Calcium Hemostasis

1. Calcium Hemostasis Mohsen Al-Atawi , King Abduallh Specialized Children Hospital MNGHA Mohsen Al-Atawi , MD

2. Biological Challenges Humans & Land animals Sea animals (e.g fish) Hypocalcaemia Hypercalcemia Well- developed parathyroid glands + huge storage of calcium (bones) Well-developed Calcitonin- apparatus Mohsen Al-Atawi , MD

3. 4 glands controlling 1 element “Ca2+” • Because “Ca2+” needed for more than 100 biological functions • Just examples : • Cell growth & divisions • Bone formation • Clotting factors • Neurotransmitters • Hormone secretions • Ca-voltage channels • Muscle contractions • etc Mohsen Al-Atawi , MD

4. PTH & Calcium homeostasis Therefore, the Ca2+ balance is tightly controlled through constant regulation of 3 physiologic processes: • Intestinal absorption • Renal (re)absorption • Bone resorption (getting Ca2+from the bone) plasma Calcium : (under normal pH) 45% percent exists as the ionized (or free) Ca2+. 40% is bound to albumin 15% is complexed with citrate, sulfate, or phosphate Most of the body Ca2+ and much of the phosphate exist as “hydroxyapatite” [main mineral component of bone]. Mohsen Al-Atawi , MD

5. GIT absorption of Ca & phosphate the GIT absorption of Ca2+ and phosphate is never complete because : the need for vitamin D the formation of “insoluble salts” in the intestinal lumen, such as Calcium phosphate Calcium oxalate Magnesium phosphate. As a result around 50% of dietary Ca / po4 lost in in urine / stool Mohsen Al-Atawi , MD

6. PTH-Ca2+ relationship The PTH-Ca2+ relationship is S-shaped “very sensitive” Means very little change in Serum Ca2+ provoke a huge release PTH PTH Ca2+ As little as 0.1 changes in ionized Ca2+ can either (+) or (-) PTH Mohsen Al-Atawi , MD

7. How the Parathyroid glands sense changes in the plasma ionized Ca2+ Mohsen Al-Atawi , MD

8. Activation of the PTH1R by PTH or PTHrP causes an acute increase in several intracellular signaling molecules which include the 2 classic G protein signaling cascades, adenylate cyclase (AC) and phospholipase C(PLC) • Stimulation of the AC signaling cascade leads to activation of protein-kinase A (PKA) and phosphorylation of transcription factors, such as CREB, which regulates transcription of PTH target genes. Stimulation of the PLC signaling cascade leads to accumulation of inositol trisphosphate (IP3) and diacylglycerol (DAG); IP3 increases intracellular calcium concentration and DAG activates protein kinase C (PKC); and consequently genomic effects through transcription factors regulated by the calcium and PKC Mohsen Al-Atawi , MD

9. Continuous administration of PTH or PTHrP induces bone resorption by activating osteoclasts indirectly through their actions on osteoblastic cells When osteoclasts were physically separated from osteoblasts they did not respond to PTH; however, PTH induced resorption only after adding osteoblasts or osteoblast like cells to the cultured osteoclasts Although osteoblastic cells mediate osteoclastic responsiveness to PTH, some studies indicated that osteoclasts from several species possess functional PTH receptors. PTH stimulated osteoclast activity in the absence of osteoblasts, proposing direct and indirect actions of PTH on osteoclasts. In addition to osteoclastic bone resorption PTH is also a potent activator of osteoclastic mobility Mohsen Al-Atawi , MD

10. PTH has several effects on osteoclast formation are mediated by its actions on the production of the receptor activator of nuclear factor-κB ligand (RANKL( and its soluble decoy receptor for RANKL, osteoprotegerin (OPG) PTH stimulates (+) RANKL and inhibits (-)OPG mRNA expressionand dependent on the stage of differentiation of the osteoblastic cells OPG selectively inhibited osteoclast differentiation and function in vitro and in vivo Mohsen Al-Atawi , MD

11. Which bone to attack? Mohsen Al-Atawi , MD

12. Calcium Disorders • Hypocalcaemia (low Calcium) • Low serum “total calcium” • Definition (age-dependent) • -premature if Calcium < 1.75 mmol/L • -infant if Calcium < 2 mmol/L • Children & adult if calcium < 2.25 mmol/l

13. Hypocalcaemia-Causes Parathyroid Glands PTH Mohsen Al-Atawi , MD

14. Hypoparathyroidism-Genetic 1- DiGeorge syndrome: Hypoparathyroidism (aplasia or hypoplasia). Thymic (aplasia or hypoplasia) Cardiac defect (outflow tract) Developmental delay Facial appearance (prominent nose, squared nasal root). It is a result of abnormal development of the 3rd -4th and fourth branchial pouches.Most cases are sporadic but familial cases with autosomal dominant inheritance have been reported. Most patients have deletion of the region of chromosome 22q11.2 2- HDR syndrome : Features : • Hypoparathyroidism (AD) (low PTH) • Renal dysplasia • Deafness (sensorineural) Cause : Mutations in GATA3, a gene localized to the chromosome region 10p14-15 • GATA3 is a transcription factor that is involved in the embryonic development of the parathyroid glands, kidneys, inner ears, thymus, and central nervous findings.

