The Vitamins 169Vitamin B 12 is absorbed from the distal third of the
ileum. There are intrinsic factor–vitamin B 12 binding
sites on the brush border of the mucosal cells in this
region; neither free intrinsic factor nor free vitamin
B 12 interacts with these receptors.
In plasma, vitamin B 12 circulates bound to transco-
balamin I, which is required for tissue uptake of the
vitamin, and transcobalamin II, which seems to be a
storage form of the vitamin.
Enterohepatic circulation of vitamin B 12
There is a considerable enterohepatic circulation of
vitamin B 12. A third plasma vitamin B 12 binding
protein, transcobalamin III, is rapidly cleared by the
liver, with a plasma half-life of the order of 5 min.
This provides a mechanism for returning vitamin B 12
and its metabolites from peripheral tissues to the liver,
as well as for clearance of other corrinoids without
vitamin activity, which may arise from either foods or
the products of intestinal bacterial action, and be
absorbed passively across the lower gut.
These corrinoids are then secreted into the bile,
bound to cobalophilins; 3–8 μg (2.25–6 nmol) of
vitamin B 12 may be secreted in the bile each day, about
the same as the dietary intake. Like dietary vitamin
B 12 bound to salivary cobalophilin, the biliary coba-
lophilins are hydrolyzed in the duodenum, and the
vitamin binds to intrinsic factor, so permitting reab-
sorption in the ileum. Although cobalophilins and
transcorrin III have low specifi city, and will bind a
variety of corrinoids, intrinsic factor binds only
cobalamins, and so only the biologically active vitamin
is reabsorbed.
Metabolic functions of vitamin B 12
There are three vitamin B 12 -dependent enzymes in
human tissues: methylmalonyl-CoA mutase (dis-
cussed below under methylmalonic aciduria), leucine
amino-mutase, and methionine synthetase (discussed
in Section 8.11).
Vitamin B 12 defi ciency: pernicious anemia
Vitamin B 12 defi ciency causes pernicious anemia; the
release into the bloodstream of immature precursors
of red blood cells (megaloblastic anemia). As dis-
cussed below, vitamin B 12 defi ciency causes functional
folate defi ciency; this is what disturbs the rapid mul-
tiplication of red blood cells, causing immature pre-
cursors to be released into the circulation.
The other clinical feature of vitamin B 12 defi ciency,
which is rarely seen in folic acid defi ciency, is degen-
eration of the spinal cord; hence the name “perni-
cious” for the anemia of vitamin B 12 defi ciency. The
spinal cord degeneration is due to a failure of the
methylation of one arginine residue in myelin basic
protein. About one-third of patients who present with
megaloblastic anemia due to vitamin B 12 defi ciency
also have spinal cord degeneration, and about one-
third of defi cient subjects present with neurological
signs but no anemia.
The most common cause of pernicious anemia is
failure of the absorption of vitamin B 12 , rather than
dietary defi ciency. Classical pernicious anemia is due
to failure of intrinsic factor secretion, commonly the
result of autoimmune disease, with production of anti-
bodies against either the gastric parietal cells or intrin-
sic factor. Atrophic gastritis with increasing age also
leads to progressive failure of vitamin B 12 absorption.
Dietary defi ciency of vitamin B 12 does occur, rarely,
in strict vegetarians (vegans). The rarity of vitamin
B 12 defi ciency among people who have no apparent
dietary source of the vitamin suggests that bacterial
contamination of water and foods with vitamin B 12 -
producing organisms will provide minimally adequate
amounts of the vitamin. The fruit bat develops
vitamin B 12 defi ciency when fed on washed fruit
under laboratory conditions, but in the wild micro-
bial contamination of the outside of the fruit provides
an adequate intake of the vitamin.Vitamin B 12 requirements
Most estimates of vitamin B 12 requirements are based
on the amounts given parenterally to maintain normal
health in patients with pernicious anemia due to a
failure of vitamin B 12 absorption. This overestimates
normal requirements, because of the enterohepatic
circulation of vitamin B 12 ; in people lacking intrinsic
factor, or secreting anti-intrinsic factor antibodies,
the vitamin that is excreted in the bile will be lost in
the feces, whereas normally it is almost completely
reabsorbed.
The total body pool of vitamin B 12 is of the order
of 2.5 mg (1.8 μmol), with a minimum desirable body
pool of about 1 mg (0.3 μmol). The daily loss is about
0.1% of the body pool in subjects with normal entero-
hepatic circulation of the vitamin; on this basis
requirements are about 1–2.5 μg/day and reference
intakes for adults range between 1.4 μg and 2.0 μg.