Definition
Pernicious anemia is an autoimmune cause of Vitamin B12 deficiency in which autoimmune destruction of gastric parietal cells and/or antibodies to Intrinsic factor impair cobalamin absorption, producing megaloblastic anemia and neurological complications; the term is classically synonymous with late-stage Autoimmune gastritis. According to the U.S. National Cancer Institute’s dictionary, most cases arise when autoimmunity targets intrinsic factor or the parietal cells that make it, and untreated disease can damage the nervous system. NCI Dictionary of Cancer Terms;
StatPearls—Pernicious Anemia.
Etiology and pathophysiology
Autoimmune gastritis leads to corpus‑predominant atrophy, loss of acid secretion (achlorhydria), and loss of intrinsic factor, preventing ileal uptake of vitamin B12. Antibodies to intrinsic factor (blocking and binding types) and to the gastric H+/K+ ATPase on parietal cells are typical immunologic features. StatPearls—Pernicious Anemia;
StatPearls—Gastric Intrinsic Factor. Molecular mimicry between H. pylori antigens and the H+/K+ ATPase has been proposed as a trigger in some individuals.
StatPearls—Gastric Intrinsic Factor.
Pernicious anemia frequently coexists with other autoimmune disorders, including autoimmune thyroid disease, type 1 diabetes, and vitiligo. StatPearls—Pernicious Anemia;
AGA Clinical Practice Update.
Epidemiology
Prevalence estimates approximate 0.1% in the general population and approach 1.9% in those older than 60 years, with highest rates reported in people of Northern European ancestry; cases occur across all ethnic groups. StatPearls—Pernicious Anemia;
Diagnosis and classification of pernicious anemia.
Clinical manifestations
Hematologic findings include macrocytic (megaloblastic) anemia with hypersegmented neutrophils and possible mild hemolysis. Neurologic involvement ranges from peripheral neuropathy to subacute combined degeneration of the spinal cord (posterior and lateral column demyelination) with gait ataxia and proprioceptive loss. Psychiatric and cognitive symptoms may occur. StatPearls—Vitamin B12 Deficiency;
StatPearls—Subacute Combined Degeneration;
MedlinePlus.
Diagnosis
- –Initial laboratory evaluation uses serum vitamin B12. Borderline or discordant values warrant functional testing with Methylmalonic acid (MMA) and homocysteine; MMA is more specific for tissue B12 deficiency, while both MMA and homocysteine typically rise in B12 deficiency and only homocysteine rises in folate deficiency.
Mayo Clinic Laboratories—Vitamin B12 Assay;
StatPearls—Vitamin B12 Deficiency.
- –Autoantibody testing supports etiology: anti–intrinsic factor antibodies are highly specific but less sensitive (~60%); anti‑parietal cell antibodies are more sensitive (~90%) but less specific.
Diagnosis and classification of pernicious anemia;
- –Many guidelines consider pernicious anemia a late manifestation of Autoimmune gastritis; in newly diagnosed cases without recent endoscopy, upper endoscopy with topographic biopsies can confirm corpus‑predominant atrophic gastritis and assess neoplasia risk.
American Gastroenterological Association.
- –The historic Schilling test for B12 absorption is now obsolete and no longer performed.
The 2024 NICE guideline on B12 deficiency (NG239) recommends recognising autoimmune gastritis as the cause of malabsorption, using B12 levels with follow‑on MMA where appropriate, and not delaying treatment when megaloblastic anemia with neurological symptoms is suspected. NICE NG239;
NCBI Bookshelf—NICE NG239.
Differential diagnosis
Other causes of cobalamin deficiency include dietary deficiency (e.g., strict vegan diets), malabsorption after gastric/ileal surgery, inflammatory bowel disease, celiac disease, pancreatic or bacterial overgrowth, and nitrous oxide exposure; folate deficiency produces a similar megaloblastic hematology but with normal MMA. StatPearls—Vitamin B12 Deficiency.
Management
- –Lifelong cobalamin replacement is standard when pernicious anemia/autoimmune gastritis is the cause. In many health systems, intramuscular hydroxocobalamin is preferred, with typical regimens of 1 mg three times weekly for 2 weeks (no neurologic involvement) followed by 1 mg every 2–3 months for life; with neurologic involvement, 1 mg on alternate days until no further improvement, then every 2 months.
NHS medicines advice;
UK SmPC—Hydroxocobalamin;
Pharmaceutical Journal.
- –High‑dose oral cobalamin (e.g., 1,000–2,000 µg/day) can normalize B12 levels in many patients via passive diffusion and may be an option for long‑term maintenance where appropriate. A 2018 Cochrane review found oral and intramuscular therapy produced similar short‑term biochemical outcomes, with 2,000 µg/day oral producing higher serum levels than 1,000 µg/day IM in one trial.
Cochrane Review;
AAFP Evidence Summary. The NICE NG239 pathway includes both IM and oral options depending on cause and circumstance.
NICE NG239.
- –After initiating therapy, clinicians monitor clinical response; serum B12 rises irrespective of adequacy, so routine re‑measurement is often unnecessary once treatment is established. NHS advice notes that symptoms may begin improving within days to weeks, while product labeling cautions about rare hypokalemia‑related arrhythmias during initial therapy.
Complications and associated risks
- –Gastric neoplasia: Pernicious anemia is associated with increased risks of non‑cardia Gastric cancer and type 1 gastric carcinoid tumors. A large SEER‑Medicare study found odds ratios of 2.18 for noncardia gastric adenocarcinoma and 11.43 for gastric carcinoid.
- –Surveillance: The American Gastroenterological Association advises that newly diagnosed pernicious anemia without recent endoscopy undergo endoscopy with biopsies to confirm corpus‑predominant atrophic gastritis and to rule out prevalent neoplasia; intervals thereafter are individualized, with surveillance every 1–2 years for type 1 gastric neuroendocrine tumors after resection.
Genetics and rare forms
Rare congenital or juvenile forms result from intrinsic factor defects or other absorption disorders and follow autosomal recessive patterns; these are distinct from the common late‑onset autoimmune form. StatPearls—Pernicious Anemia.
Terminology and current guidance
Some contemporary guidelines prefer “autoimmune gastritis with B12 deficiency” and avoid the term “pernicious anemia,” reserving it for late‑stage disease with megaloblastic anemia; NG239 (6 March 2024) adopts this framework for adults ≥16 years and provides algorithms for recognition, diagnosis, replacement therapy, follow‑up, and gastric cancer risk considerations. NICE NG239;
NCBI Bookshelf—NICE NG239.
History
Thomas Addison described a “very remarkable form of general anemia” in 1849; in 1926 George R. Minot and William P. Murphy, building on George H. Whipple’s work, demonstrated that a liver‑rich diet could reverse the condition, a discovery recognized by the 1934 Nobel Prize in Physiology or Medicine. Nobel Prize—Minot;
Nobel Prize—Whipple;
Nobel Prize—Murphy;
Britannica—William P. Murphy.