Folic Acid Deficiency

Folic Acid Deficiency



Background

Folic acid deficiency is often under reported. Here is a brief account of folate deficiency

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

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).

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.

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.

Effects of folate deficiency:

Hematologic manifestations

Folate deficiency can cause anemia. The presentation typically consists of macrocytosis and hypersegmented polymorphonuclear leucocytes (PMNs). More detailed lab 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 (1990) found that a group of 170 men with premature coronary artery disease had a significantly higher average level of homocysteine (13.7 ± 6.4). In another study, Coull et al (1990) found that among 99 patients with stroke or transient ischemic attacks (TIAs), about one third had elevated homocysteine.

Elevated homocysteine levels might act as an atherogenic factor by converting a stable plaque into an unstable, potentially occlusive, lesion. Wang et al (2004) found that in patients with acute coronary syndromes, levels of homocysteine and monocyte chemoattractant protein-1 (MCP-1) were significantly higher. 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 (2005) found that among patients with CAD, the homocysteine level correlates independently with left ventricular systolic function. 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. Similarly, in the trial of Bonaa et al (2006) treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction.

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 (1999) examined 8 studies that demonstrated association between hyperhomocystinemia and placental abruption/infarction. Folate deficiency also was a risk factor for placental abruption/infarction, although less statistically significant.

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.

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. With regard to the underlying mechanism, Blount et al (1997) showed that folate deficiency can cause a massive incorporation of uracil into human DNA leading to chromosome breaks. Another study by Kim et al (1997) suggested that folate deficiency induces DNA strand breaks and hypomethylation within the p53 gene.

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 adults and high homocysteine level is an independent predictor of cognitive impairment among long-term stay geriatric patients.

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.

Lab Studies

Serum folate (reference range 2.5-20 ng/mL) and serum cobalamin (reference range 200-900 pg/mL)
As the initial test, ruling out cobalamin deficiency is very important because folate treatment will not improve neurologic abnormalities due to cobalamin deficiency.
By statistical definition, 2-5% of healthy individuals will have serum folate of less than 2.5 ng/mL; hence, the serum folate level cannot be used alone to establish the diagnosis of folate deficiency. Therefore, the serum folate test is useful only to rule out folate deficiency in patients with serum folate greater than 5.0 ng/mL. Otherwise, additional follow-up tests include serum homocysteine (reference range 5-16 mmol/L), which is elevated in B-12 and folate deficiency, and serum methylmalonic acid (reference range 70-270 mmol/L), which is elevated in B-12 deficiency only.
Red blood cell folate levels (reference range >140 ng/mL) tend to reflect chronic folate status rather than acute changes in folate that are reflected in serum folate levels, although many confounding factors, such as transfused red cells, can make this unreliable as a test for folate deficiency states.
Other than folate or cobalamin deficiency, the only other confounding causes for elevation of these compounds include renal failure, intravascular volume depletion, and some rare inborn errors of metabolism involving folate or cobalamin-dependent enzymes.
Procedures

Bone marrow biopsy and aspirate may show a hypercellular bone marrow with a megaloblastic maturation of cells. This cannot be differentiated from changes observed with vitamin B-12 deficiency.

Treatment:

Medical Care

Fruits and vegetables constitute the primary dietary source of folic acid. The minimal daily requirement is about 50 mcg, but this may be increased several fold during periods of enhanced metabolic demand such as pregnancy.
Consultations

Consult a dietitian.

Diet should include fruits and vegetables.

Folic acid (Folvite):
Megaloblastic anemia: 0.4 mg PO/IM/SC qd for 4-5 d; not to exceed 1 mg/d
Pregnancy: 1 mg PO/IM/SC qd
Nutritional supplementation: 0.15-0.2 mg PO/IM/SC qd for men; 0.15-0.18 mg PO/IM/SC qd for women