Thyroid hormone effect and mechanism of action
Download as PPTX, PDF65 likes31,376 views
Thyroid hormones act by binding to thyroid hormone receptors in the nucleus. T3 has a higher binding affinity than T4. The hormone-receptor complex then regulates gene expression. Thyroid hormones increase metabolism, heart rate, and have widespread effects on growth, development, and multiple organ systems. They are essential for normal neurological development and function.
Thyroid hormone effect and mechanism of action
- 2. O Acts by binding to a specific nuclear thyroid hormone receptor (TR). O T3 has a 15-fold higher binding affinity for TRs than does T4. O The hormone-receptor complex binds to DNA via zinc fingers and increases/decreases the expression of a variety of different genes that code 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 two different mRNAs and therefore two different receptor proteins.
- 3. Schematic diagram of thyroid hormone mechanism of action. The interaction of T3 with the TR that is bound as a heterodimer with retinoid X receptor (RXR) to the thyroid hormone response element (TRE), often in the 5′ flanking region of a T3-responsive gene, causes either an increase or a decrease in the transcription of that gene. coactivator proteins corepressor proteins
- 4. O The active proteins are TRα1, TRβ1, TRβ2, and TRβ3. O There are tissue-specific preferences in expression of the various TRs. O TRβ2 is found only in the brain O TRα, particularly TRα2, is thought to be important in the hypothalamus and pituitary. O TRα1 is expressed in all tissues, although its mRNA is especially highly expressed in the kidney, liver. O TRβ3 mRNA is expressed at very low levels but is more abundant in the liver, kidneys, and lungs than in other tissues.
- 5. O Experiments with inactivation of TRα and TRβ have illuminated their different physiologic roles O Feedback regulation of thyroid hormone effects and cochlear development are functions of TRβ. O Cardiac function and energy metabolism are more likely to be regulated by TRα. β β β β β
- 7. Calorigenic Action O T4 and T3 increase the O2 consumption of almost all metabolically active tissues. O Some of the calorigenic effect of thyroid hormones is due to metabolism of the fatty acids they mobilize. O Thyroid hormones increase the activity of the membrane-bound Na, K ATPase in many tissues O The resulting increased metabolic rate increases thermogenesis. O Most of the effect of thyroid hormone are secondary to its calorigenic effects.
- 8. Effects Secondary to Calorigenesis O Increase in metabolic rate by T4 and T3 in pharmacological dose increases N2 excretion; if food intake is not increased, endogenous protein and fat stores are catabolized and weight is lost.( Catabolic action) O In small doses causes positive N2 balance and stimulate growth (Anabolic action). O Excess catabolic effect along with marked creatinuria leads to muscle fatiguability (Thyrotoxic Myopathy)
- 9. O The potassium liberated during protein catabolism appears in the urine, and there is also an increase in urinary hexosamine and uric acid excretion O Bone protein mobilization Osteoporosis, hypercalcemia and subsequent hypercalciuria. O Hypothyroidism protein catabolism accumulation of osmotically active protein conjugates under skin/subcutaneous tissue coarse puffy skin (Myxoedema)
- 10. O Increased BMR increased use of co- factors and vitamins Vitamin deficiency in hyperthyroid state. O Thyroid hormone is necessary for hepatic conversion of β carotene to vitamin A. O Decreased thyroid hormone increased accumulation of β carotene in blood (Carotenemia) yellowish discoloration of skin.
- 11. Typical appearance of patients with moderately severe primary hypothyroidism or myxedema. Carotenemia versus Jaundice
- 12. O T4 is essential for maintenance of lactation. O Milk secretion is decreased in hypothyroidism and stimulated by thyroid hormones. O Thyroid hormone is involved in gonadal development and secondary sexual characteristics. O In adult women, severe hypothyroidism may be associated with diminished libido and failure of ovulation. O Secretion of progesterone is inadequate, and endometrial proliferation persists, resulting in excessive and irregular breakthrough menstrual bleeding.
- 13. O In hyperthyroidism menstrual flow is initially diminished and ultimately ceases reducing fertility. O Likely mechanism for menstrual changes: O disruption in amplitude and frequency of LH/FSH pulses caused by thyroid hormone influences on GnRH signaling.. O “spillover” of elevated TSH stimulating the luteinizing hormone (LH) receptor48 and elevated TRH initiating excess prolactin release. O A significant fraction of men with hypothyroidism or hyperthyroidism have moderate to severe erectile dysfunction that improves with treatment of the thyroid disease
- 14. Effects on the Cardiovascular System
- 15. O Circulatory T3 enters the myocytes, combines with its receptors, and enters the nucleus, where it promotes the expression of some genes and inhibits the expression 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-K ATPase, and certain K+ channels. O Those that are inhibited include the genes for b- myosin heavy chain, phospholamban, adenylyl cyclase, T3 nuclear receptors, and NCX, the Na+– Ca2+ exchanger. O The net result is increased heart rate and force of contraction
- 17. O The myosin containing β-MHC has less ATPase activity than the myosin containing α -MHC. O α -MHC predominates in the atria in adults, and its level is increased by treatment with thyroid hormone. This increases the speed of cardiac contraction. O Conversely, expression of the α -MHC gene is depressed and that of the β -MHC gene is enhanced in hypothyroidism.
