Calcium & Phosphorus. Mineral balance and bone physiology

Transcription

1 Calcium & Phosphorus Mineral balance and bone physiology

2 Calcium 5th most abundant element on earth Free form is synthesized from CaCl 2

3 Calcium Adult average: 1100 gr (99% of which is in the bones) Plasma concentration: 10mg/dl (5meq/l) Bound to plasma proteins (important for measurements) ph and other electrolytes effect plasma level Calcium ion is a very important secondary messenger Essential for blood coagulation, muscle contraction and neural activity Calcium absorbtion: Mostly active transport

4 Calcium 2 storage types in bones: Stable (mostly constant) store Dynamic store (easily mobilized) 2 independent but related homeostatic mechanisms: Plasma calcium regulation system: 500mmol / day calcium enters or leaves dynamic store in bones Constant resorption and remodeling of bones

5 Calcium 99% of calcium in ultrafiltrate is reabsorbed mostly from proxymal tubule (60%) and distal tubule Distal tubule reabsorption is regulated by PTH!!! Protein rich foods can increase reabsorption Total diffusable Total non-diffusable (bound) Ionized (Ca+2) 1,18 HCO3, citrate bound 0,16 Albumin bound 0,92 Globulin bound 0,24 1,34 1,16 TOTAL PLASMA CALCIUM (mmol/l) 2,50

6 Calcium

7 Phosphorus Non-metal, solid Colorless and transparent in pure form Insoluble in water

8 Phosphorus Important constituent of many vital molecules (ATP) and proteins Responsible for cellular functions regulation by phosphorylation and dephosphorylation Total body phosphorus: gr Total plasma P : 12 mg/dl Two third of it is in organic molecules Most of the inorganic phosphorus is in the form of phosphoric acid derivatives

9 Phosphorus Absorbed from the small intestines by active and passive transport mechanisms Absoption from intestines is increased by 1,25 D 90% of phosphorus in the ultrafiltrate is reabsorbed from proximal tubule and this reabsorption is inhibited by PTH!!!

10 Phosphorus

11 Calcium Related Hormones 1,25 dihydroxycholecalciferol (Calcitriol) Parathormone Calcitonin Parathormone related protein (PTHrP)

12 Vitamin D A group of sterols that are closely related and synthesized from provitamins with the help of UV Increases Ca and P absorption from intestines Increases Ca and P reabsorption from kidneys Increases bone resorption for remodeling

13

14 Parathormone (PTH)

15 Parathormone Polypeptide hormone (84 amino acid long) Synthesized in the chief cells of parathyroid gland Released in response to decreased plasma calcium!! Vitamin D decreases its synthesis Increased plasma phosphate compounds stimulate PTH secretion by inhibition of vitamin D production

16

17 PTH Physiopathology Primary hyperparathyroidism Secondary hyperparathyroidism Hypoparathyroidism Pseudohypoparathyroidism Hypocalcemia Hyperphosphatemia Shortness Short neck Obesity Subdermal calcifications

18 Calcitonin 32 aa straight peptide Lowers plasma calcium levels Synthesized by parafollicular C cells of thyroid gland Half life: < 10 minutes Secreted when plasma calcium is over 9.5 mg/dl Inhibits osteoclasts, lowers Ca and P Estrogen increases its secretion

19

20

21 PTHrP 140 aa Stimulates chondrocyte activity in developing cartilage tissue Synthesized by mammary glands and found in milk Breast feeding does not increase plasma level

22 Regulation of Ca & P Metabolism

23 Normal Ca & P Metabolism

24

25

26 Bone Physiology

27 Internal Structure of a Bone

28

29

30 Cell Types

31 Osteoblasts Grown in the bone marrow from fibroblasts Bone producing cells! Synthesize type I collagen and matrix proteins Mature into osteocytes (real bone cells)

32 Osteocytes Formed from low metabolic activity osteoblasts Trapped in the calcified bone tissue Low secretion activity Necessary for bones to stay alive Provide nutrient transport for bones (because the matrix is calcified) which is important for the survival of the osteocytes that are far from the capillaries Extensions of these cells shortened with age Old osteocytes die and the matrix is resorbed by osteoclasts

33 Osteoclasts Grown in the bone marrow Very large (150µm) multiple nuclei (20 50) Resorption of the bone Monocyte family; stems from the blood (hematopoietic stem cells) They reside on the surface of trabecules or on the inner surface of compact bone (resorption areas). This provides the remodeling of the bones Calcium as by-product of resorption increases plasma calcium level

34 Balance

35 Bone Compact bone 80% Outer part of all bones Haversian canal Trabecular bone 20% Interiors of flat bones Interiors of the metphysis and epiphysis regions of the short and long bones Nutrients are used by diffusion

