Calcium homeostasis, hypercalcemia, hypocalcemia

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

2. Introduction to calcium
The most abundant mineral of human
body
One of the important cation of ECF
Normal range in ECF: 2 – 2.5 meq/L
Normal range in ICF: Negligible
Serum Ca++
concentration is tightly
controlled because the Ca++
has a stabilizing
effect on voltage-gated ion channels.

3. Contd
For example:
when [Ca++
]ECF is too low (hypocalcemia),
voltage-gated ion channels start opening
spontaneously, causing nerve and muscle
cells to become hyperactive. The syndrome
of involuntary muscle spasms due to low
[Ca++
]ECF is called hypocalcemic tetany.

4. Contd
Conversely, when [Ca++
]ECF is too high
(hypercalcemia), voltage-gated ion
channels don't open easily and there is
depressed nervous system function.
Another problem of hypercalcemia is that
calcium can combine with phosphate ions,
forming deposits of calcium
phosphate (stones) in blood vessels and in
the kidneys.

5. Function of calcium
Helps in :
 Formation of bone & teeth
 Blood coagulation
 Release of hormones
Acts as intracellular 2nd
messenger in
transmembrane signaling

6. Contd
Cardiac & neuromuscular function:
 Maintenance of cardiac rhythmicity
 Muscle contraction
 Control of NM excitability
 Release of NTs

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

8. i) Tubular load of calcium
Tubular load equals to GFR X free
(ionized) Plasma calcium
concentration
= 180 L/day X 1.2 mmol/L
250 mmol/day
Or
10000 mg/day

9. ii) Tubular reabsorption of calcium
More than 95% of tubular load
i. From PCT: 70 % occurs passively [by
solvent drag following salt (NaCl) and
water reabsorption]
ii. From ALH : 20% occurs passively [by
solvent drag following salt (NaCl) and
water reabsorption]
iii. From DCT: 5 – 10% actively by PTH
with the help of calcitriol

10. Contd
Remember,
 Calcium reabsorption is directly
linked with the salt & water
reabsorption in PCT & ALH.
 So, factors influencing salt and water
reabsorption affect the calcium
reabsorption similarly

11. Contd
Process of reabsorption:
 Calcium diffuses from lumen to cell via
calcium channel followed by
transcellular shuttling of calcium to
basolateral border by CBP (calcium
binding protein)
 From cell to blood, calcium is
extruded by:
I. calcium pump (30%)
II. Na+
- Ca++
antiporter (70%)

13. iii) Renal excretion of calcium
< 5% of tubular load
It is 5 mmol/day (200 mg/day)

14. Contd
Factors regulating renal Ca++
excretion:
 1. Dietary calcium: If increases,
renal calcium excretion also
increases,
 2. ECF volume: If increases, renal
salt and water excretion increases
with increased Ca++
excretion

15. Contd
 3. PTH: It increases calcium
reabsorption from DCT, so, eventually
decreases renal Ca++
excretion
 4. Calcitriol: It increases calcium
reabsorption from DCT by enhancing
intracellular CBP synthesis, so,
eventually decreases renal Ca++
excretion
 5. Calcitonin: Increases the renal Ca++
excretion

16. Calcium homeostasis
May be discussed under following
headings:
 Body calcium content
 Distribution of calcium
 Calcium balance
 Daily turnover of calcium
&
 Regulation of calcium balance

17. Body calcium content
1 – 1.5 kg in adult
(25 – 30 mol)
[1 mmol of calcium= 40 mg]

18. Distribution of calcium
I. >99% in bone : Predominantly as
calcium phosphate crystal (hydroxy
apatite crystal)
II. 0.5% in soft tissues
III. 0.1% in ECF

19. Contd
Forms of bone calcium:
1. Labile calcium pool
2. Stable calcium pool

20. Contd
1. Labile calcium pool:
 0.5 – 1% of bone calcium
 Readily exchangeable with ECF
calcium, so can act as calcium buffer to
maintain serum calcium level in acute
calcium excess/deficit

21. Contd
2. Stable calcium pool:
 99% of bone calcium
 Slowly exchangeable with ECF calcium
 Acts for bone remodeling

22. Contd
Forms of plasma calcium:
i. Free /ionized calcium: 50%
ii. Protein (mainly albumin) bound
calcium: 45%
iii. Soluble calcium complex with anions
(citrate, phosphate, etc): 5%

23. Contd
 All these three forms of plasma
calcium are in equilibrium with each
other & together represent the plasma
calcium pool
 Protein bound calcium: Non-diffusible

Rest 2 forms of calcium: Diffusible

24. Contd
Ionic
calcium
Calcium
with
anions
Protein
bound
calcium

25. Contd
Importance of free/ionized calcium:
It is biologically active
It is controlled by hormones
Its concentration determines the body
calcium status

26. Contd
Remember,
Total plasma calcium concentration:
9 – 10.5 mg/dl or
2.2 – 2.6 mmol/L
Free /ionic calcium concentration:
4.5 – 5.6 mg/dl or
1.3 – 1,5 mmol/L

27. Calcium balance
Intake: 1000 mg/day via milk/milk
products, fish, meat, vegetables etc
Output: 1000 mg/day via
a) Urine: 200 mg/day
b) Feces: 800 mg/day

28. Contd
Calcium balance may be
 Positive: In childhood (during
growth)
 At equilibrium: In adult life
 Negative: In elderly & post
menopausal women

