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C H A P T E R 39

MEGALOBLASTIC ANEMIAS

Aśok C. Antony

The term megaloblastic anemia is used to describe a group of disorders enzymes that channel the folate across set pathways to support critical
characterized by a distinct morphologic pattern in hematopoietic synthesis of thymidine for DNA.
cells. A common feature is a defect in deoxyribonucleic acid (DNA) Indeed, the care with which cobalamin and folate are handled is
synthesis, with lesser alterations in ribonucleic acid (RNA) and analogous to the swarm of Secret Service agents escorting a president
protein synthesis, leading to a state of unbalanced cell growth and as he walks by a crowd of well-wishers, their sole aim being to prevent
impaired cell division. Most megaloblastic cells are not resting but him from getting too close to the public—to shake hands, or hug
vainly engaged in attempting to double their DNA, with frequent and kiss a baby, and the like, which could also expose him to potential
arrest in the S phase and lesser degrees of arrest in other phases of harm by an ill-wisher—and detract him from doing his primary job
the cell cycle. An increased percentage of these cells have DNA values as chief executive.
between 2 N (N is the amount of DNA in the haploid genome) and A general principle is that the preexisting store of these vitamins
4 N because of delayed cell division. This increased DNA content in will dictate the speed with which overt deficiency develops; this is
megaloblastic cells is morphologically expressed as larger-than-normal particularly relevant to pregnant women and children in developing
“immature” nuclei with finely particulate chromatin, whereas the countries with preexisting borderline stores of folate and cobalamin.
relatively unimpaired RNA and protein synthesis results in large cells The pathophysiology of cellular cobalamin and folate deficiency
with greater “mature” cytoplasm and cell volume. The net result of is most readily discerned by the clinician who approaches megalo-
megaloblastosis is a cell whose nuclear maturation is arrested (imma- blastosis with a clear understanding of the physiology of these
ture) while its cytoplasmic maturation proceeds normally indepen- vitamins. A detailed discussion of cobalamin and folate therefore
dently of the nuclear events. The microscopic appearance of this follows.
nuclear-cytoplasmic asynchrony (or dissociation) is morphologically
described as megaloblastic. Each cell lineage has a limited but unique
repertoire of expression of defective DNA synthesis. This is signifi- COBALAMIN
cantly influenced by the normal patterns of maturation of the affected
cell line. Additional variables that affect RNA and protein synthesis The term cobalamin refers to a family of compounds with the struc-
can lead to the attenuation or modification of megaloblastic expres- ture shown in Fig. 39.1. Details of the chemistry, nomenclature, and
sion (see Masked Megaloblastosis). in vivo substitutions of cobalamin are shown in Figs. 39.1 through 39.3,
Megaloblastic hematopoiesis commonly manifests as anemia, and excellent reviews are available on the colorful history, chemistry,
but this feature is only a manifestation of a more global defect and biology of cobalamin. 1–4
in DNA synthesis that affects all proliferating cells. The peripheral
blood picture is characteristic and reflective of megaloblastic hema-
topoiesis within the bone marrow. The diagnosis is therefore usually Nutrition
straightforward, but because any condition that specifically perturbs
DNA synthesis may lead to megaloblastosis, determination of the Cobalamin is produced in nature only by microorganisms, and
5,6
precise cause is necessary before institution of therapy. Inappropriate humans receive cobalamin solely from the diet. Cobalamin is
therapy can lead to disastrous consequences for the patient. The synthesized and used by some microorganisms (e.g., bacteria, fungi).
biochemical basis for megaloblastosis needs to be understood within Some strains (such as Pseudomonas denitrificans) produce cobalamin
the context of evaluation of potential and real variables affecting during fermentation, making them excellent and cheap commercial
DNA, RNA, and protein synthesis in a given patient. The most sources for cobalamin used in therapy. Herbivores obtain their dietary
common causes of megaloblastosis are true cellular deficiencies of quota of cobalamin from plants contaminated with cobalamin-
vitamin B 12 (cobalamin) or folate, vitamins that are essential for DNA producing soil bacteria (rhizobia) that grow in roots and nodules of
synthesis. legumes. Because rhizobia-related organisms are also found in the
Because of the imperative for conservation of cobalamin within large intestine of animals (and humans), volitional or inadvertent
the body, there is a finely tuned mechanism in place to ensure a coprophagy can lead to intake of cobalamin by herbivores; however,
sequential handover of this precious cargo from one protein to cobalamin from manure that contaminates plants is not likely to be
5
another—from the point of its entry into the mouth through the gut, a significant source for humans. Nevertheless, colonic cobalamin-
across the enterocyte, into the circulation with specialized uptake into producing bacteria—like Klebsiella pneumoniae that are related to
cells, passage through lysosomes into cytoplasm, and even into rhizobia—can be found in the small intestine of some individuals
mitochondria. Throughout this odyssey, cobalamin is accompanied from which cobalamin can be absorbed. For all practical purposes,
by several chaperones that sequentially bind, sequester, and thereby there is no unfortified plant food, including fermented soy products,
ensure that cobalamin does not participate in side reactions. This tempeh/tempe, seaweed (which are actually multicellular algae, such as
ensures its fitness for service for critical enzymes. nori [red algae], chlorella [green algae], spirulina [blue-green algae]),
Despite the greater abundance of folate in the diet relative to or other organic produce that can consistently provide a sufficient
cobalamin, there are also specialized means to ensure that the natural amount of active cobalamin to support daily requirements.
folates in food are first chopped and diced before being ushered across Animal protein is the major dietary cobalamin source for
the enterocyte through specialized pathways. After passage from the nonvegetarians. Meats from parenchymal organs are richest in
portal blood into the general circulation, folate is extracted by cell cobalamin (over 10 µg/100 g wet weight); fish and muscle meats,
surface folate receptors, undergoes endocytosis, and is then shunted milk products, and egg yolk have 1 to 10 µg/100 g of wet weight.
together with a proton across another channel into the cytoplasm. It An average nonvegetarian Western diet contains 5 to 7 µg/day of
is then received by an overabundance of high-affinity multifunctional cobalamin, which adequately sustains normal cobalamin equilibrium.

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