Metabolism of 

Minerals
18

18.1 Calcium

Calcium is the most significant mineral of hard tissues of the body. It is distributed
in various foods. The human body requires calcium for strength of bones and teeth.
It is also essential for many physiological functions. Calcium is necessary for con-
tractility of muscles and nerve conduction. It is essential cofactor in activity of
enzymes and hormones.

Distribution of Calcium in the Body

An adult person of 70 kg body weight contains around 1000 g calcium. It represents
around 1.5% of the total weight of the body. Endoskeleton of the body contains
around 990 g calcium. It amounts to nearly 99% of the total calcium content of the
body. Calcium in bones exists as complexes of phosphate and carbonate with cal-
cium. Skeletal calcium serves two functions. It is a labile pool of calcium to main-
tain intracellular and extracellular levels of calcium. Skeletal calcium provides
bone strength.
Non-skeletal tissues contain approximately 10g calcium which represents
nearly 1% of the total calcium content of the body. Soft tissues possess 0.5% cal-
cium, and extracellular compartment has 0.1% calcium. Normal plasma calcium
level is between 9 and 11 mg/100 ml.

Dietary Sources
Animal Sources
• A rich source is yogurt (dairy edible obtained by bacterial fermentation of
milk).
• Good sources are milk, cheese, sardine, salmon, and egg yolk.

Plant Sources
• Good sources are cereals, lentils, nuts, turnip, and cabbage.

© Springer Nature Singapore Pte Ltd. 2019 473

A. Gupta, Comprehensive Biochemistry for Dentistry,
https://doi.org/10.1007/978-981-13-1035-5_18
474 18  Metabolism of Minerals

Recommended Dietary Allowance

Adults
• RDA for adults is about 800 mg per day.

Children
• RDA for children is 1.2 g per day.

In Pregnancy and Lactation

• RDA in pregnancy and lactation is 1.5 g per day.

Forms of Calcium in Plasma

Calcium in plasma exists in three forms as:
• Ionized Calcium
–– Ionized calcium is about 51% of total non-skeletal calcium (>5 g).
–– Ionized calcium is metabolically active, and it is involved in physiological
and metabolic functions.
• Protein-Bound Calcium
–– Protein-bound calcium is nearly 40% of total non-skeletal calcium
(~ 4 g).
–– Important plasma proteins that bind to calcium are albumin and globulin.
–– Calmodulin (calcium-modulated protein) is present in cytoplasm of cells.
• Calcium Complexes
–– Calcium complexes are nearly 9% of total non-skeletal calcium (~1 g).
–– Important complexes of calcium are calcium phosphate, calcium oxalate, and
calcium carbonate.

Non-skeletal calcium performs multiple functions.

• It is necessary for cell signaling.

• It is necessary for muscle contraction.
• It is responsible for nerve impulse transmission.
• It is important in blood clotting.

Absorption of Calcium
• Dietary calcium is found in complexes like calcium carbonate, calcium
phosphate, and calcium tartrate.
• Calcium absorption occurs by mucosa of the small intestine.
• At low intraluminal calcium level
–– Calcium is absorbed by passive diffusion
–– It occurs in favor of concentration gradient and is the slow process of
absorption.
• At high intraluminal level
–– Calcium absorption occurs by active transport.
–– It is an ATP-dependent process.
–– Active transport is regulated by 1,25-dihydroxy cholecalciferol (calcitriol).
18.1 Calcium 475

–– Calcitriol controls synthesis of calbindin (calcium-binding protein located in

brush borders of duodenum).
–– Calbindin transports calcium across cell membranes of enterocytes.

Factors Influencing Absorption of Calcium

Absorption Promoters
• Calcitriol
–– Calcitriol is a hormone.
–– It governs synthesis of calcium-binding protein on the surface of
enterocytes.
–– It enhances absorption of calcium
• Parathyroid Hormone
–– Parathyroid hormone activates hydroxylase enzyme in kidneys.
–– Synthesis of calcitriol is increased.
–– Parathyroid hormone indirectly enhances calcium absorption.
• Dietary Proteins
–– High proteins in diet enhance calcium absorption.
–– Amino acids like arginine and lysine enhance calcium absorption.
• Dietary Carbohydrates
–– Dietary carbohydrates like lactose enhance calcium absorption.
–– Dietary sugars are fermented by colonic bacteria into organic acids.
–– Organic acids like citric acid enhance calcium absorption.
• Low pH of Intestinal Lumen
–– Calcium complexes like calcium carbonate and calcium phosphate are
readily soluble at low intraluminal pH.
–– Low pH of intestinal lumen enhances calcium absorption.