15. 3- Kenney-Caffey type 1 (HRD) Autosomal recessive form of Kenney-Caffey-1 Hypoparathyroidism (congenital) Dysmorphology (facial) Retardation of growth (severe failure) HRD almost exclusively in Arab families. It is caused by mutations in TBCE (tubulin specific chaperone E gene), which encodes a protein involved in tubulin folding (1q42-q43 ) 4- Hypoparathyroidism (X-linked recessive) caused by a deletion-insertion rearrangement involving chromosomes Xq27.1 - 2p25.3 Affected male infants develop hypocalcemia with seizures because of an isolated defect in the development of the parathyroid gland.

16. Hypoparathyroidism-Mitochondrial Several mitochondrial disorders have been associated with hypoparathyroidism 1-Kearns Sayre syndrome (KSS) Ophthalmoplegia Pigmentary degeneration of the retina Cardiomyopathy Hypoparathyroidism 2-MELAS syndrome: Metabolic acidosis (Lactic acidosis) Encephalopathy Stroke-like episode Hypoparathyroidism 3-Mitochondrial trifunctional protein deficiency syndrome (MTPDS) it is a fatty acid oxidation disorder Peripheral neuropathy Pigmentary retinopathy Hypoparathyroidism

17. Hypoparathyroidism- Autoimmune APECED syndrome IAutoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome ( also known as autoimmune polyglandular syndrome type 1 (APS1). Hypoparathyroidism Adrenal insufficiency (primary) Candidiasis (chronic mucocutaneous) immunologic destruction of the parathyroid gland occurs in association with destruction of other endocrine glands. APECED is due to mutations in AIRE (autoimmune regulator gene), which is expressed in the thymus, lymph nodes, pancreas, adrenal cortex

18. Hypoparathyroidism- Acquired 1- Thyroid surgery Parathyroid glands are embedded inside Thyroid gland) , as a result of manipulation of the blood supply to or removal of one or more parathyroid glands. In most cases, the hypoparathyroidism and hypocalcemia are transient. 2- Parathyroidectomy to remove a parathyroid adenoma or hyperplastic gland (eg, in patients with end-stage renal failure and hyperparathyroidism). The pre-surgical hypercalcemia suppresses PTH from the remaining glands or tissue, resulting in transient hypoparathyroidism and hypocalcemia immediately after surgery. In addition, some patients may develop the hungry bone syndrome because of an increase in bone resorption, which increases the severity of hypocalcemia post-operatively. (3- 3-Deposition of certain elements in the parathyroid glands like in patients requiring chronic transfusions (eg, beta thalassemia major) or Copper deposition in patients with Wilson's disease .the deposition lead to parathyroid destruction 4- Gram-negative sepsis, toxic shock syndrome, and AIDS. (The etiology of the hypoparathyroidism in these condition is unknown but may be related to macrophage-generated cytokines, which can affect PTH and vitamin D secretion and action.

19. Hypocalcaemia Parathyroid Glands PTH Mohsen Al-Atawi , MD

20. Hypoparathyroidism - CaSR defect(Calcium-sensing receptor) Autosomal dominant hypoparathyroidism — ADHH (CaSR defect) often confused with the diagnosis of isolated primary hypoparathyroidism. The following finding should alert you for the ADHH (CaSR defect) Hypocalcemia with hypercalcemia (high Urine Calcium). PTH (normal) Recurrent nephrolithiasis / nephrocalcinosis Caused by activating (+) mutation in the calcium-sensing receptor (CaSR). This causes hypocalcemia by shifting the set point of CaSR, such that PTH is not released at serum calcium concentrations that normally trigger PTH release. Present in the neonatal period with hypocalcaemia .Not uncommon for subjects to be asymptomatic with mild to moderate hypocalcemia. During periods of stress such as a febrile illness, patients can become symptomatic with seizures, and neuromuscular irritability (tetany).

21. Hypocalcaemia Parathyroid Glands PTH Mohsen Al-Atawi , MD

22. Hypoparathyriodism-Mg2+ • Hypoparathyriodism can be due to Mg2+ Because Mg2+ rapture the PTH vesicles to to allow PTH exit

23. Hypocalcaemia Parathyroid Glands PTH Resistance Mohsen Al-Atawi , MD

24. Pseudo-hypoparathyroidism 1-Pseudo-hypoparathyroidism (PHP) refers to a group of heterogeneous disorders defined by targeted organ (kidney and bone) unresponsiveness to PTH. PTH resistance is characterized by Hypocalcemia Hyperphosphatemia High PTH concentrations (pseudo-hypoparathyriodsim) maternally transmitted mutations that result in loss of GNAS1 function mutations of GNAS1, a gene encoding the alpha subunit of the G protein, coupled to the PTH receptor [These gene mutations result in the G protein's inability to activate adenyl cyclase upon the binding of PTH to its receptor 2-PesudoPesudohypoparathyriodism Caused by paternal loss of GNAS1 function mutations of GNAS1

25. Hypocalcaemia Parathyroid Glands PTH Mohsen Al-Atawi , MD

26. Hypovitaminosis D Disruption of vitamin D metabolism results in decrease concentrations of its most active metabolite, 1,25-dihyroxyvitamin D. • Decreased intake or production of vitamin D • Increased catabolism of vitamin D and its metabolites by the liver • Decreased 25-hydroxylation by the liver • Decreased 1-hydroxylation by the kidney END