Transcript Document 7682357

Calcium Metabolism,
Homeostasis
&
Related Diseases
Objectives of Lectures
By the end of these lectures, students should be able to:
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Recall Calcium Sources, Distributions & Functions
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Understand Organ & Endocrinal Homeostasis of Calcium with recognition of the
roles of:
- Vitamin D
- Parathyroid Hormone (PTH)
- Calcitonin Hormone
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Verify Main Causes of Hypocalcaemia & Hypercalcemia
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Recognize the biochemical and Clinical Interrelations of Metabolic diseases of bone:
- Rickets & Osteomalacia
- Osteoporosis
Components of Bones
Bone is a specialized mineralized connective tissue containing:
1- Cellular Elements:
- Osteoblasts (bone forming cells)
- Osteoclasts (bone resorping cells)
2- Organic Matrix
- Proteins:
Type I Collagen
Proteoglycan
- Inorganic Minerals: Calcium & Phosphate
- Others: small amount of hydroxide & carbonate
• Calcium is tightly regulated with phosphorous in the body
Calcium
 Calcium is the most abundant mineral in the body:
about 1 kg in a 70 kg man
 ~ 99% of the body’s calcium is present in the bone
where it is combined with phosphate
Dietary Sources of Calcium
 Rich:
Milk, milk products as cheese & yoghurt
 Fair
Legumes, vegetables
Biological Functions of Calcium
Bone
Formation
Total
Calcium
Of the
Body
99 %
in bone
Reservoir for
ECF [Ca2+]
Blood Clotting
ECF
Excitability of
Nerve & Muscle
1%
ICF
Metabolic
Regulation for
Action of
Hormones &
Enzyme Activation
Calcium in Blood
Organ Calcium Homeostasis
Organ Calcium Homeostasis
cont.
The concentration of calcium, phosphorous &
magnesium in the plasma depends on
ORGAN PHYSIOLOGY:
 Net effect of bone mineral deposition & resorption
 Intestinal absorption
 Renal excretion
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Parathyroid Hormone (PTH)
Blood
[Ca2+]
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Active Vitamin D (Calcitriol or 1,25 DHCC)
is Regulated
By:
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Calcitonin Hormone
Vitamin D
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A group of sterols with a hormone-like function.
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Sources of Vitamin D
1- Skin synthesis (On Exposure to Sun Lights):
In the skin, 7 dehydrocholesterol is converted to vitamin D3 by exposure to
sunlight
2- Diet:
- Animal Source Cholecalciferol (Vitamins D3)
- Plant Source: Ergocalciferol (Vitamin D2)
Vitamin D2 & D3 are NOT biologically active
–
Activation of cholecalciferol (vitamin D3)
Cholecalciferol (Vitamin D3) is activated in the body to the biologically active
form by two hydroxylations: first in the liver (at position 25) by 25 hydroxylase
& then in the kidney at positions 1 by 1 α hydroxylase
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Active Vitamin D
1, 25 dihydroxycholecalciferol (Calcitriol or DHCC)
SOURCES OF VITAMIN D
Vitamin D2
plant source
DIET VITAMINs D
Vitamin D3
animal source
fatty fish
Liver
egg yolk
Sun
Rays
7-dehydrocholesterol
In the skin
Vitamin D metabolism
 Cholecalciferol (Vitamin D3) is derived from 7-dehydrocholesterol in
the skin by sunlight or supplied in the diet
 In liver:
Cholecalciferol is converted to 25-hydroxycholecalciferol (25-HCC)
by the enzyme 25 hydroxylase
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25-hydroxycholecalciferol is the predominant form of vitamin D
in blood
25-hydroxycholecalciferol is the main storage form of vitamin
in the body
 In kidneys:
The 1 α hydroxylase enzyme converts 25 hydroxycholecalciferol to
1,25-dihydroxycholecalciferol (1, 25 DHCC or Calcitriol)
which is the biologically active form of vitamin D
Functions of Vitamin D
Active vitamin D (1, 25 DHCC or Calcitriol) regulates calcium levels in the
body (calcium homeostasis)
Through:
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Increasing absorption of calcium by the intestine
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Minimizing loss of calcium by kidney
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Stimulating resorption of bone (when necessary)
Mechanism of Action of Vitamin D
Parathyroid hormone (PTH)
Functions of Parathyroid Hormone (PTH)
 The active hormone is secreted in response to al fall in plasma Ca2+
resulting in in Ca2+ increase in blood.
