Macrocytosis is a rise in the mean cell volume (MCV) of red cells above the normal range (in adults 80–95 fl). It is detected using a blood count, in which the MCV and other red cell indices are meas- ured. The MCV is lower in children than in adults, with a normal mean of 70 fl at 1 year of age, rising by about 1 fl each year until it reaches the adult volume at puberty.
The causes of macrocytosis fall into two groups: (i) deficiency of vitamin B12 (cobalamin) or folate (or rarely abnormalities of their metabolism), in which the bone marrow is megaloblastic (Box 2.1) and (ii) other causes (Box 2.2), in which the bone marrow is usually normoblastic. In this chapter, the two groups are considered sepa- rately. The steps to diagnose the cause of macrocytosis and subse- quently to manage it are then considered.
Megaloblastic bone marrow
Megaloblastic bone marrow is exemplified by developing red blood cells that are larger than normal, with nuclei that are more immature than the cytoplasm. The underlying mechanism is defective DNA synthesis.
Defects of vitamin B12 metabolism, for example, transcobalamin II deficiency, nitrous oxide anaesthesia, or of folate metabolism (such as methotrexate treatment), or rare inherited defects of DNA synthesis, may all cause megaloblastic anaemia.
Deficiency of vitamin B12 or folate
Vitamin B12 deficiency
The body’s requirement for vitamin B12 is about 1 µg daily. This is
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Figure 2.1
Patient with vitiligo on neck and back.
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amply supplied by a normal Western diet (vitamin B12 content 10– 30 µg daily) but not by a strict vegan diet, which excludes all animal produce (including milk, eggs and cheese). Absorption of vitamin B12 is through the ileum, facilitated by intrinsic factor, which is secreted by the parietal cells of the stomach. Absorption by this mechanism is limited to 2–3 µg daily.
In Britain, vitamin B12 deficiency is usually due to pernicious anaemia, which now accounts for up to 80% of all cases of megalo- blastic anaemia. The incidence of the disease is 1:10 000 in northern Europe and the disease occurs in all races. The underlying mecha- nism is an autoimmune gastritis that results in achlorhydria and the absence of intrinsic factor. The incidence of pernicious anaemia peaks at 60 years of age; the condition has a female : male incidence of 1.6 : 1.0 and is more common in those with early greying of hair, blue eyes, blood group A and in those with a family history of pernicious anaemia or associated diseases, for example, vitiligo (Fig. 2.1), myxoedema, Hashimoto’s disease, Addison’s disease and hypoparathyroidism.
Other causes of vitamin B12 deficiency are infrequent in the UK. A vegan lifestyle is an unusual cause of severe deficiency, as most veg- etarians and vegans include some vitamin B12 in their diet. Moreover, unlike in pernicious anaemia, the enterohepatic circulation for vita- min B12 is intact in vegans, so vitamin B12 stores are conserved. Gastric resection and intestinal causes of malabsorption of vitamin B12, for example, ileal resection or the intestinal stagnant loop syndrome, are less common now that abdominal tuberculosis is infrequent and H2 antagonists have been introduced for treating peptic ulceration, thus reducing the need for gastrectomy.
Folate deficiency
The daily requirement for folate is 100–200 µg and a normal mixed diet contains about 200–300 µg. Natural folates are largely found in the polyglutamate form and these are absorbed through the upper small intestine after deconjugation and conversion to the monogluta- mate 5-methyltetrahydrofolate. Body stores are sufficient for only about 4 months. Folate defi- ciency may arise because of inadequate dietary intake, malabsorp- tion (especially coeliac disease; Fig. 2.2), or excessive use caused by proliferating cells, which degrade folate. Deficiency in pregnancy
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Figure 2.2
Patient with coeliac disease:
underweight and low stature.
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may be due partly to inadequate diet, partly to transfer of folate to the fetus and partly to increased folate degradation.
