1

Chemical Pathology
Calcium Metabolism Disorders
Lecturer: Dr. D. McGrowder
1.1 Calcium balance

Calcium is the most important mineral in the human body. The average adult
body contains approximately 25,000 mmol (1 kg), of which 99% is bound in the
skeleton. The total calcium content of the extracellular fluid (ECF) is only 22.5
mmol, of which about 9 mmol is in the plasma.

Most of the calcium in the bone is stable but approximately 500 mmol/24 h
moves between bone and the ECF to support calcium homeostasis.
Approximately 7.5 mmol/24 h moves between the stable pool and the ECF in the
course of bone remodeling.

In the kidneys, ionized calcium is filtered by the glomeruli (240 mmol/24 h).
Most of this is reabsorbed in the tubules and normal renal excretion is 2.75
7.5 mmol/24 h. Obligatory renal calcium excretion is approximately 2.5 mmol/24
h. Because of faecal loss, the minimum dietary requirement is about 12.5
mmol/L (though it is higher during growth, pregnancy and lactation).

Gastrointestinal secretions contain calcium, some of which is reabsorbed together

with dietary calcium. Since calcium in the ECF is effectively exchanged through
the kidneys, gut and bone about 33 times every 24 hours, a small change in any of
these fluxes can have a profound effect on ECF, and hence plasma calcium
concentration.

Calcium has many important functions in the body. Its effect on neuromuscular
activity is of particular importance in the symptomatology of hypocalcaemia and
hypercalcaemia.

1.2 Plasma Calcium

(i)
(ii)
(iii)

In the plasma, calcium is present in three forms.

equilibrium. These are:

These three forms are in

Ionized (Ca2+) physiologically active (47%)

Protein-bound (approximately 80% to albumin) 46%
Complexed (citrates, phosphates etc) 7%

The biologically active fraction is Ca2+, affecting properties such as

neuromuscular excitability, enzyme activity and parathyroid hormone (PTH)
release from the parathyroid glands. The inactive fraction is non-convalently
bound to albumin, with the rest associated with globulins and lipoproteins.

The measurement of plasma calcium and albumin, inorganic phosphate and

alkaline phosphatase (ALP), sometimes PTH and vitamin D metabolites underlie
the diagnosis of most disorders of calcium metabolism.

Plasma calcium (reference range 2.25 2.75 mmol/L) is measured routinely by

most laboratories even though the physiologically important fraction is [Ca2+].

Because albumin is the principal binding protein for calcium, a fall in plasma
[albumin] will lead to a fall in bound calcium and a decrease in total [calcium]
and vice versa. The unbound plasma [Ca2+], the physiologically important
fraction, will be maintained at normal levels by PTH. Hence, a low or high
plasma [calcium] should always alert the clinician to measure plasma [albumin] to
avoid misdiagnosis of hypocalcaemia or hypercalcaemia respectively. The
plasma [calcium] in mmol/L can be approximately corrected to take account of
an abnormal albumin (in g/L) using the formula such:

Corrected [calcium]
for [Alb] < 38 g/L

= measured [calcium] + 0.02 x (38 [albumin]) mmol/L,

Corrected [calcium]
for [Alb] > 52 g/L

= measured [calcium] - 0.02 x ([albumin] - 52) mmol/L,

* The distribution of calcium amongst the fractions is affected by plasma pH:

pH

Ca2+

In an acute acidosis, the protonation of albumin reduces its ability to bind

calcium leading to an increase in ionized [calcium].

In alkalosis, hydrogen ions dissociate from albumin, and calcium binding

increases. There is also an increase in calcium complex formation. As a result,
the concentration of ionized calcium falls, and this may be sufficient to produce
clinical symptoms and signs of hypocalcaemia although total plasma calcium
concentration is increased.

The most frequently used methods of determining plasma calcium concentration

measure the total calcium, although ionized calcium can be measured using ionselective electrode.

