Definition

Hypercalcemic disorder resulting from ingestion of vitamin D rodenticide preparations, excessive dietary and vitamin supplementation, ingestion of congeners of vitamin D metabolites used for treatment of psoriasis and other immune-mediated human disorders, or diets high in vitamin D.

Pathophysiology

• Cholecalciferol is metabolized to 25-hydroxycholecalciferol in the liver. 25-hydroxycholecalciferol is metabolized to several metabolites in the kidney, including calcitriol, the most potent metabolite in terms of enhancing calcium absorption from the gut and calcium resorption from bones under physiologic conditions.
• 1,25-Dihydroxycholecalciferol is the active metabolite of cholecalciferol under physiologic conditions.
• Under toxic conditions, 25-hydroxycholecalciferol is the predominant circulating and active metabolite.
• Calcipotriol (Dovonex), a congener of calcitriol, does not require activation; has immediate but limited action due to a short half-life (100 minutes).
• 25-Hydroxycholecalciferol, calcitriol, and calcipotriol increase absorption of calcium from the gut, stimulate bone resorption, and enhance calcium absorption in renal distal tubules, resulting in hypercalcemia (serum calcium >12.5 mg/dL).
• Serum phosphorus is also increased (>8 mg/dL).
• The outcome is metastatic and dystrophic mineralization of soft tissues, resulting in pathophysiology of the affected organs.

Systems Affected

• Cardiovascular-mineralization, arrhythmias.
• Gastrointestinal-anorexia; mineralization; emesis; hematemesis; constipation; increased gastric acid secretion.
• Musculoskeletal-demineralization; muscle tremors.
• Nervous-seizures or depression.
• Renal/Urologic-calcification, proximal tubular necrosis, and renal failure.
• Respiratory-mineralization; dyspnea.

Incidence/Prevalence

• Cholecalciferol rodenticide toxicosis-most common cause of vitamin D poisoning in dogs and cats.
• Vitamin D3 poisoning from excessive vitamin D3 in a commercial dog food in January of 2000, April of 2006, and October of 2010 led to pet food recalls.
• Calcipotriol ointment (Dovonex; 50 µg calcipotriol/g) antipsoriasis medication-leading cause of vitamin D congener toxicity in dogs.
• Suckling pups and kittens can be poisoned through milk.
• Overall incidence of vitamin D toxicity is unknown.

Signalment

Signs

Causes

• Cholecalciferol rodenticides (0.075%)-Quintox, Rampage, Ortho Rat-B-Gone, Ortho Mouse-B-Gone, others; clinically normal dogs and cats have developed hypercalcemia at 0.5 mg/kg bw; signs have occurred in dogs and cats at 0.1 mg/kg bw.
• Calcipotriol: Ingesting 1.8–3.6 µg/kg BW is toxic to dogs.
• Diet: In dogs, daily ingestion of vitamin D3 in excess of the recommended dietary maximum of 1.43 kIU/1,000 kcal of ME causes chronic toxicosis.
• In cats, chronic intake of diets containing more than the recommended maximum vitamin D3 concentrations of 2.5 kIU/1,000 kcal ME is toxic.

• In the 2006 dog food outbreak, dietary concentrations of vitamin D3 were found between 1.51 and 2.67 kIU/1,000 kcal ME.

Risk Factors

• Preexisting renal, gastrointestinal, cardiac, lung, or CNS diseases
• Dehydration
• Neoplasia
• Primary hyperparathyroidism
• Hypoadrenocorticism
• Granulomatous diseases (e.g., blastomycosis)
• Juvenile hypercalcemia
• Age-young animals are most susceptible
• Feline idiopathic hypercalcemia

Differential Diagnosis

• Other hypercalcemic disorders, including lymphosarcoma and other malignancies, hypoadrenocorticism, chronic renal failure, primary hyperparathyroidism, and granulomatous lesions in soft tissues. Vitamin D and congener toxicosis can be differentiated from these diseases because it suppresses intact parathyroid hormone. In other conditions, iPTH is either normal or increased.
• Juvenile hypercalcemia.
• Anticoagulant rodenticide and NSAID toxicity-due to hematemesis and melena.

CBC/Biochemistry/Urinalysis

• Calcium-hypercalcemia (total serum calcium >12.5 mg/dL, ionized calcium >6.0 mg/dL). Hypercalcemia is immediate (2–3 hours) and transient (will decline to normal within 24 hours post-ingestion) with calcipotriol ingestion. In cholecalciferol rodenticide toxicity, hypercalcemia is evident 12 hours post-ingestion and persists for weeks if not treated.
• Hyperphosphatemia (>8 mg/dL), may preceded hypercalcemia.
• Hypokalemia.
• Azotemia.
• Hyposthenuria, proteinuria, and glucosuria.
• Metabolic acidosis.
• Calcipotriol-other abnormalities include hypoalbuminemia, increased ALP, ALT, and AST activity, thrombocytopenia, prolonged APTT, and increased fibrinogen concentration.