Consequences of vitamin B12 or folate deficiency
Megaloblastic anaemia
Clinical features include pallor and jaundice. The onset is gradual, and a severely anaemic patient may present with congestive heart failure or only when an infection supervenes. The blood film shows oval macro- cytes and hypersegmented neutrophil nuclei (with six or more lobes) (Fig. 2.3). In severe cases, the white cell count and platelet count also fall (pancytopenia). The bone marrow shows characteristic megalob- lastic erythroblasts and giant metamyelocytes (granulocyte precur-
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sors). Biochemically, there is an increase of unconjugated bilirubin and serum lactic dehydrogenase in the plasma, with, in severe cases, an absence of haptoglobins and presence of haemosiderin in the urine. These changes, including jaundice, are due to increased destruction of red cell precursors in the marrow (ineffective erythropoiesis).
Vitamin B12 neuropathy
A minority of patients with vitamin B12 deficiency develop a neuropathy due to symmetrical damage to the peripheral nerves and posterior and lateral columns of the spinal cord, the legs being more affected than the arms. Psychiatric abnormalities and visual dis- turbance may also occur. Men are more commonly affected than women. The neuropathy may occur in the absence of anaemia. Psy- chiatric changes and, at most, a mild peripheral neuropathy may be ascribed to folate deficiency.
Neural tube defects
Folic acid supplements in pregnancy have been shown to reduce the incidence of neural tube defects (spina bifida, encephalocoele and anencephaly) in the fetus, and may also reduce the incidence of cleft palate and harelip (Box 2.3). No clear relation exists between the incidence of these defects and any folate deficiency in the mother, although the lower the maternal red cell folate (and serum vitamin B12) concentrations, even within the normal range, the more likely neural tube defects are to occur in the fetus. An underlying mecha- nism in a minority of cases is a genetic defect in folate metabolism, a mutation in the enzyme 5,10-methylene-tetrahydrofolate reductase. An autoantibody to folate receptors has been detected in pregnancy in some women wwho have babies with neural tube defects.
Gonadal dysfunction
Deficiency of either vitamin B12 or folate may cause sterility, which is reversible with appropriate vitamin supplementation.
Epithelial cell changes
Glossitis may occur, and other epithelial surfaces may show cytologi- cal abnormalities (Fig. 2.4).
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| Figure 2.4 Glossitis due to vitamin B12 deficiency. |
Cardiovascular disease
Raised serum homocysteine concentrations have been associated with arterial obstruction (myocardial infarct, peripheral vascular disease or stroke) and venous thrombosis. Trials are under way to determine whether folic acid supplementation reduces the incidence of these vascular diseases.
Other causes of macrocytosis
The most common cause of macrocytosis in the UK is alcohol. Fairly small quantities of alcohol, for example, two gin and tonics or half a bottle of wine a day, especially in women, may cause a rise of MCV to > 100 fl, typically without anaemia or any detectable change in liver function.
The mechanism for the rise in MCV is uncertain. In liver disease, the red cell volume may rise as a result of excessive lipid deposition on red cell membranes, and the rise is particularly pronounced in liver disease caused by alcohol. A modest rise in MCV is found in severe thyroid deficiency. Physiological causes of macrocytosis are pregnancy and the neo- natal period. In other causes of macrocytosis, other haematologi- cal abnormalities are usually present; in myelodysplasia (a frequent cause of macrocytosis in elderly people), there are usually quanti- tative or qualitative changes in the white cells and platelets in the blood. In aplastic anaemia, pancytopenia is present; pure red cell aplasia may also cause macrocytosis. Changes in plasma proteins, for example, presence of a paraprotein (as in myeloma), may cause a rise in MCV without macrocytes being present in the blood film. Drugs that affect DNA synthesis, for example, hydroxyurea and aza- thioprine, can cause macrocytosis with or without megaloblastic changes. Finally, a rare, benign familial type of macrocytosis has been described.
