Vitamin D Toxicity in a Dog

WHAT IS YOUR DIAGNOSIS? A 21 month old, female neutered Cockapoo presented with a 5 day history of trembling. The dog had been in the owners’ possession since a 7 week old puppy, and was up-to-date with her vaccinations and parasite prophylaxis. She was reported to be eating normally (balanced dried dog-food) with no gastrointestinal signs reported. Thirst and urination were reported to be normal, although she had been diagnosed with a urinary tract infection 4 months’ previously. She was exercising normally, and was always on the lead to prevent scavenging and straying. There was no known access to toxins. She had been spayed at 6 months old without any reported problems. The referring vet had documented pyrexia (39.9°C) 3 days prior to presentation and administered meloxicam and amoxicillin-clavulanate. After 48 hours there was minimal improvement, and the dog was admitted for intravenous fluid therapy as she appeared dehydrated. Haematology and biochemistry were assessed at this time. Haematology identified an increased red blood cell count, haematocrit and haemoglobin concentration, consistent with dehydration. The biochemistry results were as follows: page 1 of 8 Paramameter Reference Range Result Day 1 Glucose 4.11-7.95 mmol/l 5.72 Urea 2.5-9.6 mmol/l 12.0 Creatinine 44-159 µmol/l 209 Phosphate 0.81-2.20 mmol/l 1.35 Calcium 1.98-3.00 mmol/l 3.42 Total Protein 52-82 g/l 62 Albumin 23-40 g/l 30 Globulin 25-45 g/l 32 ALT 10-100 IU/l 27 ALKP 23-212 IU/l 55 Total Bilirubin 0-15 µmol/l 5 Cholesterol 2.84-8.26 mmol/l 6.37 Amylase 500-1500 IU/l 947 Lipase 200-1800 IU/l 294 Sodium 144-160 mmol/l 151 Potassium 3.5-5.8 mmol/l 4.1 Chloride 109-122 mmol/l 115 Question 1 What differential diagnoses are there for the elevated urea and creatinine, and how might you narrow down these differentials? page 2 of 8 Answer 1 Pre-renal azotaemia – causes might include:  dehydration,  cardiac disease,  hypovolaemia,  vasoconstriction. Evaluation of a urine sample would generally identify concentrated urine (USG > 1.025). Renal azotaemia – causes might include:  acute kidney injury from toxins (e.g. ethylene glycol, raisins, hypercalcaemia), drugs (e.g. NSAIDs, gentamicin), ischaemia (e.g. hypotension), infection (e.g. Leptospirosis, sepsis), infarction (e.g. thrombo-embolic disease)  chronic kidney disease  neoplasia  pyelonephritis Evaluation of a urine sample would generally identify isosthenuric urine (USG 1.008-1.012) Post-renal azotaemia – causes might include:  Urolithiasis (obstruction of urethra or ureters)  Uroabdomen  Neoplasia (causing obstruction of urethra or bladder trigone) The history makes this unlikely as there is no history of dysuria or stranguria, or trauma that might lead to rupture of the bladder page 3 of 8 Question 2 What differential diagnoses are there for hypercalcaemia? Answer 2 (G –Hard-Ions pneumonic!) G – granulomatous disease (e.g. Mycobacterial infection; fungal infections) H – hyperparathyroidism A – addison’s disease R – renal disease D – vitamin D toxicosis I – idiopathic (especially cats) O – osteolysis (e.g. bone tumours, multiple myeloma)) N – neoplasia (e.g lymphoma, apocrine cell carcinoma, squamous cell carcinoma) S – spurious (e.g. dehydration, lipaemia) Question 3 Which fluid would be best to give to a patient with hypercalcaemia? Answer 3 0.9% NaCl is chosen, as Hartmann’s and Ringers both contain calcium. In addition, the high levels of sodium should theoretically promote increased excretion of sodium in the proximal tubule. As calcium absorption parallels sodium and water reabsorption, sodium diuresis also promotes loss of calcium. Monitoring After 24 hours of intra-venous fluid therapy, the blood tests were repeated. The red blood cell parameters had reduced into the reference range, consistent with rehydration therapy. Parameter Reference Range Result Day 1 Result Day 2 Glucose 4.11-7.95 mmol/l 5.72 6.15 Urea 2.5-9.6 mmol/l 12.0 14.5 Creatinine 44-159 µmol/l 209 201 page 4 of 8 Phosphate 0.81-2.20 mmol/l 1.35 2.20 Calcium 1.98-3.00 mmol/l 3.42 3.34 Total Protein 52-82 g/l 62 61 Albumin 23-40 g/l 30 29 Globulin 25-45 g/l 32 32 ALT 10-100 IU/l 27 27 ALKP 23-212 IU/l 55 50 Total Bilirubin 0-15 µmol/l 5 4 Cholesterol 2.84-8.26 mmol/l 6.37 6.03 Amylase 500-1500 IU/l 947 823 Lipase 200-1800 IU/l 294 328 Sodium 144-160 mmol/l 151 156 Potassium 3.5-5.8 mmol/l 4.1 4.5 Chloride 109-122 mmol/l 115 121 Question 4 Which parameter shows the most worrying increase? Answer 4 Urea and creatinine might have been expected to reduce with fluid therapy, but the increase is only marginal. Although still within the reference range (just), phosphate has shown a 63% rise. This is of concern due to the increased risk of soft tissue mineralisation when both calcium and phosphate are high. If the calcium phosphate product exceeds 4.8 then there is high risk of soft tissue mineralisation. For this patient it was 7.35. page 5 of 8 Further Investigations At this point the dog was referred for more intensive management