Other Laboratory Tests

• Currently there are no confirmatory tests for calcipotriol intoxication. Serum 25-hydroxy vitamin D and calcitriol are normal.
• In acute, one-time ingestions, serum 25-hydroxy vitamin D concentration is increased at least 10 times normal (normal ranges: dogs, 60–215 nmol/L; cats, 65–170 nmol/L) in cholecalciferol toxicosis.
• In chronic intoxications, serum 25-hydroxy vitamin D concentrations can increase from 1.5 to 5 times above normal values.
• Serum 1,25 dihydroxy vitamin D is only transiently increased and is of limited diagnostic value.
• The total calcium-to-total phosphorus ratio in renal cortex of deceased dogs is in the range of 0.4–0.9 for all vitamin D–related intoxications.
• Renal cortical 25-hydroxy vitamin D concentration >80 nmol/L supports a diagnosis of cholecalciferol toxicosis.
• Biliary 25-hydroxy vitamin D concentration >100 nmol/L supports a diagnosis of cholecalciferol toxicosis.
• Decreased iPTH (normal in dogs is 3–17 pmol/L and for cats is 0–4 pmol/L).
• Normal Na/K ratio.

Imaging

Ultrasonography-renal, gastric wall, lung hyperechogenicity

Diagnostic Procedures

• ECG-may show bradycardia, sinus tachycardia, ventricular premature complexes.
• Endoscopy-may reveal erosive/hemorrhagic gastric mucosa.

Pathologic Findings

• Diffuse mineralization of gastric wall and intestines; hemorrhage in gastric mucosa; mineralization of the soft palate, salivary glands, other soft tissues.
• Necrosis and mineralization of myocardium (especially the atria) and large blood vessels; myocardial degeneration.
• Mineralization of glomerular mesangium and capsule, and renal tubular basement membranes.
• Tubular necrosis.
• Mineralization of lungs.

Appropriate Health Care

• Calcipotriol-emergency treatment is recommended; prognosis is guarded, and hospitalization is required.
• Cholecalciferol-once clinical signs show (usually 24–36 hours post-ingestion), gastric decontamination is not worthwhile..
• Hospitalization with close observation in all cases for at least 48 hours post-ingestion.

Nursing Care

• Correct dehydration and electrolyte imbalances (hypokalemia).
• Enhance calciuresis with fluid therapy-strongly recommended for all patients.
• Peritoneal dialysis with a calcium-free dialysate-for severe azotemia and hypercalcemia.
• Blood transfusion-if anemia is severe or in case of hypovolemia.
• Antibiotic therapy-to prevent secondary bacterial infection because of broken defense barrier in gut.
• Parenteral alimentation-recommended to rest the gut and to overcome anorexia.

Diet

Offer low-calcium, low-phosphorus diets.

Client Education

• Caution client to keep all rodenticide products in places that are inaccessible to pets.
• Caution client to secure all medications where pets cannot reach them.
• Warn client that vitamin D toxicity is a severe and costly disease to treat with prolonged therapy and hospitalization.

Drug(s) Of Choice

• Pamidronate disodium-to treat hypercalcemia
• Salmon calcitonin-to treat hypercalcemia

Precautions

• Supratherapeutic doses of pamidronate disodium may worsen renal failure.
• Salmon calcitonin-associated with side effects: anorexia, anaphylaxis, and emesis. Rarely used.
• Xylazine-may aggravate respiratory depression and result in vagal-mediated slowing of the heart rate.
• Prolonged prednisolone therapy may result in adrenocortical suppression; taper doses gradually over a 2–4-week treatment period.

Patient Monitoring

• Following pamidronate therapy-serum calcium and BUN at 24, 48, and 72 hours following exposure; if hypercalcemia is present, fluid diuresis is recommended; if hypercalcemia still present, repeat pamidronate infusion 72 or 96 hours after the first infusion and monitor serum calcium and BUN q48h.
• Following calcitonin therapy-serum calcium and BUN; monitor q24h and continue adjusting dose until calcium returns to normal (24–48 hours for calcipotriol, or 2–4 weeks for cholecalciferol).
• Calcipotriol causes short-term hypercalcemia (24–48 hours) with massive soft tissue mineralization; requires long-term aggressive fluid and supportive therapy.
• Cholecalciferol-induced hypercalcemia is persistent, requiring long-term management and supportive care (2-4 weeks).

Prevention/Avoidance

• Keep rodenticides and medications out of reach of pets.
• Avoid diets high in vitamin D.

Possible Complications

• Chronic renal failure-inability to concentrate urine.
• Secondary bacterial infection from injury in the gut.
• Subclinical renal, cardiovascular, and gastrointestinal injury-due to mineralization.

Expected Course and Prognosis

• Calcipotriol-guarded prognosis unless aggressive therapy is immediate due to peracute nature of condition and associated massive soft tissue mineralization.
• Cholecalciferol-depends on severity and duration of hypercalcemia; if hypercalcemia is unresponsive or severe mineralization occurs before therapy is initiated, prognosis is poor.

Age-Related Factors

Distinguish from normal juvenile hypercalcemia.

Pregnancy/Fertility/Breeding

Teratogenic effects-calcipotriol and vitamin D have antiproliferative effects and potential for teratogenesis.

Synonyms

• Calcipotriol toxicosis
• Cholecalciferol toxicosis
• Dovonex toxicosis
• Vitamin D congener toxicosis

Abbreviations

• ALP = alanine phosphatase
• ALT = alanine aminotransferase
• APTT = activated partial thromboplastin time
• AST = aspartate aminotransferase
• CNS = central nervous system
• ECG = electrocardiogram
• iPTH = intact parathyroid hormone
• ME = metabolizable energy
• NSAID = nonsteroidal anti-inflammatory drug