Anemia with large red cells 2 Folic acid

I hesitate to put up a diagram of folate metabolism because it is so complicated. The correct name for folic acid is pteroylglutamic acid. Humans cannot synthesize it so we must take it in as a vitamin. Bacteria do synthesize it from pteridine, p-amino benzoic acid and glutamic acid, but this is inhibited by suphonamides which are therefore toxic to bacteria but harmless to humans.

I don't know whether the second diagram is more understandable, but if you focus on the top right hand corner, this is the bit that is relevant for megaloblastic anemia. The rest of the diagram is all about how various forms of chemotherapy interact with folate metabolism and we may come back to that. The part I am referring to is the change from dUMP to dTMP.

DNA and RNA differ in a number of ways. DNA is where the information for the genes is stored. Its structure is well known by now; the famous double helix where a chain of sugar molecules forms the banisters and interlocking purine and pyrimidine bases form the steps of the spiral staircase.
The bases are Guanine that always mates with Cytosine and Adenine that always mates with Thymine. The order of the bases is the basis of the code. RNA is single stranded and acts as both the messenger and the template for protein production; three bases representing a single amino acid. But the bases for RNA are different: instead of Thymine we have Uracil.


These molecules are very similar but thymine has an extra methyl (CH3) group hanging on one of the benzene rings. In Man thymine can only be made from uracil and there is a special enzyme that does it called thymidilate synthetase. One form of folic acid, 5, 10-methylene tetrahydrofolate, acts as the donor of the CH3 group to make thymine.

So although a patient without enough folic acid or who can't get it into the right form because of an absence of B12, although such a patient can make RNA, he can't make DNA properly. I was once buttonholed by a cytologist who told me that she had just diagnosed pernicious anemia from a cervical smear; a timely reminder that the megaloblastic process is not confined to blood cells, but is found in any tissue that is making new cells and therefore new DNA. Again it should be emphasized that B12 deficiency and folate deficiency both end up with identical blood pictures - megaloblastic anemia.

Diagnosis of folate deficiency is made by measuring the red cell folate, having first ascertained that the serum B12 is normal (red cell folate may be low in B12 deficiency). The serum folate is not a useful investigation - it merely tells you what sort of diet the patient has been having recently.

How can you get folate deficient? Folic acid is present in green vegetables so it is possible for those who live on tea and jam and bread to become deficient because of a poor diet, but it is unusual. Alcoholics are among those most likely to have a poor diet. More commonly there is an overuse of folic acid leading to a relative shortage. Typically, any condition where there is increased cell turnover puts the patient at risk. Pregnancy used to be one of the commonest causes, but most pregnant mums get folate supplements. Hemolytic anemia, any severe skin condition like eczema or psoriasis and any rapidly growing cancer or leukemia can cause a shortage of folate. Patients in intensive care may also develop folate deficiency.

Then there is malabsorption. Folate is absorbed from the small bowel and the condition most commonly associated with folate deficiency is celiac disease. Tropical sprue may be a problem in the Tropics (its why the ex-pats used to take Marmite with them), and Crohns disease, sclerodema of the gut and surgical resections may all be a cause. Some drugs interfere with folate absortion, notably phenytoin and sulphasalazine.

Folate deficiency is not associated with neurological syndromes apart from neural tube defeccts for which pregnant women should receive 400 micrograms a day as prophylaxis. This is thought to act through the methionine to homocysteine interaction. Eaised levels of homocytsteine are also associated with thrombotic lesions, for which folic acid is also a remedy.

Megaloblastic anemia generally has a low red cell count and a high red cell distribution width (RDW). Thrombocytopenia and neutropenia are also common and sometimes the presentation is of severe pancytopenia.

There are rare enzyme deficiencies like orotic aciuria and Lesch-Nyan syndrome that cause megaloblastic anemia, and certain drugs have an antifolate activity like methotrexate. Other drugs that interfere with DNA synthesis can cause megloblastosis with normal B12 and folate levels incude hydroxocarbamide, 5-fluorouracil, cytosine arabinoside, 6-mercaptopurine, azathiaprine, and anti-retroviral drugs. Megaloblastic changes may also be seen in some myelodysplastic syndromes.