Download - Phosphate Homeostasis - Slides
Phosphate Homeostasis, Assessment & Disorders
Felicity Stokes
Senior Clinical Biochemist
Royal Liverpool & Broadgreen University Hospital Trust
Talk Outline
• Introduction to phosphate
• Phosphate Homeostasis
• Assessment of phosphate status
• Disorders of phosphate homeostasis– Hypophosphataemia– Hyperphosphataemia
• Causes• Clinical Manifestations• Investigation• Management
Introduction• Phosphate ~ 23 mol in body
• Present in the body as Pi or organic phosphate
In the blood (ECF) 1%
Inorganic (Pi)
HPO42- & H2PO4
-
4 : 1
10% protein bound35% complexed with Ca2+/Mg2+
55% Free
Organic
Phospholipids etc
In cells (ICF) 14%
Inorganic (Pi)
Organic – Most PO4-
Intermediary metabolites
ATP
DNA
2,3 – biphosphoglycerate (RBCs)
85%
Hydroxyapatite crystals• ECF Pi measured – 0.8 – 1.5 mmol/L
(higher in children)
Functions• Mineralisation of bone (hydroxyapatite crystals with Ca2+)
• Formation of ATP from ADP
• Nucleic acid synthesis - DNA
• Intracellular metabolic pathways (glycolysis, pentose phosphate pathway, NADP)
• Phospholipids
• Oxygenation of tissues (2,3-biphosphoglycerate)
• Co-factor of enzyme reactions
• To act as a buffer in urine (HPO42- to H2PO4
-)
• Signalling pathways (cAMP, kinase cascades)
Phosphate Homeostasis
Intake
Excretion
1,25 Vitamin D
Absorbed from intestine
Plasma (1%)0.8 – 1.5 mmol/L
ICF (14%)Pi & organic phosphate
Excretion
Reabsorption by kidney into blood ~80%
PTH
PTH FGF23
Bone: 85% of total body phosphate
~45 mmol/day +
~ 19 mmol/day
~ 7 mmol/day
Present is a wide range of food, rare to have inadequate intake on Western diet
1,25 Vit D increases in low phosphate intake to increase amount that is absorbed
+
~ 7 mmol/day ~ 7 mmol/day
~ 33 mmol/day
-
~25 mmol/day
Renal Handling of phosphatePhosphate is reabsorbed primarily in proximal tubule by Na+/PO4
- co-transporters
~80% of phosphate filtered by glomerulus is reabsorbed
Phosphate excreted in urine is an important buffer
Na+ PO4-
PTH
FGF-23
• Parathyroid hormone (PTH)
• 1,25-dihydroxyvitamin D (active Vitamin D)
• Phosphatonins:
Fibroblast Growth Factor-23 (FGF-23)
Phosphate homeostasisMost foods phosphate rich. Therefore phosphate regulated mostly by altering renal excretion
PO4-
Ca2+
+
Phosphate homeostasis
PTH
Activation of Vitamin D
++ Reabsorption of Ca2+
Excretion of PO4-
Bone resorption to release Ca2+ & PO4
-
PO4- +
FGF-23
Absorption of Ca2+ and PO4-
PTH
PO4- & Ca2+ Ca2+ PO4
-
PTH
+
PO4- & Ca2+ PO4
-
+
-
FGF-23
Overall effect of PTH Ca2+ PO4-
Overall effect of FGF-23 PO4-
Assessment of phosphate status
Serum • U&Es – Renal function• Bone profile
– Calcium, phosphate, albumin, ALP• Parathyroid hormone (PTH)• 25-OH Vitamin D• Magnesium – nutritional status• FGF-23
Urine Urine phosphateCalculation of TmP/GFRAmino acids & glucose – fanconi syndrome
Hypophosphataemia
• Causes
• Signs & symptoms
• Investigation
• Management
Increased Loss
GI loss
Diarrhoea
Renal loss
Alcoholism – diuresis
Hyperparathyroidism
Fanconi syndrome
Post kidney transplant/dialysis
Hypophosphataemic rickets
Malignancy
Hypophosphatemia - Causes
Redistribution (into cells)Refeeding syndrome
Recovery from DKA
Alkalosis – Especially respiratory
ICF
Redistribution (into bone)Hungry bone syndrome
Plasma (0.8 – 1.5 mmol/L)
Inadequate intake/absorptionMalnutrition Alcoholism
Malabsorption
Vitamin D deficiency
Use of antacids
Redistribution
Plasma (0.8 – 1.5 mmol/L)
Re-feeding syndrome
Period of malnutrition, followed by intake of carbohydrates
Intracellular ions – Mg2+, PO4-, K+ which have leaked out of cells and been lost in
urine during malnutrition (causing a deficiency) are rapidly taken up by cells
Severe deficiency in plasma levels
All patients at risk of re-feeding are given:
Electrolytes BEFORE or WITH carbohydrate load
Mg2+
K+ PO4-Glucose
