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![PHOSPHORUS
• MOST ABUNDANT INTRACELLULAR ANION
• PARTICIPATES IN GLYCOLYSIS AND HIGH ENERGY PHOSPHATE (ATP) PRODUCTION
• BOTH AS THE FREE ANION(S) AND AS A COMPONENT OF NUMEROUS ORGANOPHOSPHATE COMPOUNDS,
INCLUDING STRUCTURAL PROTEINS, ENZYMES, TRANSCRIPTION FACTORS, CARBOHYDRATE AND LIPID
INTERMEDIATES, HIGH-ENERGY STORES (ATP [ADENOSINE TRIPHOSPHATE], CREATINE PHOSPHATE), AND
NUCLEIC ACIDS](https://image.slidesharecdn.com/phosphorus-200508152920/75/Phosphorus-metabolism-6-2048.jpg)
Uploaded byTONY SCARIA
Phosphorus metabolism
Phosphorus is essential for bone formation and cellular energy metabolism, with 85% stored in bones. Serum phosphorus levels fluctuate throughout the day and can be affected by dietary intake and hormonal regulation, with various disorders leading to hypophosphatemia or hyperphosphatemia. Conditions causing hypophosphatemia include inadequate absorption, excessive renal excretion, and specific genetic syndromes, while hyperphosphatemia arises from impaired renal filtration and tissue destruction.
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Phosphorus metabolism
- 1.
- 2. PHOSPHORUS • CRITICAL FORBONE FORMATION AND CELLULAR ENERGY METABOLISM • TOTAL BODY PHOSPHOROUS IS 600 G • 85 % IN BONES
- 3. PHOSPHOROUS EXIST INSEVERAL FORMS
- 4. COMPONENTS OF TOTALPLASMA PHOSPHATE
- 5. • IN CELLSAND IN THE ECF, PHOSPHORUS EXISTS IN SEVERAL FORMS • PREDOMINANTLY AS H2PO4– OR NAHPO4– , WITH PERHAPS 10% AS HPO42– .
- 6. PHOSPHORUS • MOST ABUNDANTINTRACELLULAR ANION • PARTICIPATES IN GLYCOLYSIS AND HIGH ENERGY PHOSPHATE (ATP) PRODUCTION • BOTH AS THE FREE ANION(S) AND AS A COMPONENT OF NUMEROUS ORGANOPHOSPHATE COMPOUNDS, INCLUDING STRUCTURAL PROTEINS, ENZYMES, TRANSCRIPTION FACTORS, CARBOHYDRATE AND LIPID INTERMEDIATES, HIGH-ENERGY STORES (ATP [ADENOSINE TRIPHOSPHATE], CREATINE PHOSPHATE), AND NUCLEIC ACIDS
- 7. • APPROXIMATELY 85%OF TOTAL BODY PHOSPHORUS IS IN BONE, AND MOST OF THE REMAINDER IS WITHIN CELLS. THUS, SERUM PHOSPHORUS LEVELS MAY NOT REFLECT TOTAL BODY PHOSPHORUS STORES • 1% OF TOTAL BODY PHOSPHATE IN ECF
- 8. • NORMAL SERUMPHOSPHATE IS 3.0-4.5 MG/DL • BEST MEASURED IN FASTING • DUE TO DIURNAL VARIATION • LOWER VALUE IN MORNING • HIGHER AT NIGHT • HIGHER AT POST MEALS
- 9.
- 10. DIURNAL VARIATION INPHOSPHOROUS LEVEL • SERUM PHOSPHATE LEVELS VARY BY AS MUCH AS 50% ON A NORMAL DAY. THIS REFLECTS THE EFFECT OF FOOD INTAKE BUT ALSO AN UNDERLYING CIRCADIAN RHYTHM THAT PRODUCES A NADIR BETWEEN 7 AND 10 A.M
- 12.
