Etiology and pathogenesis
The main cause of megaloblastic anemias is a shortage 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: inadequate 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 of vitamins in the body.
- Increased demand: during intensive DNA synthesis (pregnancy, advanced tumors, chronic hemolysis).
- Drug therapy: use of folic acid antagonist medications (methotrexate, trimethoprim, etc.).
When DNA synthesis decreases, actively dividing cells suffer first. A megaloblastic type of hematopoiesis forms in the bone marrow. Epithelial atrophy develops in the gastrointestinal tract (atrophic glossitis, gastritis, small intestinal villous atrophy). Maturation of germ cells is also impaired, which can lead to infertility.
An important distinction between B12 deficiency and folic acid shortage is the presence of neurological symptoms. Vitamin B12 is essential for the formation of the myelin sheath of 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
In the peripheral blood, pancytopenia is observed—a decrease in the count of cells from all hematopoietic lineages (erythrocytes, leukocytes, and platelets).
Erythrocyte changes:
- Macrocytosis (large cells) and elevated mean corpuscular volume (MCV).
- Anisocytosis (variation in size) and poikilocytosis (variation in shape).
- In later stages, nucleated red blood cells and Howell-Jolly bodies appear.
- Reticulocyte count is decreased.
Changes in other cells:
- Neutropenia develops, and large neutrophils (macropolycytes) appear.
- Neutrophil nuclei are hypersegmented (6 or more lobes).
- Thrombocytopenia is observed.
Bone marrow and organs: In severe cases, the bone marrow of tubular bones becomes red, resembling "raspberry jelly". The spleen may be mildly enlarged due to intense destruction of defective erythrocytes (erythrophagocytosis) and extramedullary hematopoiesis.
Bone marrow microscopy reveals damage to all hematopoietic lineages. The erythroid lineage shows hyperplasia and megaloblastic changes. Maturation dissociation occurs: nuclear maturation lags behind hemoglobin synthesis. Polyploidy and nuclear fragmentation are observed.
Pernicious anemia
Pernicious anemia (Pernicious anemia) is a malignant variant of megaloblastic anemia associated with vitamin B12 deficiency. It occurs against the background of chronic autoimmune gastritis (type A) or following gastrectomy.
The pathogenesis is based on intrinsic factor deficiency (gastromuco-protein), which is normally produced by parietal cells of the gastric fundus and is necessary 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 it from binding to receptors in the ileum.
This disease is often associated with other autoimmune pathologies, such as thyroiditis, Addison's disease, or type 1 diabetes mellitus.
Briefly: answers to topical questions
What pathological inclusions can be found in erythrocytes in megaloblastic anemia?
In megaloblastic anemia, erythrocytes contain pathological inclusions that represent remnants of intracellular structures.
- Howell-Jolly bodies (Howell-Jolly bodies) are small rounded purple inclusions representing remnants of nuclear chromatin or normoblast DNA.
- Cabot rings (Cabot rings) are thin thread-like formations in the shape of a ring, figure-eight, or treble clef, representing remnants of the mitotic spindle, microtubules, or nuclear envelope.
- Basophilic stippling—numerous small blue granules representing aggregates of RNA.
What is the biochemical mechanism of impaired myelin synthesis in vitamin B12 deficiency?
The biochemical mechanism of impaired myelin synthesis in vitamin B12 deficiency is due to disrupted fatty acid metabolism and the accumulation of neurotoxic compounds. The coenzyme shortage leads to the cumulation of methylmalonic acid, propionic acid, and homocysteine. These toxic metabolites damage nerve cells and cause demyelination of nerve fibers with axonal damage. As a result, myelin content decreases and funicular myelosis develops—degeneration of the posterior and lateral columns of the spinal cord.
Which parasitic infestations lead to the development of B12-deficiency anemia?
B12-deficiency anemia is caused by infestation with a large tapeworm—the fish tapeworm.
- Fish tapeworm (Diphyllobothrium latum)—causes the disease diphyllobothriasis.
The pathogenesis of anemia in this parasitic infestation is related to the helminth actively absorbing vitamin B12, which it requires for its own growth and reproduction. This creates a pronounced nutritional deficiency of the nutrient in the host, leading to megaloblastic anemia.
Which drug classes can provoke megaloblastic anemia?
Megaloblastic anemia can be provoked by drugs that disrupt folate metabolism or DNA synthesis. Such medications include:
- Folic acid antagonists: methotrexate, pyrimethamine, triamterene, trimethoprim, sulfasalazine.
- Antiepileptic drugs: ethosuximide.
The use of these drugs can lead to iatrogenic megaloblastic anemia as a side effect of therapy.
Class and exam questions
What is the main difference between B12-deficiency anemia and folate-deficiency anemia?
In vitamin B12 deficiency, in addition to typical hematological and gastroenterological changes, specific neurological symptoms develop (funicular myelosis) due to impaired myelin synthesis.
What is maturation arrest in megaloblastic anemia?
This is a phenomenon in which DNA synthesis and cell nuclear maturation are severely delayed, while hemoglobin synthesis (in the cytoplasm) is affected to a lesser degree. As a result, large cells with an immature nucleus are formed.
Why is vitamin B12 not absorbed in pernicious anemia?
Due to autoimmune destruction of gastric parietal cells, intrinsic factor (gastromucoprotein) ceases to be produced. Without it, vitamin B12 cannot be absorbed in the ileum.
What else to study on this topic
- Normal mechanisms of absorption and transport of vitamin B12 and folic acid
- Differential diagnosis of megaloblastic anemias with other macrocytic states
- Pathomorphology of funicular myelosis in B12 deficiency
- Features of hematopoiesis and ineffective erythropoiesis in megaloblastic states
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