1. CALCIUM HOMEOSTASIS AND DISORDERS
Dr.Hardik Patel

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

3. 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

4. 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)

5. 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

6. 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

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

8. 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

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

10. 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 (4-serum albumin)

11. 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: , 2008

12. 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

13. 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.

14. 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

15. 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

16. 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

17. 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

18. 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

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

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

21. 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

22. 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

23. 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)

27. 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

28. 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

29. 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

30. Disorders related to vitamin D
Abnormal metabolism of vit D:
VIT D dependent rickets: type 1, AR, 25(OH) Vit D 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

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

32. 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

33. 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

34. 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)

35. 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

36. 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

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

38. Box 5.28: Vitamin D deficiency

39. Box 5.28: Vitamin D deficiency

40. 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

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

42. 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

43. 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?

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

45. 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

46. 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 mg
Calcitriol ( rocaltrol ) 0.25 and 1 micro gram

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

48. 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.

49. 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

50. 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.

51. 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.

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

53. 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.

54. 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

55. 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

56. 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

57. 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

58. Thank you