Intrinsic Factor Blocking Antibodies

Overview:

Intrinsic factor is a glycoprotein (produced by the parietal cells of the stomach) that is required for the absorption of vitamin B12 from the diet.1 During digestion, stomach acids dissociate B12 from food and intrinsic factor binds to it and allows it to be absorbed in the small intestine. Conditions that impair intrinsic factor production lead to B12 malabsorption and deficiency. Laboratory findings for B12 deficiency include decreased serum B12 levels, increased methylmalonic acid and megaloblastic anemia.2-6 Impaired hemoglobin synthesis associated with B12 deficiency is characterized by abnormal maturation of erythrocyte precursors in the bone marrow, which results in the presence of megaloblasts with hypersegmented neutrophils and decreased erythrocyte survival.4 Vitamin B12 deficiency is also associated with neurological abnormalities.5,6 A leading cause of vitamin B12 deficiency is pernicious anemia (PA) caused by intrinsic factor deficiency.7-10 The condition is referred to as "pernicious" because it is clinically silent initially and only becomes manifest when patients experience generalized symptoms, such as weakness, diminished energy and (less commonly) dyspepsia.9,11 The incidence of PA increases with age and is relatively rare in individuals younger than 30 years of age.10 The highest prevalence is seen in Northern Europeans, although PA has been reported in virtually every ethnic group.10 PA can be caused by pathologic conditions that damage or remove a portion of the stomach's parietal cells, including bariatric surgery, gastric tumors, gastric ulcers, and excessive consumption of alcohol. Autoimmune ABG is caused by CD4 T cell-mediated autoimmune response directed against the gastric H/K-ATPase.11 Diagnosis of autoimmune PA relies on histologically proven atrophic body gastritis, megaloblastic anemia, B12 deficiency, and antibodies to intrinsic factor and to gastric parietal cells.10 Antiparietal cell antibodies are found in 90% of patients with PA, but have low specificity and are seen in atrophic gastritis without megaloblastic anemia as well as in various autoimmune disorders.10 Anti-intrinsic factor antibodies are less sensitive, being found in only 60% of patients with PA, but they are considered highly specific for PA.9,11-13 Laboratory diagnosis is further supported by increased levels of fasting gastrin and decreased levels of pepsinogen I.7,9 Epidemiological evidence and genetic studies suggest that PA has a significant heritable component and leucocyte antigen-DR genotypes suggest a role for genetic susceptibility.9,13,14 Long-standing Helicobacter pylori infection may play a predisposing role in many patients in whom the active infectious process has been gradually supplanted by an autoimmune disease that terminates in a burned-out infection and the irreversible destruction of the gastric body mucosa.9 PA is frequently associated with autoimmune thyroid disease (40%) and other autoimmune disorders, such as diabetes mellitus (10%), as part of the autoimmune polyendocrine syndrome.8,9 PA incidence is also increased in patients with primary biliary cirrhosis compared to controls.15 Autoimmune gastritis may predispose to gastric carcinoid tumors or adenocarcinomas.8

1. Burtis AC, Ashwood ER. Vitamin B12. In: Tietz NW, ed. Textbook of Clinical Chemistry. 3rd ed. Philadelphia, Pa: WB Sanders Co;1999:999-1028.

2. Langan RC, Zawistoski KJ. Update on vitamin B12 deficiency. Am Fam Physician. 2011 Jun 15; 83(12):1425-1430. PubMed 21671542

3. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency—An update. Haematologica. 2006 Nov; 91(11):1506-1512. PubMed 17043022

4. Ryan-Harshman M, Aldoori W. Vitamin B12 and health. Can Fam Physician. 2008 Apr; 54(4):536-541.

5. Selhub J, Morris MS, Jacques PF, Rosenberg IH. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009 Feb; 89(2):702S-706S. PubMed 19141696

6. Tangney CC, Tang Y, Evans DA, Morris MC. Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline. Neurology. 2009 Jan 27; 72(4):361-367. PubMed 19171834

7. Annibale B, Lahner E, Fave GD. Diagnosis and management of pernicious anemia. Curr Curr Gastroenterol Rep. 2011 Dec; 13(6):518-524. PubMed 21947876

8. De Block CE, De Leeuw IH, Van Gaal LF. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. J Clin Endocrinol Metab. 2008 Feb; 93(2):363-371.

9. Lahner E, Norman GL, Severi C et al. Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency. Am J Gastroenterol. 2009 Aug; 104(8):2071-2079. PubMed 19491828

10. Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014 Apr-May; 13(4-5):565-568. PubMed 24424200

11. Toh BH, Chan J, Kyaw T, Alderuccio F. Cutting edge issues in autoimmune gastritis. Clin Rev Allergy Immunol. 2012 Jun; 42(3):269-278. PubMed 21174235

12. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009 Jul; 161(1):11-20. PubMed 19411300

13. Toh BH. Diagnosis and classification of autoimmune gastritis. Autoimmun Rev. 2014 Apr-May; 13(4-5):459-462. PubMed 24424193

14. Banka S, Ryan K, Thomson W, Newman WG. Pernicious anemia—genetic insights. Autoimmun Rev. 2011 Jun; 10(8):455-459. PubMed 21296191

15. Liaskos C, Norman GL, Moulas A et al. Prevalence of gastric parietal cell antibodies and intrinsic factor antibodies in primary biliary. Clin Chim Acta. 2010 Mar; 411(5-6):411-415. PubMed 20026019

Bunting RW, Bitzer AM, Kenney RM, Ellman L. Prevalence of intrinsic factor antibodies and vitamin B12 malabsorption in older patients admitted to a rehabilitation hospital. J Am Geriatr Soc. 1990 Jul; 38(7):743-747. PubMed 2370393

Harty RF, Leibach JR. Immune disorders of the gastrointestinal tract and liver. Med Clin North Am. 1985 Jul; 69(4):675-704 (review). PubMed 3903375