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{{Macrocytic anemia}}
{{Macrocytic anemia}}
{{CMG}}
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==Overview==
==Overview==
==Pathophysiology==
[[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.


===Biochemical Review===
==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.<ref name="pmid7833482">{{cite journal |vauthors=d'Onofrio G, Chirillo R, Zini G, Caenaro G, Tommasi M, Micciulli G |title=Simultaneous measurement of reticulocyte and red blood cell indices in healthy subjects and patients with microcytic and macrocytic anemia |journal=Blood |volume=85 |issue=3 |pages=818–23 |date=February 1995 |pmid=7833482 |doi= |url=}}</ref><ref name="pmid1280483">{{cite journal |vauthors=Houwen B |title=Reticulocyte maturation |journal=Blood Cells |volume=18 |issue=2 |pages=167–86 |date=1992 |pmid=1280483 |doi= |url=}}</ref><ref name="pmid9040391">{{cite journal |vauthors=Hoffbrand V, Provan D |title=ABC of clinical haematology. Macrocytic anaemias |journal=BMJ |volume=314 |issue=7078 |pages=430–3 |date=February 1997 |pmid=9040391 |pmc=2125890 |doi= |url=}}</ref><ref name="pmid1578958">{{cite journal |vauthors=Colon-Otero G, Menke D, Hook CC |title=A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia |journal=Med. Clin. North Am. |volume=76 |issue=3 |pages=581–97 |date=May 1992 |pmid=1578958 |doi= |url=}}</ref><ref name="pmid368738">{{cite journal |vauthors=Ward PC |title=Investigation of macrocytic anemia |journal=Postgrad Med |volume=65 |issue=2 |pages=203–7, 209, 212–3 |date=February 1979 |pmid=368738 |doi= |url=}}</ref><ref name="pmid19202968">{{cite journal |vauthors=Kaferle J, Strzoda CE |title=Evaluation of macrocytosis |journal=Am Fam Physician |volume=79 |issue=3 |pages=203–8 |date=February 2009 |pmid=19202968 |doi= |url=}}</ref>
 
====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]].  
* [[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.  
* 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.<ref name="pmid27352093">{{cite journal |vauthors=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 |title=Causes of macrocytic anemia among 628 patients: mean corpuscular volumes of 114 and 130 fL as critical markers for categorization |journal=Int. J. Hematol. |volume=104 |issue=3 |pages=344–57 |date=September 2016 |pmid=27352093 |doi=10.1007/s12185-016-2043-x |url=}}</ref><ref name="pmid16988104">{{cite journal |vauthors=Aslinia F, Mazza JJ, Yale SH |title=Megaloblastic anemia and other causes of macrocytosis |journal=Clin Med Res |volume=4 |issue=3 |pages=236–41 |date=September 2006 |pmid=16988104 |pmc=1570488 |doi= |url=}}</ref> <ref name="pmid8546042">{{cite journal |vauthors=Davenport J |title=Macrocytic anemia |journal=Am Fam Physician |volume=53 |issue=1 |pages=155–62 |date=January 1996 |pmid=8546042 |doi= |url=}}</ref>
* 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.
* 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.
* 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===
====Body Stores====
====Folate====
====Folate====
* Folate has minimum daily requirement of 50 mcg per day this requirement can increase substantially in settings such as pregnancy.
* Folate has minimum daily requirement of 50 mcg per day this requirement can increase substantially in settings such as pregnancy.<ref name="pmid13361587">{{cite journal |vauthors=CONLEY CL, KREVANS JR, MCINTYRE PA, SACHS MV |title=Pathogenesis and treatment of macrocytic anemia; information obtained with radioactive vitamin B12 |journal=AMA Arch Intern Med |volume=98 |issue=5 |pages=541–9 |date=November 1956 |pmid=13361587 |doi= |url=}}</ref><ref name="pmid5602978">{{cite journal |vauthors=Hoffbrand AV, Hobbs JR, Kremenchuzky S, Mollin DL |title=Incidence and pathogenesis of megaloblastic erythropoiesis in multiple myeloma |journal=J. Clin. Pathol. |volume=20 |issue=5 |pages=699–705 |date=September 1967 |pmid=5602978 |pmc=473554 |doi= |url=}}</ref>
* 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.  
* 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.
* 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.
Line 20: Line 25:
* Obviously, it takes much longer to become B12 (3-6 years) versus folate (3 months) if intake ceased abruptly.  
* 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.
* The test for B12 is variable.
<br>
==Associated Conditions==
* [[Hyperhomocysteinemia]]
* [[Chemotherapy]]
* [[Polyglandular autoimmune syndrome]]
* [[Gastritis]]<ref name="pmid8309266">{{cite journal |vauthors=Pruthi RK, Tefferi A |title=Pernicious anemia revisited |journal=Mayo Clin. Proc. |volume=69 |issue=2 |pages=144–50 |date=February 1994 |pmid=8309266 |doi= |url=}}</ref>
* [[Hemodialysis]]


