Calcium Metabolism and Hypercalcemia

1. Calcium Metabolism and Hypercalcemia Alex Yartsev

2. Calcium • Element number 20 • Makes up 3% of the Earths crust • Calcium ion: Ca2+ • Divalent cation Wikipedia

3. Calcium in the human body • 5th most abundant element in the human body • After cremation, a third of the remaining mass (1kg) • Makes up 70% of hydroxyapatite (Ca10(PO4)6(OH)2) • Most is present in this fixed form: bones and teeth • A little is in the cytoplasm of all the cells • A tiny amount circulates bound to albumin • Miniscule portion is circulating as Ca++ ion • the only physiologically active form is the Ca++ ion Endocrine Physiology, 3rd ed. P.E. Molina; Chapter 5 (Via CIAP)

4. Distribution of calcium in the human body 1% of total body calcium is present in the cells 0.1% of total body calcium is in the extracellular fluid: Ionised Calcium: Ca++ 50% 1.2 mmol/L • Present as free, active cation • Diffuses easily across capillary membranes Hydroxyapatite 98.9% = 31 mol = 1250g 1% of which is available as an exchangeable pool Protein-bound Calcium: 41% 1.2 mmol/L • Bound mainly to albumin • Cannot diffuse across capillary membranes Anion-bound calcium: 9 %, 0.2 mmol/L • Bound to small anionic molecules, eg. phosphate and citrate • diffuses easily across capillary membranes Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

5. What are we measuring, exactly • CMP calcium from venous blood • Total calcium: ionized calcium + protein bound + anion bound; should be 2.2 to 2.6 mmol/L • Corrected calcium: • when the albumin is low, protein-bound calcium will also be low; • however the levels of ionized calcium remain unchanged • Corrected calcium is what the total calcium WOULD BE if the patient had a normal albumin level. • corrected [Ca] in mmol/L = = measured total [Ca] (mmol/L) + 0.02 x (40 – serum albumin in g/L) Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

6. What are we measuring, exactly • ABG calcium: • Just the ionised fraction • This is the fraction that is under homeostatic control • Measured precisely with ion-selective glass electrode • The most accurate impression of whether somebody is hypo or hypercalcemic • Especially in patients on TPN, acidotic patients, ICU patients with low albumin, patients on dialysis, cases of hyperparathyroidism, and patients receiving citrated blood (because citrate binds ionized calcium) Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79 McLean et al, Clinical Estimation and Significance of Calcium-Ion Concentrations in the Blood ; Am J Med Sci may 1935 vol. 189:5 pp21-612 Calvi et.al, When Is It Appropriate to Order an Ionized Calcium? 2008 J Am Soc Nephrol 19: 1257-1260, 2008

7. What is the point of calcium • Muscle contraction caused by Ca++ efflux from sarcoplasmic reticulum • Neurotransmitter release caused by Ca++ influx into presynaptic terminal • Conduction system of the heart • Myocardial contraction • Clotting cascade • Bone integrity Uses Ca++ instead of Na+ to depolarise Ca++ influx is responsible for the plateau phase of the action potential Ca++ is a cofactor required at most factor activation steps, that’s why blood bank purple top tubes contain a calcium chelator (EDTA) Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

8. Daily dietary calcium requirements 40 mg = 1 mmol National Health and Medical Research Council. (2006) Executive Summary of Nutrient Reference Values for Australia and New Zealand Including Recommended Dietary Intakes. Commonwealth Department of Health and Aging, Australia, Ministry of Health, New Zealand.

