Handout: Disorders of the Thyroid Gland PDF

1/21/20 Learning objectives Disorders...

1/21/20 Learning objectives Disorders of the At the end of the class, the student should be able to: 1. Recall the anatomy, physiology, and regulation of the THYROID GLAND thyroid axis 2. Identify which diagnostic tests to request in the evaluation of thyroid dysfunction and how to interpret them 3. Recognise the various causes, clinical manifestations, and treatment of: Dr. Anna Angelica 1. Hypothyroidism Macalalad-Josue 2. Hyperthyroidism and thyrotoxicosis 3. Thyroiditis PHYSIOLOGICAL ANATOMY OF THE THYROID GLAND thyroglobulin contains the thyroid hormones the large glycoprotein that is Thyroid hormone synthesis, the major constituent of colloid metabolism, and action Thyroid - very efficient in Step 1: Iodide extracting iodine Pendrin Pendred syndrome from the circulation trapping – Transports I- out of the thyroid cell into Sodium iodide the follicle symporter (NIS) – Cl--I- – Cotransports 1 countertransport iodide (I-) ion along with 2Na Pendred syndrome – Powered by the Na- K ATPase pump – Mutation of gene encoding the – Concentrated [I-] to Pendrin transporter about 30x is plasma concentration – Defective organificaton of – Rate is influenced iodine mostly by TSH – Goiter and – Also present in the sensorineural salivary gland, deafness lactating breast, and placenta Basolateral Apical Basolateral Apical membrane membrane (plasma) membrane (plasma) membrane (follicle) (follicle) 1  1/21/20 Step 2: Formation and Oxidation of Step 3: Oxidation of secretion of Thyroglobulin (Tg) Iodine – Promoted by thyroid the Iodide ion (I- àI2) peroxidase (TPO) accompanied by Thyroglobulin hydrogen peroxide – Large glycoprotein produced by DUOX molecule and DUOX maturation factor – Synthesized from – Inhibited by 70 tyrosine amino propylthiouracil acids (PTU) – Thyroid hormones form within Tg Basolateral Basolateral membrane Apical membrane Apical (plasma) membrane (plasma) membrane (follicle) (follicle) Organification Step 5: Coupling of MIT and Step 4: Organification of I2 Coupling rxn: – Binding of iodine with the tyrosine – MIT+DIT=T3 or DIT residues in the Tg rT3 moleculeà – DIT+DIT=T4 Monoiodotyrosine Iodinated (MIT) and diiodotyrosine (DIT) thyroglobulin – Hastened by TPO – stored in the follicular lumen Wolff chaikoff until the thyroid effect gland is stimulated to – High levels of I– secrete thyroid inhibit organification hormones. and, therefore, inhibit synthesis of T4> T3 thyroid hormone Basolateral T3 more active Basolateral membrane Apical membrane Apical (plasma) membrane (plasma) membrane (follicle) (follicle) Step 6: Release of thyroid Chemistry of thyroxine (T4) and Iodinated Tg is taken hormones (Stimulation of triiodothyronine (T3) formation. back into the thyroid cells by TSH) follicular cells by pinocytosis or Iodinated tyrosines are endocytosis freed from Tg – Lysosomes form digestive vesicles Deiodinase enzyme – – Proteases – digest cleaves the iodine from the Tg molecules and release T3 and T3à them for recycling within diffuse the gland for additional Endocytosis thyroid hormones – Tg binds to megalin à carried across by Basolateral Apical transcytosis membrane (plasma) membrane (follicle) 2  1/21/20 Iodine Worldwide iodine nutrition Autoregulation of iodine uptake Consequences of iodine deficiency High iodine levels decrease iodine transport into follicular cells Low iodine levels increase iodine transport into mental and growth retardation in children follicular cells who live in iodine deficient regions Not treated with iodine of thyroid hormone to restore normal thyroid hormone levels during early age TSH increases thyroid secretion 1. éproteolysis of the Tg 2. éactivity of the iodide pump REGULATION OF THYROID 3. éiodination of tyrosine 4. ésize andé secretory HORMONE SECRETION activity of the thyroid cells 5. é number of thyroid cells Mediated by cAMP TSH binds to TSH-receptor - loss or gain of function mutations 3  1/21/20 TRH regulates TSH secretion by the anterior pituitary Storage of Thyroglobulin TRH Thyroid gland is unusual in its ability to – éExposure of an animal to cold store large amounts of hormone Excitation of the hypothalamic centers thyroid hormones are stored in the follicles for body temperature in an amount sufficient to supply the body control Arctic region: BMR with its normal requirements of thyroid é15-20% hormones for 2 to 3 months TSH – Excitement and anxiety can cause an acute decrease Transport of T4 and T3 to tissues T3 vs T4 most of the T3 and T4 is bound to thyroxine-binding globulin (TBG) – Much less to transthyretin (TTR) and albumin hepatic failure, androgens, nephrotic syndrome – êTBG levels, à êtotal thyroid hormone, normal levels of free hormone. pregnancy – éTBG levels, increases sialylation and delays TBG clearance – leading to an increase in total T4 and T3, normal levels of free hormone – à i.e., clinically euthyroid – Increase LT4 requirements among hypothyroid patients who become pregnant Functions Increase the pool of circulating hormone delay hormone clearance Affinity to plasma protein Lower higher may modulate hormone delivery to selected tissue sites Thyroid hormone activation and inactivation in a Peripheral conversion of T4àT3 cell expressing the iodothyronine deiodinases D2 and D3 >90% of thyroid hormone molecules that bind with the receptors is T3 Type I deiodinase (D1) – relatively low affinity for T4; thyroid, liver, kidneys Type II (D2)– higher affinity for T4; pituitary, brain, brown fat and thyroid - expression of this enzyme allows it to regulate T3 concentration locally D2: éT4àT3 - Induced by hypothyroidism - Impaired by fassting, systemic illness, acute trauma, oral contrast agents, medications (PTU, propranolol, amiodarone, glucocorticoids) Type III (D3 ) – inactivated T4 and T3 àrT3 -activated in sick euthyroid syndrome 4  1/21/20 Hormone binding dissociates the co-repressors and allows the recruitment of co-activators that enhance Thyroid hormone action transcription. (TRE) (stimulate of inhibit) Thyroid hormones enter cells through Passive diffucion Transporters: MCT8, MCT10, 1C1 Thyroid hormones increase cellular metabolic activity Effect of thyroid hormone on growth basal metabolic rate (BMR) é60-100% Promote growth and above normal when large quantities of the development of the brain hormones are secreted act synergistically with growth é rate of utilization of foods for energy hormone and somatomedins à mental processes are excited bone formation éactivities of most of the other endocrine (+) Bone maturation: ossification glands and fusion of growth plates é number and activity of mitochondria Thyroid hormone deficiency: bone age is < chronologic age é active transport of ions through cell 36y/o female Carpal bone age ~ 3 yrs membrances eg. Na-K-ATPase pump Distal bones ~1 y and 3mo Effects of thyroid hormone on specific body functions écarbohydrate metabolism – Rapid glucose uptake by cells – enhanced glycolysis, enhanced gluconeogenesis, – éabsorption from the gastrointestinal tract, – éinsulin secretion éFat metabolism – lipids are mobilized rapidly from the fat tissue – êthe fat stores – é free fatty acid concentration in the plasma – éFatty acid oxidation éProtein synthesis and degradation êbody weight Overall effect of thyroid hormone is CATABOLIC. 5  1/21/20 Excitatory Effects on the Nervous Effect of Thyroid Hormone on System Sexual Function CNS Men Women – Hyperthyroidism: hyperexcitability and irritability. – Hypothyroidism: listlessness, slowed speech, somnolence, Hypothyroid: loss of libido Hyperthyroid: impaired memory, and êmental capacity. Hyperthyroid: impotence – menorrhagia and ANS polymenorrhea (excessive – same actions as the sympathetic nervous system because and frequent menses) it up-regulates a -adrenergic receptors in the heart 1 – Oligomenorrhea is also – Use beta-blockers such as propranolol common Sleep Hypothyroid: amenorrhea – Hyperthyroid: difficult to sleep bec of the excitable efects on the synapses Decreased libido – Hypothyroid: extreme somnolence Thyroid hormone resistance The spectrum of thyroid dysfunctiom Mutations in the TRβ gene – loss of receptor Hyperthyroidism function – ↑T3/T4, N or ↑TSH Subclinical – Goiter, attention deficit disorder, mild reduction in IQ, delayed skeletal maturation, tachycardia, and hyperthyroidism impaired metabolic responses to thyroid hormone mutations in the TRα gene – congenital hypothyroidism including growth Subclinical retardation, skeletal dysplasia, and severe constipation hypothyroidism – ↓or N T4, N or ↑T3, N TSH Hypothyroidism Lab evaluation Thyroid function test TSH FT4 Total T3 TSH is the most sensitive marker of thyroid status or FT3 Check TSH normal TSH level usually excludes primary thyroid levels pathology (therefore could be secondary) Hyperthyroidism (overt) ê é T3 thyrotoxicosis ê N é If TSH is Subclinical hyperthyroidism ê N Check FT4 abnormal Subclinical hypothyroidism é N Hypothyroidism (overt) é ê Check FT3 If FT4 is Isolated hypothyroxinemia N ê or total T3 normal Isolated hyperthyroxinemia N é No need to always measure ALL THREE at the same time. These are not DIAGNOSES! Unnecessary tests cost money and resources. Base your differential