Thyroid glandThyroid gland

The name "thyroid" comes from the Greek word which means "shield"

•Thyroid gland, the largest single endocrine gland (20-25 g), is located just below the level of the larynx

•It has two lobes joined by a central isthmus at tracheal rings 2, 3, 4

•Blood flow is ~ 5mL/min from superior and inferior thyroid arteries

•Composed of numerous spherical follicles with outer layer of cuboidal epithelium and filled with proteinous colloid (proteinaceous depot of thyroid hormone precursor)

•A few C cells (parafollicular cells) are seen in the walls of the follicles that produce calcitonin, a hypocalcemic hormone

Ca++

•About 80 μg/day of iodine is utilized for thyroid hormone synthesis

•Activity of the gland is regulated by TRH-TSH axis

•TRH (a tripeptide) thyrotrops TSH T4, T3

• T4, T3 TSH receptors on thyroid gland T4, T3

•TSH stimulates all steps of thyroid hormones synthesis

•TSH binds with membrane receptors adenylate cyclase c-AMP protein kinases effects

• T4, T3 TSH secretion

•Circulating T4 & T3 act directly on the anterior pituitary (negative feedback loop)

•Hypothalamus receives input and sends a signal to the Anterior Pituitary via TRH Thyrotrophin Releasing Hormone.

•TRH stimulates the Anterior Pituitary to release TSH.

•Thyrotrophin which travels in the blood to the Thyroid Gland.

•Thyrotrophin increases I- uptake and stimulates production of M.I.T., D.I.T. And hence production of T3 and T4.

•Somatostatin released by the Hypothalamus inhibits TRH release.

•Protirelin is a synthetic compound that mimics TRH.

Thyrotrophin

There is negative feedback between Thyrotrophin and T4 secreted by the Thyroid gland. Thyrotrophin stimulates follicle cell receptors, which leads to:

•increased uptake of I- (main mechanism of action) •stimulates cAMP production inside the follicle cells

•increases synthesis of thyroglobulin •leads to generation of H2O2 for the iodination of iodine

Plasma Iodide Concentration

•This has a pronounced effect on Thyroid function. •Daily intake of Iodide (70mg) is required to maintain T4 production.

•Decreased Iodide in the diet causes decreased hormone production and stimulates TSH release.

•Very slow response (weeks) to changed Iodide levels in the blood. •Can take a long time for imbalances to manifest in symptoms.

Hormone synthesisHormone synthesis Iodine trapping and organification:-extracellular iodide is trapped into follicular cells oxidesed (peroxidase in presence of H2O2) iodine + tyrosine molecule in thyroglobulin MIT & DIT

Coupling (peroxidase enzyme):-MIT + DIT T3 (triiodothyronine)-2 DIT T4 (thyroxine)-T3 & T4 remain stored in the colloid

Release:-T4, T3, MIT, DIT on thyroglobulin endocytosis lysosomes

(stimulated by TSH) proteolysis of the thyroglobulin molecule T4, T3

secreted- MIT & DIT are deiodinized iodine is reused for thyroid hormone synthesis

Steps of thyroid hormone synthesis

Iodine trapping (using iodide pump); thyroglobulin synthesis; oxidation of iodide to iodine;iodination of tyrosine molecules within the thyroglobulin molecule to give MIT and DIT at the

apical border of the cell; coupling of MIT and DIT to give T3 and T4 still within thethyroglobulin molecule in the colloid; pinocytosis of thyroglobulin and proteolysis of

thyroglobulin and release of T3 and T4

Transport of Thyroid Hormones

Once T3 and T4 are released into the blood they are bound to a serum protein,thyroxine-binding globulin (TBG), albumin and prealbumin

Only free (unbound) hormone is metabolically active

Total hormone level increases when TBG increases (in pregnancy or with oralcontraceptive treatment)

Concentrations of T3 and T4 are quite different in blood and inside cells:

T3•Small pool in the body •Mostly found inside tissue cells •Fast turnover rate in the body

T4 •Large pool in the body •Mostly found in the blood •Slow turnover rate in the body •T4 is often regarded as a prohormone as it is converted to T3 once inside cells.

