Post on 12-May-2019
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Hormone Control of Calcium Metabolism
ผศ.ดร.พญ.สุวัฒณี คุปติวฒิุ
ภาควิชาสรีรวิทยา
คณะแพทยศาสตรศิริราชพยาบาล
Aims
Calcium HomeostasisHormone Control Calcium Metabolism
Vitamin DPTHCalcitoninOther hormones
Calcium and Phosphate function
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Calcium homeostasis
INTESTINAL ABSORPTION
DIETARY HABITS,
SUPPLEMENTS BLOOD CALCIUM
BONE
KIDNEYS
URINE
THE ONLY “IN”
THE PRINCIPLE “OUT”
Bone release Ca++Bone release Ca++ Bone incorporates Ca++Bone incorporates Ca++
Intestine absorbs Ca++Intestine absorbs Ca++Kidney conserve Ca++Kidney conserve Ca++
Ca++ is excreted in urineCa++ is excreted in urine Ca++ is excreted from dietCa++ is excreted from diet
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Parathyroid hormone (PTH)84-amino acids polypeptide hormonePTH is released from the chief cells of
the parathyroid gland.A decreased in plasma Ca2+mediates the
release of PTH through calcium sensing receptor(CaSR).
PTH binds to PTH/PTHrP receptor.
2nd messenger of PTH is cAMP (PKA pathway).
Parathyroid glandsParathyroid glands
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PTH actions (Kidney)Direct
PTH increases PO43 - and HCO3- excretion
in the urine.
PTH inhibit NPT2a at proximal tubule.
PTH increases Ca2+ reabsorption at the distal
convoluted tubules (transcellular).
PTH action (distal tubules)
PTH
TrpV 5&6: epithelium calcium channels
NCX: sodium/calcium exchanger
Paracellular (proximal tubule)CaCa2+2+CaCa2+2+
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Proximal tubule
NPT2aNPT2a
PTHPTH
PTH RPTH RPiPi
PiPi
PiPi
NPT2aNPT2a
Indirect
PTH actions (Kidney)
25 HCC 1,25 DHCC1-α hydroxylase
PTH
Intestinal absorption of Ca2+
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PTH acts on osteoblasts to inhibit the synthesis of collagen (inhibition of bone formation).
PTH actions (Bone)
PTH acts on osteoblasts to stimulate secretion of RANKL , which acts on the osteoclasts to promote demineralization and Ca2+release (osteoclastic bone resorption)
RANKL: receptor activator of NF-kB ligand
PTH also activates Ca2+pumps within the surface osteoblasts to move Ca2+out of bone fluid and into the extracellular fluid (ECF).
PTH actions (Bone)
[Ca2+] ×[PO43 - ] = คาคงที่คาคงที่
[Ca2+] [PO43 - ]
[Ca2+] [PO43 - ]
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Osteoblasts
Osteoclast precursor cell RANKL
Osteoclast
PTH actions (Bone)PTH (basal level)
Osteoblasts
Bone formation
Osteoclasts
Bone resorption
Bone remodeling
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PTH actionsPTH actionsDecrease blood Ca++Decrease blood Ca++
Parathyroid glandsParathyroid glands
Increase blood Ca++Increase blood Ca++
Bone releases Ca++Bone releases Ca++ Kidney conserve Ca++Kidney conserve Ca++ Increase active Increase active VitVit D D Intestine absorbs Intestine absorbs
Ca++Ca++
Abnormal PTH secretion
PTH deficit parathyroidectomyHypocalcemia signs and symptoms
PTH excess Primary hyperparathyroidism
is the most common cause of hypercalcemia.The defect lies with the parathyroid tissue ex. adenoma
Secondary hyperparathyroidismThe defect is from other tissue such as chronic renal disease.
Hypercalcemia signs and symptoms
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Vitamin D synthesis
SKIN LIVER KIDNEY
7-DEHYDROCHOLESTEROL
VITAMIN D3
VITAMIN D3
25(OH)VITAMIN D
(25-HCC)
hν25-HYDROXYLASE
25(OH)VITAMIN D
1,25(OH)2 VITAMIN D
(1,25-DHCC)
(ACTIVE METABOLITE)
1α-HYDROXYLASE
TISSUE-SPECIFIC VITAMIN D RESPONSES
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Vitamin D mechanism of actionThe action of Vit. D is mediated by altered gene
transcription resulting in the synthesis of specific proteins.
