Calcium, Phosphate, and Magnesium Metabolism

Metabolism of Calcium, Phosphate, and Magnesium

• Calcium, phosphate, and magnesium are inorganic minerals.
• They are key components of bone.
• They share homeostatic and metabolic mechanisms.
• In bones 99% of calcium, 81% of phosphate, and 65% of magnesium are held.
• These ions participate either inside or outside the cell.
• They are involved in hormone secretion, neural transmission, muscle contraction, energetic metabolism and blood coagulation.
• They act as secondary messengers.
• Plasma concentrations are tightly regulated by complex mechanisms.

Biochemistry of Calcium

• Calcium is the most abundant mineral in the body.
• The human body contains approximately 25 mol (1 kg) of calcium in a 70 kg adult.
• Nearly all body calcium (99%) is present in the bone as crystals.
• Crystals in bone are similar in composition to hydroxyapatite (Ca10(PO4)6(OH)2).
• Soft tissues and extracellular fluid contain about 1% of the body’s calcium.
• In blood, almost all of calcium is present in the plasma.
• Mean plasma concentration ≈9.5 mg/dL (2.38 mmol/L).
• Calcium exists in three physicochemical states in plasma:
  • ≈50% is free (ionized).
  • 40% is bound to plasma proteins.
  • 10% is complexed with small diffusible inorganic and organic anions.
• The free calcium fraction is the biologically active form.

Regulation of Calcium

• Serum Calcium 2+ is regulated by three hormones:
  • PTH
  • Vitamin D
  • Calcitonin
• They work by altering their secretion rate in response to changes in ionized Ca2+.
• Parathyroid hormone (PTH) is the principal acute regulator of plasma [Ca2+].
• PTH is released from the parathyroid glands behind the thyroid gland in the neck.
• PTH is a polypeptide of 84 amino acid residues, synthesized as a precursor prepoPTH (115 amino acids).
• Secretion of the active hormone increases in response to a fall in plasma [Ca2+].
• PTH actions are directed to increase plasma [Ca2+].
• An increase in plasma [Ca2+] suppresses secretion of PTH.
• PTH creates major effects on bone and kidney.
• In the bone: PTH activates a process known as bone resorption.
• In the kidneys: PTH conserves Ca2+ by increasing tubular reabsorption of Ca2+ ions.
• PTH also stimulates renal production of active vitamin D.
• Calcitriol is a hormone derived from cholecalciferol (vitamin D) by the action of UV light.
• Calcitriol stimulates increased absorption of calcium from the GIT.
• It also stimulates increased absorption of calcium from the small intestine.
• It induces the synthesis of a Calcium 2+ binding protein in the intestinal epithelial cell that is necessary for the absorption of calcium.
• Calcitriol increases renal tubular reabsorption of calcium.
• It reduces losses of calcium in urine.
• It stimulates the release of calcium from the bone by acting upon osteoclasts.
• Calcitriol causes bone resorption which raises plasma calcium concentration.
• Calcitriol inhibits the release of calcitonin, a hormone.
• Calcitonin reduces plasma calcium by inhibiting release of calcium from bone.
• Calcitonin is a hormone containing 32 amino acid residues.
• Calcitonin is secreted by the parafollicular or C cells of the thyroid gland.
• Calcitonin opposes functions of those of PTH.
• Other hormones that can impact calcium levels:
  • Sex hormones
  • Glucocorticoids
  • Thyroid hormones
  • Somatotropin
  • Insulin

Plasma Calcium Concentrations

• Reference range for serum or plasma calcium is typically normally 2.1 – 2.6 mmol/L for total calcium.
• The reference range for ionized calcium (Ca2+) os 1.20 – 1.37 mmol/L .
• Only ionized calcium is physiologically active.
• Only ionized calcium is regulated by homeostatic mechanisms.

Hypocalcemia

• Tetanus is the symptom that suggests the presence of low plasma [Ca2+].
• It may occur in any of the following pathological conditions:
• Decreased GIT absorption: vitamin D deficiency
• Increased renal loss: renal failure
• Decreased bone loss: hypoparathyroidism, pseudohypoparathyroidism, hungry bone syndrome.
• Other factors involved include: acute pancreatitis, magnesium administration, phosphate administration, rhabdomyolysis.
• The condition is typically identified artefactual due to collection of blood in tube containing EDTA.
• A feature to look out for in hypocalcemia:
• Trousseau's sign is a spasm of the hand and forearm that occurs when the upper arm is compressed.
• Chvostek's sign, tapping of the cheekbone can cause a spasm of the face muscles.

