Transcript 13_Hormonal regulation of calcium and phosphorus homeostasis

HORMONAL CONTROL OF
CALCIUM and PHOSPHORUS
METABOLISM
HORMONES INVOLVED…
1,25 Dihydrocholecalciferol
Parathyroid hormone
Calcitonoin
Parathyroid hormone related protein
{ PTHrP}
Miscellaneous hormones :
Glucocorticoids, Growth hormone,
Estrogen
CALCIUM & PHOSPHATE
METABOLISM
NORMAL VALUES
Total body calcium – 1100 g {27.5 mol / L}
99 % in bones
Plasma calcium : 9 – 11 mg / dL
{5 m Eq / L or 2.5 mmol / L}
Ionized calcium – 50 % {1.2 mmol / L}
Protein bound – 41 % {1.0 mmol / L}
Complexed with anions – 9 % {0.2 mmol / L}
FUNCTIONS OF CALCIUM
FREE IONIZED CALCIUM
Blood coagulation
Muscle contraction
Transmission of nerve impulses
Formation of skeleton ,etc.
Calcium
• Regulate neuromuscular
excitability
• Blood coagulation
• Secretory processes
• Membrane integrity
• Plasma membrane transport
• Enzyme reactions
• Release of hormones and
neurotransmitters
• Bone mineralization
Calcium Homeostasis
EFFECTS OF ALTERED CALCIUM
HYPOCALCEMIA
• Nerve and muscle cells becomes hyperexcitable.
increased neuronal membrane
permeability to Na + channels
HYPOCALCEMIC TETANY – latent or manifest
Calcium at 6 mg / dL --- TETANY
at 4 mg / dL --- LETHAL
Alkaline pH – tetany at higher values.
SIGNS OF MANIFEST TETANY
CARPOPEDAL SPAM
• Laryngeal stridor
• Convulsions
• Visceral features like
intestinal spasm,
bronchospasm and
profuse sweating.
Obstetric hand /
Main d’ acconcheur hand
LATENT TETANY
• CHVOSTEK’S SIGN
• TROUSSEAU’S SIGN
HYPERCALCEMIA
CALCIUM LEVEL > 12 mg / dL
• Nervous system is depressed
• Reflex activities are sluggish
• Decreased QT interval
• Lack of appetite
CALCIUM IN BONE
Two types
1. Readily exchangeable reservoir
{500 mmol of Ca2+ is exchanged}
2. Stable calcium
{7.5 mmol of Ca2+ is exchanged}
CALCIUM IN KIDNEYS
• 98 % - 99 % is reabsorbed
60 % in PCT
40 % in Ascending limb of LOH
Distal tubule
PARATHYROID HORMONE
CALCIUM IN GIT
• 30 – 80 % of ingested calcium is absorbed
• Actively transported out of the intestinal cells with
the help of
Ca 2+ dependent ATPase
1,25 Vitamin D3
• Increased plasma calcium – decreased absorption
from the gut
• Decreased by phosphates and oxalates and alkalis
• Increased by high protein diet
DIET
25mmol (1000 mg)
BONE
RAPID
EXCHANGE
ABSORPTION
GIT
15 mmol
SECRETION
500 mmol
ECF
35 mmol
REABSORPTION
12.5 mmol
7.5 mmol
FECES
22.5mmol
EXCHANGEABLE
100 mmol
REABSORPTION
247.5
mmol GLOMERULAR
FILTRATE
250 mmol
URINE
2.5 mmol
STABLE
27,200 mmol
PHOSPHATE METABOLISM
NORMAL VALUES
• Total body phosphate – 500 to 800 g.
• 85 – 90 % in skeleton
• Plasma phosphate – 12 mg / dL
2/3rd – organic
1/3rd – inorganic {Pi}
ex. PO43- , HPO42-, H2PO42-
FUNCTIONS
ATPase , c AMP , 2-3, DPG
Phosphorylation and Dephosphorylation
BONE:
3 mg of PO4 enters and is again reabsorbed.
