Hypocalcemia after Surgical Removal of an Anal Sac Adenocarcinoma in a Dog

My patient is a 55 pound (25 kg), 11-year old, female English Springer who presented with polyuria,  polydipsia, and a decreased appetite.  Physical examination revealed a huge (apple-sized) anal sac mass and enlarged sublumbar lymph nodes on rectal palpation (presumably metastatic disease).

Routine blood work revealed severe hypercalcemia (16.5 mg/dl). Fortunately, the renal function still appeared to be adequate, as evidenced by the normal serum concentrations of both urea nitrogen and creatinine. However, the urine specific gravity was low at 1.007.

Hypercalcemia was confirmed by finding a very high serum ionized calcium concentration (2.1 mmol/L; reference interval, 1.25-1.45 mmol/L). A serum parathyroid hormone (PTH) concentration was suppressed (0.2 pmol/L; reference interval, 0.5 - 5.8 pmol/L), consistent with PTH-independent (e.g., malignant) hypercalcemia.

One week ago, I removed the anal sac tumor along with the enlarged sublumbar lymph nodes (lymphadenectomy). The dog did well in the immediate post-surgical period, but she started showing anxiety and facial itching 3 to 4 days ago. Yesterday, the owner finally brought her back for a recheck, and she was exhibiting severe signs of hypocalcemia, with muscle twitching, anxiety, and panting. We don't have the ability to measure ionized calcium in-house, but her total calcium value was low at 4.8 mg/dl.

I administered calcium gluconate slowly by intravenous injection "to effect," which resolved the sigs of hypocalcemia.  Over the next 2 hours, multiple IV doses were required to prevent return of her twitching and other signs of hypocalcemia. Therefore, we started her on a constant rate infusion (CRI) of calcium gluconate to maintain the serum calcium concentration in the low-normal range and prevent clinical signs.

We also started the dog on calcitriol (Rocaltrol) later that day as soon as she could swallow, using an initial dose of 0.5 µg, followed by a second dose of 0.25 µg 12 hours later. We also started oral calcium carbonate (Tums) at a dose of 3000 mg divided TID. This protocol worked well, bringing her serum calcium up to 8.4 mg/dl the following morning, with no return of clinical signs of hypocalcemia. She started eating within an hour of first infusion.

I weaned her off CRI throughout today. After 4 hours, the serum calcium concentration had fallen to 7.4 mg/dl, but she had no clinical signs and acted great. Now 18 hours later, she is still doing well clinically on twice daily oral calcium and calcitriol (0.25 µg).

So I assume I will be treating her with calcitriol for a few weeks at a tapering dose. I understand the standard maintenance is 5-15 µg/kg/day divided BID with food (1,2). Of course, that means that I'll have to have the drug compounded into that dosage by a compounding pharmacy, with its cost and delay. Is there an alternative dosing scheme that would work for her?

My Response:

Malignancies commonly associated with hypercalcemia in dogs include T cell lymphoma and adenocarcinomas derived from the apocrine glands of the anal sac (3,4). In a recent study, lymphoma accounted for ≈75% of the dogs with ionized hypercalcemia and cancer (5).

Tumors in the apocrine glands of the anal sac appear primarily in middle-aged dogs and commonly lead to hypercalcemia. Clinical signs are referable to hypercalcemia (polyuria, polydipsia, anorexia, and weakness), a mass in the perineum (tenesmus, ribbon-like stools, increased odor, and protruding mass), a mass in the sublumbar region, or more distant metastases (6-12).

In addition to anal sac carcinoma, humeral hypercalcemia of malignancy can also develop in dogs with thymoma, myeloma, melanoma, or carcinomas originating in the lungs, pancreas, thyroid gland, skin, mammary gland, nasal cavity or adrenal medulla (3.4).

Hypocalcemia after treatment of malignant hypercalcemia
It is very unusual to see post-operative hypocalcemia in a dog suffering from a malignant tumor that has resulted in hypercalcemia of malignancy, but it certainly is possible if you have removed most or all of the cancerous tissue (13). Severe hypercalcemia, no matter what the cause, will suppress normal parathyroid hormone secretion (1-4); so now that the underlying cause of the hypercalcemia has been removed (the anal sac tumor), the dog currently has iatrogenic hypoparathyroidism.

