Clinical Biochemistry Unit 4 Metabolism PDF

CLINICAL BIOCHEMISTRY UNIT 4 Metabolism of Ca2+, PO43-, and Mg2+ Prof. Juan Carlos Frías Dept. Ciencias Biomédicas [email protected]  Metabolism of Ca2+, PO43- and Mg2+ Calcium, phosphate, and magnesium ions are inorganic minerals and key...

CLINICAL BIOCHEMISTRY UNIT 4 Metabolism of Ca2+, PO43-, and Mg2+ Prof. Juan Carlos Frías Dept. Ciencias Biomédicas [email protected]  Metabolism of Ca2+, PO43- and Mg2+ Calcium, phosphate, and magnesium ions are inorganic minerals and key components of bone. They share homeostatic and metabolic mechanisms. A 99% of calcium, 81% of phosphate, and 65% of magnesium of total ions are present in bones. Their ions Ca2+, Mg2+, PO43-, HPO42-, H2PO4- participate either inside or outside the cell. Calcium, Magnesium, phosphate, hydrogen phosphate, dihydrogen phosphate They are involved in: - hormone secretion - neural transmission - muscle contraction - energetic metabolism - blood coagulation - action (as a secondary messenger) Their concentrations in plasma are tightly regulated by complex mechanisms. 2  Metabolism of Ca2+, PO43- and Mg2+ Biochemistry Calcium is the most abundant mineral in the body, there being about 25 mol (1 kg) in a 70 kg adult. Nearly all body calcium (99%) is present in the bone in the form of crystals similar in composition of hydroxyapatite (Ca10(PO4)6(OH)2). Soft tissues and extracellular fluid contain about 1% of the body’s calcium. meaning it is composed of 10 calcium (Ca) atoms, 6 phosphate (PO4) groups, and 2 hydroxide (OH) groups 3  Metabolism of Ca2+, PO43- and Mg2+ Biochemistry In blood, virtually all of the calcium is found in the plasma, which has a mean calcium concentration of ≈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. 4  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium Three hormones, PTH, vitamin D, and calcitonin, are known to regulate serum Ca2+ by altering their secretion rate in response to changes in ionized Ca2+. · Parathyroid hormone (PTH) PTH is the principal acute regulator of plasma [Ca2+]. PTH is released from the parathyroid glands found behind the thyroid gland in the neck. It is a polypeptide of 84 amino acid residues synthesized as a precursor prepoPTH (115 amino acids). The active hormone is secreted in response to a fall in plasma [Ca2+], and its actions are directed to increase plasma [Ca2+]. An increase in plasma [Ca2+] suppresses PTH secretion. PTH exerts three major effects on both 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 5  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium · Parathyroid hormone (PTH) 6  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium · Parathyroid hormone (PTH) 7  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium · Calcitriol Calcitriol is a hormone derived from cholecalciferol (vitamin D) by the action of UV light. 25(OH)D3-1-hydroxylase 8  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium 9  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium 10  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium · Calcitriol Calcitriol can stimulate increased absorption of calcium from the GIT. It induces the synthesis of a Ca2+-binding protein in the intestinal epithelial cell necessary for the absorption of calcium from the small intestine. Calcitriol stimulates an increase in the renal tubular reabsorption of calcium therefore reducing losses of calcium in the urine. Calcitriol also stimulates the release of calcium from the bone by acting on osteoclasts in the bone, causing bone resorption which increases plasma calcium concentration. Calcitriol inhibits the release of calcitonin, a hormone that reduces plasma calcium by inhibiting release of calcium from bone. 11  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium · Calcitriol 12  Metabolism of Ca2+, PO43- and Mg2+ Regulation of calcium · Calcitonin The hormone, calcitonin consists of 32 amino acid residues and is secreted by the parafolicular or C cells of the thyroid gland. The functions of calcitonin oppose those of PTH. · Other hormones - Sex hormones - Glucocorticoids - Thyroid hormones - Somatotropin - Insulin 13  Metabolism of