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![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
• Corrected calcium = (4.0 mg/dl - [plasma albumin]) X 0.8 +
[serum calcium]](https://image.slidesharecdn.com/hypercalcemia-130724141819-phpapp01/75/Hypercalcemia-4-2048.jpg)
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Hypercalcemia
- 1. Hypercalcemia • Commonly encounteredin Practice • Diagnosis often is made incidentally • The most common causes are primary hyperparathyroidism and malignancy • Diagnostic work-up includes measurement of serum calcium, intact parathyroid hormone (I-PTH), h/o any medications • Hypercalcemic crisis is a life-threatening emergency
- 2. Hypercalcemia • The skeletoncontains 98 percent of total body calcium; the remaining 2 percent circulates throughout the body • One half of circulating calcium is free (ionized) calcium, the only form that has physiologic effects. • The remainder is bound to albumin, globulin, and other inorganic molecules
- 3. Distribution Of Calcium CALCIUM ECF 8.5-10.6mg/dl 2.25-2.65 mmol//l ICF CYTOPLASMIC FREE 50-100 nmol/l PROTEIN BOUND 45% DIFFUSIBLE ULTRAFILTRABLE 55% IONIZED 45% COMPLEXED 10%90% ALBUMIN 10% GLOBULIN
- 4. Protein binding ofcalcium • 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 • Corrected calcium = (4.0 mg/dl - [plasma albumin]) X 0.8 + [serum calcium]
- 5. CALCIUM PHYSIOLOGY: BLOOD CALCIUM •Blood Calcium Is Tightly Regulated –Principle Organ Systems –Gut, Bone, Kidneys –Hormones – Parathyroid Hormone (PTH),calcitonin,vitamin D –Integrated Physiology Of Organ Systems And Hormones Maintain Blood Calcium
- 6. CALCIUM PHYSIOLOGY: BLOOD CALCIUM •Calcium Flux Into And Out Of Blood – “In” Factors: Intestinal Absorption, Bone Resorption – “Out” Factors: Renal Excretion, Bone Formation (Ca INCORPATION INTO BONE) – Balance Between “In” And “Out” Factors – Organ Physiology Of Gut, Bone, And Kidney – Hormone Function Of PTH And Vitmamin D
- 7. CALCIUM HOMEOSTASIS DIETARY CALCIUM INTESTINALABSORPTION ORGAN PHYSIOLOGY ENDOCRINE PHYSIOLOGY DIETARY HABITS, SUPPLEMENTS BLOOD CALCIUM BONE KIDNEYS URINE THE ONLY “IN” THE PRINCIPLE “OUT” ORGAN PHYS. ENDOCRINE PHYS. ORGAN, ENDOCRINE
- 8. TRANSCELLULAR CALCIUM ABSORPTION TRP V5 NUCLEU S CCALBINDIN D9k NCX1PMCA1b CaSR calcium LUMEN BLOOD
- 9. Factors affecting calciumabsorption in gut • Increased • Decreased• Vit D • Ingestion with alkali • PTH • GH • Acidic milieu • High po4 content in diet • High veg fibre • High fat content • Corticosteroid treatment • Estrogen deficiency • Advanced age • Gastrectomy • Intestinal malabsorption syndrome • DM • Renal failure
- 10. RENAL HANDLING OFCALCIUM • 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 % • DCT, CNT : 5% PASSIVE ACTIVE
- 11. DISTAL TUBULE CALCIUMABSORPTION
- 12. KLOTHO • Klotho isinvolved in the – Renal control of calcium, phosphate and vitamin D metabolism – Suppresses phosphate re-absorption in renal proximal tubule, by directly binding to FGF receptors – Regulates Ca2+ re-absorption in the distal convoluted tubule by – Stabilizing the TRPV5 Ca2+ channel in the plasma membrane Nephrol Dial Transplant 2007; 22: 1524–1526
- 13. KLOTHO Inhibits renal 1-alpha25 hydroxylase activity and thereby Decreases circulating calcitriol levels – Therefore appears to – Synergize with the renal tubular effects of parathyroid hormone (PTH) on Ca2+ and phosphate transport, whereas – Antagonizes the stimulatory effect of PTH on calcitriol synthesis by the kidney Nephrol Dial Transplant 2007; 22: 1524–1526
- 14. PTH/Calcium Homeostasis Low circulatingserum calcium concentrations stimulate the parathyroid glands to secrete PTH, which mobilizes calcium from bones by osteoclastic stimulation. PTH also stimulates the kidneys to reabsorb calcium and to convert 25- hydroxyvitamin D3 (produced in the liver) to the active form, 1,25-dihydroxyvitamin D3, which stimulates GI calcium absorption. High serum calcium concentrations have a negative feedback effect on PTH secretion.
