Megaloblastic Anemia

Megaloblastic Anemia

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Megaloblastosis describes a heterogeneous group of disorders that share common morphologic characteristics: large cells with an arrest in nuclear maturation. Nuclear maturation is immature relative to cytoplasmic maturity. Hence, these cells, which can be seen in bone marrow aspirates and in peripheral smears, have been called megaloblasts. These abnormalities are due to impaired DNA synthesis and, to a lesser extent, RNA and protein synthesis.

Megaloblastic changes are most apparent in rapidly dividing cells such as blood cells and gastrointestinal cells. [1, 2] 3 In addition to large nucleated red blood cells (megaloblasts), hypersegmented neutrophils can be seen on peripheral smears, and giant bands occur in bone marrow. 

Megaloblastosis can be associated with severe anemia and pancytopenia, gastrointestinal dysfunction and glossitis, personality changes, psychosis, and neurological disorders. [2] Megaloblastic changes can occur in HIV infections and myelodysplastic disorders as a result of interference of DNA synthesis. [1, 2, 3]

Vitamin B-12 and folic acid deficiencies and certain medications are the most common causes of megaloblastic anemia, a macrocytic anemia. Vitamin B-12 differs from other water-soluble vitamins in that it is stored in the liver. In addition, vitamin B-12 has to be protected during its passage through the gastrointestinal tract to the distal ileum, the site of B-12 absorption.

See 21 Hidden Clues to Diagnosing Nutritional Deficiencies, a Critical Images slideshow, to help identify clues to conditions associated with malnutrition.

The objectives of this article are to review the pathophysiology, clinical presentation, diagnosis, and management of megaloblastic anemias. An overview of the physiology and biochemistry of vitamin B-12 and folate under normal and pathological conditions are discussed.

Go to Pediatric Megaloblastic Anemia, Anemia, Chronic Anemia, Myelophthisic Anemia, Hemolytic Anemia, and Sideroblastic Anemias for complete information on these topics.

The common feature in megaloblastosis is a defect in DNA synthesis in rapidly dividing cells. To a lesser extent, RNA and protein synthesis are impaired. Unbalanced cell growth and impaired cell division occur since nuclear maturation is arrested. More mature RBC precursors are destroyed in the bone marrow prior to entering the blood stream (intramedullary hemolysis). [1, 3]

The most common causes for megaloblastosis are vitamin B-12 and folate deficiencies, medications, and direct interference of DNA synthesis by HIV infections and myelodysplastic disorders.

The primary sources of cobalamin (Clb), a cobalt-containing vitamin, are meat, fish, and dairy products and not vegetables and fruit. Cyano Clb is not a natural form but is an in vitro artifact. However, cyano-Clb, the form used in supplements, is readily converted into biologically active forms in humans and other mammals. 5’-Deoxyladenosyl-Clb, methyl-Clb, are the active forms of cobalamin.

Clb is a cofactor for only 2 enzymes in mammals, methionine synthase and L-methylmalonyl-CoA mutase. Methyl-Clb is the cofactor for methionine synthase, and 5’-deoxyladenosyl-Clb is the cofactor for L-methylmalonyl-CoA mutase.

Methionine synthase that requires cofactor methyl-Clb is important for one carbon transfer and is a key enzyme in the methionine cycle. This enzyme is needed to convert homocysteine to methionine involving the transfer of a methyl group. Tetrahydrofolate is a cofactor in this reaction. Methionine, in turn, is required for the synthesis of S-adenosylmethionine (SAM), a methyl group donor used in many biological methylation reactions, including the methylation of sites in DNA and RNA. Diminished activity of methionine synthase or decreased tetrahydrofolate can cause defective DNA maturation and megaloblastic changes. Diminished methionine synthase leads to the “folate trap” in which 5-methyl-THF accumulates and cannot serve as a methyl donor and cannot be converted to the THF needed for methionine synthesis (ie, biological dead end).

L-methylmalonyl-CoA mutase requires cofactor 5-deoxyadenosylcobalamin and catalyzes the conversion of L-methylmalonyl-CoA to succinyl-CoA, a key component of the tricarboxylic acid cycle. This biochemical reaction is important for the production of energy from fats and proteins. Succinyl CoA is also required for the synthesis of hemoglobin, the oxygen carrying pigment in red blood cells. The substrate of methylmalonyl-CoA mutase, methylmalonyl-CoA, is derived from propionyl-CoA from the catabolism of valine, threonine, methionine, thymine, cholesterol, and odd-chain fatty acids.

