eMedicine Specialties > Hematology > Red Blood Cells and Disorders
Pernicious Anemia: Differential Diagnoses & Workup
Updated: Aug 26, 2009
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- Differential Diagnoses & Workup
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Differential Diagnoses
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Workup
Laboratory Studies
- Peripheral blood: The peripheral blood usually shows a macrocytic anemia with a mild leukopenia and thrombocytopenia. The mean cell volume (MCV) and mean cell hemoglobin (MCH) are increased, with a mean corpuscular hemoglobin concentration (MCHC) within the reference range. The leukopenia and thrombocytopenia usually parallel the severity of the anemia (see Images 4-5 or below).
Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.
The peripheral smear shows oval macrocytes, hypersegmented granulocytes, and anisopoikilocytosis. In severe anemia, red blood cell inclusions may include Howell-Jolly bodies, Cabot rings, and punctate basophilia. The macrocytosis can be obscured by the coexistence of iron deficiency, thalassemia minor, or inflammatory disease.
Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.
- Serum: The indirect bilirubin may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. The serum lactic dehydrogenase usually is markedly increased. Increased values for other red blood cells, enzymes, and serum iron saturation also are observed. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased.
- Gastric secretions: Total gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. IF is either absent or markedly decreased.
- Serum Cbl levels: The serum Cbl is low in patients with pernicious anemia; however, it may be within the reference range in certain patients with other forms of Cbl deficiency. These include some inborn areas of Cbl deficiency, TC II deficiency, and Cbl deficiency due to nitrous oxide.
- Conversely, serum Cbl levels may be low in patients who are pregnant, have TC I deficiency, have severe folic acid deficiency, and following large doses of ascorbic acid.
- Screening of individuals who are older has shown that 10-20% have low serum Cbl levels, and half of these patients have increased levels of homocysteine and methylmalonic acid, indicating a tissue Cbl deficiency.
- Methylmalonic acid and homocysteine (see Table 1): Elevated serum methylmalonic acid and homocysteine levels are found in patients with pernicious anemia. They probably are the most reliable test for Cbl deficiency in patients who do not have a congenital metabolism disorder. In the absence of an inborn error of methylmalonic acid metabolism, methylmalonic aciduria is a sign of Cbl deficiency. Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cbl and Folic Acid Deficiency
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Patient Condition Methylmalonic Acid Homocysteine Healthy Normal Normal Vitamin B-12 deficiency Elevated Elevated Folate deficiency Normal Elevated Patient Condition Methylmalonic Acid Homocysteine Healthy Normal Normal Vitamin B-12 deficiency Elevated Elevated Folate deficiency Normal Elevated - Schilling test (see Table 2): The Schilling test measures Cbl absorption by increasing urine radioactivity after an oral dose of radioactive Cbl. The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of Cbl deficiency. Likewise, it is helpful because it is used to identify patients with classic pernicious anemia, even after they have been treated with vitamin B-12. Table 2. Schilling Test Results
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Patient Condition Stage I
WaterStage II
Intrinsic FactorStage III
AntibioticStage IV
Pancreatic ExtractHealthy Normal … … … Pernicious anemia Low Normal … … Bacterial overgrowth Low Low Normal … Pancreatic insufficiency Low Low Low Normal Defect in ileum Low Low Low Low Patient Condition Stage I
WaterStage II
Intrinsic FactorStage III
AntibioticStage IV
Pancreatic ExtractHealthy Normal … … … Pernicious anemia Low Normal … … Bacterial overgrowth Low Low Normal … Pancreatic insufficiency Low Low Low Normal Defect in ileum Low Low Low Low - The test is performed by administering 0.5-2.0 mCi of radioactive cyanocobalamin in a glass of water to patients who have fasted. Two hours later, the patient is injected with 1 mg of unlabeled vitamin B-12 to saturate circulating transcobalamins. A 24-hour urine sample is collected, and the radioactivity in the specimen is measured and compared to a standard. Specimens with less than 7% excretion represent abnormal findings and indicate that poor absorption of the oral test dose occurred. If abnormal low values are obtained, a stage II Schilling test is performed. In this test, 60 mg of active hog IF is administered with the oral test dose to determine if this enhances the absorption of vitamin B-12. If poor absorption of vitamin B-12 is normalized, the patient presumably has classic pernicious anemia.
- If poor absorption is observed in a stage II test, search for other causes of vitamin B-12 malabsorption. Performance of a stage I Schilling test after 5 days of tetracycline therapy is used to exclude a blind loop as the etiology for Cbl deficiency (stage III). Similarly, if administration of trypsin or pancreatic enzyme with the radiolabeled test dose corrects the absorption of vitamin B-12, suspect pancreatic disease (stage IV).
- False-positive Schilling test results are observed in patients with incomplete 24-hour urine collections or renal insufficiency, false-positive results are observed when inactive IF is used, and false-positive results occur because of neutralization of the IF in the stage II test by any IF antibodies in the stomach and severe ileal megaloblastosis.
- Occasionally Cbl deficiency and a normal result on stage I Schilling test are observed. These patients can absorb vitamin B-12 in the fasting state but not when it is presented with food. Adding the radiolabeled vitamin B-12 to egg white and testing the absorption usually reveals this cause of Cbl deficiency.
- Clinical trial: The administration of 1000 mcg of vitamin B-12 intramuscularly can be used as a clinical trial for suspected Cbl deficiency. Subjectively, this usually provides a marked sense of well-being in patients who are Cbl deficient within 24 hours after administration. Objectively, this produces a marked reticulocytosis, which is maximal in 5-7 days after the administration of the Cbl, and a correction of the anemia occurs in about 3 weeks (see Image 6 or below).
