B12 Deficiency / Pernicious Anaemia

Physiology

• Absorption pathway: food-bound B12 is released in the stomach’s acidic environment and binds R protein (haptocorrin).
• Pancreatic enzymes cleave the B12–R-protein complex in the small intestine.
• Intrinsic factor (IF), secreted by gastric parietal cells, then binds B12, and IF is required for B12 absorption, which takes place in the terminal ileum.
• In plasma B12 is carried on transcobalamins I and II, with transcobalamin II delivering B12 to tissues.
• B12 is needed for DNA synthesis, methyl transfer, and myelin synthesis and repair, and is closely linked with folate — each depends on the other for activation.
• The liver stores large amounts of B12; these stores can sustain physiological needs for 3 to 5 years after intake stops (for example in someone who becomes vegan), and for months to a year if enterohepatic reabsorption is lost.

Pernicious anaemia

• Pernicious anaemia specifically refers to anaemia from B12 deficiency caused by an autoimmune metaplastic atrophic gastritis with loss of intrinsic factor.
• Anti-IF antibodies prevent B12 binding to IF or block the B12/IF complex, preventing intestinal absorption.
• It is a relatively rare autoimmune disorder, and classic pernicious anaemia is most often described in younger and middle-aged adults, though B12 deficiency overall becomes more common with age.
• Pernicious anaemia is found in up to 25% of patients with autoimmune gastritis, and is regarded as a late-stage manifestation of that spectrum.
• Iron deficiency anaemia is present in up to 50% of patients with autoimmune gastritis.
• Patients have a higher incidence of co-occurring autoimmune conditions — type 1 diabetes, autoimmune thyroid disease, vitiligo.
• Classic pernicious anaemia also carries an increased risk of gastric and other gastrointestinal cancers, most strikingly gastric carcinoid (neuroendocrine) tumours, though the absolute risk is low.

Effects of deficiency

• Effects of deficiency: megaloblastic anaemia from impaired red cell formation, and neurological damage to spinal cord and brain white matter (subacute combined degeneration), peripheral neuropathy, optic atrophy and cognitive change.
• Loss of position and vibration sense occurs early and progresses; advanced disease can cause paranoia (“megaloblastic madness”), delirium and confusion.
• Neurological disease can occur without anaemia or macrocytosis.
• B12 is continually secreted and reabsorbed in the gut, so pure dietary deficiency is rare — usually only in strict vegans, or breastfed infants of vegan mothers, who can become deficient by 4–6 months because of limited liver stores and rapid growth.

Causes

Cause	Source
Inadequate diet	Vegan diet; breastfeeding of infants by vegan mothers; fad diets
Impaired absorption	Lack of intrinsic factor (autoimmune metaplastic atrophic gastritis, destruction of gastric mucosa, gastric or bypass surgery); intrinsic factor inhibition; decreased acid secretion (common in older adults — crystalline/supplement B12 is still absorbed, food-bound B12 is not); small-bowel disorders (IBD, coeliac disease, cancer, biliary/pancreatic disease, ileal resection); competition for B12 (fish tapeworm, blind loop / small intestinal bacterial overgrowth); advanced HIV infection
Inadequate utilisation	Enzyme deficiencies; liver disorders; transport protein abnormality
Drugs	Antacids/PPIs; metformin; nitrous oxide (repeated exposure)

Inadequate absorption is the most common cause; inadequate intake is otherwise unlikely outside veganism.

Diagnosis

Test for B12 (and folate) deficiency for unexplained anaemia or macrocytosis, suspected malabsorption, restrictive diets, a family history of pernicious anaemia, and — even without any haematological abnormality — unexplained neurological or neuropsychiatric symptoms such as peripheral neuropathy or cognitive decline. Blood tests should be taken before B12 therapy begins, or the underlying deficiency may become impossible to identify.

• FBC and blood film, plus serum B12 and folate. A B12 level below 200 pg/mL (about 145 pmol/L) indicates deficiency. Folate is measured because folate supplementation can mask B12 deficiency and allow neurological deficits to progress.
• When B12 is low-normal (about 200–350 pg/mL) or indices are normal, serum methylmalonic acid (raised in B12 but not folate deficiency, also raised in renal failure) or homocysteine (raised in either) can help.
• For suspected pernicious anaemia, anti-intrinsic-factor antibodies are ~40–60% sensitive but almost 100% specific; antiparietal cell antibodies are present in ~90% but less specific. A serum cobalamin below 200 ng/L with anti-IF antibodies confirms the diagnosis. The Schilling test is now essentially obsolete.
• Endoscopy with topographical biopsies is recommended for a new pernicious anaemia diagnosis without recent endoscopy — to confirm corpus-predominant atrophic gastritis, risk-stratify, and exclude gastric neoplasia including neuroendocrine tumours.

Management

• Initial: for severe deficiency or neurological involvement, B12 1 mg IM given several times a week for 1–2 weeks (e.g. hydroxocobalamin on alternate days) until haematological abnormalities correct; less intensive replacement if neither is present. Reticulocytes should improve within a week and the blood picture within ~6 weeks; neurological recovery is slower and deficits present for months to years may be irreversible.
• Maintenance: hydroxocobalamin 1 mg IM every 2–3 months. High-dose oral B12 (cyanocobalamin 1000–2000 mcg daily) is an effective alternative for maintenance even when intrinsic factor is absent, because large oral doses are absorbed by mass action. Treatment is lifelong unless the underlying cause is corrected.
• Dietary sources: meat (especially beef, pork, organ meats), poultry, eggs, fish and seafood, milk and milk products, fortified cereals and soy milk. Infants of vegan mothers should receive supplemental B12 from birth.

Keep a low threshold for testing and treating at-risk patients (autoimmune disease, atrophic gastritis, unexplained neurological symptoms) rather than waiting for a classic macrocytic anaemia.