Calcium basics

Report
Calcium
PTH
Vitamin D
basics
Amani Alhozali
Endocrine fellow R5
Objective
 Calcium homeostasis
 PTH structure and function
 CaR structure and actions
 Vitamin D metabolism and action
 Calcitonin.
Calcium metabolism
 Calcium ions are of critical importance for variety of vital bodily
function.
 Intracellular calcium is a key intracellular second messenger
play role in controlling various cellular processes such as
secretion ,differentiation , proliferation , motility ,and cell death.
 Extracellular calcium is crucial for proper functioning of many
tissue
»excitation-contraction coupling in the heart
&other muscles.
»synaptic transmission and other CNS function
»platelet aggregation and coagulation.
»hormones secretion
Calcium metabolism
 Extracellular and intracellular calcium level are tightly
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controlled within normal range.
About 50% of total Ca in the serum is present in
ionized form, the remainder 40% bound to albumin
and 10% complexed with PO4 or citrate.
It is the ionized ca that is regulated in extracellular
fluid.
The concentration of ionized ca 1.25±0.07mmol/L
Serum ionized calcium maintained within a very
narrow range by the close relationship of serum
ionized calcium and PTH.
This relationship is described by an inverse sigmoidal
curve.
PTH response to hypocalcaemia
 Second to minuets : exocytosis of PTH from
secretory vesicle into the extracellular fluid.
 Minutes to one hour: reduction in the intracellular
degradation of PTH.
 Hours to days : increased in PTH gene expression.
(also stimulated by low serum calcitriol)
 Days to weeks : proliferation of parathyroid cells.
( also stimulated by low serum calcitriol)
PTH Glands
 PTH secreted from four parathyroid glands
located adjacent to thyroid gland.
 The glands weigh 40 mg of each.
 Location is variable, the tow superior glands
found near posterior aspect of thyroid gland.
 The inferior glands located near the inferior
thyroid margin
 12-15%of normal persons have 5th gland
 Parathyroid gland arise from 3rd&4th branchial
pouches.
PTH
 PTH is 84- amino –acid peptide with a
molecular weight of 9300.
 PTH half-life 2-4 minutes after secretion.
 PTH cleaved to produce an amino terminal
fragment and a carboxyl terminal fragment.
 Activities of PTH are encoded in the amino
terminal.
 PTH is cleared in the liver and kidney.
PTH assay
PTH Receptors.
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There are two mammalian receptor for PTH.
PTH-1 receptor binds PTH and PTHrP with equal affinity.
PTH1R binds intact PTH and N-terminal residues.
Activation of PTH1R activates multiple cellular pathways and
release intracellular calcium stores.
PTH1R heavily expressed in bone and kidney,and also present
in other tissue such as breast ,skin ,heart ,blood vessels and
pancreas .
PTH2R selectively binds PTH only.
PTH2R expressed heavily in the CNS,CVS ,GIT, lung and
testes.
New PTH receptors (C-PTHRs) with specificity to carboxylterminal region of PTH,PTH 7-84 and shown to possess
hypocalcemic activity ,that is reserved by PTH1-34and PTH 184.the C-PTHRs are present in different tissue but expressed
heavily in bone .
PTH
 PTH regulate ionized ca level by effect on 3 target
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organ: bone ,intestine, and kidney.
PTH has direct effect on tubular reabsorption of
calcium ,phosphate and bicarbonate.
In the kidney PTH increase the reabsorption of
calcium from distal convoluted tubule.
PTH inhibit reabsorption of phosphate in renal
proximal tubule.
mild hyperchloremic metabolic acidosis in
hyperparathyrodism due to impaired bicarbonate
reabsorption.
Actions of PTH
 Classical effect of PTH mediated through
PTH1R, a G-coupled receptor expressed in
kidney and bone.
elevation of serum calcium
phosphaturia
calcitriol synthesis
Skeletal actions of PTH
 PTH acts on bone to release calcium in two phases:
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1- immediate effect to mobilize calcium from skeletal store.
2-later PTH stimulates release of calcium by activation of bone
resorption.
