MINERAL METABOLISMMr.Tapeshwar Yadav (Lecturer)B.M.L.T, D.N.H.EM.Sc. Medical Biochemistry

Minerals

Minerals are essential for normal growth and maintenance of the body.

Major elements : Requirement >100 mg /day Calcium Chloride Magnesium Sulphur Phosphorous Fluoride Sodium Potassium

Contd….

Trace Elements : Requirement <100mg/day

Iron Zinc Iodine Molybdenum Copper Selenium Manganese

Contd….

Some are necessary for the body but their exact functions are not known.

Ex.: Chromium, Nickel, Bromide, Lithium, Barium

Non-Essentials : seen in tissues. Contaminants in food stuffs.

Ex.: Rubedium, Silver, Gold, Bismuth Toxic : should be avoided. Ex.: Aluminium, Lead, Cadmium, Mercury

CALCIUM (Ca)Total Calcium in human body: 1 – 1.5 Kg In Bones – 99 % In extra cellular fluid – 1 % Sources : - Milk (Cow’s Milk – 100mg/100ml)

- Egg, Fish, Vegetables - moderate - Cereals (wheat, rice) - poor

source

Daily RequirementAdults : 500 mg/day

Children : 1200 mg/day

Pregnancy and Lactation : 1500 mg/day

>50 yrs. : 1500 mg/day

+20µg Vit.D

(to prevent osteoporosis)

Absorption

1st and 2nd part of duodenum

Against concentration gradient and

requires energy

Requires carrier protein

Factors promoting Ca absorption

Vitamin – D (calcitriol)

synthesis of carrier protein calbindin – facilitates

absorption

Parathyroid Hormone – ↑ Ca transport from

intestinal cells

Acidity – favors Ca absorption

Amino acids – Lysine and Arginine

Factors Inhibiting Ca absorption

Phytates and oxalates - form insoluble calcium

oxalates

High dietary phosphates - precipitate as calcium

phosphate

High pH - (alkaline)

High dietary fiber

Mal absorption syndrome - Fatty acids not absorbed

and form insoluble calcium salts of fatty acid

Functions

1. Bones & Teeth :

Formation of bone & teeth.

Bones are reservoir for Ca in the body.

Osteoblasts → bone deposition

Osteoclasts → demineralization.

2. Muscle Contraction :

Ca mediates excitation & contraction of

muscle fibers.

Ca interacts with Troponin-C to trigger

muscle contraction.

Ca activates ATPase, ↑ interaction between

actin and myosin.

3. Nerve Conduction :

Transmission of nerve impulses from pre-

synaptic to post-synaptic region.

4. Secretion of hormones :

Mediates the secretion of Insulin, PTH,

Calcitonin, Vasopressin etc.

5. Second Messenger :

Ca & cyclic AMP are 2nd messengers of

different hormones. Eg: Glucogan

6. Membrane integrity & Permeability :

Influences transport of number of

substances across the membranous barrier.

7. Blood Coagulation :

Factor IV in blood coagulation cascade.

prothrombin → Thrombin

8. Action on Heart :

Ca prolongs Systole.

↑ Ca concentration → ↑ myocardial

contractility

The Calcium-Binding Region of Prothrombin

Prothrombin binds calcium ions with the modified

amino acid g-carboxyglutamate (red).

9. Activation of Enzymes :

Calmodulin – Ca binding regulatory

protein. Binds with 4 Ca ions and leads

to activation of enzymes.

Calmodulin contains four similar units in a single

polypeptide chain shown in red, yellow, blue, and

orange. Each unit binds a calcium ion (shown in green).

Plasma Calcium

Normal Plasma / Serum Calcium : 9 – 11 mg / dl Ionized Calcium : 5 mg/dl

Protein bound Calcium : 4 – 5 mg/dl

Complexed with phosphate/citrate/ bicarbonate : about 1 mg/dl

Homeostasis of Ca

The major factors that regulate the plasma

Calcium

• Calcitriol

• Parathyroid hormone

• Calcitonin

Calcitriol

• ↑ intestinal absorption of Ca.

• Stimulates Ca uptake by osteoblasts and

promotes Calcification.

P T H

Elevates serum Ca

• Demineralization of bone (Osteoclasts)

• Increases Ca reabsorption by renal tubules

• Increases intestinal absorption of Ca by

promoting synthesis of Calcitriol

Calcitonin secreted by Para follicular cells of Thyroid gland

Lowers the serum Ca levels

• Calcification of bone (by osteoblasts)

• Increases the excretion of Ca into urine

Calcitonin & PTH are directly antagonistic

Calcitriol PTH Calcitonin

Blood calcium ↑ ↑ ↓

Main action Absorption

from gut

Deminerali

-zation

Oppose

demineraliza

-tion

Disorders of Calcium Metabolism

Hypercalcemia : > 11 mg/dl

causes:Hyperparathyroidism - Parathyroid adenoma ectopic parathyroid secreting tumor Multiple myeloma Paget’s disease Metastatic carcinoma of bone.

