Haematology - Iron deficiency anaemia

It is a key functional component of oxygen transport and of many enzymes required for generation of energy (cytochromes).

Humans conserve iron by recycling it from senescent red cells. The loss of iron in a typical adult male can be met by absorbing only 1-2mg of iron per day. The total body iron is 3,000-4,000mg and the daily iron requirement for erythropoiesis is about 20mg.

Most of the iron is in the form of haemoglobin (3g) with the stored forms accounting for 1g. Physiological losses in body fluids account for 1mg a day in an adult male and an average of 2mg a day for a pre-menopausal female.

Dietary sources are primarily green vegetables, eggs, bread and red meat. Iron exists in the diet in three forms: haem iron; iron as various soluble complexes and ferric iron. Unfortunately much of our dietary iron is in the ferric form, which is largely unavailable for absorption.

The absorption of iron is strongly influenced by other dietary components. Vitamin C and alcohol will promote iron absorption while the tannic acid in tea and fibres will depress absorption.

Causes
Iron deficiency can be caused by a variety of factors. One cause is blood loss and a common cause in women is menorrhagia. GI blood loss, caused by oesophageal varices, peptic ulcer disease, ulcerative colitis, haemorrhoids or stomach or colon cancer, can also cause iron deficiency.

Other causes include malabsorption (coeliac disease, atrophic gastritis); increased requirement due to growth spurts or pregnancy and inadequate intake.

Identifying iron deficiency anaemia

The blood count
The typical change in the blood count is a microcytic anaemia with a low MCV and a low mean corpuscular haemoglobin. The MCV drops once iron stores have been depleted. The WCC should be normal, while the platelet count is frequently raised.

Examination of the blood film may show the presence of pencil cells, which are the only useful feature when assessing iron deficiency.

Physical signs
Koilonychia (spoon-shaped depression of the nails) is a specific physical sign of iron deficiency but is rarely seen these days because of the ready access to blood tests. Only individuals with very severe and longstanding iron deficiency will develop this physical sign.

Much more common is angular stomatitis or cheilosis but this is not as specific. Pallor in the conjunctivae can be difficult to assess and some people have a naturally pale complexion.

Investigation of iron deficiency
The usual differential problem in investigating a mild microcytic anaemia is whether this represents iron deficiency or thalassaemia trait.

Clues from examination include angular stomatitis suggestive of iron deficiency and underweight individuals may have an absorption problem such as coeliac disease.

The ethnic origin may be relevant as Caucasian individuals rarely have thalassaemia, whereas this is more common in Afro-Caribbean and South Asian populations.

The commonest cause of iron deficiency in a young woman is heavy menstrual loss and this is assumed to be the cause unless there are clear indications to a GI source.

Serum ferritin
The normal range of serum ferritin varies but most indicate a figure below 20mg per litre as being low. A low serum ferritin can only indicate iron deficiency but normal levels can sometimes be misleading as ferritin acts as an acute phase reactant.

Therefore, iron deficiency anaemia might be masked in the context of liver disease, inflammatory disease (especially rheumatoid arthritis) or malignancy, where the iron deficient ferritin level is pushed up to the normal range.Should iron deficiency be confirmed, the tissue transglutaminase antibody should be checked to exclude coeliac disease.

Anaemia of chronic disease
Patients with rheumatoid arthritis and other chronic diseases are difficult to diagnose as their anaemia may be either iron deficiency or chronic disease.

Typically the chronic disease anaemia is normocytic but the MCV may also be reduced.

The active inflammatory process in rheumatoid arthritis will also push the ferritin up.

Hepcidin
Hepcidin is a 25 amino acid peptide synthesised in the liver. In 2001, the absence of hepcidin in mice was shown to produce a picture that mimics human haemochromatosis.

Hepcidin was then shown to be the iron regulating hormone that acts by blocking the passage of iron from intestinal cells into the blood and its release from macrophages. It therefore plays a role in inflammatory states and the anaemia of chronic disease. In iron deficiency anaemia, hepcidin production is reduced allowing more iron absorption from the bowel and from macrophages to increase erythropoiesis.

Referral
A pre-menstrual woman with heavy menstrual loss should be referred to a gynaecologist. All patients with a suspicion of GI loss should be referred to gastroenterologists for endoscopy and colonoscopy.

Similarly, a positive transglutaminase antibody indicating coeliac disease requires referral to gastroenterology.

Treatment
The majority of patients should be managed with oral agents. There is no evidence that any other treatment is superior to ferrous sulphate, which is cheap and effective.

Slow release preparations are expensive and illogical as the iron is released beyond the proximal small bowel from where it can be absorbed. Side-effects, such as nausea and constipation, occur in up to 25 per cent of patients, especially if ferrous sulphate is administered three times daily.

Most patients will respond to one tablet daily or a smaller dose in the form of paediatric syrup (sodium feredetate). Patients who are intolerant of oral iron can receive IV preparations.

The commonest cause of failure to respond is compliance due to the side-effects. Patients with ongoing blood loss or unrecognised malabsorption will fail to respond to treatment.

Incorrect diagnosis will also cause treatment to fail.

• Dr Murray is a consultant haematologist, University Hospitals Birmingham NHS Foundation Trust