- 13. ABSORPTION OF PHOSPHATE •PHOSPHATE IS WIDELY AVAILABLE IN FOODS AND IS ABSORBED EFFICIENTLY (65%) BY THE SMALL INTESTINE EVEN IN THE ABSENCE OF VITAMIN D • ACTIVE TYPE IIB SODIUM PHOSPHATE CO TRANSPORTERS(NPT2B) ON APICAL MEMBRANE • PHOSPHATE ABSORPTIVE EFFICIENCY MAY BE ENHANCED (TO 85–90%) VIA ACTIVE TRANSPORT MECHANISMS THAT ARE STIMULATED BY 1,25(OH)2D.
- 14. REGULATION OF PHOSPHOROUSABSORPTION • PTH REGULATES THE INCORPORATION AND RELEASE OF MINERALS FROM BONE STORES AND DECREASES PROXIMAL TUBULAR REABSORPTION OF PHOSPHATE, CAUSING URINARY WASTING • PHOSPHATE CONCENTRATION ITSELF REGULATES RENAL PROXIMAL REABSORPTION • INSULIN LOWERS SERUM LEVELS BY SHIFTING PHOSPHATE INTO CELLS • CALCITRIOL • INCREASES SERUM PHOSPHATE BY ENHANCING INTESTINAL PHOSPHORUS ABSORPTION.
- 16. • DAILY DIETARYCONTENT 500–1000 MG/DL
- 22. RENAL HANDLING OFPHOSPHATE • MAJORITY OF PHOSPHATE (85%) REBSORPTION BY 3 RENAL SODIUM PHOSPHATE COTRANSPORTERS • LOCATED IN APICAL BORDER OF PCT • NPT2A • NPT2C • PIT-2
- 24. • SITE OFREGULATION OF PHOSPHATE REABSORPTION IS PROXIMAL RENAL TUBULE • CONTROL OF SERUM PHOSPHATE IS DETERMINED MAINLY BY THE RATE OF RENAL TUBULAR REABSORPTION OF THE FILTERED LOAD, WHICH IS ~4–6 G/D. • PHOSPHATE CLEARANCE IS ENHANCED BY ECF VOLUME EXPANSION AND IMPAIRED BY DEHYDRATION. • URINARY EXCRETION IS NOT CONSTANT BUT VARIES DIRECTLY WITH DIETARY INTAKE
- 25. FGF23 EFFECT ONCALCITRIOL FGF23 also leads to reduced synthesis of 1,25(OH)2D, which may worsen the resulting hypophosphatemia by lowering intestinal phosphate absorption
- 26. Levels of thesetransporters at the apical surface of these cells are reduced rapidly by PTH and FGF 23
- 28.
- 29. HYPOPHOSPHATEMIA • FASTING SERUMPHOSPHATE CONCENTRATION <2.5 MG/DL
- 30. ETIOLOGY • INADEQUATE INTESTINALPHOSPHATE ABSORPTION, • EXCESSIVE RENAL PHOSPHATE EXCRETION • RAPID REDISTRIBUTION OF PHOSPHATE FROM THE ECF INTO BONE OR SOFT TISSUE
- 31. IMPAIRED INTESTINAL PHOSPHATEABSORPTION • ALUMINUM-CONTAINING ANTACIDS • SEVALAMER
- 32. REDUCED RENAL TUBULARPHOSPHATE REABSORPTION • PTH/PTHRP-DEPENDENT • PTH/PTHRP-INDEPENDENT
- 33. PTH/PTHRP-DEPENDENT • PRIMARY HYPERPARATHYROIDISM •SECONDARY HYPERPARATHYROIDISM • VITAMIN D DEFICIENCY/RESISTANCE • CALCIUM STARVATION/MALABSORPTION • BARTTER’S SYNDROME • AUTOSOMAL RECESSIVE RENAL HYPERCALCIURIA WITH HYPOMAGNESEMIA
- 34. PTH/PTHRP-INDEPENDENT TUBULAR PHOSPHATE WASTING •WITH ASSOCIATED RICKETS AND OSTEOMALACIA. • ALL THESE DISEASES MANIFEST SEVERE HYPOPHOSPHATEMIA; RENAL PHOSPHATE WASTING, SOMETIMES ACCOMPANIED BY AMINOACIDURIA; INAPPROPRIATELY LOW BLOOD LEVELS OF 1,25(OH)2D; LOW-NORMAL SERUM LEVELS OF CALCIUM; AND EVIDENCE OF IMPAIRED CARTILAGE OR BONE MINERALIZATION • FGF23 IS SYNTHESIZED BY CELLS OF THE OSTEOBLAST LINEAGE, PRIMARILY OSTEOCYTES
