2. Iron deficiency anaemia

Anaemia

Anaemia is defined as the reduction in circulating red blood cell-mass below normal levels. It reduces the oxygen-carrying capacity of the blood, leading to tissue hypoxia. It is usually diagnosed by haematocrit and the haemoglobin concentration.

The WHO defines anaemia as a haemoglobin concentration < 13 g/dL for men and < 12 g/L for women.

Anaemias can be classified according to the morphology of the RBCs or according to the etiology.

Classification of anaemias according to morphology:

Microcytic anaemia Normocytic anaemia Macrocytic anaemia
MCV (fL) < 80 80 – 100 > 100
Pathomechanism Insufficient haemoglobin production Decreased blood volume and/or decreased erythropoiesis Insufficient RBC production and/or maturation, possibly due to defective DNA synthesis or DNA repair
Possible causes Iron deficiency anaemia Haemolytic anaemias: Vitamin B12 deficiency
Sideroblastic anaemia Sickle cell anaemia Folate deficiency
Thalassaemia G6PD deficiency Certain drugs (phenytoin, sulfa drugs, trimethoprim, hydroxyurea, methotrexate, 6-mercaptopurine)
Lead poisoning Paroxysmal nocturnal haemoglobinuria Fanconi anaemia
Hereditary spherocytosis Liver disease
Autoimmune haemolytic anaemia Alcohol abuse
Microangiopathic haemolytic anaemia Myelodysplastic syndromes
Macroangiopathic haemolytic anaemia Multiple myeloma
Non-haemolytic anaemias:
Blood loss
Aplastic anaemia
Anaemia of chronic kidney disease

Classification of anaemias according to etiology:

  • Anaemia due to blood loss
  • Anaemia due to increased RBC destruction
    • Hereditary
      • Haemoglobinopathies
        • Sickle cell disease
        • Thalassaemia
      • Red blood cell membrane disorders
        • Paroxysmal nocturnal haemoglobinuria
        • Hereditary spherocytosis
      • Red blood cell enzyme defects
        • Glucose 6-phosphate dehydrogenase deficiency
        • Pyruvate kinase deficiency
      • Porphyrias
        • Porphyria cutanea tarda
        • Acute intermittent porphyria
    • Acquired
      • Mechanical
        • Macroangiopathic haemolytic anaemias
          • Prosthetic heart valves
          • Aortic stenosis
        • Microangiopathic haemolytic anaemias
          • Haemolytic uraemic syndrome (HUS)
          • Thrombotic thrombocytopaenic purpura (TTP)
      • Antibody mediated
        • Cold agglutinin disease
        • Warm agglutinin disease
        • ABO incompatibility
        • Rhesus incompatibility
      • Hypersplenism
  • Anaemia due to decreased RBC production
    • Hereditary
      • Fanconi anaemia
      • Diamond-Blackfan syndrome
    • Acquired
      • Megaloblastic anaemias (B12, folate deficiency)
      • Iron deficiency anaemia
Iron deficiency anaemia

Iron deficiency anaemia (IDA) is the most common form of anaemia worldwide. It’s most common in children 0 – 5 years old, young women and pregnant women. >40% of pregnant women are iron deficient!

Etiology:

The etiologies can be classified based on the underlying mechanism.

Due to iron loss

Due to decreased iron intake Due to decreased iron absorption Due to increased iron demand

Gastrointestinal bleeding (occult malignancy, peptic ulcer, hookworm infestation)

Chronic malnutrition Inflammatory bowel disease Pregnancy

Menorrhagia

Strict vegan diet (without appropriate precautions) Coeliac disease

Lactation

Meckel diverticulum Excessive intake of nonfortified cow’s milk Bariatric surgery

Growth spurt

Achlorhydria

Iron in foods can be in two forms. It can be in the form of a heme group or it can be in the form of a simple iron ion (Fe2+ or Fe3+). The two forms are absorbed by different mechanisms. Iron in meat is in the heme form while iron in non-meat foods are in the iron ion form. The heme form is easily absorbed; the absorption of the ion form can be decreased by many factors, like simultaneous intake of calcium (dairy products) or tea. Normal gastric pH is needed for proper absorption of non-heme iron.

For adults the most common causes are menorrhagia, peptic ulcer disease or colon malignancies. In developing countries is hookworm infestation the most common cause. In children the most common cause is malnutrition or excessive intake of nonfortified cow’s milk.

Stages:

The development of iron deficiency can be divided into three stages: the pre-latent stage, the latent stage and manifest iron deficiency anaemia.

The pre-latent stage occurs when there is a reduction in iron stores, but the serum iron level is not yet reduced. There is no anaemia, but the serum ferritin can be low. The amount of iron in the bone marrow is decreased.

The latent stage occurs when iron stores are exhausted, but the blood haemoglobin levels are yet unaffected. There is no anaemia but the TIBC can be increased and the serum ferritin and transferrin saturation can be decreased. There is no iron in the bone marrow.

The manifest iron deficiency anaemia stage occurs when the iron deficiency actually causes anaemia. The Hb, MCV, serum ferritin and transferrin saturation are decreased, the TIBC is increased and there is no iron in the bone marrow.

