REVIEW CME MOC Daniel S. Socha, MD Sherwin I. DeSouza, MD Aron Flagg, MD Department of Laboratory Medicine, Department of Hematology and Medical Oncology, Department of Pediatric Hematology and Oncology, Robert J. Tomsich Pathology and Laboratory Taussig Cancer Institute, Cleveland Clinic Yale School of Medicine, New Haven, CT Medicine Institute, Cleveland Clinic Mikkael Sekeres, MD, MS Heesun J. Rogers, MD, PhD Department of Hematology and Medical Oncology and Department Department of Laboratory Medicine, Robert J. Tomsich Pathology and of Translational Hematology and Oncology Research, Taussig Laboratory Medicine Institute,Cleveland Clinic; Assistant Professor, Cancer Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner Cleveland Clinic Lerner College of Medicine of Case Western Reserve College of Medicine of Case Western Reserve, Cleveland, OH University, Cleveland, OH Severe megaloblastic anemia: Vitamin defi ciency and other causes ABSTRACT ot all megaloblastic anemias result N from vitamin defi ciency, but most do. De- Megaloblastic anemia causes macrocytic anemia from termining the underlying cause and initiating ineffective red blood cell production and intramedullary prompt treatment are critical, as prognosis and hemolysis. The most common causes are folate (vitamin management differ among the various condi- B9 ) defi ciency and cobalamin (vitamin B12) defi ciency. tions. Megaloblastic anemia can be diagnosed based on char- This article describes the pathobiology, acteristic morphologic and laboratory fi ndings. However, presentation, evaluation, and treatment of se- other benign and neoplastic diseases need to be con- vere megaloblastic anemia and its 2 most com- sidered, particularly in severe cases. Therapy involves mon causes: folate (vitamin B9) and cobalamin treating the underlying cause—eg, with vitamin supple- (vitamin B12) defi ciency, with 2 representative mentation in cases of defi ciency, or with discontinuation case studies. of a suspected medication. ■ MEGALOBLASTIC ANEMIA OVERVIEW KEY POINTS Megaloblastic anemia is caused by defec- The hallmark of megaloblastic anemia is macrocytic ane- tive DNA synthesis involving hematopoi- mia (mean corpuscular volume > 100 fL), often associ- etic precursors, resulting in ineffective red blood cell production (erythropoiesis) and ated with other cytopenias. intramedullary hemolysis. Macrocytic ane- mia with increased mean corpuscular vol- Dysplastic features may be present and can be diffi cult to ume (MCV), defi ned as more than 100 fL, differentiate from myelodysplastic syndrome. is the hallmark of megaloblastic anemia, but leukopenia and thrombocytopenia are also Megaloblastic anemia is most commonly caused by folate frequently present. defi ciency from dietary defi ciency, alcoholism, or malab- The incidence of macrocytosis is as high as 4% in the general population, but megalo- sorption syndromes or by vitamin B12 defi ciency, usually due to pernicious anemia. blastic anemia accounts for only a small frac- tion.1 Nonmegaloblastic causes of macrocytic anemia include ethanol abuse, myelodysplas- Both vitamin defi ciencies cause hematologic signs and tic syndrome, aplastic anemia, hypothyroid- 2,3 symptoms of anemia; vitamin B12 defi ciency also causes ism, liver disease, and drugs. Although these neurologic symptoms. causes are associated with increased MCV, they do not lead to the other features of mega- Oral supplementation is available for both vitamin loblastic anemia. The most frequent causes of megaloblastic defi ciencies; intramuscular vitamin B12 supplementa- tion should be used in cases involving severe neurologic anemia are defi ciencies of vitamin 9B (folate) or vitamin B (cobalamin) (Table 1). Less- symptoms or gastric or bowel resection. 12 frequent causes include congenital disorders doi:10.3949/ccjm.87a.19072 (inborn errors of metabolism), drugs (particu- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 87 • NUMBER 3 MARCH 2020 153 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. MEGALOBLASTIC ANEMIA TABLE 1 Characteristics of vitamin B12 vs folate defi ciency Vitamin B12 defi ciency Folate defi ciency Etiology Lack of intrinsic factor: pernicious anemia Dietary defi ciency: alcoholism, countries without food fortifi cation Malabsorption: celiac disease, prior gastric or ileal surgery Malabsorption: developed countries Dietary defi ciency less common Increased demand: pregnancy, hemolytic anemia, eczema Clinical Hematologic fi ndings: cytopenias Hematologic fi ndings: cytopenias presentation Neuropsychiatric symptoms: paresthesias, decreased proprioception and vibratory sense, dementia, confusion Evaluation Clinical history and physical examination: symptoms sec- Clinical history and physical