Vitamin D3 Toxicity: Rare but Noteworthy

Jodi Thompson, DVM, talks about the recent increase of Vitamin D3 toxicities seen at DoveLewis Emergency Animal Hospital.

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Cholecalciferol is an uncommon cause of toxicity in the dog and cat, however after seeing several cases recently, I thought that it warranted a review. Thankfully, these cases were seen shortly after ingestion and all did well with prompt decontamination and aggressive medical management. Unfortunately not all fare so well and overall prognosis is guarded.

 

Exposure:   

1. Cholecalciferol based rodenticides:  These are becoming more common as anti-coagulant rodenticides become more regulated. Concentration is typically 0.075%, or 750ppm (750mg/kg of weight). This equates to about 23mg/ ounce of rodenticide. Clinical signs are noted at > 0.5mg/kg of cholecalciferol, therefore a 20kg dog would need to eat less than 1/2 ounce (about 1 tablespoon) of bait to cause toxicity. Ingestion must be direct and relay toxicosis has not yet been reported. Because small amounts can cause severe toxicosis and death in dogs and cats, it is recommended that any known or suspected ingestion of cholecalciferol rodenticide be seen promptly and treated as indicated.

2. Vitamin D supplements:  This is the most common cause of Vitamin D toxicity that we see at DoveLewis. In order to determine cholecalciferol exposure, conversion from IU to mg is needed:  One IU contains 0.000025mg of cholecalciferol (therefore 40,000 IU = 1mg of cholecalciferol). Multivitamins contain a relatively small amount of Vitamin D, with around 400 IU of cholecalciferol or ergocalciferol/ capsule. Therefore, toxicity from multivitamin ingestion is rare unless very large quantities are ingested. However, primary Vitamin D supplements do contain enough cholecalciferol/ ergocalciferol to cause concern, with ranges of up to 50,000 IU/ capsule. 

3. Vitamin D analogues:  There are multiple different Vitamin D analogues approved for use in humans- calcipotriol/ calcipotriene or Tacalcitol which is included in psoriasis creams and typically marketed under the following trade names: Dovonex, Taclonex, Sorilux or Calcetrine; paracalcitriol, or Zemplar which is used for the treatment of secondary hyperparathyroidism, doxercalciferol, or Hectoral which is used for the reduction of pTH, among others. Most cases of exposure are acute after ingestion of tubes of psoriasis creams. Chronic toxicity is possible if dogs are routinely licking the skin where creams are being applied. When in doubt, contact an animal poison control center for further information.

4. Calcitriol:  Calcitriol is available as a capsule or injectable medication and is marketed under the following trade names: Rocaltrol, Calcijex and Vectical.

5. Food contamination:  Several commercial pet foods have been inadvertently over supplemented with Vitamin D, leading to recall and toxicity.

 

Pathogenesis:

Cholecalciferol is rapidly absorbed from the intestinal tract and converted in the liver by 25-hydroxylase to calcifediol (25-hydroxycholecalciferol). There is limited negative feedback on 25-hydroxylase, so in cases of overdose, calcifediol levels continue to rise despite rising plasma levels of calcium, calcitriol and phosphorus. The kidney converts calcifediol to calcitriol (1,25-hydrocholecalciferol) via 1-α-hydroxylase. 1-α-hydroxylase is affected by negative feedback and limits production of calcitriol when plasma concentrations rise, however calcifediol outcompetes calcitriol at Vitamin D receptors. Activation of Vitamin D receptors causes increased calcium and phosphorus absorption from the GI tract, increased renal tubular resorption of calcium and increased bone resorption of calcium and phosphorus.

Hypercalcemia decreases cell membrane permeability in the neuromuscular system, which may cause weakness, CNS depression and muscle tremors. It causes decreased GI motility and increased gastrin secretion, which can lead to ileus and gastric ulceration. It decreases renal tubular sensitivity to antidiuretic hormone, which leads to changes in the kidney's ability to regular water and sodium. Hypercalcemia causes vasoconstriction, reduced glomerular filtration and may lead to renal ischemia. Changes in myocardial contractility can be noted.