Glycolysis
Citric acid cycle
Oxidative phosphorylation
ATPInsulin
Redistribution
Also causes a decrease in plasma K+ and PO4-
after eating & treatment of DKA
FGF-23Most important phosphatonin
Synthesized by osteocytes of bone
251 amino acid peptide• Deactivated by enzymatic hydrolysis by PHEX at specific cleavage site
Activated by 1,25-OH Vitamin D and in turn deactivates 1,25-OH Vitamin D
Increased in:
• Renal failure/ dialysis patients
• High phosphate
• Hypophosphataemic rickets
Disorders of FGF-23Rare genetic disorders that lead to increased FGF-23
• X-linked hypophosphataemic rickets (XLH)Mutation in PHEX (enzyme that breaks down FGF-23 – coded for on X chromosome) decreasing FGF-23 hydrolysis
• Autosomal Dominant Hypophosphataemic Rickets (ADHR)
Mutation in FGF-23 at its cleavage site that prevents hydrolysis
• Oncogenic OsteomalaciaTumour cells that produce FGF-23
54 year old male with bowing of the tibia and femur, osteoarthritisPart of a family with known X-linked hypophosphataemic rickets
ACa2+ 2.36PO4
- 0.37
Post treatmentFGF-23 52 (<100)
Treatment
Alfacalcidol and phosphate tablets daily
Pre-treatmentFGF-23 222 (<100)
Low phosphate due to raised FGF-23
Causes ineffective mineralisation of bone – poor growth, fractures, bowing of limbs
PHEX
FGF-23FGF-23
FGF-23
FGF-23
FGF-23
Increased phosphate excretion in urine
FGF-23
ADHR
Hypophosphataemia - Signs & Symptoms
Acute• Muscle weakness – most common• Respiratory failure• Cardiac• Haematological• Reduced oxygenation of tissues
• Coma, convulsions & death – very severe
Chronic• Rickets – children
• Osteomalacia - adults
Mild hypophosphatemia has minimal clinical signs & symptoms, but severe may be associated by profound complications
Hypophosphataemia - Investigation1. RepeatPhosphate varies throughout day – transcellular shift (with insulin & glucose) also exclude transient cause – respiratory alkalosis
2. ?Serum ACa2+
Both affected by PTH & vitamin D
3. ?Serum Mg2+, PO4-, K+
All intracellular ions, low in alcoholism & re-feeding
4. Further investigation
Urine phosphate
High Ca2+ Hyperparathyroidism
Low Ca2+ Vit D deficiency
All lowAlcoholism/ re-feeding/ nutritional deficiency
Low urine PO4-
High urine PO4-
Appropriate
Renal loss
Urine amino acids & glucoseHighFanconi syndrome
25-OHVit D
PTH
Measure
Measure
FGF-23 High
XLHADHRTIO
Blood gas
Urine Phosphate• 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
FE =UPhos x PCreat
UCreat x PPhos
TmP/GFRCalculate fractional excretion (FE) of phosphate:
The renal tubular maximum reabsorption of phosphate per litre of GFR
TmP/GFR = TR x [plasma phosphate]
1-FE = TR (tubular reabsorption)
TR = Fraction of filtered PO4- that is reabsorbed
To convert to a concentration and standardise per volume of filtrate TmP/GFR
TmP/GFR = 1.6 mmol/L
Management
Contraindications to phosphate replacement
• Hypocalcaemia (will bind Ca2+ & decrease it further)• Pancreatitis – Calcium may be low due to saponification in damaged tissue • Can’t give iv with magnesium or calcium as will precipitate – administer in separate arms• Renal failure! – give a reduced amount (usually halved)
16.1 mmol PO4-
20.4 mmol Na+ 3.1 mmol K+
Oral phosphate replacementPhosphate–Sandoz soluble tablets Give up to 100mmol (6 tablets) of phosphateSide effects - diarrhoea
Intravenous phosphate replacement – acute or severe/NBM20 mmol in 500mL over 12 hoursPotassium acid phosphatePolyfusor
Treat the underlying cause – eg. Replace if Vitamin D deficient
Replace low PO4- & maintenance PO4
- when known depletion/losses
Monitor serum Ca2+, PO4-, Mg2+ and creatinine
20 mmol K+ & 20 mmol PO4- in 250ml
50 mmol PO43-, 9.5 mmol K+, 81 mmol Na+ in 500mL Discard after 20 mmol (200mL)
Hyperphosphataemia
• Causes– Pseudohyperphosphataemia
• Signs & symptoms
• Investigation
• Management
