Pernicious anemia (PA) is an autoimmune disease resulting from antibodies against gastric intrinsic factor and gastric parietal cells that results in vitamin B₁₂ deficiency due to decreased absorption and leading to megaloblastic anemia. Pernicious anemia also manifests with neurologic symptoms.

• Megaloblastic anemia resulting from vitamin B₁₂ deficiency
• Addison-Biermer anemia
• Anemia, pernicious

• •Increased incidence in females and older adults (40 to 70 yr)
• •More frequent in patients of northern European ancestry
• •Overall prevalence of undiagnosed PA after age 60 yr is 1.9%
• •Prevalence is higher in women (2.7%), particularly in Black women (4.3%)
• •Associated with other autoimmune diseases (e.g., type 1 diabetes mellitus, Graves disease, Addison disease), along with possible Helicobacter pylori association

• •Mucosal pallor and/or glossitis ("beefy red tongue")
• •Angular cheilosis
• •Mild jaundice (representative of intramedullary hemolysis of megaloblastic cells); "lemon yellow" skin due to pallor and jaundice
• •Peripheral sensory neuropathy with paresthesia initially and absent reflexes in advanced disease
• •Delirium or dementia
• •Worsening weakness and possible subacute combined degeneration of spinal cord (Fig. E1)
• •Loss of proprioception and an unsteady gait
• •GI symptoms including anorexia, pyrosis, nausea, and vomiting
• •Possible splenomegaly and mild hepatomegaly

• •Parietal cell antibodies are present in >70% of patients, while intrinsic factor antibodies are noted in >50% of patients.
• •Atrophic gastric mucosa (Fig. E2) with achlorhydria.
• •Inborn errors of cobalamin-cofactor synthesis are rare. Fig. E3 illustrates the components and mechanism of cobalamin absorption. An etiopathophysiologic classification of cobalamin deficiency is described in Section II.

• •Nutritional vitamin B₁₂ deficiency
• •Malabsorption (e.g., celiac disease)
• •Chronic alcoholism (multifactorial)
• •Chronic gastritis related to H. pylori infection
• •Folic acid deficiency
• •Myelodysplasia
• •Thyroid abnormalities
• •Atrophic gastritis
• •Paraproteinemias
• •Gastrectomy or use of H₂ blockers
• •Insufficient pancreatic enzymes (Zollinger-Ellison syndrome, chronic pancreatitis, post-Whipple procedure)

• •The clinical presentation of PA varies with the stage. Initially, patients may be asymptomatic. In advanced stages, patients may have impaired memory, depression, gait disturbances, paresthesias, and generalized weakness.
• •Investigation consists primarily of laboratory evaluation. Table 1 describes a step-wise approach to the diagnosis of cobalamin and folate deficiency.
• •Endoscopy and biopsy for atrophic gastritis may be performed in selected cases.
• •Diagnosis is crucial because failure to treat may result in irreversible neurologic deficits.

• •CBC generally reveals macrocytic anemia, thrombocytopenia, and mild leukopenia with hypersegmented neutrophils (Fig. E4).
• •Mean corpuscular volume (MCV) is significantly elevated in advanced stages.
• •Reticulocyte count is low to normal.
• •False low serum cobalamin levels can occur in patients who are pregnant or taking oral contraceptives, have multiple myeloma, have transcobalamin I (TCI) deficiency, have severe folic acid deficiency, or are taking large doses of ascorbic acid. False high normal levels in patients with cobalamin deficiency can occur in several conditions including hepatomas, severe liver disease, or monoblastic leukemias (Table 2).
• •The absence of anemia or macrocytosis does not exclude the diagnosis of cobalamin deficiency. Anemia is absent in 20% of patients with cobalamin deficiency, and macrocytosis is absent in >30% of patients at the time of diagnosis. Macrocytosis can be masked by concurrent iron deficiency, anemia of chronic disease, or thalassemia trait.
• •Laboratory tests used for detecting cobalamin deficiency in patients with normal vitamin B₁₂ levels include serum and urinary methylmalonic acid (MMA) level (elevated), total homocysteine level (elevated), and intrinsic factor antibody (positive). Cobalamin is a cofactor for the enzymes L-methylmalonyl coenzyme A mutase and methionine synthase. Inadequate levels of cobalamin will thus result in increased MMA and homocysteine levels. Plasma MMA levels can also be used to differentiate cobalamin deficiency from folate deficiency because patients with folate deficiency have normal or mild elevations of MMA levels.
• •An increased concentration of plasma MMA does not predict clinical manifestations of vitamin B₁₂ deficiency and should not be used as the only marker for diagnosis of B₁₂ deficiency.
• •Additional laboratory abnormalities can include elevated lactate dehydrogenase, direct hyperbilirubinemia, and decreased haptoglobin, due to rapid destruction of red blood cells.
• •Bone marrow aspirate is not necessary to diagnose cobalamin deficiency. It may show giant C-shaped neutrophil bands and megaloblastic normoblasts (Fig. E5).
• •Schilling test: No longer used or available. It was historically used to identify the locus of cobalamin malabsorption and the cause of cobalamin deficiency.

