You've probably heard of anaemia, but what is folate deficiency anaemia?
Lots of people jump to iron deficiency when they think of anaemia, but nutrient deficiencies causing red blood cell dysfunction (anaemia) can be caused in other ways too.
Folate deficiency anaemia is dysfunctional red blood cells due to a deficiency in (you guessed it) folate.
Classification of anaemia is determined by haemoglobin levels. Whilst folate deficiency level estimates to classify anaemia exist (3 µg/L), to definitively categorise the issue as ‘folate deficiency anaemia’, haemoglobin levels have to be as low as between 100 g/L and 130 g/L (depending on the individual’s sex, age, and pregnancy status) and be attributed to lack of folate.1
Folate is also known as vitamin B9 and, alongside vitamin B12 and amongst other responsibilities, has a key role to play in the formation of healthy red blood cells (the cells that transport oxygen around your body).2
The association with vitamin B12 is unavoidable as both vitamins have very similar roles. Due to the improved availability of folate sources compared to vitamin B12, folate deficiency is the rarer of the two issues but is similarly detrimental when lacking for its cellular developmental (and eventually in bigger and more noticeable human structures) role and its importance associated with red blood cells.
As red blood cells are vital for transporting oxygen around your body, folate deficiency anaemia can be very problematic and produce clear symptoms.
Fortunately, this article is here to inform you of the causes and dangers, and to help you prevent experiencing the negative effects of folate deficiency anaemia.
Causes of folate deficiency anaemia
Causes of folate deficiency anaemia can be narrowed down to three categories:
- Dietary lack of folate
- Digestional dysfunction
- Drugs and medication interference
- Genetic issues3
Folate can be obtained naturally in the diet via foods such as leafy greens, beef liver, or black-eyed peas (the food not the other incarnation), but many countries also legally mandate their manufacturers to add folate derivatives to more commonly consumed foods such as grain, rice and cereal.4,5,6 As such, a balanced diet should provide the recommended daily intake of 400 µg of folate, provided your diet is not overly restrictive. In addition to this, folate supplements are also readily available.
Although its easy availability means that there are good statistics on folate levels, with only 5% of the UK population deemed to be risking folate deficiency anaemia with their folate levels, around 33% of adults were deemed to be at risk of possible folate deficiency.7
As folate and derivatives (such as folic acid) are readily available in your diet, issues with overcooking (destroying micronutrient content), digestion, or nutrient absorption may be the factors to look out for that may put you at risk of developing folate deficiency anaemia.
Though you may be getting your recommended dietary allowance of folate in your diet, digestion and absorption of this may limit the amount your body actually uses, leading to a deficiency even with the correct daily intake of folate. The disruptive effects of digestive diseases such as coeliac disease can harm the digestion of folate and lead to folate deficiency anaemia.8 Folate is typically digested in the upper digestional tract, and this is also a place that is commonly damaged during the development of coeliac disease. Additionally, liver disease (commonly contributed to by chronic alcoholism) has shown links to the disruption of folate digestion due to the decreased function of the small intestine caused by liver disease.9 Finally, vitamin B12 is essential for ‘unlocking’ digested folate and allowing it to be absorbed and utilised by cells, so folate deficiency has been strongly linked to vitamin B12 deficiency.3
Alcohol is not the only drug to mess with folate absorption, with links to the rheumatoid arthritis drug methotrexate, the urinary tract infection drug nitrofurantoin, and some anti-epileptic drugs.10,11,12 All these drugs are classed as folate antagonists and have been shown to reduce folate levels by increasing the amount of folate lost to bodily waste. Though the diseases these drugs are intended to treat may well be very serious, the consideration for reduced folate levels and potential folate deficiency syndrome should be kept in mind.
Finally, there will always be unavoidable genetic predispositions to diseases. In the case of folate deficiency anaemia, this is a rare disease known as hereditary folate malabsorption. This disease is due to a defect in the genes and DNA of very few patients that can lead to an array of faults in absorbing any dietary folate, leading to an increased risk of a severe deficiency that may lead to folate deficiency anaemia.
