Calcium functions and significance

Calcium- Functions and ClinicalCalcium- Functions and Clinical
SignificanceSignificance
By –
Professor (Dr.) Namrata Chhabra
Biochemistry For Medics- Lecture Notes
07/24/14
By- Professor Namrata Chhabra (MD Biochemistry)
1

IntroductionIntroduction
Calcium(Ca) is required for the :
•Muscle contraction,
•Nerve conduction,
•Hormone release, and
•Blood coagulation
•In addition, specific Calcium concentration is
required for various other metabolic processes.
07/24/14
By- Professor Namrata Chhabra
(MD Biochemistry)
2

Sources of calciumSources of calcium
• It is an important nutrient. The daily
intake is approximately
1000mg/day, about the amount of
one litre of milk.
• Widely distributed in food
substances such as
o Milk
o Cheese
o Egg- yolk
o Fish
o Beans
o Lentils
o Nuts and
o Cabbage
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Intestinal Absorption of calciumIntestinal Absorption of calcium
Two mechanisms have been proposed-
• Simple passive diffusion
• Active transport- involving energy and calcium
pump.
o Vitamin D is important for the active process.
o Active calcium transport depends on the
presence in the intestinal cell of calbindin
protein , the biosynthesis of which is totally
dependent on vitamin D.
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Intestinal absorptionIntestinal absorption
• 30-80% of ingested calcium is absorbed,
primarily in the upper small intestine.
• Absorption is related to calcium intake.
• If intake is low, active transcellular calcium
transport in the duodenum is increased and a
larger proportion of calcium is absorbed by
the active process compared with the passive
paracellular process that occurs in the
jejunum and ileum.
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• Passive absorption in the jejunum and ileum
predominates when dietary calcium intake is
adequate or high.
• Calcium reaching the large intestine is absorbed
by active and passive processes.
• Usually, not more than 10% of total absorption
takes place in the large intestine, but this site
becomes nutritionally important in conditions of
significant small bowel resection.
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• In a balanced diet, roughly 1000 mg of Ca is ingested
each day and about another 200 mg/day is secreted
into the GI tract in the bile and other GI secretions.
• Depending on the concentration of circulating vitamin
D, particularly 1,25(OH)2D (1,25
Dihydroxycholecalciferol, Calcitriol, or active vitamin D,
roughly 200 to 400 mg of Ca is absorbed from the
intestine each day.
• The remaining 800 to 1000 mg appears in the stool.
• Ca balance is maintained through renal Ca excretion
averaging 200 mg/day.
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Factors affecting calcium absorptionFactors affecting calcium absorption
A) Factors favoring calcium absorption
• An acidic pH
• Presence of sugar acids, organic acids and citric acid
• High protein diet- Lysine and Arginine cause maximal absorption
• Presence of vitamin D
• Ca : P ratio- A ratio of dietary Ca: P not more than 2:1 is adequate
for optimal absorption, ratio of less than 1:2 reduces absorption
• State of health and intact mucosa- A healthy adult absorbs about
40% of dietary calcium.
• PTH (Parathormone) stimulates the activation of vitamin D, thus
indirectly increases absorption of vitamin D
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Factors affecting calcium absorptionFactors affecting calcium absorption
B) Factors inhibiting absorption of calcium
• Alkaline pH
• High fat diet- Fatty acids form calcium soaps that can not be
absorbed
• Presence of Phytates and oxalates- Insoluble calcium salts are
formed
• Dietary fiber in excess inhibits absorption
• Excess phosphates, magnesium and iron decrease absorption
• Glucocorticoids reduce intestinal absorption of calcium
• Calcitonin reduces calcium absorption indirectly by inhibiting the
activation of vitamin D
• Advancing age and intestinal inflammatory disorders inhibit
absorption of calcium
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Distribution of Body calciumDistribution of Body calcium
• The adult human body contains approximately 1100g
(27.5mol) of calcium.
• 99% of the calcium is in bone.
• Blood calcium levels are normally 9-10.2mg/dL (2.25-
2.55mmol/L).
• Of the total amount, 50% is free ionized calcium, 9% is
combined with various anions (including bicarbonate,
citrate, phosphate, lactate and sulphate) and the remaining
41% is bound to serum proteins mainly albumin.
• Free ionized calcium is the physiologically important
component of the total calcium.
