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Chapter 5 Macrocytic anaemias / 71
folate - supplemented foods or as folic acid) to cell folate and low serum B 12 or vitamin B 6 levels.
prevent a first occurrence of an NTD in the fetus. Although folate deficiency (and in some studies, the
Folic acid is also given to patients undergoing presence of the polymorphism in the 5,10 - MTHFR
chronic dialysis and with severe haemolytic gene) has been associated with an increased inci-
anaemias and primary myelofibrosis, and to pre- dence of cardiovascular disease, recent large rand-
mature babies. Food fortification with folic acid omized studies have not shown a reduction in the
(e.g. in flour) is currently recommended in the rate of myocardial infarction by the use of prophy-
UK to reduce the incidence of NTDs and is lactic folic acid but a reduction in incidence
already practised in over 40 countries including of stroke of about 15% has been found on
North America. meta - analysis.
Other m egaloblastic a naemias Malignant d iseases
See Table 5.1 . Various associations have been found between folate
status or polymorphisms in folate metabolizing
Abnormalities of v itamin B 12 or enzymes and malignant diseases such as colon or
f olate m etabolism breast cancer and acute lymphoblastic leukaemia in
childhood. In most but not all, reduced folate status
These include congenital deficiencies of enzymes has been associated with an increased risk of malig-
concerned in B 12 or folate metabolism or of the nancy. Large - scale studies of prophylactic folic acid
serum transport protein for B 12 , TC. Nitrous oxide undertaken for cardiovascular disease, have gener-
(N 2 O) anaesthesia causes rapid inactivation of body ally not shown in any difference in cancer incidence
B 12 by oxidizing the reduced cobalt atom of methyl between those taking folic acid and controls.
B 12 . Megaloblastic marrow changes occur with
several days of N 2 O administration and can cause
pancytopenia. Chronic exposure (as in dentists and Defects of DNA s ynthesis n ot r elated to
anaesthetists) has been associated with neurological v itamin B 12 or f olate
damage resembling B 12 defi ciency neuropathy. Congenital deficiency of one or other enzyme con-
Antifolate drugs, particularly those which inhibit cerned in purine or pyrimidine synthesis can cause
DHF reductase (e.g. methotrexate and pyrimeth- megaloblastic anaemia identical in appearance to
amine) may also cause megaloblastic change. that caused by a deficiency of B 12 or folate. Th e
Trimethoprim, which inhibits bacterial DHF best known is orotic aciduria. Th erapy with
reductase, has only a slight action against the drugs that inhibit purine or pyrimidine synthesis
human enzyme and causes megaloblastic (such as hydroxyurea, cytosine arabinoside, 6 -
change only in patients already B 12 or folate mercaptopurine and zidovudine (AZT)) and some
deficient. forms of acute myeloid leukaemia or myelodysplasia
also cause megaloblastic anaemia.
Systemic d iseases a ssociated
with f olate or v itamin B 12 Other m acrocytic a naemias
d efi ciency
There are many non - megaloblastic causes of macro-
cytic anaemia (Table 5.10 ). The exact mechanisms
Cardiovascular d iseases
creating large red cells in each of these conditions
Raised serum homocysteine levels are associated is not clear although increased lipid deposition on
with an increased incidence of myocardial infarct, the red cell membrane or alterations of erythroblast
peripheral and cerebral vascular disease and venous maturation time in the marrow may be implicated.
thrombosis (see Chapter 27 ). Raised serum homo- Alcohol is the most frequent cause of a raised MCV
cysteine levels are associated with low serum and red in the absence of anaemia. Reticulocytes are bigger