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MSC: Disease of major orgns > Phosphate: Homeostasis, Assessment and Disorder > Flashcards

Phosphate: Homeostasis, Assessment and Disorder Flashcards

1
Q

How phosphate distributed in the body?

A

Phosphate ~ 23 mol in body. Can be inorganic (Pi) or organic phosphate

  • In the blood (ECF) = 1%
  • In cells = 14%
  • Hydroxyapatite Crystals = 85%
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2
Q

What is the phosphate in the blood?

A

Inorganic (Pi) = HPO42- and H2PO4- (4:1 ratio)

  • 10% protein bound
  • 35% complexed with Ca2+/Mg2+
  • 55% Free

Organic = Phospholipids, etc.

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3
Q

What is the phosphate in the cells?

A

Inorganic (Pi)

Organic – (most PO4-) - Intermediate metabolites

  • ATP
  • DNA
  • 2,3 – biphosphoglycerate (RBCs)
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4
Q

What are 3 factors of phosphate homeostasis?

A

Three key factors:

  • Vit D
  • FGF-23
  • PTH

Also affected by:

acid-base status, corticosteroids, GH, thyroxine, insulin, calcitonin, dopamine, serotonin

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5
Q

How is phosphate handled renally?

A
  • 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
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6
Q

What influences renal handling of phosphate?

A
  • Dietary phosphate
  • PTH
  • FGF23
  • 1,25 Vit D
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7
Q

How does PTH influence Phosphate homeostasis?

A

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
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8
Q

What is the effect of FGF-23 on Phosphate homeostasis?

A

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
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9
Q

What are reference ranges for Hypophosphataemia?

A

Normal Reference range: 0.8 - 1.4 mmol/L

  • Mild deficiency: 0.35 - 0.80 mmol/L
  • Severe deficiency: <0.35 mmol/L
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10
Q

What are signs and symptoms of Hypophosphataemia?

A

Mild: often none, rickets/osteomalacia if chronic.

Severe: affects

  • Haemopoetic,
  • Muscular,
  • Nervous,
  • Gastrointestinal systems
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11
Q

What are mechanisms of Hypophosphataemia?

A
  • Inadequate absorption from intestine
  • Redistribution into cells or bone
  • Increased urinary phosphate loss
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12
Q

What are causes of phosphate distribution into bone and cells?

A

Bone

  • Hungry bone syndrome

Cells

  • Refeeding syndrome
  • DKA recovery
  • Alkalosis
  • Increased muscle uptake
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13
Q

What are causes of Inadequate intake/absorption?

A
  • Malnutrition
  • Alcoholism
  • Malabsorption
  • Vitamin D deficiency
  • Use of antacids
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14
Q

What are causes of Increase GI and Renal loss of Phosphate?

A

GI loss

  • Diarrhoea

Renal loss

  • Alcoholism – diuresis
  • Hyperparathyroidism
  • Fanconi syndrome
  • Post kidney transplant/dialysis
  • Hypophosphataemic rickets (FGF-23)
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15
Q

What is Refeeding syndrome?

A
  • 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.

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16
Q

How does Respiratory alkolosis cause redistribution of Phospate?

A
  • 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

17
Q

What causes increased FGF-23 related conditions?

A
  • Renal failure/ dialysis patients
  • High phosphate
  • Hypophosphataemic rickets
18
Q

What is FGF-23?

A
  • 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
19
Q

What are some disorders of FGF-23?

A

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
20
Q

What are genetic disorders causing hypophosphataemia?

A
  • 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
21
Q

What are investigations of Hypophosphataemia?

A
  • 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
22
Q

How can Urine phosphate be tested?

A
  • 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
23
Q

What is TmP/GFR?

A

The renal tubular maximum reabsorption of phosphate per litre of GFR

24
Q

How do you calculate Tubular Reabsorption (TRP)?

A

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]

25
Q

What does result of TRP tell you?

A

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]
26
Q

What are reference ranges for Hyperphosphataemia?

A

Reference range: 0.8 - 1.4 mmol/L

  • Moderate excess: 1.41 - 2.40 mmol/L
  • Severe excess: >2.40 mmol/L
27
Q

What are signs and symptoms of Hyperphosphataemia?

A
  • 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.
28
Q

What are mechanisms of Hyperphosphataemia?

A
  • Pseudohyperphosphataemia
  • Increased input/intake
  • Redistribution from ICF
  • Decreased phosphate excretion
29
Q

What are mechanisms of Pseudohyperphosphataemia?

A

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
30
Q

What are mechansims of Hyperphosphataemia?

A
  • Pseudohyperphosphataemia
  • Increase intake/input
  • Redistribrution from ICF
  • Decrease Phosphate excretion
31
Q

What are causes of increase intake/input?

A
  • IV/ Rectal
  • Almost impossible from dietary overload alone.
32
Q

What are causes of redistribution from ICF?

A

Cell death due to

  • Tumour lysis syndrome
  • Rhabdomyolysis
  • Heat stroke/ hyperpyrexia
33
Q

What are causes of Decreased Phosphate excretion?

A

Reduced GFR

  • AKI
  • CKD

Increased TmP/GFR

  • Physiological (youth, lactation)
  • Pathological (decreased PTH, acromegaly, thyrotoxicosis, vitD toxicity, bisphosphonates)
34
Q

What are investigations of hyperphosphataemia?

A
  • Clinical history – any IV/rectal phosphate? Possible rhabdomyolysis (measure CK)/ tumourlysis syndrome?
  • U & E profile (renal function)
  • Urine phosphate = Calculate TmP/GFR

MSC: Disease of major orgns (23 decks)

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