Diagnostic Considerations
By definition, pernicious anemia refers specifically to vitamin B12 deficiency resulting from a lack of production of intrinsic factor (IF) in the stomach. However, vitamin B12 absorption is a complex process, and other causes of vitamin B12 deficiency exist. Pernicious anemia must be differentiated from other disorders that interfere with the absorption and metabolism of vitamin B12 and produce cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications.
Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.
Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. Vitamin B12 and folic acid levels are normal. On bone marrow examination, affected individuals have megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts). Molecular genetic testing will show biallelic pathogenic variants in SLC19A2. [18]
Uncommonly, variable ocular anomalies may be present in TRMA. One case report describes symmetric bull's eye maculopathy and other ocular findings consistent with cone-rod degeneration. [19]
The anemia in TRMA is corrected with pharmacologic doses (50-100 mg/day) of thiamine (vitamin B1) . However, the red cells remain macrocytic. [18]
Other conditions to be considered include the following:
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Cestode infection
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Neurologic disorders
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Senility
Pernicious anemia may rarely be associated with liver disease (eg, primary biliary cholangitis, autoimmune hepatitis, interferon-treated hepatitis C). Yan et al report two cases of pernicious anemia in patients with cryptogenic cirrhosis, in both of whom the neuropsychiatric symptoms of pernicious anemia were initially attributed to hepatic encephalopathy. [20]
Differential Diagnoses
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Alcoholic Fatty Liver
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Pernicious anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl. The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).
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Pernicious anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).
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Pernicious anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.
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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.
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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.
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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 and lasts for about 2 weeks. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes. After 1 or 2 weeks, the Hgb concentration increases about 1 g/dL per week.
Tables
Patient Condition |
Methylmalonic Acid |
Homocysteine |
Healthy |
Normal |
Normal |
Vitamin B12 deficiency |
Elevated |
Elevated |
Folate deficiency |
Normal |
Elevated |
Patient Condition |
Stage I No Intrinsic Factor |
Stage II Intrinsic Factor |
Stage III Antibiotic |
Stage IV Pancreatic Extract |
Healthy |
Normal |
… |
… |
… |
Pernicious anemia |
Low |
Normal |
… |
… |
Bacterial overgrowth |
Low |
Low |
Normal |
… |
Pancreatic insufficiency |
Low |
Low |
Low |
Normal |
Defect in ileum |
Low |
Low |
Low |
Low |
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- CBC and Peripheral Blood Smear
- Indirect Bilirubin and Serum Lactate Dehydrogenase
- Evaluation of Gastric Secretions
- Serum Cobalamin
- Serum Folic Acid, Methylmalonic Acid, and Homocysteine
- Intrinsic Factor Antibodies
- Schilling Test
- Clinical Trial of Vitamin B12
- Bone Marrow Aspiration and Biopsy
- Other Tests
- Show All
- Treatment
- Medication
- Questions & Answers
- Media Gallery
- Tables
- References
