September 2022 COBALAMIN DOSING update and revision (TAMU recommendations):
https://vetmed.tamu.edu/gilab/research/cobalamin-information/

Cobalamin should be supplemented whenever serum cobalamin concentration is in the low normal range (i.e., less than approximately 400 ng/L) in both dogs and cats. Most commonly, cyanocobalamin is chosen for supplementation, as it is both widely available and inexpensive. Very little evidence-based information about the route and dose of cobalamin supplementation in dogs and cats is available. Recent studies in humans, dogs, and cats suggest that oral supplementation is as equally effective as parenteral supplementation.

We currently recommend either oral or parenteral cobalamin supplementation and the recommended protocol and dose for each route is as below.

For oral cobalamin supplementation:

Protocol: daily administration for a total of 12 weeks and re-check serum cobalamin concentration one week after finishing supplementation.

Dose: 250 µg in cats and 250 – 2000 µg in dogs, depending on the size of the patient:

Dogs weight (lb)	Below 22 lbs	22 to 100 lbs	Above 100 lbs
Dose of Cobalamin	250 µg	1000 µg	2000 µg

For parenteral (Injectable) cobalamin supplementation:

Protocol: weekly injections for 6 weeks, then one dose a month later, and retesting one month after the last dose.

For either oral or parenteral supplementation, if the underlying disease process has resolved and cobalamin body stores have been replenished, serum cobalamin concentration should be supranormal at the time of reevaluation. However, if serum cobalamin concentration is within the normal range, treatment should be continued at least monthly (for parenteral supplementation) and the owner should be forewarned that clinical signs may recur sometime in the future. Finally, if the serum cobalamin concentration at the time of reevaluation is subnormal, further work-up is required to definitively diagnose the underlying disease process and cobalamin supplementation should be continued weekly or bi-weekly (for parenteral supplementation) or daily (for oral supplementation).

Dose: SC injection of 250 µg per injection in cats and, 250-1500 µg per injection in dogs, depending on the size of the patient:

Cobalamin

It should be pointed out that in rare cases cobalamin supplementation fails to increase serum cobalamin concentration for reasons that are not currently understood. In these patients, another formulation of cobalamin, such as hydroxocobalamin (only available as an injectable formulation), might be effective.

2018 Oral Cobalamin
(please see the B12 Research page for details on Oral B12)

B12 levels in EPI dogs need to be in the normal upper-mid range level… normal or low-normal is not sufficient! Once upper mid-range levels are reached via B12 supplementation, the B12 supplementation must be continued for life at a frequency level that continues to maintain the upper mid range B12 level.

In the past, it was advised to only give serum B12 supplementation (shots). However, over the course of 8-10 years Epi4Dogs and other EPI groups have repeatedly reported that their EPI dogs appear (via individual before and after B12 blood tests) to do as well or often even better on oral B12 pills vs. B12 shots. TAMU (Texas A&M) recently did a mini study and had the same results as our EPI organizations… that dogs given high dose of oral B12 often do just as well as dogs give B12 shots. We leave it up to the pet owner and their personal vet to decide which protocol they prefer to use. Although we must say that we are thrilled with this recent research that supports high doses of oral B12 .. finally supporting our years observations and individual B12 blood tests…also making it much easier on pets to take oral pill with those that struggle with vet visits for the shots and/or for the pet owners that have to travel to get to their vets for the weekly shots.

For EPI dogs struggling with low B12, there are multiple good products/treatment protocols in treating low B12 either with B12 shots or high doses of oral B12. However….Epi4Dogs comfortably recommends Wonderlabs Pet Factor B12 https://www.wonderlabs.com/itemleft.php?itemnum=K9688 or Wonderlabs Trinfac B https://www.wonderlabs.com/itemleft.php?itemnum=6881 specifically because these products are made with Methycobalamin B12 + Folic Acid + Intrinsic Factor, have been widely used over many years (8/+ yrs) with great success supported by “before and after” individual cobalamin blood tests of many of our EPI pets with low B12. In our opinion, these products have a high success rate, is inexpensive and the pet owner can purchase it directly without a prescription. These Wonderlab products are also now available on Amazon.com and/or AmazonPrime.