2.0 Calcium Regulating hormones

Calcium concentration in the ECF is normally maintained within normal limits by

a control system involving two hormones: parathyroid hormone (PTH) and
calcitriol (1:25-dihydroxycholecalciferol). These hormones also control the
inorganic phosphate concentration of the ECF. Calcitonin probably has only a
minor role in calcium homoestasis.

2.1 Parathyroid hormone

This hormone is a polypeptide, comprising 84 amino acids (molecular weight,

MW 9425 Da). It is synthesized as a large precursor, pre-pro-PTH (115 amino
acids) in the parathyroid cells. Prior to secretion, two amino acid sequences are
lost. The removal of a 25 amino acid chain produces pro-PTH (90 amino acids), a
further six amino acids being lost to form PTH itself.

The biological activity resides in the N-terminal 1-34 amino acid sequence of
the hormone, which is needed for PTH receptor binding in target cells. Intact
PTH has a half-life in the blood of about 3 4 minutes. It is rapidly metabolized
in the liver, kidney and bone. Cleavage occurs mainly at residues 33 or 34,
yielding N- and C-terminal fragments. The N-terminal fragment has a half-life
similar to that of the intact hormone. The C-terminal a half-life of 2 3 hours, is
also directly by the parathyroids and do not have biological activity.

Currently used PTH immunoassays measure only intact PTH, and provide a
reliable measure of parathyroid hormone status.

Parathyroid hormone is the principal acute regulator of plasma [Ca 2+]. Plasma
PTH levels exhibit a diurnal rhythm, being highest in the early hours of the
morning and lowest at about 9 a.m.

The active hormone is secreted in response to a fall in plasma [Ca 2+], and its
actions are directed to increase plasma [Ca2+].

An increase in plasma [Ca2+] suppresses PTH secretion.

2.1.1 Actions of parathyroid hormone

On Bone: Bone remodeling is a complex process involving PTH, 1,25dihydroxycholecalciferol1, (1:25-DHCC) and other factors.

PTH has a major initiating role, stimulating an increase in the number of

osteoclasts, causing increased bone resorption and a rise in plasma Ca 2+ and
phosphate.
PTH also slowly stimulates osteoblast activity.

Biochemical measures of both increased osteoblast activity (e.g. increased

plasma alkaline phosphatase activity) and increased osteoclast activity (e.g.
raised urinary hydroxyproline and deoxypyridinoline excretion) may be evident.

In addition, PTH causes rapid release of calcium to the ECF mediated by

osteocytes.

On the kidney:
Intact PTH binds to specific receptors at various sites in the renal tubule,
activation of which has the net effect of lowering glomerular filtration rate
(GFR), increasing the reabsorption of calcium and magnesium, and decreasing
the reabsorption of phosphate and bicarbonate.

Renal loss of bicarbonate may lead to mild metabolic acidosis. PTH action after
receptor binding is via stimulation of the cyclic adenosine monophosphate
(cAMP) system, so that urinary excretion of this metabolite increases with
increased PTH activity.

An important renal action of PTH is to stimulate the conversion of 25hydroxycholecalciferol (25-HCC or calcidiol) to 1:25-DHCC, thereby
indirectly increasing intestinal uptake of calcium.

Summary:
The overall effect of PTH on plasma is to raise the level of calcium by bone
resorption and renal retention, and lower that of phosphate by renal excretion.

Actions of PTH:

Target organ

Action

Bone

Rapid release of calcium

osteoclastic resorption

Kidney

calcium reabsorption
phosphate reabsorption
1-hydroxylation of
25-hydroxycholecalciferol

Effect
plasma [Ca2+]
plasma [Ca2+]
plasma [PO42-]
calcium and phosphate
absorption from gut

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bicarbonate reabsorption

metabolic acidosis

2.2 Calcitriol

Vitamin D is a compound that requires two metabolic conversions before its

biological activity as a hormone can be expressed. Dietary sources rich in vitamin
D3 (cholecalciferol) include cod liver oil, whilst the D2 compound (ergocalciferol)
is found only in plants and can undergo the same metabolic steps as D3.