- 35. FGF23 cells of theosteoblast lineage, primarily osteocytes renal phosphate wasting severe hypophosphatemia low blood levels of 1,25(OH)2D impaired cartilage or bone mineralization low-normal serum levels of calcium
- 36. AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS (ADHR) •AUTOSOMAL DOMINANT • ACTIVATING FGF23 MUTATIONS • THESE MUTATIONS ALTER A CLEAVAGE SITE THAT ORDINARILY ALLOWS FOR INACTIVATION OF INTACT FGF23
- 37. X-LINKED HYPOPHOSPHATEMIC RICKETS(XLH) • WHICH RESULTS FROM INACTIVATING MUTATIONS IN AN ENDOPEPTIDASE TERMED PHEX (PHOSPHATE-REGULATING GENE WITH HOMOLOGIES TO ENDOPEPTIDASES ON THE X CHROMOSOME) THAT IS EXPRESSED MOST ABUNDANTLY ON THE SURFACE OF OSTEOCYTES AND MATURE OSTEOBLASTS • HIGH FGF23 LEVELS
- 40. AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC SYNDROMES ectonucleotide pyrophosphatase/ phosphodiesterase1 (ENPP1) dentin matrix protein-1 (DMP1) both of which normally are highly expressed in bone and presumably regulate FGF23 production
- 41. TUMOR-INDUCED OSTEOMALACIA (TIO) •ACQUIRED DISORDER IN WHICH TUMORS, USUALLY OF MESENCHYMAL ORIGIN AND GENERALLY HISTOLOGICALLY BENIGN, SECRETE FGF23 AND/OR OTHER MOLECULES THAT INDUCE RENAL PHOSPHATE WASTING. • SUCH TUMORS TYPICALLY EXPRESS LARGE AMOUNTS OF FGF23 MRNA, AND PATIENTS WITH TIO USUALLY EXHIBIT ELEVATIONS OF FGF23 IN THEIR BLOOD. • RESOLVES COMPLETELY WITHIN HOURS TO DAYS AFTER SUCCESSFUL RESECTION OF THE RESPONSIBLE TUMOR.
- 43.
- 44. DENTS DISEASE • X-LINKEDRECESSIVE DISORDER • CAUSED BY INACTIVATING MUTATIONS IN CLCN5, A CHLORIDE TRANSPORTER EXPRESSED IN ENDOSOMES OF THE PROXIMAL TUBULE; • FEATURES INCLUDE • HYPERCALCIURIA, • HYPOPHOSPHATEMIA, • RECURRENT KIDNEY STONE
- 45. RENAL PHOSPHATE WASTING •POORLY CONTROLLED DIABETIC PATIENTS • ALCOHOLICS • DIURETICS • CERTAIN OTHER DRUGS AND TOXINS
- 46. CAUSES OF PTH/PTHRP-INDEPENDENT TUBULARPHOSPHATE WASTING • EXCESS FGF23 OR OTHER “PHOSPHATONINS” • INTRINSIC RENAL DISEASE • OTHER SYSTEMIC DISORDERS • DRUGS OR TOXINS
- 47. EXCESS FGF23 OROTHER “PHOSPHATONINS” • X-LINKED HYPOPHOSPHATEMIC RICKETS (XLH) • AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIA (ARHP) • AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS (ADHR) (DMP1, ENPP1 DEFICIENCY) • TUMOR-INDUCED OSTEOMALACIA SYNDROME (TIO) • MCCUNE-ALBRIGHT SYNDROME (FIBROUS DYSPLASIA) • EPIDERMAL NEVUS SYNDROME
- 48. DECREASED RENAL PHOSPHATEREABSORPTION • HYPOCALCEMIA, • HYPOMAGNESEMIA, • SEVERE HYPOPHOSPHATEMIA.
