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Clinical Chemistry of Parathyroid disorders

Clinical Chemistry of Parathyroid disorders. BONE. H 2 O. Inorganic Ca-hydroxyapatit e. Ca 2+ 10-x (H 3 O + ) 2x (PO 4 3- ) 6 (OH - ) 2. Organic (osteoid). osteocalcin osteonectin osteopontin. Proteoglycans lipids. collagen (type I). 88%. 12%. CELLS IN BONE. 1. Osteoblast

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Clinical Chemistry of Parathyroid disorders

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  1. Clinical Chemistry of Parathyroid disorders

  2. BONE H2O Inorganic Ca-hydroxyapatite Ca 2+10-x (H3O+)2x(PO4 3-)6(OH-)2 Organic (osteoid) osteocalcin osteonectin osteopontin Proteoglycans lipids collagen (type I) 88% 12%

  3. CELLS IN BONE • 1. Osteoblast • - production of organic matrix (osteoid) • - potentiate and control mineralisation • - potentiate production of alkaline phosphatase • 2. Osteocyte • - connection with extracellular fluid • - regulation of Ca and Pi movement between bone and extracellular fluid • 3. Osteoclast • - polynuclear specific macrophages • - bone resorption

  4. Ca 2+ PROTEIN (albumin) Ca 2+ Anion Ca 2+ Ca 2+ Ca 2+ - - - - - - - - - - - - - - Anions HCO3- H2PO4- HPO4-2 Citrate Lactate - - - - Complexed calcium 7% Protein bound calcium 46% Free calcium 47% Total calcium (2.1-2.6 mmol/l)

  5. Hormones regulating plasma calcium concentration • Parathyroid hormone (PTH) • parathyroid glands • Calcitriol - 1-25 DHCC (active vitamin D) • Formed after hydroxylation!(liver, renal) • Calcitonin (thyreoidea C cells) • Its physiological function is not well characterized

  6. A parathyroid hormone (PTH) • Polypeptide (84 aminoacids) • Product of chief cells of parathyroid glands • N-terminal 34 AA fragment and intact PTH • are biologically active • increase of serum Ca2+ • decrease of serum phosphate

  7. Half life: 3-4 min Half life: 2-3 hours

  8. Target organs for PTH • Bone: • Ca and Pi resorption by osteoclasts • Kidney • tubular Ca reabsorption • tubular Mg reabsorption • tubular P reabsorption • tubular HCO3 reabsorption • Intestine • 1-25 DHCC production in kidneys

  9. PTH regulation and mechanism of action Stimulatory effects: Se Ca 2+ Mild hypomagnesaemia Inhibition: Se Ca 2+ Severe hypomagnesaemia Calcitriol PTH release PTH binding to the target cell receptors (Mg dependent) Adenylate cyclase cAMP Ca 2+ cellular influx to the target cells

  10. Abnormal functions of parathyroid glands • Hyperparathyroidism • Primary • Secondary (PTH increase is physiological response) • Tertiary (autonome PTH secretion) • Hypoparathyroidism • Congenital/acquired • Pseudohypoparathyroidism

  11. Secondary hyperparathyreoidism A/ With osteomalacia or rickets a. Decrease of Ca and vitamin D uptake or absorptionCa, vitamin D deficient diet, Steatorrhoea or malabsorption b. Defect in production of active vitamin D Chronic renal failure Chronic hepatopathia lack of alpha hydroxylation c.Increased inactivation of vitamin D anticonvulsive therapy d. Lack of 25 HCC transport protein e. D vitamin receptor defect B/ Without osteomalacia and rickets a. acute pancreatitis b. neonatal hypocalcaemia

  12. Secondary Tertiary Primary Se Ca2+ Phosphate Alkaline phosphatase PTH Typical biochemical features of hyperparathyroidism or N or or N or N or

  13. Parathyroid hormone-related peptide • It is elevated in 50-90% of patients with • hypercalcemia associated with malignancy • Its gene on chr 12 (PTH gene on chr 11) • 3 isoforms • N terminal end shows homology to PTH • Can bind to PTH receptors and mimic its • biological action

  14. Serum calcium Normal or decreased Increased PTH PTH Increased Increased Normal Decreased Secondary HPT Primary HPT Tumor hypercalcemia Creatinine Other causes of Hyper- calcemia Increased Normal Other causes of secondary HPT Renal disease

  15. Hypoparathyreoidism Congenital e.g. DiGeorge synd. (immunodeficiency + thymic aplasia) - Pseudohypoparathyroidism Acquired 1/ Operation a. total or partial thyroidectomy b. laryngectomy c. parathyroidectomy 2/ Autoimmune disorder 3/ Haemochromatosis 4/ infiltrative states

  16. Pseudohypoparathyroidism Hereditary disorders, plasma PTH are elevated, but superficially resembles hypoparathyroidism Type 1 Activation of adenyl cyclase is defective and cyclic AMP is not formed Rounded face and skeletal abnormalities, learning difficulties Type 2 cAMP is formed, but the responses to it are blocked Differentiation: Urinary cAMP after PTH: elevated in type 2

  17. Typical biochemical features of hypoparathyroidism True Pseudo Se Ca2+ Phosphate Alkaline phosphatase N N PTH

  18. Calcitriol • Derived from Vitamin D by successive hydroxylation UV 7-dehydrocholesterol Cholecalciferol Liver 25-(OH)-Cholecalciferol (Calcidiol) Kidney 1,25-(OH)2- Cholecalciferol (Calcitriol) 24,25-(OH)2- Cholecalciferol

  19. Regulation of hydroxylation in the kidney Synthesis of a Ca2+-binding protein (calbindin D) Longer term stimulatory effect:GH, prolactin, estrogen

  20. Calcitriol • Effects: • Ca and P absorption from intestine • Ca and P resorption from bones by osteoclasts • Receptors of calcitriol in other tissues • Cellular differentiation (normal and malignant cells) • Immunomodulatory effect : • Stimulation of production of cytokines

  21. Calcitonin • Polypeptide hormone • Thyreoid C cells • Its physiological function is unknown / under investigation • after total thyreoidectomy no clinical symptoms! • calcium homeostasis is normal • Its level is elevated • pregnancy • lactation • Has been detected • gut • CNS (neurotransmitter) • Experimentally • inhibit osteoclast activity, thus bone resorption • Clinical significance • medullary carcinoma, small cell cc

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