Workup Show
Approach ConsiderationsThe workup for pernicious anemia may include the following:
CBC and Peripheral Blood SmearThe mean corpuscular volume (MCV) and mean cell hemoglobin (MCH) are increased, with a mean corpuscular hemoglobin concentration (MCHC) within the reference range. The peripheral blood usually shows a macrocytic anemia with a mild leukopenia and thrombocytopenia (see the image below). The leukopenia and thrombocytopenia usually parallel the severity of the anemia. 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. Indirect Bilirubin and Serum Lactate DehydrogenaseThe indirect bilirubin level may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. The serum lactate dehydrogenase (LDH) concentration usually is markedly increased. Hemolysis is intramedullary. 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. Evaluation of Gastric SecretionsTotal gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. Intrinsic factor (IF) is either absent or markedly decreased. Serum CobalaminSerum cobalamin reference ranges may vary slightly among different laboratories, but are generally from 200–900 pg/mL. Values of 180-250 pg/mL are considered bordeline, while less than 150 pg/mL is considered diagnostic of vitamin B12 deficiency. The serum cobalamin level is usually low in patients with pernicious anemia. However, up to a third of patients can present with normal vitamin B12 levels and normocytic anemia, which often delays diagnosis. [21] Certain patients with other forms of cobalamin deficiency, such as some inborn forms of cobalamin deficiency, transcobalamin II (TCII) deficiency, and cobalamin deficiency due to nitrous oxide, can also present with normal serum cobalamin levels. Conversely, serum cobalamin levels may be low in patients with no clinical or identifiable metabolic abnormality. [22] Causes of falsely low serum cobalamin levels inclue the following:
Serum cobalamin levels can be in the low reference range in patients with clinical vitamin B12 deficiency. In these cases, elevated levels of methylmalonic acid and total homocysteine can confirm the diagnosis. [23] Screening of older individuals has shown that 10-20% have low serum cobalamin levels, and half of these patients have increased levels of homocysteine and methylmalonic acid, indicating a tissue cobalamin deficiency. Serum Folic Acid, Methylmalonic Acid, and HomocysteineA serum folic acid assay is useful for ruling out folic acid deficiency. The reference range is 2.5-20 ng/mL. Blood should be drawn before patients have a single hospital meal since food can restore serum folic acid levels to normal. Red blood cell folic acid level is not influenced by food. (For more information, see Megaloblastic Anemia and Folic Acid Deficiency). A significantly decreased serum cobalamin level along with a typical clinical presentation, a characteristic peripheral smear, and an increased indirect bilirubin and LDH level is sufficient evidence for the diagnosis of a megaloblastic anemia. Serum methylmalonic acid and homocysteine tests are important confirmatory tests but are not first-line tests. Elevated serum methylmalonic acid and homocysteine levels are found in patients with pernicious anemia. They probably are the most reliable test for cobalamin deficiency in patients who do not have a congenital metabolism disorder (see the table below). In the absence of an inborn error of methylmalonic acid metabolism, methylmalonic aciduria is a sign of cobalamin deficiency. Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cobalamin and Folic Acid Deficiency (Open Table in a new window)
Intrinsic Factor AntibodiesDemonstration of circulating intrinsic factor autoantibodies is almost diagnostic of type A (autoimmune) gastritis and pernicious anemia. Intrinsic factor (IF) antibodies are specific for this disorder and can be used to confirm the diagnosis. There are two types of IF antibodies. Type I IF antibodies block binding of vitamin B12 to intrinsic factor and are found in 70% to 90% of patients with pernicious anemia. Type II IF antibodies prevent attachment of the vitamin B12–IF complex to ileal receptors and are present in approximately 35% to 50% of patients with pernicious anemia; they rarely occur in the absence of type I IF antibodies. Both type I and type II antibodies are detected more often in gastric juice than in the serum. [3] In one case report, the presence of IF antibodies was used to diagnose cobalamin deficiency in a patient with severe leukoencephalopathy. Interestingly, serum vitamin B12, homocysteine, and methylmalonic acid levels were normal. The patient responded to intensive cobalamin therapy. [24] Parietal cell antibodies occurs in 90% of patients with pernicious anemia. However, these antibodies are not specific for pernicious anemia. Schilling TestThe Schilling test measures cobalamin absorption by assessing increased urine radioactivity after an oral dose of radioactive cobalamin. The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of cobalamin deficiency (see the table below). It is also useful for identifying patients with classic pernicious anemia, even after they have been treated with vitamin B12. Howeve, the Schilling test is no longer available in most medical centers. Table 2. Schilling test results (Open Table in a new window)