• In plasma, the ionized calcium concentration is normally
maintained within a tight range (1.0-1.25mmol/l).
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(MD Biochemistry)
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07/24/14
By- Professor Namrata Chhabra (MD
Biochemistry)
11

• Both extracellular and intracellular Ca concentrations are
tightly regulated by bidirectional Ca transport across the
plasma membrane of cells and intracellular organelles,
such as the endoplasmic reticulum, the sarcoplasmic
reticulum of muscle cells, and the mitochondria.
• Cytosolic ionized Ca is maintained within the micromolar
range (<1/1000 of the serum concentration).
• Despite its important intracellular roles, roughly 99% of
body Ca is in bone, mainly as hydroxyapatite crystals.
• Roughly 1% of bone Ca is freely exchangeable with the ECF
and, therefore, is available for buffering changes in Ca
balance.
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Influences on calcium concentrationsInfluences on calcium concentrations
• The plasma pH and the total plasma protein concentration
influence the total calcium levels
• Since a significant proportion of calcium in the blood is
bound to albumin, it is important to know the plasma
albumin concentration when evaluating the total plasma
calcium.
• In general, 0.2mmol/L must be added to the total calcium
concentration for each 1g/dL decrease in albumin
concentration
• Ionized calcium increases with acidosis, and decreases with
alkalosis.
• Therefore, for each 0.1 decrease in pH, ionized calcium
rises by about 0.05mmol/L.
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Physiological functions of calcium
1) Calcium is necessary for several physiological
processes including neuromuscular
transmission, smooth and skeletal muscle
contraction, cardiac automaticity, nerve
function, cell division and movement, and
certain oxidative processes.
2) It is also a co-factor for many steps during
blood coagulation.
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Physiological functions of calciumPhysiological functions of calcium
3) Ca is also involved in the action of other
intracellular messengers, such as cyclic
adenosine monophosphate (cAMP) and
Inositol 1,4,5-triphosphate, and thus mediates
the cellular response to numerous hormones,
including epinephrine, glucagon, ADH
(vasopressin), secretin, and cholecystokinin.
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4) Calcium binding proteins
• Many different calcium binding proteins have
been described, but the two with well
established functions are troponin and
calmodulin.
• Troponin is involved in muscle contraction,
whereas calmodulin causes configurational
changes to proteins and enzyme activation.
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6) Release of neurotransmitters and hormones-
Intracellular calcium levels are much lower than
the extracellular, due to relative membrane
impermeability and membrane pumps employing
active transport.
• Calcium entry via specific channels leads to direct
effects, e.g. neurotransmitter release in neurons,
or further calcium release from intracellular
organelles, e.g. in cardiac and skeletal muscle.
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Regulation of calcium homeostasisRegulation of calcium homeostasis
Three principal hormones are involved in calcium
homeostasis
• Vitamin D,
• Parathormone and
• Calcitonin
Acting at three target organs,
• Intestine,
• Bone and
• Kidneys
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Role of vitamin D in calciumRole of vitamin D in calcium
homeostasishomeostasis
•Vitamin D is a group of closely related sterols produced
by the action of ultraviolet light.
•Vitamin D3 (Cholecalciferol) is produced by the action of
sunlight and is converted to 25-hydroxycholecalciferol in
the liver.
•The 25-hydroxy-cholaecalciferol is converted in the
proximal tubules of the kidneys to the more active
metabolite 1,25-hydroxy-cholaecalciferol.
•1,25-hydroxychlecalceriferol synthesis is regulated in a
feedback fashion by serum calcium and phosphate.
•Its formation is facilitated by parathyroid hormone.
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Role of vitamin D in calciumRole of vitamin D in calcium
The actions of Vitamin D are as follows:
1. Enhances calcium absorption from the
intestine
2. Facilitates calcium absorption in the kidney
3. Increases bone calcification and
mineralization
4. In excess, mobilizes bone calcium and
phosphate
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Role of Parathyroid hormone (PTH)Role of Parathyroid hormone (PTH)
• Parathyroid hormone is a linear polypeptide
containing 84 amino acid residues.
• It is secreted by the chief cells in the four
parathyroid glands.
• Plasma ionized calcium acts directly on the
parathyroid glands in a feedback manner to
regulate the secretion of PTH.
• In hypercalcemia, secretion is inhibited, and the
calcium is deposited in the bones.