Hypocalcemia

TETANY

Ca < 8.5 mg/dl → mild tremors

< 7.5 mg/dl → typical Tetany

Causes :

Accidental removal of parathyroid glands

Autoimmune disease

Symptoms :

• Neuromuscular irritability

• Carpopedal spasms

• Laryngismus → stridor (noisy breathing)

laryngeal spasms may lead to death.

Signs : Chovstek’s sign +

Trousseau’s sign +

↑ Q-T interval in ECG

Chovstek’s sign• A twitch of the facial

muscles following

gentle tapping over the

facial nerve in front of

the ear that indicates

hyperirritability of the

facial nerve

Trousseau’s sign

• A test for latent tetany in which carpal

spasm is induced by inflating a

sphygmomanometer cuff on the upper arm

to a pressure exceeding systolic blood

pressure for 3 minutes.

Carpopedal spasm

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MINERALS

• Total body iron content : 3 - 5 gm • Iron is present in almost all cells• Heme containing proteins: Hb,

myoglobin, cytochromes, cytochrome oxidase, catalase, peroxidase, xanthine oxidase & Trp pyrrolase

• 75% of total Fe is in Hb & 5% in myoglobin

• Non-heme iron containing proteins : ferritin, transferrin, hemosiderin, lactoferin (milk) & neutrophils

Tissue Respiration :Iron can change readily between Ferrous and Ferric states and function in electron transfer reactions.

Cytochromes NADH dehydrogenase Succinate dehydrogenase

Transport of gases : Able to bind with molecular O2 and CO2.

The main function is to coordinate the O2

molecule into heme of hemoglobin, so that it can be transported from the lungs to the tissues.

Oxidative Reactions : Component of various oxidoreductase enzymes

-vital role in oxidative reactions.

Immune Response :Required for effective activity of lysosomal enzyme peroxidase – helps in phagocytic and bactericidal activity of neutrophils.

Indian diet contain >10 – 20 mg of Iron.

only about 10% of it is absorbed. 1 mg is eliminated each day from human

body by shredding of skin epithelial cells & cells lining urinary tract & small extent in urine + sweat.

20-40 mg - blood loss in each menstrual cycle.

↑ daily demand to 3-4 mg in pregnant & lactating women.

900 mg – diversion of Iron to foetus in pregnancy.

blood loss during delivery subsequent breast

feeding

Children : 10 mg/dayAdultsAdults Males : 10-12 mg/dayWomen Premenopausal : 18 mg/dayPostmenopausal : 10 mg / dayPregnant & Lactating : 40 mg/day

Good sources: Leafy vegetables (20mg/100g), pulses (10mg/100g), cereals (5mg/100g), liver (5mg/100g), meat (2mg/100g), fish, dried fruits, jaggery and iron cookware

Poor sources: Milk (0.1 mg/100 ml), wheat, polished rice

Ferric ions are reduced with the help of gastric HCl, ascorbic acid, cys. and -SH groups of pro. --------- favors absorption.

Ca, Cu, Zn, Pb ------------- inhibit absorption. Phytates (in cereals), oxalates (leafy veg) &

phosphates in the diet reduce absorption by forming insoluble iron salts.

Marginal ↓ by tea & eggs.

Mucosal block theory Absorbed by upper part of duodenum Homeostasis is maintained at the level of

absorption Iron stores depleted - absorption ↑ Iron stores adequate - absorption ↓

Only Fe++ (ferrous) form is absorbed and not Fe+++ (ferric) form.

Ferrous Iron binds to mucosal cell protein called Divalent Metal Transporter - 1 (DMT-1).

This bound Iron is then transported into the mucosal cell.

Unabsorbed Iron is excreted.

Lumen of GIT Mucosal cells of GIT Plasma Tissues

Food Fe Apoferritin Apotransferrin HCl Organic acids Ferritin Transferrin

(Fe+++)Fe+++ Fe+++ Ferro- Fe+++

Ascorbic acid reductase Cysteine Ferroxidase Fe++ Ceruloplasmin

or Ferroxidase IIFe++ Fe++ Fe++

Iron absorption and transport

LiverFerritin

hemosiderin

Bone marrow (Hb)

Muscle (Mb)Other tissues

Iron oxidized to ferric state.complexed with apoferritin to form Ferritin.

