EPI * Exocrine Pancreatic Insufficiency

Journal of Veterinary Internal Medicine

The results of a study " Prognostic Factors in Canine Exocrine Pancreatic Insufficiency: Prolonged Survival is Likely if Clinical Remission is Achieved" performed at the University of Liverpool School of Veterinary Science by Daniel J. Batchelor, Peter-John M. Noble, Rebecca H. Taylor, Peter J. Cripps, Alexander J. German, published in the Journal of Veterinary Internal Medicine in February 2008 concludes that "Long-term prognosis in canine EPI is favorable for dogs that survive the initial treatment period. Although there are few predictors of good RIT (Response to Initial Treatment) or long-term survival, severe cobalamin deficiency is associated with shorter survival. Therefore, parenteral cobalamin supplementation should be considered when hypocobalaminemia is documented." 

The ABSTRACT of the study is as follows:

Background: Response to therapy in canine exocrine pancreatic insufficiency (EPI) varies considerably, making it difficult to determine prognosis for individual patients.
Hypothesis: Response to initial treatment (RIT) and survival are affected by signalment, clinical variables, and therapeutic regimen employed.
Animals: Client-owned dogs diagnosed with EPI between 1990 and 2002 were included in this study.
Methods: The study comprised a retrospective, questionnaire-based review.

Results: One hundred seventy-eight completed questionnaires were returned. RIT was good in 60% of treated dogs, partial in 17%, and poor in 23%. On univariate analysis, dogs that received antibiotics (P = .037) or had high serum folate concentration (P = .037) had a poorer RIT. On multivariate analysis, there were no strong predictors of good RIT. Nineteen percent of treated dogs were euthanized within 1 year, but overall median survival time for treated dogs was 1919 days. No clear benefit of changing to a fat-restricted diet could be demonstrated, but marked hypocobalaminemia (< 100 ng/L) was associated with shorter survival (P = .012). Use of uncoated pancreatic enzyme supplements, antibacterials, or H2 antagonists was not associated with longer survival. Breed, sex, age at diagnosis (≥4 years or > 4 years), and clinical signs at diagnosis also made no difference.   

Texas A&M Guidelines  http://www.cvm.tamu.edu/gilab/assays/b12folate.shtml

     The normal range for Cobalamin (B12) is   252-908 ng/L .... low B12 levels are an indication that there is a B12 deficiency. It is absorbed in the distal small intestine (in the ileum). Low B12 levels are seen in dogs with EPI...  due to bacterial overgrowth in the upper small intestine, or disease affecting the distal small intestine.  

The normal range for Folate is  7.7 - 24.4 µg/L ... high folate levels are an indication of SIBO (small bacterial intestinal overgrowth). Values above the normal range are consistent with bacterial overgrowth in the upper small intestine. 

The following is the Texas A&M University - GI lab requirements for a B12 (and Folate) blood test. The absolute minimum SERUM requirements for a Cobalamin & Folate test is 400 µl (if doing a cTLI test add 500 µl). Any volume less than this can result in cancellation or incomplete testing. http://www.cvm.tamu.edu/gilab/assays/sampleguidelines.shtml        

Sample Handling Requirements:
For our tests, we require a 12 hour fasted serum sample. Please note that the serum MUST be separated from the blood clot and serum should be transferred into a new tube. The serum sample may be sent in a red top tube or any other leak-proof tube without additives as long as the serum is separated from the clot. Wrap the tube in enough absorbent material (e.g., paper towels) to absorb its entire contents in case of a spill, and place it in a plastic (i.e., ziploc) bag. Include at least one gel ice pack with your shipment to keep the sample at cool temperatures. Do not include ice cubes. Please note that lipemia and hemolysis may interfere with some test results, therefore we prefer a clear serum sample that is not lipemic or hemolytic to avoid inaccurate results.                                 

