Download - CALCIUM & Phos Metabolism
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Calcium- Phosphorus -
homeostasis
Nirmal Baral MD
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Calcium
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Regulation of the synthesis of 1,25-DHCC:
Plasma Phosphate activity of 1 hydroxylase.
Plasma Calcium production of PTH activates 1
hydroxylase.Thus
Action of phosphate on kidney 1 hydroxylase is direct
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ACTION OF CALCITRIOL ON THE INTESTINE
CALCITRIOL Absorption of Ca & P from GIT
Like steroid hormone Calcitriol + Cytosolic Receptor
[Intestinal cell ]
Calcitriol Receptor Complex
nucleus
mRNA
Calcium Binding Protein
Ca uptake by the intestine
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ON BONE:
CALCITRIOL n. & activity of osteoblasts;also secretion of ALP by osteoblasts mineralization of bone
Mineralization of bones
Calcitriol Osteoblast
Ca uptake fordeposition as calcium phosphate.
ON KIDNEY:
Calcitriol excretion and reabsorption of Ca & P plasma Ca & P
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Calcitriol also ses renal excretion of Ca S Ca
Net effect =
-+ + ++
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Secretion ofPTH is under negative feedback regulation by S Ca
Low S CaPTH secretion
Action of PTH- via cAMP S Ca
1. Action on Bone - demineralization or decalcification of bone byosteoclasts [bone resorption]
S Ca [at the expense of loss of Ca from bone].
Quantitatively most important action.
2. Action on Kidney - Ca reabsorption by DCT S Ca
Most rapid but quantitatively less imp as compared to action on bone
[PTH at PCT ses PO4 reabsorption U excretion S phosphate].
3. Action via Calcitriol - by activation of activity of 1 -hydroxylase on
intestine, bone, kidney S Ca
PTH - parathyroid glands S Ca
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Calcitonin- parafollicular cells of ThyroidS Ca
Calcitonin action on calcium is antagonistic to thatofPTH
1. Calcitonin promotes calcification by increasingactivity of osteoblasts [v/s PTH- decalcification]
2. Calcitonin ses bone resorption by osteoclasts[v/s PTH- bone resorption by osteoclasts]
3. Calcitonin ses Ca excretion in urine [v/s PTH- Ca
reabsorption by DCT]
Calcitonin
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S CaCalcitonin & PTH
S Ca Calcitonin & PTH
demineralization & effect on kidney & PTH via 1 hydroxylase
S Ca
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Low pH
Increased secretion of PTH
Increased urinary excretion of
phosphate
Increased net acid excretion byincreased buffering of excreting
H+ ions
Effect of pH onCalcium/Phosphate Metabolism:
Regulation of PTHSecretion:
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HypercalcemiaSymptoms: Polyuria, dehydration, confusion, depression, fatigue,
nausea/vomiting, anorexia, abdominal pain, and renal stones.
Signs: Diminished reflexes, short QT interval on ECG.
Etiologies:1. Increased GI Absorption of Calcium:
Milk-alkali syndrome
Elevated Calcitriol: causes-Vitamin D excess
Chronic granulomatous diseases mc in sarcoidosis, but also in TB &histoplasmosis. Due to calcitriol produced by activated macrophages withingranulomas.
Excessive vitamin D intake Acromegaly (acromegaly + hypercalcemia should suggest MEN I)
Lymphoma
Elevated PTH [by ing 1 -hydroxylase ] Hypophosphatemia [by ing 1 -hydroxylase ]
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2. Increased Calcium Loss From Bone: Increased Bone Resorption
Elevated PTH Primary hyperparathyroidism
Adenoma (80% of 1 hyperparathyroidism)
Hyperplasia (15%)
Carcinoma (
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3. Decreased Bone Mineralization: Aluminum intoxication seen in end-stage renal disease.
Elevated PTH (see above)
4. Decreased Urinary Calcium Excretion: Thiazide diuretics
Familial hypocalciuric hypercalcemia
Elevated calcitriol (see above)
5. Pseudohypercalcemia(due to increased protein binding ofcalcium in hyperprotiein states)
Severe dehydration (due to concentration of albumin)
Multiple Myeloma
In ambulatory patients, 90% of cases will be due tohyperparathyroidism.
In hospitalized patients, 65% of cases will be due to malignancy.
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Diagnosis Phosphate PTH Calcitriol UrinaryCalcium
PrimaryHyperparathyroidism
Variable / Normal
Malignancy Variable / Normal
Vitamin D Excess / Normal
/ Normal
Milk-Alkali Syndrome / Normal / Normal Normal Normal
Granulomatous Disease
/ Normal
Thiazide Diuretics / Normal / Normal Normal
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Hypocalcemia
Symptoms: Irritability, muscle cramps, depression, psychosis, bronchospasm, andseizures.
