When iron deficiency is developing, the reticuloendothelial stores (haemosiderin and ferritin) become completely depleted before anaemia occurs (Fig. 3.6). As the condition develops, the patient may show the general symptoms and signs of anaemia (see p. 20) and also a painless glossitis, angular stomatitis, brittle, ridged or spoon nails (koilonychia) (Fig. 3.7) and unusual dietary cravings (pica). The cause of the epithelial cell changes is not clear but may be related to reduction of iron‐containing enzymes. In children, iron deficiency is particularly significant as it can cause irritability, poor cognitive function and a decline in psychomotor development. There is also evidence that oral or parenteral iron may reduce fatigue in iron‐deficient (low serum ferritin) non‐anaemic women.
Causes of iron deficiency
In developed countries, chronic blood loss, especially uterine or from the gastrointestinal tract, is the dominant cause of iron deficiency (Table 3.4) and dietary deficiency is rarely a cause on its own. Five hundred millilitres of blood contain approximately 250 mg iron and, despite the increased absorption of food iron at an early stage of iron deficiency, negative iron balance is usual in chronic blood loss.
Increased demands during infancy, adolescence, pregnancy, lactation and in menstruating women account for the high risk of iron deficiency anaemia in these particular clinical groups. Newborn infants have a store of iron derived from delayed clamping of the cord and the breakdown of excess red cells. From 3 to 6 months there is a tendency for negative iron balance because of growth. From 6 months, supplemented formula milk and mixed feeding, particularly with iron‐forti-fied foods, prevents iron deficiency.
In pregnancy increased iron is needed for an increased maternal red cell mass of approximately 35%, transfer of 300 mg of iron to the fetus and because of blood loss at delivery. Although iron absorption is also increased, iron therapy is often needed if the haemoglobin (Hb) falls below 100 g/L or the mean cell volume (MCV) is below 82 fL in the third trimester.
Menorrhagia (a loss of 80 mL or more of blood at each cycle) is difficult to assess clinically, although the loss of clots, the use of large numbers of pads or tampons or prolonged periods all suggest excessive loss.
It takes about 8 years for a normal adult male to develop iron deficiency anaemia solely as a result of a poor diet or malabsorption resulting in no iron intake at all. In developed countries inadequate intake or malabsorption are only rarely the sole cause of iron deficiency anaemia. Gluten‐induced enteropathy, partial or total gastrectomy and atrophic gastritis (often autoimmune and with Helicobacter pylori infection) may, however, predispose to iron deficiency. In developing countries, iron deficiency may occur as a result of a life‐long poor diet, consisting mainly of cereals and vegetables. Hookworm may aggravate iron deficiency, as may repeated pregnancies or growth and menorrhagia in young females.
These are summarized and contrasted with those in other hypochromic anaemias in Table 3.7.
Red cell indices and blood film
Even before anaemia occurs, the red cell indices fall and they fall progressively as the anaemia becomes more severe. The blood film shows hypochromic, microcytic cells with occasional target cells and pencil‐shaped poikilocytes (Fig. 3.8). The reticulocyte count is low in relation to the degree of anaemia. When iron deficiency is associated with severe folate or vitamin B12 deficiency, a ‘dimorphic’ film occurs with a dual population of red cells of which one is macrocytic and the other microcytic and hypochromic; the indices may be normal. A dimorphic blood film is also seen in patients with iron deficiency anaemia who have received recent iron therapy and produced a population of new haemoglobinized normal‐sized red cells (Fig. 3.9) and when the patient has been transfused. The platelet count is often moderately raised in iron deficiency, particularly when haemorrhage is continuing.
Bone marrow iron
Bone marrow examination is not essential to assess iron stores except in complicated cases. In iron deficiency anaemia there is a complete absence of iron from stores (macrophages) and from developing erythroblasts (Fig. 3.10). The erythroblasts are small and have a ragged cytoplasm.
Serum iron and total iron‐binding capacity
The serum iron falls and total iron‐binding capacity (TIBC) rises so that the TIBC is less than 20% saturated (Fig. 3.11). This contrasts both with the anaemia of chronic disorders (see below), when the serum iron and the TIBC are both reduced, and with other hypochromic anaemias where the serum iron is normal or even raised.
