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Calcium metabolism & hypercalcemia
 

Calcium metabolism & hypercalcemia

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    Calcium metabolism & hypercalcemia Calcium metabolism & hypercalcemia Presentation Transcript

    • ATUL DESAI 21/5/12
    • 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.
    • DISTRIBUTION OF CALCIUM CALCIUM ECF ICF 8.5-10.6 mg/dl CYTOPLASMIC FREE 2.25-2.65 mmol//l 50-100 nmol/l IONIZED 45%PROTEIN BOUND DIFFUSIBLE 45% ULTRAFILTRABLE 55% COMPLEXED 10% 90% ALBUMIN 10% GLOBULIN
    • Protein binding of calcium Influenced by pH. Metabolic acidosis decrease protein binding increase ionized calcium. Metabolic alkalosis  increase protein binding decrease ionized calcium. Fall in pH by o.1 increases serum calcium by 0.1 mmol/L As ionized form is the active form of calcium, serum calcium levels should be adjusted for abnormal serum albumin levels.
    • Corrected calcium For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Corrected calcium = measured Ca+ [0.8x(4-measured albumin)] (Calcium in mg/dl; albumin in g/dl)
    • FUNCTIONS Muscle contraction Neuromuscular / nerve conduction Intracellular signalling Bone formation Coagulation Enzyme regulation
    • CALCIUM HOMEOSTASIS
    • 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% ingested Ca absorbed.
    • TRANSCELLULAR CALCIUMABSORPTION BLOOD NCX1 PMCA1b CaSR NUCLE US CCALBINDIN D9k TR PV 5 calciumLUMEN
    • Factors affecting calciumabsorption in gut Increased  Decreased • High po4 content in diet • High veg fibre • High fat content • Corticosteroid • Vit D treatment • Ingestion with alkali • Estrogen deficiency • PTH • Advanced age • GH • Gastrectomy • Acidic milieu • Intestinal malabsorption syndrome • DM • Renal failure
    • 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
    • DISTAL TUBULE CALCIUMABSORPTION
    • TRPV5 Member of TRP channel superfamily. Has intracellular NH2 & CHO terminals. 6 trans membrane segments. A hydrophobic stretch = pore forming region, between segments 5 & 6
    • TRPV5• N glycosylated region• Extracellular Klotho acts Phosphorylation site for PKA & C. PTH & tissue kalikrien regulate TRPV5 functionRequired for channelassembly & proteinprotein interaction
    • TRPV5 100 times larger selectivity for calcium, compared to Na. Its expression in PM is limited Present in subcellular location, in intracellular vesicles. Expressed on PM on stimulation. Present in closed and open state. Calcium enters during open state. Internalized via dynamin and clathrin dependent process.
    • Regulators of TRPV5
    • DRUGS AFFECTING TRPV5 TACROLIMUS : decreased expression of TRPV5 also of calbindin D9k : mechanism ? thus causes hypercalciuria. Cyclosporine downregulates only calbindin not TRPV5
    • CALBINDIN D 28k Vit D dependent calcium binding protein. High calcium affinity. Calcium bound to it is shuttled toward basolateral membrane Ca extrusion systems.
    • Effect of diuretics on renal calciumhandling mTALH Furosemide: NA NK NKCC2 2Cl ATPase • Increases the K expression of TRPV5 & ROMK calbindin D28k in DCT LUMEN + & CNT !!? CALCIUM CALCIUM lumen blood
    • 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
    •  Second hypothesis: increased NaCa exchanger in BL membrane of DCT & CNT. Not proved.
    • Response to change in serumcalcium levels
    • 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 5.6-8 mg/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)
    • Epidemiology Relatively common disorder Incidence 1-2 case per 1000 adults. Higher incidence in South Africa and Scandinavia. Males > females: difference diminishes with increasing age. Hypercalcemia from all cause increase with advancing age.
    • Causes : • Humoral hypercalcemia of malignancy : • ◦Primary hyperparathyroidism increased PTHrP (80%) Breast CA Malignancy related : •• ■Solitary adenoma Osteolytic hypercalcemia from osteoclastic Lung CA 90% • ■Generalized hyperplasia activity and bone resorption surrounding the RCC PTH related : • ■Multiplemyeloma tumor tissue (20%) neoplasia type Multiple endocrine • 1Secretion of active vitamin D by some or type 2A • Leukemia, lymphoma lymphomas • ◦Lithium-related release of PTH Vit D related : vit D toxicity or granulomatousrare Ectopic PTH secretion - Very • Hyperthyroidism PTH ◦Familial cases of high disorders. • Immobilization (Pagets’ disease) Related to high bone turnover : • Thiazides • Vit A intoxication Milk alkali syndrome. Idiopathic infantile hypercalcemia ( Williams syndrome)  increased intestinal calcium absorption.
    • Causes: Familial hypocalciuric hypercalcemia (decreased renal calcium 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
    • Presentation: The mnemonic "stones," "bones," "abdominal moans," and "psychic groans" describes the constellation of symptoms and signs of hypercalcemia The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Mild increase : Rapid rise or severe Asymptomatic, hypercalcemia have Or may have recurring dramatic symptoms: problems like kidney conusion, lethargy, may stones lead to death
    • CLINICAL FEATURES:
    • PATHOPHYSIOLOGY: The CNS effects are thought to be due to the direct depressant effect of hypercalcemia. Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease.
    •  Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2. Renal function may decrease due to hypercalcemia- induced renal vasoconstriction or if hypercalcemia is prolonged  calcium deposition (nephrocalcinosis) and interstitial renal disease.
