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SOE 597: Thyroid Physiology & Drugs

Introduction

Regarding the thyroid gland…

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Question No. 2

Q: Which hormones are produced by the thyroid gland?

Answer No. 2

Hormone
Function
Thyroxine (T4) - carries 4 iodine atoms)
Regulation of metabolism and growth
Triiodothyronine (T3) - carries 3 iodine atoms)
Regulation of metabolism and growth
Reverse-triiodothyronine (r-T3) - formed by peripheral conversion of T3
Metabolically inactive
Calcitonin
Regulation of calcium and phosphate levels (lowers serum levels through deposition in bone and renal excretion)

Question No. 3

Q: How is thyroid hormone (T3 & T4) synthesised, stored and released?

Answer No. 3

Can be considered in 4 steps:

1. Iodide Trapping
  • Iodine obtained in diet from dairy, grains and meat (150mg/day required)
  • Reduced to the inorganic form iodide (I-)
  • Actively taken up by thyroid follicular cells, stimulated by TSH:
    • Transported against a concentration gradient by Na+/I- Symporter (NIS)
2. Iodide Oxidation & Organification
  • Moves apically in the cell where is oxidised to iodine (I+)
  • Requires the membrane bound enzyme thyroperoxidase
  • I+ covalently binds to tyrosine residues on thyroglobulin in the colloid
  • May be iodinated at one or two positions forming:
    • Monoiodotyrosine (MIT)
    • Diiodotyrosine (DIT)
3. Storage in Colloid with Thyroglobulin
  • Tyrosine residues couple to form precursors of thryroid hormones:
    • MIT & DIT couple to form T3
    • DIT & DIT couple to from T4
  • T3 & T4 remain attached to the thyroglobulin molecule for storage in colloid
4. Secretion of Thyroid Hormones
  • When stimulated by TSH, thyroglobulin is internalised into the thyrocyte membrane via endocytosis
  • Lysosomal endopeptidase cleaves the thyroglobulin releasing T3 and T4
  • Thyroid hormones are released into the cytoplasm and diffuse into the bloodstream through the basement membrane
Thyroid hormone formation, synthesis and release

Question No. 4

Q: What are the functions of thyroid hormone (T3 & T4)?

Answer No. 4

Effects on Metabolism
  • Increase basal metabolic rate of most tissues (Long duration of action):
    • Increased heat production
    • Increases cardiac metabolic rate:
      • Ionotropic / chronotropic effect
    • Increased lipolysis & gluconeogenesis
Effect on Beta Receptors
  • Increases number and sensitivity of B adrenoceptors
    • Sensitises catecholamines
    • Sensitises effects of insulin
  • Increase in heart rate (HR) and myocardial contractility leading to an increase in cardiac output
Effect on Growth and Development
  • Increases Growth hormone
  • Vital in growth and development of nervous system:
    • Neuronal myelination
    • Nerve axon growth

Question No. 5

Q: Compare T3 and T4?

Answer No. 5

T3
  • Active form of thyroid hormone - 3x more potent than T4
  • 20% of T3 secreted directly from the thyroid
  • 80% converted peripherally from T4
T4
  • Often referred to as the prohormone due to low biological coactivity
  • Approximately 90% is converted in peripheral tissues to more active T3 form - principally in the liver and kidneys
  • Can also be converted to metabolically inactive reverse T3 (rT3)
    • Fasting increases the ratio of rT3:T3.

Question No. 6

Q: What are the causes of hyperthyroidism?

