eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Folic Acid Deficiency

Author: Angela Gentili, MD, Director of Geriatrics Fellowship Program, Associate Professor, Department of Internal Medicine, Virginia Commonwealth University Health System and McGuire Veterans Affairs Medical Center
Coauthor(s): Muhammad Vohra, MD, Assistant Professor, Department of Internal Medicine, Hamdard University Hospital, Pakistan; Subir Vij, MD, MPH, Assistant Professor, Department of Medicine, Eastern Virginia Medical School; Medical Director, Portsmouth Community Health Center; David Kuan-Hua Chen, MD, Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center; Waleed Siddiqi, MD, Fellow in Geriatrics, Department of Internal Medicine, Division of General Internal Medicine/Primary Care, Medical College of Virginia
Contributor Information and Disclosures

Updated: Aug 24, 2009

Introduction

Background

The prevalence of folic acid deficiency has decreased since the United States and Canada introduced a mandatory folic acid food fortification program in November 1998. People with excessive alcohol intake and malnutrition are still at high risk of folic acid deficiency.

• An association of folate deficiency with elevated homocysteine, leading to increased arteriosclerosis risks¹
• The reduced incidence of neural tube defects with folate supplementation
• The role of folate in the occurrence of cancer

Hence, folic acid clearly is of consequence in public health in the United States, especially because heart disease and cancer constitute the number 1 and number 2 causes of mortality in the United States. This article explores the mechanisms and manifestations behind folate deficiency, as well as its ramifications with regard to health and disease at large.

Pathophysiology

Folic acid is composed of a pterin ring connected to p-aminobenzoic acid (PABA) and conjugated with one or more glutamate residues. It is distributed widely in green leafy vegetables, citrus fruits, and animal products. Humans do not generate folate endogenously because they cannot synthesize PABA, nor can they conjugate the first glutamate.

Folates are present in natural foods and tissues as polyglutamates because these forms serve to keep the folates within cells. In plasma and urine, they are found as monoglutamates because this is the only form that can be transported across membranes. Enzymes in the lumen of the small intestine convert the polyglutamate form to the monoglutamate form of the folate, which is absorbed in the proximal jejunum via both active and passive transport.

Within the plasma, folate is present, mostly in the 5-methyltetrahydrofolate (5-methyl THFA) form, and is loosely associated with plasma albumin in circulation. The 5-methyl THFA enters the cell via a diverse range of folate transporters with differing affinities and mechanisms (ie, adenosine triphosphate [ATP]–dependent H⁺ cotransporter or anion exchanger). Once inside, 5-methyl THFA may be demethylated to THFA, the active form participating in folate-dependent enzymatic reactions. Cobalamin (B-12) is required in this conversion, and in its absence, folate is "trapped" as 5-methyl THFA.

From then on, folate no longer is able to participate in its metabolic pathways, and megaloblastic anemia results. Large doses of supplemental folate can bypass the folate trap, and megaloblastic anemia will not occur. However, the neurologic/psychiatric abnormalities associated with B-12 deficiency ensue progressively.

The biologically active form of folic acid is tetrahydrofolic acid (THFA), which is derived by the 2-step reduction of folate involving dihydrofolate reductase. THFA plays a key role in the transfer of 1-carbon units (such as methyl, methylene, and formyl groups) to the essential substrates involved in the synthesis of DNA, RNA, and proteins. More specifically, THFA is involved with the enzymatic reactions necessary to synthesis of purine, thymidine, and amino acid. Manifestations of folate deficiency thereafter, not surprisingly, would involve impairment of cell division, accumulation of possibly toxic metabolites such as homocysteine, and impairment of methylation reactions involved in the regulation of gene expression, thus increasing neoplastic risks.

A healthy individual has about 500-20,000 mcg of folate in body stores. Humans need to absorb approximately 50-100 mcg of folate per day in order to replenish the daily degradation and loss through urine and bile. Otherwise, signs and symptoms of deficiency can manifest after 4 months.

