Acute vitamin D toxicosis in an adult cat

Abstract

Case summary

A 4-year-old, female spayed domestic shorthair cat was presented to the Michigan State University emergency service for evaluation of vomiting 4 days after exposure to vitamin D supplements. On intake, the patient was found to have ionized hypercalcemia and azotemia. The patient was hospitalized for calciuresis therapy including fluid diuresis, diuretics, steroids, bisphosphonates and a nasogastric feeding tube. She was discharged and presented for a recheck evaluation and was then hospitalized a second time for the same therapy as her first hospitalization. Eventually the patient was discharged for at-home care with subcutaneous fluids and oral medications because of financial constraints. Approximately 52 days after exposure, the cat was noted to have persistently normal ionized calcium and all medications were discontinued.

Relevance and novel information

This case provides a unique example of acute vitamin D toxicosis in a cat and a financially conservative approach in treating a toxicity with a significant half-life.

Introduction

Vitamin D is a fat-soluble vitamin obtained via the diet or ultraviolet (UV) rays in humans. ¹ The most common dietary form of vitamin D is cholecalciferol, or vitamin D3, and is found to be highest naturally in fish and may also be supplemented. ¹ Vitamin D that is obtained through ingestion or cutaneous UV synthesis must undergo metabolism to be activated for use in the human body. ¹

Dogs and cats are unable to synthesize vitamin D from UV rays and instead rely on dietary sources. ² Once ingested, cholecalciferol is absorbed in the gastrointestinal tract and metabolized by the liver to calcidiol (also known as 25-hydroxyvitamin D (25(OH)D)) by the enzyme 25-hydroxylase. ² Calcidiol is converted to the most biologically potent form of vitamin D, calcitriol (or 1,25(OH)2 D), by 1-alpha-hydroxylase in the proximal renal tubular cells. ² Increased levels of calcitriol provide negative feedback to inhibit 1-alpha-hydroxylase, preventing further conversion of calcidiol to calcitriol. In cases of vitamin D toxicosis, excessive amounts of calcidiol are metabolized by the liver but cannot be converted to calcitriol. Calcidiol, in excessive concentrations, competes with calcitriol at vitamin D receptors, leading to hypercalcemia and hyperphosphatemia. ³

Initially, clinical signs of vitamin D toxicosis include polyuria, polydipsia, muscle weakness, anorexia, depression and vomiting. ⁴ Signs may progress to organ dysfunction secondary to metastatic calcification from prolonged elevations in both calcium and phosphorus. ³ Diagnosis is mainly based on historic exposure, but laboratory tests will show elevated total and ionized calcium (iCa), hyperphosphatemia and azotemia (elevated urea nitrogen [BUN] and/or creatinine) if there is acute kidney injury (AKI).^3,5 Measurement of serum vitamin D metabolites can assist with confirmation.

The oral median lethal dose is 88 mg/kg, although clinical signs can occur with dosages as little as 0.1 mg/kg; dosages greater than 0.5 mg/kg will lead to hypercalcemia. ⁴ Decontamination through induction of emesis and activated charcoal administration should be considered in any patient that ingests more than 0.1 mg/kg. ⁴ Charcoal should be administered q8h for 1–2 days for enterohepatic circulation. ⁴ Cholestyramine may also be alternatively considered to inhibit intestinal absorption and enterohepatic circulation owing to it being a bile acid sequestrant that binds lipoproteins and bile acids. ⁶ Serial monitoring of iCa, kidney values and phosphorus levels is recommended 24 and 48 h after decontamination. Symptomatic or hypercalcemic patients should be hospitalized for calciuresis. Vitamin D’s fat solubility and long half-life of approximately 60 days make it challenging to treat. ¹ This case report describes the successful management of vitamin D toxicosis in a feline patient treated as an inpatient and outpatient because of the long half-life of the toxin.

