Case A 2-year – old boy of normal weight and

height is brought to a clinic because of excessive fatigue.

Blood work indicates an anemia with Microcytic Hypochromic red cells.

The boy lives in a old apartment building and has been caught ingesting paint chips and sand.

His parents indicate that the child eats a healthy diet.

His anemia is most likely attributable to a deficiency of which trace element?

Dr. SaidunnisaProfessor of Biochemistry

IRON METABOLISM

Learning objectives

At the end of the session the student should be able to :

1. Explain the mechanism of iron absorption

2. Interpret the diseases associated and give the biochemical explanation for it

3. List the sources and R.D.A

Iron

Iron is one of the most essential trace elements of the body.

In spite of the fact that iron is the fourth most abundant element in the earths crust iron deficiency is one of the most important prevalent nutritional deficiencies.

Functions

Oxygen transport (hemoglobin) Myoglobin Electron transport (cytochromes) Transformation and

detoxification (cyt P450) Cell and tissue proliferation Immunity

Toxic element

Generates reactive oxygen species

Hydroxyl radical (OH.) can be formed from Hydrogen Peroxide (H2O2 )n the presence of Fe 3+ or Cu+ (Fenton reaction)

Distribution of iron in adults

Total content of iron in an adult body of 70kg weight is 3-5g.

Blood contain 14.5g Hb /dl.

About 70% of this occurs in the RBC as a constituent of Hb.

5% is present in myoglobin of muscle.

15% in Ferritin

It is ingested in the diet either as heme which is readily absorbed

or Nonheme iron in plants is not

readily absorbed because of phytates and oxalates

Distribution of iron in adults

RDA (Recommended dietary Allowance)

Adult man : Asian :20mg/day , Non-Asian: 15mg/day Children: 20-30 mg/day Menstruating woman: 25 mg/day Pregnant and lactating woman :

40mg/day. Transfer of iron and calcium from

mother to fetus occurs in last trimester of pregnancy during this period mother’s food should contain surplus quantities of these.

RDA

In the first 3 months of life iron intake is negligible because milk is a poor source of iron.

During this time child is dependent on the iron reserve received from mother.

In premature babies the trans placental transfer of iron might not have taken place hence these babies are at risk of iron deficiency.

Sources Rich sources: Organ meats (liver, heart, kidney)

Good sources: Leafy vegetables, pulses, cereals , apples , dried fruits, jaggery

Poor sources: Milk, wheat, polished rice

Cooking in iron utensils will improve iron content of the diet.

Iron absorption

Factors Affecting Fe Absorption

Iron is absorbed by the upper part of the duodenum.

Reduced from of iron only Fe++ (Ferrous) is absorbed.

1. Acidity (Gastric Hcl) , vit C , and cysteine promote

2. Phytates ( cereals) oxalate ( leafy vegetables) interfere

3. Copper deficiency decreases the absorption4. Partial or total surgical gastrectomy decreases5. Iron losses from the body are minimal (<1mg)

Absorption

Enterocytes in the proximal duodenum are responsible for absorption of iron.

Iron in the Fe+++ state is reduced to Fe++ by a ferrireductase present on the surface of enterocytes.

Vit C favors this reduction. The transfer of iron from apical

surfaces to the enterocytes interior is performed by divalent metal transporter (DMT1)

Iron Absorption

Heme is transported into the enterocytes by a separate heme transporter (HT) and heme oxidase (HO) releases Fe++ from the heme.

Some of the intracellular fe++ is converted to fe+++ and bound to ferritin, and remainder binds to basolateral fe++ transporter i.e. ferroprotin and is transported into the blood stream aided by hephaestin (HP) which is a copper-containing protein similar to ceruloplasmin.

Thus the fe++ in blood is converted to fe+++ and

Bound to apotransferin and circulates as transferrin.

Transport of iron in the plasma

Each transferrin molecule can bind with two atoms of ferric iron (fe+++).

The plasma transferrin concentration is 250mg/dl can bind with 300ug iron/dl plasma . this is called total iron binding capacity (TIBC).

Transferrin Receptors These receptors (TfR1and

TfR2) are present on the surface of many cells.

Transferrin binds to it and this complex Tf-R is internalized by endocytosis

The acid pH in the lysosomes causes the iron to dissociate from the protein to deliver to the needy cells

Receptor returns back to the surface to pick up more iron to deliver to the cells.