Ca2+, PO43- and Mg2+ Plasma calcium concentrations The reference range for calcium in the serum or plasma is typically 2.1 – 2.6 mmol/L for total calcium and 1.20 – 1.37 mmol/L for ionized calcium (Ca2+). However, only the ionized form of calcium is physiologically active and it is this fraction which is regulated by homeostatic mechanisms. Wide variation in the concentrations of compounds that bind calcium in blood may be noted; this variation will affect the measured total calcium concentration without changing the free calcium fraction. Several types of calculation have been suggested to “ adjust ” the measured calcium concentration. [Ca2+]adjusted (mmol/L) = [Ca2+]measured (mmol/L) + 0.02(47-[albumin (g/L)]) 14  Metabolism of Ca2+, PO43- and Mg2+ Plasma calcium concentrations [Ca2+]adjusted (mmol/L) = [Ca2+]measured + 0.02(47 - [albumin]) [Ca2+]adjusted (mmol/L) = 2.4 + 0.02(47 - 47) [Ca2+]adjusted (mmol/L) = 2.4 [Ca2+]adjusted (mmol/L) = [Ca2+]measured + 0.02(47 - [albumin]) [Ca2+]adjusted (mmol/L) = 2.0 + 0.02(47 - 27) [Ca2+]adjusted (mmol/L) = 2.4 [Ca2+]adjusted (mmol/L) = [Ca2+]measured + 0.02(47 - [albumin]) [Ca2+]adjusted (mmol/L) = 2.0 + 0.02(47 - 47) [Ca2+]adjusted (mmol/L) = 2.0 15  Metabolism of Ca2+, PO43- and Mg2+ Hypocalcemia Tetany is the symptom that classically suggests the presence of a low plasma [Ca2+]. It may occur in any of the pathological conditions listed below: - Decreased GIT absorption: · vitamin D deficiency - Increased renal loss: · renal failure - Decreased bone loss: · hypoparathyroidism · pseudohypoparathyroidism · hungry bone syndrome · acute pancreatitis · magnesium administration · phosphate administration · rhabdomyolysis - Artefactual: · collection of blood in tube containing EDTA 16  Metabolism of Ca2+, PO43- and Mg2+ Hypocalcemia A feature to look out for in hypocalcemia is the Trousseau’s sign, which is a spasm of the hand and forearm that occurs when the upper arm is compressed. Similarly, tapping of the cheekbone can cause a spasm of the face muscles, which is referred to as the Chvostek’s sign. 17  Metabolism of Ca2+, PO43- and Mg2+ Hypocalcemia Trousseau’s sign and Chvostek’s sign 18  Metabolism of Ca2+, PO43- and Mg2+ Hypocalcemia 2.1 19  Metabolism of Ca2+, PO43- and Mg2+ Hypercalcemia Increased plasma [Ca2+] is a potentially serious problem that can lead to: - renal damage - cardiac arrhythmias and - general ill-health Hypercalcemia arises due to: - Increased GIT absorption: · excess vitamin D intake · tuberculosis - Decreased renal excretion: · thiazide diuretics · milk-alkali syndrome - Increased bone loss: · malignancy · primary hyperparathyroidism · Paget’s disease disorder that causes bones to grow larger and become weaker than normal · hyperthyroidism 20  Metabolism of Ca2+, PO43- and Mg2+ Hypercalcemia 21  Metabolism of Ca2+, PO43- and Mg2+ Familial hypocalciuric hypercalcemia It is an autosomal dominant condition which develops from childhood and is characterized by chronic hypercalcemia but is usually asymptomatic. Most cases are due to mutations in the CaSR gene that code for calcium-sensing receptors in cells of the parathyroid glands and kidneys. The parathyroid gland produces inappropriately high levels of PTH which causes hypercalcemia. In addition to hypercalcemia, these patients present with hypocalciuria. 22  Metabolism of Ca2+, PO43- and Mg2+ Regulation of phosphate The total body content of phosphate is over 20 mols. It is distributed: - 80 - 85% in the bone - 15% in the ICF - 0.1% in the ECF 23  Metabolism of Ca2+, PO43- and Mg2+ Regulation of phosphate A crucial role of phosphate is that it combines with calcium to form hydroxyapatite which is the mineral component of bone and teeth. Phosphate is required in the body to: - maintain cell wall integrity - metabolic processes such glycolysis and oxidative phosphorylation. It is a key component of molecules such as ATP and ADP. Phosphate functions as a urinary buffer for excretion of H+ ions in the kidneys. Phosphate is required for phosphorylation and dephosphorylation reactions, that control the activity of many enzymes. Inorganic phosphate in the plasma exists in three forms: - ≈80% free inorganic phosphate - ≈15% protein-bound phosphate - ≈5% complexed with calcium or magnesium 24  Metabolism of Ca2+, PO43- and Mg2+ Regulation of phosphate The reference range for phosphate in the serum or plasma is typically 0.7 – 1.5 mmol/L. Phosphate concentrations in the plasma are controlled by two hormones: - PTH Parathyroid hormone decreases phosphate reabsorption in the kidneys causing loss of phosphate in the urine and a fall in plasma phosphate concentration. - Calcitriol Calcitriol increases phosphate absorption in the gut and therefore raises the concentration of plasma phosphate. 