Page created on April 9, 2022. Last updated on April 21, 2023 at 21:02

Introduction to anaemia

Introduction and epidemiology

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 diagnosed by haemoglobin concentration. The WHO defines anaemia as a haemoglobin concentration < 13 g/dL for men and < 12 g/dL for women, but the normal ranges vary a bit from laboratory to laboratory.

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	Increased RBC loss 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
	Anaemia of chronic disease (late phase)	Sickle cell anaemia	Folate deficiency
	Thalassaemia	G6PD deficiency	Certain drugs (phenytoin, sulfa drugs)
	Lead poisoning	Paroxysmal nocturnal haemoglobinuria	Fanconi anaemia
	Chronic blood loss	Hereditary spherocytosis	Liver disease
		Autoimmune haemolytic anaemia	Alcohol abuse
		Microangiopathic haemolytic anaemia (TTP/HUS)
		Macroangiopathic haemolytic anaemia
		Non-haemolytic anaemias:
		Acute blood loss
		Aplastic anaemia
		Anaemia of chronic disease (early phase)

General features of anaemia

• Fatigue
• Pallor – especially of lips and conjunctiva
• Weakness
• Exercise intolerance
• Palpitations
• Tachycardia

Iron deficiency anaemia

Introduction and epidemiology

Iron deficiency anaemia (IDA) is the most common form of anaemia worldwide. It’s most common in children, young women and pregnant women. >40% of women are iron deficient, of which 50% have iron deficiency anaemia!

It’s easily diagnosable and treatable. However, it’s most often a symptom of an underlying disorder, and so the underlying cause must be sought.

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 (malignancy, peptic ulcer, hookworm infestation)	Malnutrition	Inflammatory bowel disease	Pregnancy
Menorrhagia	Strict vegan diet (without appropriate precautions)	Coeliac disease	Lactation
Meckel diverticulum		Bariatric surgery	Growing child
		Achlorhydria

For adults the most common causes are menorrhagia, peptic ulcer disease, and 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.

Iron absorption and metabolism

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 is 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 and can be increased by consumption of vitamin C. Normal gastric pH is needed for proper absorption of non-heme iron.

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.

Pathomechanism

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 is 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	↓	↓	↑	↓	↓	↓	↓↓

Clinical features

In addition to the general symptoms of anaemia, there are some 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 – due to oesophageal webs

Iron deficiency even without manifest anaemia may cause impaired cognition and fatigue.

Diagnosis and evaluation

The diagnosis is made when there is evidence of microcytic anaemia and iron deficiency.

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, and so decreased serum iron alone is not diagnostic for iron deficiency.

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

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 increases when the iron availability decreases, just like serum transferrin. Unlike serum transferrin, soluble transferrin receptor is not confounded by inflammation.

To evaluate whether iron is being absorbed or not, an iron load/iron absorption test can be used. In a fasting state, serum iron is measured. The patient is then administered a standardised iron solution/supplement, and serum iron is measured after 30 and 60 minutes. Failure of the ingested iron to increase serum iron levels sufficiently points toward iron absorption deficiency.

In summary, the following laboratory results are present in iron deficiency anaemia:

• Complete blood count
  • Haemoglobin ↓ (< 12 g/dL in men, < 12 g/dL in women)
  • MCV ↓ (< 80 fL) (may be normal in early stage)
  • RDW ↑ (anisocytosis)
• Iron studies
  • Serum iron ↓
  • Serum ferritin ↓
  • Serum transferrin ↑
  • Total iron binding capacity ↑ (rarely required)
  • Transferrin saturation ↓ (rarely required)
  • Soluble transferrin receptor ↑ (rarely required)
• Peripheral blood smear
  • Anisocytosis
  • Increased central pallor of RBCs
• Bone marrow biopsy (rarely required)
  • Low bone marrow iron

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.

Treatment

Iron deficiency anaemia itself is not a disease but should be managed as a symptom of an underlying illness until all possible causes have been ruled out. While investigating for underlying illness, IDA should always be treated with iron supplements. It can take weeks or months for the anaemia to be normalized after iron supplement therapy has begun. However, if iron supplements don’t improve the patient’s symptoms, the diagnosis must be reconsidered.

Dietary changes may be necessary. Introduction of iron-fortified foods and increasing consumption of iron-rich foods like meat and green leafy vegetables is effective.

Oral iron supplement is in the ferrous (Fe²⁺) form. The optimal daily dose is 200 mg of elemental iron. Treatment should last for 6 months and may need to be continued even after the anaemia has been corrected.

Parenteral iron is an alternative if oral iron fails to improve the patient’s condition (e.g. due to malabsorption), if the patient doesn’t tolerate oral iron, or if the patient is non-compliant.