Ferric Iron is released, reduced to Ferrous state crosses the cell membrane.

Lumen of GIT Mucosal cells of GIT Plasma Tissues

Food Fe Apoferritin Apotransferrin HCl Organic acids Ferritin Transferrin

(Fe+++)Fe+++ Fe+++ Ferro- Fe+++

Ascorbic acid reductase Cysteine Ferroxidase Fe++ Ceruloplasmin

or Ferroxidase IIFe++ Fe++ Fe++

Iron absorption and transport

LiverFerritin

hemosiderin

Bone marrow (Hb)

Muscle (Mb)Other tissues

Reoxidized to Ferric state by Ceruloplasmin Ferric Iron bound with Transferrin and

transported to tissues.

Lumen of GIT Mucosal cells of GIT Plasma Tissues

Food Fe Apoferritin Apotransferrin HCl Organic acids Ferritin Transferrin

(Fe+++)Fe+++ Fe+++ Ferro- Fe+++

Ascorbic acid reductase Cysteine Ferroxidase Fe++ Ceruloplasmin

or Ferroxidase IIFe++ Fe++ Fe++

Iron absorption and transport

LiverFerritin

hemosiderin

Bone marrow (Hb)

Muscle (Mb)Other tissues

One-way element (very little of it is excreted)

Almost no iron is excreted through urine Any type of bleeding will cause the loss

Normal level in plasma -------- 50 - 175 µg/dl

Iron deficiency anemiaIron deficiency anemia is the most common nutritional deficiency diseases

Characterized by microcytic microcytic hypochromic anemiahypochromic anemia (blood Hb <12 g/dl)

Clinical Manifestations: Anemia, Apathy Achlorhydria Impaired attention, Irritability, Lowered

memory Koilonychia (spoon nails)

Koilonychia

Hookworm infection Nephrosis Repeated pregnancy Lack of absorption Nutritional deficiency of Fe Chronic blood loss (piles, peptic ulcer,

uterine hemorrhage)

HEMOSIDEROSIS --------- uncommon Occurs in persons receiving repeated blood

transfusion (in hemophilia, hemolytic anemia).

Common in Bantu tribe, because of staple diet, corn, is low in phosphates, and their habit of cooking foods in iron vessels.

It is manifested when total body iron is >25-30

gm, where hemosiderin is deposited in almost all

tissues.

Primary Hemochromatosis :- genetic disorder – excessive

storage of Iron in tissues → tissue damage.

Secondary Hemochromatosis :- repeated blood transfusions- excessive oral intake of Iron

eg. as in African Bantu tribes

Deposition of iron Liver cell death ------ cirrhosiscirrhosis Pancreatic cell death -------- diabetesdiabetes Deposits under the skin cause yellow-brown

discoloration ---------- hemochromatosishemochromatosis

The triad of cirrhosis, diabetes and hemochromatosis ------- bronze diabetesbronze diabetes

The total body phosphate – 1 kg 80 % - Bone & Teeth 10 % - MusclesMainly Intracellular ion – seen in

all cells.

Formation of bone & teeth Production of high energy phosphates: ATP CTP GTP creatine phosphate Synthesis of nucleoside co-enzymes: NAD+ and NADP+

DNA and RNA synthesis: Phosho-diester linkages –backbone of structure

Formation of phosphate esters: Glucose 6-phosphate, phospholipids Formation of phosphoprotein: Casein Activation of enzymes by

phophorylation Phosphate buffer system of blood: maintain the pH of blood at 7.4.

500 mg/day Milk - good source cereals Nuts moderate source Meat Calcitriol increases phosphate

absorption

Normal adults - 3 – 4 mg/dl Children - 5 – 6 mg/dl Whole blood phosphate – 40 mg/dl

Decrease in phosphate levels:Hyperparathyroidism

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SODIUMSODIUM

Chief cation of Extracellular fluid.Total body Sodium – 4000 mEq 50 % in bones 40 % in extracellular

fluid 10 % in soft tissues

Biochemical FunctionsBiochemical Functions

Sodium (as sodium bicarbonate) regulates the body acid base balance.

Sodium regulates ECF volume: Sodium pump is operating in all cells,

so as to keep Sodium extracellular. This mechanism is ATP dependent.

Required for maintenance of osmotic pressure and fluid balance.

Necessary for normal muscle irritability and cell permeability.

Daily requirementDaily requirementNormal diet contains 5 – 10 gm of

sodium mainly as sodium

chlorideSources : Common salt used in cooking

medium Bread whole grains Nuts leafy vegetables Eggs Milk

AbsorptionAbsorptionReadily absorbed in the GI tract. very little < 2 % is found in

faeces.

