Iron-Deficiency Anaemia (IDA)

Iron deficiency is the most common cause of anaemia. The World Health Organisation defines anaemia as a haemoglobin value of:¹

• <13g/dl in men
• <12g/dl in women
• <11g/dl in children aged 6 months to 6 years
• <12g/dl in children aged 6-14 years

Haemoglobin values have a gaussian distribution in the population and so the use of such fixed values means that a number of patients with slightly low Hb levels may have no pathology.

A state of non-anaemic iron deficiency usually precedes actual anaemia. It is 3 times as common as iron deficiency anaemia (IDA) but there is little consensus about investigating the former. Failure to investigate IDA properly by practitioners in primary care causes significant delay in final diagnosis with associated morbidity.²

In the developed world prevalence is:

• Children 0-14 years 12%
• Children 5-12 years 7%
• Women aged 15-49 years 11%
• Pregnant women 14%
• Men aged 15-59 years 3%

There is increasing prevalence over the age of 75 years.

In developing countries, around 50% of women and children and 25% of men have iron deficiency anaemia.¹

• Female sex
• Vegetarian diet
• Chronic illness
• Chronic renal failure
• Post gastrectomy

Especially in young people, there may be remarkably little in terms of complaints despite a significant fall in haemoglobin. Iron deficiency anaemia is often an incidental finding rather than a presenting feature.

Symptoms

• Fatigue
• Shortness of breath on exertion
• Palpitations
• Irritability
• Sore tongue
• Changes in the hair or hair loss
• Exceptionally there may be dysphagia due to an oesophageal web with chronic iron deficiency. This is the Paterson-Brown-Kelly Syndrome and it can progress to postcricoid carcinoma.

Signs

• The patient may look pale but this is best seen in the mucosa of tongue and mouth, especially in people with dark skin.
• There may be koilonychia with spoon shaped nails. There may also be longitudinal ridging.
• There may be angular cheilitis.
• In marked anaemia there may be a bounding pulse, warm extremities and a flow murmur.

• Stigmata of chronic liver disease, perhaps cirrhosis
• Multiple telangiectasia may be a feature of Hereditary Haemorrhagic Telangiectasia, also called Osler-Weber-Rendu Syndrome.
• Pigmentation of the lips and buccal mucosa may suggest Peutz-Jegher's syndrome

Always examine the abdomen. There may be modest splenomegaly in small proportion of patients although a spleen has to be at least twice its normal size to be palpable. Examine for abdominal masses, lymphadenopathy and any other features of intra-abdominal disease. Consider rectal examination if appropriate.

Further Inquiry

If iron deficiency anaemia (IDA) is suspected or confirmed, there are a number of specific questions that should be asked. Remember that there may be more than one cause of deficiency. A rather poor intake may have sufficed until there was increased demand.

• In a woman of relevant age, take a menstrual history. What constitutes heavy menstruation is highly subjective. It is not just heaviness of flow but duration that is important. The article on menorrhagia discusses this in much greater detail.
• Note any recent pregnancies
• Enquire about diet. Is the patient on any special diet, perhaps for weight loss?
• Ask about bowel habit and in particular any change. This is discussed in Gastrointestinal History and Examination.
• Ask about drugs, both prescribed and OTC. Aspirin, NSAIDs and heavy use of antacids may all raise questions.
• Note any previous GI disease or surgery
• Ask about blood donation
• Note any foreign travel
• Is there a family history of IDA?
• Have there been nosebleeds?

Causes of iron deficiency may be classified as:

• Excessive blood loss
• Inadequate amount of available iron in the diet
• Failure to absorb adequate amounts of iron
• Excessive requirements

Blood Loss

The commonest cause of iron deficiency anaemia is blood loss. At least 90% of iron required for erythropoiesis is recycled from senescent erythrocytes. Haemolytic anaemia does not cause iron deficiency as the iron is not lost to the body. However, the demand for new red blood cells may lead to a folate deficiency.

• In women of the relevant age, the first question is about menstrual loss.
• In women after the menopause and in men, the most likely lesion is bleeding from the gastrointestinal tract. This may occur with:
  • Malignancy at any level from carcinoma of oesophagus to carcinoma of rectum and including carcinoma of pancreas
  • Gastro-oesophageal reflux disease
  • Bleeding oesophageal varices in cirrhosis
  • Gastric ulcer or duodenal ulcer including erosions from NSAIDs
  • Inflammatory bowel disease
  • Diverticula may bleed but suspect carcinoma of colon
  • Haemorrhoids can cause significant blood loss
  • Other less usual sources include Meckel's diverticula, angiodysplastic lesions and benign ulcerating tumours such as haematomas and leiomyomas.
• Recurrent epistaxis
• After major surgery of major trauma if replacement has been inadequate
• Blood may also be lost in malignancy of the renal tract

In other countries, infestation of the gut may be relevant, especially with hookworm.

