2. CALCIUM
• Divalent cation
• Fifth most common element.
• Structural &metabolic functions
• Average body contains approx .1kg of calcium.
• Calcium is found mainly in three compartments:
a)Skeleton
b)Soft tissues
c)Extracellular fluid.
3. CALCIUM
• 2% of body weight
• 99% in bones [present as
hydroxyapaptiteCa10(PO4)6 (OH)2]
• 1% in body fluids & soft tissues
• Plasma (Extracellular fluid)
2.25 – 2.75 mmol/l
• Cell (Intracellular fluid)
10-8 – 10-7 mol/l = 10-5 – 10-4 mmol/l
5. PLASMA CALCIUM
• For each 0.1 unit change in pH approx 0.2mg/dl
(0.05mmol/l)of inverse change occurs in serum free
calcium concentration.
• Alkalosis causes a decrease in free calcium and acidosis
increases free calcium.
• Corrected total calcium:
Total calcium= total calcium (mg/dl)+0.8(4-albumin[g/dl])
• Free form of calcium is the biologically active form.
6. Calcium/Phosphate: Distribution
Tissue Calcium Phosphate
Skeleton 99% 85%
Soft tissue 1% 15%
ECF <0.2% <0.1%
Total 1000 gm 600 gm
State Calcium Phosphate
Free (ionized) 50% 55%
Protein bound (albumin) 40% 10%
Complexed with anions 10% 35%
Total 8.6-10.3 mg/dL
2.15-2.57mmol/l
2.5-4.5 mg/dL
0.81-1.45mmol/l
7. ROLE OF CALCIUM
• excitability of cell membranes
• neuromuscular transmission and muscle
contraction
• Transmission of nerve impulses from presynaptic
to post synaptic region
• “second messenger”
• stimulates secretory activity of exocrine glands
and releasing of hormones
• contractility of myocardium
• blood coagulation
8. Sources & daily requirement of
calcium
• Milk, cheese ,yoghurt, egg, fish, vegetables are
good sources of calcium.
• Cereals contain only small amounts of calcium
but being staple diet in India, constitute the
major source of calcium.
• Daily requirement of calcium is :
• 500mg/day in adults.
• 1200mg/day in Child.
• 1500mg/day in pregnancy & lactation.
9. Absorption of calcium
• Absorbed mainly in the duodenum.
• Absorbed against a concentration gradient &
requires energy.
• Absorption requires a carrier protein helped
by calcium dependent ATPase.
10. Factors causing increased absorption
• Vitamin D: Calcitriol induces synthesis of
carrier protein(calbindin) in the intestinal
epithelial cells hence facilitating absorption.
• Parathyroid hormone: Increases calcium
transport from intestinal cells.
• Acidity favours calcium absorption.
• Amino acids like lysine & arginine increase
calcium absorption.
11. Factors causing decreased absorption
• Phytic acid: hexaphosphate of inositol is present
in cereals. Fermentation & cooking reduce
phytate content.
• Oxalates: present in some leafy vegetables which
forms insoluble calcium oxalates.
• Malabsorption :fatty acid is not absorbed causing
formation of insoluble calcium salt of fatty acid.
• Phosphate: high phosphate content causes
precipitation as calcium phosphate.
12. Calcium fluxes
• Three principal organs are involved in body’s
handling of calcium:
a)GIT
b)Bone
c)kidneys
14. Calcium balance:
• In adults: normally, calcium intake = output .
• In infancy and childhood: input > output positive
balance , due to active skeletal growth.
• In old age: calcium output > input negative balance;
marked in women after menopause, postmenopausal
osteoporosis.
16. Parathyroid hormone(PTH)
• Secreted by four parathyroid glands embedded in thyroid
tissue.
• Synthesized as pre-pro PTH with 115 aminoacids.
• In the endoplasmic reticulum & golgi apparatus prepro –
PTH is broken to form is broken to form mature PTH with
84amino acids .Storage of PTH is only for 1hour.
• The first 35 amino acids (constituting the N-terminal )are
the biologically active form.
• Normal range of PTH: 15-65ng/l
• Decreased serum calcium stimulates PTH secretion within
seconds.
• t1/2 of PTH in serum is 4minutes.
18. Effects of PTH
Bones:
• Resorption by osteoclasts;
indirectly stimulated by
PTH;
• binds to osteoblasts,
stimulates osteoblasts to
express RANKL,
• bind to osteoclast
precursors containing
RANK,
• stimulates these
precursors to fuse, forming
new osteoclasts;
• ↑ resorption of bone.
19. Effects of PTH
Kidneys:
Enhances reabsorption of calcium from tubules; increases the
excretion of phosphate; stimulates kidney to produce 1,25-
dihydroxyvitamin D (25-hydroxyvitamin D3 1-alpha-
hydroxylase activity ), ↑ urinary cAMP
Intestine:
Vitamin D enhances the absorption of calcium in intestine;
activated vitamin D affects the absorption of calcium (as Ca2+
ions) by the intestine via calbindin.
