Hypocobalaminemia

Background & Pathophysiology

Cobalamin (ie, vitamin B₁₂) is a water-soluble vitamin that plays an important role in DNA and RNA synthesis, amino acid (eg, cysteine, homocysteine) metabolism, and energy production. Following ingestion of cobalamin-rich nutrients (eg, fish, poultry, eggs, red meat, dairy products), cobalamin first binds to haptocorrin, which is produced in both the salivary gland and the stomach. In the duodenum, cobalamin is bound to intrinsic factor—a protein produced primarily in the pancreas of dogs and cats—and is later absorbed in the distal small intestine. 

Any disease that affects the production of intrinsic factor or interferes with the intestinal absorption of cobalamin can cause cobalamin deficiency (Table). Dogs and cats with exocrine pancreatic insufficiency (EPI) may have decreased production of intrinsic factor. Intestinal diseases (eg, inflammatory bowel disease, food-responsive enteropathy, intestinal lymphoma, dysbiosis, lymphangiectasia) can result in compromised ileal function and inadequate absorption of cobalamin.^1,2 Familial cobalamin deficiency resulting from a loss-of-function mutation in the receptor responsible for intestinal cobalamin absorption is an uncommon cause of hypocobalaminemia but should be considered in young patients presented with GI and neurologic signs, especially in predisposed breeds such as giant schnauzers, Australian shepherd dogs, border collies, beagles, shar-peis, and Komondors.^3,4

Diseases Associated with Low Cobalamin

History & Clinical Signs

Common signs of cobalamin deficiency in dogs and cats include GI signs (eg, anorexia, weight loss), which often mimic those observed in animals with chronic GI disease; thus, the clinician may not immediately consider cobalamin deficiency as a contributing factor. Additional clinical signs of hypocobalaminemia can include failure to thrive, immunodeficiency, and neuropathies. These clinical signs may be more commonly observed in dogs with familial cobalamin deficiency. Unlike those occurring with pancreatic and GI disease, clinical signs induced by familial hypocobalaminemia are responsive to cobalamin supplementation alone.⁵ In one case report, a border collie with selective cobalamin malabsorption was presented with hepatic encephalopathy secondary to hypocobalaminemia, which resolved following cobalamin supplementation.⁶ In another report, a Yorkshire terrier with selective cobalamin malabsorption was presented with seizures that also resolved with parenteral cobalamin supplementation.⁷ Thus, cobalamin deficiency should be considered in any animal presented with chronic GI signs, especially when in combination with neurologic signs.

Diagnosis

Hypocobalaminemic cats often do not respond as readily as normocobalaminemic cats to treatment of the primary disease unless supplemented with cobalamin; this is unproven but, in the authors’ clinical experience, is also suspected in hypocobalaminemic dogs. Thus, cobalamin deficiency is an important clinical consideration in any patient presented with signs of chronic enteropathy or pancreatic disease. Diagnosis of hypocobalaminemia requires measurement of serum cobalamin concentrations. However, patients may have serum cobalamin levels that are low-normal (250-350 ng/L) and still have critically low tissue cobalamin concentrations. In these cases, evaluating biomarkers of tissue cobalamin deficiency (eg, methylmalonic acid [MMA], homocysteine) may provide more insight, as these biomarkers often increase with tissue cobalamin deficiency in dogs.^4,8-10 In cats, MMA may be a better indicator of tissue cobalamin deficiency as compared with homocysteine.⁶

Treatment & Management

Cobalamin therapy (see Suggested Reading for dose, frequency, and administration information) should be instituted when serum concentrations fall below 250 ng/L. Additional consideration for supplementation is recommended in patients with a low-normal serum cobalamin (250-350 ng/L) and/or signs of intestinal or pancreatic disease. Hypocobalaminemia secondary to GI disease has anecdotally been thought to require parenteral supplementation of cobalamin until the intestinal or pancreatic disease was appropriately treated because of the inability to absorb cobalamin or produce intrinsic factor, respectively. However, recent research has suggested that oral administration of cobalamin in dogs and cats with chronic enteropathies^11,12 and dogs with EPI¹³ is effective in restoring normal cobalamin concentrations. This may be secondary to enhanced passive absorption of cobalamin along the length of the small intestine.

Prognosis & Prevention

The prognosis for hypocobalaminemic patients depends largely on the underlying disease process and how the patient responds to treatment of the primary disease. Low cobalamin concentration is associated with shorter survival with some diseases, including EPI and multicentric lymphoma.^13,14 Lack of recovery for dogs with chronic diarrhea due to inflammatory idiopathic or neoplastic disease may also be more likely when severe hypocobalaminemia (<200 ng/L) is present.¹⁵ The benefit of supplementation in these disease states has not been definitively proven; however, it is recommended to evaluate the patient’s serum cobalamin concentration and provide supplementation when hypocobalaminemia is identified. Prognosis for familial cobalamin deficiency is good with long-term supplementation.

Clinical Follow-Up & Monitoring

Daily oral cobalamin supplementation or a 6-week course of weekly parenteral supplementation followed by a single injection 30 days later and retesting after 30 days is recommended.^1,16 Some patients, especially those with EPI or ongoing intestinal disease, may require continued monthly cobalamin supplementation. If resolution of the primary disease cannot be achieved, more frequent cobalamin administration may be required. If remission of the underlying disease (eg, food-responsive enteropathy) is achieved, long-term supplementation may not be necessary; however, re-evaluation of the patient’s serum cobalamin concentration is recommended if disease relapse occurs.

EPI = exocrine pancreatic insufficiency, MMA = methylmalonic acid