 On bone:
PTH stimulates bone resorption by osteoclasts resulting in release of
calcium ions from bones to blood in cases of hypocalcemia
 On kidney:
1- PTH increases reabsorption of calcium from kidney tubules.
2- PTH promotes activity of 1a hydroxylase of the kidney (with more
hydroxylation of 25 hydroxycholecalciferol (25 HCC) to 1,25 DHCC
(activation of vitamin D) which increases intestinal absorption of
calcium
So, action of PTH on intestine is indirect (via Vitamin D)
Role of Parathyroid Hormone (PTH) in
Hypocalcemia
PTH
is the principal
acute regulator of
blood [Ca2+]
PTH
is a hypercalcemic
hormone in case of
hypocalcemia
Calcitonin Hormone
Calcitonin hormone is :
– Secreted by the parafollicular or “C” cells of the thyroid gland
– Released in response to high blood calcium (hypercalcemia)
In cases of hypercalcemia,
Calcitonin Hormone   blood [Ca2+] by:
–  Osteoclast activity (preventing release of calcium to blood)
–  Renal reabsorption of calcium
Net result of its action   blood calcium
CALCITONIN IS THE ONLY HYPOCALCEMIC HORMONE
MAIN CAUSES of
HYPERCALCEMIA
Primary hyperparathyroidism:
due to adenomas (single or multiple) of the parathyroid gld
 Blood PTH is high (or upper normal range *)
 Blood calcium is high & Blood phosphate is low
 Urine calcium & phosphorous are high (hypercalciuria & hyperphasphatruria)
Tumors
 Humoral hypercalcemia of malignancy due to PTHrP (PTH related protein) released
by some kinds of tumor cells.
 PTHrP is not responsive to negative feedback by calcium
Hypervitaminosis D:
 Excessive intake of vitamin D
 Extrarenal hydroxylation of 25HCC as in granulmotaous diseases as sarcoidosis
MAIN CAUSES of
HYPOCALCEMIA
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Hypoparathyroidism ( PTH)
Vitamin D deficiencies
Renal disease :low 1 a hydroxylase activity & by hyperphosphaturia
Hypoalbuminemia: low blood albumin
Nutritional calcium deficiency
Intestinal disorders causing inadequate calcium or vit.D absorption
Metabolic Diseases of Bone:
Rickets & Osteomalacia
Rickets & osteomalacia are metabolic bone diseases occurring due to
poor mineralization (calcium content) of bone
Causes of poor calcification of bones:
I. Vitamin D deficiency
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1- Deficiency of sources of vitamin D3:
BOTH:
Nutrional Vitamin D deficiency (vitamin D3)
Poor exposure to sun light
2- Impaired vitamin D metabolism:
Renal Rickets: deficiency of 1 hydroxylase of the kidney
Deficiency of parathyroid hormone : decrease activity of 1 α hydroxylase
Genetic defects in vitamin D metabolism (defect in its activation)
Genetic defects of vitamin D receptors or abnormal ligand binding
II. Calcium deficiency (nutritional
or defect in intestinal absorption)
Rickets &
Osteomalacia
Metabolic
Diseases
of Bones
RICKETS
Normal formation of the collagen matrix
BUT
Incomplete mineralization (poor calcification)
Soft Bones
CLINICALLY: Bone Deformity
OSTEOMALACIA
Demineralization (poor calcification) of preexisting bones
with
CLINICALLY: More Susceptibility to Fracture
Renal Rickets
Renal Osteodystrophy
In Chronic Renal Failure
Low activity of Renal 1a-Hydroxylase
Decreased ability to form the
active form of vitamin D
(1, 25 DHCC will be low)
Treatment: 1,25 DHCC (Calcitriol)
Laboratory Investigations for the Diagnosis of
Rickets & Osteomalacia
Investigations to confirm the diagnosis of rickets:
  Blood levels of 25-hydroxycholecalciferol (25 HCC)
 Blood calcium, (hypocalcemia)
  Blood Alkaline phosphatase (ALP)
Investigations to diagnose the cause of rickets:
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Kidney function tests (KFT)
Blood 1, 25 dihydroxycholecalciferol (1, 25 DHCC)
Blood PTH
Others i.e. molecular genetics (if indicated)
Metabolic Diseases of Bone:
Osteoporosis
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Most prevalent metabolic bone disease in adults
It means reduction in bone mass per unit volume
i.e. bone matrix composition is normal, but it is reduced
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Typically silent (without symptoms) until it leads to fracture at a degree of trauma
that would not have caused a fracture in a non-osteoprotic skeleton.
