Iron Metabolism & Iron Deficiency Anaemia

Question 1

excessive loss of iron frequently occurs due to

Answer 1

haemorrhage

Question 2

What is the most common cause of anaemia throughout the world?

Answer 2

Iron deficiency

Question 3

Total body iron in males and females

Answer 3

Male — 50mg/kg
Female — 40mg/kg

Question 4

How much Iron in red cell mass haemoglobin (65%) in males and females?

Answer 4

Male — 2.4g
Female — 1.7g

Question 5

What are the Iron stores of the body and where are they located?
What is their quantity in males and females?

Answer 5

ferritin (all cells) & haemosiderin (RES – liver, bone marrow, spleen) (30%)

Male — 1g (0.3-1.5)
Female — 300mg (0-1.0)

Question 6

How much Myoglobin in muscles (3.5%) in males and females?

Answer 6

Male — 0.15g
Female — 0.12g

Question 7

How much Haem enzymes (cytochromes, catalase, peroxidases, flavoproteins) (0.5%) are in males and females?

Answer 7

Male — 0.02g
Female — 0.015g

Question 8

How much Serum transferrin-bound iron (0.1%) males and females

Answer 8

Male — 0.004g
Female — 0.003g

Serum ferritin (0.9%)

Question 9

How much Fe is lost per day and how?

Answer 9

about 1mg of iron is lost by exfoliation of the epithelial cells from GIT, urinary tract and skin in feaces, urine and sweat respectively. This is matched with amount required

Question 10

Required amount of Fe in:

Full term babies
Preterm
Infants
Adolescents
Adult males and non-menstruating females
Menstruating females
Pregnant womenwomen

Answer 10

Full term babies up to 4 month — 0.5mg/day because they need to double the red cell mass within 12 months and also for growth. So, they may become iron depleted between 6 and 12 months
Preterm babies
Infants up to 5-12 months and children — 1mg
Adolescents — 1.6-2.6mg/day (increase in blood volume and lean body mass, in addition to onset of menstruation in females)
Adult males and non-menstruating females — 1mg
Menstruating females — 2-3mg
Pregnant women — 3-4mg (maternal red cell expansion, fetal organogenesis and erythropoiesis, placenta)

Question 11

Sources of dietary iron

Answer 11

is mainly non-haem iron (cereals fortified with iron and leafy vegetables). Other form is the haem iron (meats, eggs, diary products, fish)

Question 12

Factors that affect iron absorption

Answer 12

Dietary factors
Luminal factors
Systemic factors
Mucosal factors
Bioavailability

Question 13

Dietary factors

Answer 13

Haem (better absorbed)/non-haem (non-haem is less well absorbed)
Ferrous (better absorbed) /ferric iron salts (less well absorbed)

Question 14

Luminal factors

Answer 14

Acid pH (gastric acid)/alkalis (antacids/pancreatic secretion)

Low molecular weight soluble chelates (vit C, sugars, amino acids )/insoluble iron complexes (phytates, tannates in tea, bran)

Question 15

Systemic factors

Answer 15

Iron def/iron overload
Increased/decreased erythropoiesis
Ineffective erythropoiesis/inflammatory disorders (hepcidin)
Pregnancy
Hypoxia

Question 16

Mucosal factors

Answer 16

Iron is maximally absorbed from the duodenum and less well from the jejunum

Question 17

What are the 2 pathways of iron absorption?
Where do they occur?

Answer 17

There are 2 pathways of iron absorption mainly occurring in the epithelial cells lining the villi close to the gastroduodenal junction:

1. Absorption of Inorganic (non-haem)/elemental iron (fe3+)
2. Absorption of haem iron (fe2+)

Question 18

How is Fe absorbed (via the 2 pathways) ?

Answer 18

NON-HAEM PATHWAY
* Inorganic (non-haem)/elemental iron (fe3+) is reduced to fe2+ by duodenal cytochrome b (Dcyt b)/ ferroreductase at the brush border of duodenum

• Fe2+ enters into the labile iron pool within the enterocytes via the divalent metal transporter (DMT1)

HAEM PATHWAY
* Haem iron is released from apoprotein by the gastric acid

• About ¼ of haem is absorbed directly and after cellular uptake, it is broken down and iron is released
• Some haem are oxidized to its ferric state to form haemin which is absorbed by unclear mechanism probably via haem carrier protein 1(HCP-1)
• It is assumed that iron enters the labile pool and some may be incorporated into ferritin and lost when cells are exfoliated
• While iron destined for retention by the body is transported into plasma via ferroportin 1 in the basolateral serosal membrane, it is 1st converted from fe2+ to fe3+ by haphaestin, a copper containing ferroxidase expressed predominantly in villous cells of the small intestine

Question 19

How is iron absorption regulated?