Osteoblasts express PTH receptors.
PTH stimulate osteoblasts ,which stimulate the transformation of
preosteoclast to mature osteoclast. Osteoclast dissolve the
mineralized collagen matrex in bone.
Chronic hyperparathyroidism result in bone resorption.
Intermittent administration of PTH stimulate bone formation
more than resorption and decrease risk of both vertebral and
non vertebral fracture in patient with osteoprosis.
Positive effect of intermittent PTH on bone mediated through
PTH1R.
Renal actions of PTH
 Reabsorption of calcium
1- calcium reabsorbed passively in the proximal
tubule and loop of Henle.
2- calcium transport actively according to chang in
calcium balance in distal tubule under control of PTH.
 PTH inhibit phosphate reabsorption mostly in
proximal tubule .
 PTH stimulates the synthesis 1- hydroxylase in
proximal tubules and thus conversion of calcidiol to
calcitriol.
Calcium sensing receptors
 CaR is a120-KDa G protein-coupled receptor. It is
member of family C of the superfamily of seven
transmembrane (7TM).
 It is expressed abundantly in
parathyroid, thyroid C cells and kidney.
 Activation of the CaR by increased extracellular
Ca2+ inhibits parathyroid hormone (PTH) secretion,
stimulates calcitonin secretion, and promotes urinary
Ca2+ excretion, and thereby maintains the
extracellular Ca2+ at the normal level .
 CaR has seven membrane- spanning domain, the
intracellular loops are directly involved in coupling the
receptor to G protein.
Calcium sensing Receptors
In Parathyroid gland:
The CaSR is normally
expressed at high
levels on the surface of
the parathyroid chief
cells . High
extracellular ionized
calcium activate CaSR
which in turn promote
calcium released from
endoplasmic reticulum
(ER) and elevation of
intracellular calcium
which inhibit PTH
secretion ,synthesis
and parathyroid
cellular proliferation.
CaSR action in the kidney
 CaSR is an important regulator of urinary calcium excretion.
 CaSR expressed on the basolateral membrane on the cells of
the thick ascending limb of the loop henle.
 Calcium binding to the receptor lead to the generation of
arachidonic acid metabolite that then inhibits K channel in the
luminal membrane and the Na-K ATPase pump in the
basolateral membrane
 Inhibition of K recycling reduces Na-Cl reabsorption via the NaK-2Cl transporter, diminishing the generation of the lumen
positive electrical gradient and therefor passive reabsorption of
ca and mg.
 Inhibition of the Na pump reduces the driving force for Na and Cl
entry from tubular fluid by Na-K2Cl cotransporter.
CaSR action in the Kidney.
 Inorganic phosphate (Pi) is absorbed by
proximal
tubules through a cellular
pathway that is inhibited by parathyroid
hormone (PTH).
 The calcium-sensing receptor (CaSR) is
expressed on apical membranes of proximal
tubule.
 CaSR activation blocks PTH-inhibitable
phosphate absorption.
case
 A 41 old woman was noted to have an elevated serum ionized
calcium level of 1.39mmol/l(1.1-1.3) during an evaluation for
infertility. her only complaints were fatigue and occasional
headaches.
She did not have any history of constipation, nausea, vomiting
,kidney stones or fractures. she was not aware of any family
history of hypercalcemia.
Her physical exam was unremarkable
Laboratory blood test;
Total calcium =2.6 mmol/l
Ionized calcium = 1.36 mmol/l
Po4 = 1.26 mmol/l
Albumin ,creatinine normal
PTH intact = 5.5 pmol/L
24 hour calcium = 3.23 mmol/l(129 mg)
Familial Hypocalciuric
Hypercalcaemia
 FHH result from an inactivation mutation in the
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calcium sensing receptor gene.
The mutation in FHH makes the receptor less
sensitive to calcium.
In the parathyroid glands a higher than normal
serum calcium required to reduce PTH .
In the kidney increase tubular calcium and
magnesium reabsorption.
The net effect is hypercalcemia , hypocalciuria , and
frequently hypermagnesemia.