Why do we commonly see postoperative hypocalcemia after removal of a parathyroid tumor (primary hyperparathyroidism) but only rarely see postoperative hypocalcemia after removal of a tumor associated with hypercalcemia of malignancy? Most likely, the difference is due to the fact that it is usually difficult to remove enough of the malignant, metastatic tissue responsible for the dog's hypercalcemia, whereas it's relatively easy to remove a parathyroid tumor(s) — at least once it's identified— since most of these parathyroid nodules are benign.

Protocol for treating postoperative (iatrogenic) hypocalcemia
With severe postoperative hypocalcemia, as seen in this dog, it's generally best to just go straight to a constant rate infusion of 10% calcium gluconate after initial stabilization (1,2).  To that end, 10% calcium gluconate should initially be given 0.5–1.5 ml/kg, IV, slowly over 20–30 minutes until clinical signs have subsided. An ECG should be used to monitor cardiac effects and the infusion stopped if there is ST segment elevation, QT shortening, or if arrhythmias develop. Thereafter, a continuous rate infusion should be used at 10–15 mg/kg/h (10–15 ml/kg over 24 hours) until oral therapy allows better control.

If you use intermittent injections of calcium gluconate, these must be be given via the intravenous route. Calcium salts should never be used subcutaneously, as this can lead to sterile abscess formation and skin sloughing in dogs (2).

Longer-term treatment for postoperative hypocalcemia includes the use of oral calcium and vitamin D (calcitriol) supplementation.  Successful management of this condition is rather expensive and requires intense monitoring, with serum total or ionized calcium measured at least once weekly and dose adjustment made as needed (1,2).

Eventually, this dog can be tapered off of both the calcium and vitamin D supplementation, but how quickly this will occur is impossible to predict. It could be days to many months, but recovery will likely occur within the next 2 to 3 months.This could be a good sign, indicating that the parathyroid glands are functioning again. On the other hand, this may also be a bad prognostic indicator, since this could also mean that the cancer (and humeral hypercalcemia) is recurring.

So it's not likely that you will need to keep this dog on the standard maintenance dosage (5-15 ng/kg/day divided bid) of calcitriol for very long (perhaps a couple weeks to a month) before you can try weaning completely off the drug.  In most of these dogs, the sizes of the Rocaltrol oral capsules (0.25 µg and 0.5 µg) are too large for maintenance. In these cases, an oral solution of calcitriol (Rocaltrol Oral Solution; 1 µg/ml) is available (14), or the calcitriol can be reformulated to the required concentration by a compounding pharmacy to assure accurate dosing.

References:

1. Chew D, Nagode L. Treatment of hypoparathyroidism. In: Bonagura JD, ed. Kirk’s Current Veterinary Therapy: XIII: Small Animal Practice. Philadelphia: Saunders; 2000:340–345.
2. Skelly BJ. Hypoparathyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012.
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. Bergman PJ. Paraneoplastic hypercalcemia. Top Companion Anim Med  2012;27:156-158.
5. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). J Vet Intern Med 2009;23:514-519.
6. Hause WR, DVM, Stevenson S, DVM, MS, Meuten DJD, et al. Pseudohyperparathyroidism associated with adenocarcinomas of anal sac origin on four dogs. J Am Anim Hosp Assoc 1981;17:373-379.
7. Meuten DJ, Cooper BJ, Capen CC, et al. Hypercalcemia associated with an adenocarcinoma derived from the apocrine glands of the anal sac. Vet Pathol 1981;18:454-471. 
8. Goldschmidt MH, Zoltowski C. Anal sac gland adenocarcinoma in the dog: 14 cases. J Small Anim Pract 1981;22:119-128. 
9. Ross JT, Scavelli TD, Matthiesen DT, et al. Adenocarcinoma of the apocrine glands of the anal sac in dogs: a review of 32 cases. J Am Anim Hosp Assoc 1991;27:349 - 355.
10. Bennett PF, DeNicola DB, Bonney P, et al. Canine anal sac adenocarcinomas: clinical presentation and response to therapy. J Vet Intern Med 2002;16:100-104. 
11. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223:825-831.
12. Hobson HP, Brown MR, Rogers KS. Surgery of metastatic anal sac adenocarcinoma in five dogs. Vet Surg 2006;35:267-270.
13. Saba C, Ellis A, Cornell K. Hypocalcemia following surgical treatment of metastatic anal sac adenocarcinoma in a dog. J Am Anim Hosp Assoc 2011;47:e173-177. 
14. Rocaltrol (calcitrol) web site. Assessed April 30, 2014.

