1.ATUL DESAI 21/5/12

2. INTRODUCTION Approx 1000 to 1200 g calcium present in adult 99.3 % in bone & teeth as hydroxyapatite crystals 0.6% in soft tissues 0.1% in ECF. 3. DISTRIBUTION OF CALCIUM CALCIUMECF ICF 8.5-10.6 mg/dl CYTOPLASMIC FREE 2.25-2.65 mmol//l 50-100 nmol/lIONIZED45%PROTEIN BOUNDDIFFUSIBLE 45% ULTRAFILTRABLE55% COMPLEXED 10% 90% ALBUMIN 10% GLOBULIN 4. Protein binding of calcium Influenced by pH. Metabolic acidosis decrease protein bindingincrease ionized calcium. Metabolic alkalosis increase protein bindingdecrease ionized calcium. Fall in pH by o.1 increases serum calcium by 0.1mmol/L As ionized form is the active form of calcium, serumcalcium levels should be adjusted for abnormal serumalbumin levels. 5. Corrected calcium For every 1-g/dL drop in serum albumin below 4g/dL, measured serum calcium decreases by 0.8mg/dL. Corrected calcium = measured Ca+ [0.8x(4-measuredalbumin)] (Calcium in mg/dl; albumin in g/dl) 6. FUNCTIONS Muscle contraction Neuromuscular / nerve conduction Intracellular signalling Bone formation Coagulation Enzyme regulation 7. CALCIUM HOMEOSTASIS 8. INTESTINAL HANDLING OFCALCIUM Approx 1000 mg calcium ingested per day. 200 mg absorbed. Mainly in duodenum & jejunum. Absorption is both passive and active Passive : paracellular route, non saturable, 5 %ingested Ca absorbed by this route. Active: transcellular: receptor mediated, 25% ingestedCa absorbed. 9. TRANSCELLULAR CALCIUMABSORPTIONBLOOD NCX1 PMCA1b CaSRNUCLE USCCALBINDIN D9kTRPV 5calciumLUMEN 10. Factors affecting calciumabsorption in gut Increased Decreased High po4 content indiet High veg fibre High fat content Corticosteroid Vit Dtreatment Ingestion with alkali Estrogen deficiency PTH Advanced age GH Gastrectomy Acidic milieu Intestinalmalabsorptionsyndrome DM Renal failure 11. RENAL HANDLING OF CALCIUM 8-10 g calcium filtered across the glomerulus per day. 200 mg = 2 % is excreted Rest reabsorbed across renal tubules. PCT: 60-65% mTALH: 20 %PASSIVE DCT, CNT : 5%ACTIVE 12. DISTAL TUBULE CALCIUMABSORPTION 13. TRPV5 Member of TRP channelsuperfamily. Has intracellular NH2 &CHO terminals. 6 trans membranesegments. A hydrophobic stretch =pore formingregion, betweensegments 5 & 6 14. TRPV5 N glycosylated region Extracellular KlothoactsPhosphorylationsite for PKA & C.PTH & tissuekalikrien regulateTRPV5 functionRequired for channelassembly & proteinprotein interaction 15. TRPV5 100 times larger selectivity for calcium, compared toNa. Its expression in PM is limited Present in subcellular location, in intracellularvesicles. Expressed on PM on stimulation. Present in closed and open state. Calcium entersduring open state. Internalized via dynamin and clathrin dependentprocess. 16. Regulators of TRPV5 17. DRUGS AFFECTING TRPV5 TACROLIMUS : decreased expression of TRPV5 also of calbindin D9k : mechanism ? thus causes hypercalciuria. Cyclosporine downregulates only calbindin not TRPV5 18. CALBINDIN D 28k Vit D dependent calcium binding protein. High calcium affinity. Calcium bound to it is shuttled toward basolateral membrane Ca extrusion systems. 19. Effect of diuretics on renal calciumhandlingmTALH Furosemide:NA NKNKCC2 2Cl ATPase Increases the K expression of TRPV5 & ROMKcalbindin D28k in DCTLUMEN +& CNT !!?CALCIUM CALCIUMlumenblood 20. Thiazide diuretics Increase calcium reabsorption. Mechanism: 2 hypothesis proposed. First hypothesis :ECF depletion Increased water & Na absortion in PCTDecreased calcium filtrate driving increased Ca absorption in PCT 21. Second hypothesis: increased NaCa exchanger in BL membrane of DCT & CNT. Not proved. 