- 50. DUE TO RAPIDUPTAKE INTO AND UTILIZATION BY CELLS • INSULIN THERAPY FOR DIABETIC KETOACIDOSIS • METABOLIC OR RESPIRATORY ALKALOSIS • RECOVERY FROM METABOLIC ACIDOSIS • IV DEXTROSE SOLUTIONS • REFEEDING SYNDROME • ANTECEDENT STARVATION OR MALNUTRITION, • ADMINISTRATION OF IV GLUCOSE WITHOUT OTHER NUTRIENTS, • ELEVATED BLOOD CATECHOLAMINES (ENDOGENOUS OR EXOGENOUS)
- 51. HYPOPHOSPHATEMIA • DURING THEPHASE OF ACCELERATED NET BONE FORMATION • PARATHYROIDECTOMYAFTER SEVERE PRIMARY HYPERPARATHYROIDISM • DURING TREATMENT OF VITAMIN D DEFICIENCY • LYTIC PAGET’S DISEASE • OSTEOBLASTIC METASTASES
- 52. RESPIRATORY ALKALOSIS Respiratory alkalosis increaseintracellular pH accelerates glycolysis increase in glucose utilization increase in glucose and phosphorus movement into cells
- 53. PROLONGED HYPERGLYCEMIA • GLUCOSELOADING IS SEEN IN PATIENTS WITH PROLONGED HYPERGLYCEMIA WHO RECEIVE INSULIN
- 54. hyperglycemia osmotic diuresis (fromglycosuria) insulin is given (which drives PO4 into cells hypophosphatemia
- 55. severe hypophosphatemia ATP depletion shiftfrom oxidative phosphorylation toward glycolysis associated tissue or organ dysfunction
- 57. OXYHEMOGLOBIN DISSOCIATION CURVE Phosphate depletion depletionof 2,3-diphosphoglycerate shifts the oxyhemoglobin dissociation curve to the left less likely to release oxygen to the tissues
- 58. HEMOLYTIC ANEMIA INHYPOPHOSPHATEMIA Reduction of high energy phosphate production from glycolysis reduce the deformability of red cells hemolytic anemia
- 59. REVERSIBLE HEART FAILURE Phosphatedepletion impair myocardial contractility reduce cardiac output
- 61.
- 62. Acute, hypophosphatemia Chronichypophosphatemia Severe less severe occurs mainly or exclusively in hospitalized patients with underlying serious medical or surgical illness and preexisting phosphate depletion due to excessive urinary losses, severe malabsorption, or malnutrition with a clinical presentation dominated by musculoskeletal complaints such as bone osteomalacia, pseudofractures, and proximal muscle weakness or, in children, rickets and short stature
- 63. Acute Hypophosphatemia Muscular abnormalities •Proximal muscle weakness, • rhabdomyolysis, • impaired diaphragmatic function, • respiratory failure • congestive heart failure Neurological abnormalities • Parasthesia, • dysarthria, • confusion, • seizures or coma Haematological Enhanced oxygen dissociation causes tissue hypoxia, and haemolysis. Impaired phagocytosis and opsonization leading to increased susceptibility to bacterial and fungal infections. mineralization defect leading to rickets in children ahd osteomalacia in adults
- 64. CF • FAILURE TOWEAN FROM MECHANICALVENTILATION IN PATIENTS WITH SEVERE HYPOPHOSPHATEMIA
- 66. • THE NORMALDAILY MAINTENANCE DOSE OF PHOSPHORUS IS 1,200 MG IF GIVEN ORALLY • THE IV MAINTENANCE DOSE OF PO4 IS LOWER, AT 800 MG/DAY, BECAUSE ONLY 70% OF ORALLY ADMINISTERED PHOSPHATE IS ABSORBED FROM THE GI TRACT
- 67. • SERIOUS SEQUELAESUCH AS PARALYSIS, CONFUSION, AND SEIZURES ARE LIKELY ONLY AT PHOSPHATE CONCENTRATIONS <0.25 MMOL/L (<0.8 MG/DL). • RHABDOMYOLYSIS MAY DEVELOP DURING RAPIDLY PROGRESSIVE HYPOPHOSPHATEMIA
- 69. • SERUM LEVELSOF PHOSPHATE AND CALCIUM MUST BE MONITORED CLOSELY (EVERY 6–12 H) THROUGHOUT TREATMENT
- 70.