In Diarrhea – large quantities of sodium

is lost in faeces.

ExcretionExcretionKidney – major route of sodium

excretion800 gm/day of Na filtered in glomuruli 99 % - reabsorbed by proximal

convoluted tubule. ↑ reabsorption in distal tubules

controlled by aldosterone.

In edema – water & sodium content of the body increase.

Diuretic drugs – excrete Na also along with water.

Normal ValuesNormal ValuesIn plasma - 136 – 145 mEq/LIn cells - 35 mEq/LMineralocorticoids influence Na metabolism

in adrenocortical insufficiency ↓ plasma Na ↑ urinary excretion of Na

HypernatremiaHypernatremiaCushing’s diseaseProlonged cortisone therapyIn dehydration – water

predominantly lost the blood volume decreased with apparent ↑conc. of sodium

HyponatremiaHyponatremiaVomitingDiarrheaBurnsAddison’s disease (adrenal insufficiency)In severe sweating, Na is lost

considerably - muscle cramps & headache.

Biochemical estimation Biochemical estimation Flame photometerIon selective electrodes

POTASSIUM

Principal intraracellular cation.Total body Potassium – 3500 mEq 75 % in skeletal muscleRequired for regulation of acid base balance and water balance in cells.

Maintains intracellular osmotic pressure.Required for transmission of nerve impulse.

Enzyme – Pyruvate kinase (of glycolysis) depend on K+ for optimal activity.

Adequate intracellular concentration of K+ is necessary for proper biosynthesis of proteins by ribosomes.

Extracellular K+ influences cardiac muscle activity.

Dietary requirement3 – 4 g / daySources : Banana Potato

Orange Beans Pineapple Chicken Liver Tender coconut water – rich source

Absorption & excretionAbsorption: From GI tract – very efficient (90%)

In diarrhea – good proportion of K+ is lost in feces

Excretion : Through urineAldosterone ↑excretion of potassium.

Normal valuesIn plasma : 3.4 – 5.0 mEq/LIn whole blood : 50 mEq/LEither high or low concentrations are dangerous since K+ affects contractility of cardiac muscle

HypokalemiaOver activity of Adrenal cortex (Cushing’s syndrome)

Prolonged cortisone therapyProlonged diarrhea & vomitingDiuretics used for CCF may cause K+

excretionS/S: irritability, muscular weakness,

tachycardia, cardiomegaly & cardiac arrest

ECG - flattened waves with T ↓

HyperkalemiaRenal failureAdrenocortical insufficiency (Addison’s

disease)Diabetic comaS/S : depression of CNS mental confusion numbness bradycardia - cardiac arrest ECG - T ↑

Prevents dental cariesIncreases hardness of bones and teeth

Sources: drinking waterRequirementsChildren : 0.5-2.5 mg/dayAdults : 2.0-5.0 mg/daySafe limit of fluoride : 1 ppm (parts

per million)1 ppm: 1 gm of F in million gm of water,

which is equal to 1 mg per 1000ml

Dental caries: < 0.5 ppmDental fluorosis: > 2 ppm

In children; mottling of enamel & discoloration of teeth. In adults; chronic intestinal upset, loss of weight, loss of appetite & gastroenteritis

Skeletal fluorosis: >20 ppm; toxicOsteoporosis & osteosclerosis, with

brittle bones

Ligaments of spine & collagen of bones get calcified

Genu valgum: advanced cases of skeletal fluorosis (stiff joints)

Plasma: normal value : 4 µg/dlfluorosis : 50 µg/dl

Iodine• Total body iodine : 25-30 mg (80% in

thyroid gland)

Formation of thyroid hormones (T3 & T4)

Requirements:Children : 40-120 µg/dayAdults : 100-150 µg/dayPregnant women : 175 µg/day

Commercial source: seaweedsOther sources: drinking water, vegetables,

fruits, iodized salt Absorption: small intestine

only 30% of iodine in food is absorbedGoiterogenousGoiterogenous substancessubstances prevent absorption of iodine

Eg: i, Cabbage & tapioca contain thiocyanatethiocyanate, which inhibits iodine uptake by thyroidii, Mustard seed contains thioureathiourea, which inhibits iodination of thyroglobulin

Storage: iodothyroglobulin (glycoprotein)

Excretion: mainly through urine and also through bile, saliva and skin

Plasma: 4-10 µg/dl

Deficiency:

Children : cretinism

Adults : goiter, hypothyroidism, myxedema

Zinc Total body Zn: 2 gm (99% is intracellular)

60% in skeletal muscle

30% in bones

Prostate gland contains 100 µg/g & liver 50 µg/g

Sources: grains, beans, nuts, cheese, eggs, milk, meat & shell fish

Absorption: duodenum

Cu, Ca, Cd, Fe & phytate interfere absorption.

