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Calcium Metabolism, Homeostasis & Related Diseases

Calcium Metabolism, Homeostasis & Related Diseases. Objectives of Lectures. By the end of these lectures, students should be able to: Recall Calcium Sources, Distributions & Functions Understand Organ & Endocrinal Homeostasis of Calcium with recognition of the roles of:

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Calcium Metabolism, Homeostasis & Related Diseases

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  1. Calcium Metabolism,Homeostasis & Related Diseases

  2. Objectives of Lectures By the end of these lectures, students should be able to: • Recall Calcium Sources, Distributions & Functions • Understand Organ & Endocrinal Homeostasis of Calcium with recognition of the roles of: - Vitamin D - Parathyroid Hormone (PTH) - Calcitonin Hormone • Verify Main Causes of Hypocalcaemia & Hypercalcemia • Recognize the biochemical and Clinical Interrelations of Metabolic diseases of bone: - Rickets & Osteomalacia - Osteoporosis

  3. 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

  4. 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

  5. Dietary Sources of Calcium • Rich: Milk, milk products as cheese & yoghurt • Fair Legumes, vegetables

  6. Biological Functions of Calcium • Bone Formation • 99 % • in bone • Reservoir for ECF [Ca2+] Total Calcium Of the Body • Blood Clotting • ECF • Excitability of Nerve & Muscle • 1 % • Metabolic Regulation for Action of Hormones & Enzyme Activation • ICF

  7. Calcium in Blood

  8. Organ Calcium Homeostasis

  9. Organ Calcium Homeostasis cont. The concentration of calcium, phosphorous & magnesium in the plasma depends on ORGAN PHYSIOLOGY: • Net effect of bonemineral deposition & resorption • Intestinalabsorption • Renalexcretion

  10. Endocrinal Calcium Homeostasis • Parathyroid Hormone (PTH) • Active Vitamin D(Calcitriolor 1,25 DHCC) • CalcitoninHormone Blood [Ca2+] is Regulated By:

  11. Vitamin D A group of sterols with a hormone-like function. 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 NOTbiologically 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 Active Vitamin D 1, 25 dihydroxycholecalciferol (Calcitriol or DHCC)

  12. 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

  13. 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 • 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 biologicallyactive form of vitamin D

  14. Functions of Vitamin D Active vitamin D (1, 25 DHCC or Calcitriol) regulates calcium levels in the body (calcium homeostasis) Through: • Increasing absorption of calcium by the intestine • Minimizing loss of calcium by kidney • Stimulating resorption of bone(when necessary) Deficiency of Active Vitamin D (1, 25-DHCC or Calcitriol) Defective Bone Mineralization (poor calcification)

  15. Mechanism of Action of Vitamin D In the intestine: 1, 25-DHCC bind to vitamin D receptors forming a complex that binds to the vitamin D response element upstream of the transcription start site of vitamin D influenced genes causing enhancing gene transcription of genes of calcium transport from intestinal lumen (calcium absorption). In the bones: 1, 25-DHCC stimulates terminal differentiation of osteoclasts precursors to osteoclasts & also stimulates osteoblasts to influence osteoclasts to mobilize bone calcium 1, 25-DHCC does not directly affect mature osteoclastic physiology

  16. Parathyroid hormone (PTH)

  17. 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)

  18. 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

  19. 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

  20. 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

  21. MAIN CAUSESof HYPOCALCEMIA • 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.Dabsorption

  22. 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 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)

  23. Rickets & Osteomalacia Metabolic Diseases of Bones RICKETS Normal formation of the collagen matrix BUT Incomplete mineralization (poor calcification) SoftBones CLINICALLY: Bone Deformity OSTEOMALACIA Demineralization (poor calcification) of preexisting bones with CLINICALLY: More Susceptibility toFracture

  24. Renal RicketsRenal 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)

  25. Laboratory Investigations for the Diagnosisof 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: • Kidney function tests (KFT) • Blood 1, 25 dihydroxycholecalciferol (1, 25 DHCC) • Blood PTH • Others i.e. molecular genetics (if indicated)

  26. Metabolic Diseases of Bone: Osteoporosis • Mostprevalent 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 • 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) • Post-menopausal women lose more bone mass than men (primary osteoporosis) • Osteoporosis diagnosis is by dual energy x-ray absorpitometry (DXA) scan • Lab diagnosis: notconclusive

  27. Metabolic Diseases of BoneOsteoporosis

  28. Secondary OsteoporosisRisk Factors Secondary osteoporosis may be caused by reduced bone mass with increased consequent risk of fractures Risk Factors for osteoporosis: • 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

  29. Case Study-1 • 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 • 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)

  30. DIAGNOSIS of Case-1 The parathyroid glands were removed during thyroidectomy  PTH undetectable  Hypocalcemia  Clinical Manifestations of hypocalcemia (increased reflexes & muscular cramping)

  31. Case Study-2 • 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)

  32. DIAGNOSIS of Case-2 Pseudohyperparathyroidism  In which there is genetic mutations in the stimulatory G-protein  IN ACTIVE G Protein  No activation of adenylatecyclase  NO cAMP  NO EFFECT OF PTH HYPOCALCEMIA  INCREASE OF PTH (HYPERPARATHYROIDISM WITH HYPOCALCEMIA)  TO BE CONFIRMED by MOLECULAR GENETIC ANALYSIS

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