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34 Cards in this Set
- Front
- Back
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CALCIUM TURNOVER |
Calcium is stored within skeleton=1kg Ideal consumption per day =1g If you don’t consume food with high calcium content the intake per day should be 400mg Only a small proportion is absorbed by intestine: active way in duodenum and jejunum, passive in ilium In 1g ingested = 40% absorbed Net absorption = 200mg Secretion=200mg Balance between influx and efflux = 0 When the balance is in favor of efflux with aging= osteoporosis |
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PTH |
Hormone regulating all organs involved in calcium metabolism and stimulates bone development Stimulates production of active form of vitamin D through hydroxylation at carbon 1 = calcium absorption in intestine + calcium reabsorption in kidneys PTH regulates serum calcium via bone reabsorption through osteoclasts = calcium balance between absorption and excretion |
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Ionized form of calcium Ca2+ |
Regulates biochemical activities: coagulation, muscle construction, enzyme processes |
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Vitamin D activity |
Increase intestinal absorption Stimulates correct bone formation Stimulates tubular reabsorption of calcium through the expression of a carrier where PTH increases its activity (of carrier) Two metabolites of vitamin D: 1.hydroxylated in liver at position 25 and in kidney at position 1 2.stimulated by PTH |
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Calcium absorption in kidney |
Filtered calcium (ionized calcium) is absorbed in proximal tubule Up to 10g of Ca are filtered per day per glomerulus 70% of calcium is reabsorbed in proximal tubule Regulation of excretion of calcium performed in distant tubule in thick ascending limb Absorption in paracellular and passive Tight regulation of calcium occurs in distal segment of nephron, mainly the ascending limbs which reabsorb 20% of filtered calcium Distal convoluted tubules reabsorb in a passive and active way 5-10% Final portion of filtered calcium is reabsorbed by collecting duct in a passive and active way Distal reabsorption is PTH dependent |
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Calcium concentration |
-Calcium is present in blood and linked to proteins: albumin and gamma-globulin -Half of its concentration in plasma is free -1,25mg is the mean concentration of calcium in 1L of plasma -both ends of intestinal mucosa or tubules are polar, have apical and basolateral membrane -apical membrane has calcium channels of different types which mediate influx of Ca ions from lumen into cell -calcium is bound to proteins called calbindin= carries Ca to basolateral side of cell where it is excreted in interstitium by a pump using ATP -Ca ATPase is a high affinity carrier and can maintain very low concentrations of Ca
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Sodium calcium pump |
-Mechanism to remove calcium from the cell -no high affinity but is a regulator of calcium concentration |
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Paracellular pathway |
-Calcium passes through tight junctions where we find proteins called claudins -every segment of kidney and intestines presents different types of caludins -in the epithelia caludins created channels for calcium transport which can cross tight junctions according to concentration gradients |
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Bone and calcium homeostasis |
-Osteoblasts are responsible for bone formation and with the stimulation by PTH hormones they activate osteoclasts. They are also responsible for bone deposition. RANKL is a protein used by osteoblasts to activate osteoclasts -concentration of Ca in interstitium fluid of bones is very high = 20-40 mmol/L -bone remodeling cycle: delivery of growing factor that helps osteoclasts activity. It may influence osteoblast activity and bone formation -osteoclasts: responsible for reabsorption of bone tissue. They produce the lacunae that can be filled by new bone tissue by the osteoblasts stimulated by the removed calcium ions -osteocytes are mature osteoblasts that have been engulfed by their own matrix and act as a mechano-receptor. They produce factors and hormones that regulate the activity of osteoblasts and osteoclasts. They also regulate Ca and phosphate metabolism. -at the end of bone remodeling cycle osteoblasts become lining cells at the bone surface and regulate Ca and ion flux. They also become osteocytes, mechano-receptor cells sensitive to mechanical and dynamic stimuli and may produce factors like FGF23 a hormone for reabsorption of phosphate in kidney tubules. |
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PTH secretion and regulation |