KIDNEYS:
85 % - 90 % of filtered Pi is reabsorbed by
Active Transport in PCT
Overflow mechanism
PTH
GIT
• Absorbed in duodenum and small intestine
by Active transport and passive diffusion.
• Absorption is linear to dietary intake.
• All PO4 excreted in urine.
VITAMIN D 3
FORMATION OF VITAMIN D3
7 DEHYDROCHOLESTEROL
SUNLIGHT
PREVITAMIN D3
VITAMIN D3
CHOLECACIFEEROL
25 HYDROXYLASE
LIVER
25- HYDROXY CHOLECALCIFEROL
24 α HYDROXYLASE
1 α HYDROXYLASE
KIDNEY
24, 25 DIHYDROXY
CHOLECALCIFEROL
1, 25 DIHYDROXY
CHOLECALCIFEROL
MECHANISM OF ACTION
• 1,25 – dihydroxycholecalciferol is a steroid
compound (secosteroid)
• Acts via the steroid receptor superfamily
• Exposes the DNA – binding domain and
results in increased transcription of some
mRNAs.
ACTIONS OF VITAMIN D3
1. Promotes intestinal calcium absorption
BY
1. Formation of calcium binding protein
(calbindin)
2. Formation of calcium stimulated ATPase
3. Formation of alkaline phosphatase
25-HYDROXYLASE
2. Promotes phosphate absorption by the
intestines
• As a direct effect
• Calcium acts as a transport mediator for
phosphate.
3. Decreases renal excretion of calcium &
phosphate
• Increases reabsorption of Ca and PO4 by the
renal tubules
4. Increases both bone resorption and bone
mineralization
BONE RESORPTION – by stimulating PTH.
Calcitriol receptors are present in osteobasts
Receptor – calcitriol complex – stimulate osteoblasts
--- activation & differentiation of osteoclasts.
BONE MINERALIZATION – by stimulation
osteoblasts and alkaline phosphatase secretion
REGULATION OF SYNTHESIS
PTH
25 –OH D3
24,25- (OH)2 D3
Ca
1,25 (OH)2 D3
BONE
&
INTESTINES
PO4
RICKETS & OSTEOMALACIA
VITAMIN D deficiency in children and adults
- defective bone mineralization and calcification
- failure to deliver adequate Ca and PO4
FEATURES:
Weakness and bowing of weight bearing bones,
dental defects and hypocalcemia.
Responsive to Vitamin D therapy.
VITAMIN D RESISTANT RICKETS:
mutations in the gene coding for the enzyme
1 α HYDROXYLASE
Rickety rosary
STRUCTURE
•
FOUR parathyroid
glands located behind
the thyroid gland
•
6 x 3 x 2 mm
•
Two types of cells
1. Chief cells
2. Oxyphil cells
CHEMISTRY
Pre pro PTH ( 115 aa)
Pro PTH ( 90 aa )
PTH ( 84 aa )
Normal plasma PTH
10 -55 pg / mL
Half life – 10 mins
ACTIONS OF PTH
I.
Increases calcium and phosphate
absorption from the bones
II. Decreases excretion of calcium by the
kidneys
III. Increases the excretion of phosphate by
the kidneys
IV. Increases intestinal absorption of calcium
and phosphate.
INCREASED PLASMA CALCIUM
 Hyperfunction
(Recklinghausen’s
disease)
- Hypercalciemia
-
hypophosphatemia
hyperphosphaturia
osteoporosis
Accumulation of Са in
tissues
 Hypofunction
-
hypocalciemia
hyperphosphatemia
hypophosphaturia
tetanus
Hyperparathyroidism: adenoma
or hyperplasia or ectopic
Hypocalcemia
DISORDERS OF PTH
• HYPOPARATHYROIDISM
• HYPERPARATHYROIDISM
primary and secondary
• PSEUDOHYPOPARATHYROIDISM
HYPOPARATHYROIDISM
•
•
•
•
Body calcium level decreases
Osteoclasts are inactive
Sudden removal – signs of tetany appears
Responds to treatment with PTH or Vitamin D3
PSEUDOHYPOPARATHYROIDISM
PTH is normal
Defect is in PTH receptors
Not responsive to hormone therapy
PRIMARY
HYPERPARATHYROIDISM
• Tumors – adenoma of parathyroid glands
• More common in women.
