29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

Home / Rare Diseases / Anemia, Megaloblastic

Anemia, Megaloblastic

Last updated: August 25, 2021

Years published: 1987, 1989, 2003, 2008

Disease Overview
Megaloblastic anemia is a condition in which the bone marrow produces unusually large, structurally
abnormal, immature red blood cells (megaloblasts). Bone marrow, the soft spongy material found
inside certain bones, produces the main blood cells of the body -red cells, white cells, and platelets.
Anemia is a condition characterized by the low levels of circulating, red blood cells. Red blood cells are
released from the marrow into the bloodstream where they travel throughout the body delivering
oxygen to tissue. A deficiency in healthy, fully-matured red blood cells can result in fatigue, paleness of
the skin (pallor), lightheadedness and additional findings. Megaloblastic anemia has several different
causes – deficiencies of either cobalamin (vitamin B12) or folate (vitamin B9) are the two most
common causes. These vitamins play an essential role in the production of red blood cells.

Show Less Print / Download As PDF

Synonyms
Folate Deficiency Anemia
Folic Acid Deficiency Anemia
Vitamin B12 Deficiency Anemia

Signs & Symptoms

In most cases, megaloblastic anemia develops slowly and affected individuals may remain without any
apparent symptoms (asymptomatic) for many years. Symptoms common to anemia usually develop at
some point and may include fatigue, paleness of the skin (pallor), shortness of breath, lightheadedness,
dizziness and a fast or irregular heartbeat. The specific symptoms present in each individual can vary
greatly.

https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 1/7
29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

Additional common symptoms include aches and pains, muscle weakness, and difficulty breathing
(dyspnea). Individuals with megaloblastic anemia may also develop gastrointestinal abnormalities
including diarrhea, nausea, and loss of appetite. Some affected individuals may develop a sore,
reddened tongue. These abnormalities may result in unintended weight loss. Mild enlargement of the
liver (hepatomegaly) and a slight yellowing of the skin or eyes (jaundice) may also occur.

Megaloblastic anemia resulting from cobalamin deficiency may also be associated with neurological
symptoms. The initial neurological symptom may be tingling or numbness in the hands or feet.
Additional symptoms develop over time including balance or gait problems, vision loss due to
degeneration (atrophy) of the nerve that transmits impulses from the retina to the brain (optic nerve),
and mental confusion or memory loss. A variety of psychiatric abnormalities have also been reported
in individuals with cobalamin deficiency including depression, insomnia, listlessness, and panic attacks.
The spectrum of potential neuropsychological symptoms potentially associated with cobalamin
deficiency is large and varied.

In rare cases of cobalamin deficiency, neurological symptoms may occur before the characteristic
findings of anemia. Folate deficiency is generally considered not to result in neurological symptoms,
although some recent research suggests that, in rare cases, it may cause some neurological symptoms.

Causes
The most common causes of megaloblastic anemia are deficiency of either cobalamin (vitamin B12) or
folate (vitamin B9). These two vitamins serve as building blocks and are essential for the production of
healthy cells such as the precursors to red blood cells. Without these essential vitamins, the creation
(synthesis) of deoxyribonucleic acid (DNA), the genetic material found in all cells, is hampered.

Vitamin deficiency resulting in megaloblastic anemia may result from inadequate intake of cobalamin
and folate in the diet, poor absorption of these vitamins by the intestines or improper utilization of
these vitamins by the body. Folate deficiency may also result from conditions which use up or require
excessive amounts of folate.

