Summary
Definition
Megaloblastic anemia without neuropathy is the classic manifestation of folate deficiency.[1]
Folate, also known as vitamin B9, is present in green vegetables, legumes, and some fruits.
Deficiency arises due to malabsorption, drugs and toxins, increased demand, or dietary deficiency.[Figure caption and citation for the preceding image starts]: Megaloblastic macrocytic anemia: A. Peripheral blood smear of a patient with megaloblastic anemia. B. Peripheral blood smear of healthy individualPhotomicrograph from Mark J. Koury, MD; used with permission [Citation ends].
History and exam
Other diagnostic factors
- prolonged diarrhea
- loss of appetite and weight loss
- fatigue
- shortness of breath
- dizziness
- pallor
- headache
- tachycardia
- tachypnea
- heart murmur
- signs of heart failure
- signs of chronic alcohol misuse
- signs of hemolytic anemia
- signs of exfoliative dermatitis
- painful swallowing
- petechiae
- glossitis
- angular stomatitis
- neurologic deficits in children
Risk factors
- low dietary folate intake
- age >65 years
- alcohol-use disorder
- pregnant or lactating
- prematurity
- intestinal malabsorptive disorders
- use of trimethoprim, methotrexate, sulfasalazine, pyrimethamine, or anticonvulsants (e.g., phenytoin, phenobarbital)
- infantile intake of goats' milk
- congenital defects in folate absorption and metabolism
- states of increased cell turnover
- intake of special diet
- chronic peritoneal dialysis
Diagnostic tests
1st tests to order
- peripheral blood smear
- CBC
- reticulocyte count
Tests to avoid
- red blood cell folate
Tests to consider
- serum folate
- serum vitamin B12
- serum LDH
- serum unconjugated bilirubin
- serum iron panel
- plasma or serum methylmalonic acid
- plasma homocysteine
- bone marrow aspirate/biopsy
Treatment algorithm
at risk of folate deficiency due to pregnancy or lactation
at risk of folate deficiency due to malabsorptive disorders, chronic hemolytic disorder, or chronic peritoneal dialysis
at risk of folate deficiency due to medication
acquired: macrocytosis without anemia
acquired: macrocytic anemia and pancytopenia
congenital folate metabolism defects
congenital folate malabsorption
congenital cerebral folate transport deficiency
Contributors
Authors
Mark Koury, MD
Professor of Medicine, Emeritus (Hematology/Oncology)
Vanderbilt University Medical Center
Nashville
TN
Disclosures
MK declares that he has no competing interests.
Allison P. Wheeler, MD
Assistant Professor of Pathology, Microbiology, and Immunology
Assistant Professor of Pediatrics (Pediatric Hematology-Oncology)
Vanderbilt University Medical Center
Nashville
TN
Disclosures
APW declares that she has no competing interests.
Mohammed Sika, PhD
Research Professor of Medicine (Nephrology)
Vanderbilt University Medical Center
Nashville
TN
Disclosures
MS declares that he has no competing interests.
Acknowledgements
Dr Mark Koury, Dr Allison Wheeler, and Dr Mohammed Sika would like to gratefully acknowledge Dr Lakshmi V. Srivaths and Donald Mahoney Jr., previous contributors to this topic.
Disclosures
LVS and DM declare that they have no competing interests.
Peer reviewers
Ralph Green, MD, PhD, FRCPath
Professor and Chair
Department of Pathology and Laboratory Medicine
University of California Davis School of Medicine
Sacramento
CA
Disclosures
RG is the author of reference(s) cited in this topic.
Jack Metz, MB, BCh, MD, DSc(Med), FRCPath, FCAP, FRCPA, FRS(SA), DSc Med(Hon Caus)
Emeritus Professor and Consultant Haematologist
Dorevitch Pathology
Heidelberg
Victoria
Australia
Disclosures
JM declares that he has no competing interests.
References
Key articles
Pfeiffer CM, Sternberg MR, Zhang M, et al. Folate status in the US population 20 y after the introduction of folic acid fortification. Am J Clin Nutr. 2019 Nov 1;110(5):1088-97.Full text Abstract
Wickramasinghe SN. Diagnosis of megaloblastic anaemias. Blood Rev. 2006 Nov;20(6):299-318. Abstract
Allen LH. Causes of vitamin B12 and folate deficiency. Food Nutr Bull. 2008 Jun;29(2 suppl):S20-34. Abstract
Whitehead VM. Acquired and inherited disorders of cobalamin and folate in children. Br J Haematol. 2006 Jul;134(2):125-36.Full text Abstract
MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991 Jul 20;338(8760):131-7. Abstract
Institute of Medicine. Dietary reference intakes for thiamine, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998.
Reference articles
A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.
Differentials
- Vitamin B12 (cobalamin) deficiency
- Thiamine-responsive megaloblastic anemia
- Hereditary orotic aciduria
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