Megaloblastic anemias

• Come from either a deficiency of vitamin B₁₂ and/or folate (cofactors in the conversion of UMP to TMP during DNA synthesis) or interference with either one of the cofactors such that it cannot be used

• Peripheral smears will show marked anisocytosis (increased RDW), macroovalocytes (large, oval RBCs), and neutrophilic hypersegmentation (normal neutrophil nuclei have < 5 segments…these have many more); reticulocyte count is decreased and nucleated RBC precursors may be present

• Granulocyte and platelet numbers may also be decreased, as their maturation is also affected

• There is a decreased myeloid to erythroid ratio and the marrow is hypercellular due to a hyperplasia of erythroid precursors

• Ineffective erythropoiesis causes intramedullary and peripheral hemolysis

• Vitamin B₁₂ deficiency

  • Causes

    • Most commonly from pernicious anemia

      • Which comes from an idiopathic atrophic gastritis (which causes a lack of intrinsic factor) that is seen in the 5^th – 8^th decades of life (slightly more common in males)

      • Pernicious anemia is characterized by a lack of intrinsic factor, which is essential for absorption of B₁₂ in the terminal ileum

    • Other causes are gastrectomy, malabsorption, competitive uptake by intestinal parasites (e.g., fish tapeworms), bacterial overgrowth in divertivuli, dietary deficiency (must be very prolonged), or increased requirements (e.g., pregnancy, hyperthyroidism, and disseminated CA)

  • Neurological abnormalities (weakness and numbness progressing to paralysis) may be seen with B₁₂ deficiency of any cause

    • B₁₂ is a cofactor in the conversion of methylmalonic acid to succinate; lack of B₁₂ leads to accumulation of methylmalonic acid and propionate (a precursor), which cause the breakdown of the myelin sheath

    • B₁₂ is also a cofactor in the conversion of homocysteine to methionine; in the process, serum folic acid is converted into THF, which is needed for DNA production

    • The DNA abnormalities from B₁₂ deficiency can be corrected by giving a lot of folate, but the neurological abnormalities will remain or get worse

  • Diagnosis can be done by measuring serum B₁₂, demonstration of anti-parietal cell and/or anti-intrinsic factor Abs, gastric biopsy, marrow exam, and a Shilling’s test

  • Shilling’s test

    • Urinary excretion of radiolabeled B₁₂ is measured with and without exogenous intrinsic factor

    • Absence of B₁₂ in the urine (which means it’s not being absorbed) that is corrected with exogenous intrinsic factor is seen with pernicious anemia and post-gastrectomy…this is not seen with other causes of malabsorption

  • 3 types of Abs are seen in patients with pernicious anemia (not all may be seen)

    • Blocking Abs: block B₁₂ binding to intrinsic factor

    • Binding Abs: reacts with IF and IF-B₁₂ complex

    • Anti-parietal cell canalicular Abs: blocks absorption at the microvilli

  • The risk of gastric carcinoma is increased in adult patients with pernicious anemia

  • Pernicious anemia is rarely seen in kids; when it is seen, it may display AR inheritance and there are no associated gastric abnormalities

• Folate deficiency

  • Produces a megaloblastic anemia without neurological defects

  • Causes: dietary deficiency (seen in alcoholics), malabsorption, increased requirement (e.g., pregnancy, disseminated CA), people taking folate blockers (e.g., methotrexate, mercaptopurines, cyclophosphamide) and losses with dialysis

  • Diagnosis requires measurement of RBC [folate], as serum levels are quickly corrected with supplementation (the lifespan of the RBC allows one to get a more accurate picture)

• Congenital megaloblastic anemias – these are pretty rare and include pyridoxine (vitamin B₆) and thiamine responsive megaloblastic anemias

Category: Medical Subject Notes , Pathology Notes