A comprehensive guide to the management of anaemia

A systematic approach to evaluation and investigation is key to the successful management of anaemia. This article examines the classification of anaemia, its underlying causes and clinical manifestations, and the range of treatments available.

Anaemia continues to be a significant health problem, occurring in 12% of the population of developed countries. Severe anaemia is rare in UK practice nowadays, but mild to moderate forms are common and require thoughtful, systematic evaluation and initial investigation in primary care. A simple approach to understanding and classifying anaemia is presented here to help physicians achieve effective diagnosis, management and triage of anaemias encountered in clinical practice.

Management principles

Anaemia is a sign of an underlying condition and not a complete diagnosis in itself. Appropriate evaluation, investigation and management of anaemia are based on a systematic approach. Accurate diagnosis of iron-deficiency anaemia, for example, can be a key finding in identifying adult patients with a possible diagnosis of bowel cancer.

Any condition that can impair the production or increase the rate of destruction or loss of erythrocytes can result in anaemia, if the bone marrow is not able to compensate for the rate of loss of red blood cells (RBCs). This situation can arise in nutritional deficiencies, systemic disease, primary bone marrow disorders, autoimmune conditions, primary abnormalities of erythrocytes and blood loss.

The ease with which anaemia due to haematinic deficiency – iron, folate and vitamin B12 – can be corrected may tempt empirical therapy or self-treatment, which can lead to significant diagnostic errors. Wherever possible, the clinician should aim to understand the cause of anaemia in a given individual rather than resort to empiricism that may lead to missed or delayed diagnosis in many cases. In the UK, advice and guidance on possible causation and further investigation and/or referral of unexplained or atypical anaemias can always be obtained through local haematology departments.

Pathogenesis of anaemia

The basic mechanisms of anaemia can be summarised as:
• Impaired ability of the bone marrow to produce sufficient numbers of RBCs
• Accelerated destruction or loss of RBCs
• Combinations of both of the above.

Anaemia is considered to be present when the haemoglobin level is lower than 130g/L in men, 120g/L in non-pregnant women and 110g/L in pregnant women.

Mean cell volume (MCV) – a measure of average RBC size (normal range 78–98fl) – is used to classify anaemia and thus determine further investigation and management. This represents a functional approach to dealing with anaemia in primary care. Table 1 illustrates the causes of anaemia classified by the MCV.


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Table 1
. Causes of micro-, macro- and normocytic anaemias

Low MCV – hypochromic microcytic anaemias

Anaemia in this form arises from impaired haemoglobin synthesis and is a result of reduced production of either haem or globin.
Decreased haem synthesis is seen in:
• Iron deficiency – The commonest worldwide cause of anaemia and is due to iron losses exceeding intake.
• Chronic disorders – Chronic infectious or inflammatory diseases or cancer can also cause anaemia by impairing the utilisation of available iron. Paradoxically, in many of these conditions stored iron is increased. There is also impaired responsiveness to erythropoietin, the hormone that stimulates RBC production. Variable degrees of reduction in the MCV may result, causing confusion with iron deficiency.

Decreased/altered globin synthesis is seen in:
• Thalassaemia – Alpha- and beta-thalassaemia syndromes resulting from inherited disorders of alpha- or beta-globin synthesis. Homozygous forms usually result in serious, transfusion-dependent congenital anaemia. Heterozygous ‘trait’ forms typically produce microcytosis with or without anaemia; mild degrees of anaemia are more typically associated with the beta-thalassaemia trait.
• Haemoglobinopathies – A variety of mutations in the beta-globin gene causing amino acid changes in the haemoglobin molecule are recognised, most commonly haemoglobins S, C and E. Some of these can present with a microcytic anaemia. However, their presence is usually apparent because of other clinical problems in addition to anaemia, such as painful crisis in sickle cell anaemia. (See haemolytic anaemias below for further details.)

Sideroblastic anaemias are rare inherited or acquired disorders of haem synthesis that can result in microcytic anaemia. Most commonly found in adults, sideroblastic anaemia is a form of myelodysplastic syndrome. Lead poisoning can also be a cause.