Haemoglobin MCV TIBC Serum ferritin Serum iron Transferrin saturation Marrow iron
Pre-latent stage

Normal

Normal Normal Normal Normal
Latent stage

Normal

Normal

↓↓

Iron deficiency anaemia

↓↓

Iron metabolism:

Iron is toxic to cells and must be stored inside cells as part of the ferritin protein. It is transported in the blood in the form of transferrin. Cells which need iron express a transferrin receptor on their cell surface. Transferrin binds to this receptor, and the transferrin-transferrin receptor complex is endocytosed.

A soluble transferrin receptor, which is not attached to the cell surface but rather dissolved in the serum, also exists.

Diagnosis:

Many parameters can be important in diagnosing iron deficiency anaemia. Most of them are so-called iron studies.

Serum iron corresponds to the amount of circulating iron, most of which is bound to transferrin. However, serum iron fluctuates significantly daily and isn’t really a good measure of the body’s iron situation. Decreased serum iron alone is not diagnostic for iron deficiency. The below parameters are more important.

Serum ferritin corresponds to the body’s iron stores. If serum ferritin is low, it’s likely that the body’s stores of iron are low as well. However, ferritin is an acute phase protein, so it can be increased independent of iron store status and must be therefore be interpreted with caution in patients with ongoing inflammation. Despite this, serum ferritin is the most important parameter in IDA. Decreased serum ferritin alone is diagnostic for IDA.

Serum transferrin corresponds to the body’s need for iron. When the cells which need iron, most importantly the erythropoietic cells of the bone marrow, are starving for iron the body will produce more serum transferrin. However, transferrin is a negative acute phase protein and it’s therefore decreased in patients with inflammation.

Total iron binding capacity (TIBC) reflects the blood’s capacity to bind iron with transferrin. Instead of measuring the amount of transferrin in the serum directly it measures how much free capacity the serum transferrin has to bind more iron. If the iron binding capacity is increased the circulating transferrin is not saturated with iron.

Transferrin saturation indicates the amount of iron bound to transferrin. The transferrin saturation and TIBC are closely related. Transferrin saturation is calculated from the serum iron and TIBC.

Soluble transferrin receptor or serum transferrin receptor measures the amount of soluble transferrin receptor. Its concentration in serum decreases when the iron availability decreases, just like serum transferrin. Unlike serum transferrin soluble transferrin receptor is not confounded by inflammation.

In cases where iron deficiency anaemia is suspected by peripheral blood results are inconclusive a bone marrow biopsy and measurement of bone marrow iron is diagnostic.

Free erythrocyte protoporphyrin (FEP) measures the amount of protoporphyrin in the serum. Protoporphyrin is the last intermediate in the heme synthesis pathway. If iron stores are depleted protoporphyrin cannot be converted into heme and instead accumulates in the serum.

Laboratory test in iron deficiency anaemia:

  • Complete blood count
    • Haemoglobin ↓ (< 14 g/dL in men, < 12 g/dL in women)
    • Haematocrit ↓ (< 41 % in men, < 36 % in women)
    • MCV ↓ (< 80 fL)
    • MCH ↓ (< 27 pg)
    • RDW ↑ (anisocytosis)
  • Iron studies
    • Serum iron ↓
    • Serum ferritin ↓
    • Serum transferrin ↑
    • Total iron binding capacity ↑
    • Transferrin saturation ↓
    • Soluble transferrin receptor ↑
    • Free erythrocyte protoporphyrin ↑
  • Peripheral blood smear
    • Anisocytosis
    • Increased central pallor of RBCs
  • Bone marrow biopsy
    • Low bone marrow iron

Early iron deficiency anaemia can be normochromic and normocytic.

The most important differential diagnosis for iron deficiency anaemia is anaemia of chronic disease (ACD), which is also microcytic. In ACD the ferritin is normal or elevated, transferrin is decreased and RDW is normal.

Clinical features:

  • General symptoms of anaemia
    • Fatigue
    • Pallor
      • Especially of lips and conjunctiva
    • Weakness
  • Specific signs of iron deficiency anaemia
    • Koilonychia – spoon-shaped concave nails
    • Hair loss
    • Pica – appetite for and ingestion of substances like ice, hair, paint, paper, clay, etc.
    • Angular cheilitis – fissuring of the angles of the mouth
    • Atrophic glossitis – painful, smooth tongue
    • Dysphagia – often due to oesophageal webs

Treatment:

Iron deficiency anaemia itself is not a disease but rather a symptom of an underlying illness. IDA should always be treated with just iron supplements, but any underlying causes must be ruled out also. If malnutrition or bad diet is the cause the diet must be changed. Introduction of iron-fortified foods and increasing consumption of iron-rich foods like meat and green leafy vegetables is effective.

Oral iron is in the ferrous (Fe2+) form. The optimal daily dose is 200 mg of elemental iron. Iron is better absorbed when the stomach is empty. Absorption is enhanced by vitamin C, meat and inhibited by cereals, tea and milk. Treatment should last for 6 months and should be continued even after the anaemia has been corrected.

Parenteral iron is indicated if there is malabsorption, if the patient doesn’t tolerate oral iron or if the patient is non-compliant.

It can take weeks or months for the anaemia to be normalized after iron supplement therapy has begun.


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4. Haemolytic anaemias (inherited and acquired)

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