Monday, October 15, 2012

Hypercalcemia in Canine Hypothyroidism

Hypercalcemia in a Dog with Primary Hypothyroidism

R. G. Lobettia

Hypercalcemia is a relatively common problem in dogs, with the most common cause being malignancy-associated hypercalcemia (i.e., resulting from lymphoma, anal gland adenocarcinoma, multiple myeloma, or various other carcinomas). Other common causes include primary hyperparathyroidism, hypoadrenocorticism (Addison’s disease) chronic renal failure, and vitamin D toxicosis (1-3).

Hypothyroidism is not generally considered in the differential diagnosis or hypercalcemia in dogs. However, hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5), and, if left untreated, these hypothyroid dogs may continue to show slightly high serum calcium concentrations during adulthood (4).

In this case report (6), Lobetti describes a middle-aged dog with primary hypothyroidism that also developed symptomatic hypercalcemia. After instituting thyroid replacement therapy, both the hypercalcemia and associated clinical signs of polyuria resolved. This is the first report of this association between adult-onset hypothyroidism and symptomatic hypercalcemia in dogs.

Case Report
A 7-year old female beagle was examined because of polyuria and polydipsia, poor appetite, and weight gain. Physical examination revealed that the dog was slightly obese, with bradycardia (80 bpm). Routine blood work revealed marked hypercalcemia (3.27 mmol/L [13.1 mg/dl]; reference range, 2–3 mmol/L). A tentative diagnosis of hypothyroidism was made on the basis of a low serum T4 concentration (<6 nmol/L; reference range, 18–45 nmol/l) together with a high serum TSH value (1.05 ng/ml; reference range, 0.02–0.8 ng/ml).  

The dog was referred for further workup. On repeat serum biochemistry analysis, abnormalities included hypercholesterolemia (13.5 mmol/L [521 mg/dl]; reference range, 3–6 mmol/L) and hypercalcemia (3.44 mmol/ L [13.8 mg/dl]). Results of a complete blood count and urinalysis revealed no abnormalities.

An abdominal ultrasound examination, survey thoracic radiographs, and fine needle aspirate cytology of the spleen, liver and peripheral lymph nodes were all normal. Therefore, hypercalcemia of malignancy was considered unlikely.

A plasma parathyroid hormone (PTH) was low (7 pg/ml; reference range, 15–25 pg/ml). In addition, ultrasonography of the parathyroid glands was normal, making primary hyperparathyroidism unlikely.

The dog was treated with L-thyroxine (300 μg, twice a day). On follow up assessment 2 weeks later, the dog was more active and the bradycardia had resolved, but the polyuria and polydipsia were still present. A repeat serum calcium concentration remained high at 3.46 mmol/L (13.8 mg/dl). Supplementation with L-T4 was continued at 300 μg twice a day.

On recheck 9 weeks later, the dog was active and had lost weight, but now the polyuria and polydipsia had resolved. The serum concentrations of both calcium (2.97 mmol/ L [11.88 mg/dl]), and total T4 (25.5 nmol/L) has normalized.

Fifteen months after the initial diagnosis, the dog’s body weight was stable and her activity normal; no polyuria and polydipsia were reported. Serum concentrations of calcium (2.93 mmol/L [11.7 mg/dl]), T4 (32 nmol/L), TSH (0.11 ng/ml), and PTH (20 pg/ml) were all within the respective reference ranges.

Bottom Line
Little is known about the effects of hypothyroidism on calcium metabolism in adult dogs (1-3), but the effects appear to be mild and clinically insignificant. In agreement with that, humans with adult-onset hypothyroidism serum concentrations of calcium and phosphorus are typically within normal limits (7-9). However, up to 25% of children with congenital hypothyroidism can exhibit mild degrees of hypercalcemia (10), and mild hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5). The proposed mechanism for the hypercalcemia in hypothyroidism is decreased renal clearance and/or increased gastrointestinal absorption of calcium (11).

In the closing paragraph of this paper, Dr. Lobettia concludes that “the only logical explanation for the cause of the hypercalcemia in this dog would be hypothyroidism, as no other etiology was discovered, the hypercalcemia resolved with thyroxine therapy, and the PTH normalized.”

Unfortunately, another cause for this dog’s hypercalcemia must be considered — spurious total hypercalcemia, rather than true ionized hypercalcemia (12-14). In this dog, only the total calcium concentrations were measured, despite the well-documented fact that it is the ionized calcium fraction that has biologic activity.

Why ionized calcium was never measured in this dog is unclear, but it is possible that the serum ionized calcium value would have been normal, and the dog’s signs of polyuria may not have been caused by hypercalcemia after all.

In one study, it was documented that measuring total calcium concentrations tended to overestimate the perceived calcium value in dogs that were truly normocalcemic based on ionized calcium measurements. (13)  Use of total calcium or adjusted total calcium concentrations to predict the ionized calcium status in dogs could cause serious mistakes in diagnosis and case management, and that may have been the situation in the dog of this case report.

So before we add another differential to the differential list for hypercalcemia in dogs, just remember — always measure an ionized calcium to confirm true hypercalcemia (12-14)!

  1. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). Journal of Veterinary Internal Medicine 2009;23:514-519.
  2. Feldman EC. Disorders of the parathyroid glands. In Ettinger S J, Feldman E C (eds), Textbook of Veterinary Internal Medicine (7th ed). Saunders Elsevier, St Louis. 2010;1722–1750.
  3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT,Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
  4. Greco D S, Peterson M E, Cho D Y, et al. Juvenile-onset hypothyroidism in a dog. Journal of the American Medical Veterinary Association 1985;187: 948–950. 
  5. Greco D S, Feldman E C, Peterson M E, et al. Congenital hypothyroid dwarfism in a family of giant schnauzers. Journal of Veterinary Internal Medicine 1991;5: 57–65.
  6. Lobetti RG. Hypercalcaemia in a dog with primary hypothyroidism. Journal of the South African Veterinary Association 2011;82:242-243. 
  7. Auwerx J, Bouillon R. Mineral and bone metabolism in thyroid disease: a review. Quarterly Journal of Medicine 1986;60: 737–752. 
  8. Begic-Karup S, Wagner B, Raber W, et al. Serum calcium in thyroid disease. Wiener Klinische Wochenschrift 2001; 113: 65–68. 
  9. Shivaleela MB, Poornima RT, Jayaprakash Murthy DS. Serum calcium and phosphorous levels in thyroid dysfunction. Indian Journal of Fundamental and Applied Life Sciences 2012;2:179 -183.
  10. Verrotti A, Greco R, Altobelli E, et al. Bone metabolism in children with congenital hypothyroidism – a longitudinal study. Journal of Pediatric Endocrinology and Metabolism 1998;11: 699–705. 
  11. Pérez A V, Picotto G, Carpentieri A R et al. Mini-review on regulation of intestinal calcium absorption. Emphasis on molecular mechanisms of transcellular pathway. Digestion 2008;77: 22–34. 
  12. Schenck PA. Calcium homeostasis in thyroid disease in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 2007;37:693–708. 
  13. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005;66:1330-1336.
  14. Schenck PA, Chew DJ. Calcium: total or ionized? Veterinary Clinics of North America: Small Animal Practice 2008;38:497-502.

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