Approach to hypophosphatemia atee new

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  • Levels of FGF-23 are increased by inactivating mutations in PHEX (as in XLH) or DMP1 (as in ARHR), by activating mutations in FGF-23 (as in ADHR), or by tumor production of FGF-23 (as in TIO). Each of these disorders leads to excessive activity of FGF-23, which suppresses the Na/Pi cotransporter and causes renal phosphate wasting. In HHRH the renal phosphate wasting is caused by a mutation in the Na/Pi cotransporter itself.
  • Approach to hypophosphatemia atee new

    1. 1. Dr Nur Karyatee binti Kassim Mpath 4th year Approach to Hypophosphatemic patients
    2. 2. Case History  65 y.o man , developed right medial knee pain while golfing.  A tibial stress fracture was identified.  He then developed a contralateral stress fracture and generalized pain and weakness in his legs and back.  He had no previous history of fracture or childhood rickets.
    3. 3. Case History  Past Medical History: Type 2 diabetes, hypercholesterolemia and hypertension  Drug History :  Glipizide, quinapril, and atorvastatin.  Tab calcium (1000mg) and vitamin D 600 units daily  acetaminophen, rofecoxib, and tramadol (pain)  Family history was unremarkable.
    4. 4. On examination  Hypertensive (147/81mmHg) wt : 99.2 kg , Ht : 182 cm.  Normal dentition, without intraoral masses.  No palpable masses in his neck or extremities.  Examination of lungs, heart, and abdomen was normal.  He required a walker to ambulate, used his arms to rise from a chair, but could do a sit-up.
    5. 5. Laboratory testing  Se Phos :ranging fr 0.35 to 0.55 mmol/L (↓)  Se Calcium : 2.22 mmol/L (N)  Se PTH : 4.95 pmol/L (N)  Se Creatinine : 71 mmol/L (N)  25-hydroxyvitamin D (25OHD) : 65 nmol/l (N)  1,25-dihydroxyvitamin D (1,25OHD) : 60 pmol/l (N)  ALP : 66  171 U/liter (↑)  FGF23:97 pg/ml ( N: <70 ) (↑)
    6. 6. DEFINITION: Hypophosphatemia  Serum inorganic phosphate concentration of less than 0.85 mmol/L (Tietz)  UMMC  Serum inorganic phosphate concentration 0.85- 1.45 mmol/L Mild 0.78 to 0.84 mmol/L asymptomatic Moderate 0.48 to 0.77 mmol/L ,weakness, fatigue Severe Less than 0.48 mmol/L Altered mental status, seizure, impaired cardiac & resp function
    7. 7. HOMEOSTASIS  Parathyroid hormone (PTH)  ↑ bone resorption  ↓kidney phosphate reabsorption  ↑ 1α hydroxylation of 25-hydroxycholecalciferol  1,25-dihydroxycholecalciferol (1,25(OH)2D3)  ↑intestinal phosphate absorption  ↑ bone resorption  ↓ 1α hydroxylation of 25-hydroxycholecalciferol
    8. 8. HOMEOSTASIS  Phosphotonins  Functions:  1.)Fibroblast growth factor-23 (FGF-23)  Klotho: cofactor  ↓ expression of sodium-phosphate-II (Na-Pi-II) cotransporters → phosphaturia  ↓ production of 1,25(OH)2D3 and ↑its metabolism  Stimulated by:  Phosphate load,high vit D & PTH
    9. 9. Hypophosphatemia  Three primary mechanism: o Increased renal excretion o Decreased intestinal absorption o Movement of phosphate from extracellular to intracellular compartments  Classified into renal and non renal causes  Renal hypophosphatemia  FGF-23 mediated  non FGF-23 mediated  Non renal↓intake/ reabsorption of PO4  Transcellular shift
    10. 10. Increased renal excretion Impaired intestinal absorption or intake Transcellular shifts FGF23- mediated Non-FGF23- mediate • XLH (PHEX) • ADHR (FGF23 • ARHR (DMP1 • TIO • FD • Postrenal transplantat ion • hypophosp hatemia • Hyperparath yroidism • HHRH • Diuretics: • Acetazolami de (CAI) • Fanconi syndrome • Impaired dietary intake • Phosphate binders • Antacids • Alcoholism • Malabsorption • Vitamin D deficiency • Vitamin D metabolism defects • 1-hydroxylase def • Refeeding syndrome • Glucose infusion • Insulin infusion • Salicylate poisoning • Hyperventilati on • Respiratory alkalosis • Hungry bone
    11. 11. XLH: X-linked hypophosphataemic rickets ADHR: Autosomal dominant hypophosphataemic rickets ARHR: Autosomal recessive hypophosphataemic rickets TIO: Tumour-induced osteomalacia (acquired) HHRH: Hereditary hypophosphataemic rickets with hypercalciuria PHEX: Phosphate regulating endopeptidase on the X chromosome DMP 1: Dentin matrix protein 1 FGF-23: Fibroblast growth factor 23 PRIMARY RENAL PHOSPHATE WASTING Isolated renal phosphate wasting Bastepe M and Jüppner H (2008)
    12. 12. Renal cause: FGF23 mediated 1.) XLH: (X-linked hypophosphatemia) /VIT D Resistant Rickets  Mutation in PHEX gene, increased bone expression of phosphate regulating hormone FGF23  Decrease Sodium- phosphate co transporter  decreases proximal tubule reabsorption of phosphate  promote excretion  Decrease production of vit D  Impaired bone mineralization
