PHTH1011 008 Calcium 1 - McGrowder.pdf

Calcium Metabolism Disorders Dr Donovan McGrowder Department of Pathology University of the West Indies Overview q Functions of calcium q Hormones that regulates calcium q Vitamin D production and metabolism INTRODUCTION Calcium Metabolism q q q q Calcium is the most abundant mineral in the body and...

Calcium Metabolism Disorders Dr Donovan McGrowder Department of Pathology University of the West Indies Overview q Functions of calcium q Hormones that regulates calcium q Vitamin D production and metabolism INTRODUCTION Calcium Metabolism q q q q Calcium is the most abundant mineral in the body and its intake and output are normally balanced. There is the movement of calcium between extracellular fluid, gut, bone and kidney. Calcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. Derangements of this mechanism lead to hypercalcemia or hypocalcemia, both of which can have important consequences for health. Calcium Balance Calcium Metabolism (Functions) q q q q Structural: Calcium also is important for the development of bone and teeth; present as calcium phosphate. Neuromuscular: Control of excitability; transmission of nerve impulses; contraction and relaxation of muscle. Enzymic: Coenzyme for coagulation factors; activation of enzyme reactions. Signalling: Intracellular second messenger for secretion of some hormones and neurotransmitters. Calcium Fractions q (i) (ii) (iii) In the plasma, calcium is present in three forms. They are: Ionized (Ca2+) – physiologically active (50%). Protein-bound (approximately 80% to albumin) – 40%. Complexed (citrates, phosphates etc) 10%. Calcium regulating hormones q Calcium concentration in the extracellular fluid (ECF) is normally maintained within normal limits by a control system involving three hormones: (i) Parathyroid hormone (PTH) (ii) Calcitriol (1:25-dihydroxycholecalciferol) (iii) Calcitonin (minor role). q These hormones also control the inorganic phosphate concentration of the ECF. Parathyroid Hormone 10 Parathyroid Gland Anatomy n n n Four parathyroid glands are usually found posterior to the thyroid gland. Total weight of parathyroid tissue is about 150 mg. Parathyroid hormone (PTH) is made by the Chief cells these glands. Parathyroid hormone Structure q q q q PTH is a polypeptide, comprising 84 amino acids (molecular weight, MW 9425 Da). It is synthesized as a large precursor, pre-pro-PTH (115 amino acids) in the parathyroid cells. The removal of a 25 amino acid chain produces pro-PTH (90 amino acids) A further six amino acids being lost to form intact PTH. Parathyroid hormone Structure Parathyroid hormone Structure q q q Intact PTH has a half-life in the blood of about 3 – 4 minutes. The biological activity resides in the N-terminal 1-34 amino acid sequence of the hormone, which is needed for PTH receptor binding in target cells. Cleavage occurs mainly at residue 34, yielding N- and Cterminal fragments. rmone (PTH) Parathyroid hormone q q q PTH is the principal acute regulator of plasma [Ca2+]. Plasma PTH levels exhibit a diurnal rhythm, being highest in the early hours of the morning and lowest at about 9 a.m. The active hormone is secreted in response to a fall in plasma [Ca2+], and its actions are directed to increase plasma [Ca2+]. Parathyroid hormone Structure q q n q PTH increases ionized calcium in the blood by acting upon the parathyroid hormone 1 receptor (high levels in bone and kidney). PTH also increase ionized calcium by acting on the parathyroid hormone 2 receptor (high levels in the central nervous system, pancreas, testis, and placenta). Binding of PTH to its receptor activates 2 signaling pathways: (i) increased cyclic AMP (ii) increased phospholipase C. An increase in plasma [Ca2+] suppresses PTH secretion. Calcium regulates PTH Actions of Parathyyroid hormone - Kidneys q q q Intact PTH binds to specific receptors at various sites in the renal tubule. This results in activation which has the net effect of lowering glomerular filtration rate (GFR), increasing the reabsorption of calcium and magnesium, and decreasing the reabsorption of phosphate and bicarbonate (increase excretion). Renal loss of bicarbonate may lead to mild metabolic acidosis. PTH and Kidney PTH acts on the distal tubule Actions of Parathyyroid hormone - Bone q PTH acts to increase degradation of bone (release of calcium). --Rapid action: Begins within minutes. --Delayed action: develops in days and weeks. q PTH has a major initiating role, stimulating an increase in the number of osteoclasts causing increased bone resorption and a rise in plasma Ca2+ and phosphate. q PTH stimulates bone stem cells to develop into osteoclasts. q PTH also slowly stimulates osteoblast activity. Actions of Parathyyroid hormone - Bone q q PTH stimulates transcription of 1-alpha hydroxylase for Vitamin D activation in kidney→the active metabolite of vitamin D3↑ (required for calcium absorption from the small intestine, bone demineralization). Net Result: Increase in plasma calcium levels. Review Questions q q What are the hormones that regulates ionize calcium in the blood? How does PTH regulates ionize calcium in the blood? Vitamin D 28 Vitamin D metabolism q q q q Most vitamin D3 (Cholecalciferol) is synthesized by the action of ultraviolet light on 7-hydrocholesterol precursor in the skin. Cholecalciferol is transported by vitamin