CALCIUM HOMEOSTATIS

OVERVIEW

Intro.Absorption.Function.Regulation of calcium homeostasis: PTH. Vitamin D. Calcitonin.Hypocalcaemia.Hypercalcaemia.References.

INTRO

Fifth most common element in the body.99% present in skeleton (reservoir).1% intracellular.0.1% extracellular.Forms of Ca in the blood: 50% is free ionised calcium. 40% is protein bound (mainly albumin). 10% is complexed to small diffusible ligands (e.g. bicarbonate,

citrate, phosphate, lactate and sulphate).Normal level 2.20 -2.6 mmol/L.

ABSORPTION

Widely distributed in food substances e.g. Milk, Cheese, Egg-yolk, Fish , Beans, and Lentils.

The 2 mechanisms of intestinal absorption of calcium are:

Active: is a saturable, transcellular process which involves calbindin (calcium-binding protein) – regulated by the active form of vitamin D.

Passive: is a nonsaturable, paracellular low efficiency process, which is not affected by calcium status or parathyroid hormone.

Both processes occur throughout the small intestine.

Absorption is related to calcium intake.

ABSORPTION Factors stimulating calcium absorption:An acidic pH.High protein diet – Lysine and Arginine cause maximal absorption.Presence of vitamin D.State of health and intact mucosa.PTH stimulates the activation of vitamin D, consequently indirectly

increasing absorption of Calcium.

ABSORPTION

Factors inhibiting calcium absorption:Alkaline pHHigh fat diet – fatty acids form calcium soaps that cannot be

absorbed.Excess phosphates, magnesium and iron.Glucocorticoids reduce intestinal absorption of calcium.Calcitonin decreases calcium absorption indirectly by inhibiting the

activation of vitamin D.Advancing age and intestinal inflammatory disorders.

FUNCTION

Major structural element in the bones and teeth.Essenial for several physiological processes such as neuromuscular

transmission, smooth, skeletal, and cardiac muscle contractions, nerve function, and cell division and movement.

Co-factor in Blood coagulation.Plays an important role in the action of other intracellular

messengers e.g. cyclic adenosine monophosphate (cAMP) and Inositol -triphosphate, which are responsible for mediating the cellular response to various hormones including epinephrine, glucagon, ADH, and secretin.

Release of neurotransmiters and hormones.

REGULATION OF CALCIUM HOMEASTASIS

The 3 main hormones involved in the homeostatic regulation:PTHVitamin DCalcitonin

Acting at 3 target organs: intestine, bone and kidneys.

PTH

Polypeptide containing 84 amino acids residues.Secreted by the chief cells in the 4 parathyroid glands.Part of a negative feedback loop to maintain calcium ions in the

extracellular fluid. In hypocalcaemia, parathyroid hormone secretion is stimulated. In hypercalacaemia, secretion is inhibited, and the calcium is deposited in the

bones.

PTH increases serum calcium levels through: Increasing bone resorption by activating osteoclastic activity. Increasing renal calcium reabsorption by the distal renal tubules. Increasing renal phosphate excretion by decreasing tubule phosphate reabsorption. Increasing the synthesis of 1,25-dihydroxyvitamin D (also called calcitriol) by

increasing the activity of alpha-hydroxylase enzyme in the kidney.

VITAMIN D

Group of closely related sterols produced by the action of UV light.

Vitamin D3 (also called Cholecalciferol) is produced by the action of sunlight and is hydroxylated to 25-hydroxy-cholecalciferol (25-HCC) in the liver.

Further hydroxylation of 25-HCC occurs in the proximal tubules of the kidney to form the active metabolite, 1,25-hydroxy-cholecalciferol (1,25-DHCC) or calcitriol.

Calcitriol's formation is facilitated by PTH.

VITAMIN D

VVitamin D maintains calcium homeostasis by:

--Increasing calcium absorption from the intestine (by interacting with a calcitriol receptor located in intestinal epithelial cells.

S-Stimulating renal tubular reabsorption of calcium.

