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Bayan Abusheikha

Saleem

Physiology

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❖ Factors affecting erythropoiesis

1- Oxygen supply; tissue oxygenation is the most essential regulator

of RBCs production.

2- Vitamins; B12 & Folic acid mainly.

3- Iron

4- Proteins; haemoglobin is mainly protein.

5- Trace elements; copper & cobalt.

6- Healthy bone marrow; where erythropoiesis occurs

7- Liver functions: storage, protein synthesis and hormone synthesis

8- Hormones; erythropoietin, androgen, thyroid hormone, growth

hormone, and corticosteroids.

We will talk about iron in this lecture :

Iron(Fe) :

● The body contains 4-5g of iron (4g in females & 5g in males)

● Iron is important for the formation of haemoglobin among other essential

elements in the body such as: myoglobin, cytochromes, cytochrome

oxidase, peroxidase, and catalase

● Daily intake of Iron is about 20-30mg but the amount absorbed is equal to

the iron loss in the body. (not the entire iron intake is absorbed)

● Usually the amount of the iron absorbed is 4% of the 20-30mg ingested iron.

(low overall absorption).

● The body usually stores iron in the liver.

● We get iron mainly from the meats (fish, liver ) and some vegetables

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● Iron in the body exists as :

Heme iron Non-heme iron Absorbed as a whole structure Must be dissolved before uptake

Absorbed more efficiently from

the whole small intestine

Absorbed poorly and only from

the duodenum

From animal food sources only From plant sources

● Iron exists as either ferric (fe+3) or ferrous (fe+2). Ferrous is the beneficial

form of iron for our bodies (Iron is absorbed in the intestine as ferrous)

(The doctor revised the length of each part of the small intestine: Duodenum:

26 cm, jejunum: 2.5 meter, ileum: 3.5 meter.

● The majority of the body’s iron supply comes from the jejunum.(

since its long )

● The amount of iron that is absorbed from the lumen of the intestine

is equal to the amount of iron that is lost from the body.

● Iron is bound to transferrin to be transported in the plasma, while it’s

bound to a protein called ferritin to be stored in the hepatocytes

❖ Iron Absorption in the intestines :

Iron movement doesn’t occur passively but requires one or more protein to

facilitate its movement in and out of the cell.

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1- Non heme iron :

o Ferric is reduced to FERROUS by

duodenal cytochrome b (DcytB)

o The ferrous binds with the divalent

metal transporter protein which carries

ferrous (and H+) from the brush border

and transports them into enterocytes.

o Ferrous either binds to ferritin for

storage or it continues as a free molecule to

the basal membrane of the enterocyte.

o In the basal membrane , ferroportin

facilitates the exit of ferrous out of the

cell

o Ferrous is converted to ferric by a ferroxidase.

o Ferric either binds to transferrin in the circulation to participate in erythropoiesis

or goes to the liver to be stored.

2- Heme iron :

It enters the intestinal cell by Heme carrier protein (HCP1) , and the heme is

catabolized by a heme oxygenase, ferrous is released and is transferred to

the basal membrane .It leaves the cell by the same ferroportin , and ferric

is produced in the same concept as non heme iron.

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❖ Daily iron requirement :

o The loss is different therefor the need is different.

o The estimated unit is mg/day.

o The first group (Adult male & post-menopausal female): the total

daily requirement ranges from 0.5 to 1 mg and the total daily loss is

0.5 to 1 mg.

o The doctor continued to read the rest of the groups from the table…

o Note that the total daily need is equal to the total daily loss

o The stared groups (menstruating females, pregnant female and

female (age 12-15)) are most likely to develop iron deficiency.

o Iron daily requirement ranges from 0.5 to 3mg

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❖ Distribution of iron in the body :

o The majority of this iron is in haemoglobin (65%).

o 30% of iron is bound to ferritin & hemosiderin to be stored in

hepatocytes (in the liver).

o 3.5% is found in myoglobin (it is an iron- and oxygen-binding protein found in

the muscle tissue)

o Note the difference in the amount of iron between males and females in

all aspects.

❖ Factors favoring and reducing iron absorption:

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o The first six favouring factors are opposite to the first six reducing

factors.

o In poor groups of people where there is high consumption of tea and

phytates** there is a higher likelihood to develop iron deficiency

anaemia.

o The acidity of stomach is stronger than the acidity of lemon juice and

therefore improves iron absorption .

o phytates :it is the storage form of phosphorous in many plant tissues, such

as: bran, seeds, cereals and grains ( in large amount in bread).

❖ Causes of iron deficiency :

The doctor read the table but for the gastrointestinal blood loss he only mentioned: peptic

ulcers, aspirin ingestion, piles (haemorrhoids).

