2. Usually seated in an atrophic gastritis, the autoimmune destruction of gastric parietal
cells (and autoantibody inactivation of intrinsic factor) leads to a lack of intrinsic
factor.[1] Since the absorption from the gut of normal dietary amounts of vitamin
B12[2] is dependent on intrinsic factor, the loss of intrinsic factor leads to vitamin B12
deficiency. While the term 'pernicious anemia' is sometimes also incorrectly used to
indicate megaloblastic anemia due to any cause of B12 deficiency, its proper usage
refers to that caused by atrophic gastritis, parietal cell loss, and lack of intrinsic factor
only.
3. The loss of ability to absorb vitamin B12 (B12) is the most
common cause of adult B12 deficiency.[3] Impaired absorption
of vitamin B12 may be due to a loss of intrinsic factor or to a
number of other conditions that decrease production of gastric
acid, which also plays a part in the absorption of B12 from foods.
4. Replacement of vitamin stores does not correct the defect in absorption from
loss of intrinsic factor. Since the defect defines the disease, a person without
the ability to absorb B12 in this way will have pernicious anemia for the
remainder of their life. However, unless the patient has sustained permanent
peripheral nerve damage before treatment, regular B12 replacement will
keep PA in check, with no anemia and no further symptoms.
Although initial treatment of the disease usually involves injections of B12 to
rapidly replace body stores, a number of studies have shown long-term
vitamin replacement treatment may be maintained with high-dose oral B12
supplements, since sufficient B12 is absorbed from these by a normal
intestine, even without any intrinsic factor. In this regard, nasal and sublingual
forms of B12 have not been found to have any special value over simple
swallowed tablets
6. Vitamin B12 cannot be produced by the human body, and must be obtained
from the diet. When foods containing B12 are eaten, the vitamin is usually
bound to protein and is released by stomach acid. Following its release, most
B12 is absorbed by the body in the small bowel (ileum) after binding to a
protein known as intrinsic factor. Intrinsic factor is produced by parietal cells
of the gastric mucosa (stomach lining) and the intrinsic factor-B12 complex is
absorbed by cubilin receptors on the ileum epithelial cells.[13][14] PA is
characterised by vitamin B12 deficiency caused by the absence of intrinsic
factor.
7. PA may be considered as an end stage of immune gastritis, a disease
characterised by stomach atrophy and the presence of antibodies to parietal
cells and intrinsic factor.[16] A specific form of chronic gastritis, Type A
Gastritis or Atrophic Body Gastritis is highly associated with PA. This
autoimmune disorder is localised to the body of the stomach, where parietal
cells are located.[15] Antibodies to intrinsic factor and parietal cells cause the
destruction of the oxyntic gastric mucosa, in which the parietal cells are
located, leading to the subsequent loss of intrinsic factor synthesis. Without
intrinsic factor, the ileum can no longer absorb the B12.[17]
8. Pernicious Anemia is an autoimmune disease that attacks the intrinsic factor.
This is a type of protein that helps your body absorb the B12 in your stomach.
The body needs the B12 to make red blood cells. If you have a B12 deficiency
it does not mean you have Pernicious Anemia. There are tests done to
diagnose you. Some people just don’t eat the proper foods to get the B12 in
their system. These people can take B12 supplements. For people with
Pernicious Anemia we need to by-pass the stomach and make sure the B12
goes right into our blood steam. I give myself shots to keep my B12 levels up.
9. In patients with pernicious anemia, malabsorption of vitamin B12 is caused by
intrinsic factor deficiency. This is due to two mechanisms: 1) the progressive
destruction of parietal cells from the gastric mucosa leading to intrinsic factor
destruction and 2) the binding of blocking autoantibodies to the vitamin B12binding site of intrinsic factor, preventing the formation of the vitamin B12intrinsic factor complex [3]. If confirmation of malabsorption due to intrinsic
factor deficiency is needed, the Schilling test can be performed. However,
parietal cell antibodies and intrinsic factor antibodies are now being used to
diagnose autoimmune gastritis and pernicious anemia, respectively [4].
10. (1) Dietary vitamin B12 is normally bound to proteins in food and is provided by food
products of animal origin.
(2) Pepsin and acid pH in the stomach will degrade these food proteins and release
vitamin B12.
(3) The vitamin B12 that is now free then binds to one of the three vitamin B12
binding proteins, called haptocorrin, which is produced by the salivary glands and the
parietal cells in the stomach. In the duodenum the pH is now less acidic and this
allows pancreatic proteases to degrade the haptocorrin, and vitamin B12 (both newly
ingested and from the bile duct) is released again and binds tightly to Intrinsic Factor
produced by parietal cells.
(4) In the mucosal cells of the distal ileum the vitamin B12-Intrinsic Factor complex is
recognised by special receptors.
11. 5) Vitamin B12 then enters the blood bound to another binding
protein, transcobalamin, the complex is known as
holotranscobalamin (Active B12). The majority of vitamin B12
(70-80%) in blood is bound to haptocorrin and only a minor
proportion (20-30%) is bound to transcobalamin.
