Thyroid Gland Hormones and Function

Thyroid Gland

• Secretes three main hormones: thyroxine (T4), triiodothyronine (T3), and calcitonin
• Thyroid hormones commonly refers to T4 and T3

Thyroid Gland Anatomy

• The functional unit is the follicle or acinus
• A single layer of epithelial cells surrounds each follicle, forming a cavity called the follicle lumen
• The follicle lumen is filled with a thick colloid containing thyroglobulin, a large glycoprotein
• A dense capillary network surrounds the follicles, resulting in high blood flow

Synthesis, Storage, and Secretion of Thyroid Hormone

• Uptake of plasma iodide by follicle cells
• Oxidation of iodide and iodination of tyrosine residues of thyroglobulin
• Coupling of iodinated tyrosine
• Secretion of thyroid hormone

Uptake of Plasma Iodide

• An energy-dependent process
• Iodide is captured from the blood and moved to the lumen via the Na+/I symporter (NIS)

Oxidation, Iodination, and Coupling

• Oxidation and iodination of iodine with tyrosine, and coupling, are catalyzed by thyroperoxidase
• Iodination of tyrosine at one position forms monoiodotyrosine (MIT)
• Iodination of tyrosine at two positions forms di-iodotyrosine (DIT)
• MIT and DIT molecules are coupled to form T3, or two DIT molecules couple to form T4
• Iodinated thyroglobulin forms a large store of thyroid hormone within the thyroid gland

Secretion and Distribution

• Thyroglobulin is taken up into the follicle cell via endocytosis
• Endocytotic vesicles fuse with lysosomes upon stimulation of the thyroid gland
• Proteolytic enzymes act on thyroglobulin, releasing T4 and T3
• T3 and T4 are secreted into the plasma
• Both T3 and T4 circulate in the blood tightly bound (>99%) to plasma proteins, primarily thyroxine-binding globulin (TBG)
• The majority (~85%) of secreted thyroid hormone is T4, which is converted to the three- to five-fold more active T3

Regulation of Thyroid Function

• TSH controls thyroid hormone synthesis and has a trophic action on thyroid cells
• TSH stimulates transcription of iodide transporter genes
• TSH stimulates the synthesis and secretion of thyroglobulin
• TSH increases blood flow through the gland
• TSH production is regulated by negative feedback, with T3 having a greater effect than T4
• TSH measurement is a key diagnostic tool for assessing thyroid function

Mechanism of Action

• Thyroid hormones act through the specific nuclear receptor, TR
• T4 is converted to T3 upon entering the cell
• T3 binds with high affinity to TR in the nucleus
• When T3 is bound, transcription is activated, resulting in mRNA and protein synthesis

Actions of Thyroid Hormones

• Affects metabolism of carbohydrates, fats, and proteins
• Controls heat production and basal metabolic rate
• Sensitizes β1 cells in the heart to regulate cardiac rate and output
• Critical for growth by direct action on cells
• Influences growth hormone production and potentiates its effects on target tissues
• T3 and T4 are important for skeletal development, normal growth, and maturation of the central nervous system

Transport and Metabolism

• Both T3 and T4 are metabolized by the liver
• Free and conjugated forms are excreted partly in the bile and partly in the urine
• T3's half-life is a few hours, while T4's half-life varies between 6-7 days

Hyperthyroidism

• Characterized by increased T3 and T4 and decreased TSH
• Subclinical hyperthyroidism presents normal T3, T4, and decreased TSH
• Excessive T3 and T4 secretion and activity leads to high metabolic rate
• Increase in skin temperature, sweating, and heat intolerance
• Leads to Nervousness, tremor, tachycardia, and increased appetite with weight loss

Types of Primary Hyperthyroidism

• Exophthalmic or diffuse toxic goitre (Graves' disease)
• Toxic nodular goitre
• Viral thyroiditis