Effects of thyroid hormonesEffects of thyroid hormonesT3/T4 enter the target cell cytoplasm T3 binds to nuclear receptorsmessenger RNA protein synthesis effects on cellular function

Calorigenic effects:- oxygen consumption (exception – brain, testes, pituitary) & heat production- basal metabolic rate (BMR)

Metabolic effects:- cellular & gastrointestinal absorption of glucose, glycolisis & gluconeogenesis- catabolism of free fatty acids + depletion of fat stores & blood lipids (cholesterol)- protein synthesis & breakdown- conversion of ß-carotene to vitamin A

CNS:- CNS activity and alertness

CVS:- enhanced effects of catecholamines cardiac output & heart rate systolic blood pressure, peripheral resistance, diastolic blood pressure mean pressure is little affected- ß-adrenergic receptors number & affinity

Genitourinary:- deficiency / excess menstrual disturbances

Growth:- essential for growth and development- congenital deficiency thyroid dwarf/ cretinism- skeletal growth in childhood- promotion of normal brain development in early postnatal period, deficiency mental retardation in cretins

Alimentary tract:- excess diarrhea- deficiency constipation

Muscle:- excess muscle weakness (thyrotoxic myopathy)

Mammary gland:- milk production

Bone marrow:- deficiency anemia

Effects of Thyroid Hormone on Basal Metabolic rate

T3

GI activityFat and carbohydrate mobilization

Heart rate BMR

Metabolic waste productsOxygen consumption

Metabolic fuels

Cardiac output RespirationActive hyperemia

Abnormalities of Thyroid Function

Essentially there are 2 main cases:

1. Hyperthyroidism (elevation of Thyroid Hormones)

2. Hypothyroidism (suppression of Thyroid Hormones)

The reasons may be varied and the symptomscan include any organ system.

Hyperthyroidism (Thyrotoxicosis)

Excess activity of the Thyroid Gland leads to elevations of T3 and T4.

The effects are often metabolic, but they can affect growth anddevelopment if elevated in children.

•Increased BMR and hence O2 consumption •Hot flushes, or difficulty thermoregulating, sweating, heat sensitive

•Agitated, tremor, weight loss, increased appetite •Fatigue, tachycardia, hypertension etc.

There are 2 common conditions associated with elevations inThyroid hormones:

1. Diffuse Toxic Goitre (or Grave's Disease) 2. Toxic Nodular Goitre

Diffuse Toxic Goitre (or Grave's Disease)

•Organ specific autoimmune disease•Thyroid-stimulating immunoglobulins (IgG) targeting the

receptor •May also involve mutations in the TRH receptor

•Often see protruding eyes (exophthalmos) •Often patients are sensitive to catecholamines

•Classic increases in metabolic processes

Toxic Nodular Goitre

•Usually associated with benign neoplasm, adenoma of thyroid •May occur in patients with chronic simple goitre •There is no exophthalmos seen in this condition

There are at least 2 conditions commonly associated with reducedthyroid hormone production:

1. Simple Goitre (or Non-Toxic Goitre) 2. Myxoedema

3. Hashimoto's Thyroiditis Simple Goitre (or Non-Toxic Goitre)

Simple Goitre (or Non-Toxic Goitre)

•Most often associated with reduced dietary iodine intake •This stimulates Thyrotrophic Hormone release and the

thyroid gland follicles make more thyroglobulin and the gland hypertrophies.

•May manifest as Cretinism if iodine deficiency occurs in children.

Myxoedema•Immunological in origin

•Symptoms include: - Low metabolic rate

- Slow speech - Deep hoarse voice

- Lethargy - Bradycardia

- Sensitivity to cold - Mental impairment

- Thickening of the skin

Hashimoto's Thyroiditis Simple Goitre (or Non-Toxic Goitre)

•This is a chronic autoimmune disease where thyroglobulin is attacked or another part of thyroid tissue •Often leads to hypothyroidism and myxoedema Simple Non-Toxic Goitre •Most often associated with reduced iodine •Leads to accumulation of thyroglobulin in the gland an it hypertrophies

The Parathyroid Gland and Calcium Homeostasis

In humans, Calcium balance is maintained by three major hormones

-parathyroid hormone-calcitonin-calcitriol

These hormones regulate Calcium levels by controlling the rate ofabsorption and excretion of Calcium from the body.

Calcium enters the body by absorption of dietary Calcium from thegut and is lost mainly through urinary excretion.