Absorption Inhibitors
• Dietary Fatty Acids
–– Free fatty acids combine with calcium salts and form insoluble calcium soap.
–– It is excreted in stools.
–– Dietary fatty acids inhibit calcium absorption.
• Dietary Phytic Acids
–– Phytic acids like inositol hexaphosphate are found in cereals.
–– They complex with calcium to form insoluble salts of calcium.
–– Phytic acids inhibit calcium absorption.
• Dietary Oxalates
–– Vegetables like spinach and cabbage possess oxalates.
–– Oxalates complex with calcium to form calcium oxalate.
–– It is poorly absorbed and excreted in stools.
–– Dietary oxalates inhibit calcium absorption.
• Dietary Fibers
–– Dietary fibers inhibit calcium absorption.
• High pH of Intestinal Lumen
–– Alkaline medium of the intestine inhibits calcium absorption.
476 18  Metabolism of Minerals

• Dietary Minerals (Phosphate, Iron, and Magnesium)

–– High level of phosphates in food form calcium phosphate which is
insoluble.
–– A ratio of (1:1) of calcium and phosphate in food is favorable for calcium
absorption.
–– High level of magnesium in food interferes in calcium absorption.
–– High iron in diet interferes in calcium absorption.
• Glucocorticoids
–– Glucocorticoids are steroids synthesized by the adrenal cortex.
–– Glucocorticoids diminish calcium absorption.

18.1.1 Functions of Calcium

Mineralization of Bones and Teeth

• Calcium and phosphate are necessary for mineralization of bones and teeth.
• Calcium is deposited in the form of hydroxyapatite crystals.
• Bones serve as a dynamic store of calcium in the body.

Clotting of Blood
• Ionized calcium represents a blood clotting factor IV.
• Calcium is necessary for formation of extrinsic and intrinsic prothrombin
activator.
• Calcium is helpful in cascade of blood clotting.

Muscle Contraction
• Calcium is necessary for formation of actin-myosin complex in the skeletal
muscle.
• Calcium plays a role in excitation-contraction coupling.
• Calcium is helpful in skeletal muscle contraction.

Myocardial Excitability
• Myocardial contractibility and excitability is dependent on calcium.
• Calcium is necessary for normal systole and diastole.

Conduction of Nerve Impulse

• Influx of calcium at a synapse is helpful in release of a neurotransmitter across
synapse.
• Thus calcium is necessary for nerve impulse conduction.

Enzyme Activity
• Activity of lipase is dependent on calcium as cofactor.
• Activity of neuronal nitric oxide synthase (secreted by specific neurons in the
brain) is dependent on calcium as cofactor.
18.1 Calcium 477

• Activity of calpain (proteolytic enzyme; cysteine protease) is dependent on cal-

cium as cofactor.
• Activity of calcineurin A, B, and B2 (protein serine/threonine phosphatase; role
in T-cell activation) is dependent on calcium as cofactor.

Activity of Calmodulin
• Calmodulin is calcium-modulated protein. It is a cytosolic protein.
• It can attach with four calcium ions and can form calcium-calmodulin complex.
• The complex activates adenylate cyclase and it regulates cell functions.

Intracellular Messenger
• Calcium (intracellular) acts as second messenger (intracellular molecule for cell
signaling).
• Calcium as second messenger is responsible for cell functions like muscle con-
traction, nerve impulse transmission, cell growth, and apoptosis.
• Other second messengers are cAMP, cGMP, inositol triphosphate, and
diglyceride.
• First messengers are peptide hormones like TSH, ACTH, prolactin, and catechol-
amines like adrenaline.
• Calcium (extracellular) acts as tertiary messenger for cell function. In gastric
mucosa, extracellular calcium acts as tertiary messenger for secretion of pepsinogen.

Permeability in Gap Junctions

• Gap junctions are found in almost all tissues of human body except erythrocytes
and sperms.
• It is an intercellular communication. Gap junction has an intercellular space of
2 nm, and it is filled with extracellular fluid.
• Calcium concentration in gap junction is helpful in transmission of electri-
cal impulse, movement of ions, and movement of metabolites between two
cells.

Activity of Neuromuscular Junction

• Transmission of nerve impulse from a neuron to skeletal muscle is regulated by
calcium.
• Influx of calcium at neuromuscular junction brings about release of
acetylcholine.
• This neurotransmitter is responsible for the activity of neuromuscular junction.

18.1.2 Regulation of Plasma Calcium Level

Normal plasma calcium level is between 9 and 11 mg/100 ml. Plasma contains cal-
cium in three forms. Ionized calcium in plasma is a metabolically active form. It
performs various functions.
Calcium homeostasis is regulated by the following factors:
478 18  Metabolism of Minerals

Role of Calcitriol
• Effect on Intestine
–– Calcitriol is 1,25-dihydroxy cholecalciferol. It is an active Vitamin D3.
–– It acts as hormone and induces the synthesis of calbindin from enterocytes.
–– Calbindin (calcium-binding protein) is located on brush border surface (api-
cal surface) of enterocytes.
–– Presence of calbindin increases absorption of dietary calcium from lumen of
gut.