- 18. Effects on the Nervous System O Thyroid hormone is essential for the development of the central nervous system. O T4 deficiency in fetus or in infants causes: O Defective myelination of axons of cortical region O Defective branching of dendrites leading to defective synapses O Marked reduction in vascularity of brain Net Result Infantile brain/mental retardation O Thyroid hormone therapy must be given to a thyroid hormone-deficient child during the first few months of postnatal life to prevent mental retardation.(critical period- 1 year of life)
- 19. O The parts of the central nervous system (CNS) most affected are the cerebral cortex, the basal ganglia and the cochlea .(mental retardation, motor rigidity, and deafness). O T4 deficiency in adults cause: O Loss of all intellectual function O Memory loss O Decrease electrical activity of brain O Slow, delayed and husky voice O Eventually Psychosis (Myxoedema Madness) O T4 excess increases response to catecholamines and stimulation of RAS anxiety, nervousness, irritability, insomnia , rythmic tremors etc
- 20. Effects on growth and development O Thyroid hormone is essential for normal growth and maturation of the skeleton. O Growth failure in thyroid deficiency is caused by impaired general protein synthesis, reduced growth hormone, and especially reduced insulin-like growth factor 1. O A major way thyroid hormones promote normal body growth is by stimulating the expression of the gene for growth hormone (GH) in the somatotrophs of the anterior pituitary gland.
- 21. O Impairment of linear growth leads to dwarfism (cretinism) in which the limbs are disproportionately short in relation to the trunk but cartilage growth is unaffected. O Children with prolonged hypothyroidism, even after adequate treatment, do not reach predicted height The consequences of untreated congenital hypothyroidism are demonstrated in this 17-year-old girl. Her tongue is enlarged, and her extremities are inappropriately short in relation to her trunk.
- 22. Effect on carbohydrate metabolism O Dual and opposite effects O Increases peripheral utilization of glucose can cause hypoglycemia O Can also cause hyperglycemia by : O Increase absorption from GI tract O Increase glycogenolysis in the liver O Increase gluconeogenesis from pyruvate O Increase breakdown of insulin O Decrese secretion of insulin O In hyperthyroidism, therefore, the plasma glucose level rises rapidly after a carbohydrate meal, sometimes exceeding the renal threshold.
- 23. Effects on lipid metabolism O Thyroid hormones lower circulating cholesterol levels. O The decrease in plasma cholesterol concentration is due to increased formation of low-density lipoprotein (LDL) receptors in the liver, resulting in increased hepatic removal of cholesterol from the circulation. O Thyroid decreases the stores of triglycerides and phospholipids by increasing the activity of lipases i.e increasing lipolysis O Dextro –thyroxine (D-T4) and TETRAC are used clinically as serum cholestrol lowering agents in atherosclerosis
- 24. Effects on Hematopoietic System O T4 deficiency leads to anaemia due to: O In response to the diminished oxygen requirements and decreased production of erythropoietin causing mild normocytic, normochromic anemia. O Decreased absorption ov vitamin B12,Folate deficiency from malabsorption or dietary inadequacy may cause macrocytic anemia. O The frequent menorrhagia and the defective absorption of iron resulting from achlorhydria may contribute to a microcytic, hypochromic anemia. O T4 excess stimulates erythropoiesis,increase production of 2,3 DPG in RBC shifting O2 dissociation curve to right. O A parallel increase in plasma volume also occurs, with the result that the hematocrit is normal.
- 25. Relation to Catecholamines O The actions of thyroid hormones and the catecholamines norepinephrine and epinephrine are intimately interrelated. O The functional synergism observed between catecholamines and thyroid hormones,arises from the ability of thyroid hormones to increase expression of catecholamine receptors and the signaling effectors to which they are linked. O The reduced adrenergic responsiveness associated with hypothyroidism has been linked to all steps of catecholamine signaling, including receptor and postreceptor actions, resulting in an impaired cAMP response.