Net effect of PTH – increase serum calcium,
decrease serum phosphorus
21. Vitamin D
• A group of sterols with a hormone-like function.
• Calcitriol (1, 25 diOH cholecalciferol = 1, 25 diOH D3) is
the biologically active molecule.
• Vitamins D2 & D3
– Preformed Vitamin D in the diet: they are needed only
when exposure to sunlight is limited.
– They are also available as supplement
– They are NOT biologically active
– They are activated in vivo to the biologically active form
• Recommended dietary allowance (RDA): 5 mg
cholecalciferol = 200 IU of vit D3 (or more)
24. VITAMIN D SYNTHESIS
SKIN LIVER KIDNEY
7-DEHYDROCHOLESTEROL
VITAMIN D3
VITAMIN D3
25(OH)VITAMIN D
UV
25-HYDROXYLASE
25(OH)VITAMIN D
1,25(OH)2 VITAMIN D
1a-
HYDROXYLASE
Predominant form
in plasma
Active vitamin D is transported in blood by vitamin D-binding protein
25.
26. Vitamin D functions
• Regulates calcium and phosphorus levels in the
body (calcium homeostasis)
• Through:
– Increasing uptake of calcium by the intestine
– Minimizing loss of calcium by kidney
– Stimulating resorption of bone when
necessary
27. Calcitonin
• Calcitonin is
– a peptide hormone
– secreted by the
parafollicular or “C” cells
of the thyroid gland
– released in response to
high plasma calcium
• Net result of its action
plasma calcium & phosphate
28. Calcitonin :
• Calcitonin plasma [Ca2+] by:
– osteoclast activity
– renal reabsorption of calcium and phosphate
thereby increasing renal clearance.
Diagnostic role:
Tumor marker for medullary carcinoma of thyroid—
malignancy of thyroid C cells
The only Hypocalcemic hormone
29. Hypercalcemia
Symptoms:
• Depending on Calcium level, rapidity of onset,
state of hydration.
• Most develop symptoms at a level > 12mg/dL,
virtually all symptomatic > 14mg/dl
• Vague symptoms – fatigue, weakness,
anorexia, nausea, polyuria, dehydration,
lethargy, confusion, depression ,stupor, coma.
30. When to check serum calcium?
• Neurological symptoms: irritability ,seizures.
• Renal calculi
• Polyuria, polydypsia
• Ectopic calcification
• Chronic renal failure
• Suspected malignancy
• Prolonged drug treatment with thiazides,
vitamin D etc…
• Elevated ALP.
31. Hypercalcemia - Etiology
• Primary Hyperparathyroidism
• Cancer (metastatic,lymphoma) – most common in
hospitalized patients
• Multiple Myeloma
• Hyperthyroidism
• Hypervitaminosis D (or A)
• Immobilization
• Sarcoidosis
• Addisonian crisis
32. Hypercalcemia
• Idiopathic/spurious – venous stasis, postmenopausal
women
• Thiazide diuretics
• lithium
• Hypocalciuria – Familial Hypocalciuric Hypercalcemia
• Paget’s disease – hypercalcemia in conjunction with
immobilization
• Milk-Alkali syndrome – excessive intake of NaHCO3
and milk (calcium salt).
• Aluminum toxicity - rare
33. Hypercalcemia - Treatment
• Treat if symptomatic (mental status changes,
confusion, delusions)
• Treat if serum calcium > 15mg/dl
– Normal Saline bolus until volume restored to maintain
adequate hydration.
– Furosemide diuretics to promote calcium excretion
– Bisphosphonates(inhibitors of bone resorption)
– Calcitonin
– Steroids if vitamin D excess
– Empirical Mg and K therapy
– Treatment of underlying cause
34. Hyperparathyroidism
• Most common disorder of hypercalcemia
(ambulatory patients)
• Patients usually > 50 years of age
• Females > males 4 : 1
Symptoms:
• Painful bones, renal stones, abdominal groans,
and psychic moans
• Bone and joint pain, renal stones – late findings
35. Hyperparathyroidism - Diagnosis
• Elevated serum calcium
– Repeated measurements (can vary, minimal venous
occlusion, fasting)
– Ionized calcium may be more accurate, but not widely
available, must be sent on ice, etc.
– Corrected for serum albumin
• Elevated serum parathyroid hormone (intact)
• Usually found during workup for osteoporosis or
elevated calcium in lab work .
37. Hyperparathyroidism
• Secondary
– Results from physiologic or pathophysiologic
response to hypocalcemia.
– Can result from vitamin D deficiency or decreased
calcium intake(dietary or malabsorption).