Calcitriol increases plasma calcium level.

• Effect on Bones
–– Calcitriol stimulates osteoblastic activity in bones. Osteoblasts express alka-
line phosphatase enzyme in cell membrane.
–– Alkaline phosphatase increases level of phosphorous in developing
bones.
–– It results in increased mineralization of bones.

Calcitriol enhances mineralization of bones.

Role of Parathyroid Hormone (PTH)

Parathyroid hormone is a peptide hormone. It is secreted by chief cells of two pairs
of parathyroid glands. It binds with receptors located on target tissues. It acts on the
following tissues:

• Effect on Bones
–– Bones are dynamic store house of calcium.
–– PTH enhances osteoclastic activity in bones. The number of osteoclasts is
increased in the bone.
–– Osteoclasts secrete lactic acid and collagenase enzyme.
–– It results in demineralization of the bone.

PTH enhances demineralization of the bones.

• Effect on Kidneys
–– PTH stimulates reabsorption of calcium ions through distal convoluted tubules
and collecting tubules (daily excretion of calcium is 5 mmol/day).
–– It diminishes excretion of calcium ions by renal tubules.
–– PTH decreases reabsorption of phosphates by proximal renal tubules.
–– PTH stimulates hydroxylation of 25-hydroxy cholecalciferol into
1,25-­dihydroxy cholecalciferol.

PTH decreases plasma phosphate level.

PTH increases plasma calcium level.
18.1 Calcium 479

• Effect on Intestine
–– PTH enhances absorption of calcium indirectly.

Role of Calcitonin
Calcitonin is a peptide hormone. It is secreted by parafollicular cells of the thyroid
gland.

• Calcitonin is antagonistic to PTH.

• Calcitonin inhibits osteoclastic activity in bones.
• Calcitonin increases mineralization of bones.
• Calcitonin diminishes plasma calcium level.
• Calcitonin increases excretion of phosphates by kidneys.

Role of Kidneys
• Kidneys bring about hydroxylation of 25-hydroxy cholecalciferol.
• Kidneys reabsorb calcium.
• Kidneys excrete phosphate.

Role of Intestine
• The small intestine absorbs calcium and phosphates.

Role of Bones
• Bones are reservoir of calcium.
• Bones undergo mineralization and demineralization (bone remodeling) under the
control of hormones.

18.1.3 Disorders of Calcium Metabolism

Hypercalcemia
It is a clinical condition characterized by an increase in plasma calcium level
more than reference value (>11 mg/100 ml).

Etiology
• Hyperparathyroidism
• It may be caused by any one of the following factors:
–– Parathyroid adenoma (benign tumor)
–– Parathyroid malignancy
• Iatrogenic (drug-induced)
–– Loop diuretics like thiazides
• Granulomatous diseases
–– Tuberculosis
–– Sarcoidosis
480 18  Metabolism of Minerals

Characteristic Features
• Lethargy (weakness)
• Nausea, vomiting, and constipation
• Polyuria and renal calculi
• Increase in cardiac contractility
• Decrease in deep tendon reflex (normal reflex is knee jerk on striking with rubber
hammer)
• Confusion (lack of clarity)

Hypocalcemia
It is a clinical condition characterized by a decrease in plasma calcium level
lower than reference value (<8.5 mg/100 ml).

Etiology
• Decrease plasma albumin level
• Hypoparathyroidism
• Renal disease
• Acute pancreatitis
• Iatrogenic (glucocorticoids)

Characteristic Features
• Convulsions
• Cardiac arrhythmia
–– Irregular heart beat either very slow or high, palpitation, angina pectoris, and
decrease in cardiac contractility
• Tetany
• It is a sudden, forceful, and involuntary contraction of muscles (muscle
spasm). The following events occur in tetany:
–– Low calcium in plasma and ECF.
–– Increase in sensitivity of voltage-gated sodium channels.
–– Low-threshold stimulus can open sodium channels across neuronal
membrane.
–– Influx of sodium ions.
–– Rapid and progressive depolarization of neurons.
–– Muscle spasm.
–– Carpopedal spasm
It is the involuntary contraction of muscles of the hand and feet.
It may be elicited by applying a blood pressure cuff over the upper arm for 3 min.
It is called as Trousseau’s sign.
–– Facial Spasm
It is the involuntary contraction of facial muscles.
It may be elicited by tapping over bones of the cheek.
It is called as Chvostek’s sign.
–– Laryngospasm
Sudden and involuntary contraction of vocal cords.
Difficulty in breathing, inhalation is difficult.
18.2 Phosphorus 481

• Hyperactive deep tendon reflex

• Irritability of muscles and nerves

18.2 Phosphorus

Phosphorus is important mineral of hard tissues of the body. It interacts with the
calcium mineral for the calcification of bones and teeth. Phosphorus has equally
important role in synthesis of nucleic acids in the body. It is essential structural
constituent of all biological membranes. It is necessary in the oxidative phosphory-
lation to produce energy.

Distribution of Phosphorus in Body

The human body contains nearly 700 g of phosphorus. About 80% of total phos-
phorus is found in association with calcium ions in hard tissues of the body.
Muscles and blood contain about 10% phosphorus which exists in bound state
with proteins (phosphoproteins), carbohydrates, and lipids (phospholipids). The
residual 10% phosphorus is disseminated in the form of organic compounds in
tissues.

Sources
Animal Sources
• Animal sources are milk, cheese, and eggs.

Plant Sources
• Plant sources are vegetables and cereals.

Recommended Dietary Allowance

Adults
• RDA for adults is 800 mg per day.

Children
• RDA for children varies between 500 mg and 1.2 g per day.

Absorption of Phosphorus
Dietary phosphorus is absorbed through intestinal mucosa (jejunum).

Factors Regulating Absorption of Phosphorus

Promoters
• Parathyroid hormone and calcitriol promote absorption of phosphorus.
• Low pH in intestinal lumen promotes absorption of phosphorus.
• Calcium: Phosphorus ratio governs absorption of phosphorus in the intestine.

Inhibitors
• Organic compound like phytic acid in diet retards absorption of phosphorus.
482 18  Metabolism of Minerals

Excretion
• Phosphorus is excreted by kidneys. Phosphate ions (80%) are reabsorbed in
proximal convolute tubules. Excretion of phosphate is regulated by dietary intake
of phosphorus. Nearly 500 mg of phosphorus is excreted in urine daily.

Biochemical Functions
• Phosphorus is essential for calcification of teeth and bones.
• It is necessary for synthesis of phospholipids, phosphoproteins, and nucleic
acids.
• Phosphorus is essential for synthesis of high-energy phosphate compounds like
ATP and GTP.
• Phosphorus is a structural component of coenzymes like NAD+, FAD, FMN, and
NADP+.
• Phosphate is a component in the phosphate buffer system.

Clinical Significance
• In renal failure, serum phosphate level is raised.
• In serum phosphate level is affected by disease of parathyroid gland. In hyper-
parathyroidism, serum phosphate level is declined, while in hypoparathyroidism,
it is elevated.
• In renal rickets, serum phosphate level is reduced.

18.3 Selenium

Selenium is a trace mineral. It is an antioxidant element in the human body. In 1957,

Schwartz and Flotz observed that selenium was helpful in the prevention of liver
cell necrosis.

Distribution of Selenium
• Selenium is extensively distributed in body tissues. In the liver and kidneys, con-
centration of selenium is the highest, while less vascular organs like the muscle
and adipose tissues contain low concentration of selenium.
• Selenium exists in association with amino acids as selenomethionine and
selenocysteine.

Dietary Sources
• Cereals are average source of selenium (0.1–0.7 μg).
• Vegetables, fruits, and milk products are poor source of selenium.

Absorption and Transport

• Dietary selenium is absorbed in the duodenum. It enters blood circulation in
selenomethionine.
• It complexes with lipoprotein in blood circulation and is distributed to
tissues.
18.4 Copper 483

• Selenomethionine is taken up by body tissues like adipose tissues, myosin, and

myoglobin.

Biochemical Functions
• Selenium (selenocysteine) is a prosthetic group in glutathione peroxidase
enzyme. This enzyme is located in mitochondria and cytosol. Glutathione per-
oxidase catalyzes reduction of H2O2 into water and oxygen. It is an important
antioxidant enzyme in cells.
• Selenium, ascorbic acid, and vitamin E are antioxidants in cells. Selenium pro-
tects tissues against oxidative damage.
• Selenium has affinity to heavy metals like cadmium, mercury, and silver.
Selenium protects tissues against toxic effects of heavy metals.

Selenium Toxicity
• Excessive intake of selenium results into clinical condition called as selenosis. It
is manifested as:
–– GIT disturbances like nausea, vomiting, and loss of weight
–– Change in behavior
–– Garlic odor from the mouth owing to formation of dimethyl selenide

18.4 Copper

Copper is a trace element. The human body contains around 100 mg of copper in
tissues.

Dietary Sources
• Copper is found in cereals, nuts, egg yolk, and green leafy vegetables.
• Milk is a poor source of copper.

Recommended Dietary Allowance

• RDA for adults is 2 mg per day.
• RDA for children is 0.5 mg per day to 1.5 mg per day.

Absorption
• Dietary copper is absorbed in duodenum.
• Metallothionein is a conjugated protein. It helps in the absorption of copper.
• Zinc, molybdenum, and phytic acid retard absorption of copper in
duodenum.

Transport in Blood Circulation

• About 95% of copper exists as ceruloplasmin in blood circulation. The remain-
ing 5% of copper is bound to albumin in circulation.
–– Ceruloplasmin
484 18  Metabolism of Minerals

Normal serum ceruloplasmin concentration is 25–50 mg/100 ml. It contains

6–8 copper atoms which are present in cuprous state and cupric state. It is a
storage protein.
• Normal serum copper concentration is 100–200 μg/100 ml.

Biochemical Functions
• Copper is a structural component of ALA synthase enzyme. It is necessary for
synthesis of hemoglobin.
• Copper is a component of superoxide dismutase, catalase, cytochrome oxidase
and other copper-dependent enzymes.
• Ceruloplasmin is a copper containing protein. It is essential for oxidation of iron
in blood circulation. Oxidized iron (Fe3+) is distributed in form of transferring in
circulation.
• Copper is necessary for myelination of nerves in the brain.

Clinical Significance
Menkes’ Disease
• Disease is characterized by impaired absorption of copper in intestinal mucosa.
Probably, copper remains chelated by metallothionein within enterocytes.
• Serum copper concentration is decreased.
• Copper deficiency leads to anemia.

Wilson’s Disease
• It is a disorder of copper metabolism. Excessive deposition of copper occurs in
the liver and brain leading to liver necrosis and brain necrosis.
• Serum copper concentration is reduced.
• Serum ceruloplasmin concentration is decreased.
• Copper is deposited in renal tubules leading to renal necrosis.

18.5 Zinc

Zinc is a trace mineral. The human body contains around 2 g of zinc.

Dietary Sources
• Vegetables, cereals, beans, and milk are good sources of zinc.

Recommended Dietary Allowance

• RDA for adults is 10 mg per day.
• RDA in pregnancy and lactation is about 15 mg per day.

Absorption
• It is absorbed in duodenal mucosa.
• Conjugated protein metallothionein helps in the absorption of zinc through intes-
tinal mucosa.
• Divalent metal ions like copper, iron, and calcium interfere in absorption of zinc.
18.6 Fluorine 485

• Peptides promote zinc absorption.

Biochemical Functions
• Zinc is a structural component of enzymes like alcohol dehydrogenase, carbonic
anhydrase, alkaline phosphatase, and carboxypeptidase.
• Zinc is essential for storage of insulin in the pancreas.
• Zinc has a role in normal reproductive function.

18.6 Fluorine

Fluorine is an electronegative element. It is widely distributed in its oxidized form

(fluoride) in nature. It is found in drinking water in varying proportions.

Dietary Sources
• Drinking water is the exclusive, easily accessible, and most probable source of
fluorides for consumption to humans.
• Alternate sources of fluorides can be salmon, sardine, and tea leaves.

Recommended Dietary Allowance

• According to WHO recommendation, safe dose of fluoride in water is between
0.5 and 1.0 mg/L.
• Lethal dose of fluoride is 2.5 g.

Absorption and Transport

• Dietary fluoride enters the stomach. It combines with HCl to form hydrogen
fluoride (HF). It is absorbed from the mucosa of the stomach in two
forms.
• At low pH, hydrofluoric acid remains in undissociated form. It is absorbed by
diffusion through the mucosa.
• At high pH (>2.5), hydrogen fluoride is ionized into hydrogen and fluoride ions.
Diffusibility of fluoride from the stomach is pH-dependent and carrier-­
independent. It is owing to the sensitivity of phospholipid layer of plasma mem-
brane hydrogen fluoride. Phospholipid layer is highly permeable to hydrogen
fluoride than fluoride ions. Therefore, HF can rapidly pass through plasma
membrane in favor of pH gradient in the body.
• Large proportion of fluorides is absorbed through intestinal mucosa. Its
absorption in the small intestine is pH-independent and carrier-dependent.

Transport
• Absorbed fluoride rapidly enters blood circulation. It exists in ionic fluoride
and organic fluorocompounds with lipids. From plasma, fluorides are distrib-
uted to hard tissues of the body.
• In bones, fluorides are deposited in bone matrix, as well as fluorides are
incorporated in hydroxyapatite crystal structure.
486 18  Metabolism of Minerals

Excretion
• Dietary fluorides are chiefly excreted by kidneys. Excretion of fluoride in
urine is again pH-dependent. Alkaline urine (owing to intake of fruits and salad)
suppresses excretion of fluorides, while acidic urine (owing to intake of protein
enriched diet) promotes urinary excretion of fluorides.
• Dietary fluorides which are not absorbed from the small intestine are excreted in
feces.
• Dietary fluorides are also secreted in saliva in trace amounts (0.01–0.03 ppm).
Salivary fluorides have biological significance as they are involved in excreting
anticariogenic effect on the teeth.

