Pernicious Anemia

Background

• Pernicious anemia is an autoimmune disorder characterized by the destruction of gastric parietal cells, which synthesize intrinsic factor, important for vitamin B12 absorption by the terminal ileum. This leads to vitamin B12 deficiency and results in ineffective erythropoiesis (anemia and other cytopenias) and/or defective myelin synthesis (neuropathy).
• Pernicious anemia is the most common cause of severe vitamin B12 deficiency. It affects both sexes equally with a median age at diagnosis of 60 years and is more prevalent in Northern Europeans, especially Scandinavians, and in persons of African ancestry.
• Vitamin B12 is an essential cofactor that is required for DNA and RNA synthesis and other cellular metabolism. Vitamin B12 is obtained from dietary sources including meat, eggs, and dairy products. 50%-60% of consumed vitamin B12 is absorbed. The recommended dietary allowance of vitamin B12 in adults is 2.4 mcg/day.
• Patients may be asymptomatic, or may present with symptoms of anemia, pancytopenia, neurological impairment (such as numbness, motor weakness, as well as neuropsychiatric complications), or gastrointestinal dysfunction.
• Pernicious anemia is associated with a number other autoimmune diseases, especially autoimmune thyroid disease.

Evaluation

• Suspect pernicious anemia in patients who present with glossitis, hypoproliferative macrocytic anemia with low haptoglobin and elevated lactate dehydrogenase, or neuropathy.
• For patients with strong clinical suspicion of vitamin B12 deficiency:
  • Measure serum vitamin B12 level.
  • Confirm normal serum folate level.
  • Start empiric vitamin B12 replacement while awaiting results of further testing (including anti-intrinsic factor antibodies, methylmalonic acid levels).
  • Test for anti-intrinsic factor antibodies, regardless of vitamin B12 levels (Strong recommendation).
  • If serum vitamin B12 > 200 ng/L (148 pmol/L), measure methylmalonic acid (MMA) levels to rule out a false-normal B12 level.
• Diagnosis of pernicious anemia can be made in patients if there is strong suspicion of cobalamin deficiency and any of the following:
  • positive test for anti-intrinsic factor antibodies
  • elevated MMA (irrespective of presence of anti-intrinsic factor antibodies)
  • objective clinical response to vitamin B12 treatment (irrespective of presence of anti-intrinsic factor antibodies)
• For patients without symptoms of anemia or other malabsorptive causes of vitamin B12 deficiency who are found to have low serum vitamin B12 (< 150 ng/L [111 pmol/L]), consider testing for anti-intrinsic factor antibodies (Weak recommendation).

Management

• Start empiric vitamin B12 replacement therapy in patients with strong clinical suspicion of vitamin B12 deficiency while awaiting results from testing for anti-intrinsic factor antibodies, methylmalonic acid (MMA), and homocysteine testing, if performed.
• Lifelong vitamin B12 replacement therapy:
  • Offer to patients who are positive for anti-intrinsic factor antibodies (Strong recommendation).
  • Consider offering to patients who are negative for anti-intrinsic factor antibodies and who have no other cause of deficiency, as long as there is objective clinical response to treatment (Weak recommendation).
• Intramuscular vitamin B12 replacement is standard therapy for initial treatment of pernicious anemia.
• The typical dosing schedule for intramuscular cyanocobalamin for replacement therapy is 1,000 mcg/day or every other day for 1 week, then weekly for 4 weeks, and then monthly for life.
• Oral vitamin B12 replacement therapy may not be appropriate for initial treatment, but may be considered for maintenance therapy or for normalizing suboptimal levels in asymptomatic patients (Weak recommendation). Its use in patients with pernicious anemia is not universally accepted.
• Treat iron and folate deficiencies if present.