Raised MCV – macrocytic anaemias

The macrocytic anaemias are usually subclassified as megaloblastic and non-megaloblastic based on findings from bone marrow examination.
• Macrocytic anaemias with megaloblastic marrow changes – Megaloblastic anaemias occur whenever there is a significant deficiency of key substrates in the DNA synthetic pathways in red blood cell precursors. Peripheral blood macrocytosis (increased MCV) results, together with varying degrees of anaemia. These anaemias occur in deficiencies of cobalamin (vitamin B12, eg pernicious anaemia) and folate, and in association with drug therapy that interferes with nucleic acid metabolism, eg antineoplastic agents – hydroxycarbamide, methotrexate and azathioprine. Excessive alcohol intake can occasionally produce megaloblastic changes on its own; these changes are usually associated with nutritional deficiency of folic acid.
• Macrocytic anaemias without megaloblastic marrow changes – Excess alcohol intake and liver disease are common causes, although macrocytosis without anaemia is the more frequent manifestation. Co-existent nutritional deficiency of folic acid may also be a contributing factor in some cases. Liver disease, drug therapy (anticonvulsants or chemotherapy), thyroid disease (thyrotoxicosis or myxoedema) and aplastic anaemia (a rare condition of failure of all marrow elements) may also be responsible, and myelodysplastic syndrome may present with an isolated macrocytic anaemia. Tobacco smoking and pregnancy can also cause a mild macrocytosis.

Normal MCV – normocytic anaemias

Anaemia in this form is very common with many causes, including those that can cause microcytic chronic-disorder anaemias. The most important cause of acute-onset normocytic anaemia is acute blood loss, and this must always be considered in initial clinical assessment of anaemia as well as other causes. Mixed haematinic deficiency, ie a combination of iron deficiency with B12 and/or folate deficiency, can cause a normocytic anaemia. Additional possible causes include erythropoietin deficiency (associated with chronic renal dysfunction) and reduced responsiveness to erythropoietin.

Haemolytic anaemias

Haemolytic anaemias result from increased red cell destruction; the lifespan of circulating RBCs is reduced, and these may present with low, normal or raised MCV. The rate of RBC destruction exceeds the ability of the bone marrow to compensate, and worsening, sometimes life-threatening, anaemia may ensue.

In haemolytic anaemias, serum bilirubin levels are often, but not always, raised due to increased breakdown of haemoglobin. Other markers of haemolysis include a raised lactate dehydrogenase (LDH), reduced haptoglobin and an increased number of early red cells (reticulocytes) in the peripheral blood.

The types of haemolytic anaemias encountered in UK practice are listed in Table 2.


Table 2
. Classification of haemolytic anaemias

Dilutional anaemia (pseudoanaemia)

An increase in plasma volume will result in reduced haemoglobin concentration, haematocrit and RBC count without any decrease in the patient’s total RBC mass. For example, in pregnancy the haemoglobin level can fall as low as about 100g/L (physiological anaemia of pregnancy). No treatment is required if iron and folate stores are sufficient. Hyperviscosity syndromes such as myeloma or Waldenström’s macroglobulinaemia can lead to a similar problem.


Table 3
. Symptoms and signs of anaemias

Clinical manifestations of anaemia

Specific signs and symptoms of anaemia vary widely (see Table 3), even in patients with the same degree of anaemia. Key factors that influence anaemic symptoms include the degree of anaemia, rapidity of its onset and co-morbidity such as cardiac disease. Compensatory mechanisms often limit symptoms in anaemia with a chronic onset: slowly developing or longstanding anaemia can be asymptomatic even with surprisingly low haemoglobin levels. Where patients are well adapted to their anaemia, there is no clinical urgency to normalise the haemoglobin level – in older patients, rapid correction of chronic anaemia by transfusion can be potentially harmful as such an approach can result in cardiac failure.

There are no reliable clinical findings. Pallor may occur, and jaundice may be seen in haemolytic anaemia. Specific features in the clinical history or physical signs may point towards a specific cause for the anaemia. Classical signs of iron deficiency such as koilonychia or oesophageal webs are nowadays extremely rare in UK clinical practice.