• In hypocalcaemia, parathyroid hormone
secretion is stimulated.
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Parathyroid glandsParathyroid glands
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Biochemistry)
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Role of Parathyroid hormone (PTH)Role of Parathyroid hormone (PTH)
The actions of PTH are aimed at raising serum calcium. It -
1. Increases bone resorption by activating osteoclastic activity
2. Increases renal calcium reabsorption by the distal renal
tubules
3. Increases renal phosphate excretion by decreasing tubule
phosphate reabsorption
4. Increases the formation of 1,25-dihydrocholecalciferol by
increasing the activity of alpha-hydroxyls in the kidney
A large amount of calcium is filtered in the kidneys, but 99%
of the filtered calcium is reabsorbed. About 60% is
reabsorbed in the proximal tubules and the remainder in
the ascending limb of the loop of Henle and the distal
tubule. Distal tubule absorption is regulated by parathyroid
hormone.
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Regulation of calcium homeostasisRegulation of calcium homeostasis
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Role of CalcitoninRole of Calcitonin
Calcitonin is a 32 amino acid polypeptide secreted by the
parafollicular cells in the thyroid gland.
It tends to decrease serum calcium concentration and, in
general, has effects opposite to those of PTH.
The actions of calcitonin are as follows:
1. Inhibits bone resorption
2. Increases renal calcium excretion
The exact physiological role of calcitonin in calcium
homeostasis is uncertain.
The effects of calcitonin on bone metabolism are much
weaker than those of either PTH or vitamin D.
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Role of Calcitonin, Calcitriol and PTHRole of Calcitonin, Calcitriol and PTH
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Glucocorticoids and calciumGlucocorticoids and calcium
• Glucocorticoids lower serum calcium levels by
inhibiting osteoclast formation and activity, but
over long periods they cause osteoporosis by
decreasing bone formation and increasing bone
resorption.
• They also decrease the absorption of calcium
from the intestine by an anti-vitamin D action
and increased its renal excretion.
• The decrease in serum calcium concentration
increases the secretion of parathyroid hormone,
and bone resorption is facilitated.
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Growth hormone and calcium levelsGrowth hormone and calcium levels
• Growth hormone increases calcium excretion
in the urine
• it also increases intestinal absorption of
calcium, and
• this effect may be greater than the effect on
excretion, with
• a resultant positive calcium balance.
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Effect of other hormones on calciumEffect of other hormones on calcium
levelslevels
• Thyroid hormones may cause hypercalcemia,
hypercalciuria, and, in some instances,
osteoporosis.
• Oestrogens prevent osteoporosis, probably by
a direct effect on osteoblasts.
• Insulin increases bone formation, and there is
significant bone loss in untreated diabetes.
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Bone and calciumBone and calcium
The calcium in bone exists in two forms:
1.A readily exchangeable pool and which is about 0.5 to 1%
of the total calcium salts and is the first line of defense against
changes in plasma calcium. It provides a rapid buffering
mechanism to keep the serum calcium ion concentration in
the extracellular fluids from rising to excessive levels or falling
to very low levels under transient conditions of excess or
hypo availability of calcium.
2.Stable Pool- The other system is mainly concerned with
bone remodeling by the constant interplay of bone resorption
and deposition, which accounts for 95% of bone formation.
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Extracellular calcium homeostasisExtracellular calcium homeostasis
Calcium-sensing receptor (C ASR)
The CASR plays an essential role in maintaining
calcium ion homeostasis-
• This receptor is expressed in all tissues related to
calcium control, i.e. parathyroid glands, thyroid
C-cells, kidneys, intestines and bones.
• It has the ability to sense small changes in plasma
calcium concentration
• This information is conveyed to intracellular
signaling pathways that modify PTH secretion or
renal calcium handling.
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Calcium-sensing receptor (C ASR)Calcium-sensing receptor (C ASR)
It is a G protein-coupled receptor that plays an essential
part in regulation of extracellular calcium homeostasis.
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Key points in calcium homeostasis
•Calcium homeostasis is regulated by
three hormones, parathyroid
hormone, vitamin D and calcitonin.
•Parathyroid hormone increases
plasma calcium by mobilizing it from
bone, increases reabsorption from
the kidney and also increases the
formation of 1, 25
dihydrocholecalciferol.