FHH
 FHH is a bening cause of hypocalcaemia
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characterized by AD inheritance.
Affected heterozygous patient typically present with
hypercalcaemia ,hypocalciuria and mild to moderate
hypermagnesemia.
Homozygous state lead to more sever neonatal
hyperparathyroidism and sever hypocalcaemia.
FHH have normal or very slightly high serum PTH.
Patient usually asymptomatic or mild symptom and
sign of hypercacemia.
Distinction from primary
hyperparathyroidism
 Absence of osteopenia ,osteitis fibrosa
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,nephrolithiasis ,polyuria ,or mental changes;
however pancreatitis and gallstones is associated in
some cases of FHH.
The presence of hypercalcemia in family members.
Reduce urinary excretion of cacium.
Normal excretion of urinary cyclic AMP.
No evidence of abnormal parathyroid tissue on
ultrasound or scan.
Benign disease and no surgical parathyroidectomy.
Calcium excretion — Measurements of 24-hour urinary collection for
calcium (Ca) and creatinine (Cr) can confirm the diagnosis of FHH and
distinguish it from primary hyperparathyroidism.
Approximately 40 percent of patients with hyperparathyroid have
hypercalciuria (24-hour calcium excretion above 250 mg [6.2 mmol] in
women and 300 mg [7.5 mmol] in men) .
Calcium excretion is typically below 200 mg/day (5 mmol/day) in patients
with FHH
Calculation of the Ca/Cr clearance ratio most useful test to differentiat 2
disorders.
The ratio of calcium clearance to creatinine clerance is less than 0.01
(1%) in patient with FHH and generally between 0.02 to 0.05 (2 -5%) in
patient with primary hyperparathyroidism.
This ratio is calculated from the following formula:
Ca/Cr clearance ratio = [Urine Ca x serum Cr] ÷ [Serum Ca x Urine
Cr]
Autosomal Dominant Hpocalcemic
Hypercalciuria.
 Autosomal dominant hypocalcemia is the mirror image of FHH:
familial hypocalcemia with urinary calcium excretion which is
inappropriately high-normal or elevated in the basal state.
 The serum calcium concentration is usually in the range of 6 to
8 mg/dL (1.5 to 2.0 mmol/L).
 This disorder is associated with an activating mutation in the
calcium-sensing receptor; as a result, a low serum calcium
concentration is perceived as normal .
 Serum PTH concentrations are normal and, in contrast to other
causes of hypocalcemia, urinary calcium excretion is normal or
high, presumably due to increased activation of the calciumsensing receptor in the loop of Henle.
The diagnosis of autosomal dominant hypocalcemia
should be suspected in hypocalcemic patients with the
following features
 Normal (or only slightly low) serum PTH
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concentrations
Frequently, few if any symptoms of hypocalcemia,
despite reductions in the serum calcium
concentration that would be expected to cause
symptoms
High or high normal urinary calcium excretion rather
than the expected low excretion
A family history of hypocalcemia
Recurrent nephrolithiasis
No previous normal serum calcium values
Low serum magnesium concentration
 Treatment —
 As the serum calcium concentration increases, the activating
mutation in the calcium-sensing receptor in the loop of Henle will
lead to a marked increase in urinary calcium excretion, which
can cause renal stones, nephrocalcinosis and renal insufficiency
 Thus, the goal of therapy in symptomatic patients with
autosomal dominant (or sporadic) hypocalcemia with
hypercalciuria is to maintain a serum calcium concentration just
sufficient to alleviate the symptoms.
 A possible adjunct in patients who remain symptomatic despite
hypercalciuria is to give a thiazide diuretic to reduce urinary
calcium excretion and raise the serum calcium concentration.
Vitamin D
 The term vitamin D (calciferol) refers to two secosteroids: vitamin D2
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(ergocalciferol) and vitamin D3 ( cholecalciferol ).
Both are produced by photolysis from naturally occurring sterol
precursor.
Vitamin D3 is formed in the skin from 7-dehydrocholesterol,wich
distributed in epidermis and dermis .
