Hypercalcemia

1. Hypercalcemia Heidi Chamberlain Shea, MD Endocrine Associates of Dallas

2. Goals of Discussion • Review Calcium metabolism • Differential Diagnosis of Hypercalcemia • Treatment options • Calcium case presentations

3. Calcium Physiology • An essential intracellular and extracellular cation • Extracellular calcium is required to maintain normal biological function of nervous system, the musculoskeletal system, and blood coagulation • Intracellular calcium is needed for normal activity of many enzymes • Preservation of the integrity of cellular membrane • Regulation of endocrine and exocrine secretory activities • Activation of compliment system • Bone metabolism

4. Role of Calcium • Bone mineralization • Muscle contraction • Skeletal • Cardiac • Smooth muscle • Blood clotting • Nerve impulse transmission

5. Bone metabolism • Parathyroid hormone (PTH) • Calcium • Phosphorus • Vitamin D • Calcitonin

6. Calcium • 41% combined with plasma proteins • Not diffusible • One gram per deciliter of albumin binds approximately 0.8 mg/dl of calcium • 9% combined with anionic substances • Citrate and phosphate • Not ionized • Diffusible • 50% is diffusible and ionized • Most important in bodily functions

7. Effects of CalciumHypocalcemia • Increased neuronal membrane permeability to sodium ions facilitates action potentials • When calcium levels < 6mg/dl • Tetany • Chvostek’s sign • Trousseau’s sign • Calcium <4mg/dl = Death

8. Calcium >12 mg/dl Nervous system depressed Fatigue Depression Constipation Anorexia Polyuria Most common nocturia Parathyroid poisoning Calcium > 17mg/dl Calcium phosphate crystals precipitate Effects of Hypercalcemia

9. Findings with Hypercalcemia • Bony tenderness • Hyperactive tendon reflexes • Tongue fasciculations • Hypercalcemia in pregnancy • May cause hypocalcemia in the neonate • Suppressing the fetal parathyroid • Hypercalcemia • Small decrease in GFR • Hemodynamic effects & hyposthenuria (a loss of renal concentrating abilities)

10. Findings with HypercalcemiaBand Keratopathy • Deposition of Calcium • Corneal opacities • Long standing hypercalcemia • Associated with primary hyperparathyroidism • Calcium deposition begins near the limbus at the 3 & 9 o’clock position • Less friction from the lids near the limbus • Tear film is most alkaline in the most exposed area, band running across the cornea from the 3 to 9 o’clock position

11. Complications of Hypercalcemia • Sinus bradycardia • Increase in the degree of a heart block • Cardiac arrhythmia • Hypertension • Pancreatitis • Peptic ulcer disease • Nephrolithiasis • Accelerated vascular calcification

12. Hormones PTH Vitamin D Calcitonin Organs Bone Kidney Small intestine Calcium Homeostasis

14. 1,25-OH Vitamin D

15. Calcium PhysiologyTarget Organs • Small intestine : approx. 40% absorbed, 50% of that - excreted into bile and other intestinal secretions. So only 20% of the total amount of Ca ingested daily is available to circulate between bone and extracellular fluid. • Kidney : Glomerulus filters out the Ca that is not bound to protein. • Proximal tubule - approx. 50% to 70% is reabsorbed, Ca reabsorption mirrors Na reabsorption. • Ascending limb of the loop of henle - approx. 30% to 40% reabsorbed • Distal nephron - about 10% reabsorbed. PTH and activated Vit D increases Ca absorption during Ca deficient states. Normally kidney excretes approx. 200 mg /day of Ca to maintain homeostasis. During states of severe Ca depletion, the Kidney can decrease urinary excretion to 50mg /day or less.

16. CALCIUM REGULATION _ PTH + _ + 1,25(OH)2 D3 + + + CALCITONIN _ GI Tract ECF Pool of Calcium BONE URINE

17. Parathyroid • Four glands located behind the thyroid • Length 6 millimeters • Width 3 millimeters • Thickness 2 millimeters • Often accidentally removed • Normal function with at least 2 glands

18. Parathyroid • Composed • Chief cells • Synthesize, secrete and store PTH • Oxyphil cells • ? function • Responsible for calcium homeostasis • Kidney • Bone

19. Parathyroid Actions • Increases calcium • Regulates intestinal absorption • 25-OH vitamin D 1,25-OH vitamin D • Renal absorption of calcium/excretion of phosphorus • Bone reabsorption • Osteolysis