Signs and symptoms of folate deficiency anaemia
The symptoms of this disease are quite broad due to the vital role healthy red blood cells have to play in transporting oxygen in the body. Earlier symptoms that may be more obviously due to this issue include, but are not limited to:
- Constant fatigue and tiredness
- ‘Sickly’ pale skin tone
- Loss of appetite
- Shortness of breath and/or rapid breathing
These symptoms may be milder and can be signs of early-stage anaemia. If left undiagnosed or untreated, the deficiency can become more extreme and the symptoms can become more problematic.
Coronary artery disease, a blood vessel disorder and precursor to heart failure, has been shown to have links to folate deficiency anaemia, whilst folate supplementation has been shown to significantly reduce the risk of cardiovascular disease (heart disease).13,14
Ultimately, a deficiency that creates issues with oxygen transport can create a whole host of issues and early detection is vital.
Experiencing symptoms is a reason to approach your healthcare professional about this issue. After investigating, they will likely request a series of blood tests where they will assess the amount of folate (and B12) in your blood, the size of red blood cells, and haemoglobin levels (amount of oxygen-transporting molecule within red blood cells).
As the symptoms of this form of anaemia are very similar to other forms (iron deficiency anaemia, B12 deficiency anaemia), a diagnosis should not be made before performing blood tests for each micronutrient/mineral.
After diagnosis of the condition is made, further investigations are likely to take place to determine the cause of folate deficiency anaemia.
Management and treatment for folate deficiency anaemia
Treatment for this issue varies slightly depending on the cause of folate deficiency anaemia but is fairly simple:
Supplementation of folate and/or increased folate-rich dietary choices.
Everything revolves around this solution but additional management of anti-folate factors may also be considered, depending on the cause.
B12 supplementation, alcohol intake reduction, or treatment for underlying conditions may be recommended.
This issue should be treated on a case-by-case basis but the likely solution to a folate deficiency is increasing folate intake, with between 5 mg and 15 mg daily supplementation recommended depending on the situation of the patient.15
Pregnant people are thought to require more folate due to the vital role oxygenated blood, and folate as a whole, plays in all forms of human physical development. Those who are folate deficient whilst pregnant risk serious negative side effects for their child, with research suggesting that impaired neurological development and birth defects are at an increased risk with a lack of folate in the pregnant mother.3,16
Whilst poor digestive health appears to cause folate deficiency anaemia, it may also be a symptom of this disease.17 For this reason, any consistent digestive issues should be investigated as a symptom and a cause.
Finally, excess folate can also be an issue. Though the research is not yet undeniable, links have been suggested between excess folate and increased colorectal cancer, impaired immune system, and other negative side effects. For this reason, the daily recommended upper limit for folate supplementation (no set limit for food-based intake) is 1000 mg/day.18
Whilst healthcare professionals will likely have thought about this, it is important to think about the risks of stopping any medications which also contribute to folate deficiency anaemia. Though this issue can become serious, it may not be advisable to limit medications (e.g. epileptic or arthritic treatments) if possible, due to the additional risk of these conditions on your quality/quantity of life.
How can I prevent folate deficiency anaemia?
Consume a balanced diet rich in fortified grains/cereals and leafy greens.
How common is folate deficiency anaemia?
No more than 5% of the worldwide population have a folate deficiency whilst statistics are lacking for the anaemic form of this issue.1
When should I see a doctor?
Upon the onset of persistent early symptoms such as:
- ‘Sickly’ skin tone
- Loss of appetite
Folate deficiency anaemia is a rare form of micronutrient deficiency that can result in issues both minor and majorly detrimental, due to the key role this vitamin plays in oxygen transport and development. Pregnant people in particular, may have more significant risks. The cause of folate deficiency anaemia is complex but treatment is simple so early diagnosis is key. The issue can be dealt with effectively by early diagnosis, increased folate intake via diet and supplementation, and addressing any underlying conditions to prevent any serious damage from folate deficiency anaemia.