Signs: Increased reflexes, prolonged QT interval on ECG (the only cause of a prolongedQT with a normal duration of the T wave itself)
Chvosteks sign Tapping of the facial nerve induces contractions of the facial muscles Trousseaus sign Inflation of a blood pressure cuff induces carpal spasm
Etiologies:
A. Decreased GI Absorption of Calcium Poor dietary intake of calcium Decreased GI absorption with normal dietary intake
B. Decreased calcitriol1. Vitamin D deficiency Poor dietary intake of vitamin D
Inadequate sunlight exposure- purda, burka etc Malabsorption syndromes Drugs Any drug which increased activity of the P-450 system, increases
inactivation of vitamin D. These include isoniazid, theophylline, rifampin,and most anticonvulsants.
Nephrotic syndrome Due to loss of vitamin D binding protein in the urine
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Hypocalcemia cont
2. Decreased conversion of vitamin D to calcitriol Liver failure
Renal failure Low PTH Hyperphosphatemia Vitamin D dependent rickets, type 1 (psuedovitamin D deficient
rickets) AR due to deficiency of 1 hydroxylase.
C. Vitamin D resistanceHereditary vitamin D resistant rickets (formerly called vitamin Ddependent rickets, type 2) A disorder which manifests as end-organresistance to calcitriol, due to mutations in the calcitriol receptor.
D. Increased Bone Mineralization
Low PTH PTH resistance Hungry bones syndrome The rapid mineralization of bones
following parathyroidectomy Osteoblastic metastases seen in patients with metastatic prostate
or breast cancer.
E D d B R ti
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E. Decreased Bone Resorption Low PTH PTH resistance Decreased calcitriol
F. Increased Urinary Excretion of Calcium1. Low PTH (hypoparathyroidism)-
a. Post-Thyroidectomy complication (most common cause)b. Post I131 therapy for Graves disease or thyroid cancer
c. Autoimmune hypoparathyroidismi. Isolatedii. Polyglandular Autoimmune Failure, type I a combination of
hypoparathyroidism, Addisons disease, and chronic mucocutaneouscandidiasis
d. Hereditary hypothyroidism
e. Infiltration of the parathyroidi. Hemochromatosisii. Wilsons diseaseiii. Metastatic cancer
f. Congenital hypoparathyroidismi. Autosomal dominant hypocalcemia.ii. DiGeorge Syndrome
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2. PTH Resistance (pseudohypoparathyroidism) Aheterogeneous group of disorders characterized by end-organresistance to PTH, classified as types 1a, 1b, 1c, 2, andpseudopseudohypoparathyroidism
3. Deficiency of calcitriol
G. Internal Redistribution
Pancreatitis (due to formation of calcium salts inretroperitoneal fat)
H. Intravascular Binding
Citrate excess from multiple transfusions Citratechelate calcium in the serum, dropping levels of the activeionized form, without affecting total calcium levels.
Acute respiratory alkalosis Elevated pH causes morecalcium to become bound to albumin, also dropping levels ofionized calcium.
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Phosphorus Adult body 1 kg
Distribution - 80% in combination with Ca inbones and teeth
- 1% in muscle and blood
- 1% in various chemical compounds
Dietary Requirements: Same as Ca (Adult 800mg)
Ca: P Ratio is 1:1
Sources: Milk, cereals, leafy vegetables, egg, meats, etc.
Excretion: Urine and feces.
Renal threshold for phosphorus 2mg/dl
Ph h
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PhosphorusSerum Phosphate= Adult: 3 5 mg/dl; Children: 4.5 to 6.5 mg/dl
Absorption- From Jejunum.- Calcitriol PO4 absorption along with Ca.
plasma Ca & P- Acidity favours while Phytate.
PTH at Kidney PCT
ses PO4 reabsorption U excretion S phosphate
Calcitriol on Kidney excretion and reabsorption of Ca & P plasma Ca & P
PTH on Bone the mobilization of Ca & P plasma Ca & P
NET EFFECT OF PTH ON BONE &KIDNEY IS TO ECF Ca & P
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Physiological Functions:
Intracellular functions:- For high energy phosphate (ATP)
- muscle contractility
- neurological functions- electrolyte transport
Constituent of nucleotides enzymes:
NAD, NADP, ADP, AMP.
Hyperphosphatemia
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Hyperphosphatemia Symptoms: When they occur, they are usually related to concurrent hypocalcemia.
Etiologies:
1. Increased GI intake Laxative
2. Decreased urinary renal excretiona) Renal Failure (occurs when GFR < 20-25 mL/min)
b) Increased active renal reabsorption of phosphatei. Hypoparathyroidism
ii. Acromegaly
iii.Bisphosphonates
iv. Hyperthyroidism
v. Dehydration
vi. Familial tumoral calcinosis - A rare autosomal recessive disorder characterized byhyperphosphatemia, calcified soft-tissue masses, and normal [Ca+2].
3. Internal Redistributiona) Cell lysis
i. Tumor lysis syndromeii. Rhabdomyolysis
b) Transmembrane shift Metabolic acidosis This results from decreased glycolysis and decreased intracellular
phosphate utilization.
4. Pseudohyperphosphatemia
Multiple Myeloma
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Causes of hyperphosphataemia
Chronic renal failure
Phosphate-containing enemas
Tumour lysis
Myeloma-abnormal phosphate-binding
protein
Rhabdomyolysis
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Causes of hypophosphataemia
Hypophosphatemia
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Hypophosphatemia
Symptoms: Mild symptoms not seen until S phosphate < 2.0 mg/dL.Serious symptoms do not occur until serum phosphate < 1.0 mg/dL.