Hyperphosphataemia - Causes
Increased exogenous loadi.v. infusion
Vitamin D toxicity
Phosphate-containing enemas
Redistribution (from cells)Tumour lysis syndrome
Rhabdomyolysis
In vivo haemolysis
Acidosis – esp Lactic acidosis
Decreased Urinary ExcretionRenal failure – AKI/ CKD
Hypoparathyroidism
PseudohyperphosphatemiaHaemolysis
Delayed separation
Plasma (0.8 – 1.5 mmol/L)
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 PO4
-/other abnormalities except a K+ due to same mechanism
• Paediatrics – make sure you are using age-related reference ranges
[Plasma phosphate] high in neonates & falls progressively throughout childhood
64 year old lady with known multiple myeloma
Routine bloods before a bisphosphonate infusion
Sodium 144 Potassium 4.3 Chloride 102 Bicarb. 28 Urea 4.9 Creatinine 55 eGFR >90
Adj Ca 2.45 Phosphate 3.16 Calcium 2.38Albumin 39Protein 92Globulin 53ALP 46
High protein and globulins due to paraprotein
Very high phosphate - ?Cause
1. Rule out spurious – not old or haemolysed
2. Normal renal function
3. Normal calcium – not hypoparathyroidism
4. Normal K+ and no clinical details to suggest cell lysis – rhabdomyolysis/ tumour lysis
5. If no obvious clinical causes – think rare causes/ interference
Paraproteins previously reported to cause interference in phosphate assays
Usually IgM – as these are large molecules and can interfere with the absorbance. Diluting the sample may dilute out some of the interfering immunoglobulins
This patient had an IgG paraprotein
Sample diluted 1 in 3 - result = 0.34 mmol/L
Multiply by 3 to correct for dilution factor = 1.02 mmol/L
Sample had an abnormal reaction profile
Patient has a normal phosphate concentration
Sodium 153Potassium 4.4Chloride 99Bicarb. 14Urea 25.2Creatinine 166eGFR 25
Adj Ca 1.54Phosphate >11.00Calcium 1.46Albumin 38Protein 61Globulin 23Alk Phos 88
Magnesium 1.00
CRP 96
ALT 27Alk Phos 88Bilirubin 18GGT 64
85 year old lady with bowel obstruction. Results were phoned to ward overnight by lab
Main abnormalities:
Renal failure
Very low ACa2+
Very high PO4-
?Genuine/ ?Spurious - ?Cause
Results from the previous day
Sodium 139Potassium - 2.6Chloride 95Bicarb. 19Urea 20.0Creatinine 127eGFR 35
Adj Ca 1.94Phosphate 4.10Albumin 37Protein 63Globulin 26
Look genuine as results were similar previous day
What could cause such deranged results? Adj Ca 1.54Phosphate >11.00Calcium 1.46Albumin 38Protein 61Globulin 23Alk Phos 88
Patient had a bowel obstruction and was given repeated phosphate enemas to clear it
Reduced renal function means phosphate could not be cleared
High phosphate – complexed with Ca2+ and caused low Ca2+
Mainly due to binding with calcium
Acute– Hypocalcaemia
• Tetany, pins & needle
Chronic– Precipitation - calcification of blood vessels & soft tissues
• Renal failure• Cardiovascular complications
Signs & Symptoms
Hyperphosphataemia - Investigation1. ?GenuineExclude age-related (children have higher [PO4
-]), delayed separation, haemolysis and iatrogenic (over-replacement)
2. ?Renal functionRenal failure most common cause of PO4
-
U&Es – high urea & creat AKI/CKD
3. ?Serum ACa2+
Both affected by PTH & Vitamin D
High Ca2+ Vitamin D toxicity, malignancy
Measure
25-OH Vit D
Low Ca2+ Hypoparathyroidism PTH & Mg2+
4. Urine PO4- Low
High AppropriateRedistribution – cell lysisIncreased intake Malignancy
5. Markers of cell lysisCK, urate High Rhabdomyolysis/ Tumour lysis syndrome
Normal Ca2+ Lactic acidosis Lactate
Management
Chronic• Dietary restriction of phosphate – difficult – present in lots of foods• Administration of Phosphate binders
– Selevamer– Calcium - hypercalcaemia– Aluminium hydroxide – aluminium toxicity
Acute• Aggressive fluid hydration• Administration of insulin & dextrose – only temporary• Haemodialysis
Treat the underlying cause
Thank you
Any questions?