5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE
TRANSCRIPTION START SITE
VIT D / VDR
RNA POL
IN THE NUCLEUS
Ex: CaBPs, Vitamin D3receptor
Vitamin D actionGUT
Ca2+ and PO4 3-absorption from the gut
epithelium
Ca2+ binding protein (CaBP) or by affecting Ca2+ transport directly
plasma membrane Ca2+ ATPase pump Ca2+
(PMCA) from enterocyte to blood
BONEmineralization from blood Ca2+ to bone
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Vitamin D action (enterocyte)
IMCal: Intestinal membrane calcium binding protein
Eletrochemical gradient
TrpV 5 & 6
TrpV 5&6: epithelium calcium channels
Ca2+
Ca2+
Ca2+Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Vitamin D action
KIDNEY
tubular calcium reabsorption, possibly by the action of CaBP
PARATHYROID
Inhibit transcription of the PTH gene (feedback regulation)
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Abnormal Vitamin D secretionVitamin D deficit
Uncalcified osteoid tissue Clinical syndromes broadly categorized as Ricketsand Osteomalacia.Decreased blood calcium.
Vitamin D excessHypercalcemia (rare).
Rickets / Osteomalacia
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Calcium, PTH, and Vitamin D feedback loop
NORMAL BLOOD Ca2+
RISING BLOOD Ca2+
FALLING BLOOD Ca2+
SUPPRESS PTH
STIMULATE PTH
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
Calcitonin32 amino acids peptide.
Calcitonin is released from parafollicular(C or clear cells) of the thyroid gland.
Increased plasma Ca2+can stimulate calcitonin release.cAMP is the second messenger in the secretory
process.
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Parafollicular cells
Calcitonin action
The exact physiologic role of calcitonin is uncertain.
BONEthe osteclastic activity.
KIDNEY
Ca2+excretion in urine.
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Calcium homeostasis
INTESTINAL ABSORPTION
DIETARY HABITS,
SUPPLEMENTS BLOOD CALCIUM
BONE
KIDNEYS
URINE
THE ONLY “IN”
THE PRINCIPLE “OUT”
Active vitamin DPTH
Vit DPTHCalcitonin
CalcitoninVit D
PTH
Other HormonesGH, IGFs
Thyroid hormone
Activate chondrocytesintestinal Ca2+absorption.renal PO4
3 – reabsorption.
Physiological level: Increase bone formation.
Excess: Increase bone resorption by decrease1,25 DHCC and increase renal Ca2+excretion.
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Sex hormones
Estrogen Androgen
PTH action on bone PTH action on kidney
Bone resorption Ca2+ excretion
Bone formation
Sex hormones Osteoporosis
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Other HormonesGlucocorticoids
Osteoporosis
GI Ca2+absorption.Renal Ca2+excretion.
PTH.
Blood Calcium FunctionStructure of bone and teeth
Hormone secretion and hormone action
Neurotransmission
Muscle contraction
Blood Clotting
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Blood Phosphate Function
Structure of bone and teeth
A covalent modifier of the activity of numerous enzymes.
A component of many intermediates in glucosemetabolism eg G-6-P.
A component of all high energy transfer compounds eg ATP, NADP.
Blood Calcium
Blood calcium are tightly regulated at approximately 10 mg/dl.
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Hypocalcemia: sign and symptoms
NEUROMUSCULAR: INVOLUNTARY MUSCLE CONTRACTION (TETANY), 7TH CRANIAL NERVE EXCITABILITY (CHVOSTEK’S SIGN), NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET, TROUSSEAU’S SIGN
CNS: IRRITABILITY, SEIZURES
CARDIOVASCULAR: QT PROLONGATION ON ECG
Hypercalcemia: sign and symptoms
CNS: lethargy, depression, decreased alertness, confusion, and comaGI: anorexia, constipation, nausea, and vomitingRENAL: diuresis, impaired concentrating ability, dehydration. Hypercalciuria is a risk for kidney stones.SKELETAL: most causes of hypercalcemia are associated with increased bone resorption, and thus, fracture riskCARDIOVASCULAR: shortened QT interval
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Integrated regulation of calcium and phosphate
Plasma calcium
PTH secretion
Plasma Phosphate
Renal Phosphate
1,25 DHCC
INTESTINAL ABSORPTION
BONE RESORPTION
Plasma phosphate
Urine phosphate
Urine calcium
Plasmacalcium
Calcitonin secretion
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Trousseau’s sign
Chvostek’s sign
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CaSRCaSR
CaCa2+2+
PTH gene
Gq +Gi
Down stream signaling pathway
--
PTH mRNA
prepro-PTH
pro-PTH
PTH
PTH
--
NucleusNucleus
CaSRCaSRCaCa2+2+
PTH gene
Gq +Gi
Down stream signaling pathway
--
PTH mRNA
prepro-PTH
pro-PTH
PTH
PTH
--
NucleusNucleus
1,251,25--Vit DVit D
--
CaSR gene++