Most vitamin D3 is synthesized by the action of ultraviolet light on 7hydrocholesterol precursor in the skin. Once formed, cholecalciferol is
transported by vitamin D-binding protein to the liver where one enzyme catalyse a
specific hydroxylation to form 25-hydroxycholecalciferol (25-HCC, calcidiol), a
biologically inactive metabolite with a plasma half-life of 15 25 days.

Calcidiol undergoes a further 1 -hydroxylation in the kidney to form the active

metabolite 1:25-DHCC (calcitriol). The 1-hydroxylase enzyme for this
conversion is located in the proximal convoluted tubules of the nephrons. The
enzyme is also present in macrophages.

During pregnancy the placenta also produces 1:25-DHCC.

The activity of 1-hydroxylase is tightly controlled, being directly stimulated

by PTH and by hypophosphataemia, and inhibited by 1:25-DHCC and by
hyperphosphataemia.

Plasma Ca2+ indirectly regulates 1:25-DHCC production via PTH. When 1:25DHCC production is adequate, 25-HCC is also hydroxylated to inactive 24:25DHCC, the reaction being stimulated by 1:25-DHCC. The enzyme involved is
24-hydroxylase.

2.2.1 Actions of calcitriol (1:25-DHCC)

Following renal production, 1:25-DHCC is transported in plasma by the vitamin

D-binding protein. It interacts with a specific intracellular receptor that is present
in most tissues, leading to both rapid metabolic effects and longer term regulation
of the expression of a wide range of genes.

Intestine:
1:25-DHCC stimulates the intestinal mucosal synthesis of calbindin-D, a
calcium-binding protein that promotes the absorption of calcium and
phosphate from the gut lumen to the plasma compartment.

There is some evidence that 1:25-DHCC also directly stimulates a very rapid
uptake of calcium.

Bone:
1:25-DHCC plays a vital role in bone mineralization and resorption, but the
detailed mechanisms are uncertain.

Overall, 1:25-DHCC increases the availability of calcium and phosphate via

intestinal uptake, and promotes osteoblast activity.

The binding of 1:25-DHCC to osteoblasts increases the production of alkaline

phosphatase and a calcium-binding protein osteocalcin, the exact function of
which is uncertain.

Summary:
The overall effects of 1:25-DHCC are to raise plasma Ca2+ and phosphate by:
(1) intestinal absorption
(2) resorption from bone

Plasma 1:25-DHCC is raised in: primary hyperparathyroidism, sarcoidosis,

absorptive hypercalciuria.

It is reduced in; hypoparathyroidism, renal failure, liver disease, hypercalcaemia

of malignancy/immobilization, drugs (phenytoin, phenobatbital where there is
increased catabolism), isoniazid (decreased 25-hydroxylation), prolonged sunlight
deprivation +/- low dietary intake/malabsorption, vitamin D-dependent rickets
type I.

2.3 Calcitonin

32 residue polypeptide hormone released by the parafolicullar cells of the

thyroid gland in response to raised plasma [Ca2+].

Although calcitonin can decrease plasma [Ca2+] by reducing osteoclasts activity

and reducing renal reabsorption of calcium and phosphate, its actions are
transient, and chronic excess or deficiency is not associated with disordered
calcium of bone metabolism.

Bone:
Opposes resorption
hypophosphataemia.
Kidney:

by

inhibiting

osteoclast

action

and

promotes

Increases clearance of calcium and phosphate. The physiological significance of

calcitonin in normal calcium homeostasis is not known.
Subjects who have had a total thyroidectomy do not develop a clinical syndrome
that can be ascribed to calcitonin deficiency.
Plasma [calcitonin] is elevated during pregnancy and lactation.

2.4 Laboratory investigation of calcium metabolism

The most useful biochemical tests for the initial investigation of hyper- or
hypocalcaemia are:

Plasma: total/ionized calcium, albumin, creatinine, phosphate, alkaline phosphatase,

electrolytes.

Depending on the clinical problem and the outcome of the initial investigations,
the following tests are useful:

Plasma: PTH, gamma-glutamyltransferase, alkaline phosphatase isoenzymes.

Urine: 24-h calcium excretion, phosphate excretion, hydroxyproline excretion.