diagnosis from your TFT interpretation 6  1/21/20 Tests to Determine the Etiology of Thyroid function test Thyroid Dysfunction TSH FT4 Total T3 Anti-TPO – autoimmune thyroid disease (i.e. or FT3 Hashitmoto’s thyroiditis) Hyperthyroidism (overt) ê é Anti-Tg - autoimmune thyroid disease T3 thyrotoxicosis ê N é TRAb (TSH receptor antibody) – Graves’ disease, Subclinical hyperthyroidism ê N predict neonatal thyrotoxicosis in the last trimester of pregnancy Subclinical hypothyroidism é N Serum Tg (thyroglobulin) Hypothyroidism (overt) é ê – elevated in all types of thyrotoxicosis except Isolated hypothyroxinemia N ê Thyrotoxicosis factitia Isolated hyperthyroxinemia N é – Used for post-op surveillance monitoring thyroid cancer (if detectable à possible tumor recurrence) Lab evaluation – monitoring treatment Radioiodine Uptake and Thyroid Scanning TSH thyroid gland selectively transports – adequacy of LT4 replacement for primary hypothyroidism – Only check as early as 6 weeks or every 3-6 months if not radioisotopes of iodine (123I, 125I, 131I) and clinically hypothyroid 99mTc pertechnetate à NIS FT4 – adequacy of LT4 replacement for central hypothyroidism (TSH unreliable) – Adequacy of anti-thyroid drug (ATD) therapy in hyperthyroidism No need to always measure BOTH in monitoring response to treatment. Unnecessary tests cost money and resources. Radioiodine Uptake and Thyroid Scanning Functioning or “hot” nodules – almost never malignant à FNA biopsy is not indicated Radioiodine Uptake and Thyroid Scanning non-functioning or “Cold” nodules à – Benign or malignant 131I whole body scan – used to confirm thyroid remnant ablation (after radioactive iodine therapy for differentiated thyroid cancer) 7  1/21/20 Thyroid ultrasound Radioiodine Uptake and Thyroid Scanning Recommend for all patients suspected of 131I whole body scan having thyroid – detect any functioning nodules by either PE metastasis, surveillance or another imaging monitoring in differentiated study thyroid cancer Certain patterns suggestive of malignancy or benignity Whole-body scan of a 45-year-old woman with Monitoring nodule metastatic follicular thyroid carcinoma. A = size physiologic nasopharygneal 131-I excretion; E = 131-I in gastrointestinal tract; and G = 131-I in the bladder. Aspiration of nodules Metastatic foci are present in the right shoulder (B), (FNA) or cystic lesion left humerus (C), right lung and ribs (D), and T12 vertebra (F). The patient was subsequently treated with 200 mCi (7400 MBq) of 131-I. Thyroid ultrasound Hypoechoic, inhomogenous solid thyroid nodule with enlarged AP diameter (papillary carcinoma) in the left lobe show suspicious patterns of malignancy THYROTOXICOSIS state of thyroid hormone excess hyperthyroidism - result of excessive thyroid function Causes of Thyrotoxicosis Primary Hyperthyroidism Graves’ disease (60-80%) Toxic multinodular goiter Toxic adenoma Functioning thyroid carcinoma metastases Activating mutation of the TSH receptor Activating mutation of GSα (McCune-Albright syndrome) Struma ovarii Drugs: iodine excess (Jod-Basedow phenomenon) 8  1/21/20 Causes of Thyrotoxicosis Causes of Thyrotoxicosis Thyrotoxicosis without Hyperthyroidism Secondary Hyperthyroidism Subacute thyroiditis TSH-secreting pituitary adenoma Silent thyroiditis Thyroid hormone resistance syndrome: Other causes of thyroid destruction: occasional patients may have amiodarone, radiation, infarction of features of thyrotoxicosis adenoma Chorionic gonadotropin-secreting tumorsa Ingestion of excess thyroid hormone Gestational thyrotoxicosisa (thyrotoxicosis factitia) or thyroid tissue aCirculatingTSH levels are low in these forms of secondary hyperthyroidism. Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency) Symptoms Signsa Hyperactivity, irritability, Tachycardia; atrial fibrillation in dysphoria the elderly Heat intolerance and Hypertension (usually systolic), inc pulse pressure sweating Fine Tremor, hyperkinesis, Palpitations hyperreflexia Features of GD: Fatigue and weakness Goiter aDiffuse goiter, positive TPO Weight loss with increased Warm, moist skin antibodies or TRAb, appetite Hair loss ophthalmopathy, dermopathy. Hyperdefecation (diarrhea) Muscle weakness, proximal myopathy Low radionuclide uptake Polyuria and thirst Lid retraction or lag bCan be confirmed by radionuclide Oligomenorrhea or scan. Gynecomastia amenorrhea, loss of libido Mental status and modd changes (e.g mania or Everything is fast! depression) Patient with symptoms and signs suggesting Patient with symptoms and signs suggesting thyrotoxicosis, no amiodarone; thyrotoxicosis, no amiodarone; TSH