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Anaemia: diagnosis and treatment

Ivor Cavill
PhD FRCPath
Senior Lecturer in Haematology
University of Wales College of Medicine
Cardiff
E:cavilli@cf.ac.uk

Anaemia is a serious condition - for the patient and the doctor. It may not in itself be life-threatening, but it is certainly life-limiting - it is not something to be borne with resignation and fortitude as an inevitable consequence of disease or even therapy.
Haemoglobin concentration is only one of the many factors limiting adequate oxygen delivery to all tissues, but it is the one that can and should be dealt with most easily. Failure to do this will impair cognitive function and the ability to work, and can have profound social and economic consequences as well as imposing life-sapping fatigue. It may even influence the effectiveness of therapy and will, in chronic conditions, contribute to heart failure and mortality.

What is anaemia?
Anaemia is the failure of the marrow to produce sufficient red blood cells to match red blood cell destruction. With the advent of better ways of assessing the anaemic process, it is likely that anaemia may be detected without having to wait for the haemoglobin concentration to fall as a consequence. The use of modern red blood cell analysers, and in particular the reticulocyte count, can help to detect the disordered process. The haemoglobin concentration measurement is only an indirect reflection of the total red blood cells in the circulation. In pregnancy in particular it can be quite misleading. This can make the definition of an abnormal result difficult. The fact that many women have a lower haemoglobin concentration than men does not mean that they should have. Moreover, today's haemoglobin level may be "normal" but significantly lower than last month's as the anaemic process bites, and the patient may well sense and ­complain of this change.
New red blood cells are produced at the rate of 2-3 million per second. To keep up with this production the marrow requires two things - massive DNA synthesis and a continuous supply of readily available iron. Of course it also needs an appropriate stimulus and an intact marrow infrastructure. DNA synthesis requires appropriate vitamin B12 and folic acid to support nucleotide synthesis. DNA synthesis antagonists, in particular cytotoxic chemotherapy, will inhibit this. Impaired DNA synthesis results in diminished mitotic activity and a reduced number of divisions in the developing red blood cell pathway. The consequence is fewer divisions in the developing red blood cells, and those that do emerge are larger than normal - macrocytic.
When the developing red blood cells can proliferate by repeated division the ability to synthesise haemoglobin becomes critical. Anything that interferes with haemoglobin synthesis will result in cells emerging with sub­optimal amounts of haemoglobin within them and they will be smaller - microcytic. The most common limiting factor is the supply of iron. This must be delivered at the rate of 30-40mg per day to the marrow. In normal circumstances the source of this iron is the red blood cells themselves, which at the end of their lifespan release their iron for recycling to the developing red blood cells. There is little lost in this process, and only 1-2mg of iron per day are required to top up the system. Iron not required in this process is dumped in the "stores". This is insoluble haemosiderin iron. Once deposited it can be released only slowly. Serum ferritin concentration can give an indirect reflection of the iron in the stores, but it is not a storage iron protein. Indeed, serum ferritin contains virtually no iron, and its metabolic role is completely unknown! In many chronic conditions the rate at which "storage" iron can be mobilised is insufficient to meet either increased red blood cell demand or decreased supply from the red blood cells. There will frequently be an apparent paradoxical situation with adequate iron stores, reflected by the serum ferritin, but iron-starved red blood cell production.

Causes of anaemia
Although textbooks show many causes of anaemia, the two most common causes of inadequate red blood cell production are vitamin B12/folate limitation and iron supply-related problems. Dietary limitation, both of B12/folic acid and iron, can be complex, often related as much to social issues as to the disease itself. As far as iron is concerned, the diet may be well endowed but it has to be in the right form. Iron in vegetable materials is poorly absorbed - and from spinach not at all! Moreover, vegetables may themselves inhibit iron absorption from other foodstuffs. Excessive tea drinking can completely abolish iron absorption. It is an inescapable fact that the major source of iron in the diet is from meat. Haem iron is readily absorbed and is not easily inhibited by those other factors. Dietary circumstances or preferences that exclude meat will pose problems.
In men there is a daily iron loss through the gut of about 1mg, while in women menstrual blood loss means that the average iron requirement is nearer 2mg per day. When frank iron deficiency supervenes, this is a clear indication that blood loss, the only way in which iron can be lost from the body, has exceeded itaken. Determining the cause of this blood loss is clearly necessary before any therapy can be decided upon.

Iron therapy
In the past, the only iron therapy that has been generally available has been oral ferrous compounds. They can be very effective - but at a price. Ferrous iron is not a natural substance and is rapidly converted to a ferric form with the release of activated hydroxyl radicals. These highly reactive species are what cause gastrointestinal discomfort. This can be modified by taking the tablets with food, but the chief effect of this is to diminish the amount of iron that can be absorbed. Slow-release tablets avoid the side-effect by not releasing iron in the stomach, so the iron is not absorbed!
Compliance is a major issue with oral ferrous iron therapy. In hospital practice the availability of dextran-free intravenous iron compounds that are safe has meant that compliance is not an issue. It has meant that sufficient amounts of iron can be delivered to the marrow cells safely and effectively. The anxieties of a decade or more ago regarding the anaphylaxis associated with dextran-based iron products led to trepidation in the use of nondextran intravenous iron. It is now well established that iron sucrose can be given safely as a slow intravenous push, and its use in general practice is now being actively considered. It is likely to be particularly effective when social and dietary factors lead to diminished dietary iron and where compliance is a significant issue. In patients such as those with renal anaemia, where the GP prescribes erythropoietin therapy, intravenous iron support will have a major effect on its efficacy. It will also enable the drug to be used most economically.
Using the haemoglobin concentration as the starting point, the diagnostic pathway leads straight to red blood cell size, traditionally reflected in the mean cell volume (MCV), but more reliably by the mean cell haemoglobin (MCH). If the cells are big (MCH >34pg), go straight to vitamin B12 and folate assays. If they are small (MCH

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Resources
Anemia Lifeline
W:www.anemia.com
Anaemia Institute  for Research & Education
W:www.aca.uk.com
"Anaemia - a logical approach" is a poster Conveniently detailing
Dr Cavill's ­expert diagnostic ­pathway in anaemia.
Its production was supported by an unrestricted educational grant from Syner-Med.
To request a copy please contact Dipak Bhatti:
E:dipakb@syner-med.com