M e g a l o b l a s t i c A n e m i a
General
A. Macrocytic anemia: one in which the MCV > 100.
B. Two kinds of macrocytic anemia:
1. Megaloblastic (most common)
• Almost always caused by decreased B /folate.
• Specific "megaloblastic" morphologic changes
(see morphology section below).
• Usually caused by alcoholism; sometimes cause is unexplained.
• No "megaloblastic" changes.
Pathogenesis
Retarded DNA synthesis (causing cells to divide more slowly), but unimpaired RNA synthesis (allowing cytoplasm to mature at normal speed), leads to big cells with immature nuclei but mature cytoplasm (nuclear/cytoplasmic asynchrony).
Vitamin and/or folate deficiency is the most common cause of retarded DNA synthesis. You need both and folate to make DNA.
• Using B , methyl tetrahydrofolate is converted into methylene
tetrahydrofolate (which is used in DNA synthesis).
• Without B , folate gets "trapped" as methyl FH , a deficiency of
methylene FH ensues, and DNA synthesis is impaired
Vitamin
Sources
• Meat, dairy products, breakfast cereal (added as a supplement)
• Not in plants!
How does get to red cells?
• Ingested binds to intrinsic factor (secreted by gastric parietal cells)
• IF- is absorbed in the distal ileum.
• is transported by transcobalamin II) to organs and reticulocytes
What else do you need for?
• is also necessary for conversion of homocysteine to methionine.
• You need methionine for myelin maintenance (patients with untreated
deficiency eventually get an irreversible demyelinating disease of the spinal
cord called “subacute combined degeneration”).
• So…even if you know a patient has a folate deficiency, always check for a
concurrent deficiency! 
Causes of deficiency
• Diet (rare!). If you stopped eating completely, it would take several
years to become anemic.
• Lack of IF
1) Pernicious anemia
• Patients have autoantibodies to their parietal cells (as these are
destroyed, less IF is produced).
• Once dreaded and lethal (“pernicious”), now easily treated with
injections.
• To see how well a patient absorbs , you can do a Shilling test .
2) Other causes (gastrectomy)
• Pancreatic damage (without pancreatic enzymes, patients can't
liberate in the stomach, therefore can't bind to IF.)
• Ileal disease/resection ( -IF can't be absorbed).
• Bugs (tapeworms, bacterial overgrowth) in the small intestine (these
compete for ).
Folate ("folic" = "leafy")
Sources
• Lots!
• Green leafy vegetables, but also yeast, organ meats (mmmm), fruit,
breakfast cereals, dairy products.
How does folate get to red cells?
• Absorbed mostly in jejunum.
• Converted to methyl-FH during absorption.
• Transported freely (mostly) to liver, red blood cells.
Causes of folate deficiency
• Diet. Folate stores are relatively small! If you stopped eating folate
completely, it would only take a few months to become anemic.
• Alcohol abuse (malnutrition, poor absorption of folate, inhibition of folate
metabolism).
• Jejunal disease (sprue, inflammatory bowel disease)/resection.
• Drugs (especially chemotherapeutic drugs, many of which are folate
antagonists!).
Morphology
Blood
• Macrocytic anemia.
• Oval macrocytes.
• Hypersegmented neutrophils.
Bone marrow
• Megaloblastic erythroblasts (BIG cells with big, immature nucleus but
maturing cytoplasm).
• Megaloblastic neutrophils and precursors (giant metamyelocytes and
hypersegmented neutrophils.
