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‫الدكتور الصيدالني‬
‫احمد يحيى دالل باشي‬
‫أستاذ في الكيمياء الحياتية الطبية‬
‫رئيس فرع الكيمياء الحياتية‬
‫كلية الطب‪/‬جامعة الموصل‬
‫مدير وحدة التعليم الطبي في زاخو‬
Disorders of Calcium
Calcium is the most abundant mineral in the body , there
being about 25 mol (1 Kg) calcium in a 70 kg man
compared with about 80g sodium, 120 g potassium
and 24 g magnesium .
In adults calcium intake and output are normally in 
balance. In infancy and childhood, there is normally a
positive balance with net retention of calcium , especially
at times of active skeletal growth. In older age, and in
some diseases calcium output may exceed input and a
state of negative balance then exist.
The normal dietary intake of calcium is about 25 
mmol/day (1 g/day); the minimum daily requirement in
adult is about o.5 g. Significant amounts of calcium (over
3 mmol/day) are normally contained in gastrointestinal
secretions. Absorption of calcium occur from the small
intestine and is considerably influenced by hormonal
action .
Calcium excreted in feces is derived partly from the diet
and partly from intestinal secretions . The efficiency of
calcium absorption tends to decrease with age and
increased dietary intake may be needed in the elderly .
About 99% of the body's calcium is present in the bones.
Calcium salts in bone have a mechanical role, but are not
metabolically inert, there being a constant state of turnove
in the skeleton associated with deposition of calcium in
site of bone formation and release at site of bone
resorption. Calcium in bone acts as a reservoir which
helps to stabilize the [Ca++] in the extra cellular fluids
(ECF).
.
Functions:




Important functions related to the ECF [Ca++] are the
effects of Ca++ on bone structure(prevent osteoporosis),
neuromuscular activity, membrane permeability, blood
clotting and the activity of many enzymes. Calcium ions
are also very important inside cells where calcium acts as
a second messenger.
Second messengers are intracellular molecules do certain physiological changes such as proliferation, migration and so on.
Examples of second messenger molecules include cyclic AMP , calcium...etc.. The cell releases second messenger molecules in
response to exposure to extracellular signaling molecules (first messengers).
First messengers are extracellular factors, often hormones or neurotransmitters that contain peptides, which are
biochemically hydrophilic molecules, these first messengers may not physically cross the phospholipid bilayer to initiate
changes within the cell directly.
Types of Calcium:
Calcium: Total calcium (ionized Ca++, protein-bound, &
complexes components)
Ca++: Only calcium ions are being considered. 
Plasma [calcium]: Total concentration of calcium 
Plasma [Ca++]: Concentration of calcium ions 

Calcium components in plasma
Components
% of total plasma
calcium
Ionized Calcium (Ca++)
50-65
Bound to protein (mainly albumin)
30-45
Complexes with organic ions (e.g. citrate)
5-10
Hormonal control of plasma calcium
Calcium present in plasma in 3 forms in equilibrium with one
another which can be changed by changes in plasma
[protein] and [H+] and by chelating agent such as infusion of
EDTA. The most important is that of plasma [Ca++].
plasma [Ca++] which is the same as interstitial fluid [Ca++] is
closely regulated by 2 hormones :
parathyroid hormone (PTH) and
1:25 dihydroxycholecalceferol (1:25-DHCC),
both act to increase plasma [Ca++] and hence [calcium].
The calcium- lowering hormones, calcitonin and katacalcin,
is less well established.
Growth hormone , glucocorticoids (e.g. cortisol), estrogens,
testosterone and the thyroid hormones (T3 & T4) also exert a
minor influence.
The body's responses to a fall in plasma [Ca++], in terms of
changes in PTH and 1:25-DHCC production
Parathyroid hormone (PTH):

Pure PTH contains 84 amino acids. The secretion of 
PTH is controlled by the ECF [Ca++].
The direct effects of PTH on bone lead to release of 
Ca++ from bone crystals.
In addition PTH may have effect on the kidney, by 
stimulating the production of 1:25-DHCC, and by its
effects on the proximal tubule, reducing clearance of
calcium.
It will apparent that all the major effects of PTH act so 
as to increase ECF [Ca++] and thus ECF [calcium].
However, in the presence of hypercalcaemia due to the
effect of excess PTH, there may be increased renal
excretion of calcium despite the fact that PTH reduces
its renal clearance ; this is because hypercalcaemia
increases the amount of calcium filtered at the
glomerulus, and this effect dominates.