Graves' Disease

• An organ-specific autoimmune disease caused by autoantibodies to the TSH receptor, which activates it, increasing T4 secretion
• Diffuse enlargement of the gland (diffuse goitre)
• Protrusion of the eyeballs (exophthalmos) caused by the presence of TSH receptor-like proteins in orbital tissues

Toxic Nodular Goitre

• Caused by a benign tumor, and may develop in patients with long-standing simple goitre
• Presence of a single nodule (solitary nodular) or several nodules (multinodular)
• No concomitant exophthalmos

DRUGS USED IN DISEASES OF THE THYROID HYPERTHYROIDISM

• Hyperthyroidism can be managed pharmacologically or surgically, surgery corrects mechanical problems affecting trachea via compression
• Pharmacological treatments:
• Thioureylenes
• Radioiodine
• Beta Blockers

Thioureylenes

• Group of drugs including carbimazole, methimazole (metabolite of carbimazole), and propylthiouracil
• These decrease the output of thyroid hormones from the gland over 3-4 weeks by inhibiting thyroperoxidase-catalyzed reactions
• Inhibition of oxidation, iodination, and coupling of T3 and T4 occurs
• Propylthiouracil has the added effect of reducing the deiodination of T4 to T3 in peripheral tissues

Pharmacokinetics of Thioureylenes

• Given orally
• A full clinical response takes several weeks due to large thyroid hormone stores
• Propylthiouracil acts rapidly by inhibiting peripheral conversion of T4 to T3
• Initial carbimazole dose: 30 mg (high dose) for 4 weeks until euthyroid state, followed by 15 mg for 12-18 months, then gradual withdrawal
• Initial propylthiouracil dose: 300 mg for 4 weeks, then 150 mg for 12-18 months, then gradual withdrawal

Thioureylenes in Pregnancy

• Carbimazole and methimazole can cross the placenta and affect the fetal thyroid gland and are found in breast milk
• Propylthiouracil is less likely to cross the placenta or breast milk because it is more strongly bound to plasma protein

Undesired Effects of Thioureylenes

• Most dangerous adverse effect is neutropenia and agranulocytosis
• Rare (0.1%-1.2% incidence), reversible if treatment is stopped
• Sore throat and fever should be immediately reported
• Rashes (2%-25%)
• Arthralgia
• Rare cases of fetal abnormalities with carbimazole

Radioiodine

• Used as 131I (usually as the sodium salt)
• The radioactive isotope emits beta radiation for a powerful cytotoxic action
• Uptake of 123I and other iodine isotopes are used diagnostically for assessing thyroid function
• Administered as a single dose, with cytotoxic effects delayed for 1-2 months, eventually leading to hypothyroidism
• Contraindicated in children or pregnant patients

Other Drugs

• β-adrenoceptor antagonists (propranolol) alleviate tachycardia, dysrhythmias, tremor, and agitation
• β-adrenoceptor antagonists also prepare thyrotoxic patients for surgery, and treat hyperthyroid crisis
• Guanethidine eye drops relax sympathetically innervated smooth muscles

Surgery Preparation

• High dose of iodine/iodide (Lugol's solution) inhibits secretion of thyroid hormones
• Given prior to thyroid surgery for 10–14 days, reduces vascularity, shrinks and hardens gland
• This mechanism may inhibit iodination of thyroglobulin, and synthesis of thyroid hormones

Main uses of Iodine/Iodide

• Preparation of hyperthyroid subjects to manage the gland for surgical resection
• Part of the treatment for severe thyrotoxic crisis (thyroid storm)
• Can cause Allergic reactions (angio-oedema, rashes), lacrimation, conjunctivitis, pain in the salivary glands and a cold-like syndrome

Hypothyroidism

• Characterized by decreased T3 and T4 and increased TSH
• Subclinical hypothyroidism presents normal T3, T4 and increased TSH
• Symptoms include low metabolic rate, slow speech, and deep hoarse voice
• Additional symptoms include lethargy, bradycardia, and sensitivity to cold
• Also causes mental impairment, and characteristic thickening of the skin (myxoedema)

