Etiology and Pathogenesis
The primary cause of megaloblastic anemias is a deficiency of vitamin B12 or folic acid. These substances act as coenzymes critically important for normal DNA synthesis, cell division, and cellular function.
Deficiency can develop through several pathways:
- Dietary: Insufficient dietary intake (e.g., in elderly individuals, premature infants, or chronic alcoholism).
- Malabsorption: Impaired gastrointestinal absorption (celiac disease, Crohn's disease, post-gastrectomy state).
- Impaired Transport: Disrupted vitamin transport in the body.
- Increased Demand: High-turnover states requiring intensive DNA synthesis (pregnancy, advanced malignancies, chronic hemolysis).
- Pharmacotherapy: Use of folate antagonist drugs (methotrexate, trimethoprim, etc.).
When DNA synthesis is impaired, actively dividing cells are affected first. A megaloblastic type of hematopoiesis develops in the bone marrow. Epithelial atrophy occurs in the gastrointestinal tract (atrophic glossitis, gastritis, small intestinal villous atrophy). Maturation of germ cells is also disrupted, which may lead to infertility.
An important distinction between B12 deficiency and folate deficiency is the presence of neurologic symptoms. Vitamin B12 is essential for the formation of the myelin sheath around nerve fibers. Its deficiency causes subacute combined degeneration of the spinal cord (funicular myelosis) with demyelination of the pyramidal tracts and posterior columns, as well as focal demyelination in the brain and peripheral nerves.
Morphology and Blood Picture
Peripheral blood findings demonstrate pancytopenia—a reduction in all blood cell lineages (erythrocytes, leukocytes, and platelets).
Erythrocyte Changes:
- Macrocytosis (large cells) and an elevated mean corpuscular volume (MCV).
- Anisocytosis (variation in size) and poikilocytosis (variation in shape).
- Nucleated red blood cells and Howell-Jolly bodies appear in later stages.
- Reticulocyte count is decreased.
Changes in Other Cells:
- Neutropenia develops, along with large neutrophils (macropolocytes).
- Neutrophil nuclei are hypersegmented (6 or more lobes).
- Thrombocytopenia is present.
Bone Marrow and Organs: In severe cases, the bone marrow of long bones becomes red, resembling "raspberry jelly." The spleen may be mildly enlarged due to the accelerated destruction of defective erythrocytes (erythrophagocytosis) and extramedullary hematopoiesis.
Bone marrow microscopy reveals involvement of all hematopoietic lineages. The erythroid series shows hyperplasia and megaloblastic changes. Maturation-1 dissociation (nuclear-cytoplasmic dissociation) occurs: nuclear maturation lags behind hemoglobin synthesis. Polyploidy and nuclear fragmentation are observed.
Pernicious Anemia
Pernicious anemia is a specific autoimmune variant of megaloblastic anemia associated with vitamin B12 deficiency. It develops in the setting of chronic autoimmune gastritis (Type A) or following gastrectomy.
The underlying pathogenesis is a deficiency of intrinsic factor (gastromucoprotein), which is normally secreted by parietal cells in the gastric fundus and is required for B12 absorption.
In autoimmune gastritis, antibodies are produced:
- Parietal canalicular antibodies (in 90% of patients)—destroy the microvilli of parietal cells.
- Blocking antibodies (in 60%)—prevent the formation of the "B12–intrinsic factor" complex.
- Binding antibodies (in 50%)—attack the preformed complex, preventing its attachment to receptors in the terminal ileum.
This disease is frequently associated with other autoimmune disorders, such as Hashimoto's thyroiditis, Addison's disease, or type 1 diabetes mellitus.