3.0 Disorders of calcium metabolism

The plasma phosphate concentration, interpreted with plasma urea concentration,

usually indicates whether either hyper- or hypocalcaemia is caused by an excess
of PTH or PTH-like activity (PTHRP) [non-parathyroid tissue] or some other
cause. Consequently the measurement of PTH is rarely necessary in order to
make an initial diagnosis.

3.1 Hypercalcaemia

Hypercalcaemia, as commonly defined by plasma total concentration greater

than 2.75 mmol/L.

In screening programs, subjects with mild hypercalcaemia, e.g. up to 2.85 mmol/L

are commonly encountered but on retesting many of these are found to be
normocalcaemic. This phenomenon, which reflects a combination of biological
variation, collection and methodical errors and should always be considered.
Thus variation of hypercalcaemia by evaluating further blood samples, preferably
three separate non-stasis specimens, is necessary.

The causes of hypercalcaemia can be classified as follows:

Increased intake/absorption

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Vitamin D excess
medication
sarcoidosis
Calcium
milk alkali syndrome
renal dialysis
IV therapy imbalance
Increased plasma albumin
dehydration
venous stasis during vepuncture
Increased bone resorption
malignancy
hyperparathyroidism
renal failure
thyrotoxicosis
immobilization
multiple endocrine neoplasia (MEN)
Increased renal reabsorption
thiazide diuretics
familial hypocalciuric hypercalcaemia (FHH)
Addisons disease

Screening studies indicate hypercalcaemia has a prevalence of 1- 4% in general

adult populations, primary hyperparathyroidism being the commonest (~ 70%)
in non-symptomatic individuals.

In symptomatic patients (e.g. hospitalized) malignancy is the most frequent causes of

hypercalcaemia. Together malignancy and hyperparathyroidism account for about 90%
of the cases of hypercalcaemia. Confirming and diagnosing the cause of hypercalcaemia
can pose a clinical problem in cases of mild hypercalcaemia or occult malignancy.

The clinical features of hypercalcaemia are:

Neurological symptoms (inability to concentrate, depression, confusion)

Generalized muscle weakness
Anorexia, nausea, vomiting, constipation
Polyuria with polydipsia
Nephrocalcinosis,
ECG changes (shortened Q-T interval), with bradycardia
Pancreatitis, peptic ulcer

3.1.1 Primary Hyperparathyroidism

The prevalence of this condition is of the order of one case per thousand persons.
It can occur at any age and affects both men and women but most commonly in
post- menopausal women.

There is the autonomous production of PTH which occurs from a single,

parathyroid adenoma. Diffuse hyperplasia (all four glands) or, rarely,
parathyroid carcinoma may be responsible. Adenoma may be multiple and the
conditions may be familial. It may occur as part of one of the syndromes of
multiple endocrine neoplasia (MEN).

The excess PTH leads to raised [Ca2+], with the potential for clinical problems.

Both plasma [calcium] and [albumin] should be measured, and may be repeated
since hypercalaemia can be intermittent.

Plasma [phosphate] is sometimes low as a result of the phosphaturic effect of

PTH.

A mild metabolic acidosis may be present, since PTH increases urinary HCO 3losses. Some patients develop bony problems as a result of the high PTH,
especially if the problem becomes chronic.

Treatment:

The definitive treatment for hyperparathyroidism is surgery. Although patients

with mild (< 3.0 mmol/L) asymptomatic hypercalcaemia may stay healthy for
many years without an operation, they are at risk of developing osteoporosis and
renal impairment, and should be reassessed regularly.

Indications for parathyroidectomy include:

(i)
the presence of symptoms,
(ii)
a urine calcium excretion over 9 mmol/24 h,
(iii)
a cortical radial bone density over 2 SD below normal;
(iv)
reduce creatinine clearance (if no other causes are identified);
(v)
age under 50 years.

After parathyroidectomy, plasma [calcium] falls rapidly and should be measured

several times on the first postoperative day and at least daily for the next few
days.

