DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1090 intracellular storage proteins that are released with cell
death. Vitamin B 12
bound to transcobalamin II is rapidly
cleared from plasma and preferentially distributed to
hepatic parenchymal cells. The liver is a storage depot
for other tissues. In normal adults, as much as 90% of
the body’s stores of vitamin B 12
, from 1-10 mg, is in
the liver. Vitamin B 12
is stored as the active coenzyme
with a turnover rate of 0.5-8 μg per day, depending on
the size of the body stores. The recommended daily
intake of the vitamin in adults is 2.4 μg.
Approximately 3 μg of cobalamins are secreted
into bile each day, 50-60% of which is not destined for
reabsorption. This enterohepatic cycle is important
because interference with reabsorption by intestinal disease
can progressively deplete hepatic stores of the vitamin.
This process may help explain why patients can
develop vitamin B 12
deficiency within 3-4 years of
major gastric surgery, even though a daily requirement
of 1-2 μg would not be expected to deplete hepatic
stores of more than 2 to 3 mg during this time.
The supply of vitamin B 12
available for tissues is directly
related to the size of the hepatic storage pool and the amount of
vitamin B 12
bound to transcobalamin II (Figure 37–8). The plasma
concentration of vitamin B 12
is the best routine measure of B 12
deficiency,
and normally ranges from 150-660 pmol (~200-900 pg/mL).
Deficiency should be suspected whenever the concentration falls
below 150 pmol. The correlation is excellent except when the plasma
concentrations of transcobalamin I and III are increased, as occurs
with hepatic disease or a myeloproliferative disorder. Inasmuch as
the vitamin B 12
bound to these transport proteins is relatively
unavailable to cells, tissues can become deficient when the concentration
of vitamin B 12
in plasma is normal or even high. In subjects
with congenital absence of transcobalamin II, megaloblastic anemia
occurs despite relatively normal plasma concentrations of vitamin B 12
;
the anemia will respond to parenteral doses of vitamin B 12
that
exceed the renal clearance (Hakami et al., 1971).
Defects in intracellular metabolism of vitamin B 12
have been
reported in children with methylmalonic aciduria and homocystinuria.
Potential mechanisms include an incapacity of cells to transport vitamin
B 12
or accumulate the vitamin because of a failure to synthesize
an intracellular acceptor, a defect in the formation of deoxyadenosylcobalamin,
or a congenital lack of methylmalonyl CoA isomerase.
Vitamin B 12
Deficiency. Vitamin B 12
deficiency is recognized
clinically by its impact on the hematopoietic
and nervous systems. The sensitivity of the hematopoietic
system relates to its high rate of cell turnover. Other
tissues with high rates of cell turnover (e.g., mucosa
and cervical epithelium) also have high requirements
for the vitamin.
As a result of an inadequate supply of vitamin
B 12
, DNA replication becomes highly abnormal.
Once a hematopoietic stem cell is committed to enter
a programmed series of cell divisions, the defect in
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
chromosomal replication results in an inability of
maturing cells to complete nuclear divisions while cytoplasmic
maturation continues at a relatively normal
rate. This results in the production of morphologically
abnormal cells and death of cells during maturation, a
phenomenon referred to as ineffective hematopoiesis.
These abnormalities are readily identified by examination
of the marrow and peripheral blood. Maturation of
red-cell precursors is highly abnormal (megaloblastic
erythropoiesis). Those cells that do leave the marrow
also are abnormal, and many cell fragments, poikilocytes,
and macrocytes appear in the peripheral blood.
The mean red-cell volume increases to values >110 fL.
Severe deficiency affects all cell lines, and a pronounced
pancytopenia results.
The diagnosis of a vitamin B 12
deficiency usually
can be made using measurements of the serum vitamin
B 12
and/or serum methylmalonic acid. The latter is
somewhat more sensitive and has been used to identify
metabolic deficiency in patients with normal serum
vitamin B 12
levels. As part of the clinical management
of a patient with severe megaloblastic anemia, a therapeutic
trial using very small doses of the vitamin can
be used to confirm the diagnosis. Serial measurements
of the reticulocyte count, serum iron, and hematocrit
are performed to define the characteristic recovery of
normal red-cell production. The Schilling test can be
used to measure the absorption of the vitamin and
delineate the mechanism of the disease. By performing
the Schilling test with and without added intrinsic factor,
it is possible to discriminate between intrinsic factor
deficiency by itself and primary ileal cell disease.
Vitamin B 12
deficiency can irreversibly damage
the nervous system. Progressive swelling of myelinated
neurons, demyelination, and neuronal cell death are
seen in the spinal column and cerebral cortex. This
causes a wide range of neurological signs and symptoms,
including paresthesias of the hands and feet,
decreased vibration and position senses with resultant
unsteadiness, decreased deep tendon reflexes, and in
the later stages, confusion, moodiness, loss of memory,
and even a loss of central vision. The patient may
exhibit delusions, hallucinations, or even overt psychosis.
Because the neurological damage can be dissociated
from the changes in the hematopoietic system,
vitamin B 12
deficiency must be considered in elderly
patients with dementia or psychiatric disorders, even if
they are not anemic.
Vitamin B 12
Therapy. Vitamin B 12
is available for injection
or oral administration; combinations with other