Gangguan Fungsi Tiroid

Oleh :Eli Halimah

FUNGSIFungsi Kelenjar Tiroid :Pengikat IodidaSintesis hormon tiroidPenyimpanan hormon tiroid

Fungsi Hormon Tiroid :Mengatur kecepatan metabolisme tubuhMengatur produksi panasMengatur pelepasan energi dalam ototMengatur pertumbuhan dan diferensiasi

Structure of the thyroid follicle

The Thyroid Produces and Secretes 2 Metabolic HormonesTwo principal hormonesThyroxine (T4 ) and triiodothyronine (T3)Required for homeostasis of all cellsInfluence cell differentiation, growth, and metabolismConsidered the major metabolic hormones because they target virtually every tissue

Thyroid-StimulatingHormone (TSH)Regulates thyroid hormone production, secretion, and growth

Is regulated by the negative feedback action of T4 and T3

Biosynthesis of T4 and T3The process includesDietary iodine (I) ingestionActive transport and uptake of iodide (I) by thyroid glandOxidation of I- and iodination of thyroglobulin (Tg) tyrosine residues Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3 Proteolysis of Tg with release of T4 and T3 into the circulation

Iodine SourcesAvailable through certain foods (eg, seafood, bread, dairy products), iodized salt, or dietary supplements, as a trace mineral

The recommended minimum intake is 150 g/day

Sintesis Hormon Tiroid

Thyroxine (T4)THYROID HORMONES

FEEDBACK REGULATIONTHE HYPOTHALAMIC-PITUITARY-THYROID AXISHormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones.Key players for the thyroid include:TRH - Thyrophin Releasing HormoneTSH - Thyroid Stimulating HormoneT4/T3 - Thyroid hormones

PITUITARY-THYROID AXISHM Goodman, BASIC MEDICAL ENDOCRINOLOGY 3rd Ed.+

Mekanisme Pengaturan Tiroid

Hypothalamic-Pituitary-Thyroid AxisNegative Feedback Mechanism

TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP.

TSH increases metabolic activity that is required to synthesize Thyroglobulin (Tg) and generate peroxide.

TSH stimulates both I- uptake and iodination of tyrosine resides on Tg.TSH REGULATION OF THYROID FUNCTION

ION TRANSPORT BY THETHYROID FOLLICULAR CELLI-I-COLLOIDBLOOD

COLLOIDTHYROGLOBULIN SYNTHESIS IN THETHYROID FOLLICULAR CELL

THYROID HORMONE SECRETION BY THE THYROID FOLLICULAR CELLCOLLOID

THYROID HORMONES IN THE BLOODApproximately 99.98% of T4 is bound to 3 serum proteins: Thyroid binding globulin (TBG) ~75%; Thyroid binding prealbumin (TBPA or transthyretin) 15-20%; albumin ~5-10%

Only ~0.02% of the total T4 in blood is unbound or free.Only ~0.4% of total T3 in blood is free.

BASICS OF THYROID HORMONE ACTION IN THE CELL

SPECIFIC ACTIONS OF THYROID HORMONE: METABOLICRegulates of Basal Metabolic Rate (BMR).Increases oxygen consumption in most target tissues.Permissive actions: TH increases sensitivity of target tissues to catecholamines, thereby elevating lipolysis, glycogenolysis, and gluconeogenesis.

TH is critical for normal development of the skeletal system and musculature.

TH is also essential for normal brain development and regulates synaptogenesis, neuronal integration, myelination and cell migration.

Cretinism is the term for the constellation of defects resulting from untreated neonatal hypothyroidism.SPECIFIC ACTIONS OF THYROID HORMONE: DEVELOPMENT

Risk factors for thyroid disease

personal history of thyroid diseasestrong family history of thyroid disease diagnosis of autoimmune diseasepast history of neck irradiation drug therapies such as lithium and amiodarone women over age 50 elderly patientswomen 6 weeks to 6 months post-partum

Signs/Symptoms

HypothyroidismHyperthyroidismWeight gainHair lossLethargyMenstrual irregularities (menorrhagia)Cognitive impairmentDepressionConstipationGoitreDry skinCold intolerance

