eMedicine Specialties > Hematology > Red Blood Cells and Disorders
Megaloblastic Anemia
Updated: Jan 29, 2007
Introduction
Background
Megaloblastic anemias are a heterogeneous group of disorders that share common morphologic characteristics. Erythrocytes are larger and have higher nuclear-to-cytoplasmic ratios compared to normoblastic cells. Neutrophils can be hypersegmented, and megakaryocytes are abnormal. On the molecular level in megaloblastic cells, the maturation of nuclei is delayed, while cytoplasmic development is normal.
Megaloblastosis is a generalized disorder because nonhematopoietic cells, such as gastrointestinal and uterine cervical mucosal cells, can also have megaloblastic features. The etiology of megaloblastic anemias is diverse, but a common basis is impaired DNA synthesis. The most common causes of megaloblastosis are cobalamin (vitamin B-12) and folate deficiencies. The usual causes of cobalamin deficiency are pernicious anemia (PA, see Pernicious Anemia), failure of absorption of cobalamin in the terminal ileum, and the effects of medications. Folate deficiency is usually due to folate-poor diets but may also occur in patients with tropical sprue, in patients who are pregnant, and in patients on antifolate or other medications. Current routine folate replacement during pregnancy and folate-containing multivitamin supplementation for elderly persons has led to a decline in the frequency of folate deficiency.
Some patients can be asymptomatic. The development of megaloblastic anemia is usually insidious; therefore, patients are often relatively asymptomatic because they have had time to adjust to the marked fall in hemoglobin (Hgb) levels. Patients with cobalamin deficiency may develop debilitating neurological impairment that may develop independently of anemia.
Recent trends in medical care have emphasized early therapy. Folate supplementation is recommended to prevent the atherosclerosis and thromboembolic events by reducing homocysteine levels. Folate is given during pregnancy to prevent developmental defects in the fetus. Mild cobalamin deficiencies and incipient cobalamin-related neuropsychiatric abnormalities have recently been identified in some individuals, and prompt early treatment with cobalamin is recommended to avoid progression of mental deterioration and neurological complications. A recent review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, and male reproduction) and folate nutrition and metabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins (Tamura, 2006).
Pathophysiology
The molecular basis for megaloblastosis is a failure in the synthesis and assembly of DNA. The most common causes of megaloblastosis are cobalamin and folate deficiencies. Cobalamin metabolism and folate metabolism are intricately related, and abnormalities in these pathways are believed to lead to the attenuated production of DNA.
Methotrexate-induced megaloblastosis has been ascribed to a deficiency in deoxythymidine triphosphate (dTTP) that is consumed by the methyl folate trap. Evidence exists that megaloblastosis is caused by interference of folate metabolism by the inhibition of methionine synthesis. However, because of dietary folate deficiency, the size of the dTTP pool is normal or increased in persons with megaloblastosis.
Impairment in the deoxyuridine monophosphate (dUMP) ¡ú deoxythymidine monophosphate (dTMP) pathway may be responsible for nutritional megaloblastosis. Despite this information, the biochemical basis for megaloblastosis is not fully understood. This is especially true of the cobalamin-related neuropathy that can occur independently of megaloblastic changes in hematopoietic cells. One hypothesis for the cause of cobalamin neuropathy is that a defect exists in the conversion of adenosyl-cobalamin-dependent conversion of methylmalonyl coenzyme A to succinyl coenzyme A.
A hallmark of megaloblastic anemia is ineffective erythropoiesis, as evidenced by erythroid hyperplasia in the bone marrow, a decreased peripheral reticulocyte count, and an elevation in lactate dehydrogenase (LDH) and indirect bilirubin levels. The pathogenesis of these findings is the intramedullary destruction of fragile and abnormal megaloblastic erythroid precursors.
An understanding of the source of cobalamin and folate is important to understand the pathogenesis of the development of megaloblastosis. Dietary intake is the source of cobalamin and folate because humans cannot synthesize these substances. Cobalamin must be bound to intrinsic factor (IF), and this complex is taken up in the terminal ileum. Once absorbed, cobalamin is bound to another protein, transcobalamin II (TCII), and is transported to storage sites. Abnormalities in any of these steps in cobalamin transport can lead to deficiencies in this substance. Considerable amounts of cobalamin are accumulated in storage sites; this explains why years elapse before cobalamin deficiency develops in patients who cannot take up dietary cobalamin.