Storage: in liver with a specific protein, metallothionine.

Biochemical functions Cofactor for more than 300 enzymes

eg: carboxy peptidase, carbonic anhydrase, ALP, LDH, ADH, superoxide dismutase & glutamate dehydrogenase.

Participate in the metabolism of carbohydrates, lipids, proteins & nucleic acids.

Required for transcription and translation.

Stabilizes insulin, when stored in β- cells of pancreas.

Promotes the synthesis of retinol binding protein.

GustenGusten, Zn containing protein in saliva, is important for taste sensation.

Role in growth, reproduction & wound healing.

Requirement:Children : 5-10 mg/dayAdults : 10-15 mg/dayPregnancy & lactation : 15-20 mg/dayDeficiency: HypogonadismGrowth failureImpaired wound healingDecreased taste and smell acuityPlasma : 50-150 µg/dl

COPPER (CU)

MINERALS

Introduction

Total body Cu is 100 mg; quantitatively this is next to iron and zinc

It is seen in muscles, liver, bone marrow, brain, kidney, heart and hair

Cu containing enzymes:Ceruloplasmin, cyt. oxidase, cyt. C,

tyrosinase, lysyl oxidase, ALA synthase, monoamine oxidase, cytosolic superoxide dismutase, uricase and phenol oxidase

Requirement & Sources

Infants & children : 1.5-3 mg/day

Adults : 2-3 mg/day

Sources:

• Cereals, meat, liver, kidney, egg yolk, nuts and green leafy vegetables

• Milk is a poor source

Absorption

Mainly from duodenum and is mediated by a Cu binding protein (metallothioneinmetallothionein)

Only about 10% of dietary Cu is absorbedRate of absorption is reducedreduced by phytates,

Ca, Fe, Zn and Mo in the intestines

Storage: liver & bone marrow

Transport: albumin

Excretion: bileUrine doesn't contain Cu in normal

circumstancesPlasma copper: 100-200 µg/dl 95% is tightly bound to ceruloplasminceruloplasmin Small fraction (5%) is loosely held to

histidine residues of albumin Normal serum conc. of ceruloplasmin:

25-50 mg/dl

Deficiency

microcytic normochromic anemiamicrocytic normochromic anemia

Fragility of arteries, deminiralization of bones, demyelination of neural tissue, myocardial fibrosis, hypopigmentation of skin, greying of hair

Minke’s kinky hair syndrome: results from defective cross linking of connective tissue due to Cu deficiency

Wilson’s hepatolenticular degeneration

Rare (1 in 50,000)Cu deposition Liver : hepatic cirrhosis Brain (lenticular nucleus): brain necrosisKidney : renal damage

Chronic toxicity may lead to diarrhea and blue-green discoloration of saliva.

Least abundant and most toxic of essential elements

SourcesPlants (varies with soil content), meat,

sea foodsRequirementsChildren : 10-30 µg/dayAdult male : 40-70 µg/day

female : 45-55 µg/dayPregnancy & lactation : 65-75 µg/day

Acts as a nonspecific intracellular antioxidantantioxidant by providing protection against peroxidation in tissues and cell membranes.Complementary to vit. EComplementary to vit. E; availability of vit. E reduces the Se requirement.Glutathione peroxidaseGlutathione peroxidase protects the cells against the damage caused by H2O2

.

Protects from developing liver cirrhosis. Conversion of T4 to T3 by 5´- deiodinase.5´- deiodinase.

Normal value: 13 µg/dl Most of the Se in blood is a part of

glutathoine reductase.glutathoine reductase. Inside the cells, it exists as

selenocysteineselenocysteine and selenomethionine.selenomethionine.

Absorption: : duodenum Se is Se is carcinogeniccarcinogenic in animals, its in animals, its

oncogenic influence in man is not oncogenic influence in man is not established.established.

Marginal deficiency; Marginal deficiency; when soil content is low.In animalsIn animals; hepatic necrosis, retarded growth, muscular degeneration, infertility.In humansIn humans; congestive cardiomyopathy (Keshan disease) in China.

Toxicity: selenosis selenosis ( 900 µg/day)Hair loss, dermatitis, irritability, purple streaks in nails, falling of nails, diarrhea and garlicky odor in breath (dimethyl selenide).

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