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
Reticulocytosis: Reticulocytes are immature RBCs without nuclei but some retained some messenger RNA with a typical mean corpuscular volume (MCV) of approximately 103 to 126 fL. The increase in MCV could be attributed in part to the signals from erythropoietin to increase RBC production rapidly and skipping some divisions which in turn increases reticulocytes in blood which look much bigger than normal mature RBCs, oval and lacking central pallor with a bluish color due to retained RNA. As reticulocytes are much larger than the mature RBCs, the increasing percentage of total RBCs will raise the MCV proportionately.[1][2][3][4][5][6]
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.[7][8] [9]
- 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.[10][11]
- 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[13] </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[14] </imagemap> |
<imagemap> File:Cabot ring and basophilic stippling.jpg|thumb|Cabot ring and basophillic stippling, By Dr. Roshan Nasimudeen, Source: Wikimedia commons[15] </imagemap> |
References
- ↑ d'Onofrio G, Chirillo R, Zini G, Caenaro G, Tommasi M, Micciulli G (February 1995). "Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia". Blood. 85 (3): 818–23. PMID 7833482.
- ↑ Houwen B (1992). "Reticulocyte maturation". Blood Cells. 18 (2): 167–86. PMID 1280483.
- ↑ Hoffbrand V, Provan D (February 1997). "ABC of clinical haematology. Macrocytic anaemias". BMJ. 314 (7078): 430–3. PMC 2125890. PMID 9040391.
- ↑ Colon-Otero G, Menke D, Hook CC (May 1992). "A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia". Med. Clin. North Am. 76 (3): 581–97. PMID 1578958.
- ↑ Ward PC (February 1979). "Investigation of macrocytic anemia". Postgrad Med. 65 (2): 203–7, 209, 212–3. PMID 368738.
- ↑ Kaferle J, Strzoda CE (February 2009). "Evaluation of macrocytosis". Am Fam Physician. 79 (3): 203–8. PMID 19202968.
- ↑ Takahashi N, Kameoka J, Takahashi N, Tamai Y, Murai K, Honma R, Noji H, Yokoyama H, Tomiya Y, Kato Y, Ishizawa K, Ito S, Ishida Y, Sawada K, Harigae H (September 2016). "Causes of macrocytic anemia among 628 patients: mean corpuscular volumes of 114 and 130 fL as critical markers for categorization". Int. J. Hematol. 104 (3): 344–57. doi:10.1007/s12185-016-2043-x. PMID 27352093.
- ↑ Aslinia F, Mazza JJ, Yale SH (September 2006). "Megaloblastic anemia and other causes of macrocytosis". Clin Med Res. 4 (3): 236–41. PMC 1570488. PMID 16988104.
- ↑ Davenport J (January 1996). "Macrocytic anemia". Am Fam Physician. 53 (1): 155–62. PMID 8546042.
- ↑ CONLEY CL, KREVANS JR, MCINTYRE PA, SACHS MV (November 1956). "Pathogenesis and treatment of macrocytic anemia; information obtained with radioactive vitamin B12". AMA Arch Intern Med. 98 (5): 541–9. PMID 13361587.
- ↑ Hoffbrand AV, Hobbs JR, Kremenchuzky S, Mollin DL (September 1967). "Incidence and pathogenesis of megaloblastic erythropoiesis in multiple myeloma". J. Clin. Pathol. 20 (5): 699–705. PMC 473554. PMID 5602978.
- ↑ 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