- 71. XLH,ADHR, TIO, ANDRELATED RENAL TUBULAR DISORDERS
- 72. TIO • LOCALIZED BYRADIOGRAPHIC SKELETAL SURVEY OR BONE SCAN (MANY ARE LOCATED IN BONE) OR BY RADIONUCLIDE SCANNING USING SESTAMIBI OR LABELED OCTREOTIDE • EXTIRPATION OF THE RESPONSIBLE TUMOR
- 74.
- 75. • FASTING SERUMPHOSPHATE CONCENTRATION >5.5 MG/DL • HIGHER IN CHILDREN AND NEONATES <7 MG/DL
- 76. CAUSES • IMPAIRED GLOMERULARFILTRATION, • HYPOPARATHYROIDISM, • EXCESSIVE DELIVERY OF PHOSPHATE INTO THE ECF (FROM BONE, GUT, OR PARENTERAL PHOSPHATE THERAPY) • COMBINATION OF THESE FACTORS
- 77. Decreased renal excretion• Acute renal failure • Chronic renal failure Acute tissue destruction • Tumor-lysis syndrome, • severe haemolysis, • Rhabdomyolysis, • crush injury Increased renal phosphate reabsorption • Hypoparathyroidism • Acromegaly • Thyrotoxicosis Miscellaneous • Excess phosphate administration • Vitamin-D intoxication • Metabolic or respiratory acidosis
- 79. REDUCED GFR reduced GFR chronicrenal insufficiency Hyperphosphatemia phosphate retention. impairs renal synthesis of 1,25(OH)2D secondary hyperparathyroidism
- 80. HYPOPARATHYROIDISM Hypoparathyroidism increased expression ofNaPi-2 co-transporters in the proximal tubule hyperphosphatemia
- 81. CAUSES OF HYPOPARATHYROIDISM •AUTOIMMUNE DISEASE; • DEVELOPMENTAL, • SURGICAL, • RADIATION-INDUCED ABSENCE OF FUNCTIONAL PARATHYROID TISSUE; • VITAMIN D INTOXICATION OR OTHER CAUSES OF PTH-INDEPENDENT HYPERCALCEMIA; • CELLULAR PTH RESISTANCE (PSEUDOHYPOPARATHYROIDISM OR HYPOMAGNESEMIA) • INFILTRATIVE DISORDERS SUCH AS WILSON’S DISEASE AND HEMOCHROMATOSIS • IMPAIRED PTH SECRETION CAUSED BY HYPERMAGNESEMIA, SEVERE HYPOMAGNESEMIA, • ACTIVATING MUTATIONS IN THE CASR.
- 82. TUMORAL CALCINOSIS • RAREGROUP OF GENETIC DISORDERS IN WHICH FGF23 IS PROCESSED IN A WAY THAT LEADS TO LOW LEVELS OF ACTIVE FGF23 IN THE BLOODSTREAM. • THIS MAY RESULT FROM MUTATIONS IN THE FGF23 SEQUENCE OR VIA INACTIVATING MUTATIONS IN THE GALNT3 GENE, WHICH ENCODES A GALAC-TOSAMINYL TRANSFERASE THAT NORMALLY ADDS SUGAR RESIDUES TO FGF23 THAT SLOW ITS PROTEOLYSIS • INACTIVATING MUTATIONS OF THE FGF23 CO-RECEPTOR KLOTHO
- 83.