Frequency

United States

The current standard of practice is that serum folate levels less than 3 ng/mL and a red blood cell (RBC) folate level less than 140 ng/mL puts an individual at high risk of folate deficiency. The RBC folate level generally indicates folate stored in the body, whereas the serum folate level tends to reflect acute changes in folate intake.

Data from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 indicate the prevalence of low serum folate concentrations (<6.8 nmol/L) decreased from 16% before folic acid fortification to 0.5% after folic acid fortification.² In elderly persons, the prevalence of high serum folate concentrations (>45.3 nmol/L) increased from 7% before fortification to 38% after fortification. The latest results from NHANES are available.³

International

Countries that do not have a mandatory folic acid food fortification program have higher rates of folic acid deficiency. For example, a population based study in Iran (where there is no fortification) showed an age-adjusted prevalence of hyperhomocysteinemia (Hcy ³15 micromol/L) of 73.1% in men and 41.07% in women (aged 25-64 y). 

Casey et al examined the effects over 1 year of a free weekly iron-folic acid supplementation and deworming program in 52,000 Vietnamese women of childbearing age.⁴  The investigators collected demographic data and blood and stool samples at baseline and at 3 and 12 months following the implementation of the program.

Findings included a mean Hb increase of 9.6 g/L (P < 0.001) and a reduction in the presence of anemia from 37.5% of the women at baseline to 19.3% at 12 months.⁴ Iron deficiency was also reduced, from 22.8% at baseline to 9.3% by 12 months, as well as hookworm infection (76.2% at baseline to 23.0%) in the same period. 

A discussion of selected national Australian policies is presented in Lawrence et al.⁵

Mortality/Morbidity

Hematologic manifestations

Folate deficiency can cause anemia. The presentation typically consists of macrocytosis and hypersegmented polymorphonuclear leucocytes (PMNs). More detailed laboratory findings are discussed in the Workup section.

The anemia usually progresses over several months, and the patient typically does not express symptoms as such until the hematocrit level reaches less than 20%. At that point, symptoms such as weakness, fatigue, difficulty concentrating, irritability, headache, palpitations, and shortness of breath can occur. Furthermore, heart failure can develop in light of high-output cardiac compensation for the decreased tissue oxygenation. Angina pectoris may occur in predisposed individuals due to increased cardiac work demand. Tachycardia, postural hypotension, and lactic acidosis are other common findings. Less commonly, neutropenia and thrombocytopenia also will occur, although it usually will not be as severe as the anemia. In rare cases, the absolute neutrophil count can drop below 1000/mL and the platelet count below 50,000/mL.

Elevated serum homocysteine and atherosclerosis

Folate in the 5-methyl THFA form is a cosubstrate required by methionine synthase when it converts homocysteine to methionine. As a result, in the scenario of folate deficiency, homocysteine accumulates. Several recent clinical studies have indicated that mild-to-moderate hyperhomocystinemia is highly associated with atherosclerotic vascular disease such as coronary artery disease (CAD) and stroke. In this case, mild hyperhomocystinemia is defined as total plasma concentration of 15-25 mmol/L and moderate hyperhomocystinemia is defined as 26-50 mmol/L.

Genest et al found that a group of 170 men with premature coronary artery disease had a significantly higher average level of homocysteine (13.7 ± 6.4).⁶ In another study, Coull et al found that among 99 patients with stroke or transient ischemic attacks (TIAs), about one third had elevated homocysteine.⁷

Elevated homocysteine levels might act as an atherogenic factor by converting a stable plaque into an unstable, potentially occlusive, lesion. Wang et al found that in patients with acute coronary syndromes, levels of homocysteine and monocyte chemoattractant protein-1 (MCP-1) were significantly higher.⁸ MCP-1 is a chemokine characterized by the ability to induce migration and activation of monocytes and therefore may contribute to the pathogenesis of CAD. Homocysteine is believed to have atherogenic and prothrombotic properties via multiple mechanisms.

Bokhari et al found that among patients with CAD, the homocysteine level correlates independently with left ventricular systolic function.⁹ The mechanism is unknown, but it may be due to a direct toxic effect of homocysteine on myocardial function separate from its effect on coronary atherosclerosis.

