CHATLERT PONGCHAIYAKUL MD ENDOCRINE UNIT , MEDICINE . KKU HYPERCALCEMIA HYPERCALCEMIA CHATLERT PONGCHAIYAKUL MD ENDOCRINE UNIT , MEDICINE . KKU Syed Nasrat Imam

CALCIUM An essential intracellular and extracellular cation HYPERCALCEMIA CALCIUM 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 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 Serum calcium is about half ionized One gram per deciliter of albumin binds approximately 0.8 mg/dl of calcium Respiratory alkalosis and elevated pH causes increase in the binding of calcium and 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 Syed Nasrat Imam, MD Syed Nasrat Imam

CALCIUM Respiratory alkalosis and elevated pH cause increase in the binding of calcium and 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 Total body Ca -1 to 1.5 kg, 99%- skeleton, 0.1% ECF , rest intracellular. One gram per deciliter of albumin binds approximately 0.8 mg/dl of calcium Syed Nasrat Imam, MD

FORMULA FEca = 0.8 for each gm of Albumin HYPERCALCEMIA FORMULA 0.8 for each gm of Albumin 0.16mg/dl for each gm of globulin. (Uca/Pca) (Ucr/Pcr) 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% FEca = = Uca/Pca x Pcr/Ucr Syed Nasrat Imam, MD Syed Nasrat Imam

CLINICAL MANIFESTATIONS HYPERCALCEMIA CLINICAL MANIFESTATIONS GI- Anorexia, Nausea, Vomiting, Constipation and rarely acute Pancreatitis. CVS- Hypertension, shortened QT interval, and enhanced sensitivity to digitalis. RENAL- Polyuria, Polydipsia, and occasionally Nephrocalcinosis. CNS- Cognitive difficulties, Apathy, Drowsiness, Obtundation, or even Coma. Most common symptom is probably nocturia Syed Nasrat Imam, MD Syed Nasrat Imam

HYPERCALCEMIA SYMPTONS More than 50% of all patients with primary hyperparathyroidism are asymptomatic when hypercalcemia is first discovered. Diagnostic Finding Frequency (%) Likelihood Ratio In Primary HPT In Malignancy Finding +nt Finding -nt Renal Calculi 29 4 7.3 0.74 Peptic Ulcer 13 10 1.3 0.97 Hypertension 49 25 2 0.68 Polyuria 22 29 0.76 1.1 Mental status change 23 33 0.7 1.1 GI Distress 25 34 0.74 1.1 Muscular weakness 32 36 0.89 1.1 Bone Pain 28 58 0.48 1.7 Constipation 19 58 0.33 1.9 Weight Loss 19 64 0.30 2.3 Anorexia 19 64 0.30 2.3 Fatigue 31 73 0.42 2.6 Syed Nasrat Imam, MD Syed Nasrat Imam

SIGNS * Band keratopathy HYPERCALCEMIA SIGNS * Band keratopathy The deposition of Ca as corneal opacities is usually sign of long standing hypercalcemia -most commonly associated with primary hyperparathyroidism. Calcium deposition begins near the limbus at the 3 & 9 o’clock position, presumbly because there is less friction from the lids near the limbus & because the tear film is most alkaline in the most exposed area, band running across the cornea from the 3 to 9 o’clock position Syed Nasrat Imam, MD Syed Nasrat Imam

SIGNS * Bony tenderness * Hyperactive tendon reflexes HYPERCALCEMIA SIGNS * Bony tenderness * Hyperactive tendon reflexes * Tongue fasciculations Hypercalcemia in pregnant female may cause hypocalcemia in her neonates by suppressing the fetal parathyroid. Hypercalcemia - small dec. in GFR - due to hemodynamic effects & hyposthenuria (a loss of renal concentrating abilities) Syed Nasrat Imam, MD Syed Nasrat Imam

COMPLICATIONS * Sinus bradycardia HYPERCALCEMIA COMPLICATIONS * Sinus bradycardia * Increase in the degree of a heart block * Cardiac arrhythmia * HTN * Pancreatitis * PUD * Nephrolithiasis * Accelerated vascular calcification Syed Nasrat Imam, MD Syed Nasrat Imam