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* The most critical determinants of hemoglobin concentration are availability of

iron and the presence of heme. Thus, anything affecting the availability of iron

might also affect the synthesis of heme and hemoglobin. Copper, zinc, cobalt,

manganese, and cadmium, because of their similarity in physiochemical

characteristics to iron, are able to interfere with normal iron metabolism and,

consequently, heme and hemoglobin synthesis. This is what the doctor said in

2016

In our lecture the doctor just said copper is important for enzymes while cobalt is

important for b12

❖ Hemoglobin

Hemoglobin structure

Heme (Metalloporphyrin); 4% Globin (protein part); 96%

Iron protoporphyrin

Function: it carries oxygen and CO

( reversible binding) Function: it carries CO2, H+ and

2 ,3-BPG (reversible binding)

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• Hemoglobin concentration in males is 16 g/100mL blood, while its

concentration in females is 14g/100mL blood. To consider one figure we say 15g/100mL.

• Each hemoglobin molecule is composed of four subunits; 2 α and 2 β, in the

case of adult hemoglobin.

• Each α subunit contains 141 amino acids, while each β subunit contains 146

amino acids.

• Each subunit binds one heme molecule and each heme molecule binds one

oxygen molecule (two atoms), thus one hemoglobin molecule carries 4 oxygen

molecules (8 atoms)

• How many oxygens each RBC can carry? Each hemoglobin can carry 4 O2's.

One RBC contains 250 million Hb molecules (1 RBC can carry as many as 1 billion

molecules of O2)

❖ Hemoglobin synthesis : o 65% of hemoglobin synthesis occurs in the Erythroblasts, those cells have

nuclei and the remaining (35%) occurs in the reticulocyte, those cells have

fragmented nuclei. (no hemoglobin synthesis in mature RBC)

o The synthesis of hemoglobin take place in two distinct areas:

1- Globin synthesis: The synthesis of globin part (protein) occurs in the ribosomes

in the cytosol.

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2- Heme synthesis :

1- Heme synthesis that takes place in the mitochondria begins by the

condensation (binding) of glycine with succinyl CoA to produce delta-amino

levulinic acid (delta-ALA), under the effect of ALA synthase, vitamin B6 is a

coenzyme here. The condensation of two ALA by ALA dehydratase enzyme

produces porphobilinogen. This step is stimulated by erythropoietin and

inhibited by the heme( this is what the doctor said but as in biochem it’s lead)

2- The product from step 1 undergoes further reactions to form protoporphyrin.

3- Four Protoporphyrin will bind to 4 iron to form 4 heme molecules

4- Four heme molecules will bind 4 globin subunits (2 α and 2 β) to form one

hemoglobin molecule.

1

2

3

4

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❖ The causes of hypochromic microcytic anaemia

In this type of anaemia, the cells are small (microcytic), MCV is less than 70 fL or

70 μm3, and contain low hemoglobin (hypochromia).

1- Lack of iron (iron deficiency)

2- Problem in iron release from macrophages to serum (anaemia of chronic

inflammation or malignancy)

3- Failure of protoporphyrin synthesis (this causes sideroblastic anaemia)

4- Failure of globin synthesis (this causes α or β thalassaemia)

5- Lead also inhibits heme and globin synthesis

Note that the problems are either in Iron or Protoporphyrin or Globin.

• Iron deficiency anemia is estimated to affect about 30% of the world

population.

• Iron deficiency anemia is still the most important deficiency related to

malnutrition.

• Iron deficiency anemia (IDA) and thalassaemia (TT) are the most common

forms of hypochromic microcytic anemia.

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• IDA is a common clinical problem throughout the world and an enormous

public health risk in developing and industrialized countries.

• Traditionally, several methods other than serum ferritin were used to

assess IDA (to be discriminated from thalassemia).

❖ Oxygen in the blood You can calculate how many mL of oxygen is present in your body (the whole

blood) by the following method

- 1gram hemoglobin carries 1.34mL Oxygen (almost constant).

- 100mL plasma carry 0.3 mL of Oxygen.

-In 100 mL blood there is 15gram Hb (remember 15% in average), so:

1gram Hb 1.34 mL Oxygen

15gram Hb X

X= 15gram x 1.34mL= 20 mL (20 mL oxygen in 100 mL of blood)

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❖ Types of hemoglobin

- There are 6 types of Hb, the lower three are found only in the embryo (in

the first trimester), while the first three are found in the embryo, newborn

as well as adults.

- The proportion of fetal Hb in adults is usually less than two (around 1-

1.5%), but there are some people have higher than that almost up to 2% ,

we still considered it normal, but if the fetal haemoglobin is higher than 2%

in this case we consider it abnormal.

- In new-borns 80% of Hb is fetal Hb, its replaced gradually by adult Hb and

eventually totally (90%) by the sixth month after birth, this is the usual case

sometimes it extends to the ninth month, but its important to normalise at the

end of the first year(around 2%).

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Newborns : 80% fetal hemoglobin ,

20% adult hemoglobin and less than

.5% of HbA2

Adults : 97% adult hemoglobin , 1%

fetal hemoglobin and 2.5% of HbA2