Megaloblastic anaemia

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

Print this page

This article have been viewed 1163 times

Megaloblastic anaemia

The megaloblastic anaemias are characterised by delayed maturation of the nucleus of red cells in the bone marrow due to defective synthesis of DNA. Red cells either die in the marrow (‘ineffective haematopoiesis’) or enter the bloodstream as enlarged, misshapen cells with a reduced survival time. In clinical practice megaloblastic anaemia is almost always caused by deficiency of vitamin B₁₂ (cobalamin) or folate (pteroylmonoglutamate). It is one of the most common causes of a macrocytic anaemia.

Why does deficiency of vitamin B₁₂ or folate lead to megaloblastic anaemia?

Key characteristics of these essential vitamins are summarised in Table 13.1.

Table 13.1

Vitamin B₁₂ and folate

Characteristic	Vitamin B₁₂	Folate
Average dietary intake/day (µg)	20	250¹
Minimum adequate intake/day (µg)	1–2	150¹
Major food sources	Animal produce only	Liver, vegetables
Normal body stores	Sufficient for several years	Sufficient for a few months
Mode of absorption	Combined with transport protein (IF) secreted by gastric parietal cells – then absorbed through ileum via special receptors	Dietary folate converted to methyl THF and absorbed in duodenum and jejunum

THF: tetrahydrofolate; IF: intrinsic factor.

¹ 500 µg daily required in pregnancy.

Both folate and vitamin B₁₂ are necessary for the synthesis of DNA (Fig 13.1). Folate is needed in its tetrahydrofolate form (FH₄) as a cofactor in DNA synthesis. Deficiency of B₁₂ leads to impaired conversion of homocysteine to methionine causing folate to be ‘trapped’ in the methyl form. The resultant deficiency in methylene FH₄ deprives the cell of the coenzyme necessary for DNA formation.

Fig 13.1 The cause of megaloblastic anaemia.
Both vitamin B₁₂ and folate (FH4) are necessary for normal synthesis of DNA (see text).

All dividing cells in the body suffer from the impaired DNA synthesis of B₁₂ and folate deficiency. However, the actively proliferating cells of the bone marrow are particularly affected. As RNA synthesis progresses unhindered in the cytoplasm, the erythroid cells develop nuclear–cytoplasmic imbalance with abundant basophilic cytoplasm and enlarged nuclei. The chromatin pattern in the nucleus is characteristically abnormal; one author has described it as resembling ‘fine scroll work’, another as ‘sliced salami’ (Fig 13.2). The slowed synthesis of DNA leads to prolonged cell cycling and the cells being discharged into the blood without the normal quota of divisions. Red cells are enlarged and egg-shaped and the neutrophils hypersegmented due to retention of surplus nuclear material (Fig 13.3).

Fig 13.2 Bone marrow aspirate in megaloblastic anaemia.
The immature red cells show nuclear–cytoplasmic imbalance with enlarged abnormal nuclei and basophilic cytoplasm.

Fig 13.3 Peripheral blood film in megaloblastic anaemia.
There is a macrocytosis and the neutrophils are hypersegmented.

Clinical syndromes

Vitamin B₁₂ deficiency

Pernicious anaemia

This classic cause of vitamin B₁₂ deficiency is an autoimmune disorder. Most patients have IgG autoantibodies targeted against gastric parietal cells and the B₁₂ transport protein intrinsic factor. The precise pathogenesis, and particularly the role of the autoantibodies, is incompletely understood but B₁₂ deficiency ultimately arises from reduced secretion of intrinsic factor (IF) by parietal cells and, hence, reduced availability of the B₁₂–IF complex which is absorbed in the terminal ileum.

The clinical hallmarks of pernicious anaemia are gastric parietal cell atrophy and achlorhydria, a more generalised epithelial cell atrophy and megaloblastic anaemia. The disease is most common in northern Europe in women greater than 50 years of age and is familial. Affected patients classically have premature greying of the hair and blue eyes and may develop other autoimmune disorders including vitiligo, thyroid disease and Addison’s disease. Slight jaundice is caused by the haemolysis of ineffective erythropoiesis.