THREE HORMONE AND THREE ORGAN HYPERCALCEMIA CALCIUM HOMEOSTASIS THREE HORMONE AND THREE ORGAN PTH ACTIVATED VITAMIN D CALCITONIN BONE KIDNEY SMALL INTESTINE Syed Nasrat Imam, MD Syed Nasrat Imam

*Actions on Bone *Actions on Kidney *Actions on GI HYPERCALCEMIA THREE HORMONES PTH (84 amino acid) *Actions on Bone *Actions on Kidney *Actions on GI * Parathyroid cells are unusual in the respect that hormone degradation rather than synthesis is adjusted according to physiological demand. As much as 90% can be destroyed within the chief cells. * If blood levels of ionized calcium drop by as little as 0.1 mg/dl, secretion of PTH is stimulated * Half-life of PTH is minutes Kidney reacts quickly to changes in PTH and is responsible for minute to minute adjustments of blood calcium. PTH acts directly on distal portion of the nephron to decrease urinary excretion of calcium mediated by cAMP. PTH powerfully inhibits tubular reabsorption of phosphate and thus increases the amount excreted in the urine, mainly in proximal tubules PTH stimulates the renal enzyme that converts vit D to its active form but has no direct effects on intestinal transport of calcium or phosphate. Action of PTH to increase 1,25(OH)2D is blunted in hyperphosphatemia Syed Nasrat Imam, MD Syed Nasrat Imam

ACTIONS OF PARATHYROID HORMONE The principal regulator of calcium concentration in extracellular fluid *Increases the calcium concentration and decreases the phosphate concentration in the blood. *Bone responds in 2-3 hours 1st phase to small increases of PTH. PTHReceptors on surface osteocytes intervention of GTP binding proteinactivates adenylate cyclaseIncreases permeability to of osteocytes to calcium in surrounding bone fluid compartmentCalcium enters cytosol and then extruded to ECF compartment on other side of bone membrane and shifts equilibrium to solubilization 2nd phase- becomes evident about 12 hours later characterized by widespread resorbtion of both mineral and organic components of matrix. Osteoclastic activity predominates *Activity of all bone cell types is increased by PTH but only osteocytes and osteoblasts have receptors for PTH. Activation of and recruitment of osteoclasts must be accomplished indirectly by some paracrine or endocrine signal produced by osteocytes and osteoblasts Syed Nasrat Imam, MD

VITAMIN D Activated Vit D GI - increase Ca absorption. Bone - increase Ca mobilization. Kidney - increase reabsorption within the distal tubule. Deficiency of vitamin D severely impairs intestinal transport of both calcium and phosphorous Mineralization of osteoid occurs spontaneously when adequate amounts of calcium and phosphorous are available 1,25(OH)2D3 increases the number and activity of osteoclasts but osteoblasts have the receptors Effect on calcium absorption in the distal nephron Regulation- Hydroxylation of carbon 1 by cells in the proximal tubules of the kidney which converts a nearly inactive precursor to a highly active hormone is stimulated primarily by PTH and by low phosphate concentrations. 1,25(OH)2D3 inhibits hydroxylation of carbon in the kidney and carbon 25 in the liver and stimulates hydroxylation of carbon 24 which diverts precursor to a degradative pathway. Syed Nasrat Imam, MD

CALCITONIN ( 32 amino acid ) HYPERCALCEMIA CALCITONIN ( 32 amino acid ) Parafollicular cells of the Thyroid gland in response of hypercalcemia * Decrease osteoclast activity. * Stimulating a distal tubular - mediated calciuresis. Other hormones affecting calcium balance - many including prostaglandins that mobilize calcium, various growth factors, growth hormone, somatomedins, thyroid hormones(decrease skeletal mass), gonadal hormones which help maintain bone mass, adrenal cortical hormones Syed Nasrat Imam, MD Syed Nasrat Imam

