Section 1: Aetiology and classification
Anaemia is a reduction in the total circulating number of red cells. It is defined as a reduction of more than two standard deviations below the mean of either the haemoglobin concentration (Hb), the haematocrit (Hct) or the red blood cell count (RBC).1
These normal ranges depend on multiple factors as they are all concentrations. Hb, Hct and RBC depend on both total red cell mass and plasma volume. This must be taken into account when interpreting any result.
In addition, what is 'normal' varies depending on the age, gender, race and a multitude of other physiological states particular to each individual patient. Most clinical laboratories will take some of these variations into account and publish age- and gender-specific ranges.
Anaemia can be classified in various ways. A common practice, and one that narrows down the differential diagnosis, is to classify according to the size of the predominant red cell population. Anaemia can therefore be subdivided into macrocytic, normocytic or microcytic.2
Blood film analysis
Microcytic anaemias are characterised by 'small' red blood cells. This can be defined by a mean corpuscle volume (MCV) of less than 80 fL, but should be confirmed by examination of a peripheral blood film.
On a film a normal red cell should have a diameter equal to the nucleus of a small lymphocyte. Cells smaller than this are said to be microcytic.
Examination of the blood film also allows for assessment of the uniformity of the size of the red cell population, a feature that is reflected in the red cell distribution width (RDW); the haemoglobin content of the cells, also assessed by the mean cell/corpuscle haemoglobin (MCH) and to look for other morphological features that may provide further clues as to the aetiology of the anaemia, such as pencil cells or Howell-Jolly bodies.3
Microcytosis is usually accompanied by a decrease in haemoglobin content within the red blood cell, producing hypochromic microcytic cells.
Section 2: Making the diagnosis
The three most common causes of microcytosis in clinical practice are iron deficiency, alphaor beta-thalassaemia minor, and anaemia of chronic disease.2
Iron deficiency anaemia
Iron deficiency is by far the most common, potentially serious, and treatable cause and should be excluded in the first instance.
In iron deficiency anaemia, red cell indices will show a low Hb, low MCV, low MCH but high RDW.
The single best investigation to determine iron deficiency is serum ferritin. There are mixed opinions regarding the use of other iron studies, such as total iron binding capacity and low serum iron concentration. These are not recommended as first-line investigations.
For some physicians, proof of iron deficiency anaemia requires a clinical response (that is, an increase in Hb or Hct) to treatment with iron.2
Iron deficiency anaemia per se is not a final diagnosis, and the underlying cause must be determined. The most common causes of iron deficiency anaemia depend on age and gender.
During the first few months of life, an infant's red cell mass decreases. The iron released from this is recycled and enters the infant's iron stores. Therefore, infant iron deficiency is rarely a cause of anaemia in the first three to six months of life.
Babies who are born prematurely, who have been in hospital and undergone repeated phlebotomy, who have experienced intrauterine or perinatal haemorrhage may all develop iron deficiency early in life.4
Dietary factors are the commonest cause of iron deficiency in the older infant and child.
Common factors that lead to iron deficiency include diets poor in iron, early introduction of whole cow's milk, blood loss secondary to cow's milk intolerance, medication and malabsorption.
Adolescents may develop iron deficiency anaemia as a result of rapid growth, menarche in girls, and changes in diet.
For children and adolescents presenting with a mild microcytic anaemia and in whom a presumptive diagnosis of iron deficiency anaemia is reasonable, the most cost-effective strategy is a therapeutic trial of iron (3mg/kg of elemental iron, once or twice daily between meals for four weeks).
This should produce a rise of greater than 1gm/dL in patients with iron deficiency.5
Women of reproductive age
In women of reproductive age, the most common causes of iron deficiency are menstrual loss, pregnancy and lactation. If a trial of therapeutic iron fails to correct the deficiency, then further investigations are required.6
Among men and postmenopausal women, bleeding from the GI tract is by far the commonest cause of iron deficiency.
Asymptomatic colonic carcinoma may present with iron deficiency anaemia and these patients should be investigated with colonoscopy and gastroscopy (see box for other causes and their prevalence7).
Anaemia of chronic disease
Anaemia of chronic disease is usually normocytic. However, some systemic diseases, such as rheumatoid arthritis, diabetes mellitus, polymyalgia rheumatica, renal cell carcinoma and hepatoma can be associated with a microcytic anaemia.
In its purest form, anaemia of chronic disease is usually associated with a normal or high serum ferritin, and iron studies show a low serum iron, and low total iron binding capacity.
The mechanism of anaemia in chronic disease results from interaction of mediators of inflammation on bone marrow function, regulation of erythropoiesis and iron metabolism.
It appears that iron absorption from the GI tract is reduced, and that iron is trapped within macrophages. Both of these mechanisms seem under the control of hepcidin, a negative regulator of iron and an acute phase protein.
