PARATHYROID PARATHYROID HARMONEHARMONE

PARATHYROID PARATHYROID HARMONEHARMONE

By; Dr Muhammad Waseem By; Dr Muhammad Waseem KausarKausar

IMDC IMDC

Parathyroid Gland Anatomy

• Four Parathyroid glands are usually found posterior to the thyroid gland

• Total weight of parathyroid tissue is about 150mg

• Parathyroid hormone (PTH) is made by these glands

Anatomy

Parathyroid Hormone• The blood supply to the parathyroid

glands is from the thyroid arteries. • The Chief Cells are the principal

site of PTH synthesis. • Oxyphil cells have no known

functions

PTH(bovine)

Biosynthesis, Storage & Secretion of PTH

• PTH is Synthesized (ribosomes, endoplasmic ret-, golgi

app-)as the preprohormone (Preproparathyroid Hormone).

pre- pro-hormone of 115 A.A pro-hormone of 90 A.A hormone PTH 84 A.A

• PTH is synthesized continously (it is either released from the gland or degraded)

• N-terminal A.A is alanine while C-terminal A.A is glutamine (species specific).

• core of activity lies in the sequence 1 to 29 A.A from N- terminal end.

• Methionine is imp-.• PTH is released by exocytosis in response to reduced

plasma calcium• Vitamin D feeds back to reduce PTH secretion as a

secondary mechanism

biosynthesis• mRNA codes for pre-pro PTH found

in polysomes adhering on RER. • pre- pro-hormone of 115 A.AN- terminal 25 AA pre-sequence is removed

(hydrophobic, a peptidase of RER, within 1 min- of it’s synthesis), then Pro-PTH is formed.

• pro-hormone of 90 A.ATransferred to G.App-Colipase at N- terminal removes Hexapeptide.Leaving PTH .

release• PTH 84 A.A,

time elapsed 15 – 20 min-.• Packed & stored in sec- vesicles• Secr- by exocytosis↑cAMP and ↓Ca causes its release, while ↑ Ca opposite

effect.

Ch hypocalcemia → hypertrophy & hyperplasia

Ch hypercalcemia → atrophy & hypoplasia

At normal Ca= ↓ Mg stimulates, while ↑Mg inhibit.

Ca is 2-4 times potent then Mg

Epinephrine & other β adr- =stimulates

vit D = ↓ synthesis and secretion

Regulation of PTH• The dominant regulator of PTH is

plasma Ca2+. • Secretion of PTH is inversely related

to [Ca2+]. • Maximum secretion of PTH occurs

at plasma Ca2+ below 3.5 mg/dL. • At Ca2+ above 5.5 mg/dL, PTH

secretion is maximally inhibited.

Calcium regulates PTH

• PTH secretion responds to small alterations in plasma Ca2+ within seconds.

• A unique calcium receptor within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of Ca2+.

• This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase—result is increase in intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.

Regulation of PTH

• When Ca2+ falls, cAMP rises and PTH is secreted.

• 1,25-(OH)2-D inhibits PTH gene expression, providing another level of feedback control of PTH.

• Despite close connection between Ca2+ and PO4, no direct control of PTH is exerted by phosphate levels.

Regulation of PTH

Calcium Regulation of PTH Release• Parathyroid

gland chief cell calcium receptor has two signal transduction systems– Inositol

triphosphate which reduces PTH release

– cAMP which increases PTH release

Biological Activity of PTH• BONE

– PTH stimulates bone osteoblasts to increase growth & metabolic activity

– PTH stimulated bone resorption releases calcium & phosphate into blood

• KIDNEY– PTH increases reabsorption of calcium &

reduces reabsorption of phosphate– Net effect of its action is increased

calcium & reduced phosphate in plasma

• INTESTINE– Increases calcium reabsorption via

vitamin D

Mechanism of action

• 1, increases serum Ca+ by acting on bones, kidney and intestine binds to sp- receptorsa, activates adenyl cyclase c AMP activating c AMP dependent protein kinases, which phosphorylates sp- protein in target cells

b, c AMP also Ca+ in these cells, which acts as second messenger

Metabolic role of PTHThe rise in calcium concentration is caused

principally by two effects: (1)an effect of PTH to increase calcium and

phosphate absorption from the bone (2) a rapid effect of PTH to decrease the excretion

of calcium by the kidneys. The decline in phosphate concentration is caused

by a strong effectof PTH to increase renal phosphate excretion, override

increased phosphate absorption from the bone.

• Parathyroid Hormone Increases Calcium and Phosphate Absorption from the Bone BY

• 1, a rapid phase (in minutes) and increases progressively for several hours. This phase results from activation of the already existing osteocytes to promote calcium and phosphate absorption.

• 2, slower phase , requiring several days or even weeks to become fully developed;

It results from proliferation of the osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone itself, not merely absorption of the calcium phosphosphate salts from the bone.