Although the processing and transport of ingested folate is complex, folate-induced megaloblastosis is rarely caused by abnormalities in transport but instead is most often caused by dietary insufficiency. Folate deficiency can be caused by malabsorption in patients with sprue. In contrast to cobalamin, very little folate is stored; this explains why folate deficiency can occur within months of cessation of folate ingestion.
Megaloblastosis can also be caused by disorders in which cobalamin and folate uptake and metabolism are not affected. Myeloproliferative syndromes and viral infections (eg, HIV) can lead to megaloblastosis by disrupting DNA synthesis. Megaloblastosis can occur in patients who are on certain medications, including many cancer chemotherapy drugs.
Frequency
United States
Because the etiology is diverse, determining a numerical estimate of the frequency of megaloblastic anemias is difficult.
Dietary and pregnancy-related folate deficiencies are probably the most common causes of megaloblastic anemias. However, current folate supplementation during pregnancy and vitamin supplementation for elderly persons has resulted in a low frequency of these forms of megaloblastosis.
Megaloblastosis may be caused by a small number of drugs, for instance antifolates such as methotrexate, purine analogues such as azathioprine, pyrimidine analogs such as 5-fluorouracil, ribonucleotide reductase inhibitors such as hydroxyurea, anticonvulsants such as phenytoin, and oral contraceptives.
The frequency of pernicious anemia is 0.25-0.5 cases per 1000 persons in their seventh decade of life. Other forms of megaloblastosis are rare.
International
The frequency of PA is reported to be higher in Sweden, Denmark, and the United Kingdom (100-130 cases per 100,000 population). Note that 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.
Mortality/Morbidity
The major morbidity of cobalamin deficiency is related to the severity of the anemia. In cobalamin deficiency, neurological impairment and anemia are major complications. Recent studies indicate that folate deficiency may also lead to neurological impairment. Megaloblastic anemia is more likely to be detected and treated in most industrial and Western nations. Therefore, the morbidity and mortality due to megaloblastosis have been reduced.
- Neurological impairment can occur in patients who are not anemic. The inadvertent treatment of patients with cobalamin deficiency with folate corrects the anemia but will not halt the progression of the neurological disorder. Therefore, neurological impairment continues to be a problem in some patients with cobalamin deficiency.
- Evidence suggests that folate deficiency during pregnancy can lead to neural tube defects and other development disorders in the fetus. However, folate supplements during pregnancy have reduced this morbidity.
Race
Older literature indicated that pernicious anemia occurs primarily in white persons and is more likely to occur in persons of Scandinavian descent and others of northern European descent. Recent evidence suggests that pernicious anemia also occurs in Asian and African American persons, although with much lower frequency.
Age
Pernicious anemia usually occurs in individuals older than 40 years, and the prevalence increases in older populations. Dietary folate deficiency also increases in older populations because of poor diets. Boiling foods in water dilutes folates, and excessive heating destroys folates.
Clinical
History
Anemia is a common feature of all megaloblastic anemias. However, most patients are relatively asymptomatic because anemia usually develops slowly. Therefore, the absence of symptoms of anemia does not exclude the diagnosis of megaloblastosis. When a marked decrease in Hgb occurs, patients can present with dyspnea, light-headedness, palpitations, and heart failure. Patients with cobalamin deficiency can present primarily with neurological impairment. Specific aspects of the etiology of cobalamin and folate deficiencies are described below.
- When obtaining a history with findings of possible cobalamin deficiency, obtaining evidence of anemia and neurological impairment first is important.
- Some patients can have gastrointestinal symptoms such as loss of appetite, weight loss, nausea, and constipation.
- Patients may have a sore tongue and canker sores.
- Patients may have symptoms of anemia.
- Early neurological symptoms include paresthesias in the feet and fingers, poor gait, and memory loss. At later stages, patients can have severe disturbances in gait, loss of position sense, blindness due to optic atrophy, and psychiatric disturbances. In some patients, neurological impairment can occur without anemia. Therefore, neurological symptoms may range from mild to severe, and cobalamin deficiency should be considered even with minimal neurological symptoms and the absence of anemia.
- In the next phase of eliciting relevant history, obtaining a history that can help distinguish between the causes, such as inadequate diets, malabsorption, medications, and congenital disorders, is important.
- A history of folate administration without vitamin B-12 therapy should be documented because folate may partially correct hematological abnormalities but will not stop the progression of neuropsychiatric complications.