Cobalamin is found in meat, fish and eggs. Deficiency of cobalamin due to poor dietary intake is
extremely rare, but has occurred in some total vegetarians (vegans). The most common cause of
cobalamin deficiency is impaired absorption of the vitamin by the small intestines (malabsorption). In
such cases, the diet contains enough of the vitamin, but the body cannot absorb and subsequently use
the vitamin. Malabsorption may result from surgery on the intestines, intestinal diseases such as
Crohn’s disease or tropical sprue, or infection (bacterial growth) within the gastrointestinal tract.
Pernicious anemia may also cause cobalamin deficiency. This form of anemia is characterized by a lack
of intrinsic factor, a protein that binds with cobalamin and aids in its absorption by the small intestines.
Without enough intrinsic factor, the body cannot absorb enough cobalamin.

https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 2/7
29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

In rare cases, a fish tapeworm known as Diphyllobothrium latum may take root in the small intestine
and use up cobalamin, thereby depriving the body of necessary amounts of this essential vitamin. In
some cases, bacteria may compete with the body for cobalamin as in blind loop syndrome, a disorder in
which obstruction of the small intestines results in the abnormal build up of bacteria in the
gastrointestinal tract.

Folate, which is also known as folic acid, is a B vitamin that is normally found in green leafy vegetables,
citrus fruits, and certain grains and nuts. Folate deficiency can occur in diets that supply insufficient
amounts of these foods. Alcoholics may develop folate deficiency because alcohol does not contain
folate and may impair the breakdown (metabolism) of folate in the body. Surgery involving the stomach
or intestines can result in impaired absorption of folate. Certain intestinal disorders such as Crohn’s
disease or tropical sprue can cause malabsorption and subsequent folate deficiency.

Pregnant women, women who are breastfeeding, individuals who have chronic hemolytic anemias, and
individuals undergoing hemodialysis for kidney disease all have higher-than-normal demands for
folate. Failure to adequately supplement folate in these individuals can potentially result in folate
deficiency.

Certain medications can impair the body’s ability to absorb folate including many drugs used to treat
cancer. Medications can also impair the synthesis of DNA resulting in megaloblastic anemia.

Much rarer causes of megaloblastic anemia (unrelated to vitamin deficiency) have been identified
including rare enzyme deficiencies known as inborn errors of metabolism and primary bone marrow
disorders including myelodysplastic syndromes and acute myeloid leukemia.

In some cases, the cause of megaloblastic anemia is unknown (idiopathic).

Affected populations
Megaloblastic anemia affects males and females in equal numbers. It can occur in individuals of any
racial or ethnic background. Because the causes of megaloblastic anemia vary and because some
individuals may not exhibit any obvious symptoms (asymptomatic), determining its true frequency in
the general population is difficult.

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of megaloblastic anemia. Comparisons
may be useful for a differential diagnosis.

Pernicious anemia is a rare blood disorder characterized by the inability of the body to properly utilize
vitamin B12, which is essential for the development of red blood cells. Most cases result from the lack
of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed. The

https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 3/7
29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

symptoms of pernicious anemia may include weakness, fatigue, an upset stomach, an abnormally rapid
heartbeat (tachycardia), and/or chest pains. Recurring episodes of anemia (megaloblastic) and an
abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be
an autoimmune disorder, and certain people may have a genetic predisposition to this disorder. There
is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce
effective intrinsic factor. There is also a juvenile form of the disease, but pernicious anemia typically
does not appear before the age of 30. The onset of the disease is slow and may span decades. When
the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological
complications. Nerve cells and blood cells need vitamin B12 to function properly.

(For more information on this disorder, choose “pernicious anemia” as your search term in the Rare
Disease Database.)

In some cases, the structural changes in the abnormal red cells (megaloblasts) that characterized
megaloblastic anemia have been mistaken for certain primary bone marrow disorders such as acute
myeloid leukemia, myelodysplastic syndromes and aplastic anemia. (For more information on these
disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of megaloblastic anemia is made based upon a thorough clinical evaluation, a detailed
patient history, identification of characteristic findings and a variety of blood tests. Blood tests may
reveal the abnormally large, misshapen red blood cells that characterize megaloblastic anemia. Blood
tests can also confirm cobalamin or folate deficiency as the cause of megaloblastic anemia. Additional
tests such as a Schilling test, which confirms poor absorption as the cause of cobalamin deficiency, may
be necessary.