-PTH is secreted by parathyroid gland via chief cells -Ca sensing receptor is a membrane protein sensitive to Ca concentration in serum. It is activated when Ca blood concentration increases and releases a message which inhibits PTH gene transcription -caclitriol (active form of vitamin D) is a lipidic hormone which reacts with these receptors = repress production of PTH -inhibition of PTH production: vitamin D and serum calcium -secretion of PTH: phosphate which enters the cell and favors the stabilization of mRNA for PTH |
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Effect of PTH in kidney |
-stimulates Ca reabsorption in distal tubules -stimulates synthesis of 1,25OH2D -inhibition of phosphate and sodium reabsorption in proximal tubule (phosphate has a post-transcriptional effect on PTH production= stimulation) -HYPERcalcemia stimulates the release and production of PTH with hyperphosphatemia and the lack of sufficient production of 1,25OH2D |
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Effect of PTH in bone |
-PTH has 2 opposite effects 1.continuous secretion: catabolic effect= reduction of Ca and phosphate in bones = osteoporosis, bone fractures (stimulation of osteoclasts) 2.Intermittent secretion: anabolic effect, activation of osteoblasts |
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Effects of PTH on intestines |
In direct effect on calcium and phosphate absorption by 1,25OH2D |
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Calcium sensing receptors |
-In distal tubules they control serum calcium and its effect on PTH secretion -some disorders are due to mutation of Ca sensing receptor gene expressed on PTH and kidneys -the role of this receptor is to respond to Ca concentration -the effect of Ca sensing receptor is to inhibit PTH production and Ca reabsorption -when serum Ca increases the PTH and renal response through these receptors = decrease of serum calcium through decrease of calcium reabsorption and decrease of PTH secretion = normalization of serum Ca |
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Disorders in Ca sensing receptors |
1.Autosomal dominant mutation = constitutive activation of these receptors of parathyroid gland = decreased production of PTH = hypocalcemia 2.mutation in which the receptors are inactivated =hypercalcemia via over production of PTH |
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Causes of hypercalcemia |
Hyperparathyroidsm Tumors Drugs Pseudo-hyperparathyroidsm Hypervitaminosis D Familial hypocacliuric hypercalcemia (FHH)
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HYPERPARATHYROIDISM |
-most frequent cause of hypercalcemia -high level of PTH in blood -low serum phosphate -primary hyperparathyroidism is associated with hypercalcemia due to PTH hypersecretion. It’s maybe due to genetic causes such as mutations in MAN1, MAN2 or RET genes which are associated to adenomas of PTH glands and endocrine tumors. -maybe associated with jaw tumor mutation -more often acquired post surgery in patients with thyroid gland removal |
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FHH |
-Due to an inactivating mutation of Ca sensing receptor gene. Another genetic cause of hyperparathyroidism -serum levels of PTH minimally increase with serum phosphate at normal levels and high serum calcium concentration |
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Tumors |
-May lead to hypercalcemia due to metastatic bone invasion for solid tumors -may produce osteoclasts activating factors that may be INTERLUKIN1 and factors like TNF and prostaglandins which stimulate reabsorb IgM activity of osteoclasts -can secrete PTH repeated peptide which is a protein expressed in fetal life and regulates Ca metabolism, gets repressed during adult life -low level of PTH in blood |
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Hypervitaminosis D |
-Disorder in which active metabolites of vitamin D is produced (granulomatosis= hyper-production of vitamin D) -low circulating PTH -unmodified phosphate concentration in blood |
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Pseudo-hyperparathyroidsm |
-Complex condition in which the patient has an activation mutation of the receptor for PTH = hypercalcemia + low PTH -hypocalcemia + hypophosphatemia -hight PTH which cannot work due to mutations in the receptors -phenotype: short neck, round faces and calcification of basal ganglia -malabsorption and starvation = hypocalcemia |
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Drugs |
- lithium -thiazide: diuretics in kidney tubules that lead to mild hypercalcemia + increased PTH |
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HYPOcalcemia |
-Condition opposite to hypercalcemia -most likely caused by hypoparathyroidism post surgery of thyroidectomy, post radiation therapy or due to invasion of glands (amyloidosis) -maybe caused by autoimmunity against PTH gland -most common reason is CKD which affects the ability of kidneys to hydroxylate vitamin D in position 1 + PTH resistance =very high PTH stimulated by hypocalcemia + high phosphate due to inability of kidney to eliminate it -pancreatitis due to massive deposition of Ca = decrease of serum Ca |