A further key step in the clinical evaluation of anaemia is to look at other results generated in the full blood count, specifically the white cell and platelet counts. The presence of significant abnormalities of other blood cell counts may be suggestive of, for example, drug toxicity, bone marrow pathology, liver disease or an underlying autoimmune condition. Discussion of these abnormalities is beyond the scope of this article but the physician is reminded of their relevance as part of anaemia evaluation.

The most practical approach is to base initial assessment of anaemia on the MCV (see Figure 1). The most practical ‘second-stage’ diagnostically helpful tests are serum ferritin, serum vitamin B12 and folate assays. Ferritin is an acute phase reactant and can be falsely elevated in the context of inflammation. In patients with suspected iron-deficiency anaemia with a normal ferritin, C-reactive protein (CRP) and fasting iron studies (transferrin saturation percentage, total iron binding capacity and serum iron) should be tested. As a general rule, a transferrin saturation of <20% indicates iron deficiency. Screening for thalassaemia trait with haemoglobin electrophoresis should also be considered in patients with Mediterranean, African, Middle Eastern or Far Eastern ethnicity or ancestry – it should also be considered where investigation does not clearly identify iron deficiency. Alpha-thalassaemia trait cannot be detected by haemoglobin electrophoresis so is often diagnosed on red blood cell parameters and family history. Thalassaemia-trait patients do not benefit from iron supplementation – unless they are shown to be iron deficient.


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Figure 1
. Evaluation and management of anaemia

Once the likely mechanism for a given case is identified, further referral and/or investigation should then be directed to find the likely underlying cause. In public health terms, clear and prompt identification of iron deficiency in older adults represents a key step in identification of those at risk of colorectal cancer.

Identification of iron-deficiency anaemia is a clear indication that iron loss exceeds intake and, in UK practice, is invariably an indication of chronic blood loss. The clinical history will normally identify overt bleeding that may be gynaecological, genitourinary or gastrointestinal (GI). Chronic GI bleeding may be undetected by the patient and missed on history taking.

The British Society of Gastroenterology provides guidelines on the management of iron-deficiency anaemia.1 Key practice points in these guidelines include the following statements:
• Upper and lower GI investigation should be considered in all postmenopausal females and all male patients where iron-deficiency anaemia has been confirmed unless there is a history of significant, overt non-GI blood loss.
• All patients should be screened for coeliac disease.
• In patients aged >50 years or with marked anaemia or a significant family history of colorectal carcinoma, lower GI investigation should still be considered even if coeliac disease is found.
• Only postmenopausal women and men aged >50 years should have investigation of iron deficiency without anaemia.


Table 4
. Prescribing points: iron deficiency

Treatments for anaemia

Iron deficiency – oral replacement

The treatment of choice for iron-deficiency anaemia is an oral preparation (see Table 4). The most cost-effective approach is ferrous sulphate. Current recommendations are to prescribe ferrous sulphate (FeSO4) 200mg twice daily, or three-times daily if tolerated.2 This divided dosing is recommended to compensate for limited oral iron absorption. The recommended doses are often poorly tolerated due to gastrointestinal side-effects, and there is increasing evidence that there is no benefit in giving these doses in comparison to considerably lower doses of iron.3-5

More recent understanding of the role of the iron regulatory protein hepcidin6 has allowed us to revise optimal iron dosing strategies. One study demonstrated increased iron absorption in patients given 60mg ferrous iron administered on alternate days (200mg FeSO4 contains 65mg iron) compared to once daily administration.3 This is because higher doses increase the release of hepcidin, causing inhibition of iron transport and therefore utilisation of iron.6 The study also demonstrated no benefit of divided doses of iron on a daily basis. In view of these findings, I recommend prescribing FeSO4 200mg daily, and FeSO4 200mg on alternate days can be considered for patients who tolerate daily iron poorly or do not have an appropriate rise in haemoglobin (see Table 4). Patients unable to tolerate FeSO4 may try other ferrous salts, eg ferrous gluconate (35mg ferrous iron in 300mg) and ferrous fumarate (65mg ferrous iron in 200mg), which have similar rates of absorption.