HYPERCALCEMIA TARGET ORGAN 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 : Glumerulus 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. ACTIONS ON KIDNEY Kidney reacts quickly to changes in PTH and is responsible for minute to minute adjustments of blood calcium. PTH acts directly on distal portion of the nephron to decrease urinary excretion of calcium mediated by cAMP. About 90% of the filtered calcium is reabsorbed in the proximal tubule and loop of Henle independently of PTH PTH decreases the fraction of filtered calcium that escapes the urine. PTH powerfully inhibits tubular reabsorption of phosphate and thus increases the amount excreted in the urine, mainly in proximal tubules PTH stimulates the renal enzyme that converts vit D to its active form but has no direct effects on intestinal transport of calcium or phosphate. Action of PTH to increase 1,25(OH)2D is blunted in hyperphosphatemia REGULATION OF PTH SECRETION Chief cells of the parathyroid glands secrete PTH at a rate that is inversely related to the calcium concentration in blood. Phosphate concentrations have no effect on secretion of PTH CALCITONIN Made by parafollicular cells of thyroid gland, also called C cells. No overt derangement in calcium balance or other homeostatic function is caused by deficient or excessive production of Calcitonin Calcitonin lowers blood calcium and phosphate primarily by inhibiting Osteoclastic activity At high concentrations, Calcitonin may increase urinary excretion of calcium and phosphorous, probably by acting at the proximal tubules but unlikely to be physiologically important for calcium homeostasis Parafollicular cells respond directly to ionized calcium in the blood Parafollicular cells also respond to gastrin Deficiency of vitamin D severely impairs intestinal transport of both calcium and phosphorous Mineralization of osteoid occurs spontaneously when adequate amounts of calcium and phosphorous are available 1,25(OH)2D3 increases the number and activity of osteoclasts but osteoblasts have the receptors Effect of phosphate resorbtion on the kidney is probably indirect and related to PTH Effect on calcium absorption in the distal nephron Regulation- Hydroxylation of carbon 1 by cells in the proximal tubules of the kidney which converts a nearly inactive precursor to a highly active hormone is stimulated primarily by PTH and by low phosphate concentrations. 1,25(OH)2D3 inhibits hydroxylation of carbon in the kidney and carbon 25 in the liver and stimulates hydroxylation of carbon 24 which diverts precursor to a degradative pathway. Other Hormones Affecting Calcium Balance-many including prostaglandins that mobilize calcium, various growth factors, growth hormone, somatomedins, thyroid hormones(decrease skeletal mass), gonadal hormones which help maintain bone mass, adrenal cortical hormones Syed Nasrat Imam, MD Syed Nasrat Imam

CALCIUM REGULATION _ PTH + _ + 1,25(OH)2 D3 + + CALCITONIN _ GI Tract ECF Pool of Calcium BONE URINE Syed Nasrat Imam, MD

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

HYPERPARATHYROIDISM Syed Nasrat Imam, MD

HYPERPARATHYROIDISM STONES, BONES, GROANS, AND MOANS Syed Nasrat Imam, MD

Syed Nasrat Imam, MD

Syed Nasrat Imam, MD

NIH consensus development conference recommendation PARATHYROIDECTOMY A serum calcium > 12mg/dl Hypercalciuria > 400mg/d Presence of sign and symptoms--S,B,G,M Markedly reduced cortical bone density Hypercalcemia causing decreased GFR Patient age under 50 years? NIH consensus development conference recommendation Syed Nasrat Imam, MD

TREATMENT OPTION Hydration. Furosemide. Bisphosphanate. Calcitonin. Mithramycin. Gallium nitrate. Steroids. IV Phosphate. Dialysis. Others. Syed Nasrat Imam, MD

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 CVS for volume expansion. Syed Nasrat Imam, MD

LOOP DIURETICS Facilitate urinary excretion of calcium By inhibiting calcium reabsorption in the thick ascending limb of the loop of Henle. Guard against volume overload Volume expansion must precede the administration of furosemide, because the drug’s effect depends on delivery of calcium to the ascending limb. Needs frequent measurement of lytes and water Syed Nasrat Imam, MD

