MINERALS

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Dr. Ashish Agravatt ,

MBBS, MD.

MINERALS

MINERALS

MINERALS

MINERALS

CALCIUM

CALCIUM

Calcium is the most abundant mineral in the body

SOURCES OF CALCIUM

DAILY REQUIREMENTS OF CALCIUM

METABOLISM OF CALCIUM

METABOLISM OF CALCIUM - ABSORPTION

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SITE : first part and second part of duodenum

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Calcium absorbed against concentration gradient

and requires energy and a carrier protein.

Factors affecting absorption:

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INCREASE THE ABSORPTION RATE

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1.CALCITRIOL

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2. PARATHYROID HORMONE

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3.ACIDITY

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4.AMINOACIDS – Lysine and Arginine

FACTORS THAT DECREASE ABSORPTION RATE:

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1.PHYTATES

2.OXALATES

3.HIGH PHOSPHATE CONTENT

OPTIMUM RATIO OF CALCIUM TO PHOSPHATE CONTENT– 1:2 TO

2:1----- allows maximum absorption.

4.FREE FATTY ACIDS ( FFA)

Ca+ FFA – In soluble calcium soaps (Steatorrhoea)

5. ALKALINE MEDIUM

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6. HIGH DIETARY FIBRE

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FACTORS AFFECTING CALCIUM ABSORPTION

MECHANISM OF CALCIUM ABSORPTION

Calcium absorption occurs by 1,25(OH)₂D₃ mediated mechanism.

EXCRETION OF CALCIUM

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1.Mineralisation of Bones and teeth. Bone is a mineralized connective tissue.

It contains organic (collagen – protein) and inorganic (mineral) Component,

HYDROXY APATITE, Ca10(Po4)6 (OH)₂

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- Calcium is factor IV in coagulation cascade.

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Prothromlin (factor II) contains Gla(γ Carboxy glutamate) Residues.

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Calcium forms a bridge between Gla residues of prothrombin and membrane phospholipids of platelets

Functions of Calcium

• 2. Homeostasis

-activation of clotting enzyme is the plasma

Functions of Calcium

• 1. Nerve and muscle functions
• Decreased extracellular calcium – increase excitability of excitable cells and lowers the threshold potential – less inward current is required to depolarize the threshold potential – less inward current is required to fire AP
• Hence causing tingling ad numbness (sensory) and spontaneous muscle twitches (motor neurons and muscles)

Functions of Calcium

Cross bridge cycling

• Increase in intracellular Ca²⁺ concentration 🡪 Ca²⁺ binds to troponin C 🡪 conformational change in the troponin complex 🡪 moves tropomyosin out of the way 🡪 permitting the binding of actin to the myosin heads leading cross-bridge formation and the muscle contracts as a whole

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Calmodulin is a Calcium binding regulatory protein molwt 17000

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Calmodulin can bind with 4 calcium ions

Mechanism of action of Calcium

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Mediated by Calmodulin

1. Adenyl cyclase

2. Ca⁺⁺ dependent protein kinases

3. Ca⁺⁺ -Mg⁺⁺ ATPase

4. Glycogen synthase

5. Phospholipase C

6. Phosphorylase kinase

7. Pyruvate carboxylase

8.Pyruvate dehydrogenase

9. Pyruvate kinase.

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Mediated by Calmodulin

1. Adenyl cyclase

2. Ca⁺⁺ dependent protein kinases

3. CA⁺⁺ -Mg⁺⁺ ATPase

4. Glycerol – 3 – phosphate dehydrogenase

5. Glycogen synthase

6. Phospholipase C

7. Phosphorylase kinase

8. Pyruvate carboxylase

9. Pyruvate dehydrogenase

10. Pyruvate kinase.

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Calcium is necessary for transmission of nerve impulses from pre-synaptic to post – synaptic region.

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Calcium mediates secretion of Insulin, parathyroid hormone, calcitonin, vasopressin,etc. from the cells

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Calcium and cyclic AMP are second messengers of different hormones . One example is glucagon. Calcium is used as second messenger in systems involving G proteins and inositol triphosphate.

8. MYOCARDIUM

In myocardium, Ca⁺⁺ prolongs systole.

In hypercalcemia cardiac arrest is seen in systole.

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Caution : when calcium is administered intravenously, it should be given very slowly.

DISTRIBUTION AND STORAGE OF CALCIUM

Plasma calcium : 9-11mg/100ml

FUNCTIONS OF CALCIUM

Formation of bone and teeth

Nerve conduction

Muscle contraction

Activation of enzymes

REGULATION OF ENZYME ACTIVITY

REGULATION OF PLASMA CALCIUM

Normal serum level of calcium -- 9 to 11 mg /dl

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Ionized calcium -- 5 mg/dl

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Calcium complexed

with Po4, citrate -- 1 mg/dl

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Protein bound

Calcium -- 4 mg/dl

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IONIZED CALCIUM IS METABOLICALLY /�BIOLOGICALLY ACTIVE FORM.