Calcium and phosphorus levels continue to rise, and once the calcium x phosphorus product exceeds 60 mg/dl, mineralization of the kidneys, GI tract, myocardium, skeletal muscle, blood vessels and other soft tissues can occur, leading to structural damage and organ failure.

Cholecalciferol and its metabolites undergo enterohepatic circulation and are primarily excreted through the GI tract and bile. Because they are lipid soluble, they are stored in tissues and clinical effects may persists for weeks or even months.

 

Clinical signs:

Clinical signs are relatively slow in onset and can take 12-72 hours to declare. Initial clinical signs are related to elevated serum calcium, delayed clinical signs are secondary to organ dysfunction. Clinical signs can include vomiting/hematemesis, diarrhea, melena, anorexia, depression, weakness, polyuria, polydipsia, bradycardia or other cardiac arrhythmia and death.  

 

Laboratory abnormalities and monitoring:

Calcium and phosphorus levels can begin to rise within the first 24 hours post ingestion. Phosphorus often becomes elevated prior to calcium, but both may rise simultaneously. Phosphorus elevations are typically more moderate than calcium, which can be severe. BUN and creatinine become elevated and urine becomes isosthenuric as secondary renal failure develops. 

Monitoring of total calcium, ionized calcium, phosphorus, BUN and creatinine should be performed every 12-24 hours for the first four days. Electrolytes should be closely monitored if the patient is on fluid therapy or multiple doses of activated charcoal are being administered, as hypernatremia and hypokalemia can occur. If calcium, phosphorus and renal values are normal after four days, it is unlikely that toxicity will develop.

If laboratory abnormalities do occur and treatment is started, continue to monitor calcium, phosphorus and renal values once daily for one week after discharge, then 2-3 times weekly for two weeks as medications are weaned, then once weekly for two additional weeks.

If Vitamin D toxicity is suspected but not confirmed, PTH and ionized (not total) calcium can be used to help differentiate from other causes of hypercalcemia including primary renal disease, hyperparathyroidism, osteolytic lesions, granulomatous disease and hypercalcemia of malignancy. Vitamin D toxicity results in an elevation in ionized calcium, elevation in total phosphorus and suppression of PTH. The elevation in phosphorus can help to differentiate Vitamin D toxicity from hypercalcemia of malignancy, which also results suppression of PTH and elevated ionized calcium, with normal phosphorus levels. PTHrP levels can be assessed to help rule out hypercalcemia of malignancy.

 

Treatment:

Decontamination is the first goal of treatment. In dogs, as long as the ingestion was recent (within the last 4-6 hours) and there are no patient contraindications to vomiting, vomiting should be induced with apomorphine at 0.03-0.04mg/kg IV. If injectable apomorphine is not available, a crushed apomorphine tablet can be used in the conjunctival sac or hydrogen peroxide can be administered at a dose of 2.2ml/kg, with a maximum of 45ml, repeated once. Hydrogen peroxide should be avoided in cats as they are more susceptible to adverse effects. In cats, vomiting can be attempted with either xylazine at 0.44mg/kg IM or dexmedetomidine at 10mcg/kg IM.  Unfortunately induction of vomiting in cats is often unrewarding. In cases where vomiting cannot be safely induced or with massive ingestions, gastric lavage may be indicated.

Post vomiting induction, anti-emetic medication may be indicated if residual GI upset occurs. Activated charcoal should then be administered at 2g/kg orally. The first dose should contain a cathartic, subsequent doses should be free of cathartic to avoid GI disturbance and free water loss. Because cholecalciferol and its metabolites undergo enterohepatic recirculation, additional doses of activated charcoal every 4-8 hours for the first 24-48 hours may be helpful, with a dose reduction to 0.5-1g/kg orally for repeated doses. Electrolytes must be closely monitored during this time due to the concern for iatrogenic hypernatremia with multiple doses of activated charcoal.