- 26. Catecholamines T4 • Epinephrine and nor epinephrine increases BMR,stimulates CNS,increases heart rate and force of contraction • T4 also has the same action but is prolonged and slow • Cannot increase BMR in absence of T4 • T4 potentiate the action of catecholamine and in their presence increase in BMR by T4 is more • Cause stimulation of Reticular Activating System • Same effect but : T4 action on CNS and CVS can be decreased after sympathectomy or by β blockers
- 28. Hypothyroidism O Reduced circulating levels of free T4 and T3. O The syndrome of adult hypothyroidism is generally called myxedema. O Children who are hypothyroid from birth or before are called cretins. O Hypothyroidism may be the end result of a number of diseases of the thyroid gland, or it may be secondary to pituitary or hypothalamic failure. O Treatment is almost always with levothyroxine
- 29. Causes of Hypothyroidism Primary Hypothyroidism Acquired • 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 for nonthyroidal malignancy Congenital • Maternal iodine deficiency • Fetal thyroid dysgenesis • Inborn errors of thyroid hormone synthesis • Maternal antithyroid antibodies that cross the placenta • Fetal hypopituitary hypothyroidism Transient (Post-Thyroiditis) Hypothyroidism Following subacute, painless, or postpartum thyroiditis Consumptive Hypothyroidism Rapid destruction of thyroid hormone due to D3 expression in large hemangiomas or hemangioendotheliomas Defects of Thyroxine-to-Triiodothyronine Conversion Selenocysteine insertion sequence–binding protein 2 (SBP2) defect Drug-Induced Thyroid Destruction Tyrosine kinase inhibitor (e.g., sunitinib) Central Hypothyroidism Acquired Pituitary origin (secondary) Hypothalamic disorders (tertiary) Bexarotene (retinoid X receptor agonist) Dopamine and/or severe illness Congenital TSH deficiency or structural abnormality TSH receptor defect
- 30. Signs and Symptoms of Adult Hypothyroidism Tiredness Forgetfulness/Slower Thinking Moodiness/ Irritability Depression Inability to Concentrate Thinning Hair/Hair Loss Loss of Body Hair Dry, Patchy Skin Weight Gain Cold Intolerance Elevated Cholesterol Family History of Thyroid Disease or Diabetes Muscle Weakness/ Cramps Constipation Infertility Menstrual Irregularities/ Heavy Period Slower Heartbeat Difficulty Swallowing Persistent Dry or Sore Throat Hoarseness/ Deepening of Voice Enlarged Thyroid (Goiter) Puffy Eyes
- 32. Hyperthyroidism O It is the condition resulting from increased circulating levels of free T4 and T3. O The term thyrotoxicosis, rather than hyperthyroidism, should be used for this disorder because it need not be associated with hyperfunction of the thyroid gland. The term hyperthyroidism is reserved for disorders that result from sustained overproduction and release of hormone by the thyroid itself. O It has various causes,the most common cause is Graves disease (Graves hyperthyroidism), which accounts for 60–80% of the cases
- 33. Causes of Hyperthyroidism Sustained Hormone Overproduction (Hyperthyroidism) Graves’ disease (von Basedow’s disease) Toxic multinodular goiter Toxic adenoma Chorionic gonadotropin-induced Gestational hyperthyroidism Physiologic hyperthyroidism of pregnancy Familial gestational hyperthyroidism due to TSH receptor mutations Trophoblastic tumors Amiodarone-associated hyperthyroidism due to iodide release Metastatic functioning thyroid carcinoma TSH-secreting pituitary tumors Thyroid hormone resistance with pituitary predominance Transient Hormone Excess (Thyrotoxicosis) Thyroiditis Autoimmune Lymphocytic thyroiditis (silent thyroiditis, painless thyroiditis, postpartum thyroiditis) Acute exacerbation of Hashimoto’s disease Viral or postviral Subacute (granulomatous, painful, postviral) thyroiditis Drug-induced or associated thyroiditis (Amiodarone,Lithium, interferon-α, interleukin-2, GM-CSF) Infectious thyroiditis Exogenous Thyroid Hormone Iatrogenic overreplacement Ingestion of natural products containing thyroid hormone Natural foodstuffs Thyromimetic compounds (e.g., tiratricol PLB) Occupational exposure to thyroid hormone (e.g., pill manufacturing,veterinary occupations
- 34. Nervousness/Tremor Mental Disturbances/ Irritability Difficulty Sleeping Bulging Eyes/ Unblinking Stare/ Vision Changes Enlarged Thyroid (Goiter) Menstrual Irregularities/ Light Period Frequent Bowel Movements Warm, Moist Palms First-Trimester Miscarriage/ Excessive Vomiting in Pregnancy Persistent Dry or Sore Throat Difficulty Swallowing Palpitations/ Tachycardia Impaired Fertility Weight Loss or Gain Heat Intolerance Increased Sweating Family History of Thyroid Disease or Diabetes Sudden Paralysis Hoarseness/ Deepening of Voice Signs and Symptoms of Hyperthyroidism
- 35. 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
- 36. Test Hypothyroidism Hyperthyroidism A. 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 decreases B. Based on handling of Iodine • 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 2.3 µU/ml) • Primary hypothyroidism- decreases • Secondary hypothyroidism- decreases Decreases or undetectable C.Urine Calcium Loss decreases increases T 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
- 37. Thank You…………..