Thyroid hormone effect and mechanism of actionPresentation Transcript
O Acts by binding to a specific nuclear thyroidhormone receptor (TR).O T3 has a 15-fold higher binding affinity for TRs thandoes T4.O The hormone-receptor complex binds to DNA viazinc fingers and increases/decreases theexpression of a variety of different genes thatcode for proteins that regulate cell function.O In humans, there are two TR genes, α and β.O By alternative splicing, each forms at least twodifferent mRNAs and therefore two differentreceptor proteins.
Schematic diagram of thyroid hormone mechanism of action.The interaction of T3 with the TR that is bound as a heterodimer withretinoid X receptor (RXR) to the thyroid hormone response element(TRE), often in the 5′ flanking region of a T3-responsive gene, causeseither an increase or a decrease in the transcription of that gene.coactivator proteinscorepressor proteins
O The active proteins are TRα1, TRβ1, TRβ2, andTRβ3.O There are tissue-specific preferences inexpression of the various TRs.O TRβ2 is found only in the brainO TRα, particularly TRα2, is thought to be important in thehypothalamus and pituitary.O TRα1 is expressed in all tissues, although its mRNA isespecially highly expressed in the kidney, liver.O TRβ3 mRNA is expressed at very low levels but is moreabundant in the liver, kidneys, and lungs than in othertissues.
O Experiments with inactivation of TRα and TRβhave illuminated their different physiologic rolesO Feedback regulation of thyroid hormone effectsand cochlear development are functions of TRβ.O Cardiac function and energy metabolism aremore likely to be regulated by TRα.βββ ββ
Calorigenic ActionO T4 and T3 increase the O2 consumption of almostall metabolically active tissues.O Some of the calorigenic effect of thyroidhormones is due to metabolism of the fatty acidsthey mobilize.O Thyroid hormones increase the activity of themembrane-bound Na, K ATPase in many tissuesO The resulting increased metabolic rate increasesthermogenesis.O Most of the effect of thyroid hormone aresecondary to its calorigenic effects.
Effects Secondary to CalorigenesisO Increase in metabolic rate by T4 and T3 inpharmacological dose increases N2 excretion; iffood intake is not increased, endogenous proteinand fat stores are catabolized and weight is lost.(Catabolic action)O In small doses causes positive N2 balance andstimulate growth (Anabolic action).O Excess catabolic effect along with markedcreatinuria leads to muscle fatiguability(Thyrotoxic Myopathy)
O The potassium liberated during proteincatabolism appears in the urine, and there is alsoan increase in urinary hexosamine and uric acidexcretionO Bone protein mobilization Osteoporosis,hypercalcemia and subsequent hypercalciuria.O Hypothyroidism protein catabolismaccumulation of osmotically activeproteinconjugates under skin/subcutaneous tissuecoarse puffy skin (Myxoedema)
O Increased BMR increased use of co-factors and vitamins Vitamin deficiencyin hyperthyroid state.O Thyroid hormone is necessary for hepaticconversion of β carotene to vitamin A.O Decreased thyroid hormone increasedaccumulation of β carotene in blood(Carotenemia)yellowish discoloration of skin.
Typical appearance ofpatients with moderatelysevere primaryhypothyroidism ormyxedema.CarotenemiaversusJaundice
O T4 is essential for maintenance of lactation.O Milk secretion is decreased in hypothyroidism andstimulated by thyroid hormones.O Thyroid hormone is involved in gonadaldevelopment and secondary sexualcharacteristics.O In adult women, severe hypothyroidism may beassociated with diminished libido and failure ofovulation.O Secretion of progesterone is inadequate, andendometrial proliferation persists, resulting inexcessive and irregular breakthrough menstrualbleeding.
