Intrinsic factor and Pernicious Anaemia

Pernicious Anaemia is one of the most frequent causes of vitamin B12 deficiency; it is often an immune disease. This disease is characterized by chronic inflammation and atrophy (thinning or shrivelling) of the mucous membrane of the stomach and the diminished amount, or total lack, of parietal cells and intrinsic factor.
Anaemia and macrocytosis (enlarged red blood cells) are known symptoms of Pernicious Anaemia. A large number of patients however has no anaemia or macrocytosis so this should not stand in the way of a correct diagnosis.

Intrinsic factor

Vitamin B12 can only be absorbed by the body if bonded to the intrinsic factor. The inside of the stomach has a thick mucous lining. This lining contains glands that produce the gastric juice. The lining in the lower part of the stomach contains the parietal cells. These cells produce hydrochloric acid and intrinsic factor. In the first part of the small intestine (the duodenum) B12 is bonded to the intrinsic factor. This complex moves through the small intestine towards its last part, the ileum, where it binds itself to the receptors. There the vitamin B12 is transported through the intestinal wall and in the bloodstream bound to transcobalamin, a transport protein that brings it to tissues and into cells where it is converted into methylcobalamin and adenosylcobalamin.

The deficiency of intrinsic factor in Pernicious Anaemia can be caused by two mechanisms, either by the progressive destruction and eventual loss of parietal cells, leading to a diminished production of intrinsic factor, or by the presence of blocking antibodies that prevent the bonding of  the intrinsic factor to vitamin B12.

Antibodies against  the intrinsic factor only occur in  the case of Pernicious Anaemia. The presence of parietal cell antibodies is predictive for autoimmune gastritis, which can  eventually lead to Pernicious Anemia.
Antibodies against intrinsic factor are of the type IgG, which is  found with 50 to 70 percent of people with Pernicious Anaemia.
The presence of antibodies against intrinsic factor leads to the diagnosis Pernicious Anaemia. However, a negative test result cannot exclude Pernicious Anemia.


We can distinguish two types of chronic gastritis depending on whether or not the antrum (the lowest part of the stomach) is affected.

Type A:  Autoimmune gastritis is found in the fundum (upper part) and corpus (middle part) of the stomach but not in the antrum.
Type B: Non-autoimmune gastritis can also be found in the antrum.

Type A is associated with Pernicious Anemia, antibodies against parietal cells and  against intrinsic factor, with deficient stomach acid, low concentration of pepsinogen and therefore less pepsin. In most cases there are also high serum concentrations of gastrin caused by growing number of gastrin producing cells.
Type B is caused by a Helicobacter Pylori infection and goes hand in hand with low serum values of gastrin, caused by the destruction of gastrin producing cells.

Atrophy can be determined macroscopically (by means of gastroscopy) by the diminishing number of folds in the mucous and its general thinning. Atrophy causes less pepsin to be produced. This lowers the production of stomach acid and diminishes  intrinsic factor production.
With too little intrinsic factor, or none at all, the body cannot or not sufficiently absorb vitamin B12, which leads to B12 deficiency.
Achlorhydria, stomach acid deficiency, is caused by a lack of parietal cells. In this case the Pernicious Anaemia diagnosis is also valid, since it is the only condition with a lack of stomach acid.

Genetic predisposition for Pernicious Anaemia is shown by the fact that various members of one family are affected. About 20 percent of family members of Pernicious Anaemia patients have the same disease.

Pernicious Anaemia often occurs in combination with other autoimmune diseases, such as: Hashimoto’s, Graves, Diabetes 1, Hypoparathyroidism, Myasthenia Gravis and Lambert Eaton Syndrome. Therefore it is advised to screen the vitamin B12 status of these patients regularly.

Pernicious Anemia found in children is almost alway caused by an congenital disruption of the production of intrinsic factor and almost never by atrophic gastritis. Screening older children sometimes does show antibodies.
The term Pernicious Anaemia is actually not correct. It can lead to confusion since a considerable part of the patients do not have anaemia or macrocytosis. It would be better to use the term ‘Addison-Biermer’s disease’.

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