The mechanisms for patchy demyelination and other neurological consequences of cobalamin deficiency are not well-understood. They appear to be independent and different from those responsible for the development of megaloblastic morphology and anemia. Several theories have been developed for the genesis of cobalamin neuropathy, such as the following [4] :

Reduced SAM and resultant abnormal methylation may be responsible. Methylation reactions are needed for myelin maintenance and synthesis.

Elevated methylmalonic acid (MMA) may be responsible. Cobalamin deficiency leads to reduced cofactor 5-deoxyadenosylcobalamin that is instrumental in an increase in MMA. Increased MMA is associated with the production of abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination

Cobalamin deficiency impacts a network of cytokines and growth factors that can be neurotrophic and others neurotoxic. These factors might play a role in cobalamin related neuropathy. [5]

The sources of folates are ubiquitous, and folate is found in vegetables, fruits, and animal protein. Dietary folic is usually conjugated, polyglutamate folates, and are converted to dihydrofolic acid so they can be absorbed. Dihydrofolate is processed to tetrahydrofolate that participates along with methyl-Clb in the synthesis of methionine. Tetrahydrofolate is conjugated to glutamate to function intracellularly.

The uptake of cobalamin is complex. Dietary cobalamin binds nonspecifically to dietary proteins. Cobalamin is released from food during gastric digestion at a low pH. The released cobalamin then binds to and is protected by R-proteins. R-proteins have a high affinity for finding cobalamin at a low pH. As cobalamin-R-protein complexes enter the duodenum, cobalamin is released from R-proteins because of the alkaline environment and the presence of pancreatic enzymes. Cobalamin released from R-proteins is free to bind to intrinsic factor (IF). IF has a high affinity for binding cobalamin at an alkaline pH, while R-proteins have a low affinity at an alkaline pH. IF is produced in the gastric fundus and cardia. The role of IF is to stabilize cobalamin and transport it to the terminal ileum. Cobalamin-IF complexes are processed by a receptor, cubulin, in the terminal ileum, and cobalamin is released and absorbed.

The absorbed cobalamin is bound to transcobalamin II (TC II). TC II transports cobalamin to cells that internalize and use cobalamin for DNA synthesis. Transcobalamin I (TC I) might be involved in cobalamin storage and is elevated in leukocytes in patients with chronic myelogenous leukemia.

Cobalamin is the only water-soluble vitamin stored in the body. About 3 mg of cobalamin are stored, of which 1 mg is stored in the liver. Hence, it takes 3-5 years to develop a vitamin B-12 deficiency after a total gastrectomy. In contrast, significant amounts of folate are not stored. Clinical evidence of folate deficiency can occur within a month after folate intake is stopped.

Several micrograms of cobalamin are secreted daily in bile and then reabsorbed in the terminal ileum. This enterohepatic cycle can stabilize the daily availability of cobalamin when dietary intake is low.

Physiological folate absorption and transport is receptor mediated. There is no equivalent of IF to stabilize and transport ingested folate. Uptake occurs in the jejunum and throughout the small intestine.

The daily requirement cobalamin is about 5-7 µg/.

Dietary cobalamin deficiency rarely causes megaloblastic anemia, except in strict vegetarians who avoid meat, eggs, and dairy products. Atrophic gastritis and achlorhydria commonly occur in elderly persons. [6] These conditions are responsible for the impaired release of cobalamins bound to food and, hence, the availability of cobalamin. This is a common problem in elderly persons.

There is a failure in intrinsic factor (IF) production in pernicious anemia, owing to the autoimmune destruction of gastric parietal cells. Pernicious anemia is the best-known cause for cobalamin deficiency. Significant amounts of cobalamin are not absorbed in the absence of IF. Pernicious anemia is diagnosed in about 1% of people older than 60 years. The incidence is slightly higher in women than in men. It should be noted that H2 antagonists can inhibit IF secretion.

In pancreatic insufficiency, the alkaline environment in the small intestine is insufficient for release of cobalamin from R-proteins and binding to intrinsic factor. In the Zollinger-Ellison syndrome, the acid environment also prevents binding of cobalamin to intrinsic factor. In both conditions, the diminished binding to intrinsic factor interferes with cobalamin absorption.

Disorders of the terminal ileum can result in cobalamin deficiency. Because the terminal ileum is the site of uptake of cobalamin-IF complexes, tropical sprue, inflammatory bowel disease, lymphoma, and ileal resection can lead to cobalamin deficiency. Tropical sprue is more severe than nontropical sprue (celiac disease) and can be associated with both cobalamin and folate deficiencies. It takes several years for cobalamin deficiency to develop after the onset of these disorders because of the time required to deplete cobalamin reserves.