Biochemical Functions
Tooth Development
• Fluorine has a positive role in normal tooth development. Additionally, fluorine
has anticariogenic effect on teeth.
–– During tooth development stage, fluorine is incorporated into crystal structure
and forms fluoroapatite crystals. These crystals are less soluble in oral acidic
environment than hydroxyapatite crystals. Fluoroapatite crystals have higher
resistance to attack of acids than hydroxyapatite crystals. It also maintains
normal crystal structure of teeth.

Bone Development
• Fluorine has healthy effect on normal bone development.
–– In 1 PPM dose, fluorine promotes deposition of calcium and phosphates in
organic bone matrix. Fluorine helps in retention of Ca++ in the bone, thereby
preventing demineralization of skeletal tissues.
–– Fluorine retards age-dependent osteoporosis in bones.

18.6.1 Fluoride Toxicity

Fluoride toxicity is a clinical condition characterized by excessive intake of

fluoride in water or food leading to a variety of clinical manifestations in the
body.
Fluoride toxicity can be grouped into two categories depending on its manifesta-
tions as:

Dental Fluorosis
Dental fluorosis is a disorder of tooth mineralization owing to intake of exces-
sive amount of fluoride in drinking water during tooth development stage.

Etiology
• High fluorine content in drinking water is the prime cause of dental fluorosis. A
dose of fluorine exceeding 1 PPM in drinking water during stage of tooth
development is detrimental to normal development of teeth.
18.6 Fluorine 487

Pathogenesis
• Ingested fluorides exhibit harmful effects on tooth bud through in situ mode.
High serum fluoride concentration alters normal tooth development via the fol-
lowing probable mechanisms:
–– Inhibitory effect on proteases in maturing enamel
In normal tooth development, ameloblasts lay down enamel organic matrix
rich in amelogenin proteins. These proteins provide nucleation for the growth
of hydroxyapatite crystals.
During enamel maturation stage, enamel matrix proteins are hydrolyzed
and removed from maturing enamel. Proteolysis of matrix proteins provides a
large space for the growth of hydroxyapatite crystals as enamel of the tooth is
95% inorganic by weight.
Enamel matrix proteins proteolytic enzymes
Matrix metalloproteinase-20 (MMP-20) also called as enamelysin.
Kallikrein 4 (KLK-4) also called as enamel matrix serine protease-1.
These enzymes catalyze hydrolysis of amelogenins along with enamel matrix
proteins.

High level of serum fluoride has an inhibitory effect in situ on proteases. As a

result, degradation of amelogenin and enamel matrix proteins does not take place. It
impairs deposition of calcium and phosphates in maturation stage of the tooth and
results into hypomineralization.

• Effect on Hydroxyapatite Crystals

In normal tooth mineralization, calcium and phosphates are mineralized into
hydroxyapatite crystals.
In high level of serum fluoride, excess fluoride ions are incorporated into crystal
structure. Fluoride ions replace hydroxyl ions from hydroxyapatite crystals to form
fluoroapatite crystals. Accordingly, high amount of hydroxyl ions are released in
extracellular matrix space of enamel which maintain alkaline pH.
High pH converts amelogenin into insoluble mass and impairs its removal from
extracellular matrix space. Alkaline pH additionally favors growth of apatite
crystals along the diameter than length which retains enamel proteins.
Overall effect is hypomineralization of tooth enamel.

Clinical Manifestations
Critical period in which toxic effects of fluoride intake are manifested is
between 1st year and 6th year of life.
Depending upon the severity of dental fluorosis, hypomineralized enamel exhib-
its structural deformities as follows:

1. Subsurface hypomineralization
• Mineralization of surface enamel is normal. It appears translucent, glossy,
and smooth. However, subsurface enamel shows hypomineralization and
porosity which may extend to dentinoenamel junction.
488 18  Metabolism of Minerals

2. White opaque spots

• With higher level of hypomineralization, enamel shows white opaque areas
over cusps of teeth.
3. White spots with discoloration
• White opaque spots are widespread over enamel surfaces of tooth. Appearance
of brown discoloration is also manifested on tooth surfaces.
4. Enamel discoloration with attrition
• With further rise in severity of hypomineralization, enamel surface shows
brown to black discoloration. Enamel undergoes attrition over cusps and inci-
sal edges of teeth.
• There is formation of pits over enamel surfaces.

