Cushing's Disease in Cavalier King Charles Spaniels
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The cavalier King Charles spaniel is at increased risk for Cushing's disease, also known as Cushing's syndrome or hyperadrenocorticism. It is a serious, genetic disorder which produces excess hormones from the adrenal glands. If not promptly treated, it can lead to life-threatening disorders.
The adrenal glands produce hormones which help regulate weight, mineral balance, the structure of connective tissue, some white blood cell production, and skin health.
Cushing's disease is caused by either an adrenal cortical tumor (a tumor of the cortisol-producing cells of the adrenal gland) or pituitary tumors (which produce excessive amounts of ACTH -- adrenocorticotrophic hormone, the hormone which causes the adrenal glands to produce cortisol), with the result that an excess of cortisol is released in the cavalier's body. These tumors are, of course, forms of cancer.
Symptoms include excessive drinking (polydipsia) and urination (polyuria), increased appetite (polyphagia), panting, symmetrical hair loss (alopecia), hard, calcified lumps in the skin (calcinosis cutis) and discoloration, lethargy, muscle weakness, and susceptibility to skin and urinary infections. Victims also develop bulging, sagging bellies, due to decreased muscle strength and the redistribution of fat from body storage areas to the abdomen. Left untreated, Cushing's disease can lead to life-threatening disorders such as diabetes, congestive heart failure, and liver and kidney failure, and to chronic problems of hypothyroidism, and infections of the skin, ears, gums, eyes, or bladder.
In a 1993 report, Dr. Shiela Crispin found that, especially in the cavalier King Charles spaniel, crystalline stromal dystrophy due to hyperlipoproteinaemmia (raised HDL, LDL, and VLDL) is an ocular manifestation of Cushing's syndrome. (The photo at right, from Dr. Crispin's 1993 report, shows the eye of a cavalier with crystalline stromal dystrophy secondary to hyperlipoproteinaemia associated with Cushing’s syndome. The right eye is shown and the lipid is situated immediately lateral to the camera flash.)
Cushing's disease can be diagnosed by laboratory tests of blood and urine, including a urine cortisol / creatinine ratio test (UCCR), an ACTH stimulation test, and low and high dose dexamethasone suppression (LDDS) tests. Once diagnosed, tests can also determine if it is caused by pituitary gland tumors or an adrenal gland tumor.
In two 2013 studies of dog hair specimens, both panels of researchers found that the level of cortisol in dogs' hair is much higher when the dogs have hyperadrenocorticism. In the first 2013 report, a team of Austrian researchers stated: "Measuring cortisol in hair is so much easier and less painful to the animal than other tests for the disease and we think it has real promise for use as a rapid and non-invasive method to diagnose hyperadrenocorticism." In the second 2013 study, Italian researchers found that hair cortisol concentrations are higher in dogs with Cushings, compared to sick control dogs and healthy dogs. They stated: "It is a noninvasive technique that should be further investigated as a possible diagnostic procedure for the diagnosis of HC [hypercortisolism] in dogs."
Surgery can cure an adrenal cortical tumor that has not spread to other areas of the body. However, about half of adrenal tumors are malignant and may have already spread. Pituitary Cushing's disease cannot be cured, but the treatment can prolong the cavalier's quality of life, but not to increase the lifespan. Drug therapies include lysodren (Mitotane), ketoconazole (Nizoral), anipryl (Deprenyl, Eldepryl, Selegiline, and trilostane (Modrenal, Vetoryl).
Ketoconazole, an antifungal, inhibits P-glycoprotein, the important drug efflux transporter in the GI tract, kidney(s), biliary tree, and brain. Therefore, ketoconazole can decrease the bioavailability and/or clearance of many drugs. For example, ketoconazole increases blood cyclosporine concentrations, which can allow lower therapeutic doses of cyclosporine. Ketoconazole also can as much as double ivermectin exposure in dogs. See this June 2013 report.
Trilostane reportedly can cause serum potassium levels to become elevated. Therefore, trilostane should be used with caution with ACE-inhibitors and spironolactone, drugs customarily prescrbed for dogs in advanced stages of mitral valve disease. See this September 2014 article.
There are conflicting reports regarding whether lysodren (Mitotane) may induce hypoadrenocorticism (Addison's disease) in cavaliers. Compare this 2005 report with this 2008 powerpoint presentation, both submitted by Michael E. Herrtage.
Cavaliers diagnosed with Cushing's, or otherwise determined to be pre-disposed to it, should not be bred. Any littermates of breeding stock having Cushing's disease should be taken into consideration. The Canine Inherited Disorders Database advises to breed only dogs from families with no history of the disorder. Any cavalier King Charles spaniel intended to be bred should be blood tested for Cushing's disease at least annually, the closer the examination to the breeding the better.
November 2013: ACVIM issues a Consensus Statement on diagnosis of spontaneous canine hyperadrenocorticism. The ACVIM has published a Consensus Statement on the diagnosis of Cushing's Disease (hyperadrenocorticism). In summary, it states:
"Endocrine tests should be performed only when clinical signs consistent with HAC are present. None of the biochemical screening or differentiating tests for hyperadrenocorticism are perfect. Imaging can also play a role. Awareness of hyperadrenocorticism has heightened over time. Thus, case presentation is more subtle. Due to the changes in manifestations as well as test technology the Panel believes that references ranges should be reestablished. The role of cortisol precursors and sex hormones in causing a syndrome of occult hyperadrenocorticism remains unclear."
July 2013: Italian researchers also conclude that hair cortisol concentrations are higher in dogs with Cushing's. A panel of Italian researchers compared corticsol concentrations in the hair of dogs with and without hypercortisolism (Cushing's disease). In their July 2013 study, they found that hair cortisol concentrations are higher in dogs with Cushings, compared to sick control dogs and healthy dogs. They state: "It is a noninvasive technique that should be further investigated as a possible diagnostic procedure for the diagnosis of HC [hypercortisolism] in dogs."
July 2013: Austrian researchers find dog hair samples indicate higher levels of cortisol in dogs with Cushing's disease. In an August 2013 study by researchers (Claudia Ouschan, Alexandra Kuchar, Erich Möst) at the University of Veterinary Medicine, Vienna, they found that the level of cortisol in dogs' hair is much higher when the dogs have hyperadrenocorticism. They stated: "Measuring cortisol in hair is so much easier and less painful to the animal than other tests for the disease and we think it has real promise for use as a rