Megaloblastic Anemia

Megaloblastic anaemia: caused most commonly by a deficiency of vitamin B₁₂ or folate, features…

• Abnormally large erythroid precursors (megaloblasts) whose nuclear maturation lags behind the cytoplasmic maturation

• Ineffective erythropoiesis (death of megaloblasts in the marrow) associated with compensatory hyperplasia

• Prominent anisocytosis (variability in cell size), a reflection of ineffective erythropoiesis, including abnormally large and oval red cells (macro-ovalocytes)

• Abnormal granulopoieses yielding giant metamyelocytes and hyper-segmented neutrophils (up to 6 lobes)

Pathophysiology:

Vitamin B₁₂ and folic acid are essential coenzymes in the DNA synthetic pathway. A deficiency of these nutrients results in deranged or inadequate synthesis of DNA, but the synthesis of RNA and proteins is unaffected. Therefore, cytoplasmic enlargement and maturation occur without concomitant nuclear maturation.

In addition to affecting red cell precursors, a deficiency of vitamin B₁₂ and folate affects all rapidly dividing cells, including all myeloid cells and the mucosal epithelium of the GIT.

The anaemia results from:

• Ineffective erythropoiesis

• Production of abnormal erythrocytes that are susceptible to accelerated haemolysis

Ineffective granulopoiesis and thrombopoiesis as well as premature destruction may also affect granulocyte and platelet precursors, giving rise to pancytopenia.

Vitamin B₁₂ deficiency:

Vitamin B₁₂ is absorbed through the ilium, facilitated by intrinsic factor (IF) secreted by parietal cells of the stomach; absorption is limited to 2-3mg daily (the body requires only 1mg B₁₂ daily).

The ultimate source of this vitamin is dietary animal products. The daily requirements are approximately supplied by a normal western diet 10-30mg daily, but not by strict vegetarian diet excluding all animal produce.

A deficiency of vitamin B₁₂ may result from:

• Pernicious anaemia: (1 in 10 000) an autoimmune disorder that damages gastric parietal cells and the production of IF

• Gastrectomy, which leads to loss of IF

• Resection of the ilium (preventing absorption of IF- B₁₂ complex)

• Malabsorption syndromes

• Increased requirements (e.g. pregnancy)

• Inadequate diet; uncommon because the body has large reserves

Folate deficiency:

Natural folates are largely absorbed through the upper small intestine after deconjugation and bony stores are sufficient for only about 4 months.

Daily requirement of folate is 0.1-0.2mg; normal mixed diet contains 0.2-0.3mg.

A deficiency of folate may result from:

• Inadequate dietary intake (poor quality, poverty, synthetic without added folate)

• Malabsorption through the proximal small bowel (e.g. gluten induced enteropathy, jejunal resection)

• Increased requirements (transfer of folate to the foetus in pregnancy)

Category: Pathology Notes