Phosphate: Homeostasis, Assessment and Disorder Flashcards
How phosphate distributed in the body?
Phosphate ~ 23 mol in body. Can be inorganic (Pi) or organic phosphate
- In the blood (ECF) = 1%
- In cells = 14%
- Hydroxyapatite Crystals = 85%
What is the phosphate in the blood?
Inorganic (Pi) = HPO42- and H2PO4- (4:1 ratio)
- 10% protein bound
- 35% complexed with Ca2+/Mg2+
- 55% Free
Organic = Phospholipids, etc.
What is the phosphate in the cells?
Inorganic (Pi)
Organic – (most PO4-) - Intermediate metabolites
- ATP
- DNA
- 2,3 – biphosphoglycerate (RBCs)
What are 3 factors of phosphate homeostasis?
Three key factors:
- Vit D
- FGF-23
- PTH
Also affected by:
acid-base status, corticosteroids, GH, thyroxine, insulin, calcitonin, dopamine, serotonin
How is phosphate handled renally?
- Phosphate is reabsorbed primarily in proximal tubule by Na+/PO4- co-transporters NPT2a and NPT2c
- ~80-95% of phosphate filtered by glomerulus is reabsorbed (~75% of this by proximal tubule)
- Phosphate excreted in urine is an important buffer
What influences renal handling of phosphate?
- Dietary phosphate
- PTH
- FGF23
- 1,25 Vit D
How does PTH influence Phosphate homeostasis?
PTH
- Stimulate conversion of 25-OH to 1,25 diOH vitamin D. This then stimulate intestine to increase calcium and phosphate absorption
- Reduce NPT2a/c expression. This causes increased phosphate excretion in urine
- Stimulate bone remodelling. Bone resorption occurs and release of clacium and phosphate into circulation
What is the effect of FGF-23 on Phosphate homeostasis?
FGF-23 (from osteocytes and osteoblasts)
- Inhibits conversion of 25-OH to 1,25 diOH vitamin D. This causes decreased reabsorption of PO4-
- Reduce NPT2a expression. This increase phsopahte excretion in urine
What are reference ranges for Hypophosphataemia?
Normal Reference range: 0.8 - 1.4 mmol/L
- Mild deficiency: 0.35 - 0.80 mmol/L
- Severe deficiency: <0.35 mmol/L
What are signs and symptoms of Hypophosphataemia?
Mild: often none, rickets/osteomalacia if chronic.
Severe: affects
- Haemopoetic,
- Muscular,
- Nervous,
- Gastrointestinal systems
What are mechanisms of Hypophosphataemia?
- Inadequate absorption from intestine
- Redistribution into cells or bone
- Increased urinary phosphate loss
What are causes of phosphate distribution into bone and cells?
Bone
- Hungry bone syndrome
Cells
- Refeeding syndrome
- DKA recovery
- Alkalosis
- Increased muscle uptake
What are causes of Inadequate intake/absorption?
- Malnutrition
- Alcoholism
- Malabsorption
- Vitamin D deficiency
- Use of antacids
What are causes of Increase GI and Renal loss of Phosphate?
GI loss
- Diarrhoea
Renal loss
- Alcoholism – diuresis
- Hyperparathyroidism
- Fanconi syndrome
- Post kidney transplant/dialysis
- Hypophosphataemic rickets (FGF-23)
What is Refeeding syndrome?
- Period of malnutrition, followed by intake of carbohydrates (e.g. dextrose)
- Intracellular ions – Mg2+ , PO4-, K+ which have leaked out of cells and lost in urine during malnutrition (causing a deficiency) are rapidly taken up by cells due to insulin release
All patients at risk of re-feeding are given. Electrolytes BEFORE or WITH carbohydrate load.
How does Respiratory alkolosis cause redistribution of Phospate?
- Hyperventilation causes CO2 to drop in blood and cells therefore intracellular [H+] decreases
- Activates phosphofructokinase – increases phosphorylation of glucose = phosphate is taken up rapidly.
- Will correct itself – usually within 90 minutesonce ventilation returns to normal
Caused by: Sepsis, liver disease, heat stroke, salicylate intoxication, gout, malignant neuroleptic syndrome
What causes increased FGF-23 related conditions?
- Renal failure/ dialysis patients
- High phosphate
- Hypophosphataemic rickets
What is FGF-23?
- Most important phosphatonin. 251 AA peptide
- Synthesised by osteocytes of bone
- Deactivated by enzymatic hydrolysis by PHEX at specific cleavage sites
- Activated by 1,25-OH vitamin D and in turn deactivates 1,25-OH vitamin D
What are some disorders of FGF-23?
