Cobalamin is an essential, water-soluble vitamin and an important cofactor for many biochemical reactions. Canine and feline diets contain plentiful cobalamin, making a dietary insufficiency unlikely. However, patients that are fed an exclusively non-fortified vegetarian diet for longer periods may develop cobalamin deficiency unless supplementation occurs.
The physiologic mechanism of cobalamin absorption is complex and requires a functioning digestive system (Fig. 25-7). Dietary cobalamin is bound to animal-based protein. After digestion of these carrier proteins in the stomach, the cobalamin is immediately bound to R-protein, a cobalamin transporter secreted in saliva and gastric juice. Pancreatic enzymes (i.e., trypsin and chymotrypsin) digest the R-protein in the small intestine, and the free cobalamin is bound by intrinsic factor. The exocrine pancreas is a major source of intrinsic factor in dogs and appears to be the exclusive source of intrinsic factor in cats.61 This is in contrast to humans where intrinsic factor is produced predominantly in the stomach. Intrinsic factor/cobalamin complexes are then absorbed by specific mucosal receptors located in the ileum.
Major disorders that interfere with cobalamin uptake are EPI, distal or diffuse small intestinal disease, and excess bacterial utilization of cobalamin in bacterial dysbiosis. Aberrations in the small intestinal microbiota may lead to increased competition for cobalamin resulting in decreased absorption by the host. Bacteria in the gut may compete with receptors located in the distal small intestine and prevent cobalamin uptake by enterocytes. Bacteroides spp. are the principal organisms involved because they can utilize cobalamin-intrinsic factor, whereas other bacteria can only bind free cobalamin, which is present in lower concentrations in the gut. The reported sensitivity of serum cobalamin for the diagnosis of SIBO is 25% to 55%.62
Any long-standing and severe intestinal disease (e.g., IBD, lymphoma, or fungal disease) affecting the ileum may also lead to damage of mucosal cobalamin receptors. This can cause cobalamin malabsorption with a subsequent depletion of body stores of cobalamin, and ultimately lead to a decreased serum cobalamin concentration.
Abnormalities of both vitamins are common in dogs and cats with EPI. Therefore, EPI should be ruled out in patients with GI signs and a decreased serum cobalamin concentration. Serum cobalamin must bind to intrinsic factor in order to be absorbed by receptors located in the distal ileum. Because the exocrine pancreas is the exclusive source of intrinsic factor in cats and the main source in dogs, EPI will lead to decreased secretion of intrinsic factor and, therefore, decreased uptake of cobalamin. Cats with EPI almost always have subnormal serum cobalamin concentrations. Similar subnormal cobalamin concentrations have been described in excess of 80% in dogs with EPI.63
The measurement of serum concentrations of cobalamin is only an indirect test for assessing cobalamin deficiency. Cobalamin deficiency leads to accumulation of serum or urine methylmalonic acid (MMA), the concentrations of which are often dramatically increased in patients with cobalamin deficiency and have been shown to decrease with cobalamin supplementation.64 It has also been shown that some patients with low normal serum cobalamin concentrations have increased MMA concentrations, indicating cobalamin deficiency on a cellular level.64 Therefore, cobalamin deficiency may even be present when serum cobalamin concentration is in the low end of the reference interval (<350 ng/L) and parenteral cobalamin supplementation should be considered in patients with compatible clinical signs. The measurement of MMA concentration is technically challenging and currently only available through few laboratories. Very young puppies (up to 13 weeks) have been shown to have lower serum cobalamin concentrations than adult dogs. Also, a hereditary form of cobalamin deficiency has been reported in both dogs and cats, and affected animals present usually at a young age (6 to 12 weeks).65