O In hyperthyroidism menstrual flow is initiallydiminished and ultimately ceases reducingfertility.O Likely mechanism for menstrual changes:O disruption in amplitude and frequency of LH/FSHpulses caused by thyroid hormone influences onGnRH signaling..O “spillover” of elevated TSH stimulating the luteinizinghormone (LH) receptor48 and elevated TRH initiatingexcess prolactin release.O A significant fraction of men with hypothyroidismor hyperthyroidism have moderate to severeerectile dysfunction that improves with treatmentof the thyroid disease
Effects on the Cardiovascular System
O Circulatory T3 enters the myocytes, combines with itsreceptors, and enters the nucleus, where it promotesthe expression of some genes and inhibits theexpression of others.O Those that are enhanced include the genes for a -myosin heavy chain, sarcoplasmic reticulum Ca2+ATPase, b-adrenergic receptors, G proteins, Na-KATPase, and certain K+ channels.O Those that are inhibited include the genes for b-myosin heavy chain, phospholamban, adenylylcyclase, T3 nuclear receptors, and NCX, the Na+–Ca2+ exchanger.O The net result is increased heart rate and force ofcontraction
O The myosin containing β-MHC has less ATPaseactivity than the myosin containing α -MHC.O α -MHC predominates in the atria in adults, andits level is increased by treatment with thyroidhormone. This increases the speed of cardiaccontraction.O Conversely, expression of the α -MHC gene isdepressed and that of the β -MHC gene isenhanced in hypothyroidism.
Effects on the Nervous SystemO Thyroid hormone is essential for the development ofthe central nervous system.O T4 deficiency in fetus or in infants causes:O Defective myelination of axons of cortical regionO Defective branching of dendrites leading to defectivesynapsesO Marked reduction in vascularity of brainNet Result Infantile brain/mental retardationO Thyroid hormone therapy must be given to a thyroidhormone-deficient child during the first few months ofpostnatal life to prevent mental retardation.(criticalperiod- 1 year of life)
O The parts of the central nervous system (CNS) mostaffected are the cerebral cortex, the basal ganglia andthe cochlea .(mental retardation, motor rigidity, anddeafness).O T4 deficiency in adults cause:O Loss of all intellectual functionO Memory lossO Decrease electrical activity of brainO Slow, delayed and husky voiceO Eventually Psychosis (MyxoedemaMadness)O T4 excess increases response tocatecholamines and stimulation of RASanxiety, nervousness, irritability, insomnia , rythmictremors etc
Effects on growth and developmentO Thyroid hormone is essential for normal growth andmaturation of the skeleton.O Growth failure in thyroid deficiency is caused byimpaired general protein synthesis, reduced growthhormone, and especially reduced insulin-like growthfactor 1.O A major way thyroid hormones promote normal bodygrowth is by stimulating the expression of the genefor growth hormone (GH) in the somatotrophs of theanterior pituitary gland.
O Impairment of linear growth leads to dwarfism(cretinism) in which the limbs are disproportionatelyshort in relation to the trunk but cartilage growth isunaffected.O Children with prolonged hypothyroidism, even afteradequate treatment, do not reach predicted heightThe consequences of untreatedcongenital hypothyroidism aredemonstrated in this 17-year-oldgirl.Her tongue is enlarged, and herextremities are inappropriately shortin relation to her trunk.
Effect on carbohydrate metabolismO Dual and opposite effectsO Increases peripheral utilization of glucose cancause hypoglycemiaO Can also cause hyperglycemia by :O Increase absorption from GI tractO Increase glycogenolysis in the liverO Increase gluconeogenesis from pyruvateO Increase breakdown of insulinO Decrese secretion of insulinO In hyperthyroidism, therefore, the plasma glucoselevel rises rapidly after a carbohydrate meal,sometimes exceeding the renal threshold.