Avoid folic acid supplementation without proper vitamin B₁₂ supplementation. Folic acid supplementation alone may result in hematologic remission in patients with vitamin B₁₂ deficiency but will not treat or prevent neurologic manifestations.

Traditional therapy of cobalamin deficiency consists of intramuscular (IM) or deep subcutaneous (SC) injections of vitamin B₁₂ 1000 mcg/day for 1 wk followed by a weekly administration for 1 to 2 mo and then monthly lifelong. Monitor response and increase dosing if serum B₁₂ levels decline.

• •Parenteral vitamin B₁₂ 1000 mcg/mo or intranasal cyanocobalamin 500 mcg/wk for the remainder of life.
• •In patients who have no nervous system involvement, intranasal cyanocobalamin may be used in place of parenteral cyanocobalamin after hematologic parameters have returned to normal range. Macrocytosis correction can be noted during the first mo of treatment. The initial dose of intranasal cyanocobalamin is 1 spray (500 mcg) in one nostril once per wk. However, intranasal formulations are not routinely recommended due to variable absorption, rhinorrhea, and higher cost.
• •Oral cobalamin (1000 to 2000 mcg/day) is also effective in mild cases of pernicious anemia because approximately 1% of an oral dose is absorbed by passive diffusion, a pathway that does not require intrinsic factor. Cost for 1 mo of therapy is approximately $5. Consider returning to IM vitamin B₁₂ supplementation if decline recurs.

Anemia generally resolves with appropriate cobalamin replacement therapy. Neurologic deficits, on the other hand, may be corrected only if treated early on.

Gastroenterology referral for endoscopy on diagnosis of PA followed by periodic surveillance endoscopies to rule out gastric adenocarcinoma or carcinoid tumors.

• •Early manifestations of negative cobalamin balance are increased serum methylmalonic acid and total homocysteine levels. This occurs when the total cobalamin in serum is still in the low-normal range.
• •Vitamin B₁₂ deficiency that is allowed to progress for longer than 3 mo may produce permanent degenerative lesions of the spinal cord (e.g., subacute combined degeneration of spinal cord).
• •Vitamin B₁₂ deficiency may suppress signs of polycythemia vera; treatment of B₁₂ deficiency may unmask this disorder.
• •Blunted or impeded therapeutic response to vitamin B₁₂ may be due to concurrent iron or folic acid deficiency, uremia, infections, or use of drugs with bone marrow suppressant properties. Causes of megaloblastosis not responding to therapy with cobalamin or folate are summarized in Table 3.
• •Drugs that interfere with B₁₂ absorption include metformin, colchicine, neomycin, and aminosalicylic acid.
• •Patients must understand that cobalamin replacement therapy is lifelong.
• •Self-injection of vitamin B₁₂ may be taught in selected patients. Cost of monthly injections is less than $10.
• •Patients who have had bariatric surgery should receive 1 mg of oral vitamin B₁₂ per day indefinitely.

• Pernicious Anemia (Patient Information)