Calcium,
Phosphorus
,
Magnesium
and
Related
Disorders
(By Basil OM Saleh)
Objective
: 1.
Calcium & Phosphorus
homeostasis,
Hypercalcaemia
, and
Hypocalcaemia.
2.
Magnesium homeostasis ,
Hypo- and Hyper-
Magnesiemia.
References
: 1.
Clinical chemistry & Metabolic Medicine 2006
2.
Tietz Text book of Clinical Chemistry &Molecular Diagnostics
Calcium
is the most abundant mineral in
the human body; 1 Kg in a 70 Kg adult human.
Approximately 99 % of it is found in the bone
in
combination
with
phosphate
(as
hydroxyapatite).
Phosphate
is also one of abundant
mineral; approximately 600 mg (0.60 Kg)
present in 70 Kg adult human mainly 85 % is
in
the
bone.
The small fraction (~1 %) of body’s calcium is
found in the extra-osseous compartment that
is very important for normal physiology of
human body because of its effect on
neuromuscular
excitability
and
cardiac
muscle
physiology.
In blood, calcium is found in three forms:
1. biologically and functionally active
fraction; the ionized or Free calcium Ca
++
(50-65 %),
2. Calcium-protein bound-mainly
albumin (30-45 %),
3. Calcium Complexed
with anions like citrate, oxalate,.., (5-10 %).
The measured serum or plasma Total Ca is
the summation of these three forms, but the
physiologically active one is the Free Ca.
Terms:
Free Ca (Ca
++
),
Hypocalcaemia
(abnormal
low
circulated
Ca
++
),
Hypercalcaemia (abnormal high circulated
Ca
++
),
active vitamin D (Dihydroxy
cholecalciferol [Dihydroxy D3 (DOHD3)].
The intracellular calcium-binding protein is
Calmodulin.
This protein is very important to
regulate the intracellular calcium and its
release from the sarcoplasmic reticulum
(Muscle’ s mitochondria) into the sarcoplasm
(cytoplasm of muscle) and subsequent
muscle
contraction
and relaxation.
Important
Notes
• Plasma albumin concentration: Change in
serum or plasma protein (in particular
albumin) leads to parallel change in serum
calcium-protein bound fraction and so total
calcium concentration, but the free calcium
(the ionized Ca
++
) concentration remains
unchanged.
Therefore, measurement of serum Free
calcium Ca
++
is the correct choice, if
technically difficult, measurement of
both
Total Calcium and albumin (or total protein) is
preferred rather than the total Ca alone to
correct
for
protein
concentration
abnormalities.
•Changes in Hydrogen ion concentration [H+]
is accompanied by parallel changes in Free
calcium concentration, but the total calcium
remains unchanged.
In alkalosis, [H
+
] is
decreased , the Ca
++
is decreased and
Tetany
may occur even the measured total
Ca level is normal.
In case of acidosis the free Ca
++
is
increased due to increasing of [H+] ions
and also because of buffering of the
bone by acid media (increase Ca
solubility) and so increasing release of
Ca from the bones into the ECF.
Homeostasis
of
Blood
Calcium:
Control of Blood (plasma or serum) Ca is
maintained in the presence of several
factors
and
organs;
These
factors
are:
-Parathyroid
Hormone
PTH
-Active Vitamin D3 [1,25 dihydroxy
cholecalciferol (or dihydroxy Vitamin D3,
DOHVD3)]
Normal Functioning of Organs, include:
1. Intestine 2. Parathyroid Gland 3. Kidneys.
First,
about
Factors:
DOHVD3.
There are two types of vitamin D; D2
(ergocalciferol-plant source and D3-animal
source. In our body, the animal Vitamin D (D3)
is the important source and it is synthesized
from cholesterol in skin under UV effect of
the
sun
light.
However,
when
the
requirements of vitamin D is high, as during
growth & pregnancy, and when the animal
source is low because of low sunlight
exposure as in elderly and chronically sick
subjects who are confined indoor and in
infants, the plant dietary sources are
important.