Patients usually have symptoms of anaemia and the generalised epithelial abnormality can manifest as glossitis (Fig 13.4) and angular stomatitis. The archetypal neurological complication – ‘subacute combined degeneration’ – arises from demyelination of the dorsal and lateral columns of the spinal cord. Patients most commonly complain of an unsteady gait, and if B₁₂ deficiency is not corrected there can be progression to irreversible damage of the central nervous system with paralysis and dementia. There is a possible increased incidence of carcinoma of the stomach and colorectal cancer in pernicious anaemia.

Fig 13.4 Painful glossitis in pernicious anaemia.

Diagnosis:

1. Blood count and film. There is a macrocytic anaemia with the typical film appearance of megaloblastic anaemia. There may be leucopenia and thrombocytopenia.

2. Bone marrow aspirate. This is not always necessary. It will confirm megaloblastic anaemia but will not illuminate the underlying cause.

3. Estimation of vitamin B₁₂ and folate levels. In pernicious anaemia the serum vitamin B₁₂ level is normally very low but the assay is not entirely reliable and a trial of therapy may be justified where clinical and blood features strongly suggest deficiency. Serum methylmalonate and homocysteine levels are raised in B₁₂ deficiency but their role in diagnosis is limited by their being often increased in normal people and a range of other disorders. Serum folate may be elevated and the red cell folate reduced (folate is trapped in its extracellular methyl FH₄ form – see Fig 13.1).

4. Autoantibodies. Parietal cell antibodies are found more commonly in the serum than IF antibodies (90% vs 50%) but whereas IF antibodies are almost diagnostic of pernicious anaemia, parietal cell antibodies occur in about 15% of healthy elderly people.

5. Tests for vitamin B₁₂ absorption. The urinary secretion (Schilling) test was formerly much used but radioactive cyanocobalamin is not available now and the test is obsolete.

Treatment: Vitamin B₁₂ levels are usually replenished by intramuscular injection of the vitamin. Several injections of 1 mg hydroxycobalamin are given over the first few weeks and then either one injection every 3 months or daily oral vitamin B₁₂ 1–2 mg daily for life. The increase in reticulocytes in the blood peaks 6–7 days after the start of treatment.

In practice, ill patients with megaloblastic anaemia are often started on both B₁₂ and folate supplements after a blood sample has been taken for assay of the vitamins. When the results are known the unnecessary vitamin can be stopped. Blood transfusion is best avoided as it may lead to circulatory overload – where judged necessary to correct hypoxia, it is undertaken with extreme caution. Platelet transfusion is used for bleeding caused by severe thrombocytopenia but this is unusual. Hypokalaemia occasionally requires correction.

Other causes of vitamin B₁₂ deficiency

These are mostly abnormalities of the stomach and ileum (Table 13.2). As normal body stores are sufficient for 2 years, clinically apparent deficiency from any cause will develop slowly.

Table 13.2

The megaloblastic anaemias

Folate deficiency

Folate deficiency is caused by dietary insufficiency, malabsorption, excessive utilisation or a combination of these (Table 13.2). Patients may complain of symptoms of anaemia or of an underlying disease. The increased risk of thrombosis is because of associated hyperhomocysteinaemia (see p. 79). There is a macrocytic anaemia and a megaloblastic bone marrow. In significant deficiency both serum and red cell folate are usually low but the latter is the better measure of tissue stores. In addition to a thorough dietary history patients may need investigations for malabsorption (e.g. jejunal biopsy).

Folate deficiency is treated with oral folic acid 5 mg once daily. This is given for several months at least, the precise duration of therapy depending on the underlying cause. Folate is prescribed prophylactically in pregnancy (400 µg daily) with a reduction in neural tube defects in the fetus and also in groups of patients at high risk of deficiency (Table 13.2). Before folate is prescribed, vitamin B₁₂ deficiency must be excluded (or corrected) as subacute combined degeneration of the cord can be precipitated.

Megaloblastic anaemia

Megaloblastic anaemia is a common cause of a macrocytic anaemia.