Although in multiple observational studies elevated plasma homocysteine levels have been positively associated with increased risk of atherosclerosis, randomized trials have not been able to demonstrate the utility of homocysteine-lowering therapy. In the Heart Outcomes Prevention Evaluation (HOPE) 2 trial, supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease.¹⁰ Similarly, in the trial of Bonaa et al treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction.¹¹

Pregnancy complications

Possible pregnancy complications secondary to maternal folate status may include spontaneous abortion, abruption placentae, and congenital malformations (eg, neural tube defect). In a literature review, Ray et al examined 8 studies that demonstrated association between hyperhomocystinemia and placental abruption/infarction.¹² Folate deficiency also was a risk factor for placental abruption/infarction, although less statistically significant.¹³

Several observational and controlled trials have shown that neural tube defects can be reduced by 80% or more when folic acid supplementation is started before conception. In countries like the United States and Canada, the policy of widespread fortification of flour with folic acid has proved effective in reducing the number of neural tube defects.¹⁴

Although the exact mechanism is not understood, a relative folate shortage may exacerbate an underlying genetic predisposition to neural tube defects.

Effects on carcinogens

Diminished folate status is associated with enhanced carcinogenesis. A number of epidemiologic and case-control studies have shown that folic acid intake is inversely related to colon cancer risk.¹⁵ With regard to the underlying mechanism, Blount et al showed that folate deficiency can cause a massive incorporation of uracil into human DNA leading to chromosome breaks.¹⁶ Another study by Kim et al suggested that folate deficiency induces DNA strand breaks and hypomethylation within the p53 gene.¹⁷

Effects on cognitive function

Several studies have shown that an elevated homocysteine level correlates with cognitive decline. In Herbert's classic study in which a human subject (himself) was in induced folate deficiency from diet restriction, he noted that CNS effects, including irritability, forgetfulness, and progressive sleeplessness, appeared within 4-5 months. Interestingly, all CNS symptoms were reported to disappear within 48 hours after oral folate intake.

Low folate and high homocysteine levels are a risk factor for cognitive decline in high-functioning older adults¹⁸ and high homocysteine level is an independent predictor of cognitive impairment among long-term stay geriatric patients.¹⁹

Mechanistically speaking, current theory proposes that folate is essential for synthesis of S- adenosylmethionine, which is involved in numerous methylation reactions. This methylation process is central to the biochemical basis of proper neuropsychiatric functioning.

Despite the association of high homocysteine level and poor cognitive function, homocysteine-lowering therapy using supplementation with vitamins B-12 and B-6 was not associated with improved cognitive performance after two years in a double-blind, randomized trial in healthy older adults with elevated homocysteine levels.²⁰

Sex

Women who are pregnant are at higher risk of developing folate deficiency because of increased requirements.

Age

Elderly people also may be more susceptible to folate deficiency in light of their predisposition to mental status changes, social isolation, low intake of leafy vegetables and fruits, malnutrition, and comorbid medical conditions. The greatest risk appears to be among low-income populations and institutionalized elderly people and less risk among the free-living elderly population.

Clinical

History

In folate deficiency, the patient's history is important because it may reveal the underlying disorder. Very often, a patient presents with a history of excessive alcohol intake with concurrent poor diet intake. Other times, patients may be pregnant or lactating; may take certain drugs, such as phenytoin, sulfonamides, or methotrexate; may have chronic hemolytic anemia; or may have underlying malabsorption.

Some patients complain of a sore tongue or pain upon swallowing. The tongue may appear swollen, beefy, red, or shiny, usually around the edges and tips initially. Angular stomatitis also may be observed. These oral lesions typically occur at the time when folate depletion is severe enough to cause megaloblastic anemia, although, occasionally, lesions may occur before the anemia.

Patients may present with GI symptoms, such as nausea, vomiting, abdominal pain, and diarrhea, especially after meals. Anorexia also is common and, in combination with the above symptoms, may lead to marked weight loss. However, be aware that an underlying malabsorption disorder could be causing these symptoms, as well as folate depletion. The lack of folate itself may not be the culprit.

