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Mineral and bone metabolism

Mineral and bone metabolism. Dr.F.Iranmanesh. Calcium,Physiologic chemistry. Distribution: 5 th most common element Most prevalent cation in the body Healthy adult contain 1-1.3kg of calcim,99% in the form of hydroxyapatite,1% in ECF & Soft tissue

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Mineral and bone metabolism

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  1. Mineral and bone metabolism Dr.F.Iranmanesh

  2. Calcium,Physiologic chemistry • Distribution: • 5th most common element • Most prevalent cation in the body • Healthy adult contain 1-1.3kg of calcim,99% in the form of hydroxyapatite,1% in ECF & Soft tissue • Serum(Plasma) calcium exists in three forms: 1:Free(Ionized) #50% 2:Complex with anions #10% 3:Bound to plasma proteins#40%,Mostly Albumin,80%

  3. Calcium binds to negatively Charged sites of proteins ,so dependent to PH & Protein cncentration. • Alkalosis :↑ binding so decreased free ca. • Acidosis : ↓Binding so Increased free ca. • [Ca++][pr--]/[Capr]=ĸ Hostings &Mclean 1939 • [Ca++]=ĸ[pr--]/[Capr]

  4. Calcium Function • mineralization • Blood coagulation • Neural transmission • Maintenance of normal tone and excitabilityof • Skeletal and cardiac muscle. • Glandular synthesis and regulation of exocrine & endocrine glands. • Preservation of cell membrane integrity and permeability.

  5. Calcium intake • Average dietary Intake : 600-800mg/Day • Recommended 1200 mg during preg.& Lactation and 800-1200 mg during childhood. • Ca absorption : Active transport in Duodenum and upper jejunum.(50%) • Increased in pregnancy, lactation and rapid growth and decreased with advanced ages. • Major stimulus of ca. absorption is vitamin D.

  6. Absorption enhanced by Growth hormone,acidmedium,incresed protein intake. • Decreased with:Ca/phos ratio >2 • Phyticacid,Oxalate,Fattyacids,Cortisol, • Excessive alkalinity of intestinal contents.

  7. Ca Excretion • Sweath:15-100mg/day • Major loss:Urine 100-200mg/day • Wide variation in intake has little effect on U.Excretion • Enhanced by: • Acidosis,hypercalcemia,phosphate deprivation and glucocorticoids. • DecresedbyPTH,Diuretics,VitaminD

  8. Bone 1,25(OH)2D3 Calcitonin Thyroid c cells PTH Ca++ Hyper ca ECF Ca++ Parathyroid Intestine Hypocalemia Ca++ 1,25(OH)2D3 PTH Kidney 255 25-OH-D3 Phosphorus Liver Urine Calcium Homeostasis

  9. Analytical techniques :Total Calcium • Clark and collip method • Today 3 methods: • 1)Colorimetric analysis • 2)Atomic absorption spectrometry(AAS) • 3)Indirect Potentiometry

  10. Colorimetric • Metallochromatic indicators: • O-Cresolphthaleincomplexon(CPC) • Red color in alkaline solution. • Measured at 580nm. • Addition of 8 -hydroxyquinolone:↓Mg. • Arsenazo III ,Ca-indicator complex: • Measured at 650nm • High specificity at slightly acidic PH • Hemolysis ,lipemia,icterus,paraproteins and Mg intrfere with colorimetric methods.

  11. Calcein forms fluorescent complex • Stimulates at 490nm & emits at 590nm • Titration of complex with EDTA • AAS is the reference method • Dilution with Lanthanum hydrochloride to reduce viscosity and interference • from proteins and organic and inorganic ions. • Ind.Potentiometry:An electrode selective for ca.measures a sample that is also measured against a Na selective electrode.

  12. Analytical techniquesIonized calcium • Ion selective electrodes(ISE) • Accurate,precise,automatic determination of ionized(Free)Ca. • Consists of a membrane separating a reference solution (CaCl2,AgCl)and a reference electrode(Ag/AgCl or calomel) from the solution to be analyzed.

