Phosphate homeostasis, hyperphosphatemia, hypophosphatemia

1. Phosphate Homeostasis
& Its Related Disorders
Dr Ifat Ara Begum
Associate Professor
Dept of Biochemistry
Dhaka Medical College, Dhaka

2. Introduction to phosphate
Essential to many vital physiological
processes
One of the important anion of ICF
(140 meq/L)

3. Functions of phosphate
Bone mineralization
Participates in energy metabolism
(storage & transfer of energy)
Component of
1. Phospholipid, nucleotides & nucleic
acid
2. 2,3-BPG & regulate oxygen transport

4. Contd
Acts as
 Buffer & facilitates urinary acid excretion
 The component of intracellular 2nd
messenger
& participates in signal transduction
Regulation of enzyme activity by covalent
modification of enzyme
Facilitates respiratory chain activity

5. Renal handling of phosphate
May be discussed under following
headlines:
I. Tubular load of phosphate
II. Tubular reabsorption of phosphate
III. Renal excretion of phosphate

6. i) Tubular load of phosphate
 Tubular load equals to GFR X free
Plasma phosphate concentration
 100 - 200 mmol/day

7. ii) Tubular reabsorption of phosphate
80 - 95% of tubular load
i. From PCT: 70-80% by secondary
active transport
ii. From distal nephron : 10 - 20%

8. Contd
Remember,
 Normally, phosphate is reabsorbed
essentially from PCT & here, its
reabsorption is inhibited by PTH
 Distal nephron reabsorbs phosphate
only if hectic phosphate restriction in
diet is imposed

9. Contd
Process of tubular reabsorption of
phosphate:
Na+
- K+
pump keeps the intracellular
Na+
concentration low
So, Na+
from lumen diffuses to cell
along with phosphate via Na-PO4
symporter
Phosphate from cell goes to blood
through basolateral border by
diffusion

11. iii) Renal excretion of phosphate
< 20% of tubular load
It is <20 - 40 mmol/day

12. Contd
Factors regulating renal phosphate
excretion:
 1. Dietary phosphate intake: If
increases, renal phosphate excretion
also increases.
 2. Plasma phosphate concentration:
If increases, renal phosphate
excretion also increases.

13. Contd
 3. PTH: It inhibits the Na-PO4
symporter & increases phosphate
excretion by decreasing its
reabsorption
 4. Calcitonin: It increases the renal
excretion of phosphate

14. Contd
5. Acid base status:
 In PCT of kidney, Na-PO4 symporter
preferably entertains HPO4
-2
rather
than H2PO4
-
to be reabsorbed
 In acidosis, H2PO4
-
predominates, so renal
phosphate reabsorption decreases
 In alkalosis, HPO4
-2
predominates, so renal
phosphate reabsorption increases

15. Phosphate homeostasis
May be discussed under following
headings:
 Body phosphate content
 Distribution of phosphate
 Phosphate balance
 Daily turnover of phosphate
&
 Regulation of phosphate balance

16. Body phosphate content
600 – 700 g in adult
(20 – 25 mol)
[1 mmol of phosphate= 30 mg]

17. Distribution of phosphate
I. 80 - 85% in bone : Predominantly as
calcium phosphate crystal (hydroxy
apatite crystal)
II. 15 - 20% in soft tissues
III. 0.1% in ECF

18. Contd
Plasma phosphate:
2.5 – 4.5 mg%
Forms of plasma phosphate:
A. Organic: 70%
B. Inorganic: 30%

19. Contd
Inorganic phosphate:
 Is measured clinically as it is
biologically active
 Represents the phosphate status of an
individual

Present in 3 forms in plasma:
i. Free form (85%)
ii. Protein bound form (10%)
iii. As complex with cation (5%)

20. Phosphate balance
Intake: 1400 mg/day via milk/milk
products, fish, meat, vegetables etc
Output: 1400 mg/day via
a) Urine: 900 mg/day
b) Feces: 500 mg/day

21. Contd
Intestinal absorption of phosphate:
60 – 70% of dietary phosphate is
absorbed from intestine by vitamin D
& PTH
Intestinal absorption matches with
renal excretion in steady state

