Editing Megaloblastic anemia

{{More medical citations needed|date=September 2018}}

{{Infobox medical condition (new)
| name            = Megaloblastic anemia
| synonyms        = Megaloblastic anaemia
| image           = Hypersegmented neutrophil.png
| caption         = Peripheral blood smear showing hypersegmented neutrophils, characteristic of megaloblastic anemia.
| pronounce       =
| field           = [[Hematology]]
| symptoms        =
| complications   =
| onset           =
| duration        =
| types           =
| causes          =
| risks           =
| diagnosis       =
| differential    =
| prevention      =
| treatment       =
| medication      =
| prognosis       =
| frequency       =
| deaths          =
}}

'''Megaloblastic anemia''' is a type of [[macrocytic anemia]]. An [[anemia]] is a [[red blood cell]] defect that can lead to an undersupply of oxygen.<ref>{{Cite web|title=Anemia. Blood patient information|url=http://www.dgft.nhs.uk/anaemia/&ved=2ahUKEwiS4eaP4LzwAhWL_KQKHbaZD-0QFjAVegQILBAC&usg=AOvVaw3Ga6fW2AkPt9lWEy4ob-B9|access-date=2021-05-09|website=UK [[National Health Service]]}}{{Dead link|date=March 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Megaloblastic anemia results from inhibition of [[DNA replication|DNA synthesis]] during red blood cell production.<ref name="urlMegaloblastic Anemia: Overview - eMedicine Hematology">{{cite web |url=http://emedicine.medscape.com/article/204066-overview |title=Megaloblastic Anemia: Overview - eMedicine Hematology |access-date=2009-02-07}}</ref> When DNA synthesis is impaired, the [[cell cycle]] cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis.
Megaloblastic anemia has a rather slow onset, especially when compared to that of other anemias.
The defect in red cell DNA synthesis is most often due to [[hypovitaminosis]], specifically [[vitamin B12 deficiency]] or [[folate deficiency]]. Loss of micronutrients may also be a cause.

Megaloblastic anemia which is not caused due to hypovitaminosis may be caused by [[antimetabolite]]s that poison DNA production directly, such as some chemotherapeutic or antimicrobial agents (for example [[azathioprine]] or [[trimethoprim]]).

The pathological state of megaloblastosis is characterized by many large immature and dysfunctional red blood cells ([[megaloblast]]s) in the bone marrow<ref name="titleMegaloblastic (Pernicious) Anemia - Lucile Packard Childrens Hospital">{{cite web |url=http://www.lpch.org/DiseaseHealthInfo/HealthLibrary/hematology/megalob.html |title=Megaloblastic (Pernicious) Anemia - Lucile Packard Children's Hospital |access-date=2008-03-12 |archive-url=https://web.archive.org/web/20080323065724/http://www.lpch.org/DiseaseHealthInfo/HealthLibrary/hematology/megalob.html |archive-date=2008-03-23 |url-status=dead }}</ref> and also by [[hypersegmented neutrophil]]s (defined as the presence of neutrophils with six or more lobes or the presence of more than 3% of neutrophils with at least five lobes).<ref>{{Cite book|url=https://books.google.com/books?id=rEPUDAAAQBAJ&pg=PA85|title=Dacie and Lewis Practical Haematology E-Book|last1=Bain|first1=Barbara J.|last2=Bates|first2=Imelda|last3=Laffan|first3=Mike A.|date=2016-08-11|publisher=Elsevier Health Sciences|isbn=9780702069253|language=en}}</ref> These hypersegmented [[neutrophil]]s can be detected in the [[peripheral blood]]  (using a diagnostic smear of a blood sample).