(6) Holotranscobalamin (Active B12) is the biologically active
fraction of vitamin B12 in the blood as it is in only this form that
vitamin B12 is delivered to all the cells of the body.
(7) Vitamin B12 absorbed in the intestine subsequently gets
transported to the liver via the portal system.
(8) There is extensive enterohepatic circulation of vitamin B12
and B12 is transported from the liver, via the bile duct, to the
duodenum.
12. Cobalamin can be found in meat, milk, and eggs. Once ingested, pepsin and
hydrochloric acid in the stomach release cobalamin from the food complex. R
protein, which is released from gastric parietal cells, is conjugated with the
cobalamin in the stomach. Some of these complexes enter the gallbladder to
be stored, and some continue through to the duodenum, where pancreatic
enzymes break up the complexes and release cobalamin. Intrinsic factor,
released from gastric parietal cells, then conjugates with the free cobalamin
in the duodenum, and the complex travels to the distal 80 cm of the ileum,
where it is absorbed by the cubilin receptors.6 One study found that a small
portion of free cobalamin is also absorbed by a mechanism that is
independent of intrinsic factor.7 The plasma half-life of cobalamin is 6 days,
and liver stores can persist for 3 to 5 years.8 The overall pathway is - See more
at: http://www.clinicalgeriatrics.com/articles/Management-Vitamin-B12Deficiency-What-Role-Oral-Therapy#sthash.6pYD0xoH.dpuf
13. Microorganisms, primarily bacteria, are the only organisms known to
manufacture B12. These bacteria are thought to live in water, soil, and the
digestive tracts of animals. In animals, B12 is normally attached to a protein
either for transport or storage.
When humans eat animal foods, the B12 is protein-bound. When the proteinB12 complex reaches the stomach, the stomach secretes acids and enzymes
that detach the B12 from the protein. Then, in a process unique to B12,
another protein, R-protein (aka cobalophilin, haptocorrin, and transcobalamin
I (1)) picks up the B12 and transports it through the stomach and into the
small intestine. R-protein is found in many fluids in the human body including
saliva and stomach secretions. In addition to B12, R-protein can pick up any
corrinoid (2).
The stomach cells also produce a protein called intrinsic factor (IF), which
travels to the small intestine. When the corrinoid-R-protein complex gets to
the small intestine, the corrinoid is liberated from the R-protein by enzymes
made by the pancreas (3). Of the liberated corrinoids, only the cobalamins
attach to intrinsic factor. Intrinsic factor then carries the cobalamins to the
last section of the small intestine, the ileum.
14. The cells lining the ileum contain receptors for the cobalamin-IF complex. The
cobalamin-IF complex protects the cobalamin against bacterial and digestive
enzyme degradation (4). The IF-receptor also ensures that cobalamins will be
given priority for absorption over non-cobalamin corrinoids.
In addition to the IF mechanism, passive diffusion normally accounts for 1-3%
of B12 absorbed when obtained through normal food sources (3). Some
inactive B12 analogues are most likely absorbed through passive diffusion.
15. In supplements, B12 is not bound to protein, and therefore does not need
digestive enzymes or stomach acid to be detached from a protein. Stomach
acid is needed to dissolve some B12 tablets, especially if not chewed. When
taken in large enough doses, unbound B12 can overcome intrinsic factor
defects because so much can be absorbed through passive diffusion.
There is some preliminary evidence that unbound B12, especially when
combined with an absorption enhancer, can be directly absorbed through the
membranes under the tongue at higher rates than through passive diffusion
in the digestive tract.
16. After B12 is absorbed into the intestinal cells, it attaches to transcobalamin II (TC2).
Transcobalamin II is made in the intestinal cells (7) where it picks up B12 and
transports it to all body tissues through the blood and cerebrospinal fluid (1).
Cyanocobalamin appears in the blood no longer than 5 hours after ingestion of B12
(10).
While transcobalamin II transports B12 to cells, about 3/4 of the B12 in the blood is
stored on haptocorrin (aka transcobalamin I and cobalophilin) (11, 12).
Once the B12-TC2 complex arrives at the cell where it is needed, B12 is released from
TC2 in the form of hydroxocobalamin. It is then turned into methylcobalamin or
adenosylcobalamin (3) and used for their respective enzymes.
Transcobalamin II also transports B12 to the liver for storage on transcobalamin III.
If the circulating B12 exceeds the binding capacity of the blood, the excess is excreted
in the urine. This normally happens only after a B12 injection (5).
![Usually seated in an atrophic gastritis, the autoimmune destruction of gastric parietal
cells (and autoantibody inactivation of intrinsic factor) leads to a lack of intrinsic
factor.[1] Since the absorption from the gut of normal dietary amounts of vitamin
B12[2] is dependent on intrinsic factor, the loss of intrinsic factor leads to vitamin B12
deficiency. While the term 'pernicious anemia' is sometimes also incorrectly used to
indicate megaloblastic anemia due to any cause of B12 deficiency, its proper usage
refers to that caused by atrophic gastritis, parietal cell loss, and lack of intrinsic factor
only.](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)