Megaloblastic Anemia 

Megaloblastic anemias are a heterogeneous group of disorders that share common morphologic characteristics. The morphological hallmark of megaloblastosis is a megaloblast. Megaloblasts are large cells with an increased nuclear/cytoplasmic ratio in which nuclear maturation is delayed, while cytoplasmic maturation is more advanced. Peripheral smears reveal that RBCs are macrocytic and occasional megaloblasts are present. Megaloblasts are usually abundant in bone marrow aspirates. Megaloblastic changes are not limited to RBCs since hypersegmented neutrophils can be seen on peripheral smears, and pancytopenia occurs in megaloblastic anemias.

Megaloblastosis is a generalized disorder involving most rapidly growing cells, such as gastrointestinal and uterine cervical mucosal cells. The etiology of megaloblastosis is diverse, but a common basis is impaired DNA synthesis. The most common causes of megaloblastosis are cobalamin (vitamin B-12) and folate deficiency.

Serious organ failure can occur in individuals with megaloblastosis. Both vitamin B-12 and folate deficiencies can cause memory loss, depression, personality changes, and psychosis, as well as peripheral neuropathy. Vitamin B-12 deficiency can cause subacute combined dorsal and lateral spinal column degeneration, in which patients develop ataxia, become weak, and lose proprioceptive and vibratory senses. If not treated, mental and neurological changes can become permanent.^{[1, 2]}

The requirement for folic acid increases during pregnancy due to increased metabolism and cell turnover. Serious neural tube defects and other developmental abnormalities can occur in the fetus if additional folate has not been provided prenatally.

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 Anemia, Chronic Anemia, Megaloblastic 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 cobalamin (Cbl) and folate deficiencies, medications, and direct interference of DNA synthesis by HIV infections and myelodysplastic disorders.

Cobalamin

The primary sources of vitamin B-12 (a cobalt-containing vitamin) are meat, fish, and dairy products. Cyano - Clb is not a natural form but is an in vitro artifact. 5’-Deoxyladenosyl-Clb, methyl-Clb, and hydroxo-Clb are active forms and occur naturally.

Complex interactions between cobalamins (5’-deoxyladenosyl-Clb, methyl-Clb) and folates (pterolylpolyglutamates [PteGlus]) are important for the synthesis of methionine and thymidine and, hence, DNA synthesis. Perturbation in the availability and the metabolism of cobalamin and folate are the primary causes for the impairment of DNA synthesis in megaloblastosis. An in-depth review of this subject is beyond the scope of this article but is detailed in several references.^{[1, 3]} The mechanisms for patchy demyelination and other neurological consequences of cobalamin deficiency appear to be independent and different from those responsible for the development of a megaloblastic anemia.

The uptake of cobalamin is complex. Dietary cobalamin binds nonspecifically to proteins, and gastric digestion at a low pH releases cobalamin from these proteins. Released cobalamin then binds to R-proteins. As the cobalamin-R-protein complexes enter the duodenum, R-proteins are degraded by pancreatic enzymes and cobalamin is released. Cobalamin released from R-proteins is free to bind to intrinsic factor (IF). 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-intrinsic factor complexes are processed by receptors 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.

The sources of folates or PteGlus are ubiquitous, and folates are found in vegetables, fruits, and animal protein. Both monoglutamate and polyglutamate forms exist in nature.

Uptake of folates

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

Major causes for cobalamin deficiency

The daily requirement cobalamin is about 5-7 µg/d. As mentioned, large amounts of cobalamin are stored in liver and other sites. Therefore, cobalamin deficiency only develops about 3-4 years after the cessation of cobalamin uptake.

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.^[4] These conditions are responsible for the impaired release of protein-bound cobalamins and, hence, can interfere with cobalamin uptake. This is a common problem in elderly persons.

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

In pancreatic insufficiency, pancreatic enzymes are not available to facilitate the release of cobalamins from R-proteins and thus cobalamins are not absorbed. In Zollinger-Ellison syndrome, the secretion of large amounts of acid inactivates pancreatic enzymes.

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.

Blind loop syndrome can result in cobalamin deficiency. Bacterial colonization can occur in intestines deformed from 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, 5]}

Major causes for folate deficiency

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.

Dietary folate deficiency is a cause. In the United States, most people obtain sufficient folate from fortified foods. However, alternate diets may contain little folate. The preparation of foods is a major cause for folate deficiency, especially in elderly persons. Folates are very thermolabile. Therefore, excessive heating can lead to inactivation, especially when foods are diluted in water.

Failure to increased folate supplementation in response to increased demand can result in deficiency. There is an increased need for folate in the face of 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, 6, 7]}

Other causes for megaloblastosis

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

United States statistics

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 7500 people in the United States develops pernicious anemia each year. However, current folate administration during pregnancy and vitamin supplementation in elderly persons have decreased the incidence of megaloblastosis.

International statistics

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.

Demographics

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.^{[8, 9]}