36 Bone Organic Matrix 30% of the bone weight % collagen fibers Gelatinous medium ECF Proteoglycans Inorganic Salts 70% of the bone weight Calcium and phosphate Hydroxyapatite crystal : Ca 10 (PO 4 ) 6 (OH) 2 Collagen fibers provide stretch resistance Calcium salts provide pressure resistance

37 RANK-L Receptor activator of nuclear factor kappa-b ligand Also known as TRANCE (TNF receptor subfamily) Part of RANK/RANK-L/OPG signaling pathway Regulates osteoclast differentiation and activation Associated with bone remodeling and repair

38 Osteoprotegerin (OPG) Decoy reseptor for RANK Competes for RANK-L Regulates the stimulation of RANK signaling pathway

39

40

41 Adrenal Cortex & Medulla

42 Secretions Adrenal Cortex Steroid hormones Vital Adrenal Medulla Catecholamines A sympathetic ganglion with secretory neurons that lost their axons Not vital but necessary for adaptation

43 Adrenal Medulla 28% of the adrenal gland volume Rich in neural innervations Granular cells Adrenaline secreting type (90%) Noradrenaline secreting type (10%) Dopamine secreting type (?)

44 Adrenal Cortex Zona glomerulosa (15%) Zona fasciculata (50%) Zona reticularis (7%)

45 Adrenal Cortex Cortex cells (especially z. glomerulosa) contains high lipid All cortex layers secrete corticosterone but: Effective enzyme activity necessary for aldosterone biosynthesis is located within the z. glomerulosa For cortisol (glucocorticoids) it is located in z. fasciculata For sex steroids it is located in z. reticularis

46 Adrenal Medulla Hormones Hormone synthesis: Tyrosine hydroxylation Tyrosine decarboxylation Noradrenaline methylation PNMT activity is increased by glucocorticoids

47 Adrenal Medulla Hormones t ½ = ~2 minutes Some (35%) hormones are converted to Vanilylmandelic Acid (VMA) Some (50%) to metanephrine / normetanephrine

48 Effects of Catecholamines Mimics sympathetic activity Glycogenolysis in liver and skeletal muscle Release of free fatty acids Increase of metabolic activity and lactate production A and NA, increases cardiac contractility and rate via stimulation of beta 1 (β1) receptor A causes vasodilatation in liver and muscle cells via beta 2 (β2) receptor

49 Effects of Catecholamines Increases awakeness A causes fear and anxiety

50 Circulatory Effects

51 Adrenal Cortex Hormones Cholesterol derivatives C 21 steroids Mineralocorticoids Glucocorticoids C 19 steroids Androgens C 18 steroids

52 Adrenal Cortex Hormones Mineralocorticoids: Aldosterone Deoxycorticosterone Glucocorticoids: Cortisol Corticosterone Androgens: Dehydroepiandrosterone (DHEA) Androstenedione

53 Rate limiting enzyme Stimulated by ACTH

54 Glucocorticoids Cortisol (prototype) Corticosterone Cortisone (synthetic) Prednisolone (synthetic) Methylprednisolone (synthetic) Dexamethasone (synthetic)

55 Glucocorticoids

56 Mineralocorticoids Aldosterone (prototype) Deoxycorticosterone Corticosterone Cortisol Cortisone (synthetic) 9α Fluorocotrisol (synthetic)

57 Enzyme Deficiencies Cholesterol Desmolase Lethal, (in-utero death) 3β Hydroxysteroid dehydrogenase Increased DHEA Masculinization Hypospadias

58 Enzyme Deficiencies 17α Hydroxylase No sex hormone production Increased mineralocorticoid activity (HT) 21β Hydroxylase Congenital virilizing adrenal hyperplasia HT

59 Adrenogenital Syndrome

60 Metabolism of Cortex Hormones

61 Effects of Adrenal Sex Hormones Androgens: Effectiveness is 20% of testosterone Masculinization only with hypersecretion Estrogens: Androstenedione is converted to estrogen in circulation Important estrogen source for men and post-menopausal women

62 Effects of Glucocorticoids Most effects are achieved by gene transcription Increased protein catabolism Insulin desensitization Antiinflammatory Increase of glucose

63 Cushing Syndrome Chronic condition of high glucocorticoids Hyperglycemia Central obesity Osteoporosis HT Striations Menstrual problems

64 Glucocorticoids Increases surfactant synthesis in lungs Decreases TSH secretion Supresses GH secretion and growth in high concentrations Controlled by ACTH

65 Mineralocorticoids Sodium acumulation in extracellular fluid Increased reabsorbtion of sodium from urine, sweat, saliva and gis secretions Increased ECF volume Potassium diuresis

66 Control of Secretion