Pernicious Anemia

Pernicious Anemia

Pernicious anemia (PA) is an autoimmune disease resulting from antibodies against gastric intrinsic factor and gastric parietal cells.

Synonyms

  • Megaloblastic anemia resulting from vitamin B12 deficiency
  • Addison-Biermer anemia

Epidemiology & Demographics

  • •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

Physical Findings & Clinical Presentation

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

Etiology

  • •Parietal cell antibodies are present in >70% of patients, while intrinsic factor antibodies are noted in >50% of patients.
  • •Atrophic gastric mucosa with achlorhydria.
  • •Inborn errors of cobalamin-cofactor synthesis are rare. 

Differential Diagnosis

  • •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)

Workup

  • •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. The below table describes a step-wise approach to the diagnosis of cobalamin and folate deficiency.

Stepwise Approach to the Diagnosis of Cobalamin and Folate Deficiency

From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Saunders.

Megaloblastic Anemia or Neurologic-Psychiatric Manifestations Consistent With Cobalamin Deficiency Plus Test Results on Serum Cobalamin and Serum Folate
Cobalamin (pg/ml)Folate (ng/ml)Provisional DiagnosisProceed with Metabolites? 
>300>4Cobalamin or folate deficiency is unlikelyNo
<200>4Consistent with cobalamin deficiencyNo
200-300>4Rule out cobalamin deficiencyYes
>300<2Consistent with folate deficiencyNo
<200<2Consistent with (1) combined cobalamin plus folate deficiency or (2) isolated folate deficiencyYes
>3002-4Consistent with (1) folate deficiency or (2) an anemia unrelated to vitamin deficiencyYes
Test Results on Metabolites: Serum Methylmalonic Acid and Total Homocysteine
Methylmalonic Acid (Normal, 70-270 nM)Total Homocysteine (Normal, 5-14 μM)Diagnosis
IncreasedIncreasedCobalamin deficiency confirmed; folate deficiency still possible (i.e., combined cobalamin plus folate deficiency possible)
NormalIncreasedFolate deficiency is likely
NormalNormalCobalamin and folate deficiency is excluded

a Serum cobalamin levels: Abnormally low, <200 pg/ml; clinically relevant low-normal range, 200-300 pg/ml.

b Serum folate levels: Abnormally low, <2 ng/ml; clinically relevant low-normal range, 2-4 ng/ml.

c Any frozen-over sample from serum folate/cobalamin determination can be subjected to metabolite tests.

  • 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.

Laboratory Tests

  • •Complete blood count generally reveals macrocytic anemia, thrombocytopenia, and mild leukopenia with hypersegmented neutrophils.
  • •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.

Serum Cobalamin: False-Positive and False-Negative Test Results

From Hoffman R et al: Hematology, basic principles and practice, ed 6, Philadelphia, 2013, Saunders.

Falsely Low Serum Cobalamin in the Absence of True Cobalamin Deficiency
•Folate deficiency (one third of patients)•Multiple myeloma•TCI deficiency•Megadose vitamin C therapy•Pregnancy•Oral contraceptives
Falsely Raised Cobalamin Levels in the Presence of a True Deficiency 
•Cobalamin binders (TCI and II) increased (e.g., myeloproliferative states, hepatomas, and fibrolamellar hepatic tumors)•TCII-producing macrophages are activated (e.g., autoimmune diseases, monoblastic leukemias and lymphomas)•Release of cobalamin from hepatocytes (e.g., active liver disease)•High serum anti-IF antibody titer

IF, Intrinsic factor; TC, transcobalamin.

a Although a low serum cobalamin level is not synonymous with cobalamin deficiency, 5% of patients with true cobalamin deficiency have low-normal cobalamin levels, a potentially serious problem because the patient’s underlying cobalamin deficiency will progress if uncorrected.

  • 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.
  • •Schilling test: No longer used. It was historically used to identify the locus of cobalamin malabsorption and the cause of cobalamin deficiency.

Treatment

Nonpharmacologic Therapy

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.

Acute General Treatment

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 1000 mcg/mo, indefinitely. Monitor response and increase dosing if serum B12 levels decline.

Chronic Treatment

  • •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. Nasal cyanocobalamin is expensive.
  • •Oral cobalamin (1000 to 2000 mcg/day) is also being 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.

Disposition

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

Referral

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

Pearls & Considerations

  • •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

Causes of Megaloblastosis Not Responding to Therapy with Cobalamin or Folate

From Hoffman R et al: Hematology, basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Wrong Diagnosis
Combined folate and cobalamin deficiencies being treated with only one vitamin
Associated iron deficiency
Associated hemoglobinopathy (e.g., sickle cell disease, thalassemia)
Associated anemia of chronic disease
Associated hypothyroidism
  • 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.

Suggested Readings

  • Annibale B., et al.: Diagnosis and management of pernicious anemia. Curr Gastroenterol Rep 2011; 13: pp. 518-524.
  • Bizzaro N., Antico A.: Diagnosis and classification of pernicious anemia. Autoimmun Rev 2014; 13: pp. 565-568.
  • Green R., Datta Mitra A.: Megaloblastic anemias: nutritional and other causes. Med Clin North Am 2017; 101 (2): pp. 297-317.
  • Hesdorffer C.S., Longo D.L.: Drug-induced megaloblastic anemia. N Engl J Med 2015; 373: pp. 1649-1658.
  • Langan R.C., Goobred A.J.: Vitamin B12 deficiency: recognition and management. Am Fam Physician 2017; 96 (6): pp. 384-389.
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