{|width="70%"
==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.
{| width="70%"
|
|
<imagemap>
<imagemap>
Image:Normal RBC.jpg|240px|thumb|Normal human red blood cells appear as concave disks with a zone of central pallor that typically occupies 30% of the total size. There is minimal variation in size and shape between individual red blood cells.
Image:Macrocytosis.jpg|230px|thumb|Non-megaloblastic macrocytosis is characterized by the presence of large RBCs (macrocytes).Source: By Osarten, Wikimedia commons<ref>Wikimedia commons; https://commons.wikimedia.org/wiki/File:Macrocytosis.jpg</ref>
</imagemap>
</imagemap>
|
|
<imagemap>
<imagemap>
Image:Macrocytosis.jpg|230px|thumb|Non-megaloblastic macrocytosis is characterized by the presence of large RBCs (macrocytes). It is difficult to appreciate the increased size on an individual peripheral smear.
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<ref>Wikimedia commons; https://commons.wikimedia.org/wiki/File:Hypersegmented_neutrophil.png</ref>
</imagemap>
</imagemap>
|
|
<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).
File:Cabot ring and basophilic stippling.jpg|thumb|Cabot ring and basophillic stippling, By Dr. Roshan Nasimudeen, Source: Wikimedia commons<ref>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 </ref>
</imagemap>
</imagemap>
|}
|}


==Associated Conditions==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
==Microscopic Pathology==
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 19:08, 6 November 2018

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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.

<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

  1. ↑ 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.
  2. ↑ Houwen B (1992). "Reticulocyte maturation". Blood Cells. 18 (2): 167–86. PMID 1280483.
  3. ↑ Hoffbrand V, Provan D (February 1997). "ABC of clinical haematology. Macrocytic anaemias". BMJ. 314 (7078): 430–3. PMC 2125890. PMID 9040391.
  4. ↑ 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.
  5. ↑ Ward PC (February 1979). "Investigation of macrocytic anemia". Postgrad Med. 65 (2): 203–7, 209, 212–3. PMID 368738.
  6. ↑ Kaferle J, Strzoda CE (February 2009). "Evaluation of macrocytosis". Am Fam Physician. 79 (3): 203–8. PMID 19202968.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Davenport J (January 1996). "Macrocytic anemia". Am Fam Physician. 53 (1): 155–62. PMID 8546042.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Pruthi RK, Tefferi A (February 1994). "Pernicious anemia revisited". Mayo Clin. Proc. 69 (2): 144–50. PMID 8309266.
  13. ↑ Wikimedia commons; https://commons.wikimedia.org/wiki/File:Macrocytosis.jpg
  14. ↑ Wikimedia commons; https://commons.wikimedia.org/wiki/File:Hypersegmented_neutrophil.png
  15. ↑ 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

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