  13. Reference intervalsTotal calcium • Total ca. in adults 8.8-10.3mg/dl(2.20-2.58mmol/L) • Serum is the preferred Specimen • Heparinized plasma is also acceptable. • Citrate,Oxalate,EDTA interfere with commonly used methods. • Hemolysis ,icterus,lipemia,paraproteins and Mg interfere with colorimetric methods. • Total ca.corrected for hypoalbuminemia=total ca(measured)+[(Normal Albumin-patient,sAlb.)x0.8] • Normal albumin=4.4

  14. Reference intervalIonized calcium • 4.6-5.3mg/dl(1.16-1.32 mmol/L) • Whole blood,Heparinized plasma or serum are acceptable. • Specimens should be collected anaerbically and transported on ice and stored at 4⁰C to prevent loss of CO2 and glycolysis and stabilize PH.

  15. Reference interval Urinary calcium • Varies with diet • Average 300mg/day • Urine collection with appropriate acidification to prevent calcium salt precipitation.(15 ml hydrochloric acid)

  16. PhosphorusPhysiologic chemistry Adult body content :700mg 85% in Skeleton(Inorganic),15% in ECF & soft tissue(Organic) In blood,Plasma(Inorganic) ,cells (Organic) In serum ratio of H2PO4-:HPO4-- is pH dependent. 1:1 in acidosis,1:4 in pH 7.4,1:9 in alkalosis. Serum phosphorus 10% bound to proteins,35% complex with Na,calcium;Mg and 55% free. Only inorganic ph.is measured in routine.

  17. Function • Skeleton • Intra & extracellular role. • Nucleic acid,phospholipid,phosphoproteins • ATP and NADP.In various enzyme systems(Adenylatecyclase) • Essential for normal muscle contractility,Neurologicfunction,Electrolyte transport and oxygen carrying by Hb.

  18. Phosphorus homeostasis • Present in virtually all foods. • Average dietary intake 800- 1400 mg/day. • 60% -80% of intake is absorbed mainly by passive transport.Active transport stimulated by 1.25(OH)2D3 • Freely filtered in glomerulus. • >80% reabsorbed in proximal tubule and smaller in distal tubule. • Proximal transport:(Na-P cotransport)mainly regulated by ph.intake and PTH. • PTH inhibits Na-P Cotransport and causes phsphaturia.

  19. Reference intervals • Adults:2.8-4.5 mg/dl(0.89-1.44 mmol/L) • Higher in growing children(4.0-7.0) • Serum phosphate has DIURNAL VARIATION. • Higer levels in afternoon and evenings. • Best measured in FASTING MORNING. • Levels are influenced by dietary intake,meals,and exercise.

  20. Analytical techniques • Reaction of inorganic phosphate with ammonium molibdate to form phosphomolibdate complex measured at 340 nm in autoanalyzers. • Complex can be reduced to form molibdenum blue measured at 600 to 700 nm. • Enzymatic methods. • Serum is preferred. • Most anticoagulants(Except heparin) interfere • Prolonged storage with cells at room temperature causes ↑Ph. • Hemolyzed specimens are Unacceptable (RBC organic esters hydrolize to inorganic phosphate during storage.)

  21. Disorders of mineral metabolismHypercalcemia • ↑Serum ca is associated with: • Anorexia,Nausea,vomiting,Constipation,hypotonia ,depression,high voltage T waves on ECG,lethargy,coma • Persistent hyperca. Causes ectopic deposition of ca(vessels,connective tissue ad joints ,gastric mucosa,kidney) • Most common causes:Primaryhyperpara,Malignancy • Others :Renal Failure,Diuretics,Endocrinedisorderes,Vitamin A and D intoxication,Lithiumtherapy,Milk alkali synd.,immobilization,Hyperthyroidism,familialhypercalciurichypercalcemia.

