Intrinsic Factor and Parietal Cell Antibodies

Autoimmune gastritis causes pernicious anaemia through loss of gastric parietal cells and intrinsic factor, which is needed for absorption of vitamin B12 in the terminal ileum. Two antibodies are measured.

Anti-intrinsic factor antibody (IFAB) is highly specific for pernicious anaemia, and anti-parietal cell antibody (APCA, directed against the gastric H+/K+ ATPase proton pump) is sensitive but less specific. Both are detected by immunoassay (ELISA, chemiluminescence), and APCA also by immunofluorescence on rodent stomach.

Type I (blocking) IFAB prevents binding of B12 to intrinsic factor, and type II (binding) prevents the complex binding to the ileal receptor.

Pernicious anaemia affects about 0.1% of the general population and 2% of people over 60 years, with higher rates in people of Northern European and African descent and in association with autoimmune thyroid disease, type 1 diabetes, vitiligo, Addison disease and hypoparathyroidism.

APCA is positive in 80 to 90% of pernicious anaemia (but also in 2 to 10% of healthy people, rising to 20 to 30% of older people and over 30% of those with autoimmune thyroid disease), and IFAB in 50 to 70%, with specificity over 95%. Autoimmune gastritis is associated with gastric neuroendocrine tumours (type 1) and gastric adenocarcinoma (relative risk 3 to 7).

Indications. Low vitamin B12 or macrocytic anaemia of uncertain cause. Neuropsychiatric symptoms with low B12: paraesthesia, ataxia, subacute combined degeneration, cognitive decline, depression. Unexplained iron deficiency anaemia in an older patient (autoimmune gastritis reduces acid and iron absorption). Atrophic gastritis on biopsy.

Autoimmune thyroid disease, type 1 diabetes or other autoimmune disease with fatigue. Hypergastrinaemia. Unexplained glossitis. Before starting lifelong B12 replacement to confirm the cause.

Specimen. Serum 1 mL, no fasting. Stable for days at 2 to 8 °C. Samples are taken before or at least 48 hours after a B12 injection, because very high serum B12 (after recent injection) can cause false negative IFAB results by blocking the assay.

Reference values (assay dependent).

• Anti-intrinsic factor antibody: negative under 6 U/mL, equivocal 6 to 9 U/mL, positive over 9 U/mL (ELISA).
• Anti-parietal cell antibody: negative under 10 U/mL (ELISA), or negative at 1 in 20 by immunofluorescence.
• Vitamin B12 (for context): normal over 200 ng/L (150 pmol/L), borderline 150 to 200 ng/L, deficient under 150 ng/L.
• Gastrin (for context): fasting gastrin is high (over 100 ng/L, and often over 1000 ng/L) in autoimmune gastritis.

Interpretation.

• IFAB positive with low B12 and megaloblastic anaemia: pernicious anaemia is confirmed (specificity over 95%), and no further investigation to define cause is needed. Treatment is lifelong hydroxocobalamin injections.
• IFAB negative with APCA positive: autoimmune gastritis is likely, but not diagnostic of pernicious anaemia, and gastroscopy with biopsy shows atrophic body gastritis.
• IFAB negative, APCA negative with low B12: IFAB can be negative in up to 40% of true pernicious anaemia, so a second sample, gastrin, pepsinogen I (low) and gastroscopy or an alternative cause (dietary, metformin, ileal disease, proton pump inhibitors, nitrous oxide, bacterial overgrowth) are considered.
• APCA positive alone, with normal B12: possible latent autoimmune gastritis, to be followed for B12 and iron status yearly.
• Pepsinogen I to II ratio under 3 and raised gastrin support atrophic body gastritis.
• Antibody titres do not track treatment and are not repeated after diagnosis.

Critical values and findings needing immediate action.

• Severe megaloblastic anaemia (haemoglobin under 70 g/L) with heart failure or angina: urgent admission, careful transfusion only if needed and immediate parenteral B12 (with folate after B12 started and potassium monitoring).
• Neurological signs (ataxia, posterior column loss, weakness, confusion) with low B12: start intramuscular hydroxocobalamin urgently, because delay risks permanent damage.
• Pancytopenia with low B12: exclude marrow failure, and treat promptly.
• Gastric polyps or nodules in autoimmune gastritis: endoscopic resection and surveillance for neuroendocrine tumour.

Interferences and pitfalls.

• Recent B12 injection or high dose supplements can cause false negative IFAB, so serum is drawn before treatment, or the test is repeated at least 48 hours after the last dose.
• APCA is not specific and is positive in healthy older people, autoimmune thyroid disease, type 1 diabetes, Helicobacter pylori gastritis and some drug reactions. A positive APCA without B12 deficiency or anaemia does not require treatment.
• Folate supplementation corrects the anaemia but not the neurological damage in B12 deficiency, so it is never given alone.
• Serum B12 is falsely normal in liver disease, myeloproliferative disease, renal failure and intrinsic factor antibody interference with some assays, and methylmalonic acid and homocysteine are raised in true deficiency.
• The Schilling test is obsolete.
• Metformin, proton pump inhibitors, H2 blockers, nitrous oxide, vegan diet, ileal resection and Crohn disease are other causes of B12 deficiency, and antibodies are normal.
• Helicobacter pylori infection may precede or trigger autoimmune gastritis, and its detection is relevant for gastric cancer risk.
• Coexisting iron deficiency can mask the macrocytosis (mixed picture, with a raised red cell distribution width).

Special groups.

• Children: juvenile pernicious anaemia is rare and associated with autoimmune polyendocrine syndromes. Inherited B12 malabsorption (Imerslund-Grasbeck syndrome, intrinsic factor deficiency) has no antibodies.
• Pregnancy: B12 deficiency raises risk of neural tube defects and foetal growth restriction, and treatment is the same.
• Older adults: pernicious anaemia is a disease of the elderly, often with cognitive decline attributed to ageing, so B12 and antibodies are checked in dementia workup.
• Regions: dietary deficiency, tropical sprue, fish tapeworm and Helicobacter pylori are other causes, and autoimmune pernicious anaemia is well described in African populations.

Follow up tests. Full blood count with red cell indices and blood film (macro-ovalocytes, hypersegmented neutrophils), vitamin B12 and folate, methylmalonic acid, homocysteine, ferritin, reticulocyte count, lactate dehydrogenase and bilirubin, fasting gastrin, pepsinogen I and II, upper gastrointestinal endoscopy with biopsies (including Helicobacter pylori),

thyroid function and antibodies, glucose or HbA1c, adrenal antibodies if symptoms suggest, bone density scan, and endoscopic surveillance for gastric neoplasia.