Top Endocrine Publications of 2012: Canine and Feline Endocrine Nutrition

In my 11th and last compilation of canine and feline endocrine publications of 2012, I’m finishing up with endocrine nutrition and treatment of obesity in dogs and cats. Starting in February of 2014, I'm planning to start posting the endocrine publications for 2013. I'm only waiting for the final papers published in December to come out so they can be included in my lists and reviews.

Listed below are 31 research papers written in 2012 that deal with a variety of topics concerning endocrine nutrition or obesity in the dog and cat. Remember that adipose tissue is the largest endocrine gland in the body, making a number of hormones, including leptin, adiponectin, and resistin. These hormones generally influence energy metabolism, which is of great interest to the understanding and treatment of type 2 diabetes and obesity.

These papers range from the studies of the effects of calcium deficiency in growing and adult dogs (1) to studies of the effect of dietary fat intake on circulating lipids in cats (2); from cause, prevalence, and management of obesity in dogs and cats (3,4,12-16,21,25-27,30) to the effect of nutrition on calcium oxalate and calcium excretion in cats (7,8); and from the effects on dietary L-carnitine supplementation on metabolism in cats (4) to the changes in fat-free mass and leptin in hyperthyroid cats before and after treatment (11,18).

Other research studies include the influence of dietary composition on the circulating glucose and insulin response to feeding (9,10) to factors that regulate serum leptin and adiponectin concentrations in dogs and cats (12,20,21,23) and studies of the role of dietary selenium and iodine on nutrition and metabolism (22,31). Finally, this lists also includes a excellent paper on dietary hyperthyroidism in dogs (19) — where we are reminded that not all dogs with thyrotoxicosis have a hyperfunctioning thyroid carcinoma!