Primary hyperparathyroidism may be one of the abnormalities of the so-called

MEN syndrome. MEN denotes a disease in which several endocrine organs
develop hyperplasia or tumours (malignant or benign). The tumours may or may

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not produce hormone, so the clinical presentation is diverse. Three types of
MEN syndrome have been described, all of them familial.
MEN 1

MEN IIa

MEN IIb

pancreas
adrenal medulla
adrenal medulla
parathyroid
parathyroid
neuromuscular tissue
pituitary
thyroid medulla
thyroid medulla
The involvement of the parathyroid glands means that hypercalcaemia is often detected in
patients with these diseases.

3.1.2 Secondary hyperparathyroidism

Secondary hyperparathyroidism refers to the excessive secretion of parathyroid

hormone (PTH) by the parathyroid glands in response to hypocalcemia (low
blood calcium levels) and associated hypertrophy of the glands.

Secondary hyperparathyroidism occurs to some degree in virtually all patients

with dialysis-dependent chronic renal failure. Vitamin D deficiency is common
and is underdiagnosed.

In renal failure, the stimuli for overproduction of PTH are multifactorial. Factors
include hypocalcemia, impaired 1,25-dihydroxyvitamin D production by the
diseased kidneys, and hyperphosphatemia.

The hyperphosphatemia and damaged renal parenchyma leads to a reduction of

renal production of 1,25-dihydroxycholecalciferol (1,25-DHCC). Decreased
intestinal absorption of vitamin D follows, which impairs mobilization of calcium
from the bones due to PTH resistance.

Hyperphosphatemia appears to be particularly important in the development of

parathyroid hyperplasia. These stimuli cause multi-gland hyperplasia, resulting in
increased PTH production.

Secondary hyperparathyroidism is characterized by pronounced parathyroid gland

hyperplasia resulting from end-organ resistance to parathyroid hormone (PTH).
The consequent hypersecretion of PTH depresses calcium levels.

The clinical manifestation includes bone and joint pain and limb deformities. The
radiologic features of secondary hyperparathyroidism in the skeleton are similar
to those of primary hyperparathyroidism.

3.1.3 Tertiary hyperparathyroidism

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Tertiary hyperparathyroidism is secondary to long-standing secondary

hyperparathyroidism. Tertiary disease is characterized by the development of
autonomous hypersecretion of PTH causing hypercalcemia.

Tertiary hyperparathyroidism is observed most commonly in patients with chronic

secondary hyperparathyroidism and often after renal transplantation.

The hypertrophied parathyroid glands fail to return to normal and continue to

oversecrete PTH, despite serum calcium levels that are within the reference range
or even elevated. In these cases, the hypertrophied glands become autonomic and
cause hypercalcemia, even after withdrawal of calcium and calcitriol therapy.

The clinical manifestations of tertiary hyperparathyroidism include persistent

hyperparathyroidism after renal transplantation or new hypercalcemia in the
setting of chronic secondary hyperparathyroidism.

3.1.4 Malignancy

Malignancy is the commonest cause of hypercalcaemia in hospitalized patients.

Patients with hypercalcaemia of malignancy can be generally divided into those
with metastatic bone disease, and those without evidence of bone involvement.

In the first group the tumour deposits produce osteolytic factors that cause bone
erosion around the deposits (local osteolytic hypercalcaemia, LOH). The tumour
cells also increase bone resorption directly. Carcinoma of the breast is an
example of a solid tumour that is usually associated with hypercalcaemia only
when bone metastases are detectable, so a raised plasma calcium may be an early
or late feature of the disease. The hypercalcaemia is due to local resorption of
bone by osteolytic factors released by the tumour deposits. Factors implicated
include: tumour necrosis factor, interleukin -1 and prostaglandins. A raised
alkaline (ALP) activity often observed in these patients indicates increased bone
turnover.

In the second group the primary tumour releases a hypercalcaemic factor that
acts systematically on the skeleton (humoral hypercalcaemia of malignancy,
HHM). Solid tumours (e.g. carcinoma of the lung, head and neck), in the absence
of bony metastases, may give rise to hypercalcaemia. An important factor in this
humoral hypercalcaemia of malignancy is PTH-related protein (PTHrP), a
peptide with marked sequence homology with PTH that also acts through the
PTH receptor.
True ectopic production of PTH appears to be rare.

