Calcium, Phosphate, and Magnesium Metabolism

Calcium, Magnesium, and Phosphate Metabolism Objectives

• There are three objectives: understanding the functions of calcium, magnesium, and phosphate; describing their regulation; and knowing the disorders of their metabolism.

Why Focus on Calcium

• Structural integrity of the skeleton is provided by calcium salts in bone.
• Normal function of many biochemical processes relies on calcium ions in extracellular and cellular fluids.
• Calcium is essential for neuromuscular excitability, blood coagulation, hormonal secretion, and enzymatic regulation.

Regulation of Intracellular Calcium Concentration

• Mitochondria and the endoplasmic reticulum (ER) store calcium.
• "Pump-leak" transport systems are critical for controlling calcium concentration.
• Calcium leaks into the cytosolic compartment, then it's actively pumped into storage sites in organelles to keep cytosolic pools clear.

Extracellular Calcium Fractions

• Serum calcium has three definable fractions.
• 50% is ionized calcium.
• 40% is protein-bound calcium, with 90% of that bound to albumin and the remainder to globulins.
• 10% is calcium complexed to serum constituents like citrate and phosphate.

Hormones Regulating Calcium

• Parathyroid hormone (PTH)
• Calcitriol [1,25(OH)2D].
• Calcitonin

Parathyroid Hormone (PTH)

• PTH is a single-chain peptide that maintains extracellular fluid (ECF) calcium levels.
• Calcium sensing receptors trigger its release.
• PTH directly affects bone and kidneys and indirectly affects the gut.

Actions of Parathyroid Hormone (PTH)

• PTH increases ionized serum calcium.
• PTH increases renal reabsorption of calcium.
• PTH decreases renal phosphate and HCO3 reabsorption.
• PTH increases 1,25-(OH)2-D.
• PTH increases osteoblast proliferation and osteoclastogenesis in bone.

Vitamin D

• Vitamin D is a steroid hormone.
• Vitamin D is produced endogenously by exposure of skin to sunlight.
• It’s absorbed from foods containing or supplemented with vitamin D.
• It’s metabolized to its active form, calcitriol, in the liver and kidney.
• It regulates calcium and phosphate metabolism.

Actions of Calcitriol (1,25-(OH)2-vitamin D)

• Calcitriol increases gut absorption of calcium and phosphorus.
• It potentiates the actions of PTH on osteoblasts, osteoclasts, and osteocytes in bone.
• At high concentrations, calcitriol stimulates osteoclastic resorption.
• It normalizes phosphate levels.
• FGF23 levels increase to normalize phosphate.

Measurement of Total Calcium

• Total calcium includes the protein-bound, ionized, and complexed forms.
• Normal total calcium levels range from 2.1 to 2.55 mmol/L.
• Total calcium measurements are unreliable with low albumin, elevated plasma proteins, alkalosis, acidosis, or venous stasis.
• Total calcium measurement is sufficiently accurate for most clinical applications.

Measurement of Ionized Calcium

• Use a calcium-specific electrode on blood gas analyzers to measure ionized calcium.
• Result is immediately available.
• Normal level is 1.15 – 1.3 mmol/L.
• Measurement is independent of plasma protein levels.
• Measuring ionized calcium is recommended when there is low albumin or elevated plasma protein, alkalosis or acidosis, or rapidly changing ionized calcium, such as during blood transfusions, extracorporeal bypass, or dialysis.

Phosphorus Homeostasis

• Biological functions include hydroxyapatite crystals in bone and teeth, phosphoproteins, phospholipids, nucleic acids, cofactor for enzymes (NADP, ADP), 2nd messenger (cAMP, ITP), energy storage (phosphocreatine), oxygenation (2,3-DPG), and acid-base status (urine buffers).

Forms of Phosphorus

• Present in the body as organic (phospholipids, phosphoproteins) and inorganic compounds.
• Inorganic phosphorus in blood occurs in ionized form (53%), protein-bound form (15%), and complexed form (47%).
• Measured as total inorganic phosphorus.
• Normal phosphorus levels are 0.8 – 1.35 mmol/L for adults and 1.2 – 1.9 mmol/L for children.

Fibroblast Growth Factor 23 (FGF23) Actions

• Secreted by osteoblasts and osteocytes in response to hyperphosphatemia.
• PTH and 1,25-(OH)2-D increase.
• Klotho-FGFR1 receptor in kidney and parathyroids.
• Decreases serum phosphate (P) levels.
• Increases renal P excretion.
• Increases P deposition in bone.