Answer 19

• Iron absorption may be regulated both at the stage of mucosal uptake and at the stage of transfer to the blood
• Hepcidin is small peptide of 20-25 amino acids.
• It is predominantly expressed in the liver and it is down regulated in reduced iron stores and upregulated in increased iron stores or inflammation.
• It is a negative regulator of iron absorption in the small intestine, transport across the placenta and release from macrophages, probably by binding to ferroportin and accelerating its destruction
• It is decreased in iron deficiency, hypoxia and ineffective erythropoeisis
• HFE, transferrin receptor 2, hemojuvelin have an indirect roles in the control of iron absorption via regulation of hepcidin synthesis
• TfR2 senses the degree of saturation of transferrin with diferric iron. At high saturation, it stimulates hepcidin synthesis and vice versa.
• TfR2 is restricted to erythroid, duodenal crypt and liver cells

Question 20

Where are Transferrin receptors in high concentration?

When is the expression of surface TfRs is increased?

Answer 20

Transferrin receptors are present in high concentration on cells with a high iron requirement i.e. any rapidly dividing cells predominantly erythroid cells
The expression of surface TfRs is increased if cells have inadequate iron, and reduced if they are iron replete

Question 21

Breakdown of haemoglobin

Answer 21

Breakdown of haemoglobin

• Senescent red cells are phagocytosed by macrophages, haem released is broken by haem oxygenase to release ferrous iron.
• The ferrous iron can either enter ferritin (where it is oxidized to ferric iron by ferritin protein) or released into plasma thus binding to transferrin in ferric form which may be facilitated by a plasma ferrous oxidase (caeruloplasmin)
• The release of iron from the macrophages is controlled by hepcidin (high levels in inflammation or iron overload reduce iron release)

Question 22

Breakdown of haemoglobin

Answer 22

Senescent red cells are phagocytosed by macrophages, haem released is broken by haem oxygenase to release ferrous iron.

The ferrous iron can either enter ferritin (where it is oxidized to ferric iron by ferritin protein) or released into plasma thus binding to transferrin in ferric form which may be facilitated by a plasma ferrous oxidase (caeruloplasmin)

The release of iron from the macrophages is controlled by hepcidin (high levels in inflammation or iron overload reduce iron release)

Question 23

Important roles of liver in iron metabolism

Answer 23

The hepatocytes take up extra iron when transferrin saturation is increased

Capable of releasing iron from stores when there is greater need in other tissues

Through iron-regulated synthesis of hepicidin, it directly controls iron intestinal absorption

5-10% of haemoglobin from old RBC is normally released intravascularly, bound to haptoglobin, prior to removal by macophages. This pathway increases accumulation of iron in the liver in conditions such as haemolytic and dyserythropoietic anaemias

Large particles of colloidal iron, including therapeutic parenteral iron preparations also removed by macrophages of RE system

Question 24

What are tissue effects of iron def

Answer 24

Koilonychia
Angular stomatitis
Glossitis
Pharyngeal web (paterson-kelly syndrome)
Partial villous atrophy (minor degree of xylose & fat malabsorption reversible by iron therapy in children)
Pica
Gastric atrophy with histamine fast achlorhydria
Iron-dependent enzymes — iron def is responsible for tissue changes
Neurodevelopmental problem in infants
Premature labour

Question 25

Iron-dependent enzymes — iron def is responsible for tissue changes

Answer 25

Mitochondrial swelling
Poor lymphocyte transformation
Decreased cell mediated immunity
Impaired intracellular killing of bacteria by neutrophils

Question 26

Causes of iron def anaemia

Answer 26

Blood loss:
Hookworm infestation
GI – oesophageal varies, hiatus hernia, peptic ulcer, aspirin ingestion, gastric colonic & ceacal CA, hereditary telangiectasia, ulcerative colitis, angiodysplasia, haemorrhoids, meckel’s diverticulum
Uterine – menorrhagia, postmenopausal bleeding, prolonged bleeding during parturition
Pulmonary – haemoptysis, pulmonary idiopathic haemosiderosis, Goodpasture syndrome
Renal tracts – haematuria( renal/bladder lesion), haemoglobinuria(PNH, cardiac valve prosthesis)
Widespread bleeding disorders
Increased demands – infants, children, adolescents, pregnant & lactating women
Inadequate iron supply
Poor nutritional intake in children
malabsorption – gastrectomy, Gluten-induced enteropathy, crohn’s disease, coeliac sprue, atrophic gastritis, achlorhydria
Abnormal atransferrinaemia function – congenital atransferrinaemia, autoantibodies to transferrin receptors

Question 27

Management of IDA

Answer 27

• Aim is to restore the heamoglobin concentration, red cell indices and to replenish the iron stores
• Treatment of underlying cause will prevent further iron loss but all patients should have iron supplementation to achieve above aim
• Oral iron therapy is usually adequate to restore iron stores in most patients; it is efficient, well tolerated & cost effective
• It is well absorbed with few side effects (heartburn, abdominal pain, nausea, diarrhoea & constipation)
• When iron complexes or chelated forms (carboxylated inulin-iron complex/thiolated inulin-iron complex) are used, GI symptoms are minimal and these contain ferric chloride which is more bioavailable
• Sustained slow release / enteric coated iron should not be used as much of the iron is carried past the duodenum to the sites of poor absorption