Multiple myeloma is an example of a haematological malignancy in which

hypercalcaemia appears only with metastatic bone involvement (LOH). ALP
activity is usually normal in these cases, any elevation of activity being

12
suggestive of hepatic metastases. The very high plasma total calcium usually
observed in patients with multiple myeloma reflects increased binding of
calcium by paraprotein, whilst the ionized fraction is only slightly elevated.
Lymphomas may also cause hypercalcaemia.

3.1.5 Other causes of Hypercalcaemia

(1) Vitamin D excess:
Excess intake of vitamin D (prolonged intake of self-prescribed multivitamins)
itself is a rare cause of hypercalcaemia, but the 1-hydroxylated derivatives
(calcitriol, alfacalcidol) are extremely potent and may cause hypercalcaemia.
Plasma calcium should be monitored regularly in patients treated with these
agents.
(2) Sarcoidosis :
A rare disease of unknown aetiology, in which 10 20% of patients develop
hypercalcaemia, and many more have hypercalciuria.

Such patients have been shown to have elevated plasma levels of 1:25-DHCC
(increased intestinal absorption of calcium), suppressed PTH and raised
plasma phosphate.

Macrophages associated with sarcoid granuloma tissue are capable of unregulated

synthesis of 1:25-DHCC. The 1-hydroxylase enzyme present in macrophages
is stimulated by 25-HCC, and not inhibited by PTH, phosphate or 1:25-DHCC.

(3) Milk alkali syndrome:

The hypercalcaemia is associated with the ingestion of milk and antacids for the
control of dyspeptic syndromes.

The ingestion of alkali (NaHCO 3, MgCO3) is important in the pathogenesis of

hypercalcaemia as it is thought that it decreases renal excretion of calcium,
however the precise mechanism is unknown.

The use of calcium carbonate supplements as self-medication to prevent

postmenopausal osteoporosis has led to the reappearance of this syndrome.

(4) Drugs:
Thiazide diuretics - Mild hypercalcaemia is associated with thiazide treatment,
and generally resolves if the thiazide is withdrawn.

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The mechanism of hypercalcaemia involves reduced renal excretion, but the

precise cause is unknown, although it may involve thiazide-induced reduction in
the extracellular volume causing increased proximal tubule reabsorption of
calcium secondary to sodium.

Long-term lithium therapy can increased PTH secretion and is an occasional

cause of hypercalcaemia.

(5) Familial hypocalciuric (benign) hypercalcaemia (FHH):

This is a rare condition which is easily diagnosed
hyperparathyroidism.

as

primary

FHH is inherited as an autosomal dominant condition that is usually detected as

an asymptomatic mild hypercalcaemia (< 3.0 mmol/L) before the age of 10
years.

Biochemical features include an elevated plasma total and ionized calcium, an

inappropriately low calcium excretion relative to plasma calcium concentration
and normal alkaline phosphatase activity. Most patients also have a mild
hypermagnesaemia.

Intact PTH levels fall generally within the reference interval, which is
inappropriately high given the prevailing plasma calcium. The problem is
believed to arise because the high plasma [Ca2+] is sensed as normal with normal
plasma [PTH]. Measurement of urinary calcium excretion may be helpful.

(6) Immobilization:
Immobilization in bed for long periods causes loss of bone mass (~ 4%/month
initially), and hypercalcaemia in a proportion of patients in whom there is
relatively rapid bone turnover, e.g. children, teenagers, those with Pagets disease.

In most immobilized patient of any age there is likely to be increased urinary

excretion of calcium.

(7) Endocrine disorders:

Hypercalcaemia has been reported occasionally in
hypoadrenalism, phaeochromocytoma and thyrotoxicosis.

association

with

Mild hypercalcaemia (< 3.0 mmol/L) occurs in 20 25% of untreated thyrotoxic

patients, reflecting the direct action that thyroid hormone has on bone resorption.
There is increased osteoblast activity.

