Megaloblastic Anaemia, Folate Deficiency and Vitamin B12 Deficiency



Megaloblastic anaemia is a form of anaemia in which the mean cell volume of erythrocytes is increased.

Vitamin B12 and folate are two essential nutrients which are integral to the biochemical pathways of DNA synthesis. They are therefore in considerable demand by the bone marrow because of the high rate of DNA production and cell turnover in the bone marrow.

Deficiency of either or both of vitamin B12 and folate can cause megaloblastic anaemia.


Folate / folic acid rejoices in the formal name of pteroylglutamic acid and is a yellow, water-soluble molecule that is found in green vegetables, liver and kidney and to a lesser extent in some fruit but can be destroyed by cooking.

The normal daily requirement is approximately 100micrograms while a typical daily intake considerably exceeds this at 250micrograms. The body stores of folate are an impressive 10000 to 12000micrograms so developing a deficiency takes some doing. Folate concentrations are higher in rapidly growing tissues than stable tissues.

Folate is absorbed in the jejunum and the duodenum. The folate may be ingested in polyglutamate forms and these are deconjugated at the surface of the enterocyte. Within the enterocytes the folate is converted to methlytetrahydrofolate.

The folate is transported in the blood as two thirds unbound and one third bound to albumin. It enters cells by active transport and tends to remain inside the cell. However, hepatocytes can liberate their stores of folate.

There are many causes of folate deficiency.

Vitamin B12

Vitamin B12 is a more complex molecule than folate. Strictly speaking vitamin B12 is actually a collection of very similar molecules all of which are composed of a cobalt atom situated in a corrin ring where the corrin ring is attached to a nucleotide. The chemical name for this formation is cobalamin and various prefixes may be added to distinguish the subtypes of vitamin B12. The main form of vitamin B12 is cyanocobalamin.

Only micro-organisms are able to synthesise vitamin B12; even plants cannot manage the feat. The main dietary sources are milk, eggs, fish and meat. Clean vegetables, fruit and nuts do not contain vitamin B12 unless they are contaminated by bacteria.

The normal daily requirement of vitamin B12 is 2 micrograms and the normal intake is 5 to 30 micrograms. Total body stores are around 2000 to 5000 micrograms so there is a considerable reserve.

The absorption of vitamin B12 is quite complicated. Vitamin B12 in food is released by proteolysis in the stomach. The free vitamin B12 then binds to R factor, a glycoprotein synthesised in the stomach. The R factor protects the vitamin B12 on its journey into the small bowel. Within the small intestine pancreatic trypsin liberates the vitamin B12 from the R factor and allows it to bind to intrinsic factor. Intrinsic factor is actually made in the parietal cells of the stomach. The vitamin B12-intrinsic factor complexes makes its way down the small bowel to the terminal ileum where specific receptors allow the enterocytes to absorb the vitamin B12-intrinsic factor complex. The vitamin B12 is released from the intrinsic factor and is attached to a carrier protein, usually transcobalamin II to enter the blood.

Vitamin B12 is integral to the metabolism of folic acid and many of the consequences of vitamin B12 deficiency are actually due to an inability to generate appropriate forms of folate. However, vitamin B12 is also involved in the metabolism of fatty acids in a process that is independent of folate. This lipid metabolism is essential in the nervous system for the synthesis of myelin.

The causes of vitamin B12 deficiency include the following.

Megaloblastic Anaemia

Megaloblastic anaemia results from impaired synthesis of DNA in the bone marrow. The bone marrow cells are able to continue the development of their cytoplasm along the specialised lines which are appropriate for that type of blood cell but their nuclear division and modification is retarded. The term nuclear-cytoplasmic asynchrony may sometimes be employed.

The two commonest causes of megaloblastic anaemia are vitamin B12 deficiency and folate deficiency. A more comprehensive list is as follows.

Megaloblastic anaemia is a macrocytic anaemia. Both alcohol and hypothyroidism can cause macrocytosis without necessarily causing anaemia.

The bone marrow trephine in megaloblastic anaemia can be quite scary because it resembles an acute leukaemia due to the presence of megaloblasts and general hyperplasia. These are the large cells that have disordered nuclear maturation and are actually erythroid precursors. The defective development of the nucleus means the proportion of early precursor cells is increased. There is also hyperplasia of the myeloid cells; giant metamyelocytes are a characteristic feature.

The blood film exhibits macrocytes. Hypersegmented neutrophils are common. Poikilocytes are seen. In severe cases some megaloblasts may enter the circulation.

Clinical Features

Folate deficiency tends to produce only a macrocytic, megaloblastic anaemia. However, it should be noted that folate deficiency in early pregnancy predisposes to the development of fetal neural tube defects.

Vitamin B12 deficiency has more diverse features. There can be a sore, beefy red tongue, anorexia and weight loss. Indigestion and diarrhoea may occur. Jaundice is sometimes encountered.

Some patients who have vitamin B12 deficiency develop neurological features that include irritability, poor concentration and in severe cases dementia. Subacute combined degeneration of the cord is a syndrome in which the long tracts of the spinal cord, the posterior nerve roots and peripheral nerves are damaged due to impaired myelin metabolism. Subacute combined degeneration of the cord causes paraesthesia, including conscious proprioreception and vibration sense, decreased reflexes but upgoing plantar responses and ataxia (because proprioreceptive feedback to the cerebellum is lost).

The features of the disease which caused the deficiency of vitamin B12 and/or folate may also be present.


The full blood count will demonstrate the anaemia and macrocytosis; there may also be a reduced white cell count and/or thrombocytopenia. The blood film may disclose features that suggest megaloblastic haematopoiesis.

Vitamin B12 and folate levels should be measured. If either of them is low then appropriate investigations should be carried out to determine the cause. Iron levels should also be checked because if the deficiency is due to malabsorption this may also have impacted on iron absorption.

A bone marrow trephine will often not be necessary because detection of vitamin B12 and/or folate deficiency usually explains the anaemia.


The underlying cause of the deficiency should be treated.

Folate can be replaced with oral supplements but vitamin B12 is usually given as injections, one every three months. Care must be given when replacing folate in isolation. If the patient has an undetected vitamin B12 deficiency then the surge of folate can consume the remaining vitamin B12 and precipitate subacute combined degeneration of the spinal cord.