At the same time, there seems to be a relative insensitivity to erythropoietin and a poor erythropoietin response, coupled with decreased red cell survival.8
|Causes of Iron eficiency and prevalence|
|Occult GI blood loss|
Section 3: Management
The underlying cause of iron deficiency should be addressed. Severely symptomatic patients or those with serious comorbidities may require a red cell transfusion.
The choice of iron replacement therapy depends on the cause of anaemia and the patient's tolerability of oral iron preparations. Oral iron is cheap, safe and effective but up to 20 per cent of patients report GI side-effects. These are directly linked to the dose of elemental iron consumed and so preparations with lower iron content are usually better tolerated.
Iron is absorbed in the duodenum and proximal jejunum, therefore enteric-coated tablets or sustained release preparations are less effective and not recommended. Liquid preparations can allow for more precise dose titration and so often are an option for achieving a balance between best dose and side-effects.
Constipation can be minimised by increasing water intake and use of laxatives. Absorption can be improved by concurrent administration of vitamin C and ingestion on an empty stomach.9
The recommended treatment dose for an adult is between 150 and 200mg of elemental iron per day. Response to therapy should be monitored.
In patients with severe anaemia, one should expect to see a reticulocytosis at about one week from starting treatment.
In all patients there should be an increase in haemoglobin concentration of approximately 1-2g/dL at three weeks. The duration of treatment depends on the suspected cause of the iron deficiency.
In those with suspected dietary deficiency, or anaemia secondary to pregnancy or menorrhagia, replacement should continue for at least three to four months after normalisation of Hb to replenish iron stores.
Suspected occult bleed
However, in patients with a suspected occult bleed it may be reasonable to treat only until the Hb is normal and then to monitor, as recurrence of anaemia would indicate ongoing bleeding and trigger further investigations7 (see box for possible causes for treatment failure).
Parenteral iron replacement is more expensive, and can only be administered in settings with resuscitation facilities as it can be associated with severe adverse reactions.
Currently IV iron should be reserved for those with severe intolerance to oral iron or when the level of continued bleeding, usually GI, exceeds the ability of the GI tract to absorb iron.
However, with improved safety profile and ease of administration, this practice is likely to become more liberal in the near future.
Managing anaemia of chronic disease
Management is to treat the underlying cause; occasionally patients may need red cell transfusions or therapy with recombinant erythropoietin.
It is vital to remember that anaemia of chronic disease often co-exists with iron deficiency and can be a cause for failure of iron replacement therapy.
|Causes for failure to respond to oral iron|
Section 4: Alpha and beta thalassaemia
In patients with normal ferritin levels it is often helpful to look at previous FBCs.
If the microcytosis has always been present then it suggests a congenital aetiology and thalassaemia should be considered.
Normal adult haemoglobin, haemoglobin A, is made up of two alpha and two beta globin chains. Thalassaemia mutations in the globin chain genes (four genes for alpha chains and two genes for beta chains) result in underproduction of either alpha or beta globin chains. This results in an unbalanced haemoglobin molecule leading to premature red cell death.
Adults with thalassaemia minor are most often heterozygote for the alpha or beta forms of this syndrome.
They may have a mild microcytic anaemia, or may not be anaemic but still have microcytic red cells. There may be a family history but more often is not.
Some patients will have increased iron stores; this is thought to be due to increased gut absorption of iron triggered by the ineffective haemopoiesis.
The diagnosis of beta thalassaemia trait can often be made by haemoglobin electrophoresis (increased levels of haemoglobin A2).
Alpha thalassaemia cannot be diagnosed in this way and definitive diagnosis would require genetic testing (PCR-based DNA tests or southern blot analysis).
However, a working diagnosis can be made and genetic counselling given on the basis of ethnic origin and the findings of an otherwise unexplained microcytosis with or without anaemia. These patients do not require any specific treatment but should be offered genetic counselling.2
|Causes and Mechanisms of microcytic anaemia|
Reduced iron availability deficiency
Reduced heme synthesis
Reduced globin production
1. Hoffbrand AV, Moss PAH, Pettit JE. Essential haematology, Fifth Edition, Blackwell Publishing 2008.
2. Tefferi A. Anaemia in adults: A contemporary approach to diagnosis. Mayo Clin Proc 2003; 78: 1274-80.
3. Lewis SM, Bain BJ, Bates I. Dacie and Lewis practical haematology, 10th edition, Churchill Livingstone 2006.
4. Kivivuori SM, Virtanen M, Raivio KO et al. Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants. Eur J Pediatr 1999; 158-62.
5. Irwin JJ, Kirchner DO. Anaemia in children. Am Fam Physician 2001; 64 (8): 1379-87.
6. Killip S, Bennett J, Chambers MD. Iron deficiency anemia. Am Fam Physician 2007; 75 (5): 671-8.
7. Goddard AF, James MW, McIntyre AS et al. Guidelines for the management of iron deficiency anaemia. British Society of Gastroenterologists, May 2005.
8. Means RT Jr, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 1992; 80(7): 1639-47.
9. Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med 2008; 121(11): 943-8.
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