Thyroid PDF

1 By the end of this lecture you will understand: § Anatomy of the thyroid gland § Thyroid hormone biosynthesis, metabolism § Hypothalamic-pituitary-thyroid axis and hormones § Thyroid hormone physiological roles § Pathophysiology 2 Isthmus 3 Thyroid follicular cell Colloid C cell (parafollicular) c...

1 By the end of this lecture you will understand: § Anatomy of the thyroid gland § Thyroid hormone biosynthesis, metabolism § Hypothalamic-pituitary-thyroid axis and hormones § Thyroid hormone physiological roles § Pathophysiology 2 Isthmus 3 Thyroid follicular cell Colloid C cell (parafollicular) calcitonin Follicle: A sphere of follicular cells. Its lumen is filled with colloid 4 Collect and transport iodide into the colloid. Adults require 150 μg/d dietary iodine intake. Synthesize thyroglobulin protein - contains many tyrosines which are used as precursors to thyroid hormone Take up iodide from the blood, which is necessary for thyroid hormone synthesis. Release the thyroid hormones into circulation. 5 Non-functional metabolite Thyroid hormone precursors 23% 7% 33% 2% 35% 6 Bioactive thyroid hormones, T3 and T4 6 In the colloid, Tg is iodinated with 1 (MIT) or 2 (DIT) iodides. DITs and MITs are combined to T3 or T4 (mostly DIT + DIT = T4). This is catalyzed by thyroid peroxidase, TPO. MIT, DIT, T3 & T4 are endocytosed into follicular cell MIT, DIT are deiodinated and iodides are recycled Some T4 is deiodinated to T3, and T3 & T4 are secreted into circulation Thyroglobulin protein (Tg) synthesis Sodium-iodide symporter (NIS) Outside of cell, in contact with circulation 7 From Sherwood Physiology 7 There are three deiodinase enzymes Type 1 (D1) and 2 (D2) convert T4 to T3 Type 3 (D3) converts T4 to reverse T3, which is an inactive metabolite. 8 Thyroid follicular cells produce two hormones, T3 and T4. These are the only cells that utilize iodine. T4 is much more abundant, but it is metabolized to T3. T3 has much higher affinity for its receptor. Synthesis of thyroid hormones begins in follicular cells, continues in the colloid, resumes in follicular cells. The colloid contains thyroglobulin, a protein that is a precursor to the thyroid hormones 9 Thyroid hormones are lipophilic. Therefore, in circulation, most TH is bound to plasma proteins. Thyroxine-binding globulin (TBG) is the major transporter; binds T4 (and to a lesser extent T3) with high affinity. Transthyretin binds T4 (much lower affinity). They bind albumin, just like all lipophilic hormones. The function of binding proteins is to transport the thyroid hormones in serum, distribute them uniformly in tissues, protect against metabolism and excretion T1/2 of T4 is 6-8 days T1/2 of T3 is 1 day Only a small percentage of hormone is free (bioactive) 0.03% T4, 0.3% T3 Hypothalamus – Thyrotropin-releasing hormone (TRH). 3 amino acid peptide Receptor: GPCR on pituitary thyrotropes. Pituitary – Thyroid-stimulating hormone (TSH) = thyrotropin. 211 amino acid glycoprotein, made up of α & β subunits. Receptor: GPCR on thyroid cell membrane. Thyroid – T3, T4 Receptor: Nuclear thyroid receptor 11 § Similar to other nuclear hormone receptor mechanisms but in a § § § § § different family from steroid hormones. What is unique is that THs enter cells via thyroid hormone transporters, MCT8, MCT10. Within target cells, most T4 is converted to T3 (catalyzed by deiodinase enzymes) The nuclear receptors are localized intracellularly. When bound to the ligand, the receptor-ligand complex translocates to the nucleus. The receptor-ligand complex is a transcription factor that interacts with DNA to drive gene expression, and subsequently protein synthesis. Humans have two major TH-Rs, a and b, each with splice variants that are expressed in a tissue-specific manner. 12 ”Euthyroid” – normal thyroid hormone function and levels Growth and development Key role in brain development Congenital TH deficiency à severe mental and physical retardation (previously called cretinism) Thermogenesis and Calorigenesis Cardiovascular Metabolism Carbohydrate metabolism Cholesterol metabolism Effects on glucose tolerance, absorption 13 Hypothyroidism: Too little thyroid hormones Cretinism: congenital hypothyroidism (untreated) Myxedema: adult hypothyroidism – often due to iodine deficiency Hashimoto’s thyroiditis – autoimmune hypothyroidism due to failure/destruction of the thyroid gland by autoantibodies – TSH-R[block] Ab or TPO autoantibody Much more common in girls. Symptoms of hypothyroidism: Think “slow.” Fatigue, lethargy, cold intolerance Mental slowness, depression Slow heartrate (bradycardia) Dry skin, edema, puffiness Constipation Mild weight gain Fluid retention Myxedema coma: prolonged severe untreated hypothyroidism, usually precipitated by infection, congestive heart failure, and medical noncompliance 14 Hyperthyroidism: Too much thyroid hormones Thyrotoxicosis: elevated free THs Graves disease (60-90% of cases): Usually due to TSH receptor stimulating autoantibodies – TSH-R[stim] Ab Symptoms of hyperthyroidism: Think “fast”. Exophthalmia Excessive heat production, motor activity, and SNS activation Skin is flushed, warm and moist Muscle weakness, rapid heart rate (tachycardia) Weight loss Insomnia, anxiety Frequent bowel movements Heart arrhythmias Exophthalmia Menstrual irregularities Thyroid storm: Extreme hyperthyroidism that may be triggered by illness or surgical emergency 15 Diffuse thyroid enlargement May be due to prolonged stimulation by TSH or TSH-R [stim] Ab in Grave’s disease (hyperthyroidism). May be due to iodine deficiency (hypothyroidism) – the deficiency leads to elevated TSH due to lack of negative feedback. Goitrogens: factors that block TH synthesis – can be in food, medications. 16 Grave’s disease: TSH-R[stim] Ab (Hyperthyroid) Hashimoto’s disease: TSH-R[block] Ab (Hypothyroid) TPO autoantibody (Hypothyroid) TSH-R 17 ¡ Follicular adenoma – accounts for 30% of solitary thyroid nodules. Fewer than 10% are malignant. ¡ Thyroid cancers – rare, classified as papillary or follicular carcinoma. 18 By the end of this lecture you will understand: § Anatomy of the thyroid gland § Thyroid hormone biosynthesis, metabolism § Hypothalamic-pituitary-thyroid axis and hormones § Thyroid hormone physiological roles § Pathophysiology 19