22. Response to change in serumcalcium levels 23. HYPERCALCEMIA (definition) Serum calcium > 10.5 mg/dl (>2.5 mmol/l) Ionized calcium > 5.3 mg/dl (1.3 mmol/L) Mild :Total ca 10.5-11.9 mg/dl (2.5-3 mmol/l) (i 5.6-8mg/dl; 1.4-2 mmol/l) Moderate : Total ca 12-13.9 mg/dl (3-3.5mmol/l) i ca 8-10 mg/dl (2-2.5 mmol/l) Severe : Total ca 14-16 mg/dl (3.5-4 mmol/l) i ca 10-12 mg/dl (2.5-3 mmol/l) 24. Epidemiology Relatively common disorder Incidence 1-2 case per 1000 adults. Higher incidence in South Africa and Scandinavia. Males > females: difference diminishes with increasingage. Hypercalcemia from all cause increase with advancingage. 25. Causes : Humoral hypercalcemia of malignancy : Primary hyperparathyroidismincreased PTHrP (80%)Breast CA Malignancy related : Solitary adenomaOsteolytic hypercalcemia from osteoclasticLung CA90% Generalized hyperplasiaactivity and bone resorption surrounding theRCC PTH related : Multiplemyelomatumor tissue (20%) neoplasia typeMultiple endocrine 1Secretion of active vitamin D by some or type 2A Leukemia, lymphomalymphomas Lithium-related release of PTHVit D related : vit D toxicity or granulomatousrareEctopic PTH secretion - Very Hyperthyroidism PTH Familial cases of highdisorders. Immobilization (Pagetsdisease) Related to high bone turnover : Thiazides Vit A intoxication Milk alkali syndrome. Idiopathic infantile hypercalcemia ( Williamssyndrome) increased intestinal calcium absorption. 26. Causes: Familial hypocalciuric hypercalcemia (decreased renalcalcium excretion) Mutations of the calcium-sensing receptor Familial benign hypocalciuric hypercalcemia Neonatal severe hyperparathyroidism Uncertain mechanism Hypophosphatasia Subcutaneous fat necrosis Blue diaper syndrome Dietary phosphate deficiency 27. Presentation: The mnemonic "stones," "bones," "abdominal moans,"and "psychic groans" describes the constellation ofsymptoms and signs of hypercalcemia The history of hypercalcemia is dependent on its causeand the sensitivity of the individual to higher calciumlevels. Mild increase : Rapid rise or severe Asymptomatic, hypercalcemia have Or may have recurring dramatic symptoms: problems like kidneyconusion, lethargy, may stoneslead to death 28. CLINICAL FEATURES: 29. PATHOPHYSIOLOGY: The CNS effects are thought to be due to the directdepressant effect of hypercalcemia. Renal effects include nephrolithiasis from thehypercalciuria. Distal renal tubular acidosis may be observed, and theincrease in urine pH and hypocitraturia also maycontribute to stone disease. 30. Nephrogenic diabetes insipidus occurs from medullarycalcium deposition and inhibition of aquaporin-2. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia isprolonged calcium deposition (nephrocalcinosis)and interstitial renal disease. 31. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue 32. WORK UPHIGH 33. PRIMARY HYPERPARATHYROIDISM 50% case of hypercalcemia in general population. Prevalence : 1 %, 2% in post menopausal women. Peak incidence in 6th decade. Adenoma : single enlarged parathyroid glandresponsible in 80-85% cases Hyperplasia : in 10-15% cases. Sporadic or part of MEN Carcinoma : 0.05-1% 34. PHPTH : PRESENTATION 80 % cases: asymptomatic, diagnosed on routine labfinding of increased serum calcium 20-25% cases: chronic course with mild or intermittenthypercalcemia, recurrent renal stones, complication ofnephrolithiasis 5-10% have severe and symptomatic hypercalcemiaand overt osteitis fibrosa cystica; in these patients theparathyroid tumor is usually large (greater than 5.0 g). 