Megaloblastic anemia is a subcategory of macrocytic anemia, referring to macrocytosis (abnormally large red blood cells) in the presence of anemia. Vitamin B12 and folate deficiencies most commonly cause megaloblastic anemia by impairing DNA synthesis and red blood cell (RBC) formation. Consequently, abnormally large RBCs called megaloblasts develop in the bone marrow. Macrocytosis affects 2-4% of the general population, and 60% of people with macrocytosis have anemia. Due to wide variation in contributing factors across populations, data regarding the prevalence of megaloblastic anemia is mixed. It is, however, generally accepted that folate deficiency is the second most common cause of megaloblastic anemia after vitamin B12 deficiency. (5, 6)
This article will focus on folate deficiency anemia: what causes it, how to recognize it through physical exam and laboratory findings, and how to implement a holistic treatment plan for successful treatment.
What is Folate Deficiency Anemia?
Vitamin B9 is a water-soluble vitamin found naturally in foods as folate and in supplements as its synthetic form called folic acid. The body utilizes folate for the synthesis of DNA, the development of the nervous system, and the maturation of red blood cells. When deficient, these folate-dependent pathways are compromised, and one of the consequences is folate deficiency anemia. (2)
Folate deficiency anemia is a megaloblastic anemia resulting from impaired DNA synthesis and RBC maturation. Large RBCs, called megaloblasts, are formed in the bone marrow and circulate through the body in smaller concentrations than usual. Not only does the rate of RBC synthesis decrease in folate deficiency, but megaloblasts also have shorter lifespans compared to healthy RBCs. Both of these factors contribute to the development of anemia. (3)
The most common reasons for folate deficiency are (9):
- Inadequate intake in those with restricted diets, disordered eating habits, and alcohol use disorder
- Increased demand due to pregnancy and lactation
- Impaired absorption due to gastrointestinal conditions like Celiac disease, inflammatory bowel disease (IBD), atrophic gastritis, hypochlorhydria, and bowel resection
Some medications are also known to deplete folate levels. These include acid reducers (i.e., proton pump inhibitors, histamine H2 antagonists, and antacids), antipsychotics, anticonvulsants, oral contraceptives, metformin, and methotrexate. (9)
Folate Deficiency Anemia Symptoms
Anemia associated with folate deficiency presents with general and vague symptoms. Symptoms may appear insidiously and generally tend to become more severe as the degree of anemia and deficiency increases. Common anemia symptoms include (3):
- Cold extremities
- Irregular heart rate
- Pale skin
- Shortness of breath
Additionally, you may also experience symptoms directly related to folate deficiency (1):
- Angular Cheilitis: inflammation and cracking of the corners of the mouth
- Changes in skin, hair, and fingernails
- Cognitive impairment: difficult concentration, memory loss, confusion
- Glossitis: inflamed tongue with ulcerations
Complications Of Folate Deficiency Anemia
Unresolved anemia is associated with chronic fatigue and heart problems, as the heart must compensate for the lack of oxygen in the blood; this can lead to irregular heartbeat, enlargement of the heart, and in some cases, heart failure (3).
There are associated health risks with folate deficiency, too. Insufficient maternal folate status during pregnancy is associated with an increased risk of neural tube disorders, low infant birth weight, preterm delivery, and fetal growth restriction (2). Neuropsychiatric complications, including depression, insomnia, cognitive decline, and psychosis, are linked to folate deficiency (1).
Functional Medicine Labs to Diagnose Folate Deficiency Anemia
A complete blood count (CBC) is a panel of many biomarkers related to the various types of blood cells. The table below details CBC findings correlated with macrocytic anemia:
A blood smear, which evaluates blood cells under a microscope, is often ordered in conjunction with a CBC. Oval-shaped, enlarged RBCs and hypersegmented neutrophils are key findings of megaloblastic anemia. (6)
A reticulocyte count may also help to differentiate between causes of anemia. Reticulocytes are immature RBCs and may be measured in abnormal quantities in certain types of anemias. Reticulocytes are usually normal or low in folate deficiency anemia.
Findings of macrocytic anemia should prompt additional testing to differentiate between folate and B12 deficiency. Serum folate and vitamin B12 levels should be measured to differentiate between the anemia's cause. A serum folate level of less than 3 mcg/L indicates folate deficiency. (7)
RBC folate is a more accurate representation of folate stores. Consider ordering RBC folate for patients who have recently changed their folate intake or for those in whom you have a strong clinical suspicion of folate deficiency despite normal serum folate levels. RBC folate less than 150 mcg/L is consistent with folate deficiency. (7, 8)
Elevated homocysteine is suggestive of folate deficiency but is also elevated in vitamin B12 deficiency and kidney disease. (7)
Methylmalonic acid (MMA) can differentiate between folate and vitamin B12 deficiency because MMA levels rise in the presence of vitamin B12 deficiency but not in folate deficiency.