Types of Hypothyroidism

• Hashimoto's thyroiditis happens via immune reaction against thyroglobulin for hypothyroidism and myxoedema
• Simple non-toxic goitre result from reduced iodine intake, decreased hormone production, increased TSH and vascularity/gland hypertrophy

Other Causes of Hypothyroidism

• Destruction of glandular tissue with radioiodine when treating thyroid tumors
• Some drugs (e.g. cholecystographic agents)
• Congenital hypothyroidism affects 1 in 3000-4000 births, resulting in retardation

Treatment for Hypothyroidism

• Simple goiter is treated with iodine supply in the diet
• Hashimoto's thyroiditis is treated with synthetic T4 (levothyroxine) and T3 (liothyronine), given orally
• Levothyroxine (50–100 μg/day) is first-line
• Liothyronine has a faster onset but a shorter action duration, mostly used for myxoedema coma treatment

Adverse Effects of Hypothyroidism Treatment

• Signs and symptoms of hyperthyroidism can occur and precipitate angina pectoris, cardiac dysrhythmias or even cardiac failure
• Bone resorption is increased, leading to osteoporosis

Calcitonin

• A peptide hormone for C' cells found in the thyroid follicles
• Calcitonin inhibits bone resorption by binding to an inhibitory receptor on osteoclasts
• in the kidney, stimulates decreased reabsorption of and phosphate in the proximal tubule
• Overall effect: decrease plasma concentration
• Calcitonin is administered via SC and IM injection
• May also be given intranasally

Calcitonin Analogues

• Salcatonin (synthetic salmon calcitonin) is an analogue
• Synthetic human calcitonin is also available

Calcitonin Adverse Effects

• Nausea and vomiting
• Facial flushing
• Tingling sensation in the hands
• Unpleasant taste in the mouth

Clinical Uses of Calcitonin

• Hypercalcaemia
• Paget’s disease of bone (to relieve pain and reduce neurological complications)
• Postmenopausal and corticosteroid-induced osteoporosis (2nd line treatment)

Parathyroid Hormone

• An important physiological regulator of Ca2+ metabolism
• It acts on the PTH type 1 receptor, expressed on osteoblast cell membranes
• PTH activates the osteoblast PTH type 1 receptor to express RANKL, which binds to RANK to activate osteoclasts and stimulate resorption rate.

PTH Affects

• Mobilisation of Ca2+ from bone
• Reabsorption of Ca2+ by the kidney
• Stimulated synthesis of calcitriol for Ca2+ absorption from the intestine
• Phosphate excretion

Thus its PTH Net Effect Is

• Increased calcium concentration in the plasma
• Lowered phosphate

Sustained Levels VS Low Levels

• Note that sustained levels of PTH mobilise Ca2+ from bone and reduce renal Ca2+ excretion
• Intermittent therapeutic doses of PTH stimulate osteoblast activity

Therapeutic Treatments

• Cinacalcet increases the sensitivity of Ca receptor to plasma Ca2+ to reduce PTH
• Teriparatide and abaloparatide are clinically licensed synthetic analogues of PTH

Therapeutic Treatment Dosing

• Teriparatide is given subcutaneously once daily
• Tolerable, there is headache, arthralgias, nausea, and/or dizziness
• Patients may report hypercalcaemia and leg cramps
• Note: the length of teriparatide treatment should be limited to 24 months

Clinical Use of Parathyroid Hormone Analogues

• A 2nd line treatment from osteoporosis
• Used when patients are receiving systemic corticosteroids
• Abaloparatide is licensed for postmenopausal women with osteoporosis who at high risk of fracture, or are unable to take other treatments
• The greater abaloparatide affinity will result increase bone formation without provoking bone resorption