ALP activity can remain elevated for a significant period following a return to
euthyroidism, suggesting continued osteoblast activity as the bone mineralizes.

14

Osteoporosis can be a feature of prolonged over-replacement of thyroid hormone

in hypothyroid patients. Plasma intact PTH levels would be low or suppressed in
thyrotoxic hypercalcaemia.

3.2 Hypocalcaemia

A low plasma total calcium concentration is a common finding (5 8% of

hospitalized patients), but the majority are due to low plasma albumin levels and
the plasma ionized calcium concentrations [Ca2+] are normal (artefactual
hypocalcaemia).

True hypocalcaemia defined as low plasma [Ca2+] is less common.

Mild hypocalcaemia [Ca] > 1.80 mmol/L is often seen in clinical practice, e.g. in
renal failure, acute pancreatitis, but moderate to severe hypocalaemia ([Ca] < 1.60
mmol/L) is uncommon.

The clinical features of hypocalcaemia are:

Enhanced neuromuscular irritability; tetany

Numbness, tingling (fingers, toes)
Muscle cramps (legs, feet, lower back)
Seizures
Irritability, personality changes
ECG changes (prolonged Q-T interval)
The most common causes of hypocalcaemia are:
(i)
Hypoalbuminaemia
(ii)
Chronic renal failure
(iii)
Acute pancreatitis
(iv)
Pre-maturity
(v)
Inadequate intake oral, IV.

3.2.1 Vitamin D deficiency

Deficiency of 1:25-DHCC may result from lack of vitamin D or failure at any

stage in its conversion. Rarely the action of 1:25-DHCC defective at the receptor
level.

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The main causes of hypocalcaemia due to lack of vitamin D or other disturbances

of its metabolism include:
(i)
Nutritional deficiency of vitamin D Poor diet, inadequate exposure to
sunlight, or a combination of these can lead to vitamin D deficiency with the
development of hypocalcaemia and osteomalacia.
(ii)
Malabsorption of vitamin D- This may be due to coelic disease, or occur as a
result of fat malabsorption due to pancreatic disease, biliary obstruction, or as
a complication of gastric or intestinal surgery (e.g. intestinal bypass or
resection). Biliary obstruction is much likely to lead to vitamin D deficiency
(through malabsorption) than the theoretical possibility of 25-HCC deficiency
in parenchymal disease.
(iii)
Renal disease Destruction of the renal parenchyma leads to loss of 1hydroxylase activity, reduced formation of 1:25-DHCC consequently
malabsorption of calcium. Plasma [phosphate] is likely to be high in renal
failure, and this may interfere with the 1-hydroxylase step.

Defective absorption of calcium leads ultimately to a low plasma [Ca 2+]

accompanied by increased PTH secretion in response to low ECF [Ca 2+] (i.e.
secondary hyperparathyroidism). Plasma [phosphate] is often low, partly
through impaired absorption, but also as a result of secondary hyperthyroidism.
Plasma ALP activity is often increased reflecting increased osteoblastic activity.
Other causes of vitamin D deficiency include long term therapy with
anticonvulsant phenytoin can induce enzymes that catabolise vitamin D.

3.2.2 Acute pancreatitis

In acute pancreatitis the hypocalcaemia is transient, rarely falls below ~ 1.7

mmol/L or causes symptoms.

It usually occurs within 36 hours of the onset of pain. The causes of

hypocalcaemia are poorly understood and various mechanisms have been
proposed. These include:
(i)
Damaged pancreatic cells
(ii)
Hypoalbuminaemia as a result of shock
(iii)
Glucagon released by damaged cells. Experimental glucagons infusion lowers
plasma calcium by an unknown mechanism
(iv)
Hypomagnesaemia commonly found in alcoholics because of poor diet, low
levels of magnesium can inhibit appropriate PTH secretion.

3.2.3 Renal disease

Hypocalcaemia is common in patients with end-stage renal disease but is rarely

symptomatic.