==Causes==
* [[Vitamin B12 deficiency]]:
** [[Achlorhydria]]-induced malabsorption
** Deficient intake (e.g. vegan diet)
** [[Pernicious anemia]]
** [[Gastrectomy]]
** [[Coeliac disease|Celiac disease]]
** Biological competition for vitamin B12 by [[diverticulosis]], [[fistula]], intestinal [[anastomosis]], or infection by the marine parasite ''[[Diphyllobothrium latum]] (fish tapeworm)''
** Selective [[vitamin B12]] [[malabsorption]] (congenital—[[juvenile megaloblastic anaemia 1|juvenile megaloblastic anemia 1]]—and drug-induced)
** [[Chronic pancreatitis]]
** Ileal resection and bypass
** [[Nitrous oxide]] anesthesia (usually requires repeated instances).
* [[Folate deficiency]]:
** [[Alcoholism]]
** Deficient intake
** Increased needs: [[pregnancy]], [[infant]], rapid cellular proliferation, and [[cirrhosis]]
** [[Malabsorption]] ([[Hereditary folate malabsorption|congenital]] and drug-induced)
** Intestinal and [[jejunal]] resection
** (indirect) Deficient [[thiamine]] and factors (e.g., enzymes) responsible for [[Conditions comorbid to autism spectrum disorders#Abnormal folate metabolism|abnormal folate metabolism]].
** Tea and toast diet
* Inherited Pyrimidine Synthesis Disorders: [[Orotic aciduria]]
* Inherited [[DNA]] Synthesis Disorders
* Toxins and Drugs:
** [[Folic acid]] antagonists ([[methotrexate]])
** [[Purine]] synthesis antagonists ([[6-mercaptopurine]], [[azathioprine]])
** [[Pyrimidine]] antagonists ([[cytarabine]])
** [[Phenytoin]]
** [[Nitrous Oxide]]
* [[Erythroleukemia]]
* Inborn genetic mutations of the [[Methionine synthase]] gene
* [[Acute erythroid leukemia|Di Guglielmo's syndrome]]
* [[Congenital dyserythropoietic anemia]]
* [[Copper deficiency]] resulting from an excess of zinc from unusually high oral consumption of zinc-containing denture-fixation creams has been found to be a cause.<ref>{{Cite journal| doi = 10.1212/01.wnl.0000312375.79881.94| issn = 1526-632X| volume = 71| issue = 9| pages = 639–643| last1 = Nations| first1 = S. P.| last2 = Boyer| first2 = P. J.| last3 = Love| first3 = L. A.| last4 = Burritt| first4 = M. F.| last5 = Butz| first5 = J. A.| last6 = Wolfe| first6 = G. I.| last7 = Hynan| first7 = L. S.| last8 = Reisch| first8 = J.| last9 = Trivedi| first9 = J. R.| title = Denture cream: an unusual source of excess zinc, leading to hypocupremia and neurologic disease| journal = Neurology| date = 2008-08-26| pmid = 18525032| s2cid = 19614652}}</ref><ref>{{Cite journal| doi = 10.1038/ncpneuro1008| issn = 1745-8358| volume = 5| issue = 2| pages = 106–111| last1 = Spain| first1 = Rebecca I.| last2 = Leist| first2 = Thomas P.| last3 = De Sousa| first3 = Eduardo A.| title = When metals compete: a case of copper-deficiency myeloneuropathy and anemia| journal = Nature Clinical Practice. Neurology| date = February 2009| pmid = 19194390| s2cid = 27892441}}</ref>

== Pathophysiology ==
There is a defect in [[DNA synthesis]] in the rapidly dividing cells and to a lesser extent, [[RNA]] and [[protein synthesis]] are also impaired. Therefore, unbalanced [[Cell growth|cell proliferation]] and impaired [[cell division]] occur as a result of arrested nuclear maturation so the cells show nuclear-cytoplasmic asynchrony.

In the [[bone marrow]], most megaloblasts are destroyed prior to entering the peripheral blood ([[intramedullary]] [[hemolysis]]). Some can escape the bone marrow ([[Macrocytosis|macrocytes]]) to peripheral blood but they are destroyed by the [[Reticuloendothelial system|reticulo-endothelial system]] (extramedullary hemolysis).

==Diagnosis==
The gold standard for the diagnosis of Vitamin B{{ssub|12}} deficiency is a low blood level of Vitamin B{{ssub|12}}. A low level of blood Vitamin B{{ssub|12}} is a finding that normally can and should be treated by injections, supplementation, or dietary or lifestyle advice, but it is not a diagnosis.  Hypovitaminosis B{{ssub|12}} can result from a number of mechanisms, including those listed above. For determination of cause, further patient history, testing, and empirical therapy may be clinically indicated.

A measurement of [[methylmalonic acid]] (methylmalonate) can provide an indirect method for partially differentiating Vitamin B{{ssub|12}} and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency. Direct measurement of blood [[cobalamin]] remains the gold standard because the test for elevated methylmalonic acid is not specific enough. Vitamin B{{ssub|12}} is one necessary prosthetic group to the enzyme [[methylmalonyl-coenzyme A mutase]]. Vitamin B{{ssub|12}} deficiency is but one among the conditions that can lead to dysfunction of this enzyme and a buildup of its substrate, methylmalonic acid, the elevated level of which can be detected in the urine and blood.

Due to the lack of available radioactive Vitamin B{{ssub|12}}, the [[Schilling test]] is now largely a historical artifact.{{Citation needed|date=December 2009}}  The [[Schilling test]] was performed in the past to help determine the nature of the vitamin B{{ssub|12}} deficiency.  An advantage of the [[Schilling test]] was that it often included Vitamin B{{ssub|12}} with intrinsic factor.