Weight lossHair lossPalpitations / Tachycardia / Atrial fibrillationMenstrual irregularities (amenorrhea/oligomenorrhea)Widened pulse pressureNervousness and tremorMuscular weaknessGoitreHeat intolerance, diaphoresis, clammy handsHypertension

Causes of high thyroid-stimulating hormone (TSH)HypothyroidismRecovery from severe illnessPituitary excess due to pituitary tumours causing secondary hyperthyroidism (very rare)

Causes of low thyroid-stimulating hormone (TSH)1. Hyperthyroid Statea. Both T3 and T4 elevatedGraves' diseaseToxic multinodular goiterb. Only T3 elevated with normal T4T3 toxicosis (e.g. Autonomous nodule)Exogenous T3 ingestions (liothyronine)c. Only T4 elevated with normal T3Hyperthyroidism patient with nausea, vomiting and starvation causing decreased conversion of T4 to T32. Hypothyroid StatePituitary or hypothalamic disease (both T4 and T3 low)3. Euthyroid StateSick euthyroid (both T3, T4 low, rT3* elevated)Drugs such as glucocorticoids, octreotide, and dopamine

TSHLowHighFT4FT4 & FT3Low1 HypothyroidLowCentral HypothyroidTRH Stim.IfequivocalMRI, etc.High1 ThyrotoxicosisHigh2 thyrotoxicosisEndo consultFT3, rT3MRI, -SURAIU

A) 1 HypothyroidismB) Central HypothyroidismC) EuthyroidD) 1 Thyrotoxicosis

Thyroid Function TestsTSH 0.4 5.0 mU/L

Free T4 (thyroxine) 9.1 23.8 pM

Free T3 (triiodothyronine) 2.23-5.3 pM

HypothyroidismHypothyroidism is a disorder with multiplecauses in which the thyroid fails to secrete an adequate amount of thyroid hormone

The most common thyroid disorder Usually caused by primary thyroid gland failureAlso may result from diminished stimulation of the thyroid gland by TSH

HyperthyroidismHyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues

Typical Thyroid Hormone Levels in Thyroid Disease TSH T4 T3Hypothyroidism High Low LowHyperthyroidism Low High High

www.hsc.missouri.edu/~daveg/thyroid/thy_dis.html EXAMPLES OF THYROID DISEASES1 HypothyroidismHyperthyroidism

EXAMPLES OF THYROID DISEASESCongenital HypothyroidismJuvenile Hypothyroidism

******The Thyroid Produces and Secretes 2 Metabolic Hormones.Triiodothyronine (T3) and tetraiodothyronine1 (or thyroxine, T4) are the 2 principal hormones of the thyroid gland.2 Chemically, they are iodothyronine hormones iodine-containing amino acid derivatives of thyronine.2 They are the only known iodine-containing compounds with biological activity.1,2 Often referred to as the major metabolic hormones,3 the 2 thyroid hormones have profound effects on essential physiologic processes.1,3References1. De La Vieja D, et al. Physiol Rev. 2000;80:1083-1105.2. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1383. 3. Kirsten D. Neonatal Netw. 2000;19:11-26

*Thyroid-Stimulating Hormone (TSH).Thyroid stimulating hormone (TSH; also called thyrotropin), a glycoprotein hormone with and subunits, is secreted by the anterior pituitary gland.1,2 Thyroid stimulating hormone is inhibited by thyroid hormone in a classic endocrine negative feedback loop.2 Its synthesis and release is stimulated by thyrotropin-releasing hormone (TRH), which is the major positive regulator of TSH secretion.3 TSH is the major regulator of the thyroid gland.4 Physiological roles of TSH include stimulation of various thyroid functions, eg, iodine uptake and organification, production and release of thyroid hormone from the gland, and promotion of thyroid growth.2,5 TSH-cyclic adenosine monophosphate (cAMP) is the prime regulator of iodide uptake and concentration and T3/T4 formation.6 TSH-cAMP induces the expression and activation of the 3 necessary genes encoding proteins involved in iodide uptake and thyroid hormone formation: the sodium-iodide symporter (NIS), thyroglobulin (Tg), and thyroperoxidase (TPO).6 References1. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1390.2. Grossman M, et al. Endocr Rev. 1997;18:476-501.3. Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:208.4. Nillni EA, et al. Endocr Rev. 1999;20:599-648.5. Grossman M, et al. Mol Endocrinol. 1995;9:948-958.6. Kohn LD, et al. Trends Endocrinol Metab. 2001;12:10-16.