Shipping Guidelines:
We recommend that you send your sample with Fed-Ex or UPS. This does not have to be sent overnight, The sample may be shipped 2nd day or Ground depending on when the actual assay is run (serum samples for TLI, PLI, cobalamin, and folate are stable for up to 2 weeks at room temperature). Please note that there is NO Saturday delivery at Texas A&M University. Note: Due to delivery procedures at such a large university, packages sent with the US Postal Service can often be delayed or even lost within departments. Please DO NOT use the US Postal Service as a carrier.

Please prepare your package:
1. Plastic, leak-proof sample tubes in a sealed plastic bag with enough absorbent material to soak entire contents in case of a spill.
2. Several frozen gel ice packs to account for longer transport or dry ice (Shipping dry ice has specific regulations; please contact your carrier for instructions)
3. Packing material for extra padding
4. Fill out the appropriate carrier’s shipping label with the address noted above and attach it to the box. We cannot pay shipping fees. Please note that the GI Lab does not accept packages marked “Bill Receiver”. Unfortunately, we must refuse these packages and we are not liable for any resultant delays. Somewhere on the outside of the package, as well as on the shipping label, please mark “Exempt Animal Specimen.” This is a requirement of the Texas Department of Transportation.

International Shipments:
In addition to the guidelines listed above, please include the following:
Please attach the following statement to the outside of the box. Also include a copy inside the box on official letterhead with a signature.
“This shipment contains only canine/feline serum for diagnostic testing. These samples are not contagious or infectious, and have not been derived from animals exposed to agents of agricultural concern. This shipment has no commercial value.”

Although B12 injections  have been tested and research has proven that the injections are needed to manage Cobalamin deficiency in an EPI dog , a handful of EPI owners have recently found success with "maintaining"  B12 levels (after a regimen of B12 injections) with one particular B12 pill that is manufactured by Metagenics, that also includes the Intrinsic factor in with the B12. Metagenics is the only company that does this at this time 

http://www.metagenics.com/products/detail.asp?pid=163

Discuss this product with your vet. This may or may not be an option for you and your dog. Your vet will need to test your dog's B12 level before and after to test for effectiveness and recommended dose.

Adapted from Texas A&M G.I. Lab : http://www.cvm.tamu.edu/gilab/research/cobalamin.shtml     

Cobalamin (Vitamin B12) is a water-soluble, cobalt-containing vitamin with an important role in biochemical processes referred to as single carbon transfers. During these reactions, functional units such as methyl groups (-CH3) are transferred onto or between biologically important compounds. Cobalamin is a co-factor for at least three enzymes that carry out these types of reactions, acting as a transitional carrier of the single carbon group. A typical reaction catalyzed by a cobalamin dependant enzyme, methionine synthase, is illustrated in figure 1. Single carbon biochemistry is an area of great interest in the human population, as deficiencies in the activity of these enzymes may be associated with hyperhomocysteinemia. Hyperhomocysteinemia is a recognized risk factor for cardiovascular disease. Deficiency in cobalamin may also be associated with demyelinating neuropathies, dementia and megaloblastic
anemia (Pernicious Anemia) in human patients.

In companion animal medicine, most attention to cobalamin has been directed towards its use as a diagnostic marker for gastrointestinal disease. Recent evidence from studies at the Gastrointestinal Laboratory have also shown that supplementation of cobalamin is important to get the best response to therapy for gastrointestinal disease.

COBALAMIN DEFICIENCY IN GASTROINTESTINAL DISEASE

In animals with reduced cobalamin absorption, regardless of the cause, it is reasonable to expect that eventual depletion of bodily cobalamin stores will occur and cobalamin deficiency will ensue. As all cells in the body require cobalamin for single carbon metabolism, it has been hypothesized that cobalamin deficiency may actually contribute to the clinical signs and manifestations of gastrointestinal disease in some patients. Studies of radiolabelled cobalamin in cats have demonstrated that the half-life of this compound is significantly reduced with gastrointestinal disease.

