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A. Introduction navigator

  1. One of the major buffering anions in the body
  2. Exists in various states of protonation
    1. Phosphate (PO4) has 3 negative charges, PO4(3-)
    2. In body, equilibrium between HPO4 (2-) and H2PO4 (1-)
    3. pKa for HPO4(2-) is
    4. pKa for H2PO4(1-) is
  3. Total body phosphorus (P) content is about 70gm
    1. About 85% is present in skeleton
    2. Remaining 15% is in extracellular fluid and soft tissues
  4. Uptake by gut, excretion through kidneys
  5. Normal serum levels are 0.89-1.45 mmol/L, or 2.8-4.5 mg/dL

B. Functionsnavigator

  1. Normal component of bone, as calcium (and magnesium) salts
  2. Buffering activity: acid-base homeostasis
  3. Energy metabolism - production of ATP
    1. Normal skeletal muscle and heart function
    2. Nerve conduction
    3. Vascular tone
  4. DNA and RNA synthesis

C. Normal Regulation navigator

  1. Average daily intake is 800-1400mg P per day
    1. Between 60 and 80% is absorbed by the gut
    2. There is passive transport providing baseline uptake
    3. Active transport stimulated by 1a,25-dihydroxyvitamin D
  2. Phosphorus is freely filtered by glomerulus
    1. Reabsorption occurs of 80% occurs in proximal tubule
    2. Proximal tubule reabsorption occurs by passive transport coupled to sodium (Na)
    3. Two different Na-P cotransporters have been identified in humans
    4. These cotransporters are regulated by PO4 levels and by PTH
    5. High P intake reduces cotransporter levels, and PTH inhibits the cotransporter
    6. Low PO4 levels lead to resistance to the phosphaturic effects of PTH
  3. Parathyroid Hormone (PTH)
    1. Released in response to increased serum HPO4(-2) and decreased serum [Ca2+]
    2. Causes osteoclast activity with release of Ca2+ and PO4- from bone
    3. Causes increased renal conversion of 25-OH Vitamin D to 1a,25 dihydroxy- Vitamin D
    4. Stimulates increased renal tubular Ca2+ resorption and PO4- excretion
    5. PTH inhibits the Na-P cotransporter
    6. PTH works through both cAMP-PKA and PLC/PK-C systems
  4. 1alpha,25- Dihydroxy-Vitamin D (DHVD)
    1. Vitamin D converted to 25-OH form in liver, then to dihydroxy form in kidney
    2. Stimulates gut absorption of Ca2+ and PO4-
  5. Calcitonin
    1. Produced by parafollicular (C-) cells in the thyroid
    2. Decrease bone resorption
    3. Unclear role in normal physiological regulation of Ca2+
  6. Phosphatonin (FGF-23) [4]
    1. Certain tumors produce "phosphatonin", a hormone which causes renal phosphate wasting
    2. These tumors can cause tumor-induced osteomalacia
    3. Phosphatonin is likely FGF-23 (fibroblast growth factor 23)
    4. Phosphatonin is highly expressed in tumors that cause osteomalacia
    5. Symptoms include bone pain, low serum phosphate levels

