Thyroid Hormones ENDO412

Objectives of the Lecture Identification of the regulatory mechanism controlling thyroid hormone secretion. Identification of the biosynthesis, storage & secretion of thyroid hormones. Explaining the significance of the conversion of T4 to T3 & reverse T3 in extra thyroid tissue. Describing in brief the different actions of the thyroid hormones. Identifying causes & consequences of over secretion & under secretion of the thyroid hormones. Listing & applications of thyroid function tests.

Thyroid Hormones Thyroid hormones that are synthesized & secreted by the thyroid glands are essential for normal growth, development & metabolism of human body. Hormone production by the thyroid gland is tightly regulated through hypothalamic-pituitary-thyroid axis.

Biosynthesis & Secretion of thyroid hormones All T4 & small amount of T3 are synthesized in the thyroid gland. Process of biosynthesis of thyroid hormones: 1- Trapping of iodide from plasma by thyroid gland. 2- Oxidation of iodide to iodine by thyroid peroxidase. 3- Incorporation of iodine into tyrosine amino acids residues on thyroglobulin of the colloid of thyroid follicles to form monoiodotyrosine (MIT) & diiodotyrosine (DIT). 4- Coupling of DIT & DIT to form tetraiodothyronine (Thyroxine or T4) & Coupling of DIT & MIT to form triiodothyronine (T3). 5- T4 & T3 are spitted from the thyroglobulin & reabsorbed into cells to be released into plasma.

Biosynthesis & Secretion of Thyroid Hormones peroxidase Thyroglobulin Iodide Iodine MIT DIT T3 Colloid T4 Biosynthesis & Secretion of Thyroid Hormones Thyroid Cell T4 T3 Active uptake Blood Iodide Thyroid Follicle T4 T3

What are thyroid hormones in the body? 1- Thyroxine (T4): produced exclusively by the thyroid gland 2- T3: - 15% is produced in the thyroid gland - 85% is produced from T4 in the liver, kidney & muscles by deiodination of outer ring (as 80% of T4 is converted to T3 in extrathyroid tissues) - T3 is the biologically active form of thyroid hormones (as it is has 10 times more affinity more than T4 for thyroid receptors) 3- Reverse T3 (rT3): - Produced outside thyroid from T4 by deiodination of inner ring. - rT3 is biologically inactive.

Transport of thyroid hormones in blood Thyroid hormones are transported in blood in two forms 1-Bound forms: Thyroid hormones are transported in plasma bound to plasma proteins: - Thyroid Binding Globulin (TBG) binds 70% of plasma T4 & 80% of plasma T3 - Others: Pre-albumin & Albumin 2- Free form: 0.05% of plasma T4 & 0.02% of plasma T3 are free (not bound to plasma proteins) Only the free fraction can cross the cell membrane & affect intracellular metabolism

Transport of thyroid hormones in blood (cont.) Thyroid Binding Globulin (TBG) - produced by the liver - Synthesis of TBG is increased by estrogens (in cases of pregnancy & intake of contraceptive pills) & is decreased by androgens, glucocorticoids & liver disease. - In these cases, total T4 & total 3 are changed without changes in the free forms - Some medications as salicylates compete with T3 & T4 for binding sites on TBG causing decrease in total T3 & total T4 without decreasing free T3 or free T4.

Mechanism of action of thyroid hormones Thyroid hormones belong to group I hormones that are bound to intracellular receptors (mainly nuclear receptors). Hormone-Receptor complex binds to hormone sensitive element (HRE) of certain genes (T3 responsive genes) affecting their transcription. Products (proteins as enzymes) exert a number of effects on growth, development & cell metabolism.

General actions of thyroid hormones 1- Major effect of T3 & T4 is to enhance general protein synthesis essential for growth. for example: T3 enhances transcription of growth hormone (GH) itself. (anabolic effects of T3) However, very high T3 levels in blood causes inhibition of protein synthesis. 2- Thyroid hormones are essential for normal physical, mental & reproductive development in humans. Intrauterine or neonatal hypothyroidism causes cretinism in which there is physical & mental retardation. 3- Thyroid hormones have metabolic actions that regulates metabolism of carbohydrates, lipids & proteins. basal Metabolic rate (BMR) is increased.

Regulation of thyroid function Thyroid stimulating hormone (TSH) or thyrotropin of the anterior pituitary gland enhances synthesis & secretion of thyroid hormones by the thyroid gland. Production of TSH by the pituitary is controlled by a stimulatory effect of thyrotropin-releasing hormone (TRH) of the hypothalamus by negative feedback from circulating free T3 & free T4. Accordingly, the hypothalamus (via TRH), sets the level of thyroid hormones production required physiologically by the body.

Regulation of thyroid hormones synthesis & secretion Hypothalamus TRH Ant. Pituitary gland TSH Negative Feedback Regulation of thyroid hormones synthesis & secretion Thyroid gland Plasma T3 & T4 Peripheral tissues

Over secretion of thyroid hormones (Hyperthyroidism) 1- Primary Hyperthyroidism (thyrotoxicosis) Thyroid hormones elevation in blood due to causes in the thyroid gland itself. Most important: Graves` disease. 2- Secondary hyperthyroidism Thyroid hormones elevation due to TSH- secreting tumor of the pituitary.