Dietary Inadequacy

Not only does the diet have to contain adequate amounts of iron but it has to be in a form that may be absorbed. It can be absorbed in the ferrous state much more readily than in the ferric state. There is almost no mechanism for the excretion of iron and homeostasis is managed by regulating absorption. This fails in hereditary haemochromatosis. An iron deficient state leads to greater absorption but there is a limit to how much can be absorbed.

Dietary iron deficiency is fairly uncommon. Meat tends to be more rich in iron than vegetables and so vegetarians are at greater risk but green vegetables are a good source of iron and a proper vegetarian diet should not lead to deficiency.

Failure of Absorption

• Some substances may bind to iron and prevent absorption. Tetracyclines and quinolones chelate with iron so that neither the antibiotic nor the iron is absorbed. Meat is not only rich in iron but it enhances uptakes whilst phytate impairs it.³
• Antacids may also impair absorption but perhaps less than usually thought.⁴
• There may also be iron deficiency in diseases that cause malabsorption such as coeliac disease. It is usually accompanied by folate deficiency.
• It may occur after gastric surgery, especially as the years go by.⁵
• Infection with helicobacter pylori impairs iron absorption⁶ and if found it should be eradicated.⁷

Excessive Requirements for Iron

Times of high demand for iron should be met by greater absorption from the diet but if the diet is not completely adequate, an intake that would otherwise suffice becomes inadequate.

• Times of rapid growth in children
• Pregnancy, especially with twins
• Exfoliative skin disease

There are two components to investigation:

• Establishing the fact of iron deficiency anaemia
• Seeking the cause of iron deficiency

FBC is a very common investigation and may have been performed as a screen or for some other reason.

Confirming the Diagnosis

• FBC should show a hypochromic microcytic anaemia although a mixed picture with coexistent B12 or folate deficiency makes interpretation much more difficult.
• Hypochromia with a low mean corpuscular haemoglobin (MCH) is a more reliable marker than mean corpuscular volume (MCV) as it is less affected by variations in machines and errors from storage.⁷
• Remember that a haemoglobinopathy will also cause a hypochromic microcytic anaemia.
• Serum ferritin should always be used to confirm iron deficiency. A figure of <12 µg/l is indicative..
• Other markers of IDA are low serum transferrin saturation (<16%), raised red cell protoporphyrin and increased transferrin binding receptors (sTfR).

A therapeutic trial of oral iron may confirm the diagnosis of IDA.⁷ Bone marrow tests are occasionally needed.

Seeking the Cause

Simply giving iron tablets is not enough. The British Society of Gastroenterologists (BSG) state that any level of iron deficiency anaemia must be investigated.⁷ That does not mean that everyone requires a full GI investigation, especially where there may be a good history of menorrhagia.

• Urinalysis should be performed as 1% of patients with IDA will have a renal tract malignancy.⁷
• Coeliac Disease serology (endomysial or tissue transglutaminase antibodies) unless an obvious non-GI source of blood loss is identified. It is recommended that all pre-menopausal women are screened for coeliac disease, even if they have menorrhagia.⁷ If positive confirm by gastroscopy with duodenal biopsy. The BSG is very keen on screening for coeliac disease.
• Faecal occult bloods are of no value.⁷

With no obvious cause, always search for GI bleeding:

• All male and post-menopausal female patients with IDA should have gastroscopy and colonoscopy (or sigmoidoscopy and double contrast barium enema depending on availability). Urgent 2 week referral may be appropriate.
• If gastroscopy is done first, only the diagnosis of gastric cancer or coeliac disease negates the need for lower GI investigations.⁷
• The only group where both upper and lower GI investigations are not considered mandatory is pre-menopausal women. Screen for coeliac disease and arrange upper or lower GI investigations. Upper endoscopy is 3 times as likely as lower endoscopy to yield results.⁸
• Occasionally other X-ray studies may be necessary, from small bowel barium studies or CT/ MRI, to more complicated radiolabelled studies looking for conditions such as Meckel's Diverticulum and angiodysplasia. Rarely a diagnostic laparotomy may be necessary to identify any obscure tumours or angiodysplastic lesions.

Remember that a hypochromic microcytic anaemia also occurs with haemoglobinopathies such as thalassaemia. This is usually a state of iron overload and giving more iron is most undesirable.

• Establish the underlying cause of the IDA and treat it.
• Replace iron with oral ferrous salts at 100-200mg elemental iron daily. Giving higher doses is unlikely to increase iron absorption but it will increase adverse effects.
• Ascorbic acid (250-500mg bd) may enhance absorption by reducing ferric to ferrous iron. However, the evidence for the efficacy of this is poor.
• If the patient is unable to tolerate oral iron or there is malabsorption, parenteral iron can be given. This must be by deep IM injection. It is very painful and may stain the skin. Intravenous iron can lead to anaphylaxis.
• Transfusion is very occasionally necessary.
• Patients in chronic renal failure on erythropoietin will need parenteral iron to correct the anaemia.

In all cases, therapy should be continued until iron stores are replenished. This is usually taken as 3 months after all evidence of deficiency is corrected.

Helicobacter pylori should be eradicated if found during gastroscopy, as it appears to impair iron uptake and the gastritis may increase iron loss.