- CKS is only available in the UK [Internet]. NICE. [cited 2023 Jun 18]. Available from: https://www.nice.org.uk/cks-uk-only
- Merrell BJ, McMurry JP. Folic acid. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Jun 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK554487/
- Khan KM, Jialal I. Folic acid deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Jun 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK535377/
- Office of dietary supplements - folate [Internet]. [cited 2023 Jun 17]. Available from: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
- Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients. 2011 Mar;3(3):370–84. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257747/
- U.S. Food and Drug Administration. Food Standards: Amendment of Standards of Identity For Enriched Grain Products to Require Addition of Folic Acid. Federal Register 1996;61:8781-97. Available from: https://www.govinfo.gov/content/pkg/FR-1996-03-05/pdf/96-5014.pdf
- Datta Mitra A, Gupta A, Jialal I. Folate insufficiency due to celiac disease in a 49-year-old woman of southeast asian-indian ethnicity. Lab Med [Internet]. 2016 Aug [cited 2023 Jun 17];47(3):259–62. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985778/
- Medici V, Halsted CH. Folate, alcohol, and liver disease. Mol Nutr Food Res [Internet]. 2013 Apr [cited 2023 Jun 17];57(4):596–606. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736728/
- Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheumatol. 2001;30(3):129–34. Available from: https://pubmed.ncbi.nlm.nih.gov/11469521/
- van de Mheen L, Smits SM, Terpstra WE, Leyte A, Bekedam DJ, van den Akker ESA. Haemolytic anaemia after nitrofurantoin treatment in a pregnant woman with G6PD deficiency. BMJ Case Rep [Internet]. 2014 May 1 [cited 2023 Jun 17];2014:bcr2013010087. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025214/
- Ray K. Antiepileptic drugs reduce vitamin B12 and folate levels. Nat Rev Neurol [Internet]. 2011 Mar [cited 2023 Jun 17];7(3):125–125. Available from: https://www.nature.com/articles/nrneurol.2011.9
- Ma Y, Peng D, Liu C, Huang C, Luo J. Serum high concentrations of homocysteine and low levels of folic acid and vitamin B12 are significantly correlated with the categories of coronary artery diseases. BMC Cardiovascular Disorders [Internet]. 2017 Jan 21 [cited 2023 Jun 18];17(1):37. Available from: https://doi.org/10.1186/s12872-017-0475-8
- Wang Y, Jin Y, Wang Y, Li L, Liao Y, Zhang Y, et al. The effect of folic acid in patients with cardiovascular disease. Medicine (Baltimore) [Internet]. 2019 Sep 13 [cited 2023 Jun 18];98(37):e17095. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750242/
- Devalia V, Hamilton MS, Molloy AM, the British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol [Internet]. 2014 Aug [cited 2023 Jun 18];166(4):496–513. Available from: https://onlinelibrary.wiley.com/doi/10.1111/bjh.12959
- De Wals P, Tairou F, Van Allen MI, Uh SH, Lowry RB, Sibbald B, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med. 2007 Jul 12;357(2):135–42. Available from: https://pubmed.ncbi.nlm.nih.gov/17625125/
- Ponziani FR, Cazzato IA, Danese S, Fagiuoli S, Gionchetti P, Annicchiarico BE, et al. Folate in gastrointestinal health and disease. Eur Rev Med Pharmacol Sci. 2012 Mar;16(3):376–85. Available from: https://pubmed.ncbi.nlm.nih.gov/22530356/
- Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin b6, folate, vitamin b12, pantothenic acid, biotin, and choline [Internet]. Washington (DC): National Academies Press (US); 1998 [cited 2023 Jun 19]. (The National Academies Collection: Reports funded by National Institutes of Health). Available from: http://www.ncbi.nlm.nih.gov/books/NBK114310/