Sophie is a year old spayed female brown Siamese mix who was originally presented to the internal medicine service for further evaluation of anorexia and lethargy of one week’s duration. Roughly 5 days prior to presentation Sophie was evaluated by her primary care veterinarian for at that time a 4-day history of anorexia and lethargy.
Sophie was febrile on physical examination at 103.5. Bloodwork performed at that visit revealed an elevated total calcium at 14.2 mg/dL (reference 8-11.8), mild hyperkalemia of 5.9 mmol/L (reference 3.7-5.8), and elevated total proteins of 8.3 g/dL (reference 5.4-8.2) with high normal albumin and globulin. The CBC revealed hemoconcentration with a PCV of 45% and was otherwise unremarkable. Abdominal radiographs were performed, which revealed possible constipation. Sophie was treated with SQ fluids, Cerenia and a Convenia injection and started eating later the next day although her anorexia and lethargy returned within 2-3 days of her initial veterinary visit.
On presentation to the internal medicine service she was afebrile but estimated to be about 3-5% dehydrated. First, we performed an I-stat which confirmed a severe ionized hypercalcemia of 2.14 mmol/L (reference 1.2-1.32), the suspected cause of her symptoms.
In speaking with the owner there was no obvious source of vitamin D intoxication. We performed an abdominal and parathyroid ultrasound – both unremarkable – and ruled out azotemia on lab work.
Finally, a hypercalcemia of malignancy panel, which tests for parathyroid hormone and parathyroid hormone related protein in reference to ionized calcium, was also submitted to Michigan State. Infectious disease testing for toxoplasmosis and FIP were discussed and declined. Given Sophie’s young age, normal ultrasound, and normal kidney values including phosphorous, I suspected idiopathic hypercalcemia.
Sophie was treated with SQ fluids and a single intramuscular dose of dexamethasone in hospital. She was started on oral prednisolone, fiber supplementation, and canned Royal Canin SO diet. Her appetite returned quickly. The results of her hypercalcemia panel returned. Her PTH of 0.5 pmol/L (reference 0.4-2.5) and negative PTHrp ruled out primary hyperparathyroidism and made neoplasia unlikely.
Sophie’s first recheck was about 2 weeks later. She had been doing extremely well at home. Her ionized calcium was dramatically improved at 1.35 mmol/L (previously 2.14). Her prednisone dose was tapered.
In the period of time since her initial diagnosis, Sophie’s owner had learned of a national recall of Sophie’s former cat food brand due to excess vitamin D in the formulation. We were able to add a vitamin D level to her blood panel previously submitted to the lab, which confirmed vitamin D excess. I spoke with the veterinarian representative from the maker of Sophie’s cat food who reimbursed her owner for all of her diagnostics and treatments. Because vitamin D is a fat-soluble vitamin, we continued to monitor her calcium over a period of several months while weaning her prednisolone.
About three months after her initial diagnosis Sophie’s calcium remained slightly elevated above normal at 1.36mmol/L (reference 1.2-1.32); therefore, we have continued her on Royal Canin SO with added fiber for suspect idiopathic hypercalcemia.
There are only two reports in the literature of vitamin D intoxication from ingestion of commercial cat food. The first, a Japanese report published in 1995 was a necropsy study which concluded that cats fed a diet containing 10x the recommended daily intake had marked polysystemic calcification of the lungs, trachea, kidneys, heart, aorta, GI tract, skin and bones.
In 2013, a case series published in JFMS described three German cats with vitamin D intoxication caused by a commercial cat food (Almo brand). Two of the three cats developed azotemia secondary to severe hypercalcemia (one was euthanized; one developed chronic renal disease), and all three cats developed a generalized miliary interstitial pulmonary pattern. These cats were treated with IV saline, a tapering course of steroids and furosemide. Two of the three cats survived and did well on long-term follow up.
In the early 2000s a formulation error in a Royal Canin cat food resulted in a large outbreak of hypervitaminosis D in cats in America though the results of this incident (over 20 cats) were never published. In 2016 a vitamin D formulation error occurred in Rachel Ray Nutrish brand of cat food (Ainsworth Pet Nutrition), and in late 2018 a formulation error resulted in a massive recall of various brands of pet food sold at grocery stores across the country.
As of now none of the data collected from Ainsworth Pet Nutrition in 2016 has been, and it is not known whether any data will be, published from the most recent 2018 intoxications. With the increasing market of veterinary pet foods, consideration for dietary intoxication should always be considered. Collecting a thorough diet history is an important part of the veterinary visit, both for wellness and illness. Current food and drug recall information is available on the FDA website. https://www.fda.gov/Safety/Recalls
The half-life of calcidiol in the bloodstream is 15 days. However, calcitriol, the main biologically active metabolite of vitamin D, is a fat soluble vitamin that is metabolized slowly once stored. Thus, the half-life of toxicity from vitamin D exposure is long and difficult to predict. The clinical consequences of intoxication, particularly in the case of systematic exposure may be prolonged.
The first step in evaluating any patient with elevated total calcium is to confirm or exclude ionized hypercalcemia. Ionized calcium is the biologically active form of calcium in the body. Its value is not affected by albumin levels. Only ionized hypercalcemia is clinically significant.
There is a short list of differential causes of hypercalcemia in both dogs and cats. Differentials include renal failure (intrinsic or secondary to a toxic insult); neoplasia (of which lymphoma and apocrine gland adenocarcinoma are the most common); vitamin D intoxication (vitamin D containing rodenticide, prescription skin creams, diet); primary hyperparathyroidism idiopathic (in cats only); chronic granulomatous inflammatory/infectious diseases such as toxoplasmosis and feline infectious peritonitis (in cats); and chronic fungal diseases or schistosome infestation in both species.
The initial baseline workup for hypercalcemia should include thorough evaluation of medication and possible toxin exposure, CBC/chemistry, urinalysis, rectal examination and measurement of parathyroid hormone and ionized calcium. When the diagnosis is still elusive, the next steps include chest radiographs, abdominal and parathyroid ultrasound, lymph node aspirate, and sometimes bone marrow evaluation.
Cats with idiopathic hypercalcemia and dogs with primary hyperparathyroidism rarely feel ill. In contrast, dogs and cats with hypercalcemia secondary to neoplasia or renal failure often present quite sick.
Idiopathic hypercalcemia is the most common cause of ionized hypercalcemia in young and middle-aged cats. It is a poorly understood disease, likely an error in metabolism. The most common clinical signs of idiopathic hypercalcemia in cats are constipation (secondary to dehydration) or lower urinary signs secondary to bladder stones. Thus, an ionized calcium is recommended in the workup of any cat with constipation or urinary stones.
The first step in treatment is dietary manipulation. Adding fiber to the diet will speed intestinal transit time and slow GI absorption of calcium. Urinary diets, such as Royal Canin SO are low in calcium. If the effect of diet and fiber does not control the calcium, then oral medications such as steroids (to promote calcium excretion in the urine) or oral bisphosphonates (to inhibit bone resorption of calcium into the bloodstream) are necessary.