Megaloblastic anaemia

A defi ciency of folate gives rise to a type of anaemia
known as megaloblastic anaemia. A clinically indistinguishable
anaemia is also produced by vitamin
B12 deficiency but, because it is accompanied by
neurological damage, it is referred to as pernicious
anaemia. Both types of anaemia are the result of abnormal
nuclear maturation caused by impaired DNA
synthesis. The impaired DNA synthesis is presumed
to be attributable to reduced intracellular levels of
polyglutamyl 5,10-methylene-THF. As shown in
reaction 17.7, this important folate is involved in
the formation of deoxythymidine monophosphate,
one of the two pyrimidine nucleotide constituents of
DNA. The defect in DNA synthesis leads to a variety of
secondary disturbances which result in the premature
death of many haemopoietic cells in the bone marrow,
possibly without ever completing the S phase of cell
replication.

Megaloblastic anaemia caused by folate defi ciency
manifests as megaloblastosis of the bone marrow
and macrocytosis of the circulating erythrocytes.
Examination of the bone marrow is of great diagnostic
importance. The erythrocyte precursor cells
(erythroblasts) in the bone marrow fail to proliferate
rapidly and exist as gigantic cells called megaloblasts
at all stages of maturation. It is the existence of such
cells that gives rise to the term megaloblastic anaemia.
The increased size of megaloblasts is apparent both in
the cytoplasm and in the nucleus. The nuclei contain
smaller quantities of condensed chromatin than the
nuclei of normoblasts of similar maturity and thus
have an open, sieve-like appearance.
The circulating erythrocytes which are derived from
mature megaloblasts are also abnormally large and are
referred to as macrocytes. The mean corpuscular volume
of macrocytes ranges from 100 to 160 μm3 compared
with 90 to 95 μm3 for normal erythrocytes. The
macrocytes are generally oval in shape (erythrocytes
are biconcave discs) but some fragmented and irregularly
shaped cells are also present. There is a reduction
in red cell count and sometimes incredibly low values
are found. The haemoglobin content of individual macrocytes is increased owing to their larger size, but
there is little change in the haemoglobin concentration
of whole blood.
White cells and platelets are also produced in the
bone marrow. In the differentiating granulocyte series
of white blood cells (neutrophils, eosinophils and
basophils) giant, abnormally shaped metamyelocytes
are found. Megakaryocytes (precursors of platelets)
may also be larger than usual. In advanced folate/B12
defi ciency, the total white cell count and platelet count
may be low. Circulating neutrophils are characterized
by an increased number of nuclear segments. The
presence of hypersegmented neutrophils is a valuable
clue in diagnosing folate/B12 deficiency when red cell
changes are masked by a coexistent iron defi ciency or
the anaemia of chronic disease.
As in all cases of anaemia, the body adjusts its
cardiopulmonary system to compensate for the diminished
oxygen-carrying capacity of the blood, so
in mild anaemia the subject may not be aware of any
problems. Eventually, however, the progressing anaemia
leads to symptoms of weakness, fatigue, shortness
of breath and palpitations. The sufferer may also
experience headache, irritability and an inability to
concentrate. Visible signs of megaloblastic anaemia
in white-skinned people are a marked pallor and a
slight jaundice, giving the skin a distinctive lemonyellow
tinge.
Megaloblastosis is not confi ned to developing cells
in the bone marrow – all other rapidly dividing cell
types will be affected, including epithelial cells lining
the gastrointestinal, respiratory, and urinogenital
tracts. A notable feature is glossitis where the tongue
is sore at the edges, bright red in colour and smooth in
texture. Gastrointestinal disturbances caused by defective
gut epithelia have adverse consequences upon
overall nutritional status. Male infertility results from
impaired spermatogenesis.
Folate defi ciency can result, in the absence of disease,
from reduced ingestion or absorption, or from
increased utilization. Dietary folate defi ciency is common
among people who, for various reasons, eat little
fruit or fresh vegetables. Absorption is impaired in
alcoholics. There is an increased utilization of folate
during pregnancy owing to the need to transfer an
extra 100–300 μg of folate per day to the fetus (Beatty
& Wickramasinghe, 1993). Experimental folate
defi ciency is diffi cult to produce under normal circumstances,
but the study of patients suffering from
malabsorption problems such as tropical sprue or the
use of folate antagonists has yielded much clinical
information.