===Blood findings===
The [[blood film]] can point towards vitamin deficiency:
* Decreased [[red blood cell]] (RBC) count and [[hemoglobin]] levels<ref>{{cite web |title=Megaloblastic Anemia |url=https://www.nlm.nih.gov/medlineplus/ency/article/000567.htm |date=2012 |archive-url=https://web.archive.org/web/20121130153546/https://www.nlm.nih.gov/medlineplus/ency/article/000567.htm |archive-date=30 November 2012  |website=MedlinePlus |access-date=21 June 2015  |quote=Megaloblastic anemia is a blood disorder in which there is anemia with larger-than-normal red blood cells. Anemia is a condition in which the body does not have enough healthy red blood cells. Red blood cells provide oxygen to body tissues.}}</ref>
* Increased [[mean corpuscular volume]] (MCV, >100 [[Femtolitre|fL]]) and [[mean corpuscular hemoglobin]] (MCH)
* Normal [[mean corpuscular hemoglobin concentration]] (MCHC, 32–36 g/dL)
* Decreased [[reticulocyte]] count due to destruction of fragile and abnormal megaloblastic erythroid precursor.
* The [[platelet]] count may be reduced.<ref>{{cite web |url= https://www.lecturio.com/concepts/megaloblastic-anemia/| title= Megaloblastic Anemia
|website=The Lecturio Medical Concept Library |access-date= 10 August 2021}}</ref>
* [[Neutrophil granulocyte]]s may show [[multisegmented neutrophil|multisegmented]] nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils, which increase numbers of nuclear segments with age. {{Citation needed|reason=compensatory mechanism|date=July 2008}}
* [[Anisocytosis]] (increased variation in RBC size) and [[poikilocytosis]] (abnormally shaped RBCs).
* [[Macrocyte]]s (larger than normal RBCs) are present.
* [[Ovalocyte]]s (oval-shaped RBCs) are present.
* [[Howell-Jolly body|Howell-Jolly bodies]] (chromosomal remnant) also present.

[[Blood chemistry|Blood chemistries]] will also show:
* An increased [[lactic acid dehydrogenase]] (LDH) level. The isozyme is LDH-2 which is typical of the serum and hematopoietic cells.
* Increased [[homocysteine]] and [[methylmalonic acid]] in Vitamin B{{ssub|12}} deficiency
* Increased homocysteine in folate deficiency
Normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty.<ref>{{cite journal |vauthors=Savage DG, Lindenbaum J, Stabler SP, Allen RH |title=Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies |journal=Am. J. Med. |volume=96 |issue=3 |pages=239–46 |year=1994 |pmid=8154512 |doi= 10.1016/0002-9343(94)90149-X|doi-access= }}</ref> Elevated homocysteine and normal methylmalonic acid indicate folate deficiency, while elevated homocysteine and elevated methylmalonic acid indicate vitamin B{{ssub|12}} deficiency.

[[Bone marrow]] (not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic [[hyperplasia]].<ref>{{cite book |last=Hoffbrand |first=A. Victor |editor1-last=Longo |editor1-first=D. L. |editor2-last=Fauci |editor2-first=A. S. |editor2-link=Anthony S. Fauci |editor3-last=Kasper |editor3-first=D. L. |editor4-last=Hauser SL |editor4-first=S. L. |display-editors=etal |chapter=Chapter 105. Megaloblastic Anemias |chapter-url=http://accessmedicine.mhmedical.com/content.aspx?bookid=331&Sectionid=40726843 |chapter-url-access=subscription |title=Harrison's Principles of Internal Medicine |edition=18th |date=2012 |location=New York |publisher=McGraw-Hill |access-date=October 23, 2015}}</ref>

==See also==
* [[List of circulatory system conditions]]
* [[List of hematologic conditions]]

==References==
{{Reflist}}

== External links ==
{{Medical resources
|   DiseasesDB     = 29507
|   ICD10          = {{ICD10|D|51|1|d|50}}, {{ICD10|D|52|0|d|50}}, {{ICD10|D|53|1|d|50}}
|   ICD9           = {{ICD9|281}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    = 000567
|   eMedicineSubj  = med
|   eMedicineTopic = 1420
|   eMedicine_mult = {{eMedicine2|ped|2575}}
|   MeshID         = D000749
}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=trma GeneReview/NCBI/NIH/UW entry on Thiamine-Responsive Megaloblastic Anemia Syndrome]
* [http://www.rareanemias.webs.com Rare Anemias Foundation]

{{Diseases of RBCs}}

{{DEFAULTSORT:Megaloblastic Anemia}}
[[Category:Nutritional anemias]]
[[Category:Hematopathology]]

[[de:Anämie#Hyperchrome makrozytäre Anämie]]