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Folic Acid Deficiency Clinical Presentation

  • Author: Katherine Coffey-Vega, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Nov 18, 2015
 

History

In folate deficiency, the patient's history is important because it may reveal the underlying reason for the deficiency. Very often, a patient presents with a history of excessive alcohol intake with concurrent poor diet intake. Other 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 gastrointestinal (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.

Neurologic presentations include cognitive impairment, dementia, and depression. These manifestations overlap with those of vitamin B-12 deficiency.{ref50)

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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.

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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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Contributor Information and Disclosures
Author

Katherine Coffey-Vega, MD Fellow, Department of Internal Medicine, Division of Geriatrics, Virginia Commonwealth University School of Medicine

Katherine Coffey-Vega, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Coauthor(s)

Angela Gentili, MD Director of Geriatric Medicine Fellowship Program, Professor of Internal Medicine, Division of Geriatric Medicine, Virginia Commonwealth University Health System and McGuire Veterans Affairs Medical Center, Richmond, VA

Angela Gentili, MD is a member of the following medical societies: Virginia Geriatrics Society, American Geriatrics Society

Disclosure: Nothing to disclose.

Muhammad Vohra, MD 

Muhammad Vohra, MD is a member of the following medical societies: American Geriatrics Society

Disclosure: Nothing to disclose.

David Kuan-Hua Chen, MD Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center

David Kuan-Hua Chen, MD is a member of the following medical societies: Alpha Omega Alpha, Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthor Ahmed Mosalem, MD, to the development and writing of this article.

The authors and editors of Medscape Reference also gratefully acknowledge the contributions of previous coauthors Subir Vij, MD, MPH and Waleed Siddiqi, MD to the development and writing of this article.

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The chemical structure of folic acid and amethopterin (methotrexate), a folic acid antagonist, shows the similarity of structure.
The transformation of formiminoglutamic acid to glutamic acid is dependent upon both vitamin B-12 and tetrahydrofolate. In contrast, the transformation of homocysteine to methionine is a vitamin B-12–dependent reaction.
Both folic acid and vitamin B-12 participate in the synthesis of DNA and RNA.
Histologically, the megaloblastosis caused by folic acid deficiency cannot be differentiated from that observed with vitamin B-12 deficiency.
Peripheral smear of blood in a patient with pernicious anemia. Macrocytes are observed and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.
Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.
 
 
 
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