Case description

A 4-year-old, female spayed domestic shorthair cat was presented to the Michigan State University emergency service for vomiting. No pertinent medical history was noted. The patient was reported to have been playing with a bottle of vitamin D supplements (125 µg [5000 IU] soft gel capsules) 4 days before presentation, although definitive ingestion was unwitnessed. The cat’s initial physical examination was unremarkable. A baseline database was performed including complete blood count (CBC), serum chemistry, venous blood gas (VBG) and urinalysis. The VBG revealed azotemia with BUN 52 mg/dl (reference interval [RI] 12–27), creatinine 2.2 mg/dl (RI 0.8–1.8) and ionized hypercalcemia 2.1 mmol/l (RI 1.13–1.38). The serum chemistry showed similar findings, with BUN 62 mg/dl (RI 19–36), creatinine 2.9 mg/dl (RI 1.0–2.3), total calcium 17.9 mg/dl (RI 9.1–10.7) and hepatocellular hepatopathy with alanine transaminase 113 U/l (RI 25–76) and aspartate transaminase 39 U/l (RI 14–36). The serum phosphorus levels were found to be normal at 5.1 mg/dl (RI 2.7–5.7). The CBC revealed no significant abnormalities, and the urinalysis revealed 2+ proteinuria as well as pyuria without bacteriuria; therefore, a urine culture was submitted. Abdominal radiographs were performed with no overt abnormalities. A vitamin D profile was submitted to a veterinary diagnostic laboratory for measurement of parathyroid hormone (PTH), iCa and 25-hydroxyvitamin D concentrations, documenting severe hypervitaminosis D (25-hydroxyvitamin D 4894 nmol/l; RI 127–335) but normal PTH.

The patient was hospitalized for calciuresis and supportive care. The cat was started on 3.75 ml/kg/h 0.9% NaCl (ICU Medical), maropitant (1 mg/kg IV q24h, Cerenia; Zoetis), dexamethasone sodium phosphate (0.15 mg/kg IV q24h, Mylan), furosemide (1 mg/kg IV q12h, Salix; Merck) and a single injection of zoledronate (0.1 mg/kg IV over 15 mins, Zometa; Novaplus). Ampicillin-sulbactam (30 mg/kg IV q8h, Unasyn; Eugia US) was initiated owing to pyuria and azotemia while urine culture was pending. On day 5 after exposure, the noted laboratory abnormalities had improved (Figures 1 and 2). The patient was anorexic, and therefore enteral nutrition was initiated via a nasogastric feeding tube at 50% of its resting energy requirement (RER). The enteral nutrition included a calcium content of 0.2 g/100 ml and a vitamin D content of 280 IU/l (Recovery Liquid; Royal Canin US). On day 6 after exposure, the blood work abnormalities resolved. At that time, furosemide was discontinued and the patient’s enteral feeding was increased to 100% RER. On day 7 after exposure, the patient was in good spirits but remained anorexic. Her iCa remained just above the RI (1.13–1.38 mmol/l) (see Figure 2). Because of concern for in-hospital stress as a factor, the patient was discharged home with prednisolone (1 mg/kg PO q24h; PAI Pharma) and amoxicillin-clavulanic acid (13.75 mg/kg PO q12h, Clavamox; Zoetis) with instructions to recheck the following day.

Figure 1

Blood urea nitrogen (BUN) and creatinine after exposure. BUN is represented by square data points and a dotted line, and creatinine is represented by diamond data points and a solid line. BUN values correspond with the left vertical axis, with a reference interval (RI) of 12–27 mg/dl. Creatinine values correspond with the right vertical axis, with a RI of 0.8–1.8 mg/dl. All days are after the known date of exposure to the vitamin D, and day zero corresponds to the day of exposure.

Figure 2

Ionized calcium (iCa) after exposure. The iCa reference interval is 1.13–1.38 mmol/l. All days are after the known date of exposure to the vitamin D, and day zero corresponds to the day of exposure. Both stays in hospital and the cat’s care at home are denoted on the figure

One day after discharge (day 8 after exposure), the patient was noted to be persistently inappetent and blood work revealed an increase in iCa and a non-azotemic AKI (Figures 1 and 2). ⁷ The patient was readmitted to the hospital and received treatment with 3.75 ml/kg/h 0.9% NaCl (ICU Medical), maropitant (1 mg/kg IV q24h, Cerenia; Zoetis), dexamethasone sodium phosphate (0.15 mg/kg IV q24h, Mylan), furosemide (1 mg/kg IV q12h, Salix; Merck) and ampicillin sulbactam (30 mg/kg IV q8h, Unasyn; Eugia US). The cat remained hospitalized for an additional 11 days with serial VBG analyses. On post-exposure day 13, the patient received a second dose of zoledronate (0.1 mg/kg IV, Zometa; Novaplus) and was noted to have mild ionized hypercalcemia with normal renal values (Figures 1 and 2). Treatment with salmon calcitonin was recommended for persistent ionized hypercalcemia; however, this was declined because of cost. Antibiotics were discontinued after negative urine culture.

