Introduction

Hypercalcemia is an uncommon but important electrolyte disturbance in dogs. The frequency of finding hypercalcemia based on evaluation of the serum calcium concentration in more than 10,000 canine serum samples analyzed for 6 mo at one private veterinary diagnostic laboratory was 1.5%.¹ Among them, 62% were found to be transient, 28% were found to be from young growing dogs, and 18% were persistent and associated with pathological disease. The common causes of hypercalcemia in dogs include cancer, primary or secondary hyperparathyroidism, and hypervitaminosis D. Hypervitaminosis D has been reported to occur secondarily to accidental ingestion of either rodenticides containing cholecalciferol or antipsoriatic ointments that contain vitamin D analogues, such as calcipotriol and tacalcitol.^2–10

The present report describes a hypercalcemic dog owned by a psoriasis patient using an antipsoriatic ointment containing an active vitamin D₃ analogue as regular medicine without notification of accidental ingestion.

Case Report

A 4 yr old intact male miniature dachshund weighing 4.2 kg was presented to a referring veterinarian with lethargy and anorexia for a week. It was reported that the dog had shown signs of polyuria and polydipsia for several mo. The dog was fed only a commercial diet, and no drug or nutritional supplements had been administered. A serum biochemistry panel revealed severe azotemia and a tentative diagnosis of renal failure was made. However, the cause was unknown, and referral to Hokkaido University Veterinary Teaching Hospital was recommended.

The physical examination was unremarkable. Palpation of the submandibular, prescapular, and popliteal lymph nodes revealed that they were normal in size. The dog's anal glands were normal on rectal palpation and there were no nodules in the mammary glands. The complete blood count was unremarkable, but serum biochemistry revealed severe azotemia and hypercalcemia, and mild hyperphosphatemia (Table 1). Urinalysis was unremarkable apart from isosthenuria (specific gravity 1.014). Thoracic and abdominal radiographs and abdominal ultrasonography were all unremarkable. The differential diagnosis was occult lymphoma, hyperparathyroidism, and hypervitaminosis D. Cervical ultrasonography revealed that no parathyroid glands were enlarged. Serum intact parathormone (PTH) (Immulite intact PTH; Siemens Healthcare Diagnostics, IL) and PTH-related protein (PTHrP IRMA; Mitsubishi Chemical Co., Tokyo, Japan) were measured by a commercial veterinary diagnostic laboratory (Monolis, Inc., Tokyo, Japan), but PTH was within the normal range and PTH-related protein was undetectable (Table 1). These findings suggested that hypercalcemia in this dog was not caused by a malignant tumor or hyperparathyroidism. The owner was instructed to investigate drugs, supplements, and food containing vitamin D or calcium that could possibly have been ingested by the dog at home. The dog was treated with daily subcutaneous administration of saline (250 ml/day) by the referring veterinarian from day 1 to 6 because the owner desired ambulant treatment near his home.

Table 1 Serum Biochemistry of the Dog

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The dog was re-examined on day 7. Although the owner had reported on the first day that the dog was fed only a commercial diet and had never ingested any drugs or supplements, it was revealed that the owner's son used two tubes of maxacalcitol ointment^a (10-g tube containing maxacalcitol 25 μg/g) per day for psoriasis. Moreover, for more than a few yr, the dog had liked to eat the son's dander from the floor and to lick his skin, especially after he had applied the maxacalcitol ointment^a. A tentative diagnosis of vitamin D analogue maxacalcitol toxicity was made. The owner had already cleaned the floor to eliminate the dander and had separated the dog from his son after the first visit. The dog's demeanor and appetite improved, and biochemistry revealed the improvement of azotemia and hypercalcemia (Table 1). The owner was instructed to continue insulating the dog from the maxacalcitol ointment^a and his son as much as possible. Although it seemed to be difficult for the owner to isolate the dog from the drug completely, the hypercalcemia and azotemia improved gradually, and had mostly resolved at 3 mo (Table 1). The dog has been generally free of clinical signs without treatment for over 2 yr.

Discussion

Hypervitaminosis D is a well-known cause of hypercalcemia in dogs. The most common cause of hypervitaminosis D in dogs is accidental ingestion of rodenticide containing cholecalciferol. Hypervitaminosis D has also been recognized in dogs with ingestion of antipsoriatic ointment containing vitamin D analogues, such as calcipotriol and tacalcitol.^5–10 To the authors' knowledge, hypervitaminosis D caused by maxacalcitol ointment has not been described previously in dogs.

Typically, hypervitaminosis D with vitamin D ointment is caused by accidental ingestion of a large amount of ointment (calcipotriol ranged from about 60 μg/kg/day to 200 μg/kg/day), followed by acute onset of toxic symptoms, such as lethargy and vomiting, leading to a fatal outcome.^5,6,8,9 A toxicological study in dogs suggested that the maximum tolerable oral dose of calcipotriol ointment before laboratory abnormality was 3.6 μg/kg/day.¹¹ Thus, these dogs ingested approximately 15 to 100 times more calcipotriol than the maximum dose.

The present case developed symptomatic hypervitaminosis D without the notification of accidental ingestion of the ointment. It was strongly indicated that the dog chronically ingested maxacalcitol by eating dander or licking skin covered in maxacalcitol ointment. Although the exact ingested dose could not be determined, it must be far below 500 μg/day (120 μg/kg/day) because the daily application of ointment was about 20 g, containing 500 μg maxacalcitol. Although data from oral toxicity studies of maxacalcitol in dogs are not available, a 12 mo intravenous toxicity study of maxacalcitol in dogs indicated that the no-observed-adverse-effect level was 0.011 μg/kg/day.¹²

Injection of maxacalcitol has proved to be a very effective suppressor of PTH secretion with no calcemic activity.¹³ However, a recent study comparing the adverse effects of topical calcipotriol and maxacalcitol on human patients demonstrated that serum calcium levels were significantly higher in the maxacalcitol group than in the calcipotriol group.¹⁴ These results suggest that maxacalcitol ointment could have a higher risk of causing hypercalcemia than calcipotriol ointment. In addition, serum intact PTH in this dog was within the normal range even in the face of hypercalcemia. Although the exact reason for this inconsistency is unclear, reduced renal excretion of PTH due to chronic kidney disease might be a contributory factor. In addition, it is indicated that the set point for calcium-regulated PTH release is greater than normal in chronic kidney disease.¹⁵

Topical calcipotriol and maxacalcitol ointments are considered a relatively safe drug in humans, and people are generally unaware of the potential toxicity of ingesting topical medications, which leads to a tendency to handle topical medications less cautiously than oral medications.⁸ For small dogs, however, these drugs could be life-threatening because they seem to be palatable to dogs and only partial ingestion of these ointments could cause severe toxicosis. In human medicine, specific counseling has been encouraged when calcipotriene is prescribed, particularly for pet owners, in order to avoid tragic pet deaths.⁸ Veterinarians should also take into consideration that these ointments could cause severe hypervitaminosis D in dogs even if the owner denies the possibility of accidental ingestion of any drugs.

Conclusion

This report describes a case of hypercalcemia with chronic ingestion of maxacalcitol ointment. To the best of the authors' knowledge, symptomatic hypercalcemia caused by chronic ingestion of vitamin D ointment has not been described previously in dogs. Hypervitaminosis D should not be excluded in hypercalcemic dogs, even if there is no history of accidental ingestion.