– Most cases due to chronic renal failure –
decreased production of activated vitamin D.
38. Hyperparathyroidism
• Tertiary
– Due to prolonged hypocalcemia (usually due to
chronic renal failure).
– Renal osteodystrophy:
Hyperphosphatemia, hypocalcemia, low levels of
1,25(OH)2Vitamin D, elevated PTH.
– This results in parathyroid gland hyperplasia .
– May need parathyroidectomy.
39. Hypocalcemia - Symptoms
• Concentration of serum calcium less than
8.8mg/dl, it is hypocalcemia.
• Paresthesias, muscle stiffness and cramps,
fasciculations, tetany results if concentration
lower than 7.5mg/dl.
• Lower seizure threshold due to increased
neuromuscular excitability .
• CHF, dysrhythmia, hypotension
40. Hypocalcemia:signs
• Main manifestation is carpo-pedal spasm.
• Laryngismus & stridor are associated findings.
• Laryngeal spasm may lead to death.
• Chvotsek’s sign, trousseu’s sign.
• Increased QT interval in ECG .
43. HYPOCALCEMIA :Etiology
• Deficiency of vitamin D
• Hypoparathyroidism
• pseudohypoparathyroidism
• Increased calcitonin as in medulllary carcinoma
• Deficiency of calcium due to:
a)Pancreatitis
b)Malabsorption
c)Infusion of agents complexing calcium
d)Alkalosis
44. HYPOCALCEMIA :Etiology
• Increased phosphorus as in tumor lysis
syndrome, rhabdomyolysis
• hypoalbuminemia
• Infusion of large amounts of citrated blood as
in massive blood transfusions.
• Neonatal hypocalcemia
45. Treatment of hypocalcemia
• Oral calcium with vitamin D supplementation
• Treatment of underlying cause
• Tetany needs i.v infusion(usually 10ml 10%
calcium gluconate over 10 minutes ,followed
by slow infusion)
46. Biochemical bone diseases
Generalized defects in bone mineralization,
frequently associated with abnormal calcium or
phosphate metabolism, "biochemical or
metabolic bone diseases".
Osteoporosis
Rickets
Osteomalacia
The most
common
47. Osteomalacia and Rickets
Osteomalacia:
Defective bone mineralization in adults
Rickets:
Defective bone and cartilage mineralization in
children
Before introduction of vitamin D-
supplemented milk, children with
insufficient exposure to sunlight developed
Vit D deficiency
Not common these days as foods (milk,
oils) are now supplemented with vitamin D
48. Osteomalacia and Rickets, continued..
These conditions are due to:
Vitamin D deficiency
Impaired vitamin D metabolism
Calcium deficiency
Imbalance in calcium homeostasis
49. Osteomalacia and Rickets, continued..
Vitamin-D-dependent rickets types 1 and 2
(genetic disorders)
Rare bone diseases
Due to:
Defects in vitamin D synthesis: type 1 (can be
overcome by high doses of Vit D)
Defects in vitamin D receptor: type 2 (cannot be
overcome by high doses of Vit D, as the hormone
is unable to act)
50. Clinical features
Rickets
• Soft bones
• Bone pain
• Increased tendency of
bone fractures
• Skeletal deformity
(bowed legs)
• Muscle weakness
• Dental problems
• Growth disturbance
Osteomalacia
• Soft bones
• Bone pain
• Bone fractures
• Compressed vertebrae
• Muscle weakness
OSTEOMALACIA AND RICKETS, CONTINUED..
53. Osteoporosis
• Reduction in bone mass per unit volume
• Bone matrix composition is normal but it is reduced
• Post-menopausal women lose more bone mass than men
(primary osteoporosis)
• Increased risk for fractures.
54.
55.
56. Osteoporosis
• Secondary osteoporosis may be caused by:
– Drugs
– Immobilization
– Smoking
– Alcohol
– Cushing’s syndrome
– Gonadal failure
– Hyperthyroidism
– GI disease
57. Osteoporosis, continued..
Diagnosis
• Serial measurement of bone density
• No specific biochemical tests to diagnose or
monitor primary osteoporosis
• Secondary osteoporosis (due to other causes)
can be diagnosed by biochemical tests
• The test results overlap in healthy subjects
and patients with osteoporosis
• Common biochemical tests:
Urinary Hydroxyproline (bone resorption)
Alkaline phosphatase (bone formation)
Osteocalcin (bone formation)
Biochemistry Diagnosis is Unremarkable in Osteoporosis
58. PAGET’S DISEASE
• Localized disease of bone characterised by osteoclastic bone
resorption followed by disordered replacement of bone.
• Localized involvement of bone, all bones are not involved.
• Common in people above 40 years of age.
• Family history may be positive.
• Skull, femur ,pelvis, vertebra
• Serum ALP is more than 10 times URL.
