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PBL 5
Calcium metabolism:
Physiology, biochemistry & pathology
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Biological role of Ca2+
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protein stability
second messenger
synaptic transmission of nerve impulses
blood clotting
muscle contraction
RDI: 20-25mmol (800-1000mg)
Effects of hypocalcaemia
• Contraction
– lethal tetany at [Ca2+ ] ≤ 4mg/100ml Reduction
– spontaneous nerve discharge
– tetanic muscle
Effects of hypercalcaemia
• If normal extracellular fluid [Ca2+] increases
up to 12 mg/100ml
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depressed neuronal activity
constipation
lack of appetite
disseminated calcium phosphate precipitation
at [Ca2+ ] ≥ 17mg/100ml
Role of Ca2+ in cell regulation
• Cytosolic Ca2+ concentration (0.1 – 0.01μmol/L) is kept
much lower than extracellular levels (~1.3mmol/L)
• This is due to Ca2+ being continuously pumped from cytosol
into intracellular Ca2+ stores such as the endoplasmic
reticulum and sarcoplasmic reticulum, vesicles and
mitochondria, or it is transported out of the cell
• Ca2+ is involved in:
– myocyte contraction
– exocytosis of neurotransmitters
in presynaptic nerve endings
– endocrine and exocrine
Hormone secretion
– excitation of sensory cells
– closure of gap junctions
calmodulin can bind up to 4 Ca2+ ions when the
[Ca2+]i rises. Ca2+-calmodulin complexes activate a
number of different enzymes, including myosin light
chain kinase (MLCK), which is involved in smooth
muscle contraction
Calcium storage in the body
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In Blood:
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Normally found in concentrations of approximately 2.4 mmol/dL
Ca2+ is normally found in concentrations of 1.2mmol/L
40% is combined with plasma proteins (won’t diffuse through capillary membrane)
10% is combined with other plasma and interstitial substances (will diffuse through capillary
membrane)
– 50% is in ionised form (will diffuse through capillary membrane)
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In Bone:
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Exists in crystalline salts
Mostly of hydroxyapatite (Ca10(PO4)6(OH)2)
Relative ratio of calcium to phosphorous varies according to nutritional status
Normal extracellular fluid concentrations of calcium and phosphorous are greatly in excess of
that required to cause precipitation of hydroxyapatite
– This is inhibited by various inhibitors throughout the body
– Precipitation of calcium salts occurs along the collagen fibres of bone due to neutralisation of
the inhibitors (possibly due to secretion of pyrophosphate by the osteoblasts)
– Rapidly mobilizable calcium is found in the form of CaHPO4 and other amorphous calcium salts
Excretion
• In Faeces:
– 9/10 of daily intake of Ca2+ is
excreted in the faeces
• In Kidneys:
– 90% of Ca2+ in glomerular filtrate is
reabsorbed in the proximal tubules,
the loops of Henle and the early
distal tubules
– Selective reabsorption occurs in the
late distal tubules and early
collecting ducts
– If Ca2+ concentration in blood is low
then almost all can be reabsorbed
Control of circulating calcium
Calcium levels are under tight control
by parathyroid hormone (PTH) and the
vitamin D axis.
