Megaloblastic Anemias Overview

Study Notes

Megaloblastic Anemias

Megaloblastic anemias are a group of anemias characterized by delayed maturation of the erythroblast nucleus compared to the cytoplasm.
Erythroblasts, immature red blood cells, retain their nuclei
Asynchronous maturation results from defective DNA synthesis, evident in the bone marrow.
Megaloblastic anemias present as macrocytic anemia.

Causes of Megaloblastic Anemia

Commonly caused by deficiencies in vitamin B12 or folate.
Can also arise from abnormalities in B12 or folate metabolism.

Vitamin B12 (Cobalamin)

Synthesized by microorganisms; animals obtain it through their diet.
Exclusively found in animal products. (~50% of young adult vegans have suboptimal levels).
Primarily stored in the liver.
Body stores are sufficient for 3-4 years, so short-term dietary deficiencies are not immediately problematic.

B12 Absorption

B12 binds to dietary proteins.
Salivary glands produce R protein
Stomach parietal cells secrete intrinsic factor.
Stomach chief cells secrete pepsin
Pepsin breaks down proteins, releasing B12.
R-protein (from the mouth) binds free B12.
B12, R-protein, and intrinsic factor travel to the duodenum.
Pancreatic proteases break down R-protein, freeing B12.
B12 can now bind to intrinsic factor.
B12 must be bound to intrinsic factor for absorption.
Receptors on enterocytes recognize only the B12-intrinsic factor complex.
Intrinsic factor protects B12 from intestinal bacteria.
Only approximately 1% of B12 can be absorbed without intrinsic factor.
B12-intrinsic factor complexes are absorbed in the terminal ileum.
Absorbed B12 enters the portal blood.
Binds to transcobalamin for delivery to bone marrow and other tissues.
Megaloblastic anemia can also result from a transcobalamin deficiency, but dietary B12 intake is critical.
Inside tissues, the transcobalamin-B12 complex binds to a receptor and is endocytosed.
B12 then functions as a co-factor in essential biochemical pathways.

Folate

Humans cannot synthesize folate; dietary folate is essential.
Primarily found in green leafy vegetables.
Stored primarily in the liver.
Dietary folate (as methyltetrahydrofolate) is absorbed in the upper small intestine.
Folate-binding proteins facilitate cellular uptake.
Inside cells, folate is converted to polyglutamates.
Folate has a faster turnover, so deficiency develops more rapidly than with B12.

Folate and B12 Interaction

B12 is essential for the enzyme methionine synthetase, which converts methyltetrahydrofolate to tetrahydrofolate.
This reaction also involves the methylation of homocysteine to methionine.
B12 deficiency prevents the demethylation of methyl-THF, blocking tetrahydrofolate polyglutamate formation.
Folate deficiency also inhibits tetrahydrofolate polyglutamate formation.
Deficiencies in either B12 or folate lead to decreased DNA synthesis.
Result in delayed maturation of the nucleus in relation to the cytoplasm.
Bone marrow, with high cell turnover, typically shows the problem most.

Clinical Features of Anemia

Fatigue
Shortness of breath
Pale mucous membranes
Mild jaundice
Glossitis (inflammation of the tongue)
Nervous system disturbances (impaired vision, gait problems)
Psychiatric disturbances (mood swings, irrational behavior)

Laboratory Findings

Macrocytosis (oval-shaped red blood cells) - earliest sign of B12 deficiency, can be present before anemia.
Anisocytosis (variation in red blood cell size).
Hypersegmented neutrophils (6 or more lobes).
Results from delayed DNA synthesis but intact segmentation.
Poikilocytosis (abnormal red blood cell shape).
Howell-Jolly bodies (nuclear remnants).
Basophilic stippling (aggregated ribosomal RNA).
Elevated serum unconjugated bilirubin (due to marrow cell breakdown).
Elevated lactic acid dehydrogenase (due to marrow cell breakdown).
Normal serum iron and ferritin.
Measured using automated assays.
Serum B12 is low in cases of B12 deficiency.
Serum B12 is normal or elevated in folate deficiency.

Red Cell Folate

Low in folate deficiency.
Not specific to folate deficiency; 60% of B12 deficiency cases have low red cell folate.
More reliable indicator of tissue folate status than serum folate.

Homocysteine and Methylmalonic Acid (MMA)

Serum homocysteine is elevated in both B12 and folate deficiencies.
Serum MMA is elevated only in B12 deficiency.
Normal MMA and homocysteine levels strongly suggest no significant B12 deficiency.

Overview of Investigations

Clinical signs, blood tests, macrocytic cells on blood film, low serum B12—B12 deficiency.
Elevated MCV, low serum folate—folate deficiency.
Elevated LDH and unconjugated bilirubin, elevated MMA and homocysteine—B12 deficiency.

Description

Explore the characteristics and causes of megaloblastic anemias, focusing on vitamin B12 and folate deficiencies. Understand the role of erythroblasts and the implications of asynchronous maturation in the bone marrow. This quiz will deepen your knowledge of macrocytic anemia and its underlying factors.