Complete correction of chronic anaemia is seldom urgent. Red cell transfusion is not indicated as standard treatment of chronically deficient patients. Patients with severe chronic anaemia are at increased risk of transfusion-associated circulatory overload causing cardiac failure. Where anaemic symptoms or effects are severe, patients may be cautiously transfused 1–2 units of red blood cells.7 Intravenous iron (see below) can be administered in conjunction with 1–2 unit transfusions to enable rapid replenishment of iron stores and correction of anaemia while minimising the risks of exposure to blood products.

Iron absorption occurs best under conditions of low pH in the proximal small bowel, such as one hour before meals or at bedtime. Medication that decreases acid secretion reduces absorption, as does food intake. GI side-effects are unfortunately common and troublesome (see Table 5). They include nausea, epigastric colic and reflux, and reflect the amount of ionised iron delivered to the stomach and proximal small bowel. Pragmatically, because side-effects are minimised, the clinical recommendation is that iron supplements are taken after meals. Vitamin C enhances iron absorption but the therapeutic value of administering it with iron supplementation is minimal. Vitamin C significantly enhances the absorption of non-haem dietary iron, ie from non-meat sources,8 and patients may benefit from additional foods high in vitamin C, or supplementation with their main meal of the day. Lower GI side-effects are reported in about 25% of patients. Constipation usually responds to dietary fibre or a stool softener.


Table 5
. Side-effects of treatments for anaemia

Iron treatment must continue for three months after normalisation of haemoglobin to replenish stores – failure to do this is a common error of omission in practice and can lead to subsequent confusion in follow-up. It may also be the case that patients commonly become less adherent with continued iron supplementation simply because they feel better and have not been made aware of the importance of continued treatment to replace iron stores.

Parenteral iron

Parenteral preparations (such as parenteral iron) may be used to replenish iron stores rapidly and effectively. Parenteral iron is more efficacious at achieving a rise in haemoglobin than oral iron,9,10 and in my clinical experience produces a faster haemoglobin response than oral iron.

In the past, the risks of anaphylaxis from iron dextran infusions limited the use of intravenous iron. Newer intravenous iron preparations described below have minimal risk, but serious hypersensitivity reactions have been reported and intravenous iron should always be administered in a setting where appropriately trained staff and resuscitation facilities are immediately available. With the newer intravenous iron preparations outlined below, intramuscular administration can no longer be clinically recommended – it is painful and causes permanent skin discolouration.

A potential advantage of calculated intravenous iron infusions is that elements of uncertainty about administered dosage, absorption and adherence are eliminated – a fact that can be of great help in the setting of recurrent anaemia. There are also situations when it is helpful to replace iron stores quickly, such as before childbirth or surgery – optimising body iron stores preoperatively is also a valuable strategy to minimise the use of donor blood in elective surgery.

Evolution in these areas of clinical practice will thus likely result in increased use of intravenous iron for specific clinical situations. As a principle, however, parenteral iron should never be initiated by primary care in the absence of agreement from a relevant specialist in secondary care that it is clinically indicated.

Parenteral iron is indicated where oral iron therapy is unsuccessful due to documented malabsorption, continuing blood loss or genuine intolerance to oral preparations. Specific indications also include iron deficiency associated with active inflammatory bowel disease, in patients with renal failure on erythropoietin therapy11 and in specific groups with chemotherapy-induced anaemia, also in conjunction with erythropoietin therapy.12 Patients with concomitant anaemia of inflammation and iron deficiency may not be able to absorb iron effectively and parenteral iron may also be considered for this group.13 Adverse effects include nausea, abdominal pain and flushing. There may be increased risk of infection with parenteral iron therapy due to bacteria utilising iron as a growth factor. Iron infusions should therefore be avoided in acute or chronic infection.