A little background into the B12 science vs. application:

Intrinsic Factor: The intrinsic factor is needed to transport “digested” B12 into the blood stream. Technically the intrinsic factor delivery system should not typically be damaged by EPI, and supposedly (according to old research) the intrinsic factor should be species specific- -HOWEVER- -it has been repeatedly observed and confirmed via individual B12 blood tests that when a B12 pill includes the porcine intrinsic factor the success rate is much higher than with oral B12 pills that do not include the Intrinsic Factor. Why? We are not sure….

Methylcobalamin vs. Cyanocobalamin B12: Years ago it was only recommended to give B12 shots. The most common and inexpensive serum used in shots (in the USA) was Cyanocobalamin. Sometimes it just didn’t work, and a different version of B12 was recommended. In many of these cases, when switched to not another serum but rather oral B12 with the Methylcobalmin version of B12…the B12 levels greatly improved. Why? we are not sure….

In short, we honestly have no idea if the reason why these products tend to work is because of the (1) Intrinsic Factor or the (2) Methylcobalmin version of B12 .. (3) or both….
This does not mean that other B12 products do not work, many others work very well for many of our EPI dogs. It is up to the individual EPI pet owner to do/use what they think is best for their individual EPI pet.

If you are in the UK, you can purchase oral Methycobalamin B12+Folic Acid+Intrinsic Factor from Chemeyes, LLC. http://www.chemeyes.co.uk/

In some” cases sublingual tabs seemed to help some- -but there can be issues. Check ingredients for dangerous artificial sweeteners. Avoid Xylitol, and ask your vet if it is safe if it contains Mannitol or Sorbital. Also with sublingual tabs, there have been multiple reports of these pills working for a while (sometimes up to a year) but then they are no longer effective. We at Epi4Dogs do not support the use of sublingual B12 tabs.

If upon initial EPI diagnosis, your dog has insufficient B12 levels… also talk to your vet about also possibly treating for SID/SIBO can deplete B12 stores.

When the vet draws blood for a Cobalamin B12 blood test, you will receive a Cobalamin reading (B12) and a Folate reading (B9). When the Folate level is high, that is an indication that SID may be present. However, when the Folate reading is in the normal range, SID is still present in EPI dogs. To properly diagnose SID and whether antibiotics are needed, assess by the underlying disease (EPI) and if there are any on-going SID signs, then talk to your vet about treating for SID (small intestinal dysbiosis).

When the body’s own bugs produce spontaneous Folate (B9)…. then a high Folate value indicates possible SID/SIBO.

When the body?s folate level is high from an outside source (like taking pills) that does not cause nor encourage SID/SIBO.

To date there are no known other unintended health consequences from high Folate levels due to an outside source of Folate (like pills).

Revised TAMU (Texas A&M Univ) Cobalamin (B12) Therapy
revised January 2011
re-confirmed 9/20/12

(per 2010 Dr. Jorg Steiner (TAMU) in his presentation “Endoscopy is not enough: how lab work can help in the diagnosis of gastrointestinal problems” 82% of all EPI dogs have deficient B12 levels)

January 2011 – from TEXAS A & M UNIVERSITY website

Current Website Link: http://vetmed.tamu.edu/gilab/research/cobalamin-information

Previous Website Link: http://vetmed.tamu.edu/gilab/research/cobalamin-information#dosing

Cobalamin: Diagnostic use and therapeutic considerations

Introduction

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.

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Figure 1: A typical cobalamin dependant reaction, where a methyl group (-CH3) is added to homocysteine to make methionine

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.

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Figure 2: Serum concentrations of methylmalonic acid are extremely high in cats with cobalamin deficiency, when compared to clinically healthy cats with normal serum cobalamin.

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.