While the serum concentration of cobalamin is used diagnostically, the reactions catalyzed by cobalamin dependant enzymes occur in the mitochondria, making it difficult to assess the state of cobalamin availability in the patient. Tissue-level deficiency of cobalamin is associated with an increase in the urinary and serum concentrations of an organic acid called methylmalonic acid, which is an alternative product of a cobalamin dependant pathway within the mitochondria. Using this compound as a marker of cobalamin deficiency, we have been able to demonstrate that cats and dogs with very low serum cobalamin do indeed have a significant tissue-level cobalamin deficiency (Figure 2.). Interestingly, in cats, there was no change in serum concentration of homocysteine (see figure 1. Elevation in homocysteine is expected with cobalamin deficiency due to reduced methionine synthase activity) even in the face of extreme cobalamin deficiency. In dogs, preliminary evidence suggests that there is an increase in serum homocysteine concentration with reduced serum cobalamin concentration.

COBALAMIN THERAPY

As described above, there is compelling evidence that significant tissue-level cobalamin deficiency is present in some companion animal patients with gastrointestinal disease. The significance of this finding for the clinical management of these patients is also becoming clearer. A recent study has examined the effect of cobalamin supplementation on the outcomes of treatment for feline patients with severe cobalamin deficiency and histories suggesting chronic gastrointestinal disease.⁵ In this study, serum concentrations of methylmalonic acid normalized following parenteral cobalamin supplementation, indicating that cobalamin deficiency was the cause of the high methylmalonic acid in serum. There was an overall weight gain in these patients, and a decrease in the frequency of clinical signs such as vomiting and diarrhea. During the course of the study, there was no change to the therapeutic regime other than the introduction of parenteral cobalamin supplementation.

Dogs with exocrine pancreatic insufficiency will commonly present with subnormal serum cobalamin concentrations.
Therapy with bovine pancreatic enzyme extracts is not sufficient to restore cobalamin absorption in dogs with EPI, as intrinsic factor appears to be species specific. Failure to absorb cobalamin in dogs with EPI may be due to all three potential causes of low serum cobalamin. Pancreatic secretion of intrinsic factor is reduced or absent, secondary bacterial overgrowth of the intestine is common, and the mucosa may be compromised by the presence of excessive bacterial numbers and toxic metabolites. Dogs with exocrine pancreatic insufficiency should be considered at high risk for the development of cobalamin deficiency. As clinical signs of cobalamin deficiency include chronic wasting or failure to thrive, malaise, and gastrointestinal signs such as diarrhea, serum cobalamin concentration should be measured in any dog with poor response to enzyme replacement therapy for EPI.

THERAPEUTIC DOSING AND ROUTE

As cobalamin deficiency in companion animals is usually secondary to reduced cobalamin absorptive capacity, the use of dietary cobalamin supplementation is at best highly inefficient, and most likely ineffective, in the restoration of bodily cobalamin stores. The route of choice for cobalamin supplementation is by parenteral injection. Generic formulations of cobalamin are readily available and extremely cost effective. The doses we currently recommend for dogs and cats are given in table 1. The dose regime is typically one dose weekly for six weeks, one dose every two weeks for six weeks, then dose monthly. Remeasure serum cobalamin concentrations one month after last administration. Unless the intestinal disease is totally resolved, it is likely that the patient will continue to require regular cobalamin supplementation, the frequency necessary is assessed by regular measurement of serum cobalamin concentration.

Table 1 : Recommended dosages of cobalamin for dogs and cats

Most generic cobalamin preparations are 1mg/ml, i.e. 1000µg/ml. Multi-vitamin and B-complex injectable formulations contain very much lower concentrations of cobalamin, and often cause pain at the injection site, their use is not recommended.

Cobalamin is non-irritant and may be given subcutaneously or intramuscularly, most clinicians deliver it subcutaneously.