CALCIUM HOMEOSTASIS AND DISORDERS Dr.Hardik Patel

Calcium Element number 20 Calcium ion: Ca2+ Atomic wt 40 Divalent cation, valency 2 5th most abundant element in the human body Wikipedia

Calcium chemistry 1 mole = atomic wt in grams 1 mmole = atomic weight in mg mEq = (mg X valence)/atomic weight mg= (mEq X atomic weight)/valence 1mmol/l = 4 mg/dl = 0.2 mEq of calcium

Calcium in the human body Preservation of integrity of cellular membrane Neuromuscular activity Regulation of endocrine and exocrine secretory activities Blood coagulation Activation of complement system Bone metabolism Endocrine Physiology, 3rd ed. P.E. Molina; Chapter 5 (Via CIAP)

Calcium exists in 3 forms Protein bound calcium: 40%, of this 80-90% to albumin. It is affected by sodium level and ph. Free (ionised) calcium: 47%, biologically active, 4-4.9mg/dl. Affected by ph, freezing and thrawing of serum. Nonionized calcium: 13%, complexed calcium formed by bicarbonates, phosphates and acetates, anion bound

Calcium transport in the blood 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

Cytostolic free calcium 100 nmol/l 10000 fold lower than extracellular calcium This steep gradient maintained by plasma membrane Ca++ ATPase (PMCA)

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

Measuring Ca++ Total calcium: ionized calcium + protein bound + anion bound; Normal ranges: The plasma total calcium concentration is in the range of 2.2-2.6 mmol/L (9-10.5 mg/dL), and the normal ionized calcium is 1.3-1.5 mmol/L (4.5-5.6 mg/dL) Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79

Corrected calcium 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 Calcium = Serum Calcium + 0.8 (4-serum albumin)

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

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

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.

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

Calcium absorption NORMALLY, 30-35% of ingested calcium is absorbed 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

Calcium storage 98.9% stored in bone Stored as HYDROXYAPATITE mineral 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

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

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

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

Summary of calcium balance Calcium is regulated by combinations of Bone exchange Renal exchange and Intestinal absorption

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

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

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)

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

HYPOCALCEMIA NORMAL RANGE: 8.5-10.5 mg/dl and ionized 4.5-5.5 mg/dl CLASSIFIED INTO: Disorder related to Vit D Disorder related to PTH

Disorders related to vitamin D VITAMIN D DEFICIENCY: Lack of exposure to sunlight Nutritional Malabsorption: following gastrectomy, tropical sprue, chronic pancretitis, biliarry chirrosis, ingestion of cathartics, intestinal bypass, anticonvulsant therapy

Disorders related to vitamin D Abnormal metabolism of vit D: VIT D dependent rickets: type 1, AR, 25(OH) Vit D 1@ hydroxylase def, type 2, AR, 1,25(OH)2 vit D resistant rickets ingestion of barbiturates and anticonvulsant, renal insufficiency, hepatic dysfuntion, calcium deprivation: secondary hyperthyroidism

Disorders relared to vitamin D Renal loses of vit D: nephrotic syndrome, fanconi syndrome

Disorder related to PTH REDUCED PRODUCTION OF PTH: Hypoparathyroidism: hypocalcemia and hyper phosphatemia Secondary hypoparathyroidism: surgery thyroidectomy, multiple endocrine dysfuntions (adr insufficiency, pernitious anemia,thallasemia, wilson disease), magnesium deficiency (reduces release of pth), aminoglycosides and cytotoxic agents have toxic effect on pth glands

Disorder related to PTH REDUCED PRODUCTION OF PTH:…. Primary or idiopathic hypoparathyroidism: both AR nad AD forms, DiGeorge velocardiofacial synd CATCH 22 Syndrome: cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia Autoimmune

Disorder related to PTH IMPAIRED ACTION OF PTH DUE TO PERIPHERAL RESISTANCE: Pseudoparahypothyroidism: inherited Calcitonin: depress activity of osteoclasts, eg: medullary ca thyroid secrete calcitonin, sepsis leads to increase level of calcitonin precursors Bisphosphonates: pamidronate (bone metastasis of solid tumor), alendronate (osteoporisis)

RAPID REMOVAL CALCIUM FROM CIRCULATION: Malignant neoplasm: osteoblastic bone forming metastasis eg: prostrate and breast Hyperphosphatemia: forms calcium phosphates in bone soft tissue or both; eg:oral or iv phosphate, cows milk to infant, laxatives, enemas, renal disease arf or crf, neoplasm treated with cytotoxic agents; lymphomas, leukemias, tumor lysis, rabdomylasis

RAPID REMOVAL CALCIUM FROM CIRCULATION Acute pancreatitis: precipitation of calcium soaps in abdo cavity which results from release of lipolytic enzymes and fat necrosis Citrate, lactate, bicarbonates, Na EDTA, Foscarnet and poisoning with ethyl glycol

CLINICAL CONSEQUENCES DEPENDS ON Severity Rapidity of fall Age Chronicity Comorbid conditions

Box 5.28: Vitamin D deficiency

Box 5.28: Vitamin D deficiency

CLINICAL CONSEQUENCES Tetany Peri oral numbness and tingling Parasthesias in extremities Carpopedal spasm Laryngospasm; stridor Focal or generalised seizures Spasm of diaphragm and of intercostal muscles- respiratory arrest and asphyxia

signs Trousseau sign: carpal spasm Chvostek sign: facial muscle contraction Visual impairment: papilledema (acutely), cataract ( chronic)

Cardiac changes Acute hypocalcemia leads to hypotention Lack of compensatory tachycardia – further activates condition Prolong phase 2 of AP- repolarization time Prolongation of QT interval – VT, torsedes de pointes Chronic condition leads to dilated cardiomyopathy

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?

Treatment Symptomatic: iv calcium Forms: 10% calcium gluconate: 10 ml=90 mg elemental calcium 10% calcium chloride: 10ml=360mg elemental calcium 100-200 mg elemental calcium ( 5-10 meq) slowly over 10 min, followed by slow drip 100-200 mg diluted in 250-500ml 0.45% NS or D5W given over several hours until calcium takes over. Followed by oral calcium supplements

Oral calcium supplements: reversible or irreversible hypoparathyroidism Calcium lactate 300mg- 60mg elemental ca Calcium gluconate 1gm -90mg ele ca Calcium carbonate 650mg- 250mg ele ca Calcium citrate 950mg – 200mg ele ca

If does not respond to oral calcium supplements then vitamin D supplements 1.25 mg (50000 units) of vit D2 ergocalciferol DHT3 3 times more potent, dose 0.125 mg Calcitriol ( rocaltrol ) 0.25 and 1 micro gram

Hypercalcemia Total calcium over 2.6 mmol/L or 10mg/dl Ionized calcium over 1.23 mmol/L or 4.5mg/dl

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) 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.

Causes of hypercalcemia 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

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 Cardiac arrest 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.

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.

Management of hypercalcemia Hypercalcemia augments urinary loses of sodium and water Leading to hypovolumia – decreased GFR- futher decrease calcium excretion

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.

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

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 30mg infusion, zolendronate, etidronate… Takes 1-3 days to reach maximum effect Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders

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: 3-4 mg/kg of hydrocort, takes 1-2 days to act Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders

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

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