Parenteral iron preparations available in the UK include the following:
• Iron isomaltoside (Monofer) should be administered in either one or two 15–30 minute intravenous infusions at doses up to 2000mg one week apart; a single infusion should not exceed 20mg/kg body weight.
• Ferric carboxymaltose (Ferinject) should be administered in one to two 15 minute intravenous infusions at doses of 500 or 1000mg a week apart; a single infusion should not exceed 20mg/kg body weight.
• Iron dextran (CosmoFer) is given by slow IV infusion over several hours and carries a small risk (0.7%) of anaphylaxis. It has the advantage of requiring only one or two doses to replace iron stores.
• Iron sucrose complex (Venofer) has a very low incidence of serious adverse reactions (0.03%). The total dose is calculated with a standard formula. Its disadvantage is that replacement involves a series of infusions, typically twice a week for one to five weeks depending on the level of anaemia and patient weight.

Vitamin B12 or cobalamin deficiency

Nowadays, most patients with vitamin B12 or cobalamin deficiency rarely present with the classical florid manifestations described in textbooks; emergency treatment is thus rarely required.

Initial treatment of vitamin B12 deficiency aims to correct the anaemia and resolve neurological abnormalities where present. In acute forms of presentation, blood transfusion should be avoided as it risks exacerbating reversible cardiac dysfunction present in acute megaloblastic anaemia.

Because the disorder is caused by cobalamin malabsorption in the great majority of cases, parenteral cobalamin supplementation (hydroxocobalamin) is given intramuscularly (see Table 6). After injection, significant amounts of the vitamin (up to 80%) is excreted in the urine; therefore, initial therapy should be with several large doses of cobalamin. Injections given on alternate days replenish stores more rapidly than daily injections, and the recommended initial treatment regimen is 1mg three times a week for two weeks.


Table 6.
Prescribing points – vitamin B12 therapy

Patients with pernicious anaemia need lifelong therapy. Hence all younger patients should be tested for anti-intrinsic factor antibodies to establish whether they have pernicious anaemia or a reversible cause such as malabsorption, metformin therapy or proton pump inhibitor therapy.14

In patients with neurological damage, more frequent doses of hydroxocobalamin are needed, with initial treatment of 1mg on alternate days until clinical improvement has plateaued, then maintenance of 1mg every two months. In severe vitamin B12 deficiency, regular monitoring of serum potassium is recommended during initial therapy as hypokalaemia can occur, requiring potassium supplementation. Co-existent iron deficiency or marginal bone marrow iron stores can limit recovery and should be treated with 200mg ferrous sulphate once daily. Lifelong vitamin B12 replacement therapy is required in pernicious anaemia, achieved by administration of 1mg hydroxocobalamin every three months. Thyroid function tests are also recommended annually in these patients because of an association with other autoimmune disorders, most commonly hypothyroidism.

An oral preparation of vitamin B12, cyanocobalamin 50µg, is available and is effective in patients who do not have pernicious anaemia or malabsorption, but is significantly more expensive than intramuscular hydroxocobalamin maintenance treatment. High doses of oral cyanocobalamin (1000µg daily) can successfully replenish vitamin B12 stores in pernicious anaemia if hydroxocobalamin injections cannot be tolerated.


Table 7
. Prescribing points – folate replacement

Folic acid deficiency

In contrast to vitamin B12 deficiency, folate deficiency is usually treated with oral replacement (see Table 7). Folate absorption occurs throughout the small intestine. Megaloblastic anaemia from folic acid deficiency responds readily to 5mg folic acid daily, except in situations of severe malabsorption where a larger dose may be needed. Replenishment of folate stores can be achieved within several weeks of oral therapy. In general, maintenance therapy is not indicated except in patients on long-term haemodialysis and those with disorders of increased cellular turnover, such as chronic haemolytic states. Such patients should be advised about the necessity of lifelong therapy.

The clinical response in folic acid deficiency is very similar to that seen with vitamin B12 deficiency. No significant primary toxicity from folate treatment has been reported. There is concern about the use of folate in vitamin B12-deficient patients theoretically precipitating subacute combined degeneration of the spinal cord. While this is likely to be very rare in clinical practice, it is recommended that if patients have combined B12 and folate deficiency, hydroxocobalamin treatment should always be initiated first. Patients taking drugs that decrease normal folate absorption (eg oral contraceptives and phenytoin) may require folate supplementation if they develop evidence of folate deficiency.

