Folate Deficiency (Folic Acid)

What Is Folate?

Folate, also called folic acid or vitamin B9, is a family group of essential water-soluble B vitamins needed to produce healthy blood cells and other tissue cells.

Folate is required for healthy blood cells, the metabolism of at least 5 amino acids, the production of DNA, RNA and tRNA (genetic material), the normal development of a baby in the womb, male and female fertility, and regulation of homocysteine (amino acid) by reduction of harmful blood levels in conjunction with vitamin B6 and vitamin B12.

Urinary excretion of folate cannot be detected when vitamin intake is below the required levels. On the other hand, when intake exceeds saturation in the body, the vitamins and/or their metabolites are actively excreted into urine to prevent excessive toxicity of the vitamins.1

What Is Folate Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Relationship between folate deficiency and celiac disease. Folate deficiency is a classic symptom of celiac disease that deficiency is a symptom of celiac disease that results when the level within cells is too low to meet needs of the body for this vitamin.
• Relationship between folate deficiency and signs. Folic acid deficiency is characterized by impaired metabolic reactions involving amino acids, production of DNA and RNA which reduce the division of red and white blood cells (resulting in low blood counts) and the cells lining the stomach, intestine, vagina, and uterus (resulting in inflammation and disorders of these organs).2
• Relationship between folate deficiency and developing baby. Celiac disease induces malabsorption and deficiency of folic acid essential for the proper formation and development of organs in a fetus.3
• Relationship between folate deficiency and fertility. Folate deficiency has been implicated in elevated prolactin hormone characterized by altered estrogen production in women and androgen production in men.4
• Relationship between folate deficiency and epilepsy. There is a subgroup of patients with epilepsy who developed the syndrome of celiac disease, epilepsy, and cerebral calcifications which may be related to folate deficiency.5
• Relationship between folate deficiency and increased blood pressure due to elevated blood homocysteine level. In metabolism, homocysteine is briefly formed in the breakdown of the amino acid methionine. It is normally converted to cystathione and then to the amino acid cysteine by means of a vitamin B6 dependent enzyme.

  In the reverse, conversion of homocysteine to methionine requires an enzyme dependent on adequate folic acid and vitamin B12 levels. Insufficient methionine levels and/or inefficiency in this process results in elevated homocysteine plasma levels that are toxic to blood vessels. Folic acid, vitamin B12 and vitamin B6 are involved in the metabolic removal of homocysteine, but folic acid deficit occurs the most often.6

• Relationship between folate deficiency and diet. A study investigating life-long gluten-free diet in celiac disease patients shows that inadequate intake of folate is common (more than 10% of patients) and may relate to habitual poor food choices in addition to inherent deficiencies in the gluten free diet. “Dietary education should also address the achievement of adequate micronutrient intake.”7

How Prevalent Is Folate Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Folic acid deficiency is common in patients with untreated celiac disease.8
• Folate deficiency was seen in approximately 12% of the total sample of 405 patients at diagnosis of celiac disease at a hospital setting.9
• The prevalence for folic acid deficiency was 20% in a A Dutch study in 80 newly diagnosed adult patients with celiac disease.10

What Are The Symptoms Of Folate Deficiency?

Folic acid deficiency is marked by these symptoms:

• Fatigue.
• Apathy (lack of interest).
• Loss of appetite.
• Constipation.
• Sore, tender tongue (glossitis).
• Sore mouth.
• Diarrhea.
• Worsens malabsorption.
• Weakness.
• Depression.
• Headaches.
• Insomnia.
• Restless leg syndrome.
• Memory impairment.
• Hypertension (elevated blood pressure).
• Greying hair.
• Peptic ulcer.
• Polyneuropathy.
• Psychiatric disorders,especially paranoia.
• In men, impotence, hypogonadism, and reduced semen quality may develop.
• In women, infertility, toxemia of pregnancy, miscarriage, abruptio placenta, and restless leg syndrome can develop.
• In the developing fetus, increased risk of low birth weight, birth defects (neural tube defects, spina bifida), congenital malformations and premature birth.
• In young children, increased risk of severe language delay in whose mothers had insufficient folic acid during pregnancy.11
• In children, poor growth.
• Chronic deficiency leads to megaloblastic anemia (large cell anemia identical in appearance to vitamin B12 deficiency anemia with paleness, increased fatigue, breathlessness); hypersegmentation of neutrophils (white blood cells) caused by failure of bone marrow blood-forming cells to make DNA; elevated homocysteine blood levels which elevates blood pressure and leads to hardening of the arteries; thrombocytopenia which causes bleeding problems; cardiovascular disease; and
• With severe deficiency, intestinal sores develop.