    13. 13. A) Renal cause: FGF23 mediated XLH: (X-linked hypophosphatemia)  Presentation: signs of rickets in young children, OA with joint pain (adults)  Frequent dental abscess and calcification of tendons and ligaments  Biochemical = ↓ phosphate, ↓/N 1,25OHD and ↓ TmP/GFR
    14. 14. A.) Renal cause: FGF23 mediated 2.) ADHR: (Autosomal dominant hypophosphatemic rickets)  Mutation in the gene coding for FGF23↑FGF23 expression inhibit PO4 reabsorption & Vit D synthesis 3.) Autosomal recessive hypophosphatemic rickets (ARHR)  caused by inactivating mutations in dentin matrix protein 1 (DMP1) excess FGF23impair Po4 reabsorption 4.) Fibrous dysplasia (FD) of bone & Tumor-induced osteomalacia (TIO)   focal sites of abnormal FGF23 production
    15. 15. A.) Renal cause: FGF23 mediated Post renal transplantatio n Intravenous iron polymaltose Prolonged excess of FGF-23 Acquired during CKD ↑ FGF-23 ↓P04 reabsorption Hypophosphataemia
    16. 16. A.) Renal cause- Non FGF23 mediated 1.) Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)  Mutations in NaPi2c, a sodium-dependent phosphate cotransporter in the renal proximal tubule  impaired PO4 reabsorption  Lab ix: appropriate increase in 1,25OHD and resultant hyperabsorption of calcium, hypercalciuria.
    17. 17. 2.) FANCONI SYNDROME Congenital :Cystinosis, Wilson’s disease, hereditary fructose intolerance glycogen storage disease Acquired: Multiple myeloma, SLE, amyloidosis, antiretroviral medications Generalized defect proximal renal tubular reabsorption Hypophosphataemia Other clinical findings : Aminoaciduria, protenuria, microalbuminemia, glycosuria
    18. 18. A.) Renal cause: Non FGF23 mediated 3.) Proximally acting diuretics (Acetolamide) Impaired proximal tubule reabsorption of phosphate Hypophosphataemia
    19. 19. 4.) PRIMARY AND SECONDARY HYPERPARATHYROIDISM PRIMARY HYPERPARATHYROIDISM SECONDARY HYPERPARATHYROIDISM ↑ urinary phosphate excretion Parathyroid adenoma Diffuse hyperplasia Parathyroid carcinoma Vitamin D deficiency or resistance Hypophosphataemia
    20. 20. B.) DECREASED PHOSPHATE INTAKE ↓ renal excretion ↓ secretion into intestinal lumen ↑ bone resorption MAINTAIN ADEQUATE SERUM PHOSPHATE LEVEL Hypophosphataemia Underlying Stress, alcoholism,anor exia,sev malabsorbtion,
    21. 21. STEATORRHOEA (postgastrectomy,Chrone Disease,pancreatic insufficiency) Hypophosphataemia ↓ gut absorption phosphatevitamin D malabsorption Secondary hyperparathyroidism ↑ renal excretion Antacid(aluminiu m,Mg, Ca)/ Excess phosphate binder agent(in CKD pt ) Binding to ingested & secreted PO4 Formation insoluble Mg/Ca P
    22. 22. C.) Transcellular shift Salicylate poisoning/sep sis Resp alkalosis Intracellular CO2↓ Intracellular pH↑ Stimulate Phoshofructokinase Enhanced glycolysis Insulin treatment Glycolysis Glucose infusion ↑ cell uptake ↑ cell uptake of Po4 2ry Hyperpartyroidi sm Post parathyroidect omy Hypophosphataemia Phos move into cell Stimulate endogenous insulin ↑calcium & PO4 uptake in bone Hungry bone syndrome glycolysis
    23. 23. Clinical Approach
    24. 24. Evaluation:History Re-review History 1. Acute or Chronic ?????? Established u/lying cause: Review current treatment (DKA, medication, refeeding  clear causes of ↓ phosphate)  Consequences of low PO4: Intravascular hemolysis,rhabdomyolysis,CCF,resp failure,altered mental status  Osteomalacia and bone pain (chronic)  Drug history : medication can cause ↓ phosphate  Family history: inherited disease of ↓ phosphate
    25. 25. Evaluation – Physical Examination  Focus on Musculoskeletal system  sign of muscle weakness, pathological fractures/pseudofractures and skeletal deformities Bone pain / severe muscle pain (rhabdomyolysis) Children: Short stature / rachitic features suggesting Chronic hypophosphatemia. Decreased range of movement (spine/hip) – indicate calcified entheses ,common in XLH (adult)
    26. 26. Physical Examination Facial asymmetry/ long bone deformation – Fibrous Dysplasia (FD) (esp maxillary bone)  Other organs: Palpable soft tissue mass – Tumour induced osteomalacia (TIO) Hepatomegaly – underlying tumour / chronic alcoholism  Skin – café au lait macules (FD)
    27. 27. Laboratory assessment 1.) Renal function test:  To asses the renal status based on serum urea and creatinine. 2.) Serum Calcium :  ↑Ca , ↓ PO4 primary hyperparathyroidism,malignancy  ↓Ca , ↓ PO4  vit D def / vit D resistant rickets, Fanconi Syndrome,diuretic therapy 3.) Alkaline phosphatase (total/bone specific) :
    28. 28. Laboratory assessment 4.) Serum PTH:  ↑ PTH in hyperparathyroidism 5.) Serum 1,25OH Vit D  inappropriate low/ Normal in FGF23 mediated causes,Vitamin D deficiency.