The cleavage of the B ring of 7-dehydrocholesterol to form previtamin
D3 requires ultraviolet light.
Previtamin D3 undergoes thermal isomerization to vitamin D3.
Vitamin D2 is manufactured through the ultraviolet irradiation of
ergosterol from yeast ,and vitamin D3 lanolin. Both are used in overthe-counter vitamin D supplements.
Vitamin transported in the blood principally bind to DBP (85%) and
albumin (15%).
Production of 1,25(OH)2D in the kidney stimulated by PTH and IGF-1
and inhibited by FGF23 and high levels of calcium and phosphate.
VITAMIN D synthesis and
metabolism.
Mechanism of action of Vitamin D
 Genomic action :
1,25 (OH)2D enter target cell and binds to its receptor VDR. The VDR
then heterodimerized with the retinoid X receptor, RXR. The VDR –
RXR complex then binds to specific regions within the regulatory
portion of the genes called VDREs.the binding of the VDR-RXR
complex to theVDREs attracts number of other proteins called
coactivators to signal the beginning of transcription.
 Non-Genomic action
rapid action of vitaminD mediated through cell surface receptor.
Action of Vitamin D
Intestinal action of Vitamin D
 1,25 (OH)2D enhance the efficacy of small intestine to absorbed
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calcium and phosphorus.
Both vitamin D and VDR are required for optimal absorption of
calcium.
Vitamin D induce active cellular calcium uptake and transport
mechanisms.
Calcium uptake required epithelial calcium channel TRPV6 and
TRPV5.
Calcium uptake is the rate limiting step in intestinal calcium absorption,
which is highly dependent on vitamin D.
Vitamin D increase active phosphorus transport.
Action of Vitamin D in Bone
 Vitamin D is essential for the development
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&maintenance of mineralized skeleton.
Osteoblastic bone formation and osteoclastic bone
resorption demand both vitamin D and VDR.
1,25(OH)2D VDR system is critical in PTH induced
osteoclastogenesis.
1,25(OH)2D VDR increased the expression of
RANKL on the surface of osteoblast ,RANK
interaction with its receptor RANKL promotes
maturation of osteoclast progenitor cell & mature
osteoclast.
Vitamin D ,PTH and prostaglandin stimulate RANKL
expression.
Action of Vitamin D in Kidney
 The kidney expresses VDR, and 1,25 (OH)2D
stimulate Ca²-ATPase in distal tubule as well as
24,25(OH)2D production in the proximal tubule.
 1,25 dihydroxyvitamin D decrease its own synthesis
through negative feedback and decrease secretion
and synthesis of PTH.
 1,25 dihydroxyvitamin D increase expression of 25-
hydroxyvitamin D-24-hydroxylase to catabolize
1,25(OH)2D to the water-soluble ,biological inactive
calcitroic acid .
 Vitamin D Dependent Rickets (VDDR) type I is a rare
AR disease due to mutation in 25(OH)D 1hydroxylase gene result in rickets accompanied by
low level of 1,25(OH)2D.
 Vitamin D Dependant Rickets (VDDR) type II
is a rare AR disease due to inactivating mutation in
the VDR gene result in childhood rickets and high
level of 1,25(OH)2D.
many of these patient have alopecia
CAlCITONIN
 Calcitonin is a 32-amino-acid peptide
 Calcitonin secreted by parafollicular C cells of
the thyroid.
 Secretion of calcitonin is under the control of
ionized ca.
 CaSR expressed on C cell of thyroid ,high
extracellular calcium increase secretion of
calcitonin.
 Hypocalcaemia inhibit calcitonin secretion.
Action of CALCITONIN
 Osteoclast and proximal renal tubule cells
express calcitonin receptors.
 In the bone calcitonin inhibit osteoclastic
bone resorption.
 In the kidney calcitonin inhibits the
reabsorption of PO4 and increase renal
excretion of calcium.
CACITONIN
 Calcitonin is important as a tumure marker in
MCT.
 Calcitonin has several therapeutic uses as an
inhibitor of osteoclastic bone resorption.
THANKS

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