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• Hypoalbuminemia results in ↓ of plasma total Calcium levels
• Each 1gm of Albumin ↓ causes ↓ of 0.8mg/dl of Calcium
• Hyperproteinemias (paraproteinemia) are associated with ↑ plasma total Calcium level
• Acidosis favours release of ionized Calcium.
• Alkalosis favours binding of Calcium and decreases ionized Calcium level,but total calcium is normal.

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Acid Base Abnormality

REGULATION OF PLASMA CALCIUM

Calcium Homeostasis

• Blood calcium is tightly regulated by:

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1) Principle organ systems:

Intestine

Bone

Kidney

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2) Hormones:

Parathyroid hormone (PTH)

Vitamin D

Calcitonin

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Calcium homeostasis :

Plasma calcium is maintained within narrow limits.

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Major factors involved in homeostasis

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1. Calcitriol - increase calcium
2. Parathormone - increase calcium

3. Calcitonin - decrease calcium

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Parathyroid Hormone (PTH)

• There are 4 parathyroids glands, located on the dorsal side of the thyroid
• The blood supply to the parathyroid glands is from the thyroid arteries.

Parathyroid Glands

Parathyroid Hormone (PTH)

• Chief cells secrete PTH

• Oxyphil cells – function unknown. Probably degenerated chief cells

Parathormone

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• Secreted by chief cells of parathyroid.

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• Release of PTH is mediated by c-AMP.

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• Three independent sites of action.

they are bone , kidney and intestine.

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• All the 3 actions of PTH increase serum calcium level.

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BONE :

• acts directly on bone.
• causes demineralisation /decalcification
• increases number of osteoclasts and induces pyrophosphatase in them.

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• osteoclasts release lactate into surrounding medium which solubilise calcium and move it into ECF.
• Also secretes collagenase from osteoclasts which cause loss of matrix and bone resorption

KIDNEY

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PTH has direct action .

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• decreases renal excretion of calcium ( mainly

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by increased reabsorption of calcium from distal

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tubules)and increases phosphate excretion.

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Intestine

PTH stimulates 1 –hydroxylation of 25-cholecalciferol

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Forms calcitriol

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Calcitriol induces synthesis of calbindin

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Calbindin increase calcium absorption from intestine

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Thereby increasing calcium level in blood.

Parathyroid Hormone (PTH)

Calcitonin :

secreted by parafollicular cells of thyroid.

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• Calcitonin promotes calcification by increasing the activity of osteoblasts.

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• Calcitonin decreases bone resorption.

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• It increases the excretion of Ca in urine.

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• Overall it decreases blood Ca level.

Calcium Homeostasis

Vitamin D

Vitamin D

• Actions of vitamin D

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Importance of Ca : P ratio

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Product of Ca x P ( 10 x 4 )

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Normal Adults – 40

Children – 50

<30 Rickets

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Normal Ca : P ratio is essential for bone mineralisation.

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DISORDERS OF CALCIUM METABOLISM

HYPOCALCEMIA

HYPOCALCEMIA

�Hypocalcaemia�

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). 

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Causes include hypoparathyroidism

, vitamin D deficiency, and renal disease. 

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• 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

�Hypocalcaemia�

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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�Hypocalcaemia�

• 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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HYPOCALCEMIA - FEATURES

�Clinical manifestations of Hypocalcaemia�

• Hypocalcemia is frequently asymptomatic. 
• Major clinical manifestations of hypocalcemia are due to disturbances in cellular membrane potential, resulting in neuromuscular irritability.

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• 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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Clinical manifestations of Hypocalcaemia

• 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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Diagnosis 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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HYPOCALCEMIA – SIGNS OF TETANY

Trousseau's sign

Clinical manifestations of Acute Hypocalcaemia

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HYPOCALCEMIA - TREATMENT

�Treatment 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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HYPERCALCEMIA

HYPERCALCEMIA

Principal Causes of Hypercalcemia

A) Cancer with bone metastases

• Carcinoma
• Leukemia
• Lymphoma
• Multiple myeloma

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�Principal Causes of Hypercalcemia�

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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Principal Causes of Hypercalcemia

C) Parathyroid hormone excess

• Parathyroid carcinoma
• Primary hyperparathyroidism
• Secondary hyperparathyroidism

D) Vitamin Toxicity

• Vitamin A toxicity
• Vitamin D toxicity

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Principal Causes of Hypercalcemia

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 to hyperparathyroidism

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HYPERCALCEMIA - FEATURES

Clinical manifestations of Hypercalcaemia

• 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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Clinical manifestations of Hypercalcaemia

• 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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Clinical manifestations of Hypercalcaemia

• 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 QT_c 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 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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HYPERCALCEMIA - TREATMENT

Treatment 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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Treatment of Hypercalcaemia

• 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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Treatment of Hypercalcaemia

• 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 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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Summary of calcium metabolism

• 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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Summary of calcium metabolism

• 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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