Macrocytosis

Contributed by Dr Cecil Reid, consultant haematologist at Northwick Park and St Mark's Hospital NHS Trust, Harrow.

1. Aetiology
The term macrocytosis is used to describe larger-than-normal red blood cells. Typically, a patient is said to have macrocytosis if their red blood cells have a mean corpuscular volume (MCV) greater than 100fl (femtolitre, 10-15 litres), as measured by an automated cell analyser. The reference range varies slightly between laboratories.

Macrocytosis can have a number of causes, some of which are benign. However, it may also indicate a serious underlying condition, such as myelodysplasia or leukaemia. It is important in primary care to identify which patients with macrocytosis require referral to a haematologist.

Benign macrocytosis
Macrocytosis without anaemia is often not of serious clinical significance. An elevated MCV is normal at birth and during the early newborn period. The size of the red blood cells then falls rapidly within the first few months of life and is replaced by the physiological microcytosis of childhood. Late pregnancy can also result in a transient mild elevation of MCV, usually under 100fl.

Alcohol is a common cause of macrocytosis, even at comparatively low intake levels, and drug toxicity from treatments such as chemotherapy or antiretroviral therapy can also cause elevated MCV.

Macrocytic anaemia
Patients with macrocytic anaemia should always undergo further investigation to identify the underlying cause of the anaemia. It is sometimes caused by chronic illnesses including hypothyroidism and chronic liver disease. It can also occur in patients with haemolytic anaemia.

Deficiencies of folic acid or of vitamin B12 are the commonest causes of macrocytic anaemia, usually without neutropenia or thrombocytopenia. These deficiencies may simply be the result of poor diet, but they can also be the result of malabsorption. This may be specific, as in pernicious anaemia or more general as in coeliac disease.

Any malignant bone marrow infiltration can cause a macrocytic anaemia and multiple myeloma is not an uncommon cause. An intrinsic bone marrow disorder such as aplastic anaemia or leukaemia should be considered in any patient who has other cytopenias as well as macrocytic anaemia. The lab report should mention additional morphological changes.

2. Diagnosis
A full history and careful examination of patients with macrocytosis are needed to identify the underlying disorder.

A drug history must always be taken and alcohol intake assessed. Vitamin B12 and folate deficiency should be investigated.

Low folate may occur in diets deficient in fresh vegetables, and a low vitamin B12 level can occur as the result of a vegan diet.

The presence of a smooth tongue (glossitis) suggests vitamin B12 deficiency. Diarrhoeal symptoms may indicate a malabsorption syndrome.

Laboratory tests
A number of laboratory tests should be carried out. Levels of folic acid can be measured either in serum or as red cell folate, the latter being a better measure of total body stores.

Other tests include vitamin B12 level, TSH to screen for hypothyroidism and liver function including liver enzymes.

Symptoms of numbness of the extremities, of paraesthesia or signs of subacute combined cord degeneration may indicate pernicious anaemia. An autoantibody screen can help in identifying pernicious anaemia. If the test is positive then an intrinsic factor antibody screen should be done to confirm the diagnosis.

However, although it is highly specific this test is only 60 per cent sensitive so a negative result does not rule out a diagnosis of pernicious anaemia. If no dietary cause for the anaemia is found, a Schilling test of vitamin B12 malabsorption should be requested, although this is not available in all laboratories.

Patients with low serum vitamin B12 level should not automatically be treated with a B12 replacement injection if dietary deficiency is the suspected cause.

Instead, they should receive oral cyanocobalamin 50(mu)g daily for two months followed by a repeat assay.

If the problem is a dietary deficiency, the level usually corrects to normal ruling out the need to test for malabsorption.

Referral
If the patient is anaemic but no folate or vitamin B12 deficiency is identified, immunoglobulin levels should be measured to test for myeloma.

Although myelodysplasia is very uncommon in younger patients, it is very important that these patients are identified since many will progress to acute leukaemia within a few months.

A urine specimen is needed to test for Bence Jones myeloma. Thrombocytopenia or neutropenia may indicate myelodysplasia, leukaemia or other bone marrow malignancy and these patients should be urgently referred to a haematologist.

3. Management
Very mild macrocytosis (MCV of 105fl or under) without anaemia or any other blood abnormality in an otherwise fit patient often does not require treatment.

In many patients a high alcohol intake is the cause of macrocytosis, while in a significant minority there is no apparent cause.

Vitamin supplements
Patients with folate and vitamin B12 deficiency due to poor diet can be treated with oral supplements and do not benefit from referral. Patients with pernicious anaemia confirmed by a positive intrinsic factor antibody screen can also be managed satisfactorily in the community.

Initial treatment is with 1mg hydroxocobalamin by IM injection three times a week for two weeks followed by 1,000mg injections at three month intervals for life.

Patients suspected of malabsorption should be screened for anti-endomysial antibodies and referred to a gastroenterologist for endoscopy and small bowel biopsy. Patients with vitamin B12 deficiency and suspected malabsorption who do not test positive for pernicious anaemia in autoantibody screens should be referred to a haematologist and may require a Schilling test.

Blood transfusion
Blood transfusion remains the main treatment for myelodysplasia, although patients sometimes respond to erythropoietin treatment or to chemotherapy.

Contributed by Dr Cecil Reid, consultant haematologist at Northwick Park and St Mark's Hospital NHS Trust, Harrow.

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