Magnesium Homeostasis

• Biological functions include serving as a cofactor in phosphate transfer reactions for ATP formation, energy storage, energy utilization, and nucleic acid synthesis.
• Interacts with calcium to create resting potentials of excitable membranes in nerve and muscle cells.
• Magnesium contributes to neuromuscular excitability, nerve conduction, and hormone secretion; hypomagnesemia impairs PTH secretion and action and can impair insulin secretion.

Magnesium Absorption and Reabsorption

• Dietary intake and GIT absorption involves active and passive transport in the small intestine.
• Renal reabsorption happens, with 25% in the proximal convoluted tubule (PCT) via passive paracellular diffusion, 60% in the ascending limb of Henle (ALH) via passive diffusion, and filtered calcium and tubular ATPase activities influencing Mg movement across tubular membranes.

Measurement of Magnesium

• Magnesium is measured as total magnesium.
• Measuring includes free magnesium (60%), protein-bound magnesium (25%), and complexed magnesium (15%).
• The free fraction is biologically active.
• Measurement is unreliable if low albumin levels present or ↑ plasma proteins
• Normal plasma magnesium levels are 0.7 – 0.95 mmol/L.
• Urine magnesium increases with diuretics and renal tubular dysfunction, such as tubular damage, Fanconi syndrome, tubulopathy, and nephrotoxic drugs.

Hypercalcemia

• PTH related causes include primary hyperparathyroidism, lithium, and familial hypocalciuric hypercalcemia.
• Malignancy related includes solid or hematological malignancies.
• Vitamin D related is intoxication, granulomas, and idiopathic hypercalcemia of infancy.
• Associated with high bone turnover are hyperthyroidism, thiazides, and vitamin A intoxication.

Differentiating between Primary Hyperparathyroidism (PHPT) and Malignancy

• Elevated s-Calcium in PHPT and elevated elevated s-Calcium in Malignancy
• Duration of PHPT in Months to Years vs Days to weeks for Malignancy
• PHPT has a slow rate while Malignancy is rapid
• Renal Stones are common in PHPT vs Rare in Malignancy
• PTH is elevated in PHPT vs Suppressed in Malignancy
• Steroid suppressible is "No" in PHPT vs "Yes" in Malignancy

Hypocalcemia

• Causes include EDTA contamination, hypoparathyroidism, vitamin D deficiency, massive blood transfusion (citrate), renal failure, hypomagnesemia, pseudohyperparathyroidism, acute rhabdomyolysis, acute pancreatitis, and hyperphosphatemia.

Hyperphosphatemia

• Common causes include increased intake from phosphate-containing enemas or cow's milk in infants.
• Decreased Excretion due to CKD, Vitamin D excess, hypoparathyroidism, acromegaly
• Increased Cellular release due to DKA, rhabdomyolysis, tumor lysis syndrome, or malignant hyperthermia.

Hypophosphatemia

• Common causes include decreased intake or bioavailability as a result of alcoholism, starvation, malabsorption, vitamin D deficiency, antacids, or P-binders.
• Increased excretion as a result of Diuretics, renal tubular disease, hereditary hypophosphataemic rickets, and tumour-induced osteomalacia.
• Increased cellular uptake due to carbohydrate loading, recovery from DKA/critical illness/sepsis/burns, refeeding syndrome, hungry bone syndrome, B-agonists, and respiratory alkalosis in liver disease, pneumonia, or ICU patients.

Hypermagnesaemia

• Plasma concentrations depend on by intake and urinary output.
• Excessive intake due to Mg-containing laxatives and antacids (renal patients), Mg-sulphate for eclampsia.
• Healthy kidneys efficiently excrete Mg but is an issue if the Glomerular Filtration Rate (GFR) is <30 ml/min Clinical toxicity causes areflexia, respiratory failure, cardiac arrest at 2.5 – 5.0 mmol/L

Hypomagnesaemia

• Common causes are decreased intake due to alcoholism, vomiting, malnutrition, or malabsorption due to malabsorption: chronic diarrhoea (coeliac disease, IBD),, fistula, intestinal bypass, or laxative abuse.
• Increased cellular uptake during recovery from illness or associated with refeeding syndrome.
• Decreased renal reabsorption due to diuretics, osmotic diuresis, and renal tubular dysfunction (ATN, CKD, nephrotoxic drugs such as amphotericin B, cyclosporin, amikacin, and gentamycin)