How Does The Body Get Folate?

• Dietary folates are absorbed by active transport mainly in the jejunum (mid-section of the small intestine), but they can also be absorbed by passive diffusion.2
• Folate is poorly absorbed by patients with celiac disease and the availability for biological utilization of the major dietary folate compounds will depend on the amount of gastric acidity and of the ascorbate in the intestinal chyme (juice). Many folate compounds may be unavailable for metabolic utilization in the body.12
• The liver is the most important depot for folate, containing about half of the total body store.2

What Do Folates Do In The Body?

• Regulates red blood cell production.
• Regulates iron function.
• Required for metabolism of the amino acids methionine, histidine, tryptophan, glycine, and serine, and formate (a salt).
• Required for production of the genetic materials DNA, RNA and tRNA necessary for protein formation and cell growth.
• Required for normal organ development in fetus.
• Regulates prolactin hormone for normal production of androgen for male fertility and estrogen for female fertility.
• Regulates homocysteine (transient amino acid) in the bloodstream by reduction of harmful blood levels that stiffen blood vessel, thereby elevating blood pressure.

How Does Folate Deficiency Develop In Celiac Disease and/or Gluten Sensitivity?

Folic acid deficiency in celiac disease results from malabsorption due to these mechanisms:

• Lack of adequate acid in the stomach (low stomach acid).
• Inefficient conversion of folates to absorbable forms in the brush border (microvilli) due to inflammatory damage.
• Inefficient transport by protein carriers across absorbing cells due to protein deficiency.
• Inadequate absorptive surface area due to damage of the lining.

Does Folate Deficiency Respond To Gluten-Free Diet?

Yes. Celiac disease related folic acid deficiency responds to gluten free diet containing adequate folic acid and necessary stomach acid. Supplementation may be needed at least initially.

Adults with longstanding celiac disease taking extra B vitamins for 6 months showed normalized tHcy (plasma total homocysteine) and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.13

6 Steps To Correct Folate Deficiency In Celiac Disease and/or Gluten Sensitivity:

• 1Meet, or Exceed the RDA (Recommended Dietary Allowances) for Folic Acid in microgram ( μg) per day:

• 2Diet – Include Food Sources Richest in Folic Acid: 

 

• 3 Diet – Avoid  or Limit These Foods That Deplete or Interfere With Absorption:

• 4Monitor Medications That Deplete or Interfere With Absorption:

• 5Manage Nutritional Supplements to Obtain Folic Acid:

• 6Other Supplements That Deplete or Interfere With Absorption:

Medical Research Findings On Folate Deficiency In Celiac Disease and/or Gluten Sensitivity:

RESEARCH STUDY SUMMARIES

“Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients.” This study aiming to assess the nutritional and vitamin/mineral status of current “early diagnosed” untreated adult celiac disease (CD)-patients in the Netherlands found that vitamin/mineral deficiencies are still common in newly “early diagnosed” CD-patients.  Specifically, for folic acid  the prevalence was 20%.

Eighty newly diagnosed adult CD-patients were included and a comparable sample of 24 healthy Dutch subjects was added to compare vitamin concentrations. Nutritional status and serum concentrations of folic acid, vitamin A, B6, B12, and (25-hydroxy) D, zinc, haemoglobin (Hb) and ferritin were determined (before prescribing gluten free diet). Almost all CD-patients (87%) had at least one value below the lower limit of reference.

Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher) grade of histological intestinal damage or (impaired) nutritional status. Extensive nutritional assessments seem warranted to guide nutritional advices and follow-up in CD treatment.10

“Nutritional inadequacies of the gluten-free diet in both recently-diagnosed and long-term patients with celiac disease.” This study investigating life-long gluten-free diet in celiac disease patients aimed to determine the nutritional adequacy of the ‘no detectable gluten’ diet. Results show that inadequate intake of folate is common (more than 10%) and may relate to habitual poor food choices in addition to inherent deficiencies in the gluten free diet (GFD). “Dietary education should also address the achievement of adequate micronutrient intake.”