25  Metabolism of Ca2+, PO43- and Mg2+ Hyperphosphatemia High concentrations of plasma phosphate can be due to: - Increased intake: · oral · intravenous · vitamin D intoxication - Reduced renal loss: · renal failure · hypoparathyroidism · pseudoparathyroidism - Cellular release: · tissue destruction · intravascular hemolysis · diabetic ketoacidosis - Artefactual: · hemolysis · delayed separation of serum 26  Metabolism of Ca2+, PO43- and Mg2+ Hyperphosphatemia Hyperphosphatemia can affect calcium metabolism causing hypocalcemia as the calcium is precipitated and producing tetany. 27  Metabolism of Ca2+, PO43- and Mg2+ Hypophosphatemia Hypophosphatemia is less common than hyperphosphatemia but when it does occur causes more damage. Some of the causes of hypophosphatemia include: - Decreased intake: · starvation · vitamin D deficiency · phosphate binding agents - Increased renal loss: · primary hyperparathyroidism · secondary hyperparathyroidism · diuretic therapy - Cellular uptake: · diabetic ketoacidosis · alkalosis - Multiple causes: · chronic alcoholism 28  Metabolism of Ca2+, PO43- and Mg2+ Hypophosphatemia 29  Metabolism of Ca2+, PO43- and Mg2+ Regulation of magnesium Magnesium is the second most prevalent intracellular cation. Magnesium is a cofactor for more than 300 enzymes in the body. ≈ 1% ≈ 99% 30  Metabolism of Ca2+, PO43- and Mg2+ Regulation of magnesium Magnesium acts as a cofactor for about 300 enzymes, including many involved in energy metabolism, and protein and nucleic acid synthesis. Magnesium interacts with calcium and is required for normal cell permeability and neuromuscular function. Finally, magnesium is required for synthesis and secretion of PTH. Magnesium exits in the plasma in three different forms: - ≈55% free ionized magnesium - ≈32% protein-bound magnesium (mainly albumin) - ≈13% complexed (phosphate or citrate) The reference range for magnesium in the serum or plasma is typically 0.7 – 1.3 mmol/L. Regulation of the plasma magnesium concentration is achieved mainly by reabsorption of magnesium in the proximal tubules and loop of Henle in the kidneys. The concentration of magnesium in the plasma reflects its dietary intake and the ability of kidneys and GIT to retain it. 31  Metabolism of Ca2+, PO43- and Mg2+ Hypermagnesemia Hypermagnesemia arises due to: - Increased intake: · oral · parenteral · antacids · laxatives - Decreased excretion: · renal failure · mineralcoticoid deficiency · hypothyroidism · hypocalciuric hypercalcemia - Cellular release: · cell necrosis · diabetic ketoacidosis · tissue hypoxia 32  Metabolism of Ca2+, PO43- and Mg2+ Hypermagnesemia rare chronic condition in which your adrenal glands don't produce enough of the hormones cortisol and aldosterone. 33  Metabolism of Ca2+, PO43- and Mg2+ Hypomagnesemias Hypomagnesemia appears to reflect a shift into cells because it resolves without magnesium replacement. Magnesium deficiency is usually due to losses of magnesium from GIT or kidneys. It was observed that in patients with severe hypomagnesemia, mortality rates increase. The suppressive effect of hypomagnesemia on PTH secretion occurs even in hypocalcemia. Both hypomagnesemia and hypocalcemia cause tetany. Hypomagnesemia is more common than hypermagnesemia and arises due to: - Decreased intake: - Increases losses via GIT: · starvation · prolonged diarrhea · malabsorption · laxative abuse - Increased renal loss: · gut fistula · osmotic diuresis · diuretic therapy · alcoholism · hypercalcemia · hyperaldosteronism 34  Metabolism of Ca2+, PO43- and Mg2+ Hypomagnesemia 35