- Dietary insufficiency of cobalamin is a rare cause of megaloblastosis. A history of a long-standing vegetarian diet without dairy products or eggs can suggest the possibility of this etiology.
- Pernicious anemia is associated with autoimmune disorders. A coexistent history of autoimmune disorders such as thyroid disorders, type I diabetes, Addison disease, hypoparathyroidism, or autoimmune hemolytic anemia suggests the possibility of pernicious anemia.
- A history of a gastrectomy suggests the possibility of cobalamin deficiency. Approximately 3-5 years must elapse for cobalamin deficiency to occur after total gastrectomy and approximately 12 years must elapse after partial gastrectomy.
- A history of ileal resection, regional ileitis, and small intestinal lymphoma suggests intestinal malabsorption of cobalamin.
- Previous gastric or intestinal surgery may also suggest the possibility of blind loop syndrome.
- Zollinger-Ellison syndrome can cause megaloblastosis.
- Handling or eating raw fish tapeworm suggests that the entrenchment of the tapeworm in the small intestine may be responsible for cobalamin deficiency.
- A history of taking medications mentioned in Causes or exposure to nitrous oxide may suggest cobalamin deficiency.
- A history of megaloblastosis since childhood suggests a congenital cause of cobalamin deficiency.
- Obtaining a history in support of folate deficiency should focus on the patient's diet, evidence of increased folate turnover and consumption, indications of malabsorption and sprue, pregnancy, and medications.
- Folate deficiency develops rapidly because folate stores are minimal.
- Folate deficiency manifests primarily as anemia, but recent evidence indicates that folate deficiency may also lead to neurological syndromes.
- Dietary insufficiency is the most common cause of folate deficiency. A typical patient is an elderly person whose diet is inadequate or who cooks foods diluted in water with excessive heat. Dilution and heating can destroy folate. Alternative diets that are low in folate can produce folate deficiency.
- Impaired absorption may result in folate deficiency. Nontropical sprue should be considered in patients who have megaloblastosis and symptoms of malabsorption, such as weight loss, abdominal distention, diarrhea, and steatorrhea. These patients often have metabolic bone disease or bleeding due to deficiencies in vitamin K–dependent factors. They may describe a sensitivity to gluten. Megaloblastosis may not be evident because of the superimposed iron deficiency.
- Tropical sprue can cause folate deficiency. In addition to signs of malabsorption, these patients have a history of living or visiting tropical regions. Tropical sprue may develop years after the patients visited the tropics.
- Other intestinal disorders that may cause megaloblastosis as a result of folate malabsorption may include regional enteritis, intestinal lymphoma, surgical intestinal resection, amyloidosis, Whipple disease, and scleroderma.
- Increased folate requirements can occur during pregnancy because of transfer of folate to the fetus and during lactation. Dilantin therapy increases the requirement for folate. Patients with psoriasis and exfoliative dermatitis require additional folate because of the increased turnover of epidermal cells.
- Miscellaneous causes of folate deficiency can occur during hyperalimentation and hemodialysis because folate is lost in dialysis fluid. Megaloblastosis in persons with alcoholism is often due to coexistent folate deficiency.
- A history of drugs and antifolate agents mentioned in Causes should be elicited because these agents can cause folate deficiency.
- Folate deficiency can occur in infants who are fed goat milk (low folate content). Infants who are on synthetic diets for congenital disorders can develop folate deficiency. Premature infants can develop folate deficiency in the presence of infection or diarrhea.
- A lifelong history of megaloblastosis or folate deficiency suggests a congenital disorder.
- A history of HIV infection or a myelodysplastic syndrome may suggest that megaloblastosis is due to a direct effect of these disorders on bone marrow stem cells.
Physical
The physical examination may reveal findings indicative of the consequences of anemia in most persons with megaloblastic anemias.
- Neuropsychiatric signs are usually found only in patients with cobalamin deficiencies.
- Findings may indicate predisposing conditions or underlying disorders. For example, signs of autoimmune disorders that are associated with PA may be detected.
- Physical examination findings may range from barely detectable to markedly abnormal.
- Evidence of malabsorption indicates that the patient has sprue.
- Patients may have a lemon-yellow hue due to the combination of anemia and an increased level of indirect bilirubin. When the decrease in the Hgb level is severe, evidence of an uncompensated anemia is present, such as tachycardia and dyspnea. In many cases, the fall in the Hgb level is moderate and develops slowly; therefore, patients have compensated anemias characterized only by weakness.