22. Contd
From intestine, phosphate is absorbed
:
Actively through transcellular route by
Na-PO4 symporter stimulated by
vitamin D
&
Passively through paracellular route

24. Phosphate turnover
Available phosphate in intestine:
1600 mg
1. Diet (1400 mg/day)
2. Various intestinal secretion (200
mg/day)

25. Contd
From intestinal lumen,
 1100 mg of phosphate is absorbed by
PTH & vitamin D (with net absorption
of 900 mg) which joins ECF
phosphate pool of pool 600 – 700
mg

Remaining 500 mg of phosphate
from intestinal lumen is excreted with
stool

26. Contd
ECF phosphate pool is in reversible
equilibrium with soft tissue phosphate
pool & bone phosphate pool at a
definite turnover rate
From ECF , 900 mg calcium is
excreted through urine daily to match
with the intestinal absorption

28. Contd
Renal excretion of phosphate is
regulated by PTH
Bony phosphate turnover is regulated
by PTH & vitamin D

29. Regulation of phosphate balance

30. Contd
Remember, The net effect of :
1. Calcitriol : Hypercalcemia &
Hyperphosphatemia. Calcitriol directly
can suppress PTH secretion
2. PTH: Hypercalcemia but
hypophosphatemia
3. Calcitonin: Hypocalcemia &
hypophosphatemia

31. ↓ Plasma
PO4
↑Calcitrio
l
↑ intestinal
Calcium
absorption
↑
intestinal
PO4
absorptio
n
↓ PTH
↓ bone
resorptio
n
↓ PO4
excretion
↑ Calcium
excretion
No change / slight ↑
in plasma calcium
Serum PO4 comes
back to normal

32. Contd
Reverse events
occur in
hyperphosphate
mia.

33. Abnormalities of phosphate
homeostasis
2 types of abnormalities:
1. Hyperphosphatemia
2. Hypophosphatemia

34. 1. Hyperphosphatemia
An electrolyte disturbance in which
there is abnormally elevated level of
phosphate in blood
>4.5 mg%
Often, calcium levels are lowered
(hypocalcemia) due to precipitation of
phosphate with the calcium in tissues.

35. Contd
Causes may be listed under following
headings:
 Impaired renal excretion: RF
 Increased phosphate
intake/absorption: dietary intake,↑
ingestion of phosphate containing
supplement/bowel preparations etc
 Release from intracellular store:
Rhabdomyolysis, tumorolysis etc

36. Contd
 Endocrinopathies:
Hypoparathyroidism, Resistance to
PTH
 Shift from intracellular to extracellular
compartment: Metabolic acidosis,
lactic acidosis, DKA
 Genetic diseases: Familial tumoral
calcinosis

37. Contd (Explanation on shift)
Metabolic acidosis causes phosphorus to
shift out of cells.
In lactic acidosis, glycolysis is decreased,
which decreases intracellular utilization of
phosphate in the generation of ATP.
In DKA, glycolysis is impaired and
hyperglycemia can shift phosphate out of
cells via osmotic drag.

38. 2. Hypophosphatemia
An electrolyte disturbance in which
there is abnormally low level of
phosphate in blood
<2.5 mg%

39. Contd
Causes may be listed under following
headings:
 Increased renal excretion:
Hyperparathyroidism, metabolic
acidosis etc
 Decreased phosphate
intake/absorption: Poor intake,
malabsorption, vitamin D
deficiency/resistance, diarrhoea,
steatorrhea etc

40. Contd
 Shift from extracellular to intracellular
compartment: : Respiratory alkalosis,
elevated serum insulin or glucose levels
 Genetic diseases: Autosomal dominant
hereditary hypophosphatemic rickets
(ADHR), X-linked hypophosphatemic rickets
(XHR) etc

41. Contd (Explanation on shift)
In respiratory alkalosis, CO2 decreases in the
extracellular space, causing intracellular
CO2 to freely diffuse out of the cell.
This drop in intracellular CO2 causes a rise in
cellular pH which has a stimulating effect
on glycolysis.

42. Contd
Since the process of glycolysis requires
phosphate (the end product is ATP), the
result is a massive uptake of phosphate into
metabolically active tissue (such as muscle)
from the serum.
So hypophosphatemia develops