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Therapeutic Dosing and Route

Cobalamin should be supplemented whenever serum cobalamin concentration is in the low normal range (approximately less than 300 ng/L) in both dogs and cats. Most commonly, cyanocobalamin is chosen for supplementation, as it is both widely available and inexpensive. Very little evidence-based information about cobalamin supplementation in dogs and cats is available. However, as in people, cobalamin deficiency leads to cobalamin malabsorption so that cobalamin should always be supplemented parenterally. Since cobalamin is a water-soluble vitamin, excess cobalamin is excreted through the kidneys and clinical disease due to over-supplementation has not been described.

We currently recommend SC injection of 250 µg per injection in cats and, depending on the size of the patient, 250-1500 µg per injection in dogs. We have recently changed our suggested dosing schedule for cobalamin supplementation: q 7 days for 6 weeks, then one dose after 30 days, and retesting 30 days after the last dose. If the underlying disease process has resolved and cobalamin body stores have been replenished, serum cobalamin concentration should be supranormal at the time of reevaluation. However, if serum cobalamin concentration is within the normal range, treatment should be continued at least monthly and the owner should be forewarned that clinical signs may recur sometime in the future. Finally, if the serum cobalamin concentration at the time of reevaluation is subnormal, further work-up is required to definitively diagnose the underlying disease process and cobalamin supplementation should be continued weekly or bi-weekly.

It should be pointed out that in rare cases cobalamin supplementation fails to increase serum cobalamin concentration for reasons that are not currently understood. In these cases another formulation of cobalamin, such as hydroxocobalamin, might be effective.
Cobalamin may also have a pharmacologic effect as an appetite stimulant. Anorectic feline patients with cobalamin deficiency often start to eat again once they are being supplemented and appetite wanes once again when cobalamin is no longer administered weekly, despite a normal serum cobalamin concentration. In these patients cobalamin supplementation should be continued on a weekly or biweekly dosing schedule.

Recommendations

We currently recommend that all dogs and cats with chronic histories of gastrointestinal disease should have serum cobalamin concentrations measured. This is particularly important in any case with sub-optimal response to previously instituted therapy. As cobalamin is inexpensive, water soluble and any excess is readily disposed, cobalamin supplementation should certainly be considered for any animal with a serum cobalamin concentration lower than the laboratory reference range.

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Simpson KW, Fyfe J, Cornetta A, Sachs A, Strauss-Ayali D, Lamb SV, Reimers TJ (2001), Subnormal concentrations of serum cobalamin (Vitamin B12) in cats with gastrointestinal disease, Journal of Veterinary Internal Medicine 15: 26-32
Vaden SL, Wood PA, Ledley FD, Cornwell PE, Miller RT, Page R (1992), Cobalamin deficiency associated with methylmalonic acidemia in a cat, Journal of the American Veterinary Medical Association 200 No.8: 1101-1103
Ruaux CG, Steiner JM, Williams DA. (2001), Metabolism of amino acids in cats with severe cobalamin deficiency. American Journal of Veterinary Research 62: 1852-1858
Ruaux CG, Steiner JM, Williams DA. (2005), Early Biochemical and Clinical Responses to Cobalamin Supplementation in Cats with Signs of Gastrointestinal Disease and Severe Hypocobalaminemia. Journal of Veterinary Internal Medicine 19: 155-160
Simpson KW, Morton DB, Batt RM (1989), Effect of exocrine pancreatic insufficiency on cobalamin absorption in dogs, American Journal of Veterinary Research 50: 1233-1236

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Previous TAMU’S Cobalamin – B12 Protocol
updated January 2011 (see above)

Taken from Texas A&M G.I. Lab previous protocol for B12

COBALAMIN DEFICIENCY IN GASTROINTESTINAL DISEASE

COBALAMIN THERAPY

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

Animal Bodyweight Range	Dose/injection
cats, dogs up to 5 kg (10 lb)	250 µg
dogs, 5-15kg (10-30 lb)	400 µg
dogs, 15-30 kg (30-65 lb)	800 µg
dogs, 30-45 kg (65-100 lb)	1200 µg
dogs above 45 kg (100 lb)	1500 µg

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.

Cobalamin (B12) and Folate levels

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.