- Glossitis, characterized by a smooth tongue due to loss of papillae, occurs in persons with cobalamin deficiency.
- Dermatological signs include hyperpigmentation of the skin and depigmentation of the hair because of increased melanin synthesis.
- Neurological signs occur primarily in persons with cobalamin deficiencies but may also occur in persons with folate deficiency. The signs can vary from minimal to severe. Peripheral neuropathy, abnormal gait, loss of balance, loss of proprioception and vibratory senses, blindness due to optic atrophy, depression, loss of memory, and psychiatric disorders may occur.
- Neuropsychiatric complications of folate deficiency are usually limited to irritability and minimal changes in personality.
- Abdominal scars may be evident from gastrectomies, ileal resections, or other procedures that may lead to blind loop syndrome.
- When cobalamin deficiency is caused by lack of absorption in the terminal ileum due to regional ileitis, physical evidence of this disorder may be present.
- Patients with pernicious anemia may have signs of autoimmune disorders, including thyroid disorders, type I diabetes, and autoimmune hemolytic anemias.
- Patients with nontropical and tropical sprue may have signs of malabsorption such as weight loss, abdominal distention, diarrhea, and steatorrhea. These patients often have metabolic bone disease or bleeding due to deficiencies in vitamin K–dependent factors.
- Patients who have megaloblastosis due to HIV infection or myelodysplastic syndromes usually have signs of these disorders.
- Children with inborn errors that cause folate and cobalamin deficiencies or inborn errors that have a direct effect on stem cells may have signs of these congenital disorders.
Causes
Megaloblastic anemias can be caused by cobalamin deficiency or folate deficiency. Disorders such as myeloproliferative syndromes can disrupt DNA synthesis directly. Many pharmaceutical agents also interfere with DNA synthesis and cause megaloblastic changes in hematopoietic and other frequently dividing cells. The causes are diverse and are discussed below.- Cobalamin (vitamin B-12) deficiency can be caused by impaired gastric or intestinal absorption, inadequate dietary intake, drugs, or congenital errors in metabolism.
- Nutritional deficiency: This is a rare etiology, but it can occur in individuals who are on vegetarian diets without milk, cheese, and eggs over a number of years because depletion of cobalamin reserves stored in the liver takes years.
- Food-cobalamin malabsorption: This is characterized by the inability to release cobalamin from food, possibly because of gastric anacidity. As a result, cobalamin cannot bind to intrinsic factor (IF) and cannot be taken up. This entity has been recognized recently, and its prevalence as a cause of megaloblastosis requires further study.
- Pernicious anemia: This is the best-known cause of cobalamin deficiency. This disorder results from the absence of functional IF, which leads to impaired gastric absorption of cobalamin. In most cases, the loss of functional IF is caused by the autoimmune destruction of gastric parietal cells. However, some cases of pernicious anemia can be traced to a hereditary lack of production of IF.
- Gastrectomy: Patients develop pernicious anemia following gastrectomy because of the lack of a source of IF. Development of overt megaloblastosis requires approximately 3-5 years following total gastrectomy and approximately 12 years following partial gastrectomy. The lag is because of the time required to deplete cobalamin stores.
- Zollinger-Ellison syndrome: In this disorder, the secretion of large amounts of acid cannot be neutralized by pancreatic secretions. Therefore, the persistent acidity inactivates pancreatic proteases in the duodenum and prevents transfer of cobalamin from r-factor to IF. This factor (r-factor) is a cobalamin binder secreted by salivary glands.
- Severe abnormalities in the terminal ileum due to ileal resection, regional ileitis, or lymphoma: The terminal ileum is the site of uptake of cobalamin-IF complexes; therefore, these disorders can lead to cobalamin deficiencies. Several years are required for cobalamin deficiency to occur following the onset of these disorders because of the time required to deplete cobalamin reserves.
- Diphyllobothrium latum (ie, fish tapeworm): When the tapeworm is entrenched in the small intestine, it competes with the host for ingested cobalamin. The organism is most often found in Canada, Alaska, and the Baltic Sea.
- Blind loop syndrome: This syndrome involves bacterial colonization of intestines that are either deformed because of strictures, surgical blind loops, or anastomoses or abnormal because of scleroderma or amyloidosis. Bacteria compete with the host for cobalamin.
