Vitamin Metabolism
abnormality of TCII has been described that results in
megaloblastic anemia (Table 38-1).
Intestinal Receptor for IF-B
this receptor is not, strictly speaking, a
cobalamin-binding protein, it is essential for normal
absorption of dietary cobalamin. It is present on the
membrane of microvilli of ileal but not jejunal or
duodenal cells, with the highest concentration in the
distal 60-cm portion of the small intestine. The
purified receptor is composed of two subunits (M.W.
90,000 and 140,000) and binds free IF and IF-Bi
complex, although free IF binds more slowly.
Subsequent transport of cobalamin into enterocytes is
accomplished by an active process.
Patients have been described who have a vitamin
deficiency that is not correctable by IF. In the
Schilling test with or without added IF, these patients
have a low urinary output of radioactivity. This
finding could be due to a deficiency or defect in the
ileal receptor protein. More commonly, it occurs when
there is an acquired ileal defect such as a bacterial
overgrowth (blind loop syndrome) or tropical sprue.
The two reactions in mammalian systems in which
cobalamins participate are conversion of
L-methylmalonyl-CoA to succinyl-CoA by
methylmalonyl-CoA mutase, and methylation of
homocysteine to methionine by N5-tetrahydrofolate
homocysteine methyltransferase (Figure 38-17). The
interrelationship of vitamin B
, 2
and folic acid
derivatives are discussed below, under “Folic Acid.”
Inborn errors in the synthesis of adenosylcobalamin
or of both adenosyl- and methylcobalamins have been
described. They cause, respectively, methylmalonic
aciduria alone or combined with homocystinuria
(Table 38-1). These disorders respond to treatment
with pharmacological doses of vitamin B|2.
Methylmalonic aciduria that does not respond to
vitamin B
is probably due to an abnormal
methylmalonyl-CoA mutase.
The cobalamins are excreted in urine, bile, and
feces. Intact cobalamin molecules are the
predominant forms in urine. Urinary excretion is
highly variable, but it averages ~150 ng/d and is
somewhat higher in smokers than nonsmokers. The
principal excretory route is bile. Cobalamins destined
for biliary excretion may be transported to the liver by
TCI and TCIII. The liver is the only tissue that takes
up the TCI-cobalamin complex.
The importance and completeness of the
enterohepatic circulation are demonstrated by strict
vegetarians who consume no vitamin B12. They
require 20-30 years or more to develop vitamin B
deficiency, whereas deficiency symptoms occur
2 - 1 0
years after ileal absorption is blocked by
disease of the stomach, pancreas, or ileum or by ileal
resection. Disruption of the absorptive pathway is the
probable reason for vitamin B
deficiency in tropical
Nitrous oxide (N
0) used as an anesthetic agent inac-
tivates vitamin B)2. Subjects with marginal vitamin B
stores can develop vitamin B
deficiency within weeks
after administration of the anesthetic. Major clinical man-
ifestations of vitamin B
deficiency include hemato-
logic abnormalities (e.g., megaloblastic macrocytic ane-
mia, hypersegmentation of neutrophils) and neurological
deficiency (e.g., sensory neuropathy). In addition, since
dividing cells require vitamin Bi2, all rapidly growing cells
are affected. One visible sign of vitamin B
deficiency is
sore mouth and tongue, and the latter may be bald and
In vitamin B
deficiency, neurological damage may
sometimes occur in the absence of hematological abnor-
malities and may be mistaken for multiple sclerosis, dia-
betic neuropathy, or neuropsychiatric disorders. In some
elderly subjects malfunctioning of gastric parietal cells
leads to reduction in both intrinsic factor and H+ pro-
duction (achlorhydria) causing vitamin B
tion. Two metabolites that accumulate due to reduced cat-
alytic function of L-methylmalonyl-CoA mutase and me-
thionine synthase as a result of vitamin B
deficiency are
methylmalonic acid and homocysteine. In the clinical as-
sessment of subtle vitamin Bj
deficiency in the presence
of normal or low-normal serum levels of vitamin Bi2, mea-
surement of homocysteine and methylmalonic acid serum
levels may prove valuable in detecting incipient vitamin
| 2
deficiency. In folate deficiency, serum homocysteine
levels are also increased, but methylmalonic acid levels
remain in the normal range. In vitamin B ^-deficient sub-
jects, folate therapy may normalize homocysteine levels
along with some of the hematological abnormalities, but
it will not correct the neurological manifestations. Thus,
inappropriate folate therapy may mask vitamin Bi
ciency (discussed in the next section).
Folic Acid (Pteroylglutamic Acid)
The common nam
e folic acid
is derived from Latin
“leaf,” because this vitamin was originally isolated from
dark green, leafy vegetables such as spinach. Folic acid
metabolism was discussed in Chapter 27.
A close relationship exists between metabolism of the
folates and of vitamin Bi2. Deficiency of either pro-
duces megaloblastic anemia, and symptoms of vitamin B
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