Symptoms are generally due to one of three mechanisms:
1. Hypophospatemia induces bone resorption. Whenprolonged, this leads to osteomalacia and rickets.
2. Intracellular ATP levels fall, leading to impairment ofmuscle contractility (manifesting as proximal muscleweakness, dysphagia, ileus, respiratory failure, and acuteCHF), metabolic encephalopathy (irritability, paresthesias,confusion, coma), increased RBC rigidity (predisposing to
hemolysis), impaired phagocytosis, and impairedgranulocyte chemotaxis.
3. Red cell 2,3 DPG levels fall, increasing the affinity ofhemoglobin for oxygen, and leading to reduced oxygen
release and tissue ischemia.
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The conditions in which symptoms from hypophosphatemia areprimarily seen are alcoholism (from poor intake combined withvitamin D deficiency) and the chronic ingestion of antacids.
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Essential Macrominerals: Summary
Elements Functions Metabolism Deficiency Toxicity Sources
Calcium Constituentof bones,teeth;regulationof nerve,musclefunction.
Absorptionrequirescalcium-bindingprotein.Regulatedby vit D,parathyroidhormone,calcitonin,etc.
Children:Rickets.
Adults:Osteomalacia.May contributeto
osteoporosis.
With excessabsorption due tohypervitaminosis Dor hypercalcemiadue tohyperparathyroidism, or idiopathichypercalcemia.
Dairyproducts,beans,leafy veg.
Phosphor
us
Constituentof bones,teeth, ATP,phosphorylatedmetabolicinermediates. Nucleicacids.
Control ofabsorptionunknown (vitD?). Serumlevelsregulated bykidneyreabsorption.
Children:rickets.
Adults:osteomalacia.
Low serum Ca2+PI
ratio stimulatessecondaryhyperparathyroidism; may lead tobone loss.
Phosphatefoodadditives.
Functions Metabolism Deficiency Toxicity Source
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Functions Metabolism Deficiency Toxicity Source
Na+ Principal cationin ECF.Regulates plasmavol, acid-base
balance, nerve &muscle function,Na+/K+ - ATPase.
Regulatedbyaldosterone.
Unknown onnormal diet;secondary toinjury or illness
Hypertension(insusceptibleindividuals).
Table salt;salt addedtoprepared
food.
K+ Principal cationin ICF; nerve &muscle function,Na+/K+ - ATPase.
Alsoregulatedbyaldosterone.
Occurs secondaryto illness, injury,or diuretictherapy; muscularweaknessparalysis, mentalconfusion
Cardiacarrest, smallbowel ulcers.
Vegetables, fruit, nuts.
Cl- Fluid & electrolytebalance; gastricfluid; chloride shiftin HCO3- transportin erythrocyts
Infants fed salt-free formula.Secondary tovomiting, diuretictherapy, renaldisease.
Table salt.
Mg++ Constituent ofbones, teeth;enzyme co-factor
(kinases, etc).
Secondary tomalabsorption ordiarrhea,
alcoholism.
Depresseddeep tendonreflexes and
respiration.
Leafygreen veg.(containing
chlorophyll).
E ti l Mi i l
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Essential Microminerals:Summary of major characteristics
Elements Functions Metabolism Deficiency Toxicity Sources
Cobalt Required only as aconstituent of vitB12.
As for vitamin
B12.
Vit B12 defic. Foods of
animalorigin.
Copper Constituent ofoxidase enzymes:cytochrome coxidase, etc.Cystosolicsuperoxidedismutase. Role iniron absorption.
Transportedby albumin;bound toceruloplasmin.
Anemia(hypochromic,microcytic);secondary tomalnutrition.Menkes
syndrme
Rare;secondaryto Wilsons
disease.
Liver.
Iodine Constituent ofthyroxine,triiodothyronine.
Stored inthyroid asthyroglobulin.
Children:cretinism.Adults: goiterandhypothyroidism, myxedema.
Thyrotoxicocis, goiter. Iodizedsalt, sea-food.
Elements Functions Metabolism Deficiency Toxicity Sources
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e e ts u ct o s etabo s e c e cy o c ty Sou ces
Iron Constituent ofhemeenzymes(hb,cytochro
mes, etc).
Transported astransferrin;stored asferritin or
hemosiderin;lost insloughed cellsand bybleeding.
Anemia(hypochromic,microcytic).
Siderosis;hereditary
hemochromatosis).
Redmeat,liver,eggs.
Ironcookware.
Zinc Cofactor of
manyenzymes:lactatedehydrogenase, alkalinephosphatase,
carbonicanhydrase,etc.
Hypogonadism,
growth failure,impaired woundhealing,decreased tasteand smell acuity;secondary to
acrodermatitisenteropathica,parenteralnutrition.
Gastroint
estinalirritation,vomiting
Fluoride Increaseshardness ofbones andt th
Dental caries;osteoporosis (?).
Dentalfluorosis.
Drinkingwater.