Response to therapy with cobalamin (Cbl) in a previously untreated patient with pernicious anemia. A reticulocytosis occurs within 5 days after an injection of 1000 mcg of Cbl. This lasts for about 2 weeks after injection. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes.
Procedures
- A bone marrow aspirate and biopsy can be performed for histological examination.
Histologic Findings
The bone marrow biopsy and aspirate usually are hypercellular and show trilineage differentiation. Erythroid precursors are large and often oval (see Image 5).
Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.
The nucleus is large and contains course motley chromatin clumps, providing a checkerboard appearance. Nucleoli are visible in the more immature erythroid precursors. An imbalance in the rate of maturation of the nucleus relative to the cytoplasm exists, such that disassociation between the maturity of the nucleus and the hemoglobinization of the orthochromic megaloblastic normoblasts occurs. Giant metamyelocytes and bands are present, and the mature neutrophils and eosinophils are hypersegmented. Imbalanced growth of megakaryocytes is evidenced by hyperdiploidy of the nucleus and the presence of giant platelets in the smear. Lymphocytes and plasma cells are spared from the cellular gigantism and cytoplasmic asynchrony observed in other cell lineages.
The bone marrow histology is similar in both folic acid and Cbl deficiency. Significant changes in the histology have been observed within 12 hours after appropriate treatment is initiated. The megaloblastic changes due to Cbl deficiency can be reversed by pharmacological doses of folic acid but not the converse. Folic acid therapy may worsen the neurological consequences of Cbl deficiency despite hematological improvement.
More on Pernicious Anemia |
| Overview: Pernicious Anemia |
 Differential Diagnoses & Workup: Pernicious Anemia |
| Treatment & Medication: Pernicious Anemia |
| Follow-up: Pernicious Anemia |
| Multimedia: Pernicious Anemia |
| References |
| Further Reading |
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References
Elmadfa I, Singer I. Vitamin B-12 and homocysteine status among vegetarians: a global perspective. Am J Clin Nutr. May 2009;89(5):1693S-1698S. [Medline].
Chan JC, Liu HS, Kho BC, Lau TK, Li VL, Chan FH, et al. Longitudinal study of Chinese patients with pernicious anaemia. Postgrad Med J. Dec 2008;84(998):644-50. [Medline].
Andrès E, Vogel T, Federici L, Zimmer J, Ciobanu E, Kaltenbach G. Cobalamin deficiency in elderly patients: a personal view. Curr Gerontol Geriatr Res. 2008;848267. [Medline].
Erkurt MA, Aydogdu I, Dikilitas M, Kuku I, Kaya E, Bayraktar N, et al. Effects of cyanocobalamin on immunity in patients with pernicious anemia. Med Princ Pract. 2008;17(2):131-5. [Medline].
Beutler E, Lichtman MA, Coller BS. Williams Hematology. 6th ed. New York, NY:. McGraw-Hill;2001:425-446.
Hoffman R, Benz EJ Jr, Shattil SJ. Hematology: Basic Principles and Practice. 3rd ed. New York, NY:. Churchill Livingstone;2000:446-484.
Jandl JH. Blood: Textbook of Hematology. 2nd ed. Boston, Mass:. Little, Brown and Co;1996:251-288.
Lee GR, Foerster J, Lukens J. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md:. Williams & Wilkins;1999:941-978.
Scriver CR, Beaudet AL, Sly WS. The Metabolic and Molecular Bases of Inherited Disease. 2nd ed. New York, NY:. McGraw-Hill;1995:3129-3149.
Further Reading
Related eMedicine Topics
- Anemia
- Gastritis, Atrophic
- Gastritis, Chronic
- Megaloblastic Anemia
- Vitamin B-12 Associated Neurological Diseases
- Cobalamin Status in Young Children With Developmental Delay
- Cobalamin Status in Young Children With Gastrointestinal Symptoms or Feeding Problems
- Evaluation of Holotranscobalamin as an Indicator of Vitamin B12 Absorption
- Examining B12 Deficiency Associated With C677T Mutation on MTHFR Gene in Terms of Commonness and Endothelial Function
- Anemia in the long-term care setting. American Medical Directors Association - Professional Association. 2007. 28 pages. NGC:005655
- Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. Society of Obstetricians and Gynaecologists of Canada - Medical Specialty Society. 2007 Dec. 11 pages. NGC:006776
Keywords
pernicious anemia, vitamin B-12 deficiency, megaloblastic anemia, cobalamin deficiency, Cbl deficiency, iron deficiency anemia, addisonian anemia, Biermer anemia, Hunter-Addison anemia, Lederer anemia, Biermer-Ehrlich anemia, Addison-Biermer disease, macrocytic achylic anemia, malignant anemia,
adenosylcobalamin, methylcobalamin, intrinsic factor, IF, macrocytic anemia, neurological complications, severe gastric atrophy, achlorhydria, gastrectomy, gastric stapling, bypass procedures for obesity, extensive infiltrative disease of the gastric mucosa, Zollinger-Ellison syndrome,
tropical sprue, regional enteritis, ulcerative colitis, ileal lymphoma, Imerslünd-Grasbeck syndrome, chronic pancreatitis, sore tongue, smooth tongue with loss of papillae, paresthesias, megaloblastic madness, tapeworm infestation, Diphyllobothrium latum, congenital pernicious anemia, hereditary transcobalamin I deficiency, homocystinuria, homocystinemia