Standard Therapies
Treatment

The treatment of megaloblastic anemia depends upon the underlying cause of the disorder. Dietary
insufficiency of cobalamin and folate can be treated with appropriate changes to the diet and the
administration of supplements. In individuals who cannot absorb cobalamin or folate properly, life-
long supplemental administration of these vitamins may be necessary. Prompt treatment of cobalamin
deficiency is important because of the risk of neurological symptoms.

If underlying disorders (e.g., Crohn's disease, tropical sprue, celiac sprue, blind loop syndrome, inborn
errors of metabolism) are the cause of these vitamin deficiencies, appropriate treatment for the
specific disorder is required. Supplementation of either cobalamin or folate may also be required.

https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 4/7
29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

If medications are the cause of vitamin deficiency then use of the medication in question should be
stopped or the dosage lowered.

Preventive (prophylactic) folate supplementation may be recommended for individuals who have
higher-than-normal demands for folate such as pregnant women.

Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies
receiving U.S. government funding, and some supported by private industry, are posted on this
government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD,
contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References
TEXTBOOKS

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research
Laboratories; 2003:898-899, 990-991.

Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison’s Principles of Internal Medicine. 16th ed.
McGraw-Hill Companies. New York, NY; 2005:601-607.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co;
1996:843-851.

JOURNAL ARTICLES

Aslinia, F, Mazza JJ, Yale SH. Megaloblastic anemia and other causes of macrocytosis. Clin Med Res.
2006;4:236-241.

De Paz R, Hernandez-Navarro F. Management, prevention and control of megaloblastic anemia,

secondary to folic acid deficiency. Nutr Hosp. 2006;113-119.
https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 5/7
29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

Ward PC. Modern approaches to the investigation of vitamin B12 deficiency. Clin Lab Med.
2002;22:435-45.

Reynolds EH. Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry.
2002;72:567-71.

Neufeld EJ, Fleming JC, Tartaglini E, et al. Thiamine responsive megaloblastic anemia syndrome: a
disorder of high-affinity thiamine transport. Blood Cells Mol Dis. 2001;27:135-38.

Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in
children. Semin Hematol. 1999;36:19-34.

Wickramasinghe SN. The wide spectrum and unresolved issues of megaloblastic anemia. Semin
Hematol. 1999;36:3-18.

FROM THE INTERNET

Schick P. Davis TH. Megaloblastic Anemia. Emedicine Journal, January 29, 2007.

Available at: http://www.emedicine.com/MED/topic1420.htm

Accessed on: February 12, 2008.

Harper JL, Sarnaik S. Megaloblastic Anemia. Emedicine Journal, August 20, 2007.

Available at: http://www.emedicine.com/ped/topic2575.htm

Accessed on: February 12, 2008

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins
University; Entry No:190450; Last Update:03/17/2004. Available at:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190450 Accessed on: April 6, 2007.

Mayo Clinic for Medical Education and Research. Vitamin Deficiency Anemia. March 9, 2007.

Available at: http://www.emedicine.com/ped/topic2575.htm

Accessed On: February 12, 2008.

Programs & Resources

RareCare® Assistance Programs
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you
now, please continue to check back with us.

https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 6/7
29/03/2023, 10:54 Anemia, Megaloblastic - Symptoms, Causes, Treatment | NORD

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to
rare disease patients in emergency situations.
https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives
while managing their rare condition is a vital part of NORD’s mission.
https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed
with a rare disorder.
https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations
No patient organizations found related to this disease state.

IAMRARE® Patient Registry

Powered by NORD, the IAMRARE Registry Platform® is driving transformative change in the study of
rare disease. With input from doctors, researchers, and the US Food & Drug Administration, NORD
has created IAMRARE to facilitate patient-powered natural history studies to shape rare disease
research and treatments. The ultimate goal of IAMRARE is to unite patients and research communities
in the improvement of care and drug development.

https://rarediseases.org/rare-diseases/anemia-megaloblastic/ 7/7