Megaloblastic Anemia: Folate Deficiency & Vitamin B12 Deficiency

Megaloblastic anemia is a type of macrocytic anemia (MCV >100) characterized by the presence of megaloblasts, large nucleated red blood cells (RBCs).

The underlying mechanism of megaloblastic anemia is DNA/RNA asynchrony, where DNA maturation and cell division lag behind while RNA translation and protein production continue at a normal pace. This asynchrony disrupts cell division due to inadequate DNA maturation, causing the cytoplasm to enlarge and increase the MCV.

In megaloblastic anemia, the bone marrow is hypercellular but many of the abnormal RBCs undergo apoptosis, leading to a reduced number of circulating RBCs. These cells are also phagocytosed by macrophages, further diminishing their count in the bloodstream. Therefore, megaloblastic anemia is associated with a low reticulocyte count, unlike in hemolytic anemias where reticulocyte count is elevated.

Megaloblasts are large, oval cells featuring abundant basophilic cytoplasm and nuclei with lacy chromatin. Another characteristic is the presence of hypersegmented neutrophils, which have five or more lobes due to abnormal maturation.

Folate, or vitamin B9, is found in animal products and plants like dark green leafy vegetables. It is first converted to dihydrofolate and then to tetrahydrofolate by the enzyme dihydrofolate reductase. Methyl groups are subsequently added to tetrahydrofolate. This bioactive form of folate is crucial for purine and pyrimidine synthesis, the building blocks of DNA and RNA.

Folate deficiency can arise from multiple sources. Inadequate intake of leafy green vegetables is a common cause. Liver stores can be depleted within a few months, putting infants on goat's milk—which lacks sufficient folate—at risk. Conditions like celiac disease or short gut syndrome, which reduce small bowel surface area, also pose a risk because folate absorption occurs in the duodenum and jejunum. Excessive alcohol consumption hampers liver uptake and storage of folate. Lastly, chronic hemolysis can lead to deficiency by causing high RBC turnover, which in turn accelerates cell division and DNA synthesis, depleting folate stores.

Vitamin B12, or cobalamin, serves as a co-enzyme in methyltransferase reactions. It plays a crucial role in converting homocysteine to methionine, a reaction that also involves tetrahydrofolate and the enzyme methyl-tetrahydrofolate reductase (MTHFR). Additionally, vitamin B12 is required for the conversion of methylmalonic acid (MMA) to succinyl CoA by the enzyme methylmalonyl CoA mutase. In contrast to folate, liver stores of vitamin B12 can last for about 1,000 days.

Several factors can contribute to a vitamin B12 deficiency. A common cause is a vegan diet, which lacks natural sources of B12. Chronic alcohol consumption can also result in deficiency by affecting B12 absorption and metabolism. Additionally, conditions like achlorhydria hinder the release of B12 from food due to diminished pepsin activity.

Deficiency can also arise from insufficient intrinsic factor, which is vital for B12 absorption. This is commonly seen in pernicious anemia, where autoantibodies destroy intrinsic factor and gastric parietal cells. Other factors include pancreatic insufficiency, which impairs the separation of B12 from protein carriers by trypsin, and conditions like Crohn's disease, which damage the ileum and impede B12 absorption. Parasitic infections, such Diphyllobothrium latum, can also contribute to deficiency by competing for B12.

Neurological complications of B12 deficiency arise due to its role in myelin synthesis, which is crucial for the proper functioning of nerve cells. This leads to neuropsychiatric impairment and subacute combined degeneration, characterized by injury to both the dorsal and lateral columns due to demyelination. In SCD, the motor pathways in the lateral pyramidal tracts and the sensory pathways in the dorsal spinal column also degenerate, causing symptoms such as weakness, paralysis, paresthesias, numbness, and sensory ataxia.

B12 deficiency also results in homocysteinemia, which can contribute to a hypercoagulable state and increase the risk of cardiovascular and cerebrovascular diseases. Treating vitamin B12 deficiency with folate supplementation should be approached with caution, as it can correct the anemia but may exacerbate neurological symptoms.