History
The onset of pernicious anemia usually is insidious and vague. The classic triad of weakness, sore tongue, and paresthesias may be elicited but usually is not the chief symptom complex. Typically, medical attention is sought because of symptoms suggestive of cardiac, renal, genitourinary, gastrointestinal, infectious, mental, or neurologic disorders, and the patient is found to be anemic with macrocytic cellular indices.
General symptoms
Weight loss of 10-15 lb occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment.
Cardiac symptoms
Individuals with pernicious anemia often tolerate the anemia well, and many are ambulatory with hematocrit levels in the mid-teens. However, the cardiac output is usually increased when hematocrit levels fall below 20%, with associated accerations in heart rate. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.
Gastrointestinal symptoms
Approximately 50% of patients with pernicious anemia develop atrophic glossitis, presenting with a smooth tongue that may be painful and beefy red, with loss of papillae that is usually most marked along the edges of the tongue. These patients report burning or soreness, most particularly on the anterior third of the tongue, associated with changes in taste and loss of appetite.
Patients may report either constipation or having several semisolid bowel movements daily. These symptoms have been attributed to megaloblastic changes of the cells of the intestinal mucosa.
Nonspecific gastrointestinal (GI) symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology. Venkatesh and colleagues report the case of a patient who presented with epigastric pain, diarrhea, and vomiting and was found to have thrombosis of the portal, superior mesenteric, and splenic veins due to hyperhomocysteinemia secondary to pernicious anemia. [17]
Neurologic symptoms
The most common neurologic symptoms in vitamin B12 deficiency include paresthesias, weakness, clumsiness, and an unsteady gait. The last two symptoms are exacerbated in dark environments due to the loss of visual cues that patients often rely on, in concert with the loss of proprioception. These neurologic symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex (subacute combined degeneration).
Neurologic symptoms and findings may be present in the absence of anemia. This is more common in patients taking folic acid or on a high-folate diet.
Older patients may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace. So-called megaloblastic madness—delusions, hallucinations, outbursts, and paranoid schizophrenic ideation—is less common. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B12 administration.
While neurologic symptoms usually occur in the elderly, they can rarely occur in the young. [18] Kocaoglu et al reported a case of vitamin B12 deficiency and cerebral atrophy in a 12-month-old infant whose development had slowed since 6 months of age; the infant was exclusively breastfed and his mother was a long-time vegetarian. Neurologic recovery began within days after the infant received an intramuscular cobalamin injection. [19]
Genitourinary symptoms
Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.
Symptoms of thrombotic complications
A study of four patients revealed that pernicious anemia can lead to hyperhomocysteinemia that is significant enough to lead to venous thrombosis, even in the absence of any other risk factors for thromboembolism. [20]
Physical Examination
The finding of severe anemia in an adult patient whose constitutional symptoms are relatively mild and in whom weight loss is not a major feature should arouse suspicion of pernicious anemia.
Typically, patients with pernicious anemia are described as having a stereotypic appearance: they have a lemon-yellow waxy pallor with premature whitening of the hair, and they appear flabby, with a bulky frame that is generally incongruent with the severe anemia and weakness. It should be remembered, however, that whereas this characterization is useful in patients of northern European descent, it is less helpful in patients of other ethnic groups (who, as noted, are more commonly affected than was once believed).
The following signs may be noted:
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Low-grade fever and mild icterus are commonplace but are usually mild and easily missed.
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A beefy, red, smooth tongue may be observed.
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In patients with dark complexions, blotchy skin pigmentation may be observed.
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Tachycardia often is present and may be accompanied by flow murmurs.
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Abnormal mentation and deterioration of vision and hearing may be observed.
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With severe anemia, dyspnea, tachypnea, and evidence of congestive heart failure may be present.
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Retinal hemorrhages and exudates may accompany severe anemia.
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The liver may be enlarged in association with congestive heart failure.
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A splenic tip is palpable in about 20% of patients
Neurologic assessment
A careful neurologic assessment is important. All megaloblastic disorders can give rise to hematologic and epithelial manifestations, but only cobalamin deficiency causes neurologic deficits. Neurologic findings may occur in the absence of anemia and epithelial manifestations of pernicious anemia, making it more difficult to identify the etiology. If left untreated, they can become irreversible.
Suspect pernicious anemia in all patients with recent loss of mental capacities. Somnolence, dementia, psychotic depression, and frank psychosis may be observed, which can be reversed or improved by treatment with cobalamin. Perversion of taste and smell and visual disturbances, which can progress to optic atrophy, can likewise result from central nervous system (CNS) cobalamin deficiency.
A history of either paresthesias in the fingers and toes or difficulty with gait and balance should prompt a careful neurologic examination. Loss of position sense in the second toe and loss of vibratory sense for a 256-Hz tuning fork, but not for a 128-Hz fork, are the earliest signs of posterolateral column disease. If untreated, this can progress to spastic ataxia from demyelinization of the dorsal and lateral columns of the spinal cord.
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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
