Mineral Homeostasis (2024-2025) MSKS-321 PDF

MSKS–321 (2024-2025) Mineral Homeostasis Dr. Nadia Elamin Dr. Amir Abushouk Dr. Mohammed Gholam Lecture Objectives By the end of the lecture the student should be able to: – Explain the calcium and phosphate homeostasis as given below: Problem of acquisiti...

MSKS–321 (2024-2025) Mineral Homeostasis Dr. Nadia Elamin Dr. Amir Abushouk Dr. Mohammed Gholam Lecture Objectives By the end of the lecture the student should be able to: – Explain the calcium and phosphate homeostasis as given below: Problem of acquisition of calcium and phosphate from diet and the role of gut absorption. Bone as an organ which requires minerals and acts as an alternate source of calcium and phosphate. The kidney as a modulator of calcium and phosphate excretion. – Describe the role of the following hormones in maintaining calcium and phosphate homeostasis: Parathyroid hormone. Vitamin D. Calcitonin. – Explain the immediate and long-term consequences of normal mineral homeostasis and list the integrated responses. Calcium Importance of calcium in the body: 1. Bones and teeth formation. 2. Essential for blood coagulation. 3. Excitability of nerves and muscles. 4. Neuromuscular transmission. 5. Excitation contraction coupling. 6. Activation of many enzymes. 7. Cell signaling and cell proliferation. 8. Secretion of hormones and mediates many hormonal effects. Body Calcium Total body calcium in young adults is about 1100 grams. Distribution of calcium in the body: – ≈ 99 % in bones and teeth. – Only ≈ 1% in cells and ≈ 0.1% in ECF. Normal plasma level of calcium: – ≈ 9.5 mg/dL (8.5 - 10.5). – ≈ 2.4 mmol/L (2.2 - 2.6). Three forms of plasma calcium: I. The biologically active free ionized Ca+2 (50%). II. The non-diffusible protein-bound calcium in blood plasma. III. Diffusible un-ionized calcium complexed to anions (citrate, phosphate..).  Free ionized Ca+2 is affected by: plasma proteins, pH, and electrolytes.  Calcium Balance The daily calcium requirement in adults is about 1-1.5 g (≈25 mmol), to balance the amount excreted. The requirement increases during childhood, pregnancy, and lactation. Calcium's primary control sites: 1. GI Tract. 2. Bones. 3. Kidneys.  Calcium Absorption Calcium is absorbed mainly in the duodenum and proximal jejunum by: 1. Passive diffusion: Paracellular flux; occurs when calcium intake is adequate. 2. Active transport: Transcellular transport; increased by Vitamin D: – Calcium binds to apical Ca2+ channels (transient receptor potential vanilloid 6 (TRPV6)). – Ca2+ binds the intracellular protein Ca +2 calbindin-D9k; a vitamin D-induced cellular calcium transporter. Ca +2 – Ca2+ is transported to the ECF by Ca +2 Na+/Ca2+ exchanger (NCX1) or plasma membrane Ca2+ ATPase (PMCA). Ca +2 Ca +2 Calcium Absorption Calcium absorption is affected by: 1. pH of the intestine: – Acidity increases Ca2+ solubility and absorption. – Alkaline pH favors the formation of insoluble Ca2+ soaps. 2. Type of diet: – Ca2+ absorption increases by protein diet and sugars. – Ca2+ absorption decreases by fats, phosphate, oxalates, and phytates. 3. Hormones: – Vitamin D and growth hormone increase the active Ca2+ absorption. Calcium Absorption Factors enhance absorption Factors inhibit absorption High protein diet. Lack of stomach acidity. Sugars (Lactose). Lack of Vitamin D. Stomach acidity. High phosphorus intake. Vitamin D. High-fiber diet. Growth hormone. Phytates and oxalates. Sodium chloride. Fats. Renal Handling Of Calcium The kidneys filter about 10,000 mg of Ca2+ (250 mmol) daily. Most of the filtered Ca2+ (98-99%) is reabsorbed by active transcellular or passive paracellular mechanisms in the nephrons: – In the proximal tubules (PT): About 60%; is regulated by Vitamin D. – In the ascending limbs of the loop of Henle. – In the distal tubular (DT): Depends on TRPV5 channels, regulated by PTH. Regulation Of Calcium The free ionized calcium is very tightly regulated. Calcium concentrations affect the excitable cells: – Hypocalcemia ↑ neuronal membrane permeability to Na+ neuronal hyper-excitability. – Hypercalcemia depression of the nervous system. Calcium regulation is influenced by 3 hormones: 1. Vitamin D. 2. Parathyroid hormone (PTH). 