2THYROID GLAND Location 12 to 20 g in size In neck, anterior to trachea Between cricoid cartilage and suprasternal notchHighly vascular and soft in consistency.
3THYROID GLAND Consists of two lobes Connected by an isthmus 4 parathyroid glandsPosterior region of each poleLaryngeal nerves traverse lateral borders of gland
4Secretions Produces two related hormones Thyroxine (T4) Triiodothyronine (T3)
5Action Play a critical role in Cell differentiation during development Help to maintain thermogenic and metabolic homeostasis in adult.Act through nuclear hormone receptors to modulate gene expression
6Regulation of thyroid hormone synthesis T4 and T3 feed back to inhibitHypothalamic production of thyrotropin-releasing hormone (TRH)Pituitary production of thyroid-stimulating hormone (TSH)
7TSH-R, thyroid-stimulating hormone receptor, Tg- thyroglobulin NIS - sodium-iodide symporter; TPO- thyroid peroxidase DIT - di-iodotyrosine; MIT - monoiodotyrosine
8Thyroid Hormone Synthesis Thyroid hormones are derived from thyroglobulinLarge iodinated glycoproteinAfter secretion into the thyroid follicleTg is iodinated on selected tyrosine residues that are subsequently coupled via an ether linkageReuptake of Tg into thyroid follicular cell allows proteolysis and the release of T4 and T3.
9Iodine Metabolism and Transport Iodide uptake is a critical first step in thyroid hormone synthesisIngested iodine is bound to serum proteins (particularly albumin)Unbound iodine is excreted in urineIodine extracts from circulation in a highly efficient manner10 to 25% of radioactive tracer (e.g., 123I) is taken up by the normal thyroid gland over 24 h; this value can rise to 70 to 90% in Graves' disease.
10Na+/I- symporter (NIS) Mediate Iodide uptakeExpressed at basolateral membrane of thyroid follicular cells.ExpressedMost highly in thyroid glandLow levels in salivary glands, lactating breast, placentaLow I2 levels increase amount of NIS & stimulate uptakeHigh I2 levels suppress NIS expression & uptake
11Selective expression of NIS in thyroid allows Treatment of hyperthyroidismIsotopic scanningAbolition of thyroid cancer with radioisotopes of iodineWithout significant effects on other organsMutation of the NIS gene is a rare cause of congenital hypothyroidism
12Oranification Iodide enters thyroid Trapped and transported to apical membrane of thyroid follicular cells Oxidized in an organification reaction (Tyroid PerOxidase & H2O2 )
13CouplingReactive iodine atom is added to selected tyrosyl residues within TyroglobulinIodotyrosines in Tg are then coupled via an ether linkage in a reaction Catalyzed by TPOEither T4 or T3 can be produced by this reactionDepending on number of iodine atoms present in iodotyrosines.
14Storage, Release After coupling, Tg is taken back into thyroid cell It is processed in lysosomes to release T4 and T3Uncoupled mono- and diiodotyrosines (MIT, DIT) are deiodinated by enzyme dehalogenaseRecycling any iodide that is not converted into thyroid hormones
15Factors Influence Synthesis and Release TSH is the dominant hormonal regulator of thyroid gland growth and functionVariety of growth factors, most produced locally in thyroid gland, also influence synthesisInsulin-like growth factor I (IGF-IEpidermal growth factorTransforming growth factor β (TGF- β)EndothelinsVarious cytokines.
16Disorders of thyroid hormone synthesis Rare causes of congenital hypothyroidismMajority of disorders due to recessive mutations in TPO or TgDefects also identified inTSH-RNISPendrin anion transporterTransports I2 from cytoplasm to follicle lumenH2O2 generationDehalogenase
17Biosynthetic defect of thyroid hormone Inadequate amounts of hormone Increased TSH synthesis Goiter
18Transport And Metabolism T4 is secreted from the thyroid gland in at least 20-fold excess over T3Both circulate bound to plasma proteinsThyroxine-binding globulin (TBG)Transthyretin (TTR), formerly known as thyroxine-binding prealbumin (TBPA)Albumin
19Functions of serum-binding proteins Increase pool of circulating hormoneDelay hormone clearanceModulate hormone delivery to selected tissue sites
20Con. of TBG is relatively low (1 to 2 mg/dL) High affinity for thyroid hormones (T4 > T3), it carries about 80% of bound hormonesAlbumin has relatively low affinity for thyroid hormones (high plasma con ~3.5 g/dL)It binds up to 10% of T4 and 30% of T3.TTR carries about 10% of T4 but little T3.