20. Parathyroid and Bone • Osteoblasts + Osteocytes = Osteocytic membrane system • Osteocytic pumps • Pump calcium from bone to ECF • To maintain calcium concentration in bone fluid, osteolysis occurs and calcium phosphate is resorbed from bone • Fibrous and gel matrix remain intact

21. Parathyroid and Bone • PTH stimulates osteocytic pump • Increases permeability of osteocytic membrane allowing calcium to diffuse • Osteoblasts,cytes and clasts do not have PTH receptors • PTH stimulates osteoblasts and cytes, which then activate osteoclasts via “signaling” system • PTH indirectly stimulates formation of new osteoclasts • Both cell lines are activated but clastic activity > blastic

22. Calcitonin • Secreted by Parafollicular (C cells) in the thyroid • Temporarily lowers calcium levels • Decreases osteoclastic activity • Stimulated by high calcium levels • Stimulating a distal tubular - mediated calciuresis

23. Calcium Caveats • Respiratory alkalosis and elevated pH • Increase in the binding of calcium • Lowers ionized calcium. • Decrease in pH has the opposite effect. • As a general rule a shift of 0.1 pH unit produces a change in ionized calcium of 0.04 to 0.05 mmol/L • Chelators such as citrate may transiently decrease ionized calcium • Blood transfussions

24. Formulas for Correction • 0.8 for each gm of Albumin • 0.16mg/dl for each gm of globulin. • FEca= (uCA x sCR)/(sCA x uCR) • FEca <1% - Familial hypocalciuric hypercalcemia, • FEca >2% - primary hyperparathyroidism •  in pH will  protein bound Ca by 0.12mg/dl • 80-90% of protein bound Ca is bound to Albumin. • Increase in serum pH of 0.1 may cause decrease in ionized Ca of 0.16mg/dl • Calcium : Protein bound - 40%; Complexed - 13%; Ionized fraction - 47%

25. Etiology of Hypercalcemia Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism • T Thiazide, other drugs - Lithium • R Rabdomyolysis • A AIDS • P Paget’s disease, Parental nutrition, Pheochromocytoma, Parathyroid disease • V Vitamins • I Immobilization • T Thyrotoxicosis • A Addison’s disease • M Milk-alkali syndrome • I Inflammatory disorders • N Neoplastic related disease • S Sarcoidosis

27. Hyperparathyroidism • Stones • Bones • Groans • Moans

28. Normal bone Hyperparathyroid

29. Hyperparathyroidism

30. Serum calcium > 12mg/dl Hypercalciuria > 400mg/day Normal <200 mg/day Presence of signs and symptoms Nephrolithiasis Osteitis fibrosa Cystica Neuromuscular symptoms Markedly reduced cortical bone density Most common Long bones Decreased creatinine clearance Patient age < 50 years Markedly reduced cancellous bone density Spine HyperparathyroidismSurgical Management Silverberg et al., JCEM:1996

31. HyperparathyroidismMedical Management • Alendronate therapy • 37 patients • >50% female • 53 to 80 years • Primary Hyperparathyroidism • Cross over • 24 months Alendronate • 12 placebo and 12 treatment Khan et. al., JCEM 2004

32. HyperparathyroidismMedical Management Khan et. al., JCEM 2004

33. Treatment for Hypercalemia • Gallium nitrate • Steroids • IV Phosphate • Dialysis • Others • Hydration • Furosemide • Bisphosphonate • Calcitonin • Mithramycin

34. Treatment for Hypercalemia Hydration • First step in the management of severe hypercalcemia. --isotonic saline • Usually reduces - 1.6-2.4mg/dl • Hydration alone rarely leads to normalization in severe hypercalcemia • Rate of IV saline based on severity of hypercalcemia and tolerance of volume expansion

35. Treatment for HypercalemiaLoop Diuretics • Facilitate urinary excretion of calcium • Inhibits calcium reabsorption in the thick ascending limb of the loop of Henle • Guard against volume overload • Volume expansion must precede the administration of furosemide • Drug’s effect depends on delivery of calcium to the ascending limb. • Needs frequent measurement of lytes and urine output

36. Calcitonin Not as effective as bisphosphonate, tachyphylaxis quickly occurs and limits therapeutic efficacy Mithramycin Toxic effect limits it’s use, reserved for difficult cases of hypercalcemia that are related to malignancy Gallium Nitrate Need to infuse it over 5 days, nephrotoxity limits it’s use, not used frequently Corticosteroids For myeloma, lymphoma, Sarcoidosis, or vit D toxicity Decreases GI absorption 200-300mg hydrocortisone for up to 5 days Slow response limits it’s use Hemodialysis Zero or low calcium bath, In selected condition, eg-hypercalcemia complicated byrenal failure Treatment for Hypercalemia

37. Treatment for HypercalemiaBisphosphonate • Structurally related to pyrophosphate • P-C-P bound is a back bone that renders them resistant to phosphates. • They bind to hydroxyapatite in bone and inhibit the dissolution of crystals. • Their great affinity for bone and their resistance to degradation account for their extremely long half life in bone.