35. The diagnosis of PHPT is established by laboratory testing showing hypercalcemia, inappropriately normal or elevated blood levels of PTH, hypercalciuria, hypophosphatemia,phosphaturia ,and increased urinary excretion of cyclic adenosine monophosphate 36. Treatment Parathyroidectomy indicated in all symptomaticpatients. Asymptomatic patient : Serum calcium > 1 mg/dl above normal, reduced bone mass (T-score of less than 2.5 at any site), GFR of less than 60 mL/min, or age younger than 50 years. parathyroidectomy Hypercalciuria (>400 mg calcium per 24 hours) is nolonger regarded as an indication for parathyroidsurgery, since hypercalciuria in PHPT was notestablished as a risk factor for stone formation.If none of above things met: annual monitoring of patient for serum calcium, renal function, BMD 37. Pre operative localization of tumor Not needed in pt undergoing Sx for 1st time. Needed in pts with no improvement with priorSx, recurrence. Sestamibi scan : sensitive & most popular technique USG neck can also be used. 38. Pharmacotherapy: Indications: patient refuses surgery, or surgerycontraindicated, or pt with asymptomatichypercalcemia. Agents used :calcimimetic, bisphosphonates, estrogens, SERMS. 39. Familial HypocalciuricHypercalcemia A rare disease (estimated prevalence of 1 per 78,000) Autosomal dominant inheritance, high penetrance Loss-of-function mutations in the CASR gene locatedon chromosome arm 3q Hypercalcemia, and relative hypocalciuria. The hypercalcemia is typically mild to moderate (10.5mg/Dl to 12 mg/dL) Affected patients do not exhibit the typicalcomplications associated with elevated serum calciumconcentrations. 40. the PTH level is generally inappropriately normal, mild elevations in 15% to 20% Urinary calcium excretion is not elevated, as would beexpected in hypercalcemia. The fractional excretion of calcium is usually less than1% Hypercalcemia in FHH has a generally benign courseand is resistant to medications, except for some casessuccessfully treated with the calcimimetic agentcinacalcet 41. NEONATAL SEVEREHYPERPARATHYROIDISM rare disorder, autosomal recessive, is often reported in the offspring of consanguineousFHH parents, Characterized by severe hyperparathyroidhyperplasia, elevation of PTH levels, severehyperparathyroid bone disease, and elevatedextracellular calcium levels. Treatment is total parathyroidectomy, followed byvitamin D and calcium supplementation. This disease is usually lethal without surgicalintervention. 42. TREATMENT OF HYPERCALCEMIA Tailored to the degree of hypercalcemia, the clinicalcondition, and the underlying cause. Calcium can be decreased by : Increasing renal excretion of calcium Incresing movement of calcium into bone Decreasing bone resorption Decreasing gi absorption of calcium Remoning calcium by other means 43. Patients with mild hypercalcemia (14 mg/dL), evenwithout symptoms, should be treated intensively. 44. Volume Repletion and LoopDiuretics Correction of the ECF volumeis the first and the mostimportant step in thetreatment of severehypercalcemia from anycauses. Volume repletion can lowercalcium concentration byapproximately 1 to 3 mg/dLby increasing GFR anddecreasing sodium andcalcium reabsorption inproximal and distal tubules. 45. Once volume expansion is achieved, loop diuretics canbe given concurrently with saline to increase thecalciuresis by blocking the Na+-K+-2Cl cotransporterin the TAL. Dose of 40 to 80 mg every 6 hours, and this treatmenttogether with saline therapy may decrease serumcalcium concentration by 2 to 4 mg/dL. 46. INHIBITION OF BONE RESORPTION BISPHOSPHONATES: the agents of choice in thetreatment of mild to severe hypercalcemia, especiallythat associated with cancer. They are pyrophosphate analogs with a high affinityfor hydroxyapatite and inhibit osteoclast function inareas of high bone turnover. 47. The clinical response takes 48 to 96 hours and issustained for up to 3 weeks. Doses can be repeated after 7 days. Fever is observed in about one fifth of patients takingbisphosphonates; rare side effects include acute renal failure, collapsingglomerulopathy, and osteonecrosis of the jaw. The dosage of bisphosphonates should be adjusted inpatients with preexisting kidney disease. 48. CALCITONIN Effective inhibitor of osteoclast bone resorption. Rapid action