16

The reduction in normal renal tissue (proximal tubules) results in a reduced

capacity for 1:25-DHCC synthesis, whilst the increased amounts of intracellular
phosphate directly inhibit the activity of the 1 -hydroxylase in the remaining
functioning tubules.

Hyperphosphataemia inhibits 1:25-DHCC synthesis and a reduction of this

hormone has been shown to increase PTH secretion. As renal failure worsens
compensation fails and hypocalcaemia, hyperphosphataemia and low levels of
1:25-DHCC are observed.
There is evidence that high levels of circulating PTH are less effective in causing
calcium resorption from bone, suggesting that in advanced renal failure the
hypocalcaemia may be partly due to bone resistance to PTH action.

A raised total ALP activity associated with an elevated PTH is strongly

suggestive of renal osteodystrophy.

The pathophysiology of this disease may be due to one or more of the following
mechanism:
(i)
Vitamin D metabolism:
There is the ineffective conversion of 25-HCC to 1:25-DHCC due to loss of renal
1-hydroxylase. This causes defective calcium absorption and osteomalacia in
adults, or rickets in children,
(ii)
Phosphate retention:
This is increased plasma [phosphate], and by complexing with Ca 2+, combined with
defective calcium absorption, tends to make plasma [Ca2+] falls. This leads to
secondary hyperparathyroidism, which tends to restore plasma [phosphate] and
plasma [calcium], towards normal. Plasma phosphate retention can further inhibit the
renal 1-hydroxylase.
(iii)
Phosphate binders:
Failure of the secondary hyperparathyroidism to maintain normal plasma [phosphate]
as renal disease progress leads to treatment of patients with oral phosphate binders,
usually aluminium hydroxide.

3.2.4 Hypoparathyroidism

This can be congenital or acquired. Primary hypothyroidism is very rare.

The combination of a reduced plasma [calcium] and an increased [phosphate] in a

patient who does not have renal disease suggest the diagnosis of
hypoparathyroidism.

17

Plasma ALP activity is usually normal.

Measurement of serum [PTH] confirms the diagnosis as it is reduced to below 10

ng/L, and it is sometimes undetectable even by the most sensitive assay.

Failure to secrete PTH may be a complication of surgery, or it may be familial or

sporadic in origin. Also, the parathyroid gland may be destroyed by an autoimmune process, or as a result of infiltration or carcinoma of the thyroid or other
neoplasms.

3.2.5 Pseudohypoparathyroidism

Pseudohyperparathyroidism superficially resembles hypoparathyroidism, but

plasma concentrations of PTH are elevated.

The end-organ receptors in the bone and kidney fail to respond normally to PTH.

There are two types: both are hereditary disorders. The effects of PTH are
mediated through the formation of cyclic 3,5-AMP.

In type I, activation of adenylate cyclase is defective and cyclic AMP is not

formed in response to the binding of PTH to its receptor.

In type II, cyclic AMP is formed, but the response to it is blocked.

The two types can be distinguished by measuring urinary cyclic AMP after
administration of PTH.

3.2.5 Magnesium deficiency

Magnesium is required for both PTH secretion and its action on target tissues.
Occasionally, the parathyroid glands are suppressed as a result of magnesium
deficiency.

Magnesium deficiency can cause hypocalcaemia or render patients insensitive to

the treatment of hypocalcaemia with vitamin D or calcium, or both.

3.3 Biochemical bone diseases

These are bone diseases which are characterized by defects in bone

mineralization, frequently associated with abnormal calcium or phosphate
metabolism.

They include:

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(i)
(ii)
(iii)

Rickets and osteomalacia - caused by vitamin D deficiency or disturbed

metabolism of vitamin D,
Osteoporosis common disorder that affects one in four women and is
characterized by low bone mass and susceptibility to vertebral, forearm and
hip fracture in later life.
Pagets disease in which bone turnover is increased, with disordered bone
remodeling. Plasma [calcium] and [phosphate] are usually normal, although
hypercalcaemia can develop, especially as a result of immobilization.

The increased bone turnover leads to high plasma alkaline phosphatase activity
and an increase in indices of osteoclasts activity.