3. Calcitonin. Hypocalcemia ↑ PTH and activation of vitamin D. Hypercalcemia ↓ PTH and ↑ calcitonin. Phosphate Phosphate is the second most abundant mineral in the body. Total body phosphate is around 500 to 800 grams: – 85–90% is found with calcium in the bones as hydroxyapatite. – 10- 15 % in the cells and < 1% in ECF. The plasma phosphate level is ≈ 12 mg/dL: – Organic phosphorus-containing compounds: about 2/3. – Inorganic phosphate (Pi): mainly as PO4–3, HPO4–2 and H2PO4–. Phosphate It is a major intracellular component that has important roles in the structure and function of all living cells. Phosphate is essential for the formation: – Bones and teeth. – High energy phosphate compounds: ATP, and creatine phosphate. – Acid-base buffer system (Phosphate buffer in blood and cells). – Structural proteins, transcription factors, carbohydrate and lipid intermediates (phospholipids, phosphoproteins), and nucleic acids. – Many enzymes (phosphatases, pyrophosphatases, etc..) and several co-enzymes (NADP, ADP, AMP, and pyridoxal phosphate). Phosphate Homeostasis Phosphate is widely available in foods and is absorbed efficiently (65%) by the small intestine even in the absence of vitamin D. Good sources are meat, fish, eggs, and dairy products. Plasma phosphate level is affected by: 1. Vitamin D: stimulates active Pi absorption in duodenum and jejunum via NaPi-IIb. 2. High intake of calcium salts: inhibits phosphate absorption from the gut. 3. PTH: 85-90% of filtered Pi is reabsorbed in proximal renal tubules (NaPi-IIa and NaPi-IIc). PTH inhibits NaPi-IIa  phosphaturic action. Phosphate and calcium homeostasis are closely associated. Lecture Objectives By the end of the lecture the student should be able to: Explain the calcium and phosphate homeostasis as given below: – Problem of acquisition of calcium and phosphate from diet and the role of gut absorption. – Bone as an organ which requires minerals and acts as an alternate source of calcium and phosphate. – The kidney as a modulator of calcium and phosphate excretion. Describe the role of the following hormones in maintaining calcium and phosphate homeostasis: – Parathyroid hormone. – Vitamin D. – Calcitonin. Explain the immediate and long-term consequences of normal mineral homeostasis and list the integrated responses. Vitamin D Main forms of Vitamin D: 1. Vitamin D2 or Ergocalciferol: – Obtained from green vegetables, animals, and fortified food. 2. Vitamin D3 or Cholecalciferol: – Is a steroid hormone derived from cholesterol. – Is formed in the skin by the action of sunlight on 7-dehydrocholesterol or ingested in the diet (fish, milk,...). – Vitamin D3 is hydroxylated to 25-hydroxycholecalciferol (25(OH)D3) in the liver, then converted in the kidney by 1-hydroxylase to the active form 1,25-dihydroxycholecalciferol (1,25-(OH) 2D3) or calcitriol. Active Vitamin D3 (1,25-(OH)2D3) In the kidney the formation of the active form of vitamin D by 1-α hydroxylase is: – Stimulated by PTH (1-α hydroxylase). – Inhibited by negative feedback of serum calcium, phosphate and, 25-(OH)2D3. – Inhibited by fibroblast growth factor-23 (FGF23). At high Ca2+ levels, the kidneys produce: – Less active 1,25-dihydroxycholecalciferol. – More relatively inactive metabolite 24, 25- dihydroxycholecalciferol. Extra-renal hydroxylation to 1,25-(OH)2D3 is important for autocrine and paracrine regulation of cells’ function, differentiation and is involved in various biological effects. Actions Of Active Vitamin D3 Calcitriol acts on vitamin D receptor (VDR) and regulates expression of more than 800 target genes. 1,25-(OH)2D3 regulates calcium and phosphate by: – Increasing intestinal absorption of calcium and phosphate. – Stimulating Ca2+ re-absorption in the proximal renal tubules. – ↑ osteoblasts activity and ↑ osteoclasts formation and activity. 1,25-(OH)2D3 inhibits PTH expression and secretion: – Has direct action on parathyroid glands (↓ mRNA formation). Vitamin D Deficiency Low vitamin D can results from: – insufficient sun exposure, fat malabsorption, ↓ pro-vitamin intake. – severe renal or liver disease. – mutations in 1-hydroxylase or the VDR gene. Deficiency of Vitamin D results in: 1.Defective calcification of bone matrix: Rickets in children weakness and bowing of weight-bearing bones. Osteomalacia in adults. 2.Dental defects. 