A seven-day prospective food intake was assessed in 55 patients who were adherent to a GFD for more than 2 years and in 50 newly-diagnosed age- and sex-matched patients (18-71 years, 24% male) studied prospectively over 12 months on GFD. Historical pre-celiac intake was also assessed in the latter group. Intake was compared with Australian Nutritional Recommendations and the Australian population data.

RESULTS: Nutritional intake was similar between groups. Of macronutrients, only starch intake fell over 12 months (26% to 23%). Fibre intake was inadequate for all except in diet-experienced men. More than one in 10 of both newly-diagnosed and experienced women had inadequate thiamin, folate, vitamin A, magnesium, calcium and iron intakes. More than one in 10 newly-diagnosed men had inadequate thiamin, folate, magnesium, calcium and zinc intakes. Inadequate intake did not relate to nutrient density of the GFD. Inadequacies of folate, calcium, iron and zinc occurred more frequently than in the Australian population. The frequency of inadequacies was similar pre- and post-diagnosis, except for thiamin and vitamin A, where inadequacies were more common after GFD implementation.  Because dietary intake patterns at 12 months on a GFD are similar to longer-term intake, researchers stress that fortification of GF foods also need to be considered.”7

“Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet.” This study investigating the biochemical and clinical effects of B vitamin supplementation in adults with longstanding celiac disease found that adults with longstanding celiac disease taking extra B vitamins for 6 months showed normalized tHcy (plasma total homocysteine) and significant improvement in general well-being, suggesting that B vitamins should be considered in people advised to follow a gluten-free diet.

In a double blind placebo controlled multicenter trial, 65 celiac patients (61% women) aged 45-64 years on a strict gluten-free diet for several years were randomized to a daily dose of 0.8 mg folic acid,0.5 mg cyanocobalamin and 3 mg pyridoxine or placebo (no vitamin pill) for 6 months. The outcome measures were psychological general well-being and the plasma total homocysteine (tHcy) level, marker of B vitamin status.

Fifty-seven patients (88%) completed the trial. The tHcy level was baseline median 11.7 micromol/L (7.4-23.0), significantly higher than in matched population controls [10.2 micromol/L (6.7-22.6)]. Following vitamin supplementation, tHcy dropped a median of 34%, accompanied by significant improvement in well-being, notably anxiety and depressed mood for patients with poor well-being.14

“Anemia in celiac disease is multifactorial in etiology.” This study assessed the characteristics of anemia from a cohort of patients seen at a hospital care center for celiac disease. Hematological parameters measured less than 3 months of diagnosis and degree of villous atrophy from 405 patients diagnosed after 1995 was analyzed. Folate deficiency was seen in approximately 12% of the total sample. Macrocytic anemia with concurrent folate deficiency was 3%.15

“Serum folates in man.” This study investigating folate compounds and their breakdown compounds demonstrated that 5-ethyltetrahydrofolate is poorly absorbed by patients with celiac disease and the availability for biological utilization of the major dietary folate compounds will depend on the amount of gastric acidity and of the ascorbate in the intestinal chyme. Many folate compounds may be unavailable for metabolic utilization in the body.16

CASE REPORT SUMMARIES

“Carpopedal spasm in an elderly man: an unusual presentation of celiac disease.” This case report describes diagnosis of celiac disease in a 68-year-old single Caucasian man admitted to the hospital with a 24-hour history of carpopedal spasm of both hands. Apart from generalized weakness, he reported no other symptoms. Physical examination revealed carpopedal spasm, clubbing of fingers and cachexia (body mass index 14 kg/m2). This patient was found to have several unusual features of celiac disease, including a low folate level causing anemia, severe hypocalcemia and electrolyte disturbances as the initial manifestations, minimal gastrointestinal symptoms, and negative tTG-antibodies.

