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Calcium PTH Vitamin D basics

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Title: Calcium PTH Vitamin D basics


1
Calcium PTH Vitamin D basics
  • Amani Alhozali
  • Endocrine fellow R5

2
Objective
  • Calcium homeostasis
  • PTH structure and function
  • CaR structure and actions
  • Vitamin D metabolism and action
  • Calcitonin.

3
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

4
Calcium metabolism
  • Extracellular and intracellular calcium level are
    tightly 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 1.250.07mmol/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.

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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)

8
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
  • 12-15of normal persons have 5th gland
  • Parathyroid gland arise from 3rd4th branchial
    pouches.

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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.

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PTH assay
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PTH Receptors.
  • 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
    carboxyl-terminal region of PTH,PTH 7-84 and
    shown to possess hypocalcemic activity ,that is
    reserved by PTH1-34and PTH 1-84.the C-PTHRs are
    present in different tissue but expressed
    heavily in bone .

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PTH
  • PTH regulate ionized ca level by effect on 3
    target 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.

19
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

20
Skeletal actions of PTH
  • PTH acts on bone to release calcium in two
    phases
  • 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.

21
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.

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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.

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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.
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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 Na-K-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.

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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.

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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)

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Familial Hypocalciuric Hypercalcaemia
  • FHH result from an inactivation mutation in the
    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.

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FHH
  • FHH is a bening cause of hypocalcaemia
    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.

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Distinction from primary hyperparathyroidism
  • Absence of osteopenia ,osteitis fibrosa
    ,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.

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  • 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

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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
    calcium-sensing receptor in the loop of Henle.

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The diagnosis of autosomal dominant hypocalcemia
should be suspected in hypocalcemic patients with
the following features
  • Normal (or only slightly low) serum PTH
    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

39
  • 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.

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Vitamin D
  • The term vitamin D (calciferol) refers to two
    secosteroids vitamin D2 (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
    over-the-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.

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VITAMIN D synthesis and metabolism.
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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.

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Action of Vitamin D
  • Intestinal action of Vitamin D
  • 1,25 (OH)2D enhance the efficacy of small
    intestine to absorbed 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.

46
Action of Vitamin D in Bone
  • Vitamin D is essential for the development
    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.

47
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 .

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  • Vitamin D Dependent Rickets (VDDR) type I is a
    rare AR disease due to mutation in 25(OH)D 1-
    hydroxylase 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

50
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.

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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.

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CACITONIN
  • Calcitonin is important as a tumure marker in
    MCT.
  • Calcitonin has several therapeutic uses as an
    inhibitor of osteoclastic bone resorption.

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  • THANKS

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