Tests to Rule Out Causes of Folate Deficiency
Once folate deficiency anemia is diagnosed, the underlying cause of folate deficiency must be determined. Tests to help in this process include:
- Quantitative serum hCG to rule out pregnancy
- Celiac panel
- Elevated fecal calprotectin and lactoferrin and serum C-reactive protein (CRP) help support a diagnosis of IBD
- The AUDIT and CAGE questionnaires can help to screen for alcohol abuse. A liver panel can also help identify liver function patterns strongly suggestive of chronic alcohol consumption.
Endoscopy and colonoscopy are the preferred diagnostic imaging methods to diagnose suspected Celiac disease and IBD causing folate malabsorption.
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme responsible for methylating and activating folate in the body. Genetic variations in the MTHFR gene coding for this enzyme can decrease enzyme activity. Knowing your MTHFR genotype can be clinically valuable when treating folate deficiency.
Functional Medicine Treatment for Folate Deficiency Anemia
Folate deficiency anemia is treated by correcting folate deficiency. While this is accomplished in the short-term by utilizing folate-rich foods and folic acid supplements, the long-term maintenance of folate status and prevention of deficiency recurrence relies on addressing the factors predisposing to deficiency.
Folate is the naturally occurring form of vitamin B9 found in various foods, including green vegetables, legumes, and liver. In 1998, the FDA began requiring that cereals and grains be fortified with folic acid to prevent folic acid deficiency-related complications; since then, these foods have been large contributors of folic acid in the standard American diet. (2)
The daily value (DV) of folate is dependent on age. The DV for adult men and women is 400 mcg of dietary folate equivalents (DFE) daily. The DV increases to 600 and 500 mcg DFE daily during pregnancy and lactation. If you are not meeting recommended dietary intakes through diet alone, folic acid supplementation is recommended.
Abstaining from alcohol significantly improves folate status by improving the body's absorption, storage, and excretion of the vitamin.
Herbs & Supplements
Folic acid is the bioavailable synthetic derivative of vitamin B9 found in fortified foods and multivitamin, prenatal, and B complex supplements. Adult supplemental doses generally range from 680-1,360 mcg DFE. Supplemental doses of folic acid for an average of four months before reassessment are recommended in treating folate-deficient anemia. (2, 4, 8)
Dietary supplements containing the methylated form of folic acid, 5-MTHF, are also available. 5-MTHF may be more beneficial for those with MTHFR polymorphism(s), as it reduces the burden on the MTHFR enzyme to convert folate to its active form. (2)
Because human cells cannot synthesize folate, we depend on getting it through food or supplements. However, we know that the colonic microbiome contributes to human health in part through its ability to synthesize vitamins. Although the extent to which colonic folate synthesis influences human folate status is unclear, the microbiome does synthesize folate that enters systemic circulation (2). Therefore, implementing gut-healing protocols that optimize digestion and a balanced microbiome will favor ideal folate levels. Supplements that may be utilized in this context include:
- Digestive enzymes
- Demulcent and anti-inflammatory herbs: aloe vera, DGL, marshmallow
- Gut-healing supplements: butyrate, glutamine, and zinc carnosine
For those taking a medication that may be negatively impacting folate status, consider discussing alternative treatment plans with a functional medicine practitioner aiming to taper medication doses. This may not be possible in all cases. You should never reduce or discontinue medication on your own without first consulting a doctor.
Folate deficiency is the second most common cause of megaloblastic anemia, characterized by decreased red blood cells with an abnormally large shape. Folate deficiency causes undesirable anemia symptoms and carries the risk of other detrimental health complications. The good news is that folate deficiency and folate deficiency anemia have good prognoses when identified and addressed early through a healthy diet and supplementation. A functional medicine perspective provides a comprehensive medical approach that prevents folate deficiency recurrence and delivers better health outcomes.
Lab Tests in This Article
1. Khan, K.M., Jialal, I. (2021). Folic Acid Deficiency. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK535377/
2. National Institutes of Health. (2018, March 2). Folate Fact Sheet for Health Professionals. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
3. Nagao, T., & Hirokawa, M. (2017). Diagnosis and treatment of macrocytic anemias in adults. Journal of General and Family Medicine, 18(5), 200–204. https://doi.org/10.1002/jgf2.31
4. General Information About NTDs, Folic Acid, and Folate. (2021, July 8). Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-general-info.html
5. Hariz, A., & Bhattacharya, P. T. (2022, September 26). Megaloblastic Anemia. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537254
6. Moore, C.A., & Adil, A. (2022, July 11). Megaloblastic Anemia. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459295/
7. Johnson, L. E. (2023, January 24). Folate Deficiency. Merck Manuals Professional Edition. https://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency,-dependency,-and-toxicity/folate-deficiency
8. Devalia, V., Hamilton, M. S., & Molloy, A. M. (2014b). Guidelines for the diagnosis and treatment of cobalamin and folate disorders. British Journal of Haematology, 166(4), 496–513. https://doi.org/10.1111/bjh.12959
9. Cloyd, J. (2023, February 1). 6 Anemia Types You Need to Know About. Rupa Health. https://www.rupahealth.com/post/6-different-types-of-anemia-you-may-not-be-aware-of