Effects on lipid metabolismO Thyroid hormones lower circulating cholesterol levels.O The decrease in plasma cholesterol concentration isdue to increased formation of low-density lipoprotein(LDL) receptors in the liver, resulting in increasedhepatic removal of cholesterol from the circulation.O Thyroid decreases the stores of triglycerides andphospholipids by increasing the activity of lipases i.eincreasing lipolysisO Dextro –thyroxine (D-T4) and TETRAC are usedclinically as serum cholestrol lowering agents inatherosclerosis
Effects on Hematopoietic SystemO T4 deficiency leads to anaemia due to:O In response to the diminished oxygen requirements anddecreased production of erythropoietin causing mildnormocytic, normochromic anemia.O Decreased absorption ov vitamin B12,Folate deficiency frommalabsorption or dietary inadequacy may cause macrocyticanemia.O The frequent menorrhagia and the defective absorption of ironresulting from achlorhydria may contribute to a microcytic,hypochromic anemia.O T4 excess stimulates erythropoiesis,increase production of2,3 DPG in RBC shifting O2 dissociation curve to right.O A parallel increase in plasma volume also occurs, with theresult that the hematocrit is normal.
Relation to CatecholaminesO The actions of thyroid hormones and thecatecholamines norepinephrine and epinephrine areintimately interrelated.O The functional synergism observed betweencatecholamines and thyroid hormones,arises from theability of thyroid hormones to increase expression ofcatecholamine receptors and the signaling effectors towhich they are linked.O The reduced adrenergic responsiveness associated withhypothyroidism has been linked to all steps ofcatecholamine signaling, including receptor andpostreceptor actions, resulting in an impaired cAMPresponse.
Catecholamines T4• Epinephrine and nor epinephrineincreases BMR,stimulatesCNS,increases heart rate andforce of contraction• T4 also has the same action butis prolonged and slow• Cannot increase BMR in absenceof T4• T4 potentiate the action ofcatecholamine and in theirpresence increase in BMR by T4is more• Cause stimulation of ReticularActivating System• Same effect but :T4 action on CNS and CVS canbe decreased aftersympathectomyor by β blockers
HypothyroidismO Reduced circulating levels of free T4 and T3.O The syndrome of adult hypothyroidism is generallycalled myxedema.O Children who are hypothyroid from birth or before arecalled cretins.O Hypothyroidism may be the end result of a number ofdiseases of the thyroid gland, or it may be secondaryto pituitary or hypothalamic failure.O Treatment is almost always with levothyroxine
Causes of HypothyroidismPrimary HypothyroidismAcquired• Hashimoto’s thyroiditis• Iodine deficiency (endemic goiter)• Drugs blocking synthesis or release of T4 (e.g., lithium, ethionamide,sulfonamides, iodide)• Goitrogens in foodstuffs or as endemic substances or pollutants• Cytokines (interferon-γ, interleukin-2)• Thyroid infiltration (amyloidosis, hemochromatosis, sarcoidosis,• Postablative thyroiditis due to 131I surgery or therapeutic irradiation fornonthyroidal malignancyCongenital• Maternal iodine deficiency• Fetal thyroid dysgenesis• Inborn errors of thyroid hormone synthesis• Maternal antithyroid antibodies that cross the placenta• Fetal hypopituitary hypothyroidismTransient (Post-Thyroiditis) HypothyroidismFollowing subacute, painless, or postpartum thyroiditisConsumptive HypothyroidismRapid destruction of thyroid hormone due to D3 expression in large hemangiomas or hemangioendotheliomasDefects of Thyroxine-to-Triiodothyronine ConversionSelenocysteine insertion sequence–binding protein 2 (SBP2) defectDrug-Induced Thyroid DestructionTyrosine kinase inhibitor (e.g., sunitinib)Central HypothyroidismAcquiredPituitary origin (secondary) Hypothalamic disorders (tertiary)Bexarotene (retinoid X receptor agonist) Dopamine and/or severe illnessCongenital TSH deficiency or structural abnormalityTSH receptor defect
