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)
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.
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.
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
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.