroidismSecondaryHypothyroidism

13. Management of Hypothyroidism Pay attention to : 1. Initial dosage of thyroxin 2. The way to increase thyroxin dosage

14. The Purpose of Hypothyroidism Treatment 1. To relief symptom and sign 2. To normalize metabolism 3. To normalize TSH, level but not supressed 4. To normalize T3 & T4 levels 5. Avoid risk and complications

15. Principles to conduct thyroxine replacement therapy 1. The more severe the disease, the lower the initial and the slower the increase dosage of thyroxine 2. The older the patients should more pay attention especially in cases of angina pectoris, congestive heart failure, cardiac arythmia

16. Thyroid Hormone available on the market: L-Thyroxin (T4)  Euthyrox L-Triiodothyronine (T3) Thyroid Extract The best is L-Thyroxin Should be taken before meals Dosage Recommendation : –L-T4 : 112 ug/d or 1,6 ug/kgB.W –L-T3 : 25-50 ug (RRJ : Djoko Moeljanto, 2002)

17. Starting dose of thyroxin There is no evidence base for determining how thyroxine therapy should be initiated, but it is customary to prescribe 50 ug daily, increasing to 100 ug daily after 3-4 weeks. Measurement of serum T4 and TSH at two months after starting will dictate any further adjustment of dosage. In the elderly, symptomatic ischemic heart disease, starting dose of 25 ug/d is advisable with increments of 25 ug/3-4 weeks. A full replacement dose of 100-150 ug/d. (Toff AD, 2001; Thyroid International)

18. The TSH level can be used as a guideline to establish the substitution dosage of thyroxin TSH levelThyroxin 20 uU/ml50-75 ug/d 44-75 uU/ml100-150 ug/d 90% Hypothyroidism cases used LT4100-200ug (RRJ : Djoko Moeljanto, 2002)

19. Variation in dosage of thyroxin Once thyroxin therapy is established it is good practice to review patients annually and measure serum TSH not only to ensure compliance but also to determine whether and adjustment of dose is required.

20. Situation in which an adjustment of the dose of thyroxine may be necessary Increased dose required Use of other medication Phenobarbitone Phenytoin Carbamazepineincreased thyroxine clearance Rifampicin *Sertraline *Chloroquine Cholestyramine Sucralfate Aluminium hydroxideinterference with intestinal Ferrous sulphateabsorption Dietary fibre supplements Pregnancyincreased concentration of serum Oestrogen therapythyroxine-binding globulin After surgical or iodine-131reduced thyroidal secretion ablation of Graves’ diseasewith time Malabsorption e.g. coelic disease Decreased dose required Agingdecreased thyroxine clearance Graves’ disease developingswitch from production of blocking in patient with long-standingto stimulating TSH-receptor anti- primary hypothyroidishbodies * mechanism not fully established (Adapted : Toff AD, 2001)

21. Suggested management of patients taking thyroxine replacement therapy, depending upon pattern of thyroid function test results and clinical symptoms TSHT4T3SymptomsAction normalnormal ornormalnonenone raised normalnormal ornormalpresent  increase thyroxine by 25-50  g daily raiseduntil serum TSH is suppressed but ensure T3 unequivocally normal < 0.05 mU/lnormal ornormalnonenone raised < 0.05 mU/lnormal ornormalyes*reduce thyroxine by 25-50  g daily raisedto restore normal TSH < 0.05 mU/lnormal orhigh normalyes* or noreduce thyroxine by 25-50  g daily raisedor raisedto restore unequivocally normal T3  Symptoms of possible undertreatment might include tiredness and weight gain * Symptoms of possible overtreatment might include unexplained atrial fibrillation and reduced bone mineral density (Adapted : Toff AD, 2001)

22. Summary Some basic principles to remember that active hormone is free hormone. Cells metabolism are based on FT3 not FT4 Diagnosis established by symptom, sign, FT4 and TSH Should be careful to start and increase the dosage of thyroxine especially in case of angina pectoris,CHF,arythmia Drug of choice is L-thyroxine Target of treatment is normal TSH level