Non Anaemic Iron Deficiency

Iron deficiency is a reduced content of total body iron. Iron deficiency anaemia occurs when the deficiency is sufficient to diminish erythropoiesis and drop the haemoglobin but problems can develop before this stage.

About 20% of women, 50% of pregnant women and 3% of men are iron deficient. Iron deficiency is the most prevalent deficiency state in the world.

• Blood loss
• Poor diet
• Malabsorption, especially in children
• Excessive skin loss (exfoliative dermatitis)
• Increased physiological demand including growth, menstruation and pregnancy
• Premature birth¹
• Iron is not excreted by the kidney but haemoglobin can be lost in haemolysis including march syndrome
• Endurance athletes are at risk of iron deficiency from high loss²

Men need about 1 mg of iron a day from a diet usually containing 10 to 20 mg. Pre-menopausal women need 2 mg a day and usually eat slightly less than men. Pregnancy requires about 500 mg of iron. Cow's milk contains more calcium than human milk and this inhibits the absorption of iron so that infants who are not breast fed are at greater risk of iron deficiency.

Symptoms

• There may be no symptoms in mild cases before anaemia develops
• Fatigue
• Irritability
• Poor memory and concentration³
• Sore tongue
• Brittle nails
• Pica (there seems some doubt as to whether pica is the cause or the result of iron and zinc deficiency⁴)
• Decreased appetite, especially in children
• Frontal headache
• Susceptibility to infection, especially in children
• Developmental delay

Signs

Before anaemia develops there will probably be no signs. There may be:

• Angular cheilitis
• Glossitis
• Koilonychia (spoon nails)
• Pallor (even without anaemia)
• Check the gums as even mild bleeding each time the teeth are brushed can lead to iron deficiency.

The British Society of Gastroenterologists offers firm advice on the management of iron deficiency anaemia⁵ but there is little consensus about non-anaemic iron deficiency.

• FBC may show a microcytic, hypochromic picture before haemoglobin falls. This picture is also produced by haemoglobinopathy. A mixed picture may be produced if malabsorption or poor diet causes folate deficiency too. WCC is normal but platelets may be raised.
• Serum iron, total iron-binding capacity (TIBC), and serum ferritin should be measured. Low iron and ferritin with raised TIBC are diagnostic of iron deficiency. Low serum ferritin is almost diagnostic of iron deficiency but normal serum ferritin can occur in patients who are iron deficient but have hepatitis or anaemia of chronic disorders. In chronic disease, serum iron is low but TIBC is low too.
• Sometimes bone marrow examination for iron is required but usually the diagnosis can be made by blood tests alone.
• In the guidance on the management of iron deficiency anaemia, the British Society of Gastroenterologists advise that occult bloods are of no value.⁵
• Haemoglobinuria infers haemolysis.
• Haemoglobin electrophoresis can detect abnormal haemoglobin as a cause of a hypochromic, microcytic picture but iron will be normal or raised.
• Lead levels may be required
• Serum transferrin receptor assay is showing promise as a test for iron status that is not affected by chronic inflammation and infection, although it may be affected by the presence of some tumours.⁶ It might soon be available to assist in clinical situations where current tests of iron status are not entirely satisfactory.
• In the elderly, even without anaemia, it is worth checking ferritin levels and investigating where they are low.⁷

Ferritin is the most useful single measure of iron status, because it accurately reflects body stores and because it is usually the first laboratory measure to change in iron deficiency. It correlates well with the clinical effects. Low serum ferritin proves that the patient is iron deficient, and an appropriate lower limit of normal would be 15-16 μg/L. A normal serum ferritin does not exclude iron deficiency. Some women with very low iron stores in the marrow still have ferritin between 16 -20 μg/L. Inflammation, infection, some neoplasms, liver disease and recent strenuous exercise can raise ferritin. If ferritin is high, this may well be spurious but hereditary haemochromatosis is not a rare condition.

Ascertain that there is true iron deficiency and not a hypochromic, microcytic anaemia due to haemoglobinopathy or low iron in chronic disease.

When the diagnosis of iron deficiency is established, the next step is to seek the aetiology. In women between the menarche and menopause, menorrhagia is the commonest cause.

• Take a menstrual history where appropriate
• Ask about diet
• Note any GI symptoms. In men the usual cause is a GI malignancy, especially colon.
• Is there weight loss? (carcinoma or malabsorption)
• Ask about drugs, including NSAIDs bought OTC. Even 75 mg aspirin a day can cause iron deficiency.

There are many causes of bleeding from the GI tract. Carcinoma of stomach, cancer of the oesophagus, carcinoma of pancreas or carcinoma of colon or rectum must be considered. Bleeding can occur from gastric ulcer, duodenal ulcer, oesophagitis from gastro-oesophageal reflux or bleeding haemorrhoids. Those who have spent time in endemic areas may suffer such diseases as hookworm.

The Plummer-Vinson syndrome, also called Paterson-Brown Kelly syndrome, is usually associated with established iron deficiency anaemia rather than early iron deficiency but it can sometimes occur without anaemia and is called sideropenic dysphagia. It usually occurs in the age group 40 to 70 but a few children have been described. 90% of patients are women. There is an oesophageal web, dysphagia, features of iron deficiency and a predisposition to post cricoid carcinoma. Correction of iron deficiency reverses the changes provided that carcinoma has not yet developed but oesophageal dilatation may be required.

Non-drug

A cause for the iron deficiency must be found. Dietary advice may be required.

Drugs

Oral iron is usually given in the form of ferrous sulphate 200 mg tablets but liquid forms are used, especially in children. The rate of absorption is dependent upon the level of deficiency but is limited. There is little point in giving more than 3 tablets daily. Intolerance increases as dose rises and 1 tablet daily may suffice. Iron is absorbed in the ferrous rather than ferric state but the value of giving vitamin C to reduce the iron to the ferrous form is dubious and the BNF recommend against it. Iron injections are painful and stain the skin if not given by deeply. Unless there is serious trouble with malabsorption or compliance they are best avoided.

For children less than 15kg, the dose is 5 mg/kg/day. Between 15 and 30 kg give half the adult dose.

Treatment with iron should reverse all problems unless the underlying cause is sinister. The condition is likely to recur unless the underlying cause is addressed.

• Ideally infants should be breast fed.⁸
• Everyone should keep to a balanced, healthy diet. Although vegetarians are at greater risk of iron deficiency it is not inevitable as green vegetables are a very good source of iron.
• The ability of the body to extract iron from food is limited. It is more readily available in haem than non-haem forms.
• Vitamin C in the diet helps to absorb non-haem iron. Meat also appears to have an enhancing effect. Phytate has an inhibitory effect.⁹ Enhancers and inhibitors probably account for much of the prevalence of iron deficiency when people in an affluent society eat a mixed diet. In British society, adolescent girls are most at risk of iron deficiency and a diet including fresh fruit and meat is to be encouraged.¹⁰
• Excessive intake of tea and coffee can impair iron absorption.