  22. Primary Hyperparathyroidism(PHPT) • ↑↑PTH in the absence of an appropriate physiologic stimulus causing generalized disorder of Ca,Ph,Bone metabolism. • 100,000 case/Year in USA • F/M : 2/1 • Majority caused by solitary parathyroid adenoma. • Others:Multipleadenoma,Hyperplasia ,Rarely carcinoma. • ↑Ca,↓Phosphate,Mild acidosis(↓Renal Bicarbonate reabsorption) ↑Ca due to :1)Direct action PTH on Bone,increased resorption.2)PTH activated renal reabsorption 3)PTH stimulated increased renal biosynthesis of 1,25(OH)2D3 which increases intestinal calcium absorption ½ or more are asymptomatic.

  23. Hyperparathyroidism • PHPT:Sporadic • MEN1 (Pituitary &pancreas tumors,Zollinger Ellison synd.)MEN2A(Pheo. &Medullary CA of thyroid.) • Secondary Hyperparathyroidism: • Resistance to PTH: RF,VIT D deficincy, • Low to normal Ca,High phosphate. • Renal osteodistrophy

  24. Malignancy :the most frequent cause of Hpercalcemia in the hospital inpatient population. • Malignancy associated hypercalcemia: • With and without bony metastasis. • With B.M:Hemathologic(Multiple Myeloma,Lymphoma,lukemia)breast,Lung,others • Osteoclast activating factor,tumor necrosis factor,IL1 • Without B.M:Humoralhypercalcemia of malignancy; • Renal,hepatic,epidermoid of head,neck,lung and ilet cell of pancreas…PTH-rP • ↑Urinary CAMP excretion + ↓ or normal PTH

  25. Vitamin D intoxication • Granulomatous disorders(Sarcoidosis) • Milk alkali syndrome(↓Serumca,↓U.ca,Azotemia,Alkalosis) • Lab tests in diff DX of hypercalcemia: • Serum total & Ionized ca. ,Urine ca. • Serum &urine phosphorus • Alkaline phospatase,Albumin,PTH ,PTH-rP,Urine CAMP • VitaminD,cortisol,GH,…

  26. Magnesium • 4th most abundant cation in the body(after Na,K,Ca) • 2nd most prevalent intracellular cation. • Normal body content:1000mmol (22.66mg) • 50-60% in Bone,40-50% in soft tissue. • 1/3 skeletal Mg is exchangeable.Reservoir for extracellular Mg(1% of total body Mg) • Serum:55% Ionized(Mg2+),15%complex with phosphate,citrate,…,30% protein bound(Albumin) • 45% of TB Mg, is intracellular.(ATP,Nucleus,mith0chondria;RE)

  27. Function,Mg • Essential for >300 cellular Enzymes. (Transfer of phosphate groups,DNA replication ,transcription,RNAtranslation,ATP) Cellular energy metabolism,Membrane,nerveconduction,Cardiac muscle(K pump) ↓Mg after cardiac Surgury,causes refractory plasma electrolyte abnormalities(K)and arrythmia

  28. Mg • GI absorption,Renal Excretion • MG:diatery intake:300-350 mg/day • Sturable transport system and passive diffusion • Renal excretion:120-140 mg/24hour • Thick ascending loop of henle(60-70%) • Distal tubule(10%),Major regulation site. • Mg2+ the most important regulator.(PTH,Calcitonin,glucagon,…)

  29. Analytical techniques • Serum is preferred over plasma. • Anticoagulants interfere. • Methods: • AAS,Reference method(remove of ph. With lanthanum) • Photometric methods,Routine,Metallochromatic indicators(Calmagite:collor in Alk.sol.520nm) • Ionized(Free)Mg:ISE(Neutral ionophores selective for Mg2+)Interference with ca.

  30. Reference interval,Mg • Total Mg:1.7-2.2mg/dl(0.75-0.95 mmol/L) • No age or sex difference in total Mg concentration. • CSF Mg:2.0-2.7mg/dl • Ionized Mg:0.44-0.60 mmol/L

  31. Thank you for your attention

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