Physical

Patients with folate deficiency may have darkening of the skin and mucous membranes, particularly at the dorsal surfaces of the fingers, toes, and creases of palms and soles. Distribution typically is patchy. Fortunately, the hyperpigmentation gradually should resolve after weeks or months of folate treatment. A modest temperature elevation (<102°F) is common in patients who are folate deficient, despite the absence of any infection. Although the underlying mechanism is obscure, the temperature typically falls within 24-48 hours of vitamin treatment and returns to normal within a few days.

Causes

Folate deficiency can result from several possible causes, including inadequate ingestion, impaired absorption, impaired metabolism leading to inability to utilize folate that is absorbed, increased requirement, increased excretion, and increased destruction.

• Inadequate ingestion of folate-containing foods: Poor nutrition is prevalent among people with alcoholism and patients with psychiatric morbidities, as well as elderly people (due to conditions such as ill-fitting dentures, physical disabilities, and social isolation). Because folates are destroyed by prolonged exposure to heat, people of certain cultures that involve traditionally cooking food in kettles of boiling water may be predisposed to folate deficiency. Moreover, for patients with renal and liver failure, anorexia and restriction of foods rich in protein, potassium, and phosphate contribute to decreased folate intake.
• Impaired absorption
  • The limiting factor in folate absorption is its transport across the intestinal wall. Folate transport across the gut wall mainly is carrier mediated, saturable, substrate specific, pH dependent (optimal at low pH), sodium dependent, and susceptible to metabolic inhibitors. Passive, diffusional absorption also occurs, to a minor degree. With this in mind, a decreased absorptive area due to small bowel resection or mesenteric vascular insufficiency would decrease folate absorption.
  • Celiac disease and tropical sprue cause villous atrophy. The process of aging causes shorter and broader villi in 25% of the elderly population. Achlorhydria leads to elevation of gastric pH above the optimal level (ie, pH of 5) for folate absorption. Anticonvulsant drugs, such as Dilantin, interfere with mucosal conjugase, hence impairing folate absorption. Zinc deficiency also decreases folate absorption because zinc is required to activate mucosal conjugase. Bacterial overgrowth in blind loops, stricture formation, or jejunal diverticula likewise would decrease folate absorption.
• Impaired metabolism, leading to inability to utilize absorbed folate: Antimetabolites that are structurally analogous to the folate molecule can competitively antagonize folate utilization. Methotrexate and trimethoprim both are folate antagonists that inhibit dihydrofolate reductase. Hypothyroidism has been known to decrease hepatic levels of dihydrofolate reductase as well as methylene THFA reductase. Furthermore, congenital deficiency involving the enzymes of folate metabolism also can show impaired folate utilization. People with alcoholism can have very active alcohol dehydrogenase that binds up folate and thus interferes with folate with folate utilization.
• Increased requirement: Factors that increase the metabolic rate can increase the folic requirement. Infancy (a period of rapid growth), pregnancy (rapid fetal growth), lactation (uptake of folate into breast milk), malignancy (increased cell turnover), concurrent infection (immunoproliferative response), and chronic hemolytic anemia (increased hematopoiesis) all can result in an increased folate requirement.
• Increased excretion/loss: Increased excretion of folate can occur subsequent to vitamin B-12 deficiency. During the course of vitamin B-12 deficiency, methylene THFA is known to accumulate in the serum, which is known as the folate trap phenomenon. In turn, large amounts of folate filter through the glomerulus, and urine excretion occurs. Another mechanism of excess excretion occurs in people with chronic alcoholism who can have increased excretion of folate into the bile. Patients undergoing hemodialysis also have been known to have excess folate loss during procedures.
• Increased destruction: Superoxide, an active metabolite of ethanol metabolism, is known to inactivate folate by splitting the folate molecule in half between the C9 and N10 position. The relationship between cigarette smoking and low folate levels has been noted as possibly due to folate inactivation in exposed tissue.

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