• Parathyroid Hormone Decreases Calcium Excretion and Increases Phosphate Excretion by the Kidneys late distal tubules, collecting tubules, the early collecting ducts,

• Parathyroid Hormone Increases Intestinal Absorption of Calcium and Phosphate

by increasing the formation in the kidneys of 1,25-dihydroxycholecalciferol from vitamin D,

Interactions of PTH and Calcitonin

Control of Parathyroid Secretion

• by Calcium Ion Concentration A slight decrease in calcium ion conc- causes the

parathyroid glands to increase their rate of secretion within minutes.glands will hypertrophy in rickets, in pregnancy,during lactation

Conversely, reduced size of the parathyroid glands. Such conditions

include (1) excess quantities of calcium in the diet, (2) increased vitamin D in the diet, and (3) Bone absorption caused by factors other than PTH (for example, bone absorption caused by disuse of thebones).

• PTH-deficient hypoparathyroidism – Reduced or absent synthesis of PTH– Often due to inadvertent removal of

excessive parathyroid tissue during thyroid or parathyroid surgery

• PTH-ineffective hypoparathyroidism – Synthesis of biologically inactive PTH

Hypoparathyroidism

Hypoparathyroidism• Hypocalcemia occurs when there is

inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuli

• Hypocalcemia is often multifactorial• Hypocalcemia is invariably

associated with hypoparathyroidism• Bihormonal—concomitant decrease

in 1,25-(OH)2-D

Hypoparathyroidism

• the osteocytic reabsorption of exchangeable calcium decreases and the osteoclasts become almost totally inactive.

• the level of calcium in the body fluids decreases.• the bone usually remains strong.• When calcium level is reached 6-7 mg/dl,

tetany develop. Among the muscles of the body especially sensitive to tetanic spasm are the laryngeal muscles. Spasm of these muscles obstructs respiration, which is the usual cause of death in tetany unless appropriate treatment is applied.

Pseudohypoparathyroidism• PTH-resistant hypoparathyroidism

– Due to defect in PTH receptor-adenylate cyclase complex

• Mutation in Gs subunit• Patients are also resistant to TSH,

glucagon and gonadotropins

Hyperparathyroidism

• Primary Hyperparathyroidisminappropriate, excess PTH( hypercalcemia)causetumor of one of the parathyroid glands;

• more frequently in women than in men or children, because pregnancy and lactation

• extreme osteoclastic activity in the bones. This elevates the calcium ion concentration depressing the concentration of phosphate ions because of increased renal excretion of phosphate.

Primary Hyperparathyroidism

• Calcium homeostatic loss due to excessive PTH secretion

• adenomatous or hyperplastic parathyroid tissue

• Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption

• Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D.

Secondary Hyperparathyroidism

• high levels of PTH occur as a compensation for hypocalcemia

• caused by• vitamin D deficiency or chronic renal disease

in which the damaged kidneys are unable to produce

sufficient amounts of the active form of vitamin D, 1,25- dihydroxycholecalciferol.

Osteomalacia and rickets

Hypercalcemia of Malignancy

• Underlying cause is generally excessive bone resorption by one of three mechanisms

• 1,25-(OH)2-D synthesis by lymphomas • Local osteolytic hypercalcemia

– 20% of all hypercalcemia of malignancy

• Humoral hypercalcemia of malignancy– Over-expression of PTH-related protein

(PTHrP)

PTHrP(paratharmone-related peptide)• Produced by gene on ch- 12, while PTH gene is

on ch- 11• Three forms of PTHrP identified, all about twice

the size of native PTH• 141 AA, 8 – 13 are homologues from N

terminus.• Marked structural homology with PTH• PTHrP and PTH bind to the same receptor• PTHrP reproduce full spectrum of PTH activities• Produced by tumors, sq cell ca of lung,

esophagus, cervix, ca pancreas and breast.

PTH receptor defect• Rare disease known as Jansen’s

metaphyseal chondrodysplasia• Characterized by hypercalcemia,

hypophosphotemia, short-limbed dwarfism

• Due to activating mutation of PTH receptor

Changes in Calcium Balance

Electrolyte Causes Symptoms

Hypocalcemia

Low Calcium(<4 mEq/l)

Normal Range:

4.5 – 5.3 mEq/l)

Hypoparathyroidism, increased loss, decreased intake, elevated phosphate

Numbness and tingling of fingers, hyperactive reflexes, muscle tetany, bone fractures, laryngeal muscle spasms that lead to asphyxiation

Hypercalcemia

High Calcium(>11 mEq/l)

Hyperparathyroidism, excessive vitamin D, Paget’s disease

Lethargy, weakness, anorexia, nausea, vomiting, polyuria, itching, bone pain, depression, confusion, and coma