    29. 29. 6.) 24 hr Urine calcium, and creatinine :  Detection of hypercalciuria (Fanconi syndrome, hypercalcemic hyperparathyroidism and inherited form of hypophosphatemia 7.) Urinary phosphate excretion rate:  <3mmol/24Hrs indicate decreased intake or increase cell uptake  >3mmol/24Hrs indicate renal loss 8.) Fractional excretion of PO4: (urine phosphate x serum creatinine) X 100% (serum phosphate x urine creatinine)  < 20% extra renal cause  >20%  renal cause
    30. 30. Tmp/GFR Determine renal /non renal causes  Assessment of TmP/GFR  Tubular reabsorption of phosphate (TRP) is calculated using the formula: 1- (urine phosphate x serum creatinine) (serum phosphate x urine creatinine)  TmP/GFR (normal range) = same numerical range as the age appropriate serum phosphate concentration in mg/dL
    31. 31. Normogram for determining TmP/GFR
    32. 32. Tmp/GFR  If both serum phosphate and TmP/GFR ↓ :  inappropriate renal phosphate wasting  Normal se PO4 / ↑ TmP/GFR  renal conservation of phosphate (non renal hypophosphatemia)
    33. 33. Laboratory assessment 8.) FGF23 measurement :  not yet routinely available.  Potentially useful in evaluating chronic hypophosphatemia
    34. 34. DDX PO4 Ca PTH ALP 1,25(O H)D FGF 23 TMP/G FR U Ca FGF23 MEDIATED XLH,ADHR,ARH R,TIO,FD,post renal transplant ↓ N ↑ ↑ ↓/N ↑ ↓ ↓/N Non-FGF23 MEDIATED HHRH( NPT2C) ↓ N ↓/N ↑ ↑ ↓ ↓ ↑ Pry PTH ↓ ↑ ↑ ↑/N ↑ N/↑ ↓ N/↑ Diuretics ↓ N/↑ N N N ↓ ↓ N Fanconi syndrome ↓ N/↓ N/↑ N/↑ N/↓ ↓ ↓ ↑ Summary…
    35. 35. Non Renal Hypophospha temia PO4 Ca PTH ALP 1,25(O H)D FGF 23 TMP/G FR U Ca Impaired intestinal Absorption /intake ↓ N/↓ ↑ N/↓ ↓/N ↓ ↑ ↓ Phosphate binders ↓ N/↓ N/↑ N/↑ ↑ ↓ ↑ ↓ Intracellular uptake ↓ N ↓/N ↑ ↑ ↓ ↑ ↑ Refeeding syndrome ↓ N N N ↑/N/↑ ↓ ↑ ↓ Summary…
    36. 36. Back to the patient  TmP/GFR ↓  renal phosphate wasting  No aminoaciduria  PTH : 4.95 pmol/L (N)  Dual-energy-xray absorptiometry – T score - 2.2signifies osteopenia  FGF23 : 97pg/ml ( normal <70 pg/ml)  ALP corrected after treatment with calcitriol and phosphate  Imaging studies – cortical lesion in left iliac bone
    37. 37.  Tumour Resection – spindle cell neoplasm (phosphaturic mesenchymal tumour)  Post surgery serum phosphate 1.25mmol/L  Calcitriol and phosphate salt were tapered off  Biochemically = ( ↓PO4,N ca,N 1,25 vit D, ↑ALP,↑FGF 23,↓TMP/GFR  DX: Consistent with TIO (tumour induced osteomalacia) - secrete excess amt of FGF23
    38. 38. Management  For hypophosphataemia, rx depends on the degree and the presence of the sx.  Treatments are tailored according to the cause:  Removing causative drugs  Treatment of dietary def  In acute setting : intravenous phosphate if critically ill, enteral intake is impaired, oral phosphate is not tolerated and serum phosphate < 0.48mmol/L
    39. 39. Management  Concomittant low calcium and phosphate  vitamin def  repletion of Vit. D / calcitriol  For Chronic hypophosphatemia: (especially FGF23 mediated d/o – XLH,FD,TIO,ADHR)  Avoidance of phosphate binders  Give vit D supplement ( not in HHRH – heriditary hypophosphatemic rickets with hypercalciuria)  Phosphate supplement

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