29. Contd
Intestinal absorption of calcium:
20 – 30% of dietary calcium is
absorbed from intestine by vitamin D
& PTH
Intestinal absorption matches with
renal excretion in steady state

30. Contd
From intestine, calcium is absorbed :
Actively through transcellular route by
vitamin D
&
Passively through paracellular route

31. Contd
 Calcium diffuses from lumen to cell
via calcium channel
 Within the cell calcium binds with
CBP produced by vitamin D
 CBP facilitates transcellular shuttling
of calcium to basolateral border from
which calcium is absorbed to blood
by:
I. calcium pump
II. Ca++
- Na+
antiporter

32. Contd
Lumen Cell Blood
Ca++
Paracellr. abs.

33. Calcium turnover
Available calcium in intestine: Comes
from diet & various intestinal
secretion
From intestinal lumen,
 20 - 30% of calcium is absorbed by
vitamin D which joins ECF calcium
pool (of 1200 – 1400 mg)
 Remaining calcium is excreted with
stool

34. Contd
ECF calcium pool is in reversible
equilibrium with soft tissue calcium
pool & bone calcium pool at a definite
turnover rate
From ECF , 200 mg calcium is
excreted through urine daily to match
with the intestinal absorption
Renal excretion of calcium & bony
calcium turnover is regulated by PTH
& vitamin D

36. Regulation of calcium balance

37. Regulation of calcium balance
Three hormones are responsible:
I. Calcitriol (active form of vitamin D)
II. Parathyroid hormone (PTH)
III. Calcitonin (CT)
Three organs are involved:
I. Kidney
II. Intestine
III. Bone

40. Contd
Remember,
 Primary/ direct target organ for
calcitriol is intestine. It also facilitates
the actions of PTH on bone & kidney

41. Adjusted/corrected plasma total calcium
The projected plasma total calcium
concentration that would be found if
serum albumin concentration was
normal
It is done only in cases with abnormal
serum albumin concentration

43. Contd
The normal albumin level is defaulted to 4
mg/dl or 40 g/L if using SI Units
The empirically derived correction
factor 0.02 represents the calcium
binding capacity of albumin in terms
of mmol per gm of albumin
If adjusted calcium value is to be
expressed in mg/dl , the correction
factor will be 0.8

45. Contd
Adjusted plasma total calcium directly
stands for the body calcium status
Adjusted
calcium
Body calcium
status
High Hypercalcemia
Low Hypocalcemia
Normal Normocalcemia

46. Contd
The adjusted (corrected) plasma total
calcium concentration is normally:
8.4 – 10.2 mg/dl
Or
2.1 – 2.6 mmol/L

47. Contd
Conditions where adjusted plasma total
calcium fails to represent body calcium
status:
1. Gross paraproteinemia (M. myeloma)
2. Severe acid base disorder
3. Massive citrated blood transfusion etc
[Ionic calcium measurement is done
here to evaluate body calcium status]

48. Abnormalities of calcium
homeostasis
2 types of abnormalities:
1. Hypercalcemia
2. Hypocalcemia

49. 1. Hypercalcemia
Adjusted plasma total calcium
concentration is >10.2 mg/dl or 2.6
mmol/L

50. Contd
Causes:
 Hyperparathyroidism : primary
(mainly), secondary, tertiary
 Malignancies
 Vitamin D intoxication
 Granulomatous diseases: TB,
sarcoidosis
 Thyrotoxicosis
 Chronic immobilization etc

51. Contd
Consequences/effects/complications:
Soft tissue calcification
Cardiac arrhythmia /cardiac arrest
Gastrointestinal complication: PUD,
acute pancreatitis etc
Neuropsychiatric complications:
Psychosis, neurosis, lethargy etc

52. Contd
Hypercalcemic nephropathy:
 Renal stone formation
 Nephrocalcinosis & impaired tubular
function
 Loss of concentrating power of kidney
with ADH resistance
 Polyuria/polydypsia
 Salt & water loss with hypovolemia,
dehydration & coma

53. 2. Hypocalcemia
Adjusted plasma total calcium
concentration is <8.4 mg% or 2.1
mmol/L

54. Contd
Causes:
 Hypoparathyroidism/
Pseudohypoparathyroidism (Tissue
resistance to PTH)
 Vitamin D deficiency/ vitamin D
resistance
 CRF
 Alkalosis
 Acute pancreatitis
 Excess bone mineralization (hungry

55. Contd
Consequences/effects/complications:
Cardiac : Irritability, arrhythmia,
bradycardia, hypotension
Neuromuscular : Tetany, seizure,
brochospasm, hyperexcitability, muscle
cramps etc
Psychiatric disturbances

56. Tetany in alkalosis
Tetany is a clinical manifestation of
NM hyperexcitability following
hypocalcemia.
S/S:
 Carpopedal spasm: Carpal spasm with
extension of interphalangeal joints &
adduction and flexion of the
metacarpophalangeal joints along with the
pedal spasm
 Laryngeal stridor
 Seizures etc

57. Contd
How tetany occurs in alkalosis? :
 In alkalemia, plasma proteins along
with other body buffers participates in
buffering activity
 Acid protein (HPr) component of
protein buffer release proton (H+
) to
buffer the added base/alkali and it is
converted to negatively charged anionic
basic protein (Pr-
)

58. Contd
 This anionic basic protein (Pr-
)
combines with positive charged ionized
calcium (Ca++
) of plasma
 As a result, plasma ionic (free) calcium
concentration decreases
 This hypocalcemia leads to NM
hyperexcitability & tetany