IV fluids (0.9% NaCl) should be started at 2-3 times maintenance rate to maintain hydration, promote diuresis and renal calcium excretion. Gastric protectant medications (H2 blockers, proton pump inhibitors, sucralfate) should be started if there is concern for gastric ulceration. A low calcium diet should be fed during treatment.

If hypercalcemia develops, furosemide and prednisone should be administered. Both increase renal excretion of calcium, prednisone also inhibits absorption of calcium from the GI tract. Furosemide should be given initially as a bolus of 2-5mg/kg IV, then continued at 1-2mg/kg orally or IV every 12 hours. Alternatively, furosemide can be administered as a constant rate infusion at 0.5-1.0mg/kg/hr. Furosemide should only be administered if the patient is well hydrated and undergoing fluid therapy, as worsening azotemia and dehydration can develop.  Prednisone should be administered at 1-2mg/kg orally every 12 hours.

If hyperphosphatemia develops, aluminum hydroxide can be administered at 30-100mg/kg/day divided and given orally with food if the patient is eating.

If hypercalcemia does not resolve with fluid therapy, furosemide and prednisone administration, pamidronate should be considered at 1.3 – 2 mg/kg slow IV infusion (over 2 hours), diluted with 0.9% NaCl. This can be repeated in 5-7 days if needed. Serum calcium levels should start to fall within 24-48 hours.

Salmon calcitonin can be used but may have limited efficacy and there is concern for development of resistance during treatment. I should not be used with pamidronate and is not routinely used in our clinic.

Once hypercalcemia resolves, IV fluids can be weaned over 24-36 hours while continuing to monitor serum calcium, phosphorus and renal values as described above. If values remain normal, and the patient is clinically doing well, they can be discharged to home on oral prednisone and furosemide therapy. This should be continued and slowly weaned over the following 2-3 weeks, while monitoring values as described above.

 

Prognosis:

Prognosis is good if treatment is started prior to development of significant hypercalcemia, hyperphosphatemia and dystrophic mineralization. Prognosis becomes guarded to poor if treatment is delayed, particularly if dystrophic mineralization has already started to occur, as this can result in irreversible organ failure and death.  Gastric ulceration and hematemesis are negative prognostic indicators.

 

References/ additional reading:

Brown, A. J. (2001, November). Therapeutic uses of vitamin D analogues [Abstract]. Am J Kidney Dis, 38(5). Retrieved from http://www.ncbi.nih.gov/pubmed/11689383

Dee, T., CVT, & Hovda, L. R., DVM, MS, DACVIM. (2012, January). Toxicology Brief: Cholecalciferol Rodenticide Toxicosis. Veterinary Technician, 33(1), E1-E4. Retrieved from http://vetfolio.com/emergency-medicine/toxicology-breif-cholecalciferol-rodenticide-toxicosis

Dekker, Mees, DVM, and Linda Shell, DVM, DACVIM. "Cholecalciferol (Vitamin D3) Toxicosis." VIN Associate Database. Ed. Sharon Gwaltney-Brant. N.p., Aug.-Sept. 2015. Web. 30 Aug. 2016.

Means, C., DVM, MLIS. (2001, June 11). Small Animal Toxicoses- Rodenticides. Retrieved from http://www.wspn.org/Library/misc/VSPN_M01287.htm

Morrow, C., DVM. (2001, December). Cholecalciferol Poisoning. Veterinary Medicine. Retrieved from Vetmedpub.

Plumb, D. C. (2015). Plumb's Veterinary Drug Handbook: Desk, 8th Edition. John Wiley & Sons.

Rumbeiha W. 2013. Cholecalciferol. In: Peterson M, Talcott, P, editors. Small Animal Toxicology, 3rd ed. St. Louis (MO): Elsevier Saunders p. 489-497

Schropp, D. M., DVM, & Kovacic, J., DVM, DACVECC. (2007). Phosphorus and phosphate metabolism in veterinary patients. Journal of Veterinary Emergency and Critical Care, 17(2), 127-134. doi:10.1111/j.1476-4431.2006.00217.x

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