*Biosynthesis of T4 and T3.The major steps in the synthesis, storage, and release of thyroid hormones are: ingestion of iodine with the diet; active transport and uptake of iodide ion (I-) by the thyroid gland; the oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin (Tg); coupling of iodotyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) to generate iodothyronines; storage of iodinated Tg containing MIT, DIT, T4 and T3; and the proteolysis of Tg and the release of T4 and T 3 into the blood.1,2References Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1385. 2. Medeiros-Neto G, et al. Endocr Rev. 1993;14:165-183.

*Iodine Sources.Because of the scarcity and uneven distribution of iodine in the environment, the structure of the thyroid gland is adapted to collect and store this element in order to provide a continuous supply of thyroid hormone throughout life.1 The iodine ingested with the diet is the only source for this critical component of the thyroid hormones, but thyroid function largely depends on an adequate supply of iodine to the thyroid gland.2 Iodine is a trace element present in the human body in very small amounts (15 to 20 mg).2 The only role iodine has in the body is in the synthesis of thyroid hormones. If severe enough, iodine deficiency will impair thyroid hormonogenesis.2 The recommended daily dietary allowance (intake) of iodine for children and adults (except pregnant or lactating women) is 150 g.3References1. Nilsson M. Biofactors. 1999;10(2-3):277-85.2. Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:52, 295.3. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1549.

******Hypothalamic-Pituitary-Thyroid Axis Negative Feedback Mechanism.In this negative-feedback system, increasing levels of circulating thyroid hormone inhibit the synthesis of TSH directly at the pituitary level and indirectly at the level of the hypothalamus by reducing the secretion of TRH.1,2 TRH is the major regulator of the synthesis and secretion of TSH, and therefore it plays a central role in regulating the hypothalamic-pituitary-thyroid (HPT) axis.3 Thyroid hormone can negatively regulate TSH transcription by direct and indirect mechanisms, and can negatively regulate TRH at the transcriptional level,1,4 decreasing transcription of TSH mRNA.4References Braverman LE, Utiger RD, eds. Werner & Ingbars The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:206-207.2. Dahl GE, et al. Endocrinology. 1994;135:2392-2397.3. Nillni EA, et al. Endocr Rev. 1999;20:599-648.4. Yen PM. Physiol Rev. 2001;81:1097-1142.

********************Hypothyroidism.Hypothyroidism, known as myxedema when severe, is the most common disorder of thyroid function.1 Most cases of hypothyroidism fall under the category of primary hypothyroidism, in which the thyroid fails to produce sufficient thyroid hormone.1 More infrequently, hypothyroidism is caused by decreased thyroidal stimulation by TSH, which is termed central, hypothyrotropic, or secondary hypothyroidism.2References1. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1394.2. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:719.*Hyperthyroidism.The term hyperthyroidism is restricted to those conditions in which thyroid hormones are excessively released as a result of gland overactivity.1,2 Iodine uptake by the gland is increased1 and there can be excessive production of body heat, increased motor activity, and increased activity of the sympathetic nervous system.2 References Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill; 1996:1393-1394. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:515-516.

*Typical Thyroid Hormone Levels in Thyroid Disease.Measurement of the total plasma hormone concentration may not provide an accurate assessment of thyroid gland activity because total hormone concentration is affected by changes in either the amount of thyroxine-binding globulin (TBG) or the affinity of hormones to TBG in plasma.1 For more than 25 years, TSH methods have been able to detect the elevations in TSH that typify hypothyroidism.2 In the past 10 years, the sensitivity of TSH assays has increased to the extent that TSH measurement is now recognized as a more sensitive test than FT4 for detecting both hypo- and hyperthyroidism.2 However, some patients may be incorrectly or incompletely diagnosed if only TSH is measured.3 If serum TSH is high, serum FT4 should be measured to distinguish between mild thyroid failure and overt hypothyroidism.3 If serum TSH is low, both serum FT4 and FT3 should be assayed to identify overt thyrotoxicosis and T3 thyrotoxicosis.3References1. Hardman JG, Limbird LE, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw Hill;1996:1394.2. Thyroid. 2003;13:33-44.3. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:379.

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