•1,25-dihydrocholecalciferol increases
calcium absorption from the
intestine, mobilizes calcium from the
bone and increases calcium
reabsorption in the kidneys
•Calcitonin inhibits bone resorption
and increases the amount of calcium
in the urine, thus reducing plasma
calcium
•The calcium-sensing receptor (CASR)
plays an important role in regulation
of extracellular calcium.
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HypocalcaemiaHypocalcaemia
Hypocalcemia is total serum Ca concentration < 8.8
mg/dL (< 2.20 mmol/L) in the presence of normal plasma
protein concentrations or a serum ionized Ca
concentration < 4.7 mg/dL (< 1.17 mmol/L).
Causes include hypoparathyroidism, vitamin D deficiency,
and renal disease.
•Acute hypocalcaemia can also occur in the immediate
post-operative period, following removal of the thyroid
or parathyroid glands.
•Hypocalcaemia can occur following rapid administration
of citrated blood or large volumes of albumin and in
alkalosis caused by hyperventilation.
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Other causes of hypocalcemia include-
• Mg depletion (can cause relative PTH
deficiency and end-organ resistance to PTH
action),
• Acute pancreatitis (when lipolytic products
released from the inflamed pancreas chelate
Ca)
• Hypoproteinemia (reduces the protein-bound
fraction of serum Ca)
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• Hungry bone syndrome-(persistent hypocalcemia and
hypophosphatemia occurring after surgical or medical
correction of moderate to severe hyperparathyroidism
in patients in whom serum Ca levels had been
supported by high bone turnover induced by greatly
elevated parathyroid hormone)
• Septic shock (due to suppression of PTH release and
decreased conversion of 25(OH)D to 1,25(OH)2D)
• Drugs including anticonvulsants
(e.g., phenytoin , phenobarbital and rifampin which
alter vitamin D metabolism)
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Clinical manifestations ofClinical manifestations of
• Hypocalcemia is frequently asymptomatic.
• Major clinical manifestations of hypocalcemia are
due to disturbances in cellular membrane potential,
resulting in neuromuscular irritability.
• Clinical signs include: tetany, carpopedal spasm
and laryngeal stridor.
• Sensory symptoms consisting of paresthesias of
the lips, tongue, fingers, and feet
• Generalized muscle aching and spasm of facial
musculature are also there
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• Hypocalcaemia may lead to cardiac
Dysrhythmias, decreased cardiac contractility,
causing hypotension, heart failure or both.
• Many other abnormalities may occur with
chronic hypocalcemia, such as dry and scaly
skin, brittle nails, and coarse hair.
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Clinical manifestations of AcuteClinical manifestations of Acute
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Diagnosis of HypocalcaemiaDiagnosis of Hypocalcaemia
• Estimation of ionized Ca
• Further testing with Mg, PTH, PO4, alkaline
phosphatase, and vitamin D concentrations in
blood and cAMP and PO4 concentrations in
urine
• Electrocardiographic changes include
prolongation of the QT interval.
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Treatment of HypocalcaemiaTreatment of Hypocalcaemia
• IV Ca Gluconate for tetany
• Oral Ca for postoperative hypoparathyroidism
• Oral Ca and vitamin D for chronic
hypocalcemia
• In patients without renal failure, vitamin D is
given as a standard oral supplement (e.g.,
Cholecalciferol 800 IU once/day).
• Vitamin D therapy is not effective unless
adequate dietary or supplemental Ca and PO4
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HypercalcaemiaHypercalcaemia
Hypercalcemia is total serum Ca
concentration > 10.4 mg/dL (> 2.60 mmol/L) or
ionized serum Ca > 5.2 mg/dL (> 1.30 mmol/L).
Principal Causes of Hypercalcemia-
Hypercalcemia usually results from excessive
bone resorption. There are many causes of
hypercalcemia
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Principal Causes of HypercalcemiaPrincipal Causes of Hypercalcemia
A) Cancer with bone metastases
• Carcinoma
• Leukemia
• Lymphoma
• Multiple myeloma
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B) Immobilization
• Orthopedic casting or traction
• Paget's disease of bone
• Osteoporosis in the elderly
• Paraplegia or quadriplegia
• Young, growing patients
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C) Parathyroid hormone excess
• Parathyroid carcinoma
• Primary hyperparathyroidism
• Secondary hyperparathyroidism
D) Vitamin Toxicity
• Vitamin A toxicity
• Vitamin D toxicity
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E) Other disorders/causes
• Hyperthyroidism
• Milk-alkali syndrome
• Addison's disease
• Granulomatous disorders
• Drug therapy such as thiazides and lithium
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Hypercalcemia related toHypercalcemia related to
hyperparathyroidismhyperparathyroidism
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• In mild hypercalcemia, many patients are
asymptomatic.