9. Daily calcium requirements in the ICU • 0.1 mmol/Kg /day - INTRAVENOUSLY • Thus, a 100kg ICU pt on TPN needs 10mmol every day Oh’s Intensive Care Manual, 6th ed. R.Leonard; Chapter 87 Enteral and parenteral nutrition

10. Usual Sources of Calcium • Dairy: • 200ml yoghurt = 10mmol • 1 litre of milk = 25 mmol • Spinach • Baked beans • Oranges • Nuts • Small canned fish with intact bones: canned sardines = 10mmol per 100g www.nutritiondata.com

11. Unusual Sources of Calcium • Jevity 1cal contains ~23 mmol of calcium per litre (910 mg) • One Caltrate tablet = 15 mmol (600mg) • Calcium resonium: exchanges calcium for potassium in the gut. Calcium content is 1.6 to 2.4 mmol/g, so each 30g dose = potentially 48 to 72 mmol • Calcium gluconate: 2.2 mmol per 10ml vial • Calcium chloride: 6.6 mmol per 10ml vial http://www.abbottnutrition.ca – Jevity manufacturer http://www.caltrate.com.au/caltrate-600mg.aspx - Wyeth Consumer Healthcare website MIMS online via CIAP

12. Calcium absorption • NORMALLY, 30-35% of ingested calcium is absorbed • Thus, to get your 10mmol, you need to ingest ~ 25-30mmol; • Thus, ~ 1 litre of milk or 1.2 litres of Jevity • Absorption occurs in the duodenum • Active transport out of the gut • Rate of absorption closely linked to calcium demand • Controlling hormone is mainly Vitamin D (activated vitamin D greatly increases calcium absorption) • ~ 7 mmol is lost in the intestine as sloughed cells/juices • NET: 30mmol go in, 27 mmol come out. 3 mmol remain. • Thus, you only end up keeping 10% of the calcium you ingest Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65

13. Calcium transport in the blood • 50% as ionised, 41% bound to protein (mainly albumin, some globulins) and 9% bound to anions in soluble complexes • Ionized fraction depends on pH: • protein binding decreases as pH decreases Alkalosis: increased calcium binding to protein; decreased ionised fraction pH 7. 45 pH 7.35 Each 0.1 decrease in pH increases ionized calcium by 0.05 mmol/L Acidosis: decreased calcium binding to protein; increased ionised fraction Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

14. Calcium storage • 98.9% stored in bone • 1% stored in cytoplasm and 0.1% is present in the extracellular fluid • Stored as HYDROXYAPATITE mineral • Balance of storage is influenced by balance of osteclast vs osteoblast activity: building vs destruction of the bony matrix • This is influenced by parathyroid hormone and to a lesser degree calcitonin • SHOULD BE NEUTRAL! • 500mg (12.5mmol) per day should be deposited, • 500mg (12.5mmol) should be reabsorbed Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

15. Intestinal calcium excretion INTESTINAL LOSSES • 7 mmol (~ 250mg) lost in sloughed cells and intestinal secretions • More if there is a vitamin D deficiency • More if there is hypercalcemia Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

16. Renal calcium excretion • 2.5mmol (100mg) is excreted through the kidneys daily • The ionized calcium is the only excretable variety because protein-bound calcium does not make it past the glomerulus • 90% of the filtered calcium is reabsorbed in the proximal tubule • The reabsorption of the remaining 10% is controlled by PTH and depends on ionic calcium concentration • This remaining 10% is reabsorbed in the early collecting ducts Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65

17. Summary of calcium balance Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 65

18. Calcium homeostasis INCREASED Ca++ C Increased calcium uptake from duodenum and reuptake in the nephron Sensed by Chief cells in parathyroid gland Increased bone resorption DECREASED PARATHYROID HORMONE SECRETION Decreased osteoclast activity Decreased Vitamin D activation Increased osteoclast activity Increased Vitamin D activation Decreased bone resorption INCREASED PARATHYROID HORMONE SECRETION Decreased calcium uptake from duodenum and reuptake in the nephron Sensed by Chief cells in parathyroid gland DECREASED Ca++ C Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

19. Parathyroid hormone • Secreted by the chief cells of the parathyroid gland • Secreted in response to decreasing ionized Ca++ • Causes increased osteoclast maturation and thus increased bone resorption • Causes increased Vitamin D activation in the kidney Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

20. Vitamin D • Lipid soluble vitamin • Precursors: • Cholecalciferol in the skin (produced by UV radioation) – Vitamin D3 • Ergocalciferol from diet – Vitamin D2 • Both get hydrolysed in the liver to 25-hydroxyvitamin D3 • Then, in the kidney, get hydrolysed again to 1,25-hydroxyvitamin D • This last step is under the control of parathyroid hormone • VITAMIN D ACTIVITY: • Increased gut absorption of calcium • Increased reabsorption of calcium in the distal nephron Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