Diagnosis
Biochemical assays
The most widely used screening tests for the deficiencies are the serum vitamin B12 and folate assays (Box 2.4). A low serum con- centration implies deficiency, but a subnormal serum concentra- tion may occur in the absence of pronounced body deficiency, for example, in pregnancy (vitamin B12) and with recent poor dietary intake (folate).
Red cell folate can also be used to screen for folate deficiency; a low concentration usually implies appreciable depletion of body folate, but the concentration also falls in severe vitamin B12 deficiency, and so it is more difficult to interpret the significance of a low red cell count than serum folate concentration in patients with megaloblastic anaemia. Moreover, if the patient has received a recent blood trans- fusion, the red cell folate concentration will partly reflect the folate concentration of the transfused red cells.
Specialist investigations
Assays of serum homocysteine (raised in vitamin B12 or folate defi- ciency) or methylmalonic acid (raised in vitamin B12 deficiency) are used in some specialized laboratories. Serum homocysteine levels are also raised in renal failure and with certain drugs, such as corticos- teroids, and they increase with age and smoking.
Autoantibodies
For patients with vitamin B12 or folate deficiency, it is important to establish the underlying cause. In pernicious anaemia, intrinsic fac- tor antibodies are present in plasma in 50% of patients and in parietal cell antibodies in 90%. Antiendomysial and antitransglutaminase antibodies are usually positive in coeliac disease.
Other investigations A bone marrow examination is usually performed to confirm mega- loblastic anaemia (Fig. 2.5). It is also required for the diagnosis of myelodysplasia (Fig. 2.6), aplastic anaemia, myeloma, or other mar- row disorders associated with macrocytosis.
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| Figure 2.5 Bone marrow appearances in megaloblastic anaemia: developing red cells are larger than normal, with nuclei that are immature relative to their cytoplasm (nuclear : cytoplasmic asynchrony) |
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Figure 2.6
Bone marrow aspirate in myelodysplasia showing characteristic dysplastic neutrophils
with bilobed nuclei. Reproduced
with permission
from Clinical Haematology (AV Hoffbrand, J Pettit), 3rd edn. St Louis: CV Mosby,
2000 |
Radioactive vitamin B12 absorption studies, for example, Schill-ing’s test, show impaired absorption of the vitamin in pernicious anaemia (Table 2.1); this can be corrected by giving intrinsic factor.
In patients with an intestinal lesion, however, absorption of vitamin B12 cannot be corrected with intrinsic factor. Human intrinsic factor is no longer licensed for this test because of concern about transmis- sion of prion disease.
Endoscopy should be performed to confirm atrophic gastritis and exclude gastric carcinoma or gastric polyps, which are 2–3 times more common in patients with pernicious anaemia than in age- and sex-matched controls.
*Corrected by antibiotics.
†Human intrinsic factor no longer licensed for this test because of concern about prion transmission
If folate deficiency is diagnosed, it is important to assess dietary folate intake and to exclude coeliac disease by tests for serum antien- domysial and antitransglutaminase antibodies, endoscopy and duo- denal biopsy. The deficiency is common in patients with diseases of increased cell turnover who also have a poor diet.
Treatment
Vitamin B12 deficiency is treated initially by giving the patient six injections of hydroxocobalamin 1 mg at intervals of about 3–4 days, followed by four such injections a year for life. For patients under- going total gastrectomy or ileal resection, it is sensible to start the maintenance injections from the time of operation. For vegans, less frequent injections, for example, 1–2 per year, may be sufficient, and the patient should be advised to eat foods to which vitamin B12 has been added, such as certain fortified breads or other foods.
Folate deficiency is treated with folic acid, usually 5 mg daily orally for 4 months, which is continued only if the underlying cause can- not be corrected. As prophylaxis against folate deficiency in patients with a severe haemolytic anaemia, such as sickle cell anaemia, 5 mg folic acid once weekly is probably sufficient. Vitamin B12 deficiency must be excluded in all patients starting folic acid treatment at these doses, as such treatment may correct the anaemia in vitamin B12 deficiency but allow neurological disease to develop.
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