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 B12 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 B12. If poor absorption of vitamin B12 is normalized, the patient presumably has classic pernicious anemia. If poor absorption is observed in a stage II test, other causes of vitamin B12 malabsorption must be sought. Performance of a stage I Schilling test after 5 days of tetracycline therapy is used to exclude a blind loop as the etiology for cobalamin deficiency (stage III). Similarly, if administration of trypsin or pancreatic enzyme with the radiolabeled test dose corrects the absorption of vitamin B12, pancreatic disease (stage IV) should be suspected. False-positive Schilling test results are observed in patients with incomplete 24-hour urine collections or renal insufficiency. False-positive results are also observed when inactive IF is used. Finally, false-positive results may occur because of neutralization of the IF in the stage II test by any IF antibodies in the stomach and severe ileal megaloblastosis. Occasionally, cobalamin deficiency and a normal stage I Schilling test result are observed. Patients with these findings can absorb vitamin B12 in the fasting state, but not when it is presented with food. Adding the radiolabeled vitamin B12 to egg white and testing the absorption usually reveals this cause of cobalamin deficiency. Clinical Trial of Vitamin B12Intramuscular (IM) administration of 1000 µg of vitamin B12 can be used as a clinical trial for suspected cobalamin deficiency. Subjectively, patients who are cobalamin deficient usually begin to experience a marked sense of well-being within 24 hours after administration. Objectively, administration of cobalamin produces a marked reticulocytosis, which reaches its maximal level 5-7 days after the injection; correction of the anemia occurs in about 3 weeks (see the image below). Bone Marrow Aspiration and BiopsyBone marrow aspiration and biopsy can provide complementary information, with the aspirate revealing the numerical and cytological features of marrow cells, while the biopsy shows the spatial relationships between cells and the overall marrow structure. [25] The bone marrow biopsy and aspirate specimens usually are hypercellular and show trilineage differentiation. Erythroid precursors are large and often oval (see the image below). The nucleus is large and contains coarse 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, leading to disassociation between the maturity of the nucleus and the hemoglobinization of the orthochromic megaloblastic normoblasts. 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 in cobalamin deficiency is similar to that in folic acid deficiency. Significant changes in the histology have been observed within 12 hours after appropriate treatment is initiated. The megaloblastic changes due to cobalamin deficiency can be reversed by pharmacologic doses of folic acid. However, folic acid therapy may worsen the neurologic consequences of cobalamin deficiency, despite the hematologic improvement. Other TestsGastric biopsy demonstrating total absence of hydrochloric acid in gastric secretions (achlorhydria) is diagnostic for pernicious anemia, as it is the only gastric lesion that leads to total achlorhydria. The achlorhyria in these cases is a direct result of the loss of gastric parietal cells.
Author Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel. Coauthor(s) Chief Editor 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. Additional Contributors Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG Disclosure: Partner received none from No financial interests for none. 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. Acknowledgements David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa Disclosure: Nothing to disclose. Troy H Guthrie, Jr, MD Director of Cancer Institute, Baptist Medical Center Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association 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: Medscape Salary Employment What should I do before Schilling test?How to prepare for the Schilling test. You can't receive any intramuscular injections of vitamin B12 for 3 days before your test. Though you may drink water, you'll need to avoid food for 8 hours before the test. You can then eat normally after the test.
What is Schilling test used for?A Schilling test is also known as a Vitamin B12 absorption test. It was formerly used to determine whether a person was absorbing vitamin B12 normally. If not, then the test could pinpoint the cause of any vitamin B12 deficiency. Schilling tests are no longer used today.
Which action does the Schilling test for pernicious anemia determine?The Schilling test measures cobalamin absorption by assessing increased urine radioactivity after an oral dose of radioactive cobalamin. The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of cobalamin deficiency (see the table below).
Which foods will the nurse help the client with vitamin B12 deficiency to increase in the diet?You must eat foods that contain vitamin B12, such as meat, poultry, shellfish, eggs, fortified breakfast cereals, and dairy products. Your body must absorb enough vitamin B12. A special protein, called intrinsic factor, helps your body do this. This protein is released by cells in the stomach.
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