38. Treatment for HypercalemiaBisphosphonate • Poor GI absorption- <10% • ETIDRONATE, PAMIDRONATE,CLODRONATE • Etidronate- 7.5mg/kg iv over 4 hr for 3-7 days • Serum calcium begins to decrease within 2 days after first dose • Response better if patient is well hydrated • Oral bisphosphonate to prevent recurrent hypercalcemia. • Adverse effect-increase creatinine, phosphate • Long term use-impair bone formation, osteomalacia

39. Treatment for HypercalemiaBisphosphonate • Pamidronate • Inhibits osteoclast function • The most potent bisphosphonate • 60mg to 90 mg IV over 24hr • 70% to 100% of patients • Decreased calcium within 24 hr of treatment • 2/3rd of this group had normal calcium within 7 days • Adverse effect- • Mild transient increase in temp(<2○ C), transient leukopenia, small reduction in phosphate level • Excreted by kidney- dose adjustment

40. An inhibitor of RNA synthesis in osteoclasts IV 25 microgram/kg over 4-6 hr Begins to decrease in 12hr, max in 48-72 hr Duration of normocalcemia ranges from a few days to several weeks Depending on the extent of ongoing bone resorption Adverse effect- Nausea- Minimize with slow iv Avoid extravasation-cellulitis Hepatotoxic- in 20% patients Nephrotoxic- increase in creatinine, proteinuria Thrombocytopenia Contraindication-liver, kidney dysfunction, thrombocytopenia, or any coagulopathy Treatment for HypercalemiaMithramycin

41. Treatment for HypercalemiaGallium Nitrate • Inhibit bone resorption by adsorbing to and reducing the solubility of hydroxyapatite crystals • Adverse effect- Nephrotoxity, hypophosphatemia, small reduction in hemoglobin concentration • Clinical experience limited

42. Treatment for Hypercalemia • GLUCOCORTICOIDS- • Inhibits the growth of neoplastic lymphoid tissue, counteracting the effects of vitamin D • PHOSPHATE- • Can lower calcium rapidly and profoundly, • Very dangerous • Restricted to patient with extreme, life threatening hypercalcemia • Last resort • Contraindications-Hyperphosphatemia and azotemia

43. Mild (<12mg/dl) Hydration with saline Lasix Moderate (12-14 mg/dl) with symptoms Bisphosphonate Severe life threatening (>14mg/dl) Saline + Calcitonin + mithramycin Alternatively bisphosphonate, Steroids if sensitive Hypercalcemia secondary to malignancy- Survival after the appearance of hypercalcemia is very poor Median of 3 months. Treatment for HypercalemiaChoice of Agent

44. What Is The Diagnosis? • 52 yr old African American female presents with broken hip • Poor light exposure • Fatigue • Constipation • Difficulty concentrating • History of kidney stones

45. What Is The Diagnosis? • Calcium 13mg/dl (9-10.5) • Phosphorus 2mg/dl (3-4.5) • 25-OH vitamin D 33 ng/ml (20-40) • PTH 90 pg/ml (10-80) Diagnosis: Primary Hyperparathyroidism

46. What Is The Diagnosis? • 10 day old infant presents to ER with seizures • Calcium 5.5mg/dl (9-10.5) • Ionized calcium 3 mg/dl (4-5.6) • Phosphorus 10 mg/dl (3-4.5) • PTH 5 pg/ml (10-80) Diagnosis: Hypoparathyroidism

47. What Is The Diagnosis? • 18 month old African American male • Presents with abnormal gait • Low sunlight exposure • Breast fed as infant with current poor dairy intake • Calcium 8 mg/dl (9-10.5) • Phosphorus 4mg/dl (3-4.5) • PTH 85 pg/dl (10-80) • 25-OH Vitamin D 10 ng/ml (20-40)

48. Diagnosis • Vitamin D deficiency with secondary hyperparathyroidism • Tibial and femur bowing • Treatment: Ergocalciferol and calcium