- 84. • ELEVATED SERUM1,25(OH)2D, • PARATHYROID SUPPRESSION, • INCREASED INTESTINAL CALCIUM ABSORPTION, AND FOCAL HYPEROSTOSIS WITH LARGE, LOBULATED PERIARTICULAR HETEROTOPIC OSSIFICATIONS (ESPECIALLY AT SHOULDERS OR HIPS) AND ARE ACCOMPANIED BY HYPERPHOSPHATEMIA
- 85. elevated serum 1,25(OH)2D increasedintestinal calcium absorption hyperphosphatemia focal hyperostosis with large, lobulated periarticular heterotopic ossifications (especially at shoulders or hips) parathyroid suppression inactivating mutations in the GALNT3 gene inactivating mutations of the FGF23 co-receptor Klotho mutations in the FGF23 sequence low levels of active FGF23
- 86. • FGF23 RESISTANCEDUE TO INACTIVATING MUTATIONS OF THE FGF23 CO-RECEPTOR KLOTHO
- 87. INCREASED ECF • OVERZEALOUSIV PHOSPHATE THERAPY, • ORAL OR RECTAL ADMINISTRATION OF LARGE AMOUNTS OF PHOSPHATE-CONTAINING LAXATIVES OR ENEMAS (ESPECIALLY IN CHILDREN), • EXTENSIVE SOFT TISSUE INJURY OR NECROSIS (CRUSH INJURIES, RHABDOMYOLYSIS, HYPERTHERMIA, FULMINANT HEPATITIS, CYTOTOXIC CHEMOTHERAPY), • EXTENSIVE HEMOLYTIC ANEMIA, • TRANSCELLULAR PHOSPHATE SHIFTS INDUCED BY SEVERE METABOLIC OR RESPIRATORY ACIDOSIS
- 88. CLINICAL MANIFESTATIONS • THEFORMATION OF INSOLUBLE CALCIUM–PHOSPHATE COMPLEXES (WITH DEPOSITION INTO SOFT TISSUES) • ACUTE HYPOCALCEMIA (WITH TETANY) • PULMONARY OR CARDIAC CALCIFICATIONS (INCLUDING DEVELOPMENT OF ACUTE HEART BLOCK)
- 89. TREATMENT • VOLUME EXPANSION •ENHANCE RENAL PHOSPHATE CLEARANCE. • SALINE DIURESIS • ACETAZOLAMIDE • ALUMINUM HYDROXIDE ANTACIDS OR SEVALAMER • CHELATING AND LIMITING ABSORPTION OF OFFENDING PHOSPHATE SALTS PRESENT IN THE INTESTINE. • HEMODIALYSIS • IN THE COURSE OF SEVERE HYPERPHOSPHATEMIA, ESPECIALLY IN THE SETTING OF RENAL FAILURE AND SYMPTOMATIC HYPOCALCEMIA
- 90. • CALCIUM ACETATEAND CALCIUM CARBONATE • PREFERRED AGENTS AND ARE ADMINISTERED WITH MEALS • ALUMINIUM HYDROXIDE • MAY BE USED FOR THE SHORT TERM • CHRONIC USE IN PATIENTS WITH RENAL FAILURE SHOULD BE AVOIDED BECAUSE IT MAY CAUSE ALUMINIUM TOXICITY CAUSING ADYNAMIC BONE DISEASE, PROXIMAL MYOPATHY AND ANEMIA.
- 91. PREVENTION • RESTRICTION OFDIETARY PHOSPHATE TO 600-900 MG/DAY. AVOID PHOSPHORUS RICH PRODUCTS LIKE MILK AND DAIRY PRODUCTS AND CARBONATED BEVERAGES CONTAINING PHOSPHORIC ACID.