I-Increasing bone calcification and mineralisation (by acting on osteoclasts in the bone)

CALCITONIN

32 amino acid polypeptide secreted by the parafollicular cells in the thyroid gland.

Major stimulus for calcitonin secretion is increased serum calcium. The major action of calcitonin is to inhibit osteoclastic bone

resorption, which decreases the serum calcium concentration. Clinical use: Used in the treatment of Paget's diease.

CAUSES AND SYMPTOMS OF HYPOCALCAEMIA

Causes: Hypoalbuminaemia, Hypoparathyroidism

(idiopathic,surgical, or transient)

Magnesium deficiency (alcoholism, chemotherapy treatment)

Pseudohypoparathyroidism Vitamin D deficiency Malnutrition Renal insufficiency Acute pancreatitis

Bacterial/viral infections. Drugs including

anticonvulsants (e.g. phenytoin, phenobarbital and rifampin)

Symptoms: Asymptomatic. Neurological (tingling,

tetany, mental changes) Muscle cramps (changes in

muscle excitability) Cardiac signs (abnormal

ECG) Seizure

CAUSES OF HYPERCALCAEMIA

PTH mediated:Primary hyerparathyroidism.Lithium induced.Tertiary hyperparathyroidism.

Calcitriol mediated: Granulomatous disease. Milk alkali syndrome. Exogenous Vitamin D.

Other causes: Vitamin A toxicity. Paget's disease. Kidney stones. Adrenal insufficiency.

Cancer:Multiple myeloma. PTHrp mediated-Breast, lung,

renal cancer.Bone metastases.

SYMPTOMS OF HYPERCALCAEMIA

Neurological & psychiatric (lethargy, confusion, irritability, depression).

GI issues (anorexia, abdo pain, nausea & vomiting, constipation).

Renal issues (polyuria, renal stones). Muscoskeletal issues (bone/joint pain,

muscle weakness, cardiac arrhythmias).

DIAGNOSISTotal (amended) Calcium amended[Ca]=measured total[Ca]+0.02(40-[albumin])Albumin PTH ( high hypocalcaemia, low hypercalcaemia)Vitamin D (high hypocalcaemia, low hypercalcaemia)LFT (ALP is raised hypercalcaemia and normal in hypocalcaemia) (Phos raised in hypocalcaemia and low in hypercalcaemia)U&E (urea and creatinine increased in hypercalcaemia)Iron (raised in hypocalcaemia)PH (Acidosis increases calcium and alkalosis decreases calicum)24-hour urinary calcium (elevated in hyperparathyroidism, renal

failure and decreased in hypoparathyroidism, malabsorption disorders)

TREATMENTH

Hypocalcaemia:

Oral calcium and vitamin D supplements and Mg supplements (mildly symptomatic and chronic hypocalcaemia).

Intravenous calcium gluconate (acute symptomatic hypocalcaemia).

)

YHypercalcaemia:

MMildly symptomatic patients (3.0 – 3.5 mmol/L) must avoid factors that can aggravate hypercalcemia, e.g. thiazide diuretics and lithium carbonate therapy, and a high calcium diet.

CCa >3.5mmol/Lalways requires urgent treatment, including volume expansion with isotonic saline, administration of salmon calcitonin and zoledronic acid .

FFollow-up therapy to treat underlying disease e.g. Cancer.

References

Baynes J. (1999) Medical Biochemistry. Basildon.Harcourt Brace and Company Limited.

Baker S. et al.(2002) The essentials of Calcium, Magnesium and Phosphate Metabolism. Critical Care and resuscitation. 4(4) pp. 301-306.[online]

Nessar A. (2010) Clinical Biochemistry. New York. Oxford University Press.

Mundy G. et al. (1999) Hormonal Control of Calcium Homeostasis, Clinical Chemistry, 45 (8), pp.1347-1352.

Warrel D. et al.(2003) Oxford Textbook of Medicine. London.Oxford University Press.[online]

Peacock M. (2010) Calcium Metabolism in Health and Disease, Clinical Journal of American Society of Nephrology,5(1), pp. 23-30.[online]