Signs and Symptoms of AdultHypothyroidismTirednessForgetfulness/Slower ThinkingMoodiness/ IrritabilityDepressionInability to ConcentrateThinning Hair/Hair LossLoss of Body HairDry, Patchy SkinWeight GainCold IntoleranceElevated CholesterolFamily History of ThyroidDisease or DiabetesMuscle Weakness/CrampsConstipationInfertilityMenstrual Irregularities/Heavy PeriodSlower HeartbeatDifficulty SwallowingPersistent Dry or Sore ThroatHoarseness/Deepening of VoiceEnlarged Thyroid (Goiter)Puffy Eyes
Various manifestations ofHypothyroidism
HyperthyroidismO It is the condition resulting from increased circulatinglevels of free T4 and T3.O The term thyrotoxicosis, rather than hyperthyroidism,should be used for this disorder because it need not beassociated with hyperfunction of the thyroid gland. Theterm hyperthyroidism is reserved for disorders that resultfrom sustained overproduction and release of hormone bythe thyroid itself.O It has various causes,the most common cause is Gravesdisease (Graves hyperthyroidism), which accounts for60–80% of the cases
Causes of HyperthyroidismSustained Hormone Overproduction (Hyperthyroidism)Graves’ disease (von Basedow’s disease)Toxic multinodular goiterToxic adenomaChorionic gonadotropin-induced Gestational hyperthyroidismPhysiologic hyperthyroidism of pregnancyFamilial gestational hyperthyroidism due to TSH receptor mutationsTrophoblastic tumorsAmiodarone-associated hyperthyroidism due to iodide releaseMetastatic functioning thyroid carcinomaTSH-secreting pituitary tumorsThyroid hormone resistance with pituitary predominanceTransient Hormone Excess (Thyrotoxicosis)ThyroiditisAutoimmuneLymphocytic thyroiditis (silent thyroiditis, painless thyroiditis,postpartum thyroiditis)Acute exacerbation of Hashimoto’s diseaseViral or postviralSubacute (granulomatous, painful, postviral) thyroiditisDrug-induced or associated thyroiditis (Amiodarone,Lithium, interferon-α, interleukin-2,GM-CSF)Infectious thyroiditisExogenous Thyroid HormoneIatrogenic overreplacementIngestion of natural products containing thyroid hormoneNatural foodstuffsThyromimetic compounds (e.g., tiratricol PLB)Occupational exposure to thyroid hormone (e.g., pill manufacturing,veterinary occupations
Nervousness/TremorMental Disturbances/IrritabilityDifficulty SleepingBulging Eyes/Unblinking Stare/ Vision ChangesEnlarged Thyroid (Goiter)Menstrual Irregularities/Light PeriodFrequent Bowel MovementsWarm, Moist PalmsFirst-Trimester Miscarriage/Excessive Vomiting in PregnancyPersistent Dry or Sore ThroatDifficulty SwallowingPalpitations/TachycardiaImpaired FertilityWeight Loss or GainHeat IntoleranceIncreased SweatingFamily History ofThyroid Diseaseor DiabetesSudden ParalysisHoarseness/Deepening of VoiceSigns and Symptoms of Hyperthyroidism
Computed tomographic scans of orbits in two patients with Graves’ orbitopathy.Rare thyroid acropachy in a patient with Graves’disease.The hypermetabolic state leads to axial bone destruction
Test Hypothyroidism HyperthyroidismA. Based on metabolic Function• BMR (Normal: ±10%) Decreases to – 30% to -40% Increases from +10% to+100%• S.Creatinine (0.2 to 0.6 mg/dl) decreases increases• Fasting blood sugar decreases increases• S.Cholestrol (120-200mg/dl) increases decreasesB. Based on handling ofIodine• Total S.T4(3-8µg/dl):S.T3( 0.15µg/dl) decreases increases• Free S.T4(2ng/dl); S.T3(0.3ng/dl) decreases increases• Protein bound Iodine (3.5-7.5µg/dl) decreases increases• RAI123 uptake (normal: 20-40%) decreases <20% Increases>60%• Serum TSH level (normal 2.3µU/ml)• Primary hypothyroidism-decreases• Secondaryhypothyroidism-decreasesDecreases orundetectableC.Urine Calcium Loss decreases increasesT h y r o i d F u n c t i o n Te s t C o m p a r e d