What's Causing Idiopathic Hypercalcemia in Cats?

Over the last two decades, a syndrome of idiopathic hypercalcemia in cats has emerged and appears to be increasing in frequency (1-6). The term "idiopathic hypercalcemia" refers to a high serum ionized calcium concentration of unknown cause, even after extensive medical evaluation has been undertaken to rule out other known causes of hypercalcemia, such as primary hyperparathyroidism and neoplasia (7,8).

Multiple factors have been considered in relation to the underlying cause of idiopathic hypercalcemia. It is still unclear if increased intestinal calcium absorption, increased bone resorption, or decreased renal calcium excretion (or some combination thereof) is the key factor leading to the development of the ionized hypercalcemia in this syndrome.

Despite the fact that the underlying cause of idiopathic hypercalcemia remains elusive, this has clearly become the most common type of hypercalcemia in cats.

Is the Cat's Diet Responsible?

It has been suggested that the diet fed may predispose cats to development of idiopathic hypercalcemia, as well as formation of calcium oxalate calculi found in 10-15% of cats with this syndrome (8,9).

Acidifying diets
Many believe that feeding of acidifying, magnesium-restricted diets predisposes cats to idiopathic hypercalcemia (4,8). In support of this hypothesis is the fact that both calcium oxalate stones and hypercalcemia first became prevalent in the 1990's, shortly after the introduction of feline acidifying diets designed for prevention of struvite crystals (1-3). In addition, 3 of 5 cats in one series (1) and all 14 cats for which diet history was available in another report (2) had been fed acidifying diets designed to minimize struvite crystalluria and urolithiasis.

When fed to normal cats, such acidifying diets may lead to a state of mild systemic acidosis (10), which, in turn, promotes increased calcium resorption from bone and can produce a state of negative calcium balance. The calcium salts present in bone represent the largest store of alkaline base in the body and, therefore, act as a buffer in states of metabolic acidosis (11). Therefore, when human subjects are fed a diet that produces a net acid load, excessive calcium salt may be released from bone, resulting in increased urinary calcium excretion (11-13). In agreement with these human studies, the induction of metabolic acidosis in cats fed an acidifying diet may result in both mild ionized hypercalcemia and hypercalciuria (10).

Excessive Vitamin D
Another plausible hypothesis is that excessive dietary vitamin D content in some cat foods may contribute to this syndrome (5). Cats have a low requirement for vitamin D (1.4 μg [56 IU] cholecalciferol per 100 kcal diet) (14), at least when fed a diet with adequate concentrations (and a correct ratio) of calcium and phosphorus.

The vitamin D levels in commercial cat diets are not listed on the label and are not always included on product guides or company websites. However, if the label states that a cat diet is “complete and balanced,” the vitamin D levels must be between 3.1-62.5 μg [125-2,500 IU] per 1000 kcal to comply with AAFCO guidelines (15). Therefore, the amounts of vitamin D added to commercial cat foods could range from 2- to 50-fold higher than the minimal requirement recommended by the NRC (14). Most commercial cat foods likely contain relatively high amounts of vitamin D, which could result in hypervitaminosis D in some cats and contribute to ionized hypercalcemia in at least some of them (14,16).

The finding of “normal” serum concentrations of 25-hydroxyvitamin D and calcitriol in most cats with idiopathic hypercalcemia goes against this hypothesis that excessive dietary vitamin D levels in the diet contributes to this syndrome (2,9).  However, it is important to realize that reference range limits for 25-hydroxyvitamin D and calcitriol have all been established in clinically normal cats fed standard diets which again may be rather heavily supplemented with vitamin D.

Bottom Line

In almost all cats with idiopathic hypercalcemia, clinical signs are usually relatively mild, at least at diagnosis. In general, the severity of hypercalcemia in these cats tends to be slowly progressive. Therefore, most cats can be treated as outpatients with either dietary therapy, alone or in combination with drug therapy— i.e., glucocorticoids or bisphosphonates (4-8,17).

I generally start with diet modification as a first-line treatment. In my next post, I'll review the 5 dietary options that have been proposed for this syndrome and give you my recommendations about how to best manage these cats with dietary therapy.

References:

1. McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999;35:297-301.
2. Midkiff AM, Chew DJ, Randolph JF, et al: Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14: 619–626.
3. Savary KC, Price GS, Vaden S. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000;14:184-189.
4. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15:20–24.
5. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Philadelphia: Saunders Elsivier, 2009;236-241.
6. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34. 
7. 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.
8. Baral RM. Disorders of calcium metabolism In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;625-642.
9. Schenck PA, Chew DJ, Refsal K, et al: Calcium metabolic hormones in feline idiopathic hypercalcemia (abstract). J Vet Intern Med 2004;18:442.
10. Ching SV, Fettman MJ, Hamar DW, et al. The effect of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in the adult cat. J Nutr 1989;119:902-915.
11. Arnett TR. Extracellular pH regulates bone cell function. J Nutr 2008;138:415S-418S. 
12. Jajoo R, Song L, Rasmussen H, et al. Dietary acid-base balance, bone resorption, and calcium excretion. J Am College Nutr 2006;25:224-230.
13. Vormann J, Remer T. Dietary, metabolic, physiologic, and disease-related aspects of acid-base balance. J Nutr 2008;138:413S-414S. 
14. National Research Council. Vitamins. In: Nutrient Requirements of Dogs and Cats. Washington, DC: National Academies Press. 2006:193-245.
15. AAFCO. (Association of American Feed Control Officials). Official Publication, 2007.
16. Morita T, Awakura T, Shimada A, et al. Vitamin D toxicosis in cats: natural outbreak and experimental study. J Vet Med Sci 1995;57:831-837.
17. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Feline Med Surg 2011;13:129-134.