Vitamin D Toxicosis
Vitamin D Toxicosis – Hypercalcemic disorder resulting from the ingestion of vitamin D rodenticide preparations, excessive dietary and vitamin supplementation, ingestion of congeners of vitamin D metabolites used for the 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.
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
Species
Dogs and cats
Other species, particularly exotics
Mean Age and Range
All ages affected; younger dogs (< 6 months) and cats are the most sensitive.
SIGNS
General Comments
Calcipotriol (Dovonex)—signs develop within 6–12 hours post-ingestion
Cholecalciferol rodenticides—signs develop within 12–36 hours post-ingestion
Historical Findings
Inactivity
Vomiting
CNS depression
Weakness
Anorexia
Polydipsia
Polyuria
Diarrhea
Melena
Hematemesis
Loss in body weight
Constipation
Seizures
Muscle tremors
Physical Examination Findings
Depression
Vomiting
Diarrhea
Hematemesis
Hematochezia
Polyuria
Polydipsia
Renal pain on palpation
Gastrointestinal hemorrhage
Abdominal pain
Hypersalivation
Oropharyngeal erosive lesions
Bradycardia; ventricular premature contractions
Dyspnea
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
DIAGNOSIS
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.
TREATMENT
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.
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.
MISCELLANEOUS
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
Visit your veterinarian as early recognition, diagnosis, and treatment are essential.