3.Hypocalcemia and hypophosphatemia. Calcium Homeostasis Parathyroid Hormone (PTH) PTH is polypeptide hormone (84 a.a.) secreted from chief cells in the parathyroid glands on the posterior surface of the thyroid gland. PTH is the most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid. In a normal person, the parathyroid glands maintain the calcium level in the normal range for proper brain and muscles’ function. Hypoparathyroidism results in hypocalcemia, muscle spasms, tetany, and death if not treated. Regulation Of PTH Secretion 1. Ionized Ca2+ level: – The main stimulus for PTH release is hypocalcemia. – High Ca2+ level inhibits PTH (-ve feedback mechanism). 2. Active vitamin D (1,25-(OH)2D3): directly inhibits PTH formation. 3. Plasma phosphate level: high phosphate stimulates PTH secretion. 4. Mg2+: is required for normal PTH secretion; magnesium deficiency impairs the release of PTH and reduces its target organ responses hypocalcemia. 5. Beta receptor agonists: ↑PTH secretion. Effects Of PTH 1. In the bone: – PTH increases osteoclasts formation and activity bone resorption and calcium and phosphate mobilization. 2. In the kidneys: – Increases Ca2+ re-absorption in DT. – Inhibits phosphate re-absorption in PT (phosphaturic action). – Increases formation of active vitamin D  ↑ Ca2+ and phosphate absorption from the intestine.  Excess PTH Hypercalcemia and hypophosphatemia. Hypoparathyroidism And Hypocalcemia Hypoparathyroidism can result in life-threatening hypocalcemia. Calcium < 7 mg/dl Neuronal hyper-excitability: – Hypocalcemic tetany (extensive spasms of skeletal muscle): Tetanic muscle contractions can present early as: – Carpopedal spasm. – Trousseau’s sign: wrist and thumb flexion with extension of fingers. – Chvostek’s sign: tapping over facial nerve facial muscles spasm. Late laryngospasm airway obstructed and fatal asphyxia. – ↑ brain excitability seizures and convulsions. Trousseau’s sign Chvostek’s sign Hyperparathyroidism Excess PTH can be: 1. Primary from a PTH-secreting adenomas. 2. Secondary hyperparathyroidism: when plasma Ca2+ level is chronically low, as in chronic renal disease and rickets stimulation of the parathyroid glands causes compensatory parathyroid hypertrophy. Symptoms of hyperparathyroidism are mild and nonspecific: – Loss of appetite, nausea, vomiting, constipation, ↑thirst and urination. – The feeling of weakness and fatigue, aches and pains, or depression. – Minor personality changes, confusion, impaired thinking and memory. – Bone thinning (symptomless) but with an increased risk of fracture. – ↑ calcium and phosphorous excretion in the urine kidney stones. – Peptic ulcers, hypertension, and pancreatitis are possible complications. Hypercalcemia Hypercalcemia: Ca2+ level > 11 mg/dl can result from: – Hyperparathyroidism Hypercalcemia and hypohosphatemia. – High level of vitamin D Hypercalcemia and hyperphosphatemia. – Hypercalcemia of malignancy: Bone metastases local osteolytic hypercalcemia. Tumor secretion of parathyroid hormone-related protein (PTHrP); humoral hypercalcemia of malignancy. Hypercalcemia can lead to: – Progressive depression of the nervous system. – Skeletal muscle weakness, and constipation. – Increased myocardial contractility and cardiac arrhythmias. – ↑ urinary excretion of Ca2+ and Pi  urinary calculi. Calcium Homeostasis Calcitonin Peptide hormone (32 a.a), is secreted by the para follicular cells of the thyroid gland. Calcitonin secretion is stimulated by: 1. High plasma calcium level: calcitonin secretion starts at a Ca2+ level above 9.5 mg/dL; then its level is directly proportional to plasma Ca2+. 2. GIT hormones (Gastrin, Secretin, CCK). 3. Dopamine, estrogens, beta-adrenergic stimulating drugs. Actions of calcitonin: – ↓ plasma Ca2+ and phosphate; inhibits bone resorption and osteoclasts. – Protects the bones of the mother during pregnancy and lactation. Calcium Regulating Hormones 1. Active Vitamin D: – Increases intestinal Ca2+ absorption. – Increases osteoblast activity. 2. PTH increases Ca2+ level by: – Stimulating osteoclast activity increases Ca2+ release into the blood. – Acting on the kidney to promote: Ca2+ reabsorption in DT. Formation of active Vitamin D. 3. Calcitonin lowers Ca2+ level by: – Inhibiting activity of osteoclasts. High PTH with vitamin D deficiency can contribute to osteoporosis. References Thank You