Dental fluorosis is also called as enamel mottling.

Skeletal Fluorosis
Excessive fluoride intake is manifested into skeletal fluorosis. It has the follow-
ing manifestations:

• Initial lesion is marked by bone pain, stiffness of joints, and osteosclerosis of the
pelvis and vertebral column.
• Later stages of skeletal fluorosis are marked by chronic joint pain, arthritis, and
ligament calcification.
• Fluorosis causes increase in bone density.
• Terminal stages of skeletal fluorosis are marked by limited joint movement,
deformity of the large joints and spine, wasting of muscles, and neurological
manifestations.

18.7 Iron Metabolism

Iron is the most essential trace element in the human body. It is needed in a dose
(<100 mg) per day. Total body iron represents a small fraction (0.01%) of total body
weight in healthy person. It is around 3.5 g in adult males and 2.5 g in adult females.
Iron has multiple functions in the body. Iron is necessary for gaseous transport in
pulmonary alveoli and body tissues.

Dietary Sources of Iron

Animal Sources
• Rich sources of iron are liver, meat, spleen, and eggs.
• Liver is the richest source containing around 5 mg/100 mg of iron.

Plant Sources
• The richest source is green leafy vegetables containing around 20 mg of iron per
100 mg serving of vegetables.
• Good sources are cereals, pulses, lentils, spinach, molasses, and nuts.
• Jaggery is another good source of iron.
18.7  Iron Metabolism 489

Recommended Dietary Allowance

Adults
• RDA of iron for adults is nearly 10 mg per day.

Children
• RDA of iron for children varies between 10 and 15 mg per day.

Pregnancy and lactation

• RDA of iron in pregnancy and lactation varies between 20 and 25 mg per day.

Forms of Iron in Body Tissues

Iron is present in two forms in tissues as:
• Functional Iron
Functional form of iron is essential for iron-dependent enzymatic activity, meta-
bolic functions, transport proteins, and hemopoietic functions in the body.
Functional iron is found in the following compounds:
–– Heme-conjugated proteins
Hemoglobin
Myoglobin
Catalases
Peroxidases
–– Cytochromes
–– Other enzymes
Succinate dehydrogenase
Aconitase
• Storage Iron
• Storage form of iron is the iron reservoir of the body. Iron is stored in two forms as:
–– Ferritin
Ferritin form of iron is made up of ferric form of iron which is coplexed with
apoferritin protein. Ferritin is stored in the liver, spleen, bone marrow, blood,
and intestinal mucosa.
–– Hemosiderin
It is another form of iron storage in the body. Hemosiderin contains larger
amount of iron than ferritin. In the condition of iron overload, iron is stored in
hemosiderin. It is deposited in the liver, pancreas, and spleen.

Absorption of Dietary Iron

In a routine diet, about 10–20 mg of iron is consumed with diet. However, only 2 g
(10% of intake) of iron is absorbed in circulation. About 80–90% of total iron con-
sumed is excreted in stools.
Iron in blood circulation is in dynamic equilibrium with iron store of the body, bone
marrow uptake, uptake for synthesis of iron-dependent enzymes, and iron loss from body.
Garnick postulated mucosal block theory for absorption of dietary iron.

• Dietary iron enters the stomach. Hydrochloric acid liberates ferric form of iron
from dietary non-heme iron.
490 18  Metabolism of Minerals

• Ferric form of iron is reduced into ferrous form in the gastrointestinal tract.
Ascorbic acid in diet helps in reduction of iron and forms iron-ascorbate com-
plex. This complex is highly soluble in intestinal juices. Dietary amino acids also
help in chelation of iron as iron amino acid complex. Heme iron is absorbed
without reduction in GIT.
• Iron from non-heme iron and heme iron is absorbed in ferrous form (Fe2+)
through duodenal mucosa.
• Ferrous iron is transported across the plasma membrane of enterocytes (luminal
surface of enterocytes).
• Within cytoplasm of enterocytes, ferrous iron is oxidized into ferric form.
Reaction is catalyzed by ferroxidase I enzyme. The intracytoplasmic transport of
ferric iron is carried by intracellular iron carrier. It transports ferric iron to
apoferritin within enterocytes to form ferritin. Iron is stored in the form of fer-
ritin in enterocytes.
• Ferritin is a transient iron stored in intestinal mucosa. A fraction of ferric iron
from intracellular carrier is converted into ferrous form. It is exported through
serosal surface of enterocytes. Ferroportin helps in the export of iron.