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Symptoms of HYPERcalcemia |
-fatigue, irritability, nausea, vomit, constipation, peptic ulcers, pancreatitis, polyuria, kidney stones, acute kidney failure, nephrocalcinosis, acute/chronic interstitial nephritis, confusion, sleepiness, coma, stupor, cephalea, short QT, ventricular extrasystoles idiovenctricular rhythm |
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Symptoms of HYPOcalcemia |
Paresthesia (burning sensation in lower limbs), cramps, tetany, convulsions and spasms, laryngospasms, cataracts, calcification of basal ganglia -assesment: Chvostek sign and trousseau sign |
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Phosphate metabolism in human body |
-4 possible phosphate ions with 2 detected in human body (monovalent and bivalent form) -pH OF BLOOD 7,5 -bivalent anion is the predominant phosphate ion -in urine there is the monovalent form with a proton that can bing to the bivalent phosphate due to pH lower than 5 -phosphate storage within skeleton =energy accumulation, 70% is present in blood as pre ions -consumed phosphate =1g -PTH stimulates phosphate absorption by decreasing serum phosphate -monovalent ions: absorption of NaKCl = excretion of NaKCl |
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Phosphate reabsorption in proximal tubular cells |
- FGF23 hormone is produced by osteocytes and inhibits production of active form of vitamin D and inhibits reabsorption in proximal tubule -PT is only segment of nephron reabsorbing and managing phosphate with carriers for phosphate reabsorption on apical membrane (sodium phosphate co-transporters) -effect of FGF23 and PTH = inhibition of expression of carriers on apical membrane -FGF23 has a receptor to be active in kidney, becomes specific due to presence of cofactor called klotho -FGF23 inhibits vitamin D hydroxylation -osteocytes produce PHEX which is an endopeptidase that lysates (inactivates) FGF23 |
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Causes of hypophosphatemia |
-hereditary disorder -vitamin D deficiency -hyperparathyroidism -alcoholism, starvation,malabsorption -phosphate binders -acute respiratory alkalosis -oncogenichypophospatemia -diabetic keto acidosis, total parenteral nutrition -entry of phosphate within cell is induced by respiratory alkalosis |
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Vitamin D resistant hypophospatemia |
-increased conc. Of FGD23 due to mutation of PHEX gene = inability of PHEX to lysate FGF23 -low urine Ca -low serum phosphate -low 1,25OH2D |
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Hypercalciuric hypophosphatemia |
-low levels of 1,25OH2D -normal serum Ca -increased PTH -high urine Ca secretion |
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Type 1 and type 2 vitamin D dependence |
-low urine Ca -low serum Ca -high PTH -Normal FGF23 -low serum phosphate -low urine phosphate |
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Alteration of phosphate and Ca and CKD |
-inability of kidney to produce active vitamin D =HYPOCALCEMIA that becomes the stimulus for PTH secretion and cells proliferation -inability to manage phosphate due to mass reduction -increase in FGF23 = hyperphosphatemia -GFR decreases -increase of FGF23 70ml/min (early sign) -PT gland is stimulated for proliferation + hyperplasia of glands in neck -GFR of hyperparathyrodism= 60ml/min -overt hyperphosphatemia GFR= 30ml/min -bone damage, vascular damage, calcification of arteries and cardiopathy, osteopathic and dynamic bone disease |
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Bone damage |
Two groups of renal osteodystrophy 1.osteomalacia: dynamic bone disease + low turnover with chaotic collagen fiber deposition in blood without parallel deposition of bone lamellae 2.osteitis fibrosa: due to hyperparathyroidism = high bone turnover + increased activity of osteoblasts and osteoclasts + high velocity of remodeling with chaotic deposition of bone tissue -symptoms: frequent fractures, bone pain, bone deformities -treatment: calciferol which inhibits PTH production -a-dynamic bone disease: toxic effect on bone cells + INHIBITION of their activity |
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Other defects in patients with CKD |
1. Atherosclerosis: intimal disease characterized by focal development fibro-atheromatous plaque, intimal and medial thickness and plaque calcification. Causes vascular occlusion. 2. arteriosclerosis: medial disease with diffused development and no relationship with atherosclerotic plaques. Characterized by increased arterial collagen content, calcification, hyperplasia and hypertrophy of vascular smooth muscle cells. It causes arterial wall hypertrophy and stiffness. It can be associated with atherosclerotic calcifications. |