2012 Papers on Endocrine Nutrition and Obesity:

1. Becker N, Kienzle E, Dobenecker B. Calcium deficiency: a problem in growing and adult dogs: two case reports. Tierarztl Prax Ausg K Kleintiere Heimtiere 2012;40:135-139. 
2. Butterwick RF, Salt C, Watson TD. Effects of increases in dietary fat intake on plasma lipid and lipoprotein cholesterol concentrations and associated enzyme activities in cats. Am J Vet Res 2012;73:62-67. 
3. Cave NJ, Allan FJ, Schokkenbroek SL, et al. A cross-sectional study to compare changes in the prevalence and risk factors for feline obesity between 1993 and 2007 in New Zealand. Prev Vet Med 2012;107:121-133. 
4. Center SA, Warner KL, Randolph JF, et al. Influence of dietary supplementation with l-carnitine on metabolic rate, fatty acid oxidation, body condition, and weight loss in overweight cats. Am J Vet Res 2012;73:1002-1015. 
5. Clark MH, Hoenig M, Ferguson DC, et al. Pharmacokinetics of pioglitazone in lean and obese cats. J Vet Pharmacol Ther 2012;35:428-436. 
6. Corbee RJ, Tryfonidou MA, Meij BP, et al. Vitamin D status before and after hypophysectomy in dogs with pituitary-dependent hypercortisolism. Domest Anim Endocrinol 2012;42:43-49. 
7. Dijcker JC, Hagen-Plantinga EA, Everts H, et al. Dietary and animal-related factors associated with the rate of urinary oxalate and calcium excretion in dogs and cats. Vet Rec 2012;171:46. 
8. Dijcker JC, Kummeling A, Hagen-Plantinga EA, et al. Urinary oxalate and calcium excretion by dogs and cats diagnosed with calcium oxalate urolithiasis. Vet Rec 2012;171:646. 
9. Elliott KF, Rand JS, Fleeman LM, et al. A diet lower in digestible carbohydrate results in lower postprandial glucose concentrations compared with a traditional canine diabetes diet and an adult maintenance diet in healthy dogs. Res Vet Sci 2012;93:288-295. 
10. Farrow H, Rand JS, Morton JM, et al. Postprandial glycemia in cats fed a moderate carbohydrate meal persists for a median of 12 hours -- female cats have higher peak glucose concentrations. J Feline Med Surg 2012;14:706-705. 
11. Finch NC, Welsh CP, Hibbert A. Changes in fat-free mass (FFM) in cats undergoing radioactive iodine therapy. J Feline Med Surg 2012;14:652-653.
12. German AJ. Barking up the wrong tree: what's the deal with obesity, adiponectin and inflammation in dogs? Vet J 2012;194:272-273.
13. German AJ, Holden SL, Morris PJ, et al. Long-term follow-up after weight management in obese dogs: the role of diet in preventing regain. Vet J 2012;192:65-70. 
14. German AJ, Holden SL, Wiseman-Orr ML, et al. Quality of life is reduced in obese dogs but improves after successful weight loss. Vet J 2012;192:428-434. 
15. Haring T, Haase B, Zini E, et al. Overweight and impaired insulin sensitivity present in growing cats. J Anim Physiol Anim Nutr (Berl) 2012; doi: 10.1111/j.1439-0396.2012.01322.x. 
16. Hoenig M. The cat as a model for human obesity and diabetes. J Diabetes Sci Technol 2012;6:525-533. 
17. Hutchinson D, Freeman LM, McCarthy R, et al. Seizures and severe nutrient deficiencies in a puppy fed a homemade diet. J Am Vet Med Assoc 2012;241:477-483. 
18. Jaillardon L, Burger M, Siliart B. Leptin levels in hyperthyroid cats before and after treatment. Vet Rec 2012;170:155. 
19. Köhler B, Stengel D, Neiger R. Dietary hyperthyroidism in dogs. J Small Anim Pract 2012;53:182-184. 
20. Mazaki-Tovi M, Abood SK, Schenck PA. Effect of omega-3 polyunsaturated fatty acids and body condition on serum concentrations of adipokines in healthy dogs. Am J Vet Res 2012;73:1273-1281. 
21. Ricci R, Bevilacqua F. The potential role of leptin and adiponectin in obesity: a comparative review. Vet J 2012;191:292-298. 
22. Todd SE, Thomas DG, Bosch G, et al. Selenium status in adult cats and dogs fed high levels of dietary inorganic and organic selenium. J Anim Sci 2012;90:2549-2555. 
23. Tvarijonaviciute A, Ceron JJ, Martinez-Subiela S, et al. Serum and urinary adiponectin in dogs with renal disease from leishmaniasis. Vet Rec 2012;171:297. 
24. Tvarijonaviciute A, German AJ, Martinez-Subiela S, et al. Analytical performance of commercially-available assays for feline insulin-like growth factor 1 (IGF-1), adiponectin and ghrelin measurements. J Feline Med Surg 2012;14:138-146. 
25. Tvarijonaviciute A, Ceron JJ, Holden SL, et al. Obesity-related metabolic dysfunction in dogs: a comparison with human metabolic syndrome. BMC Vet Res 2012;8:147. h
26. Tvarijonaviciute A, Tecles F, Martinez-Subiela S, et al. Effect of weight loss on inflammatory biomarkers in obese dogs. Vet J 2012;193570-572. 
27. Tvarijonaviciute A, Ceron JJ, Holden SL, et al. Effects of weight loss in obese cats on biochemical analytes related to inflammation and glucose homeostasis. Domest Anim Endocrinol 2012;42:129-141. 
28. Verbrugghe A, Hesta M, Daminet S, et al. Nutritional modulation of insulin resistance in the true carnivorous cat: a review. Crit Rev Food Sci Nutr 2012;52:172-182. 
29. Verkest KR, Fleeman LM, Morton JM, et al. Association of postprandial serum triglyceride concentration and serum canine pancreatic lipase immunoreactivity in overweight and obese dogs. J Vet Intern Med 2012;26:46-53. 
30. Verkest KR, Rand JS, Fleeman LM, et al. Spontaneously obese dogs exhibit greater postprandial glucose, triglyceride, and insulin concentrations than lean dogs. Domest Anim Endocrinol 2012;42:103-112.
31. Zicker S, B. S. Focus on nutrition: the role of iodine in nutrition and metabolism. Compendium 2012;34:E1-E4. 

