Cobalamin is a water-soluble B vitamin essential for many physiological processes including cell metabolism, synthesis of DNA, amino acid and fatty acid metabolism, nerve myelination and haematopoeisis (Langan and Zawistoski, 2011). Cobalamin acts as a co-factor for methyl transfer in several important enzymatic reactions.
Cats and dogs are not able to synthesise cobalamin, hence they require it within their diets in the form of animal protein (eg meat, milk, fish and eggs). Subsequently, cobalamin deficiencies can occur with vegetarian and vegan diets. While some bacteria within the gastrointestinal microbiota do produce cobalamin, this occurs too distally to be of any benefit to the animal itself.
Cobalamin deficiency can affect the normal functioning of many cells and organs. Animals may present with vague and generalised clinical signs from anorexia and weight loss to neurological symptoms and a failure to thrive. Immunodeficiencies and intestinal changes including villous atrophy and malabsorption may also occur (Reed et al., 2007; Fordyce et al., 2000; Gold et al., 2015; Battersby et al., 2005; Salvadori et al., 2003; Arvanitakis, 1978). While gastrointestinal symptoms often occur, it can be difficult to ascertain if these are the initial cause or a result of the hypocobalaminaemia itself. However, it does appear to stand true that gastrointestinal clinical signs may not resolve until cobalamin levels have been restored, despite concurrent treatment of the underlying disease (eg diet change, anti-inflammatories or immunosuppressants).
It has been reported that up to 61 percent of cats and up to 55 percent of dogs with chronic enteropathies and up to 77 percent of cats and 82 percent of dogs with exocrine pancreatic insufficiency (EPI) may have low serum cobalamin levels (Simpson et al., 2001; German et al., 2003; Xenoulis et al., 2016; Batchelor et al., 2007). Hypocobalaminaemia has been identified as a negative prognostic indicator, associated with an increased risk of euthanasia in canine patients with chronic enteropathies, exocrine pancreatic insufficiency (EPI) and lymphoma (Batchelor et al., 2007; Allenspach et al., 2007; Cook et al., 2009).
The term hypocobalaminaemia refers to low serum cobalamin levels. Measurement of functional markers such as methylmalonic acid (MMA) suggests that intracellular cobalamin levels can sometimes fall before serum levels drop beneath the lower end of laboratory reference ranges (Box 1).
| Cobalamin-dependent methymalonyl-CoA mutase catalyses isomerisation of methylmalonyl-CoA to succinyl-CoA. In a cobalamin-deficient state, there is a reduced activity of the methylmalonyl-coA mutase causing an accumulation of methylmalonyl-CoA; this enters an alternative pathway, resulting in increased production of methylmalonic acid (MMA). Elevated serum and urinary MMA can therefore be used as a marker of cellular cobalamin deficiency |
Studies have shown people, dogs and cats to have elevated MMA despite normal serum cobalamin levels, suggesting intracellular deficiencies which are not yet being reflected by serum cobalamin status (Chanarin and Metz, 1997; Berghoff et al., 2012; Worhunsky et al., 2013). While not all hypocobalaminaemic patients will have elevated serum MMA (Cook et al., 2009), a lack of routine testing of these functional markers means a cautious approach is generally advised, with cobalamin supplementation recommended when serum levels reach the low end of the normal reference range (less than 400ng/l) (Steiner, 2018).
Dietary cobalamin is primarily absorbed via a complex absorption pathway requiring specific binding proteins and receptors (Box 2). Understanding this pathway aids recognition of the multiple reasons why cobalamin deficiency may occur.
| Gastric acid and pepsinogens start to break down dietary protein in the stomach, releasing cobalamin which then binds to R-proteins in the saliva and gastric fluid. On entry to the duodenum the R-protein is broken down by pancreatic proteases and cobalamin then binds to intrinsic factor (IF). IF is primarily produced by the pancreas in dogs (90 percent with 10 percent from the gastric mucosa), and in cats all IF is pancreatic in origin (Fyfe, 1993; Batt et al., 1989). Cobalamin travels through the small intestine bound to IF; only in this form, bound to IF, can it be absorbed via endocytosis by the specific cubam receptors in the ileum (Batt and Horadagoda, 1989). Cobalamin is then transported in the bloodstream bound to transcobalamin II and stored in the liver. Since cobalamin is a water-soluble vitamin, any excess is excreted in the urine. |
Alongside this complex absorption pathway, it appears that approximately 1 percent of oral cobalamin is absorbed by passive diffusion along the entire length of the intestines. This has been demonstrated by radiolabelling cobalamin in people and is the premise behind oral hypersupplementation as discussed later (Berlin et al., 1968; Okuda, 1960). It is of note that 1 percent of a normal dietary intake would not be sufficient to meet the body’s requirements.
Cobalamin, found in all tissues, is primarily stored in the liver. The half-life of cobalamin in humans is approximately one year, with hepatic stores able to prevent deficiency for months to years. While in dogs cobalamin has a shorter half-life of two months, in both species hypocobalaminaemia tends to follow chronic disease, other than congenital abnormalities (Luhby et al., 1959). Cats appear less able to store cobalamin, with a reported half-life of parenteral cobalamin of 12.75 days, which dropped to five days in cats with inflammatory bowel disease (IBD), thought to be due to reduced enterohepatic circulation (Simpson et al., 1989). Cats therefore may become hypocobalaminaemic earlier in disease states.
Any disruption to the complex absorption pathway may result in a cobalamin deficiency:
Over the past few years there has been a dramatic shift away from using parenteral cobalamin supplementation, with oral supplementation now being used in the majority of cases. This change follows publication of multiple studies supporting the use of oral hypersupplementation of cobalamin to manage hypocobalaminaemia of varying causes. Retrospective studies in dogs and cats with chronic enteropathies showed oral cobalamin to be effective at normalising hypocobalaminaemia (Toresson et al., 2016, 2017).
Two subsequent prospective studies in dogs comparing oral and parenteral supplementation demonstrated oral supplementation to have comparable efficacy to parenteral (Toresson et al., 2018; Chang et al., 2022). Both authors also looked at MMA levels and found them to reduce similarly in both groups with chronic enteropathies with no significant differences detected depending on whether oral or parenteral supplementation was used (Chang et al., 2022; Toresson et al., 2019).
The study by Chang et al. (2022) also assessed dogs with EPI; while both oral and parenteral groups experienced increased serum cobalamin, only in the oral group was the median cobalamin level more than 400ng/ml in all dogs, and serum MMA significantly reduced. Successful use of oral cobalamin has also been reported in multiple cases of hereditary hypocobalaminaemia (McCallum and Watson, 2018; Kook and Hersberger, 2018), supporting the hypothesis that a small percentage of oral cobalamin is able to be absorbed by passive diffusion.
Cobalamin, essential for many bodily functions, is taken up from the diet via a complex absorption pathway. Disruption at any point along this pathway can lead to cobalamin deficiency. Symptoms can be varied and range in severity and may not resolve without correction of the cobalamin deficiency, despite other treatments. Evidence published to date supports the use of oral cobalamin to normalise both serum and functional cobalamin status.
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