Answer No. 6

Mechanism
Cause
Primary Hypothyroidism
Primary Hypothyroidism
Loss of functional thyroid tissue
  • Autoimmune hypothyroidism:
    • Hashimoto's
  • Destructive thyroiditis
    • Postpartum
    • Subacute
  • Iatrogenic - treatment for malignancy or hyperthyroidism
  • Infiltrative disease (sarcoidosis)
Functional defects in thyroid hormone synthesis and release
  • Iodine deficiency (Most common worldwide)
      Drugs (Amiodarone, lithium, interferon)
        Congenital syndromes
Secondary Hypothyroidism
Secondary Hypothyroidism
Loss of functional hypothalamic or pituitary tissue
  • Hypopituitarism
  • Congenital lesions
Functional defects in TSH synthesis and release
  • Drugs (Dopamine, glucocorticoids)
  • Congenital syndromes
Peripheral Hypothyroidism
Peripheral Hypothyroidism
Resistance to thyroid hormones
  • Congenital syndromes

Question No. 7

Q: What are the clinical features of hyperthyroidism?

Answer No. 7

Hyperthyroidism is a multisystem disease:

General
  • Tremor
  • Weight loss
  • Heat intolerance
  • Diaphoresis
Cardiovascular
  • Palpitations
  • Tachycardia
  • Atrial fibrillation
  • High output cardiac failure (Dyspnoea, peripheral oedema)
Respiratory
  • Tachypnoea
  • Pulmonary hypertension
Neuromuscular
  • Brisk reflexes
  • Proximal muscle weakness
Neuropsychiatric
  • Jitteriness
  • Anxiety
  • Insomnia
  • Psychosis
Gastrointestinal
  • Diarrhoea
Genitourinary
  • Infertility
  • Amenorrhoea
Cutaneous
  • Onycholysis
  • Hyperpigmentation
  • Pretibial myxoedema*
  • Thyroid acropachy*
Ophthalmic
  • Exophthalmos*
  • Periorbital oedema*
  • Eyelid lag*
Other
  • Goitre

* Pathognomonic of Grave's Disease

Question No. 8

Q: Which drugs have an anti-thyroid effect and what are their mechanisms?

Answer No. 8

Examples
Mechansims
Inhibition of Ionic Trapping
  • Thiocyanate
  • Perchlorate
  • Inhibition of the sodium-iodide symporter (NIS) on the thyroid follicular cell membrane.
Inhibition of Hormone Synthesis
  • Thionamides:
    • Propylthiouracil
    • Carbimazole
    • Methimazole
  • Inhibition of thyroperixodase preventing organification or iodine
Inhibition of Hormone Release
  • Iodides:
    • Potassium Iodide (Lugol's Iodine)
    • Sodium Iodide
  • Increased resistance of thyroglobulin to proteolytic degradation
  • (Iodides also prevent ionic trapping and hormone synthesis)
Prevention of Peripheral Conversion to Thyroid Hormone
  • Corticosteroids
  • Propranolol
  • Propylthiouracil
  • Amiodarone
  • Radiocontrast media
  • Increased type 3 deiodinase activity
Destruction of Thyroid Tissue
  • Radioactive iodine (131,125,123)

Question No. 9

Q: Which drugs can be used to counteract the peripheral effects of thyroid hormones?

Answer No. 9

β-blockers (Propranolol, Esmolol)
  • Standard of acute care - most of the immediately life-threatening consequences of thyroid storm are cardiovascular
  • Effective in controlling heart rate; with a slower rate the cardiac failure may actually improve and the blood pressure may paradoxically increase
Diltiazem
  • Effective at controlling heart rate in patients in which β-blockade is contraindicated such as asthma
Corticosteroids
  • Thyroid disease (particularly long-standing hyperthyroidism) is associated with a diminished adrenal reserve
  • Routinely used in thyroid storm to address the coexisting hypoadrenal state

Question No. 10

Q: Give some examples of thionamide drugs?

Answer No. 10

  • Thiouracils:
    • Propylthiouracil
  • Imidazoles:
    • Methimazole
    • Carbimazole

Question No. 11

Q: What are the side effects of thionamide drugs?

Answer No. 11

Significant clinical side effects include:

  • Agranulocytosis (<0.5%)
  • Transient leucopaenia (10%)
  • Mucocutaneous rash
  • Hepatotoxicity
  • Vasculitis

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