Calcium PTH Vitamin D basics

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Calcium PTH Vitamin D basics

• Amani Alhozali
• Endocrine fellow R5

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Objective

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

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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

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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)

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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.

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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

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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.

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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

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• 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.

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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.

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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

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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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