Regulation of Absorption of Iron

• Mucosal block regulates absorption of dietary iron. In case iron store of the
body is exhausted, mucosal cells enhances absorption of dietary iron. Otherwise,
in condition of adequate iron store of the body, mucosal cells limit the absorption
of iron.
• Total body iron store regulates iron absorption. Whenever body iron store is
depleted, absorption of iron is increased through intestinal mucosal cells.
• Erythropoietin secretion also regulates iron absorption. In case of iron defi-
ciency in the body, juxtaglomerular apparatus of kidneys secretes erythropoietin.
It stimulates mucosal cells to enhance absorption of iron.

Factors Promoting Absorption of Iron

• Presence of ascorbic acid in diet promotes iron absorption.
• Low pH in stomach favors iron absorption.
• Protein-rich diet favors iron absorption.
• Gastroferrin in the stomach favors iron absorption.

Factors Retarding Absorption of Iron

• Presence of phytic acid in diet retards iron absorption.
• Diet rich in phosphates retards iron absorption.
• Achlorhydria retards iron absorption.

Transport of Iron
• In blood circulation, ferrous iron is converted into ferric state. It combines with
apotransferrin to form transferrin.
• Iron is chiefly transported by transferrin from GIT to the bone marrow and other
body tissues.
18.7  Iron Metabolism 491

Excretion of Iron
• Iron is an exclusive element that is primarily stored in the body. A negligible
fraction of iron is excreted from the body in the following ways:
–– Desquamated mucosal cells of GIT containing ferritin
–– Desquamated skin cells
–– Menstrual bleeding
• Iron loss in urine is non-traceable. Appearance of blood in urine is considered a
pathological condition.
• Undigested iron is lost in feces.

18.7.1 Clinical Significance

Iron metabolism is clinically oriented toward two conditions that arise either due to
iron deficiency or overload of iron in the body. These are described as follows:

Iron Deficiency
• This condition is characterized by deficiency of iron in body stores. Iron defi-
ciency is associated with the following biochemical parameters:
–– Concentration of hemoglobin is reduced.
–– RBC count is reduced.
–– Serum ferritin level is declined.
–– Erythropoiesis is retarded.

Iron deficiency is clinically manifested as iron-deficiency anemia.

Iron Overload
Iron overload is the excessive accumulation of iron in body tissues. It is generally
caused by frequent blood transfusions and or a genetic disorder.
Iron overload can be grouped into two categories as:

Hemosiderosis
Hemosiderosis is a localized excessive accumulation of iron without any injury
to body tissues. Hemosiderin is deposited in tissues.
It is of two types as follows:

• Hemosiderosis is associated with repeated blood transfusions. Hemosiderin is

deposited in the liver. It is called as transfusional hemosiderosis. It is commonly
observed in patients suffering from thalassemia, sickle cell anemia, and leukemia.
• Hemosiderosis can be idiopathic. In this condition, hemosiderin is deposited in
lungs. It is called as idiopathic pulmonary hemosiderosis.

Hemochromatosis
Hemochromatosis is generalized excessive accumulation of iron in body tissues
accompanied by irreversible cell injury.
492 18  Metabolism of Minerals

It is of two types as follows:

Primary Hemochromatosis
• It is a hereditary disorder of iron metabolism. P. hemochromatosis is caused by
autosomal recessive genes.
• It is manifested by the following signs:
–– Cirrhosis of the liver is caused by deposition of iron in hepatocytes. Liver
cell undergo irreversible injury.
–– Diabetes mellitus is caused by accumulation of iron in islets of Langerhans
in the pancreas. Beta cells are damaged.
–– Pigmentation of the skin
Skin appears bronze colored. Skin pigmentation is associated with insulin
deficiency and collectively termed as bronze diabetes.
–– Cardiomyopathy
Iron is deposited in cardia muscle fibers. It results in hypertension, arrhyth-
mia, and valvular defects.

Secondary Hemochromatosis
S. hemochromatosis is a consequence of another disorder. It is frequently fol-
lowed by the following conditions:

• Severe hemolysis
• Frequent blood transfusion
• Beta-thalassemia major
• Parental iron therapy

Muscle Spasm
• It is the sudden, forceful, and involuntary contraction of muscles.
Muscle Cramp
• Muscle cramp persisted for prolonged period.
• Quadriceps, hamstrings, and gastrocnemius muscles in thigh, back
thigh, and calve regions may undergo cramp.
Tetany
• It is caused by hypocalcemia.
• Increased neuronal membrane permeability to sodium ions.
Tetanus
• It is a bacterial disease. It is caused by invasion of Clostridium tetani.
• Bacteria release tetanospasmin (toxin) which inhibit the release of
inhibitory neurotransmitter (glycine) from Renshaw cells in the spinal
cord.
• Rapid and progressive depolarization of motor neurons.
• Persistence of skeletal muscle contraction
Suggested Readings 493

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