21. Calcitonin • Produced by parafollicular cells in the thyroid gland • Release stimulated by rising ionized calcium levels • Action: • directly inhibits osteoclast activity • Increases renal excretion of calcium by inhibiting resorption Not critical for calcium homeostasis. Removing the thyroid causes no major alteration in calcium homeostasis. Endocrine Physiology, 3rd ed. P.E. Molina; Chapter 5 (Via CIAP)

22. Hypercalcemia • Total calcium over 2.6 mmol/L • Ionized calcium over 1.23 mmol/L

23. Causes of hypercalcemia • Excessive PTH • Primary hyperparathyroidism eg. adenoma, hyperplasia of gland • Tertiary hyperparathyroidism, eg. long term stimulation of parathyroid gland in chronic renal failure • Paraneoplastic PTHrP production (solid tumours) • Excessive activated Vitamin D • Sarcoidosis, silicosis, tuberculosis, lymphomas • Vitamin D intoxication • Neoplasia, lytic bone lesions • Excessive calcium intake, eg. calcium antacids or TPN • Bone resorption due to immobilization • Hyperthyroidism, antiestrogen therapy, lithium therapy, thiazides Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.

24. Consequences of hypercalcemia • HYPERCALCEMIA = NERVOUS SYSTEM DEPRESSION • Reduced reflexes or areflexia • Reduced alertness, depression, confusion, lethargy, coma • Polyuria, polydipsia (reduced concentrating ability) • Bradycardia, AV block, short QT interval, widened T wave • Nausea, anorexia, constipation, abdominal cramps • Bone pain, pathological fractures • Pancreatitis • Peptic ulcers • Renal calculi • Symptoms are usually seen at above 3.0mmol/L • Cardiac arrest is a real possibility at levels above 3.75 mmol/L Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.

25. Diagnostic aids • Is it the albumin? Whats the corrected Ca++ • PTH levels, or PTHrP levels • Vitamin D levels • Phosphate and magnesium are done routinely with calcium • What is the renal function • Has anything happened to the neck? Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.

26. Management of mild hypercalcemia • Consider not doing anything • Consider stopping calcium replacement • Consider stopping thiazides • Consider giving a different variety of resonium next time • Rehydration (hypercalcemia inevitably leads to dehydration by polyuria) • Loop Diuretics if volume already normal Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.

27. Management of severe hypercalcemia • GOALS: • Decrease bone resorption • Increase calcium excretion • Then, deal with the primary pathology, if possible Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders

28. Management of severe hypercalcemia • Rehydrate aggressively WHILE giving loop diuretics • Aim for a daily urine output of 4-5 litres • If there are no kidneys to work with, go with dialysis. • Infusion of bisphosphonates: pamidronate, zolendronate, etidronate… • Takes 1-3 days to reach maximum effect Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders

29. Specific strategies in the management of hypercalcemia • Chloroquine for sarcoidosis- reduces serum vitamin D levels • Ketoconazole is also for sarcoidosis-induced hypercalcemia and vitamin D intoxication • Hydrocortisone for myeloma, granulomae, Vitamin D intoxication Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders

30. Abnormal management of hypercalcemia • Gallium Nitrate known to inhibit bone resorption by altering the structure of hydroxyapatite, equivalent efficacy to pamidronate but horribly nephrotoxic in 12.5% • Calcitonin was more popular before bisphosphonates • For some reason, salmon calcitonin is more powerful than human calcitonin • Plicamycin (“mithramycin”)- chemotherapy agent, also happens to lower calcium levels. Pamidronate = more effective, better tolerated • Disodium Ethylenediaminetetraacetic acid: EDTA • 15-20mg/kg acts as a calcium chelator, very rapidly lowers calcium levels;  cardiotoxicity and nephrotoxicity • Yes it’s the same stuff they put in purple top blood tubes

31. Time for questions