D. Hypophosphatemia navigator

  1. Overview of Causes
    1. Reduced Intestinal Uptake
    2. Increased Urinary Losses
    3. Internal Redistribution
  2. Decreased Intestinal Absorption
    1. Antacids containing aluminum or magnesium
    2. Steatorrhea and chronic diarrhea
    3. Inadequate intake
    4. Vitamin D deficiency or resistance
  3. Increased Urinary Losses
    1. Proximally acting diuretics
    2. Osmotic diuresis - especially with hyperglycemia
    3. Hyperparathyroidism - primary and secondary
    4. Disorders of Vitamin D - deficiency or resistance
    5. X-linked hypophosphatemic rickets - FGF-23 mutations cause renal phosphate losses [3]
    6. Renal Tubular Defects including Fanconi syndrome
    7. Tumor-induced Osteomalacia - may be due to FGF-23 overproduction [4]
    8. Acute volume expansion
    9. Kidney Transplantation
    10. Alcohol Abuse
    11. Carbonic Anhydrase Inhibition
    12. Acidosis: Metabolic or Respiratory
    13. Imatinib mesylate (Gleevec®): hyper-PTH with low or normal 1,25 VitD3 [5]
  4. Internal Redistribution
    1. Increased insulin, particularly during refeeding
    2. Acute respiratory alkalosis (pain, anxiety, salicylate poisoning, sepsis, heat stroke)
    3. Recovery from malnutrition (refeeding syndrome)
    4. Sepsis
    5. Hungry Bone Syndrome
    6. Intravenous IGF-1 administration causes acute hypophosphatemia also [2]
    7. Insulin, glucagon, epinephrine, cortisol
  5. Symptoms
    1. Usually observed with plasma levels <0.32 mmol/L (0.9mg/dL)
    2. Hypercalciuria leading to hypocalcemia
    3. Hypermagnesuria leading to hypomagnesemia
    4. Proximal skeletal myopathy
    5. Respiratory muscle weakness - may lead to respiratory failure
    6. Rhabdomyolysis - severe cases only; increased risk in alcoholics
    7. Cardiac - decreased myocardial function, heart failure, arrhythmias
    8. Gastrointestinal - nausea, vomiting, poor motility (ileus)
    9. Erythrocytes - altered RBC morphology, hemolytic anemia
    10. hrombocytopenia, impaired granulocyte function (due to ATP)
    11. Hepatic - liver dysfunction (especially in cirrhotics)
    12. Osteomalacia (long term hypophosphatemia)
    13. Serum fibroblast growth factor 23 (FGF-23) levels very high in X-linked hypophosphatemic rickets [3]
    14. Neurologic - areflexic paralysis, confusion, Guillain-Barre Syndrome
    15. Encephalopathy may occur in very severe cases
  6. Treatment
    1. Treatment required for symptoms or for serum PO4- below 0.32 mmol/L (0.9mg/dL)
    2. Oral therapy is safest, usually 1000mg/d of P
    3. Intravenous replacement of P carries a high risk of acute hypocalcemia
    4. IV phosphate infusion in normal saline (2.5mg/kg body weight over 6 hours)
    5. Serum phosphate, calcium and magnesium, and electrolytes are monitored

E. Hyperphosphatemianavigator

  1. Overview of Causes
    1. Reduced Urinary Excretion
    2. Increased Endogenous Load
    3. Increased Exogenous Load
    4. Pseudohyperphosphatemia
  2. Reduced Urinary Excretion
    1. Hypoparathyroidism
    2. Renal Failure: acute or chronic
    3. Acromegaly
    4. Tumoral calcinosis
    5. Vitamin D intoxication / overdose
    6. Bisphosphonate therapy
    7. Magnesium deficiency
    8. Thyrotoxicosis
  3. Increased Endogenous Load
    1. Tumor lysis syndrome
    2. Rhabdomyolysis
    3. Bowel infarction
    4. Malignant hyperthermia
    5. Hemolysis
    6. Acid-base abnormalities
  4. Increased Exogenous Load
    1. Overingestion of phosphates
    2. Intravenous infusion
    3. Cow's milk feeding to premature babies
    4. Phosphate-containing enemas
    5. Acute phosphate poisoning
  5. Pseudohyperphosphatemia
    1. Multiple myeloma
    2. Hemolysis in vitro
    3. Hypertriglyceridemia
  6. Soft Tissue Calcium Deposition
    1. A rise in serum calcium X phosphate product >70 leads to soft tissue deposition
    2. Calcium phosphate salts are deposited in soft tissues
    3. This leads to hypocalcemia and potentially organ damage
    4. Ectopic calcification is frequently seen with chronic renal failure
  7. Treatment
    1. Reduction of intestinal absorption is key method
    2. Ingestion of phosphate-binding salts of aluminum, magnesium, or calcium
    3. Calcium salts are preferred in chronic renal failure

Resources navigator

calcCorrected Serum Calcium for Albumin

References navigator

  1. Weisinger JR and Bellorin-Font E. 1998. Lancet. 352(9125):391 abstract
  2. Le Roith D. 1997. NEJM. 336(9):633 abstract
  3. Jonsson KB, Zahradnik R, Larsson T, et al. 2003. NEJM. 348(17):1656 abstract
  4. Jan de Beur SM. 2005. JAMA. 294(10):1260 abstract
  5. Berman E, Nicolaides M, Maki RG, et al. 2006. NEJM. 354(19):2006 abstract