PA H4 | Macrocytic Anemias & B12/Folate — Glossary

Diagnostic criterion: presence of ≥1 neutrophil with 5 or more lobes, or ≥5% of neutrophils with ≥5 lobes, is sufficient to diagnose megaloblastic disease on a smear.

The predominant circulating form of folate in plasma. It is converted to THF by methionine synthase (B12-dependent). In B12 deficiency, it accumulates and becomes metabolically inaccessible — this is the cellular basis of the folate trap.

Marked variation in both size (anisocytosis) and shape (poikilocytosis) of red blood cells; prominent in megaloblastic anaemia due to ineffective erythropoiesis producing cells of varied maturation.

Auto-antibodies (Type I blocking, Type II binding) directed against intrinsic factor. Found in approximately 60% of pernicious anaemia patients but are highly specific (>99%) for the diagnosis.

Fine blue dots within RBCs on Leishman stain, representing aggregated ribosomes. Classically associated with lead poisoning and thalassaemia; may be seen in megaloblastic anaemia but is less specific than hypersegmentation.

A thin, ring-shaped or figure-of-eight purple structure within an RBC, representing remnants of the mitotic spindle apparatus. Rare but highly characteristic of severe megaloblastic change.

An endocytic receptor complex on the brush border of terminal ileal enterocytes that binds the IF-B12 complex with high affinity, mediating the final step of B12 absorption. Disease or resection of the terminal ileum destroys these receptors.

An enzyme that reduces dietary folate and dihydrofolate (DHF) to tetrahydrofolate (THF), the active intracellular form. It is competitively inhibited by methotrexate and trimethoprim, which is the basis of their antiproliferative/antifolate pharmacology.

A peripheral smear showing two distinct populations of RBCs — typically micro-hypochromic cells (iron deficiency) alongside macro-ovalocytes (B12/folate deficiency) — seen in mixed nutritional deficiency; MCV may be misleadingly normal.

Large, abnormal granulocyte precursor seen in megaloblastic bone marrow; product of impaired DNA synthesis in the myeloid lineage; the precursor of hypersegmented neutrophils in peripheral blood.

A binding protein secreted by salivary glands and gastric mucosa that binds B12 in the acid stomach, protecting it from denaturation. It is cleaved by pancreatic proteases in the duodenum, releasing B12 for binding to intrinsic factor.

Amino acid that accumulates in both B12 and folate deficiency because methionine synthase (which converts homocysteine to methionine) requires both B12 and 5-methyl-THF as cofactors; raised homocysteine is sensitive but not specific for B12 deficiency.

A small, round, dark-purple nuclear remnant within an RBC, normally removed by the spleen. Seen in megaloblastic anaemia, post-splenectomy states, and thalassaemia — non-specific.

Cytoreductive drug that inhibits ribonucleotide reductase, blocking deoxyribonucleotide synthesis; causes megaloblastic change as a side effect; used in CML and sickle cell disease.

A neutrophil with 5 or more nuclear lobes, found in megaloblastic anaemia as a result of impaired DNA synthesis in granulocyte precursors. Presence of >5% neutrophils with ≥5 lobes on a peripheral blood smear is the earliest and most sensitive morphological indicator of megaloblastic haematopoiesis.

Death of erythroid precursors within the bone marrow before they can mature and enter peripheral blood. In megaloblastic anaemia, it causes elevated serum LDH, elevated indirect bilirubin, and a paradoxically low reticulocyte count despite hypercellular marrow.

A glycoprotein secreted by gastric parietal cells required for ileal absorption of vitamin B12. Its absence (pernicious anaemia, gastrectomy) causes B12 deficiency and megaloblastic anaemia.

A 44 kDa glycoprotein secreted by gastric parietal cells of the fundus and body. It binds free B12 in the duodenum, protecting it from digestion, and delivers it to cubilin receptors in the terminal ileum.

Intracellular enzyme released in large quantities during intramedullary haemolysis in megaloblastic anaemia; markedly elevated LDH (>5× normal) supports ineffective erythropoiesis as the diagnosis.

Total white blood cell count below 4 × 10⁹/L. In megaloblastic anaemia, impaired myeloid DNA synthesis causes leucopenia in severe disease, often accompanied by thrombocytopenia (pancytopenia).

Large, oval-shaped red cell characteristic of megaloblastic anaemia; distinguished from the round macrocytes of non-megaloblastic causes.

Synonym for hypersegmented neutrophil in the context of megaloblastic anaemia — a large neutrophil with ≥5–6 nuclear lobes caused by the same DNA-synthesis impairment affecting erythroid precursors.

The average volume of a red blood cell, measured in femtolitres (fL). Normal 80–100 fL; macrocytosis = MCV >100 fL. Can be misleadingly normal in dimorphic anaemia.

An abnormally large erythroid precursor with a lacy, open-chromatin nucleus caused by nuclear-cytoplasmic asynchrony in B12 or folate deficiency. Most megaloblasts die within the marrow (ineffective erythropoiesis) rather than entering peripheral blood.

Anaemia caused by impaired DNA synthesis in erythroid precursors, producing large, immature red cells (megaloblasts) due to B12 or folate deficiency, drugs, or inborn errors.