Hypercalcemia

• High plasma [Ca2+] creates a potential health risk associated with: renal damage and cardiac arrhythmias.
• Other factors include excess vitamin D intake and tuberculosis.
• Decreased renal excretion: thiazide diuretics and milk-alkali syndrome.
• Increased bone loss can include: malignancy, primary hyperparathyroidism , Paget's disease and hyperthyroidism.
• Familial hypocalciuric hypercalcemia:
• An autosomal dominant condition that develops from childhood.
• Characterized by chronic hypercalcemia but asymptomatic usually.
• Most cases are due to mutations in the CaSR gene that code for calcium-sensing receptors.
• Receptors are in cells of the parathyroid glands and kidneys.
• The parathyroid gland produces high levels of PTH which causes hypercalcemia.
• In addition these patients present with hypocalciuria

Regulation of Phosphate

• Total body content of phosphate is over 20 mols distributed as:
  • 80 - 85% stored in bones.
  • 15% within the ICF.
  • 0.1% within the ECF.
• Phosphate combines with calcium to form hydroxyapatite.
• Hydroxyapatite is the mineral component of bone and teeth.
• Phosphate functions as a urinary to excrete H+ ions in the kidneys.
• Phosphate required for phosphorylation and dephosphorylation reactions.
• Essential for maintaining cell wall integrity is essential for.
• Required for metabolic processes (glycolysis and oxidative phosphorylation).
• Key component of molecules (ATP and ADP). phosphate functions.
• Controls the activity of enzymes.
• Inorganic phosphate in the plasma takes three forms:
  • Approximately 80% free inorganic phosphate.
  • Approximately 15% protein-bound phosphate.
  • Around 5% complexed with calcium or magnesium.
• The reference range for phosphate in serum or plasma is typically 0.7 – 1.5 mmol/L.
• Hormone control:
• Parathyroid hormone decreases phosphate reabsorption in the kidneys = loss of phosphate in the urine.
• Calcitriol increases phosphate absorption in the gut.

Hyperphosphatemia

• Due to increased concentration of plasma phosphate.
• Factors include:
  • Increased oral consumption
  • Intravenous increase
  • Vitamin D intoxication
• Reduced renal loss.
• Contributing factors include: Renal failure, hypoparathyroidism and pseudoparathyroidism.
• Cellular release:
  • Tissue destruction
  • Intravascular hemolysis
  • Diabetic ketoacidosis
• Artefactual:
  • Hemolysis
  • Delayed separation of serum
• Hyperphosphatemia affects calcium metabolism.
• It leads to hypocalcemia as the calcium is precipitated and producing tetany

Hypophosphatemia

• Hypophosphatemia causes more damage compared to hyperphosphatemia.
• Decreased intake with starvation, vitamin D deficiency, phosphate binding agents.
• Increased renal loss causes by primary and secondary, diuretics.
• Cellular uptake factors: diabetic ketoacidosis, alkalosis and chronic alcoholism.

Regulation of Magnesium

• Second most prevalent intercellular cation
• Is a cofactor for >300 enzymes in the body.
• Interacts with calcium and is required for cell permeability and neuromuscular function.
• It is crucial for synthesis and secretion of PTH.
• Exists in three forms:
  • Approximately 55% is ionized.
  • About 32% is protein-bound (mainly albumin).
  • Around 13% complexed (phosphate or citrate).
• The reference range for magnesium in the serum or plasma is typically 0.7 – 1.3 mmol/L.
• Regulated by reabsorption of magnesium in the proximal tubules and loop of Henle in the kidneys.
• Serum levels reflects dietary intake and ability of kidneys and GIT to retain.

Hypermagnesemia

• Due to Increased concentrations of magnesium.
• Increased intake:
  • Oral, parenteral, antacids or laxatives.
• Decreased excretion: renal failure, mineralocorticoid deficiency, or hypothyroidism.
• Cell necrosis, diabetic ketoacidosis or tissue hypoxia
• Hypercalciuric hypercalcemia

Hypomagnesemias

• Appears to reflect a shift into cells because it resolves without replacement of magnesium.
• In most instances, caused by GIT or kidney loss.
• In with severe cases high mortality rates are recorded.
• Suppressive effect of the hormone PTH, which can bring on hypocalcemia and tetany.
• More common than hypermagnesemia
• Losses from GIT with diarrhea and laxatives
• Increases from diuretic and osmotic losses