Sources for circulating calcium are:
•Absorption of dietary calcium by GIT
•Reduction of calcium excretion by the
kidneys
•Release of stored calcium from bones
Regulation of plasma levels
The calcium sensing receptor (CaSR) is expressed in: parathyroid, thyroid, kidney, gastrointestinal tract, brain
Regulation of calcium is primarily done by parathyroid hormone (PTH)
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Production of parathyroid hormone is inhibited by high Ca2+ levels
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Effects of PTH:
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 Reabsorption of Ca2+ in kidney (at distal tubules)
 The action of 1-hydroxylase (which converts Vitamin D to 1,25-Dihydroxycholecalciferol)
 Resorption of bone
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 number of Ca2+ channels in osteoblasts
 Activity of osteoclasts
 Phosphate secretion
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Thus preventing phosphate and calcium from recrystallising bone
By actions of 1,25-Dihydroxycholecalciferol
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Plasma Ca2+ inhibits the conversion of 25-Hydroxycholecalciferol to 1,25-Dihydroxycholecalciferol
Lack of 1,25-Dihydroxycholecalciferol  absorption of Ca2+ from bones
Lack of 1,25-Dihydoxycholecalciferol  absorption of Ca2+ from renal tubules
By effects of Calcitonin
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Production of calcitonin is stimulated by high Ca2+ levels
Reabsorption of calcium in the kidneys
 Resorption of bone
High Ca2+ levels are sensed
by membrane receptors 
IP3 released intracellularly
triggers an increase in the
[Ca2+]i of parafollicular C cells
of the thyroid gland. This
induces the exocytosis of
calcitonin,
Disturbances in Calcium homeostasis
Causes of hypercalcaemia
>90% of
cases
Causes of hypocalcaemia
Manifestations of hypercalcaemia
Patients with mild hypercalcemia (calcium <12 mg/dl [3 mmol/L]) may be
asymptomatic, or they may report nonspecific symptoms, such as
• constipation
• fatigue
• depression.
A serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) may be well-tolerated
chronically, while an acute rise to these concentrations may cause marked symptoms,
including
• polyuria
• polydipsia
• dehydration
• anorexia
• nausea
• muscle weakness
• changes in sensorium.
In patients with severe hypercalcemia (calcium >14 mg/dL [3.5 mmol/L]), there is
often progression of these symptoms
More manifestations of hypercalcaemia
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Neuropsychiatric disturbances
– A number of mild neuropsychiatric disturbances have been associated with hypercalcemia,
mostly in patients with primary hyperparathyroidism. The most common symptoms are
• anxiety
•depression
•cognitive dysfunction
–More severe symptoms may occur in patients with severe hypercalcemia (calcium >14 mg/dL
[3.5 mmol/L]) from any cause. These symptoms are more likely to occur in the elderly and in those
with rapidly rising calcium concentrations.
•lethargy
•confusion
•stupor
•coma
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GIT abnormalities
–Gastrointestinal symptoms, such as
•constipation (may be related to decreased smooth muscle tone and/or abnormal autonomic function)
•anorexia
•nausea
•pancreatitis and peptic ulcer disease occur less frequently (Proposed mechanisms for the development of
pancreatitis include deposition of calcium in the pancreatic duct and calcium activation of trypsinogen
within the pancreatic parenchyma)
•peptic ulcer disease (has been described in patients with hypercalcemia due to primary
hyperparathyroidism and may be caused by calcium-induced increases in gastrin secretion)
More manifestations of
hypercalcaemia
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Renal dysfunction
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The most important renal manifestations are polyuria, resulting from decreased concentrating
ability in the distal tubule, nephrolithiasis, and acute and chronic renal insufficiency.
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Nephrolithiasis
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When hypercalcemia is due to primary hyperparathyroidism or sarcoidosis, it is often longstanding, and the
resulting chronic hypercalciuria may cause nephrolithiasis
Renal insufficiency
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The development of renal insufficiency in individuals with hypercalcemia is related to the degree and duration of
hypercalcemia.
– The combination of polyuria and diminished fluid intake secondary to gastrointestinal
symptoms (nausea) can lead to dehydration, which exacerbates hypercalcemia and related
symptoms.
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Cardiovascular disease
– Although uncommon, severe hypercalcemia can be associated with cardiac arrhythmia.
– Acute hypercalcemia directly shortens the myocardial action potential, which is reflected in a
shortened QT interval.
– In addition, ST-segment elevation mimicking myocardial infarction has been reported in such
patients.
– Chronic hypercalcemia may lead to deposition of calcium in heart valves, coronary arteries,
and myocardial fibers; hypertension; and cardiomyopathy
Serum changes in bone disorders