Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

IV. Water-Soluble Vitamins
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(i.e., ileum). In the small intestine, following uptake via the
IF receptor, there is subsequent proteolytic release of B 12
and binding to intracellular transcobalamin II (TcII). The
TcII receptor then transports the TcII-VB 12 complex across
the cell, whence it is released into the circulation. Vitamin
B 12 is transported in plasma by one of at least three known
transport proteins: transcobalamin I, II, or III. The transcobalamins
transport vitamin B 12 to cells, where it is again
transferred into targeted cells by endocytotic mechanisms
( Selhub, 2002 ).
Interference with R protein or intrinsic factor production
(e.g., as caused by inflammatory diseases affecting
the ileum, or overproduction of intestinal microflora) can
influence availability of vitamin B 12 . With bacterial overproduction,
there is competition between the host and bacteria
for vitamin B 12 and production of bacterial proteins
that bind B 12 and interact with its uptake. Gut bacteria can
also be a source of B 12 . Many animals obtain vitamin B 12
through coprophagy. In ruminants, vitamin B 12 is synthesized
in ample quantities by ruminal bacteria.
d . Requirements and Deficiency
The requirements for folic acid range from 1 to 10 mg per
kilogram of diet for most animals. There are some conditions
in which the folic acid requirements are conditionally
high (e.g., when either natural or pharmacological folic
acid agonists are present in the diet). With the discovery
that THFA is required for DNA synthesis, a number of
antimetabolites were developed starting in the 1950s and
1960s that function as inhibitors of folic acid reductase.
The best example is methotrexate, which ultimately inhibits
the proliferation and regeneration of rapidly replicating
cells. Cell division is blocked in the S phase, because of
impaired DNA synthesis. As a consequence, drugs such as
methotrexate are widely used in cancer chemotherapy particularly
for tumors of the lymphoreticular system ( Baily,
2007 ; Scott, 1994 ; Selhub, 2002 ).
The requirement for vitamin B 12 for most animals is in
the 2 to 15μg per kilogram of diet range. Although deficiencies
of folic acid and vitamin B 12 are uncommon in
free-ranging animals, diseases of the proximal duodenum
or stomach and ileum and pancreatic insufficiency can
affect folic acid and vitamin B 12 absorption, respectively.
Moreover, cobalt deficiency can result in vitamin B 12 deficiency
in ruminants because of the need for cobalt to vitamin
B 12 synthesis by rumen microorganisms.
Deficiencies of both vitamin B 12 and folic acid include
macrocytic anemia and dyssynchronies in growth and development
owing to the importance of folic acid to purine and
DNA synthesis ( Bohnsack, 2004 ). Chronic deficiencies of
either folic acid or B 12 can also promote fatty liver disease
and indirectly influence extracellular matrix maturation
stability by causing abnormal elevations in homocysteine.
Such signs and symptoms are attributable to both THFA
and B 12 deficiencies, because of the integral relationship
of vitamin B 12 to THFA regeneration. Dietary intakes of
folic acid, sufficient to maintain functional THFA levels,
can mask the initial signs of vitamin B 12 deficiency (e.g.,
macrocytic and megaloblastic anemia). Prolonged vitamin
B 12 deficiency can result in serious neurological disorders
(e.g., degeneration of the myelin sheath). A number of
environmental conditions can alter folate concentrations
in foodstuffs (excessive heat, UV light). Storage of eggs
for more than several weeks may depress hatchability and
increase hematological abnormalities characteristic of mild
macrocytic anemia. Such changes can result from deficiencies
of folic acid. Regarding aging animals, malabsorption
of B 12 can be a problem. Analogous to pernicious anemia
in humans, an autoimmune disease that affects the gastric
parietal cells, destruction of these cells also can occur in
old animals. This curtails the production of intrinsic factor
and subsequently limits vitamin B 12 absorption. This
should be explored in aging animals with signs of macrocytic
or megaloblastic anemia ( Baily, 2007 ; Scott, 1994 ;
Selhub, 2002 ).
In humans, it is also becoming clear that periconceptional
folic acid at the suggested optimal levels of intake
reduce the risk of neural tube and related developmental
defects (NTDs). This has led to fortification of foods in
many countries and policies for supplementation in others.
However, some potential adverse effects, such as masking
vitamin B 12 deficiency, increasing twinning rates, or accelerating
preexisting malignant neoplasms, have also been
reported ( Scott, 1994 ; Selhub, 2002 ).
e . Assessment of Vitamin B 12 and Folate Status of
Animals
An independent role of vitamin B 12 involvement in propionate
metabolism and folate in histidine metabolism provides
the basis for classical methods of assessment of clinical
adequacy, independent of their mutual roles in methyl transfer.
Vitamin B 12 is a component of the coenzyme for methylmalonyl-CoA
mutase, which catalyses the conversion of
L-methylmalonyl-CoA to succinyl-CoA. Although assays
based on B 12 absorption (e.g., the Schilling’s test) are utilized
to assess the potential for B 12 deficiency in humans,
B 12 assessments in animals most often involve administration
of a loading dose of valine (1 g/kg body weight).
L-valine is a precursor of methylmalonyl-CoA, which is
excreted in excess the urine of a vitamin B 12 −eficient animal
in that it is not converted to succinyl-CoA. Similarly
in histidine metabolism THF is required for the removal
of the formimino group from formimino glutamic acid. In
the folate-deficient animal given a loading dose of histidine
(0.2 g/kg body weight), there is enhanced urinary excretion
of unchanged formiminoglutamic acid.
Serum folate and cobalamin concentrations are also
commonly used to access status in clinical practice.