This occurs when iron losses or physiological requirements exceed absorption.

Blood loss

The most common explanation in men and post-menopausal women is gastrointestinal blood loss. This may result from occult gastric or colorectal malignancy, gastritis, peptic ulceration, inflammatory bowel disease, diverticulitis, polyps and angiodysplastic lesions. On a world-wide basis, hookworm and schistosomiasis are the most prevalent causes of gut blood loss. Gastrointestinal blood loss may be exacerbated by the chronic use of aspirin or NSAIDs, which cause intestinal erosions and impair platelet function. In women of child-bearing age, menstrual blood loss, pregnancy and breastfeeding contribute to iron deficiency by depleting iron stores; in developed countries one-third of women in this age bracket have low iron stores but only 3% display iron-deficient haematopoiesis. Rarely, chronic haemoptysis or haematuria may cause iron deficiency.

Malabsorption

A dietary assessment should be made in all patients to ascertain their iron intake. Gastric acid is required to release iron from food and helps to keep iron in the soluble ferrous state. Hypochlorhydria in the elderly or that due to drugs such as proton pump inhibitors may contribute to the lack of iron availability from the diet, as may previous gastric surgery. Iron is absorbed actively in the upper small intestine and hence can be affected by coeliac disease. Anyone with features of malabsorption or recurrent deficiency in the absence of other explanations, young men with normal diet or young women with normal menstruation and diet in association with iron deficiency, should be screened for coeliac disease.

Iron absorption, uptake and distribution in the body.

Physiological demands

At times of rapid growth such as infancy and puberty, iron demands increase and may outstrip absorption. This may be exacerbated by prematurity and breastfeeding in infants or menstruation in girls. In pregnancy, iron is diverted to the fetus, the placenta and the increased maternal red cell mass, and is lost with bleeding at parturition. There is no consensus about the routine use of iron supplementation in pregnancy but if women with a poor dietary history or previous heavy menstrual losses become pregnant and the side-effects are acceptable, it is a justifiable practice.

Investigations

Confirmation of iron deficiency

Plasma ferritin is a measure of iron stores and the best single test to confirm iron deficiency. It is a very specific test; a subnormal level is due to iron deficiency, hypothyroidism or vitamin C deficiency. Levels can be raised by liver disease and in an acute phase response; in these conditions a ferritin level of up to 100 μg/l may still be associated with absent bone marrow iron stores. Plasma iron and total iron binding capacity (TIBC) are measures of iron availability, hence are affected by many factors besides iron stores. Plasma iron has a marked diurnal and day-to-day variation and becomes very low during an acute phase response but is raised in liver disease and haemolysis. Transferrin levels are lowered by malnutrition, liver disease, an acute phase response and nephrotic syndrome but raised by pregnancy or the oral contraceptive pill. A transferrin saturation of less than 16% is consistent with iron deficiency but is less specific than a ferritin measurement.

All proliferating cells express membrane transferrin receptors to acquire iron; a small amount of this receptor is shed into blood and found in a free soluble form there. At times of poor iron stores, cells up-regulate transferrin receptor expression; hence the levels of soluble plasma transferrin receptor increase. This can now be measured by immunoassay and used to distinguish storage iron depletion in the presence of an acute phase response or liver disease where a raised level indicates iron deficiency. In difficult cases it may still be necessary to examine a bone marrow aspirate for iron stores.

Investigation of the cause

This will depend upon the age and sex of the patient as well as the history and clinical findings. In men over the age of 40 years and in post-menopausal women with a normal diet, the upper and lower gastrointestinal tract should be investigated by endoscopy or barium studies. If coeliac disease is suspected, serum antigliadin and anti-endomysium antibodies and duodenal biopsy are indicated. In the tropics stool and urine should be examined for parasites.

Management

Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not necessary and oral iron supplementation is appropriate. Ferrous sulphate 200 mg 8-hourly (120 mg of elemental iron per day) is more than adequate and should be continued for 3-6 months to replete iron stores. The occasional patient is intolerant of ferrous sulphate, with dyspepsia and altered bowel habit. In this case a reduction in dose to 200 mg 12-hourly or a switch to ferrous gluconate 300 mg 12-hourly (70 mg of elemental iron per day) should be made. Delayed-release preparations are not useful since they release iron beyond the upper small intestine where it cannot be absorbed.

The haemoglobin should rise by 10 g/l every 7-10 days and a reticulocyte response will be evident by 1 week. A failure to respond adequately may be due to non-compliance, continued blood loss, malabsorption or an incorrect diagnosis. The occasional patient with malabsorption or chronic gut disease may need parenteral iron with deep intramuscular injection of iron sorbitol (1.5 mg of iron per kg body weight). This will produce a haematological response and rapidly replete iron stores. Patients should be warned that a brown skin discoloration like a tattoo is likely to develop at the sites of administration.