of the hypercalcaemia. Physical examination was generally unremarkable, other than the dog was quieter than might be expected for a young Cockapoo, and she exhibited a mild generalised tremor. The anal glands were emptied and appeared normal, as was the rectal temperature (38°C). Further investigations included assessment of urine specific gravity (1.020 – post fluid therapy), and measurement of ionised calcium (1.56 mmol/l; ref range 1.13-1.33 mmol/l). Question 5 From the previous list of differential diagnoses, how might you prioritise the differentials and why? Answer 5 Likely causes 1) Vitamin D toxicity: this will typically cause increases in both calcium and phosphate, as vitamin D promotes absorption of both from the intestines 2) Kidney disease: although azotaemia is present, this was considered to be secondary to the hypercalcaemia. Typically when hypercalcaemia is present with renal disease, it is due to secondary renal hyperparathyroidism and the phosphate might have been expected to increase before the calcium, not the other way round. Possible causes, but rare 3) Granulomatous disease: this could cause the reported pyrexia however causes of granulomatous disease are rare in the UK, and no lymphadenopathy or nodular skin disease was detected. 4) Osteolysis is relatively rare, but could also be associated with increased phosphate release from the bone. However no lameness or bone pain was detected that would support a bone lesion. Unlikely causes page 6 of 8 5) Addison’s disease can also result in azotaemia, but it does not usually affect the phosphate levels, and the electrolytes are normal. 6) Primary hyperparathyroidism would typically cause the phosphate level to be low, as PTH promotes renal excretion of phosphate. 7) Neoplasia usually causes hypercalcaemia via production of parathyroid-hormone related peptide (PTHrP). As this mimics the action of PTH, again the phosphate level is expected to be low. Question 6 What potential sources of Vitamin D toxicity are there? Answer 6 Rodenticides containing cholecalciferol Plants (Cestrum diurnum, Solanum malacoxylon, Trisetum flavescens) Iatrogenic Vitamin D supplementation (e.g. post thyroidectomy/parathyroidectomy) Psoriasis creams (calcipotriene, calcipotriol, calcitriol) Diagnosis The owner was questioned more closely regarding access to these specific toxins. This identified that the owner applied a psoriasis ointment (Silkis) containing 3µg calcitriol/gr ointment and the dog would lick the ointment off their arms. Calcitriol is the active form of Vitamin D (1,25 OH cholecalciferol) that causes hypercalcaemia as a result of:  increased absorption of calcium from the intestine  increased release of calcium and phosphorous from bone through promoting production of osteoclasts  increased reabsorption of calcium and phosphate in the kidney page 7 of 8 Treatment Due to the high Ca x Po4 product, and as saline diuresis had resulted in no improvement, the patient was given an intravenous infusion of pamidronate over 6 hours (1mg/kg pamidronate diluted in 250ml 0.9% NaCl). Pamidronate is a bisphosphonate, which inhibits osteoclast action, thereby decreasing release of calcium and phosphate from the bone. Bisphosphonates can cause renal toxicity, hence it is important to ensure adequate fluid therapy. Oral forms are available, but they can be less consistently absorbed and may be associated with oesophagitis. Outcome Within 24 hours the ionised calcium had reduced from 1.56 mmol/l to 1.37 mmol/l, and it was normal (1.30) 48 hours after treatment. After 1 week, ionised calcium, phosphate and creatinine were all within reference range, and the marginally elevated urea was attributed to lack of fasting prior to blood-sampling. The urine specific gravity was 1.035, indicating that no lasting renal damage appeared to have occurred. Conclusions The investigation of hypercalcaemia can be extensive and expensive, often comprising radiography and/or ultrasonography to screen for neoplastic processes, bone marrow biopsy to evaluate for haematopoietic neoplasia such as lymphoma or multiple myeloma, as well as measurement of PTH and PTHrP. This case is a good example of how problem oriented medicine and careful prioritisation of the differential diagnoses from the results available enabled a key question to be asked in the history, which lead to the diagnosis at no additional cost to the owner. As such, effective treatment could be rapidly instigated, preventing further, potentially irreversible damage to the kidneys. References Mellanby, R.J., Craig, R., Evans, H., Herrtage, M.E. (2006) Plasma parathyroid hormone related protein concentrations in dogs with calcium metabolism disorders. Veterinary Record. 159, 833-838 Mellanby, R.J., Mee, A., Berry, J. and Herrtage, M.E. (2005) Hypercalcaemia in two dogs caused by excessive dietary supplemetation of vitamin D. Journal of Small Animal Practice. 46, 334-338 The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336. www.ed.ac.uk/vet/hfsa-int-med page 8 of 8