In the Imerslund-Grasbeck syndrome, there is autoimmune destruction of the ileal receptor, cubulin, for the uptake of cobalamin bound to intrinsic factor.

Blind loop syndrome can result in cobalamin deficiency. Bacterial colonization can occur in intestines deformed by strictures, surgical blind loops, scleroderma, inflammatory bowel disease, or amyloidosis. Bacteria then compete with the host for cobalamin.

The fish tapeworm Diphyllobothrium latum can compete with the host for ingested cobalamin. This organism is most often found in Canada, Alaska, and the Baltic Sea.

Nitrous oxide exposure can cause megaloblastosis by oxidative inactivation of cobalamin. Prolonged exposure to nitrous oxide can lead to severe mental and neurological disorders.

The details of hereditary disorders are beyond the scope of this review, but information can be found in other references. [1, 3]

A partial list of medications that can cause cobalamin deficiency includes purine analogs (6-mercaptopurine, 6-thioguanine, acyclovir), pyrimidine analogues (5-fluorouracil, 5-azacytidine, zidovudine), ribonucleotide reductase inhibitors (hydroxyurea, cytarabine arabinoside), and drugs that affect cobalamin metabolism (p -aminosalicylic acid, phenformin, metformin). [1, 7, 8]

The daily requirement for adults is about 0.4 mg/d. Storage is limited, and folate deficiency develops about 3-4 weeks after the cessation of folate intake.

Folate content in foods and the preparation of foods are major causes for folate deficiency, especially in elderly persons. Folates are very thermolabile. Therefore, excessive heating can lead to inactivation, especially when foods are excessively diluted in water. In the United States, most people obtain sufficient folate from fortified foods. However, alternative diets may contain little folate.

Increased demand can result in deficiency. There is an increased need for folate in hemolysis, pregnancy, lactation, rapid growth, hyperalimentation, renal dialysis, psoriasis, and exfoliative dermatitis.

Intestinal disorders that impede folate absorption include tropical sprue, nontropical sprue (celiac disease or gluten sensitivity), amyloidosis, and inflammatory bowel disease.

With alcoholism, the bioavailability of folate and folate-dependent biochemical reactions can be impaired.

A partial list of medications that can cause folate deficiency includes phenytoin, metformin, phenobarbital, dihydrofolate reductase inhibitors (trimethoprim, pyrimethamine), methotrexate and other antifolates, sulfonamides (competitive inhibitors of 4-aminobenzoic acid), and valproic acid.

The details of hereditary disorders that cause folate deficiency are beyond the scope of this review, but information can be found in other references). [1, 3, 9, 10]

Megaloblastosis in HIV infection and myelodysplastic disorders is due to a direct effect on DNA synthesis in hematopoietic and other cells.

Faulty preparation of foods and folate deficiency during pregnancy are the most common causes of megaloblastic anemias. Pernicious anemia is less common. About 1 in 7,500 people in the United States develops pernicious anemia each year. However, current folate administration during pregnancy and vitamin supplementation in elderly persons has decreased the incidence of megaloblastosis.

The frequency of megaloblastosis is highest in countries in which malnutrition is rampant and routine vitamin supplementation for elderly individuals and pregnant women is not available.

Pernicious anemia and folate deficiencies usually occur in individuals older than 40 years, and the prevalence increases in older populations.

The incidence of pernicious anemia is reported to be higher in Sweden, Denmark, and the United Kingdom than in other developed countries.

The prognosis is favorable if the etiology of megaloblastosis has been identified and appropriate treatment has been instituted. However, patients are at risk for hypokalemia and anemia-related cardiac complications during therapy for cobalamin deficiency.

Folate deficiency during pregnancy can lead to neural tube defects and other developmental disorders in the fetus. However, folate in prenatal vitamins given during pregnancy has reduced these morbidities. [11, 12]

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Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Srikanth Nagalla, MBBS, MS, FACP Associate Professor of Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

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.

Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

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.

Thomas H Davis, MD, FACP Associate Professor, Fellowship Program Director, Department of Internal Medicine, Section of Hematology/Oncology, Geisel School of Medicine at Dartmouth

Thomas H Davis, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Education, American College of Physicians, New Hampshire Medical Society, Phi Beta Kappa, Society of University Urologists

Disclosure: Nothing to disclose.

Megaloblastic Anemia

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