D-binding protein to the liver. The enzyme 25-hydoxylase catalyze the hydroxylation of cholecalciferol with the formation of 25-hydroxycholecalciferol (25HCC, calcidiol), a biologically inactive metabolite with a plasma halflife of 15 – 25 days. Calcidiol undergoes a further 1α-hydroxylation (1-α hydroxylase) in the kidney to form the active metabolite 1:25-DHCC (calcitriol). Chemistry Vitamin D metabolism q q q The 1α-hydroxylase enzyme for this conversion is located in the proximal convoluted tubules of the nephrons. The activity of 1α-hydroxylase is tightly controlled, being directly stimulated by PTH and hypophosphataemia, and inhibited by 1:25DHCC and by hyperphosphataemia. When 1:25-DHCC production is adequate, 25-HCC is also hydroxylated to inactive 24:25-DHCC, the reaction being stimulated by 1:25-DHCC. The enzyme involved is 24-hydroxylase. Anamistry Actions of Calcitriol (Active Vitamin D) q Promotes intestinal reabsorption of calcium as it stimulates the intestinal mucosal synthesis of calbindin-D, a calcium-binding protein that promotes the absorption of calcium and phosphate from the gut lumen to the plasma compartment. q q Promotes bone mobilization (stimulates mature osteoclasts therefore bone osteclastic resorption →Ca2+↑Pi ↑). The binding of 1:25-DHCC to osteoblasts increases the production of alkaline phosphatase and a calcium-binding protein osteocalcin. Actions of Calcitriol (Active Vitamin D) q q q q Osteocalcin is a protein that is produced by osteoblasts during bone formation and is released into the bloodstream as bone is remodeled. Measurement of serum osteocalcin levels can be used as a marker of bone formation and turnover. Alkaline phosphatase is an enzyme that is produced by osteoblasts and is involved in the formation of new bone. Measurement of serum alkaline phosphatase levels can be used as a marker of bone formation and remodeling. Proposed mechanism of Calcitriol Calcitriol Bone Stimulation of osteoclastic resorption Intestine promotes the absorption of calcium and phosphate from the gut lumen to the plasma compartment. Calcitonin Calcitonin q 32 amino acid residue polypeptide hormone released by the parafolicullar C cells of the thyroid gland in response to raised plasma [Ca2+]. Calcitonin q q The target cell for calcitonin is the osteoclast. It acts via increased cAMP concentrations to inhibit osteoclast activity. It also decrease plasma [Ca2+] by reducing renal reabsorption of calcium and phosphate, increasing the excretion of calcium and phosphate in urine. q q It increases osteoblastic activity. Plasma [calcitonin] is elevated during pregnancy and lactation. Calcitonin q Calcitonin counteracts PTH activity. q It inhibits Ca2+ absorption by the intestines. q q It protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation. It acts through a calcitonin receptor, found on osteoclasts and in kidney coupled to adenylyl cyclase and thereby to the generation of cAMP in target cells. Review Questions q How does vitamin D and calcitonin regulates ionize calcium in the blood? Disorders of Calcium Metabolism Causes of Hypercalcemia Common Uncommon Malignant disease, e.g. some lung cancers Renal failure Hyperparathyroidism Sarcoidosis Vitamin D toxicity (excessive intake) Multiple myeloma Primary Hyperparathyroidism q q There is the autonomous production of PTH which occurs from a single, parathyroid adenoma (tumour), diffuse hyperplasia (all four glands) or, rarely, parathyroid carcinoma may be responsible. Most people are asymptomatic; renal stones are most common single presenting complaint. Classically affects skeleton, kidneys, and GI tract. Primary Hyperparathyroidism q q q q Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D. Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption. Most serious complication is the deposition of calcium in the kidney tubules resulting in impaired renal function. The disorder is characterized by hypercalcemia, hypercalcuria, hypophosphatemia, and hyperphosphaturia. Secondary Hyperparathyroidism q q q Excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia and associated hypertrophy of the glands. It occurs in patients with chronic renal failure or in disorders where there is malabsorption of fat soluble vitamin D. The hyperphosphatemia and damaged renal parenchyma leads to a reduction of renal production of 1,25-dihydroxycholecalciferol (1,25-DHCC). Secondary Hyperparathyroidism q q The hypocalcaemia is the stimulus for PTH release (secondary hyperparathyroidism) which increases in an attempt to increase the serum calcium levels. The decreased intestinal absorption of vitamin D impairs mobilization of calcium from the bones due to end-organ resistance to parathyroid hormone (PTH). Review Questions q q What are biochemical tests that are useful in the investigation of a patient with hypercalcaemia? What are the biochemical findings that would be observed in a patient with primary hyperparathyrodism? Renal Disease q q q End stage renal failure: The reduction in normal renal tissue (proximal tubules) results in a reduced capacity for 1:25-DHCC synthesis. Increased amounts of intracellular phosphate directly inhibit the activity of the 1 -hydroxylase in the remaining functioning tubules. Hypocalcaemia results in release of PTH (in attempt to normalize the plasma calcium levels) and secondary hyperparathyroidism. Thank you