Anemia, Pernicious

Shiva Kumar R. Mukkamalla, M.D., M.P.H.,
Bharti Rathore, M.D.

Basic Information

Definition

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

ICD-10CM CODES
D51.0	Vitamin B12 deficiency anemia due to intrinsic factor deficiency
D51.8	Other vitamin B12 deficiency anemias
D51.9	Vitamin B12 deficiency anemia, unspecified
D51.1	Vitamin B12 deficiency anemia due to selective vitamin B12 malabsorption with proteinuria

Epidemiology & Demographics

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Increased incidence in females and older adults (40-70 years)
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More frequent in patients of northern European ancestry
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The overall prevalence of undiagnosed PA after age 60 years is 1.9%
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Prevalence is highest in women (2.7%), particularly in black women (4.3%)
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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

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

Etiology

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Parietal cell antibodies are present in >70% of patients, while intrinsic factor antibodies are noted in >50% of patients
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Atrophic gastric mucosa with achlorhydria
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Inborn errors of cobalamin-cofactor synthesis are rare. Fig. E1 illustrates the components and mechanism of cobalamin absorption. An etiopathophysiologic classification of cobalamin deficiency is described in Section II.

FIG.E1

Components and mechanism of cobalamin absorption.

*Cbl,* Cobalamin; *HCI,* hydrochloric acid; *IF,* intrinsic factor; R, protein ligand; *TCII,*

Diagnosis

Differential Diagnosis

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Nutritional vitamin B₁₂ deficiency
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Malabsorption (e.g., celiac disease)
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Chronic alcoholism (multifactorial)
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Chronic gastritis related to H. pylori infection
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Folic acid deficiency
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Myelodysplasia
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Thyroid abnormalities
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Atrophic gastritis

Workup

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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.

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Investigation consists primarily of laboratory evaluation. Table 1 describes a step-wise approach to the diagnosis of cobalamin and folate deficiency.

TABLE1 Stepwise Approach to the Diagnosis of Cobalamin and Folate DeficiencyFrom Hoffman R, et al.: Hematology, basic principles and practice, ed 6, Philadelphia, 2013, 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 Diagnosis	Proceed With Metabolites?^‡
>300	>4	Cobalamin or folate deficiency is unlikely	No
<200	>4	Consistent with cobalamin deficiency	No
200-300	>4	Rule out cobalamin deficiency	Yes
>300	<2	Consistent with folate deficiency	No
<200	<2	Consistent with (1) combined cobalamin plus folate deficiency or (2) isolated folate deficiency	Yes
>300	2-4	Consistent with (1) folate deficiency or (2) an anemia unrelated to vitamin deficiency	Yes
Test Results on Metabolites: Serum Methylmalonic Acid and Total Homocysteine
Methylmalonic Acid (Normal, 70-270 nM)	Total Homocysteine (Normal, 5-14 μM)	Diagnosis
Increased	Increased	Cobalamin deficiency confirmed; folate deficiency still possible (i.e., combined cobalamin plus folate deficiency possible)
Normal	Increased	Folate deficiency is likely
Normal	Normal	Cobalamin and folate deficiency is excluded

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Endoscopy and biopsy for atrophic gastritis may be performed in selected cases.
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Diagnosis is crucial because failure to treat may result in irreversible neurologic deficits.

Laboratory Tests

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Complete blood count generally reveals macrocytic anemia, thrombocytopenia, and mild leukopenia with hypersegmented neutrophils (Fig. E2).

FIG.E2

Macro-ovalocytes (A) and hypersegmented neutrophils (B) are typical features of megaloblastic anemia.

From Jaffe ES, et al.: Hematopathology, Philadelphia, 2011, Saunders.
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Mean corpuscular volume (MCV) is significantly elevated in advanced stages.
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Reticulocyte count is low to normal.

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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).

TABLE2 Serum Cobalamin: False-Positive and False-Negative Test ResultsFrom Hoffman R, et al.: Hematology, basic principles and practice, ed 6, Philadelphia, 2013, Saunders, 2013.

Falsely Low Serum Cobalamin in the Absence of True Cobalamin Deficiency

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Folate deficiency (one-third of patients)
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Multiple myeloma
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TCI deficiency
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Megadose vitamin C therapy
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Pregnancy
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Oral contraceptives

Falsely Raised Cobalamin Levels in the Presence of a True Deficiency^∗

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Cobalamin binders (TCI and II) increased (e.g., myeloproliferative states, hepatomas, and fibrolamellar hepatic tumors)
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TCII-producing macrophages are activated (e.g., autoimmune diseases, monoblastic leukemias and lymphomas)
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Release of cobalamin from hepatocytes (e.g., active liver disease)
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High serum anti-IF antibody titer

IF, Intrinsic factor; TC, transcobalamin.

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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.
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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.
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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.
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Additional laboratory abnormalities can include elevated lactate dehydrogenase, direct hyperbilirubinemia, and decreased haptoglobin.
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Bone marrow aspirate is not necessary to diagnose cobalamin deficiency. It may show giant C-shaped neutrophil bands and megaloblastic normoblasts (Fig. E3).

FIG.E3

Bone marrow aspirate from a patient with cobalamin deficiency illustrates a giant C-shaped neutrophil band and megaloblastic normoblasts.

From Jaffe ES, et al.: *Hematopathology,* Philadelphia, 2011, Saunders.

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Schilling test: No longer available in most laboratories. 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 Rx

Traditional therapy of cobalamin deficiency consists of intramuscular (IM) or deep subcutaneous (SC) injections of vitamin B₁₂ 1000 mcg/day for 1 week, followed by 1000 mcg/month, indefinitely. Monitor response and increase dosing if serum B₁₂ levels decline. Consider returning to IM vitamin B₁₂ supplementation if decline recurs.

Chronic Rx

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Parenteral vitamin B₁₂ 1000 mcg/month or intranasal cyanocobalamin 500 mcg/week for the remainder of life.
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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. The initial dose of intranasal cyanocobalamin (Nascobal) is 1 spray (500 mcg) in one nostril once per week. Nasal cyanocobalamin is expensive with costs generally exceeding $140/month.
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Oral cobalamin (1000-2000 mcg/day) has been reported as 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 month of therapy is approximately $5.

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

Comments

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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.
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Vitamin B₁₂ deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord (e.g., subacute combined degeneration of spinal cord).
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Vitamin B₁₂ deficiency may suppress signs of polycythemia vera; treatment of B₁₂ deficiency may unmask this disorder.
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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.
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Drugs that interfere with B₁₂ absorption include metformin, colchicine, neomycin, and aminosalicylic acid.
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Patients must understand that cobalamin replacement therapy is lifelong.
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Self-injection of vitamin B₁₂ may be taught in selected patients. Cost of monthly injections is less than $10.
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Patients who have had bariatric surgery should receive 1 mg of oral vitamin B₁₂ per day indefinitely.

Ferri – Anemia, Pernicious