    •  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
    • WORK UP HIGH
    • 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 gland responsible in 80-85% cases Hyperplasia : in 10-15% cases. Sporadic or part of MEN Carcinoma : 0.05-1%
    • PHPTH : PRESENTATION 80 % cases: asymptomatic, diagnosed on routine lab finding of increased serum calcium 20-25% cases: chronic course with mild or intermittent hypercalcemia, recurrent renal stones, complication of nephrolithiasis 5-10% have severe and symptomatic hypercalcemia and overt osteitis fibrosa cystica; in these patients the parathyroid tumor is usually large (greater than 5.0 g).
    •  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
    • Treatment Parathyroidectomy indicated in all symptomatic patients. 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 no longer regarded as an indication for parathyroid surgery, since hypercalciuria in PHPT was not established as a risk factor for stone formation. If none of above things met: annual monitoring of patient for serum calcium, renal function, BMD
    • Pre operative localization of tumor Not needed in pt undergoing Sx for 1st time. Needed in pts with no improvement with prior Sx, recurrence. Sestamibi scan : sensitive & most popular technique USG neck can also be used.
    • Pharmacotherapy: Indications: patient refuses surgery, or surgery contraindicated, or pt with asymptomatic hypercalcemia. Agents used : calcimimetic, bisphosphonates, estrogens, SERMS.
    • 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 located on chromosome arm 3q Hypercalcemia, and relative hypocalciuria. The hypercalcemia is typically mild to moderate (10.5 mg/Dl to 12 mg/dL) Affected patients do not exhibit the typical complications associated with elevated serum calcium concentrations.
    •  the PTH level is generally “inappropriately normal,” mild elevations in 15% to 20% Urinary calcium excretion is not elevated, as would be expected in hypercalcemia. The fractional excretion of calcium is usually less than 1% Hypercalcemia in FHH has a generally benign course and is resistant to medications, except for some cases successfully treated with the calcimimetic agent cinacalcet
    • NEONATAL SEVEREHYPERPARATHYROIDISM rare disorder, autosomal recessive, is often reported in the offspring of consanguineous FHH parents, Characterized by severe hyperparathyroid hyperplasia, elevation of PTH levels, severe hyperparathyroid bone disease, and elevated extracellular calcium levels. Treatment is total parathyroidectomy, followed by vitamin D and calcium supplementation. This disease is usually lethal without surgical intervention.
    • TREATMENT OF HYPERCALCEMIA Tailored to the degree of hypercalcemia, the clinical condition, 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
    •  Patients with mild hypercalcemia (<12 mg/dL) do not require immediate treatment. They should stop any medications implicated in causing hypercalcemia, avoid volume depletion and physical inactivity, and maintain adequate hydration. Moderate hypercalcemia (12 to 14 mg/dL), especially if acute and symptomatic, requires more aggressive therapy. Patients with severe hypercalcemia (>14 mg/dL), even without symptoms, should be treated intensively.
    • Volume Repletion and LoopDiuretics Correction of the ECF volume is the first and the most important step in the treatment of severe hypercalcemia from any causes. Volume repletion can lower calcium concentration by approximately 1 to 3 mg/dL by increasing GFR and decreasing sodium and calcium reabsorption in proximal and distal tubules.
    •  Once volume expansion is achieved, loop diuretics can be given concurrently with saline to increase the calciuresis by blocking the Na+-K+-2Cl– cotransporter in the TAL. Dose of 40 to 80 mg every 6 hours, and this treatment together with saline therapy may decrease serum calcium concentration by 2 to 4 mg/dL.
    • INHIBITION OF BONE RESORPTION BISPHOSPHONATES: the agents of choice in the treatment of mild to severe hypercalcemia, especially that associated with cancer. They are pyrophosphate analogs with a high affinity for hydroxyapatite and inhibit osteoclast function in areas of high bone turnover.
    •  The clinical response takes 48 to 96 hours and is sustained for up to 3 weeks. Doses can be repeated after 7 days. Fever is observed in about one fifth of patients taking bisphosphonates; rare side effects include acute renal failure, collapsing glomerulopathy, and osteonecrosis of the jaw. The dosage of bisphosphonates should be adjusted in patients with preexisting kidney disease.
    • CALCITONIN Effective inhibitor of osteoclast bone resorption. Rapid action <12 hrs. Effect is transient, minimal toxicity Dose: 4-8 U/kg SC Q6-12 hrs Its role is mainly to provide initial treatment of severe hypercalcemia while waiting for the more sustained effect of bisphosphonates to begin.
    • EXTRACORPOREAL REMOVAL In severely hypercalcemic patients who are comatose, have ECG changes, have severe renal failure, or cannot receive aggressive hydration, hemodialysis with a low- or no-calcium dialysate is an effective treatment. Continuous renal replacement therapy can also be used to treat severe hypercalcemia. The effect of dialysis is transitory, and it must be followed by other measures.