Macrocytic anemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Amandeep Singh M.D.[2] Omer Kamal, M.D.[3]
Overview
Folate is important in the production of various building blocks necessary for the production of biologic macromolecules. By combining with carbon moieties, tetrahydrofolate (THF) becomes methelenetetrahydofolate. This molecule is then able to donate carbon moieties to form purines, dTMP, and methionine. Of note, Vitamin B12 is also a cofactor in the production of methionine. THF is the resulting molecule after donation of carbon moieties except in the synthesis of dTMP from dUMP. DHF (dihydrofolate) results from this reaction. DHF reductase must act on DHF to participate in reactions again. The two metabolically active forms of Vitamin B12 are Methycobalamin and Adenosylcobalamin. The former is important in methionine synthesis. Methionine is necessary for the production of choline phospholipids. Adenosylcobalamin is necessary to convert methylmalonyl CoA to succinyl-CoA. Interruption of this reaction eventually leads to nonphysiologic fatty acid production and abnormal neuronal lipid production. B12 deficiency also leads to folate metabolism derangement. Tissue folate levels are reduced in the setting of Vitamin B12 deficiency through a complicated biochemical pathway. This is known as the “folate trap hypothesis” and explains why large doses of folate will help the hematological manifestations. The mechanism of the neurologic manifestations remains independent of folate metabolism.
Pathophysiology
Biochemical Review
- Folate is important in the production of various building blocks necessary for the production of biologic macromolecules. By combining with carbon moieties, tetrahydrofolate (THF) becomes methelenetetrahydofolate. This molecule is then able to donate carbon moieties to form purines, dTMP, and methionine. Of note, Vitamin B12 is also a cofactor in the production of methionine.
- THF is the resulting molecule after donation of carbon moieties except in the synthesis of dTMP from dUMP. DHF (dihydrofolate) results from this reaction. DHF reductase must act on DHF to participate in reactions again.
- The two metabolically active forms of Vitamin B12 are Methycobalamin and Adenosylcobalamin. The former is important in methionine synthesis. Methionine is necessary for the production of choline phospholipids. Adenosylcobalamin is necessary to convert methylmalonyl CoA to succinyl-CoA. Interruption of this reaction eventually leads to nonphysiologic fatty acid production and abnormal neuronal lipid production.
- B12 deficiency also leads to folate metabolism derangement. Tissue folate levels are reduced in the setting of Vitamin B12 deficiency through a complicated biochemical pathway. This is known as the “folate trap hypothesis” and explains why large doses of folate will help the hematological manifestations. The mechanism of the neurologic manifestations remains independent of folate metabolism.
Body Stores
Folate
- Folate has minimum daily requirement of 50 mcg per day this requirement can increase substantially in settings such as pregnancy.
- Total body stores are approximately 5-20mg with half held in the liver. The serum folate level is not a reliable index of tissue folate levels.
- Serum folate levels can go up or down despite normal tissue levels depending on dietary intake and EtOH intake. The RBC (red blood cell) folate level is a better measure of tissue folate stores.
Vitamin B12
- The minimum daily requirement for B12 is 2.5 mcg.
- About 4mg is stored in the body with half in the liver.
- Obviously, it takes much longer to become B12 (3-6 years) versus folate (3 months) if intake ceased abruptly.
- The test for B12 is variable.
Associated Conditions
Microscopic Pathology
- On microscopic histopathological analysis, following are characteristic findings of megaloblastic anemia:
- Macrocyte
- Hypersegmented neutrophils
- Cabot rings and basophillic stippling can also be seen.
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<imagemap> Image:Macrocytosis.jpg|230px|thumb|Non-megaloblastic macrocytosis is characterized by the presence of large RBCs (macrocytes).Source: By Osarten, Wikimedia commons[2] </imagemap> |
<imagemap> Image:Hypersegmented neutrophil.png|thumb|Megaloblastic macrocytosis is characterized by the presence of large RBCs (macrocytes) and hypersegmented neutrophils ≥ 5 lobes (red arrow).Source:Wikimedia commons[3] </imagemap> |
<imagemap> File:Cabot ring and basophilic stippling.jpg|thumb|Cabot ring and basophillic stippling, By Dr. Roshan Nasimudeen, Source: Wikimedia commons[4] </imagemap> |
References
- ↑ Pruthi RK, Tefferi A (February 1994). "Pernicious anemia revisited". Mayo Clin. Proc. 69 (2): 144–50. PMID 8309266.
- ↑ Wikimedia commons; https://commons.wikimedia.org/wiki/File:Macrocytosis.jpg
- ↑ Wikimedia commons; https://commons.wikimedia.org/wiki/File:Hypersegmented_neutrophil.png
- ↑ Dr. Roshan Nasimudeen, Department of Pathology, Government Medical College, Kozikode? Calicut medical college; Wikimedia commons; https://commons.wikimedia.org/wiki/File:Cabot_ring_and_basophilic_stippling.jpg