A small fraction of body ferritin circulates in the serum, the concentration being related to tissue, particularly reticuloendothelial, iron stores. The normal range in men is higher than in women (Fig. 3.11). In iron deficiency anaemia the serum ferritin is very low while a raised serum ferritin indicates iron overload or excess release of ferritin from damaged tissues or an acute phase response (e.g. in inflammation). The serum ferritin is normal or raised in the anaemia of chronic disorders.
Investigation of the cause of iron deficiency (Fig. 3.12)
In premenopausal women, menorrhagia and/or repeated preg nancies are the usual causes of the deficiency. If these are not present, other causes must be sought. Insome patients with menorrhagia a clotting or platelet abnormality (e.g. von Willebrand disease) is present. In men and postmenopausal women, gastrointestinal blood loss is the main cause of iron deficiency and the exact site is sought from the clinical history, physical and rectal examination, by occult blood tests, and by appropriate use of upper and lower gastrointestinal endoscopy and/or radiology (e.g. computed tomography (CT) of the pneumocolon) or virtual colonoscopy using the 3D colon system (Figs 3.12 and 3.13). Tests for parietal cell antibodies, Helicobacter infection and serum gastrin level may help to diagnose autoimmune gastritis. In difficult cases a camera in a capsule can be swal lowed which relays pictures of the gastrointestinal tract electronically. Tests for transglutaminase antibodies and duodenal biopsy to look for gluten‐induced enteropathy can be valuable. Hookworm ova are sought in stools of subjects from areas where this infestation occurs. Rarely, a coeliac axis angiogram is needed to demonstrate angiodysplasia.
If gastrointestinal blood loss is excluded, loss of iron in the urine as haematuria or haemosiderinuria (resulting from chronic intravascular haemolysis) is considered. A normal chest X‐ray excludes the rare condition of pulmonary haemosiderosis. Rarely, patients bleed themselves producing iron deficiency.
The underlying cause is treated as far as possible. In addition, iron is given to correct the anaemia and replenish iron stores.
The best preparation is ferrous sulphate which is cheap, contains 67 mg iron in each 200‐mg tablet and is best given on an empty stomach in doses spaced by at least 6 hours. Ferrous fumarate is equally cheap and effective. If side‐effects occur (e.g. nausea, abdominal pain, constipation or diarrhoea), these can be reduced by giving iron with food or by using a preparation of lower iron content (e.g. ferrous gluconate which contains less iron (37 mg) per 300‐mg tablet). An elixir is available for children. Slow‐release preparations should not be used.
Oral iron therapy should be given for long enough both to correct the anaemia and to replenish body iron stores, which usually means for at least 6 months. The haemoglobin should rise at the rate of approximately 20 g/L every 3 weeks. Failure of response to oral iron has several possible causes (Table 3.5) which should all be considered before parenteral iron is used. Iron fortification of the diet in infants in Africa reduces the incidence of anaemia but increases suceptibility to malaria.
Many different preparations are available with varying licens ing in different countries.The dose is calculated according to body weight and degree of anaemia. Iron dextran (CosmoFer®) can be given as slow intravenous injection or infusion either in small single doses or as a total dose infusion given in 1 day. Ferric carboxymaltose (Ferinject®) and ferric isomaltoside (Monofer) may also be given as a total dose in 1 day by slow intravenous infusion. Ferric hydroxide–sucrose (Venofer®) is administered by slow intravenous injection or infusion, to a maximum of 200 mg iron in each infusion. Ferumoxytol (Feraheme®) is licensed for chronic renal failure. There may be hypersensitivity or anaphylactoid reactions to parenteral iron, especially in those with a previous reaction, multiple drug allergies and severe atopy. If the reaction is severe, it is treated with intravenous hydrocortisone and possibly adrenaline. Parenteral iron is given slowly and only when there are high iron requirements as in gastrointestinal bleeding, severe menorrhagia, chronic haemodialysis, with erythropoietin therapy, and when oral iron is ineffective (e.g. iron malabsorption resulting from gluten‐induced enteropathy or atrophic gastritis) or impractical (e.g. active Crohn’s disease). The haematological response to parenteral iron is no faster than to adequate dosage of oral iron but the stores are replenished faster. Intravenous iron has also been found to increase functional capacity and quality of life in some patients with congestive heart failure, even in the absence of anaemia (see p. 326).