Megaloblastic Anemia

Disease Overview

Megaloblastic anemia is characterized by unusually large, structurally abnormal blood cells (megaloblasts) that do not function normally. Bone marrow, the soft spongy material found inside certain bones, produces the main blood cells of the body – red blood cells, white blood cells and platelets. All three cell lines may be affected in megaloblastic anemia. Anemia is a condition characterized by 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; dihydrofolate reductase deficiency is another more uncommon cause. Vitamin B12 and vitamin B9 play an essential role in the production of red blood cells. This disease can be diagnosed based on laboratory tests or characteristic findings when tissue is viewed under microscope.

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Synonyms

• constitutional megaloblastic anemia with severe neurological disease
• DHFR deficiency
• dihydrofolate reductase deficiency

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Signs & Symptoms

In most patients, megaloblastic anemia develops slowly, and affected individuals may not have 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.

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, presenting as 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 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.

Symptoms of megaloblastic anemia due to dihydrofolate reductase deficiency are currently under investigation. The onset of symptoms for this type of megaloblastic anemia may start to appear in infants (1-23 months) and young children (2-11 years).

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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.

Megaloblastic anemia may result from inadequate folate in the diet, from poor absorption of cobalamin by the intestines or improper utilization of these vitamins by the body.

Folate deficiency has become rare because many countries supplement certain foods with folate. Most often, folate deficiency occurs in patients with severe malnutrition. Folate is found in green leafy vegetables, citrus fruits, certain grains and nuts, meat and liver. Folate deficiency can occur in diets without enough of these foods or due to decreased intake caused by an alcohol use disorder or malnutrition. Alcoholics may develop folate deficiency because alcohol does not contain folate and may impair the breakdown (metabolism) of folate in the body.

Malabsorption of folate may occur in patients following gastric bypass surgery or patients with generalized inflammation of the bowel (for example those with celiac disease). Folate deficiency may result from conditions which use up or require increased amounts of folate, such as chronic eczema or hemolytic anemia.

People who are pregnant or breastfeeding 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.

Cobalamin is found in meat, fish, eggs and dairy products. Deficiency of cobalamin due to poor dietary intake is extremely rare but has occurred in people who eat a vegan diet. Cobalamin enters the body through a complex process involving the entire gastrointestinal tract. Normally, gastric parietal cells produce intrinsic factor (IF) which binds cobalamin in the gut. Unbound cobalamin is absorbed poorly and may be degraded during digestion. The IF-cobalamin complex courses down the intestines to the distal small bowel (ileum), where the most absorption of cobalamin occurs. Absorption of the IF-cobalamin complex occurs via specific receptors on enterocytes lining the ileum.

Currently, almost all cobalamin deficiencies are caused by impaired absorption of the vitamin rather than dietary deficiencies. For example, impaired gastric function may lead to cobalamin deficiency because of deficient production of intrinsic factor (IF). Structural or functional disorders of the small bowel may also lead to impaired absorption of IF-bound cobalamin by the small intestine. Malabsorption may also result from surgery that leads to shortening or removal of the ileum, intestinal diseases such as Crohn’s disease or tropical sprue, or infection in the gastrointestinal tract. Pernicious anemia – a chronic autoimmune inflammatory disorder leading to gastric atrophy – 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 intestine. Without enough intrinsic factor, the body cannot absorb enough cobalamin.

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.

Small bowel absorption of cobalamin may also be caused by inherited changes in genes (called variants or mutations) that make proteins involved in the absorption of IF-cobalamin complex in the ileum. Imerslund-Graesbeck syndrome is a rare, autosomal recessive disorder usually diagnosed in infancy or early childhood, characterized by megaloblastic anemia and often associated with increased protein loss in the urine.

Dihydrofolate reductase deficiency is a genetic disease caused by variants in the DHFR gene that can result in megaloblastic anemia.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a genetic disease caused by variants in the SLC19A2 gene that can result in megaloblastic anemia, diabetes mellitus and early-onset hearing loss.

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

In some people, 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 buildup of bacteria in the gastrointestinal tract.

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 people the cause of megaloblastic anemia is unknown.

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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, determining its true frequency in the general population is difficult. It is estimated that there are less than 1,000 people in the U.S. with the disease.

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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 blood disorder characterized by the inability of the body to properly utilize cobalamin (vitamin B12). Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed. The symptoms of pernicious anemia may include weakness, fatigue, upset stomach, abnormally rapid heartbeat (tachycardia) and/or chest pains. Recurring episodes of megaloblastic anemia and 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 factors. 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.

In some people, the structural changes in megaloblasts that characterize 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.)

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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.

Patients should be evaluated for the underlying conditions that can lead to megaloblastic anemia.

Patients with progressive sensorineural hearing loss and diabetes mellitus in addition to megaloblastic anemia should be tested for thiamine-responsive megaloblastic anemia syndrome (TRMA). Molecular genetic testing for variants in the SLC19A2 gene or genomic sequencing can confirm this diagnosis.

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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 diet supplements. In individuals who cannot absorb cobalamin or folate properly, life-long vitamin supplements may be necessary. Prompt treatment of cobalamin deficiency is important because of the risk of neurological symptoms. In patients with deficiency in both cobalamin and folate, replenishing cobalamin should be the first priority in order to avoid degeneration of the spinal cord.

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 with either cobalamin or folate may also be required.

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

In certain patients, such as those with thiamine-responsive megaloblastic anemia syndrome (TRMA), megaloblastic anemia can be treated with oral thiamine. Hearing loss cannot be reversed by thiamine treatment. Red blood cell transfusion may be used for severe cases of anemia.

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

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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: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Torrez, M, Chabot-Richards, D, Babu, D, Lockhart, E, Foucar, K. How I investigate acquired megaloblastic anemia. Int J Lab Hematol. 2022; 44: 236–247. doi:10.1111/ijlh.13789

Wu Q, Liu J, Xu X, Huang B, Zheng D, Li J. Mechanism of megaloblastic anemia combined with hemolysis. Bioengineered. 2021;12(1):6703-6712. doi:10.1080/21655979.2021.1952366

Socha DS, DeSouza SI, Flagg A, Sekeres M, Rogers HJ. Severe megaloblastic anemia: Vitamin deficiency and other causes. Cleve Clin J Med. 2020;87(3):153-164. doi:10.3949/ccjm.87a.19072

INTERNET
Hariz A, Bhattacharya PT. Megaloblastic Anemia. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537254/ Accessed August 17, 2023.

Sako S, Tsunogai T, Oishi K. Thiamine-Responsive Megaloblastic Anemia Syndrome. 2003 Oct 24 [Updated 2022 Jul 28]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1282/ Accessed August 17, 2023.

Constitutional megaloblastic anemia with severe neurologic disease. Genetic and Rare Disease Information Center. https://rarediseases.info.nih.gov/diseases/11000/megaloblastic-anemia-due-to-dihydrofolate-reductase-deficiency Accessed August 17, 2023.

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