21≈ 99.98% of T4 and 99.7% of T3 are protein-bound T3 is less tightly bound than T4Amount of free T3 > free T4Unbound (free) consT4 ~2 ´ MT3 ~6 ´ M
23DeiodinasesIn many respects, T4 may be thought of as a precursor for more potent T3T4 is converted to T3 by the deiodinase enzymesType I deiodinaseLocated primarily in thyroid, liver, kidneyHas a relatively low affinity for T4Type II deiodinaseHigher affinity for T4Found primarily in pituitary gland, brain, brown fat, thyroid gland
25T4 - T3 conversion may be impaired by FastingAcute traumaOral contraseptive agentsPropylthiouracilPropranololAmiodaroneGlucocorticoids
26THYROID HORMONE ACTION Act by binding to nuclear receptors, termed thyroid hormone receptors (TRs) ά and βBoth ά and β are expressed in most tissuesBoth receptors are variably spliced to form unique isoforms
27Thyroid hormone receptors ά Highly expressed inBrainKidneyGonadsMuscleHeartTR ά 2 isoform contains a unique carboxy terminus that prevents thyroid hormone bindingIt may function to block actions of other TR isoforms
28Thyroid hormone receptors β Highly expressed inPituitaryLiverTR β 2 isoformHas a unique amino terminusSelectively expressed in hypothalamus & pituitaryPlay a role in feedback control of thyroid axis
29(1) T4 or T3 enters the nucleus (2) T3 binding dissociates CoR from TR (3) Coactivators (CoA) are recruited to the T3-bound receptor (4) gene expression is altered
30Thyroid Hormone Resistance (RTH) An autosomal dominant disorder characterized byElevated free thyroid hormone levelsInappropriately normal or elevated TSHIndividuals with RTH (in general) do not exhibit signs and symptoms that are typical of hypothyroidismApparently hormone resistance is compensated by increased levels of thyroid hormone
31HYPOTHYROIDISMWorldwide most common cause of hypothyroidism - Iodine deficiencyOther causesAutoimmune disease (Hashimoto's thyroiditis)Iatrogenic causes (treatment of hyperthyroidism)
32Treatment T4 - 10 to 15 ug/kg/ day Dose adjusted by close monitoring of TSH levelsT4 requirements- relatively great during first year of lifeHigh circulating T4 level is usually needed to normalize TSHEarly treatment with T4 results in normal IQ levels
33Hyperthyroidism Excessive thyroid function Thyrotoxicosis State of thyroid hormone excessMajor etiologies of thyrotoxicosisHyperthyroidism caused by Graves' diseaseToxic multinodular goiterToxic adenomas
34TreatmentHyperthyroidism of Graves' disease is treated by reducing thyroid hormone synthesisAntithyroid drugsReducing the amount of thyroid tissue with radioiodine (131I)Subtotal thyroidectomyNo single approach is optimal and that patients may require multiple treatments to achieve remission.Antithyroid drugs are the predominant therapy in many centers in Europe and JapanRadioiodine is more often the first line of treatment in North America
35ANTITHYROID DRUGS (Drugs used in hyperthyroidism) Thioamides (reduce the synthesis of thyroid hoemones)CarbimazoleMethimazolePropylthiouraciliodideRadioactive iodine (I131)Iodide ( high doses)Ionic inhibitors (inhibit iodide uptake) - use is obsolete due to toxicityThiocyanatesPerchloratesNitratesPropranolol - Adjunct therapy in thyrotoxicosis
36Thioamides Mechanism Clinical use reduce the synthesis of thyroid hormones by inhibiting iodination of tyrosine and coupling of iodotyrosine to form T3 and T4Clinical useCarbimazoleGraves disease-till remission of symptoms (30-60mg) maintenance dose(5-15mg)Propylthiouracil ( mg/d orally) maintenance dose ( mg/d)Nodular toxic goiterPrior to surgery for hyperthyroidismWith radioactive iodine to decrease symptoms before radiation effects are manifestedAdverse effectsHypothyroidismVasculitis, agranulocytosis, HypoprothrombinaemiaCholestatic jaundiceHair pigmentation
37Iodides Mechanism Clinical use Selectively trapped by the thyroid gland (uptake being increased in hyperthyroidism and reduced in hypothyroidism).Large doses inhibit secretion of thyroid hormones by inhibition of thyroglobulin proteolysisInduce involution and decrease vascularity of the gland.Clinical usePreoperative use in thyroid surgery(Potassium iodide, 60 mg orally thrice daily)Thyroid crisisAccidental over dosage of radioactive iodine (to protect the thyroid follicles)Prophylactic use in endemic goiter. Added to salt (1 in 100,000 parts )as iodized salts.As an expectorant, antiseptic for topical use
39Adverse reactionsAcute hypersensitivity reactions (angioneurotic oedema, skin haemorrage, drug fever)salivation, lacrimation, soreness of throat, conjunctivitis, coryza-like symptoms, skin rashesFoetal or neonatal goiter
40Radiioactive iodine Mechanism of action Trapped by the thyroid follicles and incorporated intothyroglobulinEmits both beta and gamma rays(half-life 8 days)Beta rays - short range and act on thyroid tissue onlyThe gamma rays are more penetrative and can bedetected by Gieger counter for diagnostic use.
41Clinical Use Radioactive sodium iodide (5-8 m curie) orally. Grave’s disease, including relapse after subtotalthyroidectomy.Toxic nodular goiterThyroid carcinomaDiagnosis of thyroid function micro curie is administered.best in patients over 35 years and in the presence of cardiac diseaseClinical response is slow and may take 6-12 weeks for suppression of hyperthyroid symdrome
42Effects of drugs on thyroid functions Dopamine, l-dopa, corticosteroids, somatostatinInhibition of TRH and TSH secretion.Iodides, lithium.Inhibition of thyroxine synthesis, and hypothyroidismCholestyramine, colestipol, sucralfate, aluminium saltsInhibit thyroxine absorption from gutPhenytoin, carbamazepine, rifampicin, phenobarbitoneEnzyme induction. May enhance T3 and T4 metabolismPropylthiouracil, amiodaroneInhibit conversion of T4 to T3corticosteroids, beta-blockers Androgens, glucocorticoids,Decrease thyroxine-binding globulinOestrogens, tamoxifen, mitotaneIncrease thyroxine-binding globulinSalicylates, mefenamic acid, furosemideDisplace T3 and T4 from thyroxine –binding globulin.