Mechanism

1. The mRNA for the Tfr has cis-acting iron –responsive elements (IRE) at its 3’end.

2. IRE have a stem-loop structure that can be bound by trans – acting iron regulatory proteins (IRP).

3. When iron concentration is low in the cells, the IRP binds to IRE and stabalize the mRNA for Tfr allowing TFR synthesis.

4. When iron concentration is high in the cells, the IRP bind to iron instead of IRE.

5. The lack of IRP bound to mRNA hastens its degradation, resulting in decreased Tfr synthesis.

Challenge yourself

Spinach has been projected as a wonderful source of iron, this iron is not readily absorbed why?

Answer

Spinach has high content of phytates

Vit C favors this reduction.

Laboratory Assessment of ironSerum iron levelsTotal iron binding capacityCalculation of % saturation of transferrin

Serum ferritin

Clinical Manifestations

1. Iron deficiency

2. Iron overload ( Hemochromatosis)

( Hemosiderosis)

Iron deficiency anemia

Most common nutritional deficiency through out the world.

Causes:1. Nutritional deficiency2. Hook worm infection3. Repeated pregnancies4. Lack of absorption ( gastrectomy)5. Lead poisoning

Clinical Manifestations

Microcytic Hypochromic anemia

Hb level <10g/dl body cells lack oxygen and patient becomes uninterested in surroundings (Apathy).

Lowered memory, impaired attention.

Glosittis

(Apathy).

Peripheral Blood in normal and Iron deficiency

In normal: The RBC are uniform. The central pallor is about 1/3rd of cell diameter.

In iron deficiency anemia: The RBC are decreased in number they are small. The central area of pallor is increased (hypochromia) they contain less Hb .

Microcytic and Hypochromic anemia diagnostic of iron deficiency.

Iron deficiency.

Normal

Plummer Wilson syndrome

Prolonged iron deficiency causes Atrophy of gastric epithelium leading to achlorohydria. Which inturn causes lesser absorption of iron aggravating anemia.

Atrophy of epithelium of oral cavity and esophagus causes dysphagia termed Plummer Wilson syndrome.

which is an precancerous condition.

Spoon nails- Koilonychia Pica

Lab findings: 1.Total serum iron level decreases 2. Serum Ferritin level decreases 3.Transferrin saturation decreases 4. TIBC: Total iron binding capacity

increases.

Treatment

Oral supplementation of iron. 100mg iron + 500ug of folic acid ---

pregnant women. 20mg iron +100ug of folic acid ----

Children These are usually given with Vit C to

convert into ferrous for easy absorption. Unabsorbed iron may generate free

radicals so it advisable to give Vit E to prevent free radical generation (antioxidant).

Caution

If iron deficiency anemia is seen in a male patient, he should be checked for blood loss from GIT.

Challenge yourself

1. Why would a B6 deficiency result in Microcytic and Hypochromic anemia?

Answer

Less heme is synthesized, causing RBC to be small and pale.

Iron toxicity

Iron is stored in liver, spleen and bone –marrow in the form of Ferritin.

Iron excess is called Hemosiderosis. Hemosiderin pigments accumulates

in the body in spleen and liver when the supply of iron is in excess of body demands.

Transfusion therapy results in iron overload (Iron toxicity)

Iron overload can occur after 10-20 transfusions.

1 blood unit contains 200 mg iron. Iron chelation therapy should be

considered when patient has received approximately 20 units of blood or serum ferritin is >1000ug/L

Hemosiderosis

Due to excessive iron in the body commonly observed in subjects receiving repeated blood transfusions over years like patients of hemolytic anemia, hemophilia, Thalassaemia and sickle cell anemia's iron cannot be excreted so is deposited as Ferritin and Haemosiderin.

This is commonly observed in Bantu tribe in south Africa attributed to high intake of iron form their staple diet corn and their habit of cooking foods in iron pots.

Primary Hemosiderosis

It is also called Hereditary Hemochromatosis.

Prevalent autosomal recessive disorder in certain parts of the world ( Scotland, Ireland, and North America.) caused due to mutations in the HFE gene located on chromosome 6.

Iron absorption is increased and excessive storage of iron in tissues results leading to tissue damage.

Hemochromatosis

Total body iron ranges between 2.5-3.5g in normal adults, in Hemochromatosis it usually exceeds 15g.

The accumulated iron damages organs and tissues such as liver ( Cirrhosis)pancreatic islets (Diabetes) perhaps due to free radical injury.

Deposits under skin cause yellow-discoloration called Hemochromatosis.

The triad of cirrhosis with coexistence of diabetes mellitus and Hemochromatosis is “bronze diabetes”.