Graves` disease Etiology: A primary hyperthyroid disease which results from production of a thyroid-stimulating immunoglobulin IgG that activates TSH receptors on thyroid gland resulting in over production & secretion of thyroid hormones (T3 & T4) by thyroid gland. Clinically: Thyroid gland is diffusely enlarged Thyrotoxic manifestations: Increased heart rate & hypertension Nervousness & inability to sleep (insomnia) Sensitivity to heat (increased BMR), flushed skin & excessive sweat weight loss with increased appetite Exophalmos of the eye in some cases Diagnostic Laboratory Investigations: Plasma Free T3 & free T4 are elevated Serum TSH is markedly reduced Treatment: 1- blocking hormone production by antithyroid drugs 2- Surgical removal of the thyroid gland (subtotal thyroidectomy)

Under secretion of thyroid hormones (Hypothyroidism) Defined as low free T4 level with a normal or high TSH. Types of hypothyroidism: 1- Primary: Thyroid gland dysfunction Most common : 1- Congenital hypothyroidism (in neonates) 2- Chronic lymphocytic thyroiditis (Hashimoto`s thyroiditis) Autoimmune disease of thyroid Thyroid gland is enlarged 3- Iodine deficiency 4- Thyroid surgery 5- Radioactive iodine treatment 2- Secondary: Pituitary dysfunction (hypopitutarism due to radiation therapy or destruction of the pituitary)

Under secretion of thyroid hormones (Hypothyroidism) cont. Important clinical manifestations of hypothyroidism: Symptoms: Cold intolerance Depression Mental retardation (infants) Growth failure (children) Dry skin Constipation Dyspnoea on exersion Signs: Bradycardia Periorbital edema Slowed movement & speech Delayed relaxation phase of deep tendon reflex tendons Lab: Hypercholesterolemia Laboratory Investigation: 1- Low plasma free T4 2- Plasma TSH is normal or high in primary hypothyroidism & low in secondary hypothyroidism 2- Neonatal screening for congenital hypothyroidism (plasma TSH is elevated in affected neonates)

Thyroid Function Tests Investigations to determine thyroid status 1- Tests to establish whether there is thyroid dysfunction Thyroid hormone (free & total ) concentrations in plasma (T3 & T4) TSH 2- Tests to elucidate the cause of the thyroid dysfunction: as for examples: Thyroid autoanibodies Serum thyroglobulin Thyroid enzyme activity Biopsy of the thyroid Ultrasonography (sonar) of the thyroid Isotope scanning of the thyroid

Tests to determine thyroid status 1- Thyroid hormones concentrations in plasma: Free thyroid hormones (free T3 & free T4) concentrations in plasma are independent of changes in the concentration of thyroid binding proteins as TBG, prealbumin & albumin. So, they provide more reliable means of diagnosing thyroid dysfunction than measurement of total thyroid hormone concentrations Total thyroid hormones (total T3 & total T4) concentrations in plasma are greatly influenced by TBG which is increased in cases of oral contraceptives intake & in pregnancy. In these cases, total T3 & T4 are increased while free t3 & T4 remain normal.

Tests to determine thyroid status (cont.) 2- Plasma TSH (Thyrotropin): TSH concentration in plasma is elevated in cases of : 1- Primary hypothyroidism : under secretion of the thyroid hormones due to causes in the thyroid 2- Secondary hyperthyroidism: over secretion of the thyroid hormones due to hperfunction of the anterior pituitary that secretes TSH TSH concentration in plasma is reduced in cases of : 1- Primary hyperthyroidism: over secretion of the thyroid hormones due to causes in the thyroid itself 2- Secondary hypothyroidism : under secretion of the thyroid hormones due to hypofunction of the anterior pituitary

Tests to determine thyroid status (cont.) Measurement of TSH concentration in plasma is helpful in cases of: Normal thyroid hormones in blood with clinical manifestation of hyperthyroidism: In these cases patient is clinically hyperthyroid (enlarged gland, thyrotoxic manifestations) BUT his thyroid hormones in blood are normal (or upper normal). TSH is reduced (to below 0.1mU/L) Subclinical hyperthyroidism: In these cases, patient are clinically normal for thyroid illness (or have mild hyperthyroid) & Thyroid hormones are normal. BUT: TSH is reduced

Tests to determine thyroid status (cont.) TSH may be misleading in: 1- First trimester of pregnancy: TSH may be very low (less than 0.1 mU/L) in 3% of cases due to the weak thyrotrophic effect of human chorionic gonadotrophins(hCG) which is high in this period. 2- 50% of patients with pituitary hypothyroidism: Show normal TSH BUT: circulating TSH may show reduced bioactivity 3- First 4-6 months of treatment of hyperthyroidism: TSH may be still low even T3 & T4 are normal (or even below normal ). So, follow up of patients during this period by TSH is not reliable.

Tests to determine thyroid status (cont.) Nonthyroidal illness (NTIs): Patients with a wide range of chronic & acute non-thyroidal illness (NTIs) may show abnormal thyroid function tests (particularly low T3) & even though patients are euthyroid (not show clinical manifestations of hyper- or hpothyroidism). This is called sick euthyroid syndrome. It may result from the effects of the chronic disease on the circulating thyroid hormones (as change in thyroid hormones binding proteins etc..). Accordingly, thyroid function tests should be only requested if the reason of hospital admission is related to a thyroid problem