• Clinical manifestations of hypercalcemia
include constipation, anorexia, nausea and
vomiting, abdominal pain, and ileus.
• Impairment of the renal concentrating
mechanism leads to polyuria, nocturia, and
polydipsia.
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• Elevation of serum Ca > 12 mg/dL (> 3.00
mmol/L) can cause emotional lability,
confusion, delirium, psychosis, stupor, and
coma.
• Hypercalcemia may cause neuromuscular
symptoms, including skeletal muscle
weakness.
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• Hypercalciuria with nephrolithiasis is
common.
• Less often, prolonged or severe
hypercalcemia produces reversible acute renal
failure or irreversible renal damage due to
nephrocalcinosis (precipitation of Ca salts
within the kidney parenchyma).
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Clinical manifestations of
Hypercalcaemia
• Severe hypercalcemia causes a shortened
QTc interval on ECG, and arrhythmias may
occur
• Hypercalcemia > 18 mg/dL (> 4.50 mmol/L)
may cause shock, renal failure, and death.
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Diagnosis of HypercalcaemiaDiagnosis of Hypercalcaemia
• Total serum Ca concentration
• Chest x-ray, measurement of electrolytes,
BUN, creatinine, ionized Ca, PO4, alkaline
phosphatase, and serum protein
immunoelectrophoresis to determine the
cause
• Measurement of PTH and urinary excretion of
Ca with or without PO4
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Treatment of HypercalcaemiaTreatment of Hypercalcaemia
There are 4 main strategies for lowering serum
Ca:
• Decrease intestinal Ca absorption
• Increase urinary Ca excretion
• Decrease bone resorption
• Remove excess Ca through dialysis
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• Oral PO4 for serum Ca < 11.5 mg/dL with mild
symptoms and no kidney disease
• IV saline and diuretic (furosemide) for more
rapid correction for serum Ca < 18 mg/dL
• Bisphosphonates or other Ca-lowering drugs
for serum Ca < 18 mg/dL and > 11.5 mg/dL or
moderate symptoms
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• Hemodialysis for serum Ca > 18 mg/dL
• Surgical removal for moderate, progressive
primary hyperparathyroidism and sometimes
for mild disease
• PO4 restriction and binders and
sometimes Calcitriol for secondary
hyperparathyroidism
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Summary of calcium metabolismSummary of calcium metabolism
• Ca is required for the proper functioning of muscle
contraction, nerve conduction, hormone release,
blood coagulation and for various other metabolic
processes.
• Maintenance of body Ca stores depends on
• Dietary Ca intake
• Absorption of Ca from the GI tract
• Renal Ca excretion
• The regulation of both Ca and PO4 balance is greatly
influenced by concentrations of circulating PTH,
vitamin D, and, to a lesser extent, calcitonin.
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• Hypocalcemia is total serum Ca concentration < 8.8
mg/dL (< 2.20 mmol/L) in the presence of normal plasma
protein concentrations or a serum ionized Ca
concentration < 4.7 mg/dL (< 1.17 mmol/L).
• Causes include hypoparathyroidism, vitamin D
deficiency, and renal disease.
• Manifestations include paresthesias, tetany, and, when
severe, seizures, encephalopathy, and heart failure.
• Diagnosis involves measurement of serum Ca with
adjustment for serum albumin concentration.
• Treatment is administration of Ca, sometimes with
vitamin D.
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• Hypercalcemia is total serum Ca concentration > 10.4
mg/dL (> 2.60 mmol/L) or ionized serum Ca > 5.2 mg/dL
(> 1.30 mmol/L).
• Principal causes include hyperparathyroidism, vitamin D
toxicity, and cancer.
• Clinical features include polyuria, constipation, muscle
weakness, confusion, and coma.
• Diagnosis is by serum ionized Ca and parathyroid
hormone concentrations.
• Treatment to increase Ca excretion and reduce bone
resorption of Ca involves saline, Na diuresis, and drugs
such as pamidronate.
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