Fractures are called fragility or osteoporotic fractures)
Most affected: vertebral compression (may be asymptomatic) & hip fractures
(requires surgery in most cases)
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Post-menopausal women lose more bone mass than men (primary osteoporosis)
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Osteoporosis diagnosis is by dual energy x-ray absorpitometry (DXA) scan
Lab diagnosis: not conclusive
Metabolic Diseases of Bone
Osteoporosis
Secondary Osteoporosis
Risk Factors
Secondary osteoporosis may be caused by reduced bone mass
with increased consequent risk of fractures
Risk Factors for osteoporosis:
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Advanced age (esp. in females
Certain Drugs
Family history of osteoporosis or fractures
Immobilization
Smoking
Excess alcohol intake
Cushing’s syndrome
Long term glucocorticoids therapy
Hyperparathyroidism
Hyperthyroidism
Vitamin D disorders
Certain malignancies
In these cases, DXA is highly recommended to evaluate bone density
Case Study-1
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A 27 years old man presents to his physician 3 weeks after his thyroid surgically removed for a
thyroid cancer.
However, since he went home from the hospital, he noticed painful, involuntary muscular
cramping.
He also felt numbness and tingling around his mouth & in his hands and feet. His parents said that
he was irritable for the last 2 weeks.
He is on levothyroxine medication.
On examination
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He has a well-healing thyroidectomy scar & no palpable masses in the thyroid bed.
Blood pressure cuff inflated above the systolic pressure induces involuntary muscular contracture in
the ipsilateral hand after 60 seconds (Trousseau`s sign)
Tapping on the face interior to the ears cause twitching in the ipsilateral corner of the mouth
(Chevostek`s sign)
Lab Investigations:
Calcium: 5.6 mg/dl (N: 8.5 – 10.2)
Albumin: 4.1 g/dl (N: 3.5 – 4.8)
PTH: < 1 pg/ml (N: N: 11 – 54)
DIAGNOSIS of Case-1
The parathyroid glands were removed during
thyroidectomy
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PTH undetectable
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Hypocalcemia
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Clinical Manifestations of hypocalcemia
(increased reflexes & muscular cramping)
Case Study-2
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A 6-year old girl is brought to a pediatrician by her parents
They reported that her height is not progressing as they think it should (or like it
did for her 8 year old sister & her legs look bowed.
She takes no medications
Family history: Some cousins has the same problem
Lower Lim X-Ray:
 Bowing of long bones
 Generalized demineralizations
Clinical Chemistry Lab Investigations:
 Calcium: 7.2 mg/dl (N: 8.5 – 10.2)
 Albumin: 4.1 g/dl (N: 3.5 – 4.8)
 PTH: 866 pg/dl (N: 11 – 54)
 25 HCC: 35 ng/dl (N: 20- 57)
 1, 25 DHCC: less than 1 pg/ml (N: 20 – 75)
DIAGNOSIS of Case-2
Pseudohyperparathyroidism
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In which there is genetic mutations in the stimulatory G-protein
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IN ACTIVE G Protein
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No activation of adenylate cyclase
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NO cAMP
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NO EFFECT OF PTH
HYPOCALCEMIA
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INCREASE OF PTH (HYPERPARATHYROIDISM WITH HYPOCALCEMIA)
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TO BE CONFIRMED by
MOLECULAR GENETIC ANALYSIS