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 decrease GI absorption, 200-300mg hydrocort for upto 5 days, slow response limits it’s use HEMODIALYSIS Zero or low calcium bath, In selected condition, eg-hypercalcemia complicated by renal failure Syed Nasrat Imam, MD

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 dessolution of crystals. Their great affinity for bone and their resistance to degradation account for their extremely long half life in bone. Poor GI absorption- <10% ETIDRONATE PAMIDRONATE CLODRONATE Etidronate- 7.5mg/kg iv over 4 hr for 3-7 days, S. ca begins to decrease within 2 days after first dose. Response better if pt well hydrated before t/t. Oral to prevent recurrent hypercalcemia.. Adverse effect-increase s. cr, phosphate, long term use-impair bone formation, osteomalacia, Syed Nasrat Imam, MD

PAMIDRONATE Inhibits osteoclast function The most potent bisphosphonate. 60mg to 90 mg IV over 24hr. 70% to 100% of patients had decreased s. calcium within 24 hr of t/t, 2/3rd of this group had normal s cal within 7 days. Adverse effect- mild transient increase in temp(<2deg C), transient leukopenia, small reduction in s phosphate level. Excreted by kidney- dose adjustment. Syed Nasrat Imam, MD

MITHRAMYCIN An inhibitor of RNA synthesis in osteoclasts IV 25 microgram/kg over 4-6 hr. Begins to decrease in 12hr, maxm in 48-72 hr. Duration of normocalcemia ranges from a few days to several wks. Depending on the extent of ongoing bone resorption. Adverse effect- Nausea- can be mini- by slow iv. Avoid extravasation-cellulitis.Hepatotoxic- in 20% pt. Nephrotoxic- increase s. cr, proteinuria. Thrombocytopenia. Contraindication-liver, kidney dysfunction, thrombocytopenia, or any coagulopathy. Syed Nasrat Imam, MD

GALLIUM NITRATE Inhibit bone resorption by adsorbing to and reducing the solubility of hydroxyapatite crystals. Adverse effect- Nephrotoxity, hypophosphatemia, small reduction in Hb concentration. Clinical experience limited. Syed Nasrat Imam, MD

OTHERS GLUCOCORTICOIDS- inhibiting the growth of neoplastic lymphoid tissue, counteracting the effects of vitamin D. PHOSPHATE- Can lower rapidly and profoundly, but very dangerous. Restricted to pt with extreme, life threatening hypercalcemia in whom all other measure failed. Hyperphosphatemia and azotemia are contraindications. AMIFOSTINE(WR-2721) PG Syed Nasrat Imam, MD

CHOICE OF AGENT Mild (<3 mmol/l)-Hydration with saline. Moderate(>3.5mmol/l) with moderate symptoms- Bisphosphonate. Severe life threatening( >4mmol/l) - Saline + Calcitonin + mithramycin,alternatively bisphosphonate, if steroids sensitive + steroids. Hypercalcemia secondary to malignancy- survival after the appearance of hypercalcemia is very poor - median of 3 months. Syed Nasrat Imam, MD

REFERENCES Recognizing hypercalcemia: The ‘3-hormone, 3-organ rule’-Gregory W. Rutecki, MD and Frederick C. Whittier, MD, The journal Of Critical Illness. Vol 13, no. 1.Jan 1998 Management Of Acute Hypercalcemia, John P. Bilezikian, MD, The New England Journal Of Medicine,vol 326, No 18, April 30, 1992. Cecil’s Text Book Of Internal Medicine Harrison’s Principle Of Internal Medicine. Renal and Electrolyte Disorders, Vth edition, Robert W. Schrier. Potts Jt, ed. 1991 NIH Consensus Development Conference Statement on Primary Hyperparathyroidism. J Bone Miner Res. 1991;6:s9-s13 Mallette LE. The Hypercalcemia. Semin Nephro. 1992;12:159-190. Edelson GW, Kleenehoper M. Hypercalcemic crisis. Med Clin North Am. 1995;79:79-92 Syed Nasrat Imam, MD