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) signs and 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.

Neuropsychiatric presentations include cognitive impairment, dementia, and depression. These manifestations overlap with those of vitamin B12 deficiency.{ref50)

Physical Examination

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.

Complications

Failure to provide folic acid supplementation to pregnant females may lead to spontaneous abortion and fetal abnormalities, including neural tube defects and increased risk of severe language delay in the child.

Providing only folic acid supplementation to a patient who has cobalamin deficiency may lead to development of irreversible neuropathies.

Differential Diagnoses

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Media Gallery

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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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 I Vohra, MD Geriatrician, Lucy Corr Life Care

Muhammad I Vohra, MD is a member of the following medical societies: American College of Physicians, American Geriatrics Society, Medical Society of Virginia, Virginia 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.

Folate Deficiency Clinical Presentation

History

Physical Examination

Complications

References

Tables

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