Pathophysiology
Summary
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.
Lesson Outline
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FAQs
Megaloblastic anemia is primarily caused by a deficiency in folate or vitamin B12, which results in DNA/RNA asynchrony. DNA maturation and cell division become delayed, while RNA translation and protein production continue. This causes the cell division in the red blood cells to be impaired due to poor DNA maturation while the cytoplasm continues to grow, resulting in an increase in the mean cell volume (MCV) and the production of megaloblasts - large nucleated red blood cells. Furthermore, the abnormal red blood cells undergo apoptosis or are phagocytosed by macrophages, leading to fewer red blood cells in circulation. This also explains the low reticulocyte count noticed in patients with this condition.
Megaloblastic anemia is a subtype of macrocytic anemia characterized by the presence of megaloblasts—large, nucleated red blood cells—in the bone marrow. Unlike other forms of anemia, megaloblastic anemia is specifically caused by deficiencies in folate or vitamin B12, leading to impaired DNA maturation and cell division. This results in a high mean cell volume (MCV) and low reticulocyte count. The bone marrow in megaloblastic anemia is typically hypercellular, contrasting with other anemias where it may be normocellular or hypocellular.
Folate, also known as vitamin B9, is required for purine and pyrimidine synthesis, which are vital for DNA and RNA production. It contributes to the production of tetrahydrofolate which takes part in several metabolic reactions including carbon(methyl group) transfers. Folate deficiency can occur due to the insufficient consumption of folate-rich foods such as dark green leafy vegetables and animal products, drinking excessive amounts of alcohol, suffering from chronic hemolysis, or from insufficient small bowel surface area due to conditions like celiac disease or short gut syndrome. In infants, the exclusive consumption of goat's milk, which contains minimal folate, can also lead to deficiency.
Vitamin B12 (cobalamin) is a coenzyme that aids in methyltransferase reactions, including the conversion of homocysteine to methionine. A deficiency in vitamin B12 can cause megaloblastic anemia because insufficient amounts impair red blood cell division and maturation. Causes of vitamin B12 deficiency include following a strict vegan diet, chronic alcohol consumption, conditions that lead to achlorhydria or lack of gastric acid, decreased production of intrinsic factor, pernicious anemia, and conditions affecting the ileum such as Crohn's disease or parasitic infection by Diphyllobothrium latum. Pancreatic insufficiency can also lead to vitamin B12 deficiency.
Vitamin B12 deficiency can cause neuropsychiatric impairment due to its role in myelin synthesis, which is crucial for the proper functioning of nerve cells. This leads to subacute combined degeneration, characterized by injury to both the dorsal and lateral columns due to demyelination. 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.