• Extreme osteolytic resorption calcium and
phosphate levels.
Bone :
Punched out cystic areas in the bone filled by osteoclasts
– osteoclast tumors
‘ osteitis fibrosa cystica’
Serum Alkaline phosphatase is elevated.
Hypercalcemia:
P. Calcium – 12 – 15 mg / dL
CNS depression, muscle weakness, constipation,
abdominal pain, peptic ulcer, lack of appetite etc…
Metastatic calcification:
CaHPO4 crystals are deposited in renal tubules, lung
alveoli, thyroid glands etc…
Renal stones:
Calcium phosphate and also calcium oxalate stones
SECONDARY
HYPERPARATHYROIDISM
• Increased levels of PTH is the result of
compensatory mechanism to hypocalcemia
• Due to chronic renal disease or deficiency
of Vitamin D 3
• Produced by the parafollicular cells / C cells
of thyroid gland.
• Remnants of ultimobrachial body.
STRUCTURE:
Molecular weight – 3500 and has 32
aminoacids.
In brain “Calcitonin gene related
polypeptide ( CGrP)” is formed.
Calcitonin
- Is synthesized by
parafollicular cells of
thyroid gland
-Affects the metabolism of Са and Р
-Promotes the transferring of Са2+ from blood into
bones
-Inhibits reabsorption of Р in kidneys (decreases the
content of Р in blood due to its excretion with
urine)
Increase of
calcitonin
- hypocalciemia
- hypophosphatemia
- hyperphosphaturia
Decrease of calcitonin
- hypercalciemia
- hyperphosphatemia
- hypophosphaturia
• STIMULUS : Increased plasma calcium
Others: β adrenergic agonists, dopamine and
estrogen, GASTRIN, CCK, glucagon..
• ACTIONS:
Decreases absorptive action of osteoclasts
Deposits exchangeable Ca in bone salts
Decreases the formation of osteoclasts
• CLINICAL USE:
Used in the treatment of
PAGET’S DISEASE.
OSTEOPOROSIS
Diminished bone matrix due to poor
oeteoblastic activity
Causes:
1. Lack of physical stress
2. Malnutrition
3. Postmenopausal lack of estrogen
4. Old age
5. Lack of Vitamin C
6. Cushing’s syndrome
OTHER HORMONES
PARATHYROID HORMONE RELATED PROTEIN
( PTHrP)
• Produced by different tissues of our body
• Binds to PTH receptors
• Marked effect on growth and development of cartilage in
utero.
• Cartilage growth is stimulated by a protein called
“Indian hedgehog”
• Other uses :
Brain – prevents excitotoxic damage
Placenta – transports calcium
• Defect in PTHrP – severe skeletal deformities.
GLUCOCORTICOIDS
Lowers plasma calcium by inhibiting
osteoclasts.
Over Long periods – osteoporosis
Inhibit protein synthesis in osteoblasts,thereby
synthesis of organic matrix
Inhibit absorption of Ca and Po4 from the gut
and facilitate its excretion in the kidneys.
GROWTH HORMONE
Increases intestinal absorption of Calcium
“Positive calcium balance”
IGF – I
Stimulates protein synthesis in bone.
THYROID HORMONE
Hypercalcemia, Hypercalciuria and
Osteoporosis.
ESTROGENS
Prevents osteoporosis by inhibiting certain
cytokines
INSULIN
Increases bone formation