Blood tests showed severe hypocalcemia, with a total serum calcium of 1.06 mmol/L (normal range [NR] 2.05-2.55 mmol/L). He also had low serum potassium (2.8 mmol/L; NR 3.5-5.5 mmol/L) and magnesium (0.36 mmol/L; NR 0.65-1.05 mmol/L). Other significant results included hemoglobin 10.6 g/dL (NR 13-18 g/dL), mean corpuscular volume 98.1 fl (NR 82-98 fl), vitamin B12 157 ng/L (NR > 165 ng/L), folate 2.8 g/L (NR 3.1-17.5 μg/L), ferritin 252 μg/L (NR 30-250 μg/L), prothrombin time 20 s (NR 11-14 s), thyroid stimulating hormone 0.87 mu/L (NR 0.35-4.5 mu/L), phosphate 0.57 mmol/L (NR 0.8-1.45 mmol/L), albumin 32 g/L (NR 34-48 g/L) and alkaline phosphatase 313 IU/L (NR 47-141 IU/L). Subsequent results revealed vitamin D deficiency with a low serum 25-OH vitamin D of < 7 μg/L (NR 7-40 μg/L), a low 24-hour urinary calcium excretion of 0.9 mmol (NR 2.5-7.5 mmol) and a raised serum parathyroid hormone of 22.7 pmol/L (NR 1.6-6.9 pmol/L). Serology for tissue transglutaminase (tTG) antibodies was negative, and a serum IgA level of 4.95 g/L (NR 0.8-4.0 g/L) excluded selective IgA deficiency. Electrocardiograph at admission showed prolonged QT interval.

In view of cachexia, clubbing and negative tTG-antibodies, he was further investigated for an occult malignancy. Barium meal and follow through showed dilated proximal bowel loops and absence of normal feathery pattern of the jejunum, features suggestive of a malabsorptive state. Upper gastroscopic examination was normal; however, the duodenal biopsy showed partial and subtotal villous atrophy with increased intra-epithelial lymphocyte infiltration, consistent with the diagnosis of coeliac disease.17

1. Shibata K, Hirose J, Fukuwatari T. Relationship Between Urinary Concentrations of Nine Water-soluble Vitamins and their Vitamin Intakes in Japanese Adult Males. Nutr Metab Insights. 2014 Aug 5;7:61-75. doi: 10.4137/NMI.S17245. eCollection 2014. [↩]
2. Kathleen Mahan and Sylvia Escott-Stump, ed. Krause’s Food, Nutrition & Diet Therapy, 10th Edition. Philadelphia, PA. USA: W.B. Saunders Company, 2000. [↩] [↩] [↩]
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7. Shepherd SJ1, Gibson PR. Nutritional inadequacies of the gluten-free diet in both recently-diagnosed and long-term patients with coeliac disease. J Hum Nutr Diet. 2013 Aug;26(4):349-58. doi: 10.1111/jhn.12018. [↩] [↩]
8. Murray JA, the widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999; 69(3):354-365. [↩]
9. Harper JW, Holleran SF, Ramakrishnan R, Bhagat G, Green PH. Anemia in celiac disease is multifactorial in etiology. Am J Hematol. 2007 Nov; 82(11):996-1000. [↩]
10. Wierdsma NJ, van Bokhorst-de van der Schueren MA, Berkenpas M, Mulder CJ, van Bodegraven AA. Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients. Nutrients. 2013 Sep 30;5(10):3975-92. doi: 10.3390/nu5103975. [↩] [↩]
11. Roth C, Magnus P, Schjølberg S, Stoltenberg C, Surén P, McKeague IW, Davey Smith G, Reichborn-Kjennerud T, Susser E. Folic acid supplements in pregnancy and severe language delay in children. JAMA. 2011 Oct 12;306(14):1566-73. doi: 10.1001/jama.2011.1433. [↩]
12. Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikan V. Serum folates in man. Journal of Clinical Pathology. Mat 1977; 30(5):438-48. [↩]
13. Hallert C, Svensson M, Tholstrup J, Hultberg B. Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet. Aliment Pharmacol Ther. 2009 Apr 15;29(8):811-6. doi: 10.1111/j.1365-2036.2009.03945.x. [↩]
14. Hallert C, Svensson M, Tholstrup J, Hultberg B. Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten-free diet. Aliment Pharmacol Ther. 2009 Apr 15;29(8):811-6. doi: 10.1111/j.1365-2036.2009.03945.x. [↩]
15. Harper JW, Holleran SF, Ramakrishnan R, Bhagat G, Green PH. Anemia in celiac disease is multifactorial in etiology. Am J Hematol. 2007 Nov; 82(11):996-1000. [↩]
16. Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikan V. Serum folates in man. Journal of Clinical Pathology. May 1977; 30(5):438-48. [↩]
17. Schmidt K, Powari M, Shirazi T, Vaidya B. Carpopedal spasm in an elderly man: an unusual presentation of coeliac disease. J R Soc Med. 2007 Nov;100(11):524-5. [↩]