Physiological functions of Calcium in the body include:

•Maintenance of membrane permeability•Maintenance of excitability of nerve & muscle

•Release of neurotransmitters, many hormones & exocrine secretions•Muscle contraction

•Formation of bone and teeth•Coagulation of blood

•Activity of many enzymes

The total body calcium in adult male amounts to ~ 1200 g (30,000 mmol)

•~99% of body calcium & 80% of phosphorus is found in bone•Only 1% is found in soft tissues & body fluids•The exchangeable calcium pool in bone amounts to ~4000 mg (100 mmol)•The plasma calcium level ranges between 9.00 and 10.5 mg/dL (2.1 and 2.6 mmol/L)•~50% is mainly bound to plasma albumin•The rest (1.0 – 1.3 mmol/L) is found in ionized form•This range is kept almost constant by a delicate regulatory mechanism, involving parathyroid hormone (PTH), calcitonin and calcitriol•For Calcium balance to maintained, an intake of 12.5-20 mmol/day is recommended for infants/adults•Higher daily intake (25 – 37.5 mmol) is recommended for adolescents and for women during pregnancy, lactation and after menopause

•Intestinal absorption of calcium occurs mainly in the duodenum•Both intestinal absorption and urinary excretion of calcium are under hormonal control.

Parathyroid hormone

•Parathyroid hormone (PTH) is a polypeptide, secreted by chief cells of four parathyroid glands located posterior to the lobes of the thyroid gland•PTH is responsible for the tight control of free Calcium in ECF – is essential for life• plasma Calcium levels PTH secretion• plasma Calcium levels PTH secretion (negative feedback)• levels of calcitriol PTH secretion (negative feedback)

Actions of parathyroid hormone (PTH)•PTH plasma Calcium•PTH plasma Phosphate•In the bone PTH activates osteoclasts mobilezes Ca&PO4•In the kidney PTH - PO4 excretion - tubular reabsorption of Calcium - converts 25-hydroxycholecalciferol active 1,25-dehydroxycholecalciferol (calcitriol) promotes intestinal calcium absorption, also mobilizes Calcium from the bone

Calcitonin•Calcitonin, a poly- peptide hormone, is secreted by the “C cells” of thyroid gland•Calcitonin secretion is stimulated by: - hypercalcemia ( plasma Calcium- major) - gastrin - cholecysokinin (CCK) - glucagon

Actions of calcitoninProduces rapid in plasma Calcium by:-suppressing bone osteoclasts mobilization of bone Calcium- the activity of osteoblasts meneralization of bone ECF Calcium-in the long term, number of osteoclasts in bones-has inhibitory effects on the transport of Calcium from the intracellular fluid to the extracellular fluid

Vitamin D

•Vitamin D is a fat soluble vitamin which comes from the diet (main source) and the skin (vitamin D3 /cholecalciferol)•UV radiation from sunlight 7-dehydrocholesterol vitamin D3 (in skin) 25-hydroxycholecalciferol (25-(OH)-D ) in the liver 1,25-hydroxychlecalciferol (calcitriol) in the kidney•Formation of calcitriol is stimulated by: - PTH - plasma Calcium - plasma PO4

Vitamin D metabolism

Actions of calcitriol

•the rate of calcium uptake from the gut•Stimulate PO4 reabsorption from the gut•Stimulates Calcium and PO4

reabsorption from the kidney•High doses osteoclastic bone resorption

Clinical

Primary hyperparathyroidism ( PTH)•Results from failure of the negative feedback of plasma Calcium on parathyroid secretion•Often caused by PTH-secreting tumor•Plasma Calcium is elevated (hypercalcemia)•PO4 is reduced•Bone erosions & cyst formation•Renal calcium formationHypoparathyroidism ( PTH)•May be caused by: - parathyroid autoantibodies or - accidental damage during thyroid surgery•Hypocalcemia•Elevated plasma PO4 levels•Neuromuscular excitability muscle tetany, laryngeal spasm & convulsions

Vitamin D deficiency

•May be due to: - inadequate intake - lipid malabsorption (vitamin D is a fat-soluble vitamin) - patients with chronic renal failure•Demineralization of bone osteomalacia with bone pain in adults•Skeletal deformations (rickets) in children

Calcium pool