On post-exposure day 18, the patient was eating reliably and tolerating oral medications well and was transitioned to at-home care. She was discharged with prednisolone (1 mg/kg PO q24h; PAI Pharma), furosemide (1 mg/kg PO q12h; Hikma Pharmaceuticals USA) and 0.9% NaCl (25 ml/kg SC q12h; ICU Medical) to be administered at home for ongoing management of hypercalcemia. At 34 days after exposure, the cat’s iCa was 1.38 mmol/l (RI 1.13–1.38) (see Figure 2). The prednisolone was reduced to 0.5 mg/kg/day and furosemide was discontinued. Subcutaneous 0.9% NaCl (ICU Medical) administration was decreased to q24h.

At 52 days after exposure, the patient’s iCa was normal at 1.25 mmol/L (RI 1.13–1.38) (Figure 2). At that time, the subcutaneous fluids were discontinued, and the prednisone dose was weaned and discontinued. The iCa remained normal at post-exposure days 71 (1.32 mmol/l) and 85 (1.31 mmol/l; RI 1.13–1.38) (Figure 2). Monitoring was discontinued, and the cat remains clinically normal at home.

Discussion

Hypervitaminosis D is common in veterinary medicine, although it is more frequently seen in dogs. ⁸ There are few isolated case reports of hypervitaminosis D in cats after chronic exposure to excessive vitamin D content in feed, and three reports secondary to acute cholecalciferol rodenticide ingestion.^{9 –13} The feed-exposed patients recovered with supportive treatment of hypercalcemia.^9,10 The case reports of cats with toxicosis after cholecalciferol rodenticide ingestion had variable outcomes, with only one reported to survive after treatment.^{11 –13} The current report not only describes successful outpatient medical management of hypervitaminosis D, but it is also to the authors’ knowledge the first report of a cat presenting for vitamin D supplement poisoning. This is compared with the numerous cases of canine patients diagnosed with hypervitaminosis D, with the most common sources being cholecalciferol-containing rodenticides and human medications containing vitamin D or analogs such as calcipotriene. ¹⁴

The toxic dose of vitamin D in dogs and cats is the same; however, cats are thought to have a protective mechanism against vitamin D toxicosis. Sprinkle et al ¹⁵ described a C-3 epimerization pathway for vitamin D metabolism that is utilized in cats more than in other species. This pathway allows the epimer metabolite to bind to the vitamin D receptor with reduced activity compared with calcitriol. ¹⁶ It may also suppress PTH secretion without inducing other effects. ¹⁷ Despite this, the presented case demonstrates that it is still possible for cats to experience hypervitaminosis D. It is unknown whether this patient ingested vitamin D2 (ergocalciferol) or D3 (cholecalciferol), which is a limitation of this case report, as cholecalciferol has greater toxic effects compared with ergocalciferol. ¹⁸

Treatment of hypercalcemia consists of administration of isotonic saline to increase glomerular filtration rate and decrease calcium reabsorption and promote calcium excretion in the proximal renal tubule. ¹⁹ Additional treatments include furosemide to promote calciuresis, as well as glucocorticoids and bisphosphonates to prevent calcium resorption from bone.^{4,19 –22}

Bisphosphonate choices commonly include pamidronate and zoledronate. A human study found that zoledronate had higher success rates in normalizing calcium levels, with longer times to relapse of hypercalcemia. ²³ Although used commonly in canine patients, zoledronate use in cats has been infrequently reported.^24,25 This may be because of the perceived risk of AKI and other reported side effects in dogs, including vomiting, pancreatitis and diarrhea.^26,27 No reports of zoledronate toxicosis have been reported in feline patients, which the authors suspect is because of its infrequent use in cats. This patient received two doses of zoledronate and experienced a 33.3% decrease in iCa 2 days after the first injection; however, a similar effect was not observed after the second injection. As a result of the retrospective nature of this case writeup, the rationale for the timing of the second dose is not known, but bisphosphonate dosing would traditionally be repeated sooner. Zoledronate was utilized in this case because of availability and to minimize the risk of AKI reported in some cats administered pamidronate. ²⁸ Calcitonin can also be considered in cases that are unresponsive to traditional therapies.^3,19,29 To the authors’ knowledge, there are no reports of the use of calcitonin in cats, although it has been reported in dogs.^3,21,29 Repeat testing of the 25-hydroxyvitamin D assay was not performed owing to financial constraints, but it is noted that hypercalcemia will resolve before normalization of serum 25-hydroxyvitamin D.

Conclusions

This case provides a unique example of toxicosis in a cat and demonstrates a financially conservative approach in treating toxicosis with a significant half-life. Because of the lack of published information related to cats and treatment for hypervitaminosis D, this case brings about many opportunities for further investigation.