- Nitrous oxide: Methyl chloride is destroyed rapidly after prolonged exposure to nitrous oxide and can produce megaloblastosis.
- Folate deficiency can be due to dietary deficiency, lack of absorption, or increased folate consumption. In contrast to cobalamin deficiency, folate deficiency develops rapidly because folate stores are minimal.
- Folate depletion: This usually occurs because of dietary insufficiency, the destruction of folate by excessive heating of diluted foods, or consuming alternative diets that are low in folate.
- Impaired absorption: These patients often have metabolic bone disease or bleeding due to deficiencies in vitamin K–dependent factors. They may describe a sensitivity to gluten. Megaloblastosis may not be evident because of superimposed iron deficiency.
- Tropical sprue: Tropical sprue has a more severe effect on the distal ileum than nontropical sprue. Therefore, tropical sprue can lead to cobalamin deficiency and folate deficiencies.
- Other intestinal disorders: Megaloblastosis can occur because of folate malabsorption in patients with a history of regional enteritis, intestinal lymphoma, surgical intestinal resection, amyloidosis, Whipple disease, and scleroderma.
- Increased turnover or requirements: This can occur during pregnancy because of the transfer of folate to the fetus and during lactation. Dilantin therapy increases the requirement for folate. Patients with psoriasis and exfoliative dermatitis require additional folate because of the increased turnover of epidermal cells.
- Infants: Folate deficiency can occur in infants on a diet of goat milk (low folate content), premature infants with infection or diarrhea, and infants on synthetic diets for congenital disorders.
- Miscellaneous: Folate deficiency can occur during hyperalimentation and hemodialysis because folate is lost in dialysis fluid. Megaloblastosis in persons with alcoholism is often due to folate deficiency.
- Drugs that can cause megaloblastic anemia are as follows:
- Antifolates - Methotrexate, aminopterin
- Purine analogs - 6-Mercaptopurine, 6-thioguanine, acyclovir
- Pyrimidine analogs - 5-Fluorouracil, 5-azacytidine, zidovudine
- Ribonucleotide reductase inhibitors - Hydroxyurea, cytarabine arabinoside
- Anticonvulsants - Phenytoin, phenobarbital, primidone
- Other drugs that can depress folates - Oral contraceptives, glutethimide, cycloserine
- Drugs that affect cobalamin metabolism -p -Aminosalicylic acid, metformin, phenformin, colchicine, neomycin, biguanides
- Megaloblastic anemia in children can be caused by the following:
- Inborn errors of cobalamin metabolism
- Selective malabsorption of cobalamin with normal secretion of IF (Imerslünd-Grasbeck syndrome).
- Other causes are congenital IF deficiency, TCII deficiency, r-binder deficiency
- Methylmalonic aciduria
- Homocystinuria
- Methylmalonic aciduria and homocystinuria
- Inborn errors of folate metabolism
- Congenital folate malabsorption
- Dihydrofolate reductase deficiency
- N 5 -methyl tetrahydrofolate - Homocysteine methyltransferase deficiency
- Other inborn errors
- Hereditary orotic aciduria
- Lesch-Nyhan syndrome
- Thiamine-responsive megaloblastic anemia - This condition is an autosomal recessive disorder with features that include megaloblastic anemia, deafness, and diabetes mellitus. Thiamine uptake into cells is disturbed, and treatment with pharmacological doses of thiamine ameliorates the megaloblastic anemia and diabetes mellitus.
- Neoplastic or viral infections (eg, myelodysplastic syndromes, other clonal neoplastic diseases) and HIV infections - Can directly affect bone marrow stem cells
- Inborn errors of cobalamin metabolism
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| References |
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Further Reading
Keywords
blood disorder, megaloblastosis, cobalamin deficiency, vitamin B-12 deficiency, folate deficiency, pernicious anemia, PA, cobalamin neuropathy, ineffective erythropoiesis, food-cobalamin malabsorption, gastrectomy, Zollinger-Ellison syndrome, ZES, ileal resection, regional ileitis, intestinal lymphoma, Diphyllobothrium latum, D latum, fish tapeworm, blind loop syndrome, nitrous oxide exposure, NO exposure, surgical intestinal resection, amyloidosis, Whipple disease, scleroderma, psoriasis, exfoliative dermatitis, pregnancy, neural tube defects, drug reactions, chemotherapy, neurological impairment