Rare genetic disorders that lead to increased FGF-23
- X-linked hypophosphataemic rickets (XLH): Mutation in PHEX (gene encodes a protein that stabilises a FGF-23 stimulating protein; mutation therefore means increased FGF-23 activity as it is stimulated without this control) - therefore renal phosphate wasting occurs due to action of FGF-23.
- AD Hypophosphataemic Rickets (ADHR): Mutation in FGF-23 at its cleavage site that prevents proteolysis.
- AR Hypophosphataemic rickets(ARHR): Mutation in the DMP1 gene which encodes for a protein which restrains FGF-23 production.
- Tumour induced osteomalacia / Oncogenic osteomalacia: Tumour cells of mesenchymal origin that produce FGF-23
What are genetic disorders causing hypophosphataemia?
- Dent’s disease (autosomal recessive)
- Hereditary hypophosphataemic rickets with hypercalciuria
- Hereditary 1,25 vitamin D resistant rickets
- Vitamin D resistant rickets type 1A
- McCune-Albright Syndrome
- Familial hypocalciuric hypercalcaemia / neonatal hypercalcaemia
- Jansens disease
What are investigations of Hypophosphataemia?
- Clinical details:?diet, ?IV, history of alcoholism/eating disorders, drugs? Any renal impairment/transplant?
- Repeat phosphate measurement (diurnal rhythm, fluctuations throughout day according to glucose/insulin)
- UE profile (renal function)
- Bone profile (Ca, ALP, albumin, phosphate)
- Mg (nutritional status; K also useful for this)
- pH (alkalosis?)
- 25(OH)VitD, PTH, FGF-23, Urine phosphate(calculate TmP/GFR), Urinary amino acids and glucose
How can Urine phosphate be tested?
- Paired fasting 2nd void urine & blood for calculation of TmP/GFR
- If borderline results – fasting 2hr urine collection with bloods in middle
- TmP/GFR useful for investigation of hypophosphataemia – determine whether the cause is renal loss
What is TmP/GFR?
The renal tubular maximum reabsorption of phosphate per litre of GFR
How do you calculate Tubular Reabsorption (TRP)?
Calculate fractional excretion (FE) of phosphate:
FE = (Uphos X PCreat) / (UCreat X PPhos)
1-FE = TRP
TRP is Fraction of filtered PO4- that is reabsorbed. To convert to a concentration and standardise per volume of filtrate so TmP/GFR .
TmP/GFR = TR x [plasma phosphate]
What does result of TRP tell you?
If TRP ≤ 0.86 then phosphate reabsorption is maximal and relationship is linear
- Tmp/GFR = TRP x [plasma phosphate]
If TRP >0.86 then relationship is curvilinear
- Tmp/GFR = 0.3 x TRP / {1-(0.8 x TRP)} x [plasma phosphate]
What are reference ranges for Hyperphosphataemia?
Reference range: 0.8 - 1.4 mmol/L
- Moderate excess: 1.41 - 2.40 mmol/L
- Severe excess: >2.40 mmol/L
What are signs and symptoms of Hyperphosphataemia?
- When calcium and phosphate levels exceed a certain concentration (their solubility product); soft tissue calcification of the blood vessels, skin, lungs, hearts, kidneys and joints can occur.
- Calcification of the kidney reduces the renal capacity to excrete phosphate even further.
What are mechanisms of Hyperphosphataemia?
- Pseudohyperphosphataemia
- Increased input/intake
- Redistribution from ICF
- Decreased phosphate excretion
What are mechanisms of Pseudohyperphosphataemia?
Pseudohyperphosphataemia
Redistribution from cells
- Haemolysis – results should be automatically knocked out from LIMS & not reported.
- Delayed separation – check date of sample, especially in GP samples. Especially if no obvious cause of increased PO4-/other abnormalities except an increase in K+ due to same mechanism.
Paediatrics – make sure you are using age-related reference ranges
- [Plasma phosphate] high in neonates & falls progressively throughout
What are mechansims of Hyperphosphataemia?
- Pseudohyperphosphataemia
- Increase intake/input
- Redistribrution from ICF
- Decrease Phosphate excretion
What are causes of increase intake/input?
- IV/ Rectal
- Almost impossible from dietary overload alone.
What are causes of redistribution from ICF?
Cell death due to
- Tumour lysis syndrome
- Rhabdomyolysis
- Heat stroke/ hyperpyrexia
What are causes of Decreased Phosphate excretion?
Reduced GFR
- AKI
- CKD
Increased TmP/GFR
- Physiological (youth, lactation)
- Pathological (decreased PTH, acromegaly, thyrotoxicosis, vitD toxicity, bisphosphonates)
What are investigations of hyperphosphataemia?
- Clinical history – any IV/rectal phosphate? Possible rhabdomyolysis (measure CK)/ tumourlysis syndrome?
- U & E profile (renal function)
- Urine phosphate = Calculate TmP/GFR