- 15. CALCIUM, PTH, ANDVITAMIN D FEEDBACK LOOPS NORMAL BLOOD Ca RISING BLOOD Ca FALLING BLOOD Ca SUPPRESS PTH STIMULATE PTH BONE RESORPTION URINARY LOSS 1,25(OH)2 D PRODUCTION BONE RESORPTION URINARY LOSS 1,25(OH)2 D PRODUCTION
- 16. PTH • Renal effects(steady state maintenance) – Increased reabsorption of calcium – Stimulation of 25(OH)D-1alpha-hydroxylase • Bone effects (immediate control of blood Ca) – Causes calcium bone release within minutes – Chronic elevation increases bone remodeling and increased osteoclast- mediated bone resorption – However, PTH administered intermittently has been shown to increase bone formation and this is a potential therapy for osteoporosis
- 18. FUNCTION OF VITAMIND • Tissue Specificity – Gut – Stimulate Transepithelial Transport Of Calcium And Phosphate In The Small Intestine (Principally Duodenum) – Bone – Stimulate Terminal Differentiation Of Osteoclasts – Stimulate Osteoblasts To Stimulate Osteoclasts To Mobilize Calcium – Parathyroid – Inhibit Transcription Of The PTH Gene (Feedback Regulation)
- 19.
- 20. FUNCTIONS • Muscle contraction •Neuromuscular / nerve conduction • Intracellular signalling • Bone formation • Coagulation • Enzyme regulation
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- 22. Hypercalcemia I.Parathyroid-related -Primary hyperparathyroidism -Lithium therapy -Familialhypocalciuric hypercalcemia II. Malignancy-related -Solid tumor with metastases (breast) -Solid tumor with humoral mediation of hypercalcemia (lung, kidney) -Hematologic malignancies (multiple myeloma, lymphoma, leukemia) III. Vitamin D-related -Vitamin D intoxication - 1,25(OH)2D; sarcoidosis and other granulomatous diseases↑ -Idiopathic hypercalcemia of infancy IV. Associated with high bone turnover -Hyperthyroidism -Immobilization -Thiazides -Vitamin A intoxication V. Associated with renal failure -Severe secondary hyperparathyroidism -Aluminum intoxication -Milk-alkali syndrome Primary hyperparathyroidism and cancer account for 90% of cases of hypercalcemia
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- 24. 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%
- 25. Clinical 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).
- 26. Diagnosis The diagnosis ofPHPT 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
- 27. Treatment • Parathyroidectomy indicatedin 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. • 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. parathyroidectomy If none of above things met: annual monitoring of patient for serum calcium, renal function, BMD
- 28. Familial Hypocalciuric Hypercalcemia •Caused by an inactivating MUTATION of calcium-sensing receptors. • Sensitivity of receptors to calcium DECREASES, requiring higher calcium levels to suppress PTH secretion. • Fractional excretion of calcium is lower than 1%, despite hypercalcemia. • Hypercalcemia in FHH has a generally benign course and is resistant to medications, except for some cases successfully treated with the calcimimetic agent cinacalcet.
- 29. Clinical (>12) 1. Renal: NDI , Stone, Nephrocalcinosis 2. Gi :Nausea/Vomiting, Constipation, Peptic ulcer, Pancreatitis 3. Neuro :Weakness, Drowsiness 4. Cardio : Short Qt(<0.3),broad T, Heart Block, Vent Arrhythmia, asystole 5. Musculo : Cramps, Bone Pain, Pathologic Fx 6. Others : Band Keratopathy
- 30. Symptoms • Bones, stones,abdominal groans, and psychic moans. • Malaise, fatigue, headaches, diffuse aches and pains, constipation. • Patients are often dehydrated • Lethargy and psychosis when hypercalcemia is severe. • Calcifications in skin, cornea, conjunctiva, and kidneys.
Editor's Notes
- #24 FIRST: Check PTH If elevated, likely primary hyperparathyroidism (adenoma & MEN1 and 2A) (if high urinary excretion in 24 hour collection). This seems counter-intuitive since PTH increases renal reabsorption and should potentially decrease calcium excretion– but the kidney has direct Calcium sensors as well and attempts to correct the hypercalcemia on its own (but is overwhelmed by PTH). Familial hypocalciuric Hypercalcemia is a mutation in the calcium sensor in the parathyroid so higher levels of Ca are necessary to secrete PTH. The kidney’s sensors are somewhat reset as well hence the hypocelciuric state PTHrP elevated in squamous cell CA, RCC, bladder cell, breast, ovarian CA, Non hodgkin lymphoma, CML Increased conversion to active vitamin D (peripheral conversion) is seen in Sarcoid (all granulomatous dx including Tb, cocci) and Lymphoma SPEP and UPEP can reveal an underyling monoclonal gammopathy (like multiple myeloma). Hypercalcemia also seen in thyrotoxicosis Ingestion of vitamin D tabs!