1:25 dihydroxy colecalciferol (1:25-DHCC):
In the body, Vitamin D2 and D3 undergo 2 hydroxylation steps
before attaining full physiological activity. The first step in the
liver as 25-Hydroxylation, with the production of 25hydroxycholecalciferol (25-HCC) or calcidol. The main form of
vitamin D circulating in the plasma is 25-HCC bound to a
specific transport protein and carried to the kidney for
metabolism. further
The second step is 1α-Hydroxylation of 25-HCC in the kidney
with production of 1:25-DHCC or calcitriol, (the most active
derivative of vitamin D).
Calcitonine and katacalcin:

Calcitonine (CT) contains 32 amino acids. CT has plasma 
calcium lowering action, and katacalcin (KC) contains 21 amino
acids, both are secreted by the the thyroid. Their importance in
the physiological regulation of plasma [Ca++] is uncertain but is
at most minor by comparison with PTH and 1:25-DHCC.
Plasma calcium measurements:

Plasma [Calcium] is normally kept within narrow limits and plasma 
[Ca++] is very closely controlled. Reference values for plasma
[calcium] are approximately 2.12-2.62 mmol/L (8.5-10.5 mg/100 ml).
For plasma [Ca++ ] they are 1.1-1.3mmol/L (4.4-5.2 mg/100 ml).
The equilibrium between the three forms of calcium in plasma can be
distributed by physiological means, by treatment and by pathological
causes.
The effects of changes in plasma [albumin] and [H+] will be 
described first, since they must be taken into account when
interpreting plasma [calcium] results.

Plasma albumin:

Changes in plasma [albumin] affect the equilibrium 
between the protein-bound calcium and ionized calcium
fraction. In general changes in plasma [albumin] causes
parallel changes in plasma [calcium] while PTH maintains
plasma [Ca++] constant. In practice, the commonest
examples are:
In patients with marked hypoproteinaemia (e.g. nephrotic
syndrome, or liver disease) there is often a low plasma
[calcium] due to the fall in plasma [albumin].
Excessive venous stasis during blood collection, or the 
collection of blood from patients who have been standing
or moving about rather than recumbent, may cause raised
plasma [albumin] (by about 10-15%) , which intern
causes an increase in plasma [calcium].



Using tourniquet or standing of the patient cause fluids (water) shifts, thus alter the
concentrations of cells and large molecules including albumin and total calcium (as
part of it is protein bound) in the vascular compartment (water will ooze from the
vessels).
ionized calcium concentrations decreased as the pH in the specimen increased,
indicating the stronger binding of these ions with proteins in the more alkaline
environment.
To make use of correction factor: 
For each g/L that the plasma [albumin] is above 40 
g/L , 0.02 mmol/L should be subtracted from the
value for plasma [calcium] observed in the same
specimen.
For each g/L that the plasma [albumin] is below 40
g/L , 0.02 mmol/L should be added from the value for
plasma [calcium] observed in the same specimen.

Hypercalcaemia:
(Increased calcium level in the blood)
The two commonest pathological causes of
hypercalcaemia are malignant disease and primary
hyperparathyroidism.
Malignant disease, is the commonest cause.
Hyperparathyroidism, and vitamin D therapy are the next
most common causes in this group of patients.
Hypercalcaemia often directly damages the kidneys.
Acute alterations in plasma [calcium] may cause tubular
malfunction. The increased clearance of calcium by the
kidneys predisposes to renal stone formation.
Primary hyperparathyroidism:

This is an important disorder, usually caused by a
parathyroid adenoma ‫ ورم حميد‬and less often by multiple
adenomas, diffuse hyperplasia (an increase in number of
cells in a tissue or organ), or carcinoma.
 Classically, patients used to present with renal calculi or
with metabolic bone disease. The majority of patients
with primary hyperparathyroidism are asymptomatic
when the condition is first diagnosed.
The diagnosis of primary hyperparathyroidism depends to 
a large extent on finding hypercalcaemia accompanied by
a high or normal plasma [PTH] . Tests to be performed as
part of the initial investigation of suspected primary
hyperparathyroidism , are listed as follows:

Chemical tests and the diagnosis of primary
hyperparathyroidism
__________________________________________________
Simple investigation on plasma
[calcium]
If increased, support the diagnosis
[Albumin]
Needed as a chick on plasma [calcium]
[phosphate]
If decreased supports the diagnosis.
fasting Alkaline
Phosphatase
activity
If increased, support the diagnosis.
[Urea] or [Creatinine] Screening tests of renal function advisable in all
patients with suspected disturbances of calcium
metabolism.
Management of primary hyperparathyroidism:
Asymptomatic hyperparathyroidism is common. Surgical
operation is usually delayed if their plasma [calcium] is less
than 3 mmol/L(about 12 mg%). However, the development of
symptoms may be gradually and such patients, must be
followed at regular intervals, with further measurements of
plasma [calcium]. In most patients, it is probably advisable to
proceed to parathyroidectomy earlier, rather than later.
After parathyroidectomy , plasma [calcium] falls rapidly and
should therefore, be monitored several times during the first
post-operative day and at least daily for the next few days. If
the plasma [calcium] falls below normal, calcium gluconate
should be given and treatment with 1:25-DHCC started.
.•
Hypocalcaemia:
The commonest cause of a low plasma [calcium] is
hypoproteinaemia. Plasma [albumin] should always be
measured in these patients, to exclude this explanation. The
followings are causes of Hypocalcemia
1. Hypoprotenemia
2. Renal diseases
3. Inadequate intake of Ca &/or Vit D, (rickets and
osteomalacia).
4. Hypoparathyroidism
Chemical investigations in patients with
hypocalcemia
______________________________________________________-
Fasting
Serum
Plasma
Plasma
PTH
Alk.
Phosphate
Phosph
____________________________________________________
Chronic renal failure
↑or N
↑
↑or N
↓or N
N or ↑
Hypoparathyroidism
↑
↓
N
Renal tubular defects
↓
N
↑or N
Deficiency of Ca&Vit D
↑
Tetany:

Hypocalcaemia may be asymptomatic or associated with 
tetany, that symptom which classically suggests the
presence of a low plasma [Ca++]. It is appropriate to
distinguish between :
Low plasma [calcium] unaccompanied by tetany and 
with normal
plasma [Ca++] &
Low plasma [calcium] associated with tetany and a 
low plasma [Ca++].
Tetany occurs only if plasma [Ca++] is low , regardless of 
whether or not plasma [calcium] is low. It may also occur
whenever there is a rapid fall in plasma [H+]. Alkalosis
may develop rapidly , for instance in patients with
hysterical over breathing or in patients being given an I.V.
infusion of NaHCO3; the acute reduction in plasma [Ca++]
as plasma [H+] falls accounts for the tetany in these
patients.
Respiratory alkalosis occurs as the partial pressure of carbon dioxide decreases results in reduction of

hydrogen (H+) ion in the intracellular fluid. Alkalosis promotes the binding of calcium to albumin and can
reduce the fraction of ionized calcium in the blood.
Secondary hyperparathyroidism:

This term is used to describe conditions in which 
increased amounts of PTH are secreted in response to
some non-parathyroid disorder that has caused
hypocalcaemia and especially a reduced plasma
[Ca++] . Example include chronic renal failure and
long-standing intestinal malabsorptive disease. There
is usually hyperplasia of all four parathyroid glands , in
response to continuing hypocalcaemia or tendency to
hypocalcaemia.
Hypoparathyroidism: 
The reason may be a history of an operation on the 
neck or previous treatment with radio active iodine for
thyrotoxicosis. Hypoparathyroidism of acute onset
nearly always occurs post-operatively.
The diagnosis of hypoparathyroidism is supported by 
the following findings:
Plasma [calcium]: Reduced, some times markedly, to 
values as low as 1. 5 mmol/L (6 mg/100ml).
Plasma [Ca++]: is also much reduced. 
Plasma [phosphate]: Usually increased, some times 
markedly.
Serum [PTH]: This is reduced, being below 10 
ng/L(NR=10-65ng/L).
Metabolic bone disease:
Metabolic bone diseases are systemic bone disorders of
various etiologies including dietary(nutritional), hormonal
and toxic.
The best known metabolic bone diseases are rickets,
osteomalacia and osteoporesis..
The fundumental problem in metabolic bone diseases is
an imbalance between bone formation and resorption.
rickets ‫الكساح‬
‫ لين العظام‬osteomalacia
osteoporesis ‫ضمور او هشاشة العظام‬
Rickets and osteomalacia:
Rickets occur in growing children . There is failure of
deposition of calcium salts in new bone . As a result,
there is an increased amount of osteoid or uncalcified
matrix.
Osteomalacia is similar to rickets and is a term that
applies to disease in adult.
The etiology of rickets and Osteomalacia is a
multifactorial but generally involve defiencies of vitamin
D or phosphorous.
The commoner of these, is deficiency or impaired action
of vitamin D which as 1:25-DHCC, promotes calcium
absorption from the intestine and has a direct action on
bone. The less common mechanism is excessive loss
of phosphate in the urine usually due to an inherited or
acquired renal tubular disorder.
Osteoporosis:
The basic problem in osteoporesis is a negative balance
between formation and resorption of bone leading to
reduction of bone mass. A simple definition of osteoporesis is
“there is little bone, but what bone there is, is normal”
Osteoporesis is also referred to as bone atrophy.
In osteoporesis there is loss of matrix and reduction in bone
mass . However, deposition of calcium salts occur normally.
This is very common disorder, which is not usually diagnosed
with certainty until there is a marked loss in bone density,
revealed by radiographical investigation.
Results of routine chemical investigation are as a rule all
normal. The diagnosis depend on finding skeletal rarefaction
in a patient who does not have hyperparathyroidism,
osteomalacia, carcinoma , etc. and in whom plasma
[calcium], [phosphorous], alkaline phosphate activity etc. are
all normal.
Overview of Phosphate Balance