examination: ondary to anemia and hemolysis, neurologic symptoms similar to vitamin B12 defi ciency, except no neurologic symptoms Laboratory testing: serum vitamin B12, methylmalonic acid, homocysteine, antiparietal cell and anti-intrinsic factor Laboratory testing: serum folate, red blood antibodies, serum gastrin cell folate, methylmalonic acid, homocysteine Gastric biopsy for suspected pernicious anemia Differential Other macrocytic anemias without megaloblastic features: Other macrocytic anemias without megalo- diagnosis liver disease, thyroid dysfunction, alcohol abuse blastic features: liver disease, thyroid dysfunc- tion, alcohol abuse Myelodysplastic syndrome, acute myeloid leukemia Myelodysplastic syndrome, acute myeloid Nitrous oxide exposure leukemia Medication effect Medication effect Treatment Parenteral vitamin B12 1–2 times per week until symptoms Oral folate daily improve, then monthly High-dose oral vitamin B12 daily Monitoring Clinical follow-up for improvement of neurologic symptoms Monitor hematologic response: and follow-up complete blood cell count Monitor hematologic response: complete blood cell count Pernicious anemia: consider monitoring methylmalonic acid larly chemotherapeutics and folate antago- Folate defi ciency has 3 main causes4,5: nists), micronutrient defi ciencies, and nitrous • Reduced intake from diets lacking folate oxide exposure.4,5 (rare in countries with vitamin fortifi cation) and alcoholism (see Case 1) ■ FOLATE DEFICIENCY • Decreased absorption from disorders affect- Folate is found in green leafy vegetables, fruits, ing nutrient absorption in the small bowel, nuts, eggs, and meats. Normal body stores of eg, celiac disease, infl ammatory bowel dis- folate are 5 to 30 mg. The recommended daily ease, and tropical sprue allowance depends on age, sex, and pregnancy • Increased demand from pregnancy, hemo- status, but is generally 400 μg in adults and lytic anemia, puberty, and eczematous con- 600 μg during pregnancy.6 ditions. 154 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 87 • NUMBER 3 MARCH 2020 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. SOCHA AND COLLEAGUES ■ VITAMIN B12 DEFICIENCY TABLE 2 Vitamin B is produced by microorganisms 12 Causes of vitamin B defi ciency and is found almost exclusively in foods of 12 animal origin. Normal body stores of vitamin Common causes (related to malabsorption) B12 are 3 to 5 mg, and the recommended adult Autoimmune gastritis (pernicious anemia) daily intake is 2.4 μg.7,8 Celiac disease Causes of vitamin B12 defi ciency are listed in Table 2. Dietary defi ciency of vitamin B12 Infl ammatory bowel disease occurs less frequently than folate defi ciency because body stores can last for years owing Surgical gastrectomy, gastric bypass, ileal resection to effi cient enterohepatic recycling mecha- Less common causes nisms. Although uncommon, dietary B12 defi ciency can occur even in industrialized Nutritional countries in strict vegans and vegetarians, or (strict vegans, breastfed infants of mothers with vitamin B12 defi ciency) in breastfed infants of mothers with vitamin Nitrous oxide abuse B defi ciency. 12 Diphyllobothrium latum infection Complex absorption pathway Pancreatic insuffi ciency Dietary absorption of vitamin B12 is a complex process that begins with haptocorrin (also Drug effect (metformin, proton pump inhibitors) known as transcobalamin I or R-binder) pro- Inherited disorders affecting intrinsic factor or the cubam receptor duction by the salivary glands. Rare inherited disorder When food is digested in the stomach by (eg, methylmalonic acidemia, transcobalamin II defi ciency) gastric acid and pepsin, free vitamin B12 is re- leased and binds to haptocorrin.4,9 Information from references 4, 5, and 7. Simultaneously, gastric parietal cells se- crete intrinsic factor, which cannot interact Pernicious anemia Macrocytic with the vitamin B12-haptocorrin complex. and autoimmune gastritis Not until food moves into the duodenum, Chronic atrophic autoimmune gastritis is an anemia where trypsin and other pancreatic enzymes autoimmune process directed specifi cally at ei- with a mean cleave haptocorrin, is vitamin B free to 12 ther gastric parietal cells or intrinsic factor, or corpuscular bind to intrinsic factor.9 The resultant vi- both.10–12 Parietal cell damage leads to reduced tamin B12-intrinsic factor complex binds to production of gastric acid and intrinsic factor, volume > 100 fL the cubam receptor on the mucosal surface accompanied by a compensatory increase in is the hallmark of enterocytes in the ileum. From there, vi- serum gastrin levels. Decreased intrinsic fac- of megalo- tamin B12 is transported into the circulation tor leads to signifi cantly reduced absorption