(explanation of proximal small distal disease : “Low serum folate concentrations particularly draw attention to the possibility of dietary hypersensitivity since the proximal small intestine is exposed to the highest concentrations of food antigens. A hypersensitivity reaction causing mucosal damage is therefore most likely to result in folate malabsorption”. http://www.revmedvet.com/2000/RMV151_559_563.pdf

simply put… A food intolerance could cause the low folate:

“Decreased serum folate can therefore be suggestive of damage to the proximal small intestine, as this is the main site for the absorption of dietary folate. There may be many causes of damage at this site, including dietary sensitivity which particularly affects the proximal small intestine where intraluminal dietary antigens are at their highest concentration e.g. gluten enteropathy in Irish setters. Alternative possible causes of proximal intestinal damage include idiopathic “inflammatory bowel disease” and lymphoma”. http://www.ivis.org/journals/vetfocus/19_1/en/2.pdf )

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.”

B12 Veterinarian Protocol Summary for EPI pets

Once done with the weekly injections of B12 for 6 weeks….the next shot should be given at 30 days and then re-test after 30 days.

Or…. as recent B12 in dogs research suggests, once the daily high dose of oral B12 is completed, re-test and ascertain how much and how frequently oral B12 needs to be given to maintain optimal B12 levels.

The following are just suggestions on what B12 protocol to “start” following after you receive the B12 test results. As time passes, the B12 regimen may need to be adjusted.

if the B12 re-tested levels come back at normal B12 levels… this means the EPI dog most likely needs B12 injections to be given monthly…. and most likely for life…. because low or low normal B12 may occur yet again. If on high dose oral B12, you and your vet will need to ascertain whether to continue with daily oral B12 at same dose, or a lessened dose, or maybe just reduce the number of days the oral B12 is given. This will depend on the individual dog. Most EPI dogs on oral B12 continue with daily oral B12.
if the B12 re-tested levels come back at very high normal B12 levels… this means no shot needed right now but re-test in the future (maybe in 3 to 6 months) to ascertain what the B12 levels are at and how frequently you may need to supplement with SQ B12 to maintain appropriate high normal B12 levels. If on high dose oral B12, you and your vet will need to ascertain whether to continue with daily oral B12 at same dose, or lessened dose, or maybe just reduce the number of days the oral B12 is given. This will depend on the individual dog. Most EPI dogs on oral B12 continue with daily oral B12.
if the B12 re-tested levels come back at low-normal or low B12 levels… this means that the dog needs to be placed on weekly or bi-weekly B12 injections. If on high dose oral B12, you and your vet will need to ascertain whether to continue with a higher daily oral B12 . This will depend on the individual dog. If the oral B12 does not improve the B12 levels, then most of these dogs will be placed on injectable B12.
if the B12 re-tested levels come back at still low or low nornal B12 levels even after weekly or bi-weekly injections… this means that your EPI dog may require a different compound of B12, such as hydroxocobalamin or methycobalamin vs. cobalamin.

It is very important that people with EPI dogs realize that when these dogs develop an issue with B12… it will most likely be a lifelong issue …. but as with other aspects of EPI, you simply have to find the right balance of B12 to maintain.

Understanding B12 (references)

Very little evidence-based information about cobalamin (B12) supplementation in dogs and cats is available.
Hence, the listing below of human studies on B12.
Understanding B12

http://www.aafp.org/afp/2003/0301/p979.html#afp20030301p979-b9

http://ods.od.nih.gov/factsheets/vitaminb12-HealthProfessional/

References

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(per 2010 Dr. Jorg Steiner (TAMU) in his presentation “Endoscopy is not enough: how lab work can help in the diagnosis of gastrointestinal problems” 82% of all EPI dogs have deficient B12 levels)

Introduction

Cobalamin Deficiency in Gastrointestinal Disease

Cobalamin Therapy

Therapeutic Dosing and Route

Further Reading

COBALAMIN DEFICIENCY IN GASTROINTESTINAL DISEASE

COBALAMIN THERAPY

THERAPEUTIC DOSING AND ROUTE

References