Q & A: Calcitriol versus Vitamin D3: What's the Difference?

What is the difference between calcitriol and vitamin D3? They both appear to be 1,25-hydroxycholecalciferol.

How about vitamin D2? It that form active at all in dogs and cats with renal failure?

My Response:

Vitamin D is a fat-soluble vitamin that exists in various forms (1). The chemical structure of vitamin D was established in the early 1930's. The main forms are vitamin D2 (ergocalciferol), found in plants, yeasts and fungi and vitamin D3 (cholecalciferol) of animal origin. Vitamin D2 and D3 are not biologically active; rather, they must be modified in the body to have any effect.

Vitamin D2 or D3 must then be first hydroxylated in the liver and then in the kidneys to become active. At this point, as biologically active 1,25-OH-cholecalciferol (also called calcitriol), this form of vitamin D can exert its endocrine effects (1).

By the early 1970's, it had become clear that calcitriol was the active form of vitamin D. It is over 1,000 times as potent as Vitamin D2 and D3 in binding to the vitamin D receptor.

The sun
Vitamin D has long been considered an essential dietary ingredient, but in several species, including humans, sheep, cattle, horses, and pigs, vitamin D3 can be formed in the skin from a cholesterol metabolite (7-dehydrocholesterol) after exposure to natural sun light.

In dogs and cats, however, this skin production of vitamin D3 does not occur (2), so they are dependent entirely on a dietary source of vitamin D.

Food
Large amounts of vitamin D are not found in adequate amounts in most foods. It’s found in fish, cod liver oil, mushrooms, liver and eggs – but usually not in substantial amounts (except in cod liver oil). Thus, getting enough vitamin D naturally from whole foods is difficult.

Both vitamin D2 and D3 have been commercially synthesized and both forms seem to be effective at maintaining blood levels of vitamin D in the body.

Use of vitamin D in renal disease
In severe renal failure, the kidneys cannot produce adequate amounts of the biologically active vitamin D, and this commonly leads to abnormalities of calcium and phosphorus metabolism (3). Oral administration of active calcitriol to animals with chronic kidney disease helps compensate for the reduced production of the active hormone (4).

It is critical to understand that administration of vitamin D2 and D3 will not work to raise active vitamin D concentrations in these animals with renal disease. Active calcitriol must be used as the form of vitamin D to treat these animals (4).

References

1. Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006;92:4-8.
2. How KL, Hazewinkel HA, Mol JA. Dietary vitamin D dependence of cat and dog due to inadequate cutaneous synthesis of vitamin D. Gen Comp Endocrinol. 1994;96:12-18.
3. Gerber B, Hässig M, Reusch CE. Serum concentrations of 1,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol in clinically normal dogs and dogs with acute and chronic renal failure. Am J Vet Res. 2003;64:1161-1166.
4. Hostutler RA, DiBartola SP, Chew DJ, et al. Comparison of the effects of daily and intermittent-dose calcitriol on serum parathyroid hormone and ionized calcium concentrations in normal cats and cats with chronic renal failure. J Vet Intern Med. 2006;20:1307-1313.