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

2. Goals of Discussion Review Calcium metabolism Review Calcium metabolism Differential Diagnosis of Hypercalcemia Differential Diagnosis of Hypercalcemia Treatment options Treatment options Calcium case presentations 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 Bone mineralization Muscle contraction Muscle contraction Skeletal Skeletal Cardiac Cardiac Smooth muscle Smooth muscle Blood clotting Blood clotting Nerve impulse transmission Nerve impulse transmission

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

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

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

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

14. 1,25-OH Vitamin D

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

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

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

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

21. Parathyroid and Bone PTH stimulates osteocytic pump PTH stimulates osteocytic pump Increases permeability of osteocytic membrane allowing calcium to diffuse Increases permeability of osteocytic membrane allowing calcium to diffuse Osteoblasts,cytes and clasts do not have PTH receptors Osteoblasts,cytes and clasts do not have PTH receptors PTH stimulates osteoblasts and cytes, which then activate osteoclasts via “signaling” system PTH stimulates osteoblasts and cytes, which then activate osteoclasts via “signaling” system PTH indirectly stimulates formation of new osteoclasts PTH indirectly stimulates formation of new osteoclasts Both cell lines are activated but clastic activity > blastic 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 0.8 for each gm of Albumin 0.16mg/dl for each gm of globulin. 0.16mg/dl for each gm of globulin. FEca= (uCA x sCR)/(sCA x uCR) FEca= (uCA x sCR)/(sCA x uCR) FEca <1% - Familial hypocalciuric hypercalcemia, FEca <1% - Familial hypocalciuric hypercalcemia, FEca >2% - primary hyperparathyroidism FEca >2% - primary hyperparathyroidism  in pH will  protein bound Ca by 0.12mg/dl  in pH will  protein bound Ca by 0.12mg/dl 80-90% of protein bound Ca is bound to Albumin. 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 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% Calcium : Protein bound - 40%; Complexed - 13%; Ionized fraction - 47%

25. Etiology of Hypercalcemia TThiazide, other drugs - Lithium R Rabdomyolysis AAIDS PPaget’s disease, Parental nutrition, Pheochromocytoma, Parathyroid disease Approx. 80% of all cases are caused by Malignancy or Primary Hyperpathyroidism VVitamins VVitamins IImmobilization IImmobilization TThyrotoxicosis TThyrotoxicosis AAddison’s disease AAddison’s disease MMilk- syndrome MMilk-alkali syndrome IInflammatory IInflammatory disorders NNeoplastic disease NNeoplastic related disease SSarcoidosis SSarcoidosis

27. Hyperparathyroidism Stones ones Bones ans Groans Moans Moans

28. Normal boneHyperparathyroid

29. Hyperparathyroidism

30. Hyperparathyroidism Surgical Management 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 Silverberg et al., JCEM:1996

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

32. Hyperparathyroidism Medical 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 Hypercalemia Loop Diuretics Facilitate urinary excretion of calcium Inhibits calcium reabsorption in the thick ascending limb of the loop of Henle 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 Volume expansion must precede the administration of furosemide Drug’s effect depends on delivery of calcium to the ascending limb. Drug’s effect depends on delivery of calcium to the ascending limb. Needs frequent measurement of lytes and urine output Needs frequent measurement of lytes and urine output

36. Treatment for Hypercalemia Calcitonin Calcitonin Not as effective as bisphosphonate, tachyphylaxis quickly occurs and limits therapeutic efficacy Not as effective as bisphosphonate, tachyphylaxis quickly occurs and limits therapeutic efficacy Mithramycin Mithramycin Toxic effect limits it’s use, reserved for difficult cases of hypercalcemia that are related to malignancy Toxic effect limits it’s use, reserved for difficult cases of hypercalcemia that are related to malignancy Gallium Nitrate Gallium Nitrate Need to infuse it over 5 days, nephrotoxity limits it’s use, not used frequently 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 by renal failure

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

40. Treatment for Hypercalemia Mithramycin 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

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

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

43. Treatment for Hypercalemia Choice of Agent Mild (<12mg/dl) Mild (<12mg/dl) Hydration with saline Hydration with saline Lasix Lasix Moderate (12-14 mg/dl) with symptoms Moderate (12-14 mg/dl) with symptoms Bisphosphonate 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.

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

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

46. What Is The Diagnosis? 10 day old infant presents to ER with seizures 10 day old infant presents to ER with seizures Calcium 5.5mg/dl (9-10.5) Calcium 5.5mg/dl (9-10.5) Ionized calcium 3 mg/dl (4-5.6) Ionized calcium 3 mg/dl (4-5.6) Phosphorus 10 mg/dl (3-4.5) 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 18 month old African American male Presents with abnormal gait Presents with abnormal gait Low sunlight exposure Low sunlight exposure Breast fed as infant with current poor dairy intake Breast fed as infant with current poor dairy intake Calcium 8 mg/dl (9-10.5) Calcium 8 mg/dl (9-10.5) Phosphorus 4mg/dl (3-4.5) 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 Vitamin D deficiency with secondary hyperparathyroidism Tibial and femur bowing Tibial and femur bowing Treatment: Ergocalciferol and calcium Treatment: Ergocalciferol and calcium