In any patient with nutritional deficiency, a good understanding of the need for folate replacement must be emphasised. Patients should be educated about foods containing the best sources of folate, such as green leafy vegetables, and about the fact that folic acid is a labile vitamin and can easily be destroyed by overcooking or boiling.

Folinic acid is a reduced form of folic acid that bypasses the antifolate activity of methotrexate. It is usually administered parenterally for prevention or treatment of methotrexate toxicity.

Advances in anaemia treatment

Erythropoietin is a glycoprotein produced in the kidneys that regulates RBC production. Its gene was cloned in 1988 and recombinant forms (epoetins) became available for clinical use in 1990. Epoetins are now established as the standard therapy for anaemia in patients on renal dialysis (supported by folic acid supplementation and intravenous iron to overcome a functional iron deficiency) and in patients with established chronic renal failure who are not on dialysis. There are NICE guidelines for its use in adult patients with haemoglobin levels <11g/dl.

Epoetin use is also recognised as effective in managing:
• Cancer-related anaemia in non-myeloid malignancies12
• Anaemia in myelodysplastic sydrome.15

There is also growing evidence for the use of epoetins in anaemia of chronic disease, eg related to cardiac disease.13 Although there may be concern about increased drug costs with epoetins, these have to be balanced with potential improvements in clinical outcomes, less need for expensive and potentially hazardous donor blood and a reduction in hospital visits and nursing care.

Conclusion

Anaemia remains a significant public health problem and is a pointer to an underlying disease in most patients. Simple, inexpensive measures, such as iron replacement, continue to represent the only treatments needed for patients shown to be deficient in these factors. Treatment in primary care must be complemented by a systematic, clinically focused approach to anaemia evaluation to achieve optimum and timely referral for investigative procedures, for example GI endoscopy when iron-deficiency anaemia is identified.

Indeed, the British Society of Gastroenterology has suggested some basic quality standards for iron deficiency:
• All patients with iron-deficiency anaemia should be screened for coeliac disease.
• All patients (other than menstruating women) with iron-deficiency anaemia and no obvious cause should have both an upper GI endoscopy and either colonoscopy or radiological imaging (unless carcinoma or coeliac disease is found).
• All patients should receive appropriate iron replacement.
• All those not responding to treatment should be considered for further investigation.
• In all patients being investigated for iron-deficiency anaemia, reasonable evidence of iron-deficiency anaemia should be documented by appropriate haemoglobin, mean corpuscular haemoglobin (MCH) and MCV, ferritin or transferrin saturation values, or there should be an explanation of why iron deficiency is suspected in patients not showing typical blood test results.

These standards form a useful template for audit in primary care – particularly in relation to the common problem of iron deficiency. They focus on the importance of simple diagnostic tests available to primary care coupled with systematic clinical assessment to determine the appropriate next steps for further investigation.

Anaemia is a common finding in practice. A systematic approach to determining the likely cause is a core skill in primary care. The finding of anaemia and its significance for the individual patient combine to determine the next stages and extent of further investigation – getting this process right has profound implications for the cost-effectiveness and management of NHS resources. The approach outlined in this review aims to equip the busy primary care clinician with the skills to achieve this objective.

Declaration of interests

None to declare.

Dr Sara Boyce is a Consultant Haematologist and Blood Transfusion Lead at University Hospital Southampton NHS Foundation Trust

Acknowledgement

This article is an updated version of an original article written by Alastair Smith. Dr Smith is an Honorary Consultant Haematologist at University Hospital Southampton NHS Trust and a national clinical advisor to the National Cancer Survivorship Initiative; he is also a clinical advisor to Macmillan Cancer Support and Myeloma UK.

References

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15. Killick S, et al. Guidelines for the diagnosis and management of adult myelodysplastic syndromes. Br J Haematol 2014;164:503–25.

A comprehensive guide to the management of anaemia.

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