The synthesized vitamin in skin is
cholecalciferol (D3) which is biologically
inactive. This D3 is transported by blood to
the liver where it is converted by hepatic 25-
hydroxylase enzyme to 25 OH-cholecalciferol
(25OHD3) which still inactive
till it is
transported to the Kidneys (proximal renal
tubular cells) where it is activated to active
vitamin D3 (DOHD3 or DOHcholecalciferol) by
renal enzyme 1-alpha-hydroxylase.
This latter
enzyme is stimulated by hypophosphataemia
and high plasma PTH levels , while it is
inhibited
by
hyperphosphataemia
&
Hypercalcaemia.
So, kidney is endocrine
organ synthesizing and secreting active D3
(considered as hormone
), impairment of this
hydroxylation (1-alpha hydroxylation) leads to
hypocalcaemia as in chronic renal failure
.
The predominant form of D3 in circulation and
which is usually measured in cases of vitamin
D3 deficiencies is 25OHD3, but the active
form that is required for Ca homeostasis is
DOHD3 which its measurement is indicated in
cases of vitamin D3 metabolism defect or
impairment (kidney failure).
The actions of
active D3 (DOHD3) in Ca homeostasis
involved:
1. It is essential for intestinal
absorption of dietary Ca
++
and PO4
---
. 2. It
acts synergistically in combination with PTH
to release of Ca
++
and PO4
---
from bone
(bone resorption)
in response to decreased
circulated Ca
++
(hypocalcaemia).
PTH.
It is a single chain poly peptide
(protein) hormone with 84 amino acids and
the first N-terminal 34-amino acids the
biologically active peptide sequence. It is
secreted from parathyroid gland in response
to hypocalcaemia.
The normal actions of this
hormone in maintaining of normal blood Ca
levels are
1. indirect intestinal absorption
of Ca and inorganic phosphate; this is
achieved by PTH stimulation of renal
1-alpha-hydroxylase enzyme and the
consequent formation of active D3
(DOHD3).
2. increased the Bone resorption of
Ca
++
and PO4
---
by stimulation of
osteoclasts activities with resultant
increased blood concentrations of these
two elements.
3. PTH increases the
renal reabsorption of Ca
++
and renal
excretion of PO4
---
(phosphaturia), this
step is important in determining
the NET
action of PTH as (this latter action step-
3 overcome the sum of the previous
above actions 1 & 2).
SO, the net of PTH
action is: increases the circulated levels of
Ca and decreases that of PO4--.
Control of PTH secretion is depend on the
blood Ca++ concentration.
A fall in blood Ca
++
increases the secretion
(and so the blood) PTH levels till the correction
of Ca
++
blood levels, then
in the presence
normal physiology,
the PTH secretion (and
blood levels) returns to normal. PTH secretion
is also enhanced by
hypomagnesaemia
.
The combination of PTH and DOHD3 actions is
revealed when there is hypocalcaemia. In this
case, a fall in plasma Ca
++
level stimulates
PTH synthesis and secretion. The PTH
enhances 1-alpha-hydroxylase enzyme activity
and therefore increases the synthesis of active
D3
(DOHD3)
by
kidney.
These mechanisms act till the correction of
plasma Free Ca, hence both PTH and DOHD3
secretion
is
suppressed.
So, PTH & DOHD3 act synergistically on the
osteoclasts of bone, releasing Ca
++
into the
blood, DOHD3 also increases Ca
++
intestinal
absorption.
Human body also contains what is known the
Parathyroid related protein
PTHrP.
This
protein is structurally similar to PTH
(contains the active N-terminal 34 amino
acids sequence) and therefore activating the
PTH receptors mimicking the hormone action
in respect to Ca
++
metabolism. It is widely
distributed throughout the body but it is
repressed (inhibited).
In certain tumors as that of bronchus &
head tumors is derepressed (activated)
and may leads to abnormal condition of
Hypercalcaemia.
Another, but less important factor is
Calcitonin
hormone that is secreted from
parafollicular cells of Thyroid gland
(Thyroid medulla). This hormone has an
opposite action to blood PTH and so
decreasing the bone release of Ca
(reduce bone resorption of ca) and may
be used in
treatment of Hypercalcaemia.