PARATHYROID

PARATHYROID
HARMONE
HARMONE

By; Dr Muhammad Waseem Kausar

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.A
N- 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.A
Transferred 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
 Regulation of 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.
 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- receptors
a, 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 PTH
The 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 effect
of 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 the
bones).
 Hypoparathyroidism
• 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
• 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 Gs subunit
• Patients are also resistant to TSH,
glucagon and gonadotropins
 Hyperparathyroidism

• Primary Hyperparathyroidism
inappropriate, excess PTH( hypercalcemia)
cause
tumor 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 Hypoparathyroidism, Numbness and tingling
increased loss, decreased of fingers, hyperactive
Low Calcium intake, elevated reflexes, muscle tetany,
(<4 mEq/l) phosphate bone fractures, laryngeal
Normal Range: muscle spasms that lead
4.5 – 5.3 mEq/l) to asphyxiation

Hypercalcemia Hyperparathyroidism, Lethargy, weakness,

excessive vitamin D, anorexia, nausea,
High Calcium Paget’s disease vomiting, polyuria,
(>11 mEq/l) itching, bone pain,
depression, confusion,
and coma