A B12-dependent enzyme (cofactor: methylcobalamin) that demethylates 5-methyl-THF to THF, simultaneously converting homocysteine to methionine. Its failure in B12 deficiency creates the folate trap and raises serum homocysteine.

Antifolate drug that inhibits DHFR, blocking tetrahydrofolate synthesis and causing drug-induced megaloblastic anaemia; reversed by folinic acid (leucovorin) not folic acid.

A metabolite that accumulates in the serum and urine when methylmalonyl-CoA mutase is dysfunctional due to B12 deficiency. Elevated MMA is highly specific for B12 deficiency and does not rise in isolated folate deficiency.

A B12-dependent enzyme (cofactor: adenosylcobalamin) that converts methylmalonyl-CoA to succinyl-CoA in propionate metabolism. Its failure in B12 deficiency causes methylmalonic acid (MMA) accumulation, which is a specific biochemical marker of B12 deficiency.

The optimal area of a peripheral smear for RBC morphology assessment — where cells are just touching without overlap, approximately two-thirds from the thick end toward the feather edge.

An anaesthetic/recreational gas that irreversibly oxidises the cobalt atom in B12 from its active reduced state (Co+) to an inactive oxidised state (Co3+), completely inactivating methionine synthase and methylmalonyl-CoA mutase within hours. Can precipitate acute SCD in borderline-deficient patients.

Macrocytosis not caused by impaired DNA synthesis; causes include alcohol, liver disease, hypothyroidism, reticulocytosis, and MDS; peripheral smear shows round macrocytes without hypersegmented neutrophils.

Morphological hallmark of megaloblastic haemopoiesis: the nucleus matures more slowly than the cytoplasm, producing a cell with mature haemoglobin but an open, lacy, immature nucleus.

The hallmark morphological feature of megaloblastic anaemia: the nucleus fails to divide (blocked DNA synthesis) while the cytoplasm continues to mature normally, producing abnormally large cells with immature nuclei relative to their cytoplasmic content.

Simultaneous reduction in all three blood cell lines (red cells, white cells, platelets); occurs in severe megaloblastic anaemia when DNA synthesis failure affects all marrow lineages.

Autoimmune disease characterised by destruction of gastric parietal cells leading to absent intrinsic factor, failure of vitamin B12 absorption, and megaloblastic anaemia; associated with anti-parietal cell and anti-intrinsic factor antibodies.

An autoimmune disease characterised by CD4+ T-cell destruction of gastric parietal cells (Type A chronic atrophic gastritis), resulting in loss of intrinsic factor and consequent vitamin B12 malabsorption. The most common cause of B12 deficiency in adults.

The appearance of blue-grey (polychromatic) RBCs on Leishman stain, representing newly released reticulocytes still containing residual RNA. Indicates a regenerative marrow response, not megaloblastic change.

Folate concentration within red blood cells, reflecting tissue folate status over the prior 2–3 months; more reliable than serum folate (which fluctuates with recent diet) for diagnosing folate deficiency.

An immature RBC that has extruded its nucleus but retains residual RNA; appears blue-grey (polychromatic) on Leishman stain and is counted to assess bone marrow regenerative activity. Elevated after haemolysis or treatment response.

The universal methyl donor in over 100 methylation reactions, including myelin phospholipid synthesis. SAM is derived from methionine (itself a product of B12-dependent methionine synthase). SAM depletion in B12 deficiency is a core mechanism of subacute combined degeneration.

Historical two-stage test using oral radiolabelled B12 to diagnose pernicious anaemia and localise the site of B12 malabsorption; now largely replaced by antibody assays and metabolite testing.

Progressive demyelination of the posterior and lateral columns of the spinal cord caused by B12 deficiency; occurs independently of anaemia and may progress if folate is given without B12 correction.

Demyelination of the posterior columns and lateral corticospinal tracts of the spinal cord due to B12 deficiency. It causes loss of vibration/position sense followed by spasticity and pyramidal signs. It does not occur in isolated folate deficiency.

An RBC with a central 'bullseye' of haemoglobin surrounded by a pale ring — caused by excess membrane relative to cell volume. Seen in liver disease, thalassaemia, and haemoglobin C; NOT characteristic of megaloblastic anaemia.

The active, reduced form of folate within cells, required as a one-carbon carrier for DNA synthesis (thymidylate and purine synthesis). It is the product of the methionine synthase reaction and cannot be generated when B12 is deficient (folate trap).

A state of functional intracellular folate deficiency caused by B12 deficiency. Without functional methionine synthase, 5-methyl-THF cannot be demethylated to THF, so active folate derivatives for DNA synthesis become unavailable despite normal serum folate levels.

Platelet count below 150 × 10⁹/L. In severe megaloblastic anaemia, impaired megakaryocyte DNA synthesis reduces platelet production, contributing to the pancytopenic picture.

Main plasma transport protein for vitamin B12 that delivers it to tissues; TC II deficiency is a rare inborn error causing severe megaloblastic anaemia in infancy.

The plasma transport protein that binds B12 after absorption in the terminal ileum and delivers it to all body tissues. Its deficiency causes functional B12 deficiency even with normal absorption.

A water-soluble vitamin synthesised only by microorganisms, essential for DNA synthesis (via the folate trap) and myelin maintenance (via methylmalonyl-CoA mutase and methionine synthase). Found exclusively in animal-derived foods.