dxy

Iron deficiency

Modern automated cell counters provide measurements of the changes in red cells which accompany iron deficiency: reduced mean cell haemoglobin (MCH) – hypochromia and increased percentage of hypochromic red cells, and reduced mean cell volume (MCV) – microcytosis. MCH is probably the more reliable because it is less influenced by the counting machine used and by storage. Both microcytosis and hypochromia are sensitive indicators of iron deficiency in the absence of chronic disease or co-existent B12or folate deficiency. An increased red cell distribution width (RDW) will often indicate co-existent B12 or folate deficiency. Microcytosis and hypochromia are also present in many haemoglobinopathies (such as thalassaemia, when the MCV is often out of proportion to the level of anaemia compared with iron deficiency and, on review of previous results, has never been normal), in sideroblastic anaemia and in some cases of anaemia of chronic disease. Haemoglobin electrophoresis is especially recommended when microcytosis is longstanding and in patients of appropriate ethnic background to prevent unnecessary GI investigation (C).

The serum markers of iron deficiency are low ferritin, low iron, raised total iron binding capacity, raised red cell protoporhyrin and increased transferrin binding receptors (sTfR). Serum ferritin is the most powerful test for iron deficiency (A). The cut-off level of ferritin which is diagnostic varies between 12–15mg/L . This value only holds for patients without co-existent disease. In such settings, a cut-off value of <50mg/L is still consistent with iron deficiency1. The sTfR level is said to be a good marker of iron deficiency in healthy subjects but its utility in the clinical setting remains to be proven. Several studies show that the sTfR/log10 serum ferritin ratio provides superior discrimination to either test on its own, particularly in chronic disease.
Further tests to confirm iron deficiency are occasionally necessary. Estimation of iron concentration in bone marrow by the histochemical method14may distinguish between ‘true’ iron deficiency and other chronic disorders in which there is impaired release of iron from reticuloendothelial cells, but is subjective. A therapeutic trial of oral iron for three weeks is less invasive and may aid diagnosis, but depends on compliance. A trial of parenteral iron may be more reliable, and a measurable change in MCH should occur within 7 days when there is iron deficiency anaemia.

Functional Iron Deficiency

“Functional iron deficiency” occurs where there is an inadequate iron supply to the bone marrow in the presence of storage iron in reticuloendothelial cells. Perhaps the most important clinical setting for this is in patients with renal failure who will require parenteral iron therapy to respond to administered erythropoietin to correct anaemia.

None of the currently available tests have more than fair utility for deciding which patients will benefit from parenteral iron in this setting20. Low reticulocyte haemoglobin content provides an early indication of functional iron deficiency21, whilst a reduced percentage of hypochromic erythrocytes is a good predictor of response.

INVESTIGATIONS

History

Borderline iron deficient diets are common and a dietary history should be taken to identify poor iron intake. The use of aspirin and non-aspirin-NSAIDs should be noted and these drugs stopped where the clinical indication is weak or other choices are available. Family history of IDA (which may indicate inherited disorders of iron absorption, haematological disorders (e.g.thalassaemia), telangiectasia and bleeding disorders should be sought. A history of blood donation should be obtained. The presence of one or more of these factors in the history should not, however, usually deter further investigation.

Examination

Examination is usually non-contributory but may reveal a relevant abdominal mass or cutaneous signs of rare causes of GI blood loss (e.g. Peutz-Jeghers syndrome and hereditary haemorrhagic telangiectasia). Rectal examination should be performed (though this may be postponed until colonoscopy). Urine testing for blood is recommended in all patients with IDA (B) as approximately 1% of patients with IDA will have renal tract malignancy9. Anaemia occurs in approximately one third of patients with renal cell carcinoma24due to haematuria and haemosiderin deposition in the tumour. Further renal tract evaluation with ultrasound is recommended where suspicion of renal tract malignancy is strong followed by IVU and/or CT scan as necessary.

Upper and lower GI evaluation

Upper and lower GI investigations should be considered in all post-menopausal female and all male patients where IDA has been confirmed unless there is a history of significant overt nonGI blood loss. In the absence of suggestive symptoms (which are unreliable) the order of investigations is determined by local availability. The appropriateness of investigating patients with severe co-morbidity or other reasons (in some circumstances advanced age), especially if the result would not influence management, should be carefully discussed with patients and carers when possible.

All patients should be screened for coeliac disease (B). Ideally coeliac serology (either anti-endomysial antibody – EMA or tissue transglutaminase antibody – tTG) should be taken at presentation. If coeliac serology is negative small bowel biopsies then need not be taken at oesophago-gastro-duodenoscopy (OGD) unless there are other features which make coeliac disease more likely (B). If coeliac serology is positive, coeliac disease is likely and should be confirmed by small bowel biopsy. Further GI investigations (including colonoscopy) are not necessary in this setting. However, the lifetime risk of GI malignancy in patients with coeliac disease is slightly increased, and if IDA develops in a patient with treated coeliac disease upper and lower GI investigation is recommended.

If OGD is done as the initial GI investigation, only the presence of gastric cancer or coeliac disease should deter lower GI investigation (B). In particular, the presence of oesophagitis, erosions and peptic ulcer disease should not be accepted as the cause of IDA until lower GI investigations have been done. Small bowel biopsies should be taken at OGD if coeliac serology is positive or not done.

Colonoscopy (possibly at the same session as OGD) has the advantage that it will demonstrate angiodysplasia and allow biopsy of any lesion. However, double contrast barium enema is a sufficient alternative, with or without sigmoidoscopy26 28 especially if the facilities for colonoscopy are limited or the success rate of complete colonoscopy is poor within a particular unit.

Further evaluation

Further direct visualisation of the small bowel is probably not necessary unless the IDA is transfusion dependent (B). Followup studies have shown this approach to be safe provided dietary deficiency is corrected, NSAIDs have been stopped and the haemoglobin concentration is monitored. However, if IDA is transfusion dependent, enteroscopy may be helpful to detect and treat angiodysplasia30 31. Video capsule endoscopy (VCE) can also be used in this setting and has a diagnostic yield of 40–55%.

Many lesions detected by both enteroscopy and VCE are within the reach of a gastroscope, and repeat OGD should be considered prior to these procedures. Small bowel radiology is rarely of use unless the history is suggestive of Crohn’s disease.

Helicobacter pylori colonisation may impair iron uptake and increase iron loss thus leading to iron deficiency and IDA.
Eradication of H. pylori appears to reverse anaemia in anecdotal reports and small studies. H. pylori should be sought if OGD and colonoscopy are normal and eradicated if present (C).

Mesenteric angiography is of limited use but may be of value in transfusion dependent IDA for demonstrating vascular malformations. Similarly, diagnostic laparotomy with on-table endoscopy may be considered in cases which have defied diagnosis by other investigations.

Other investigations, including routine assessments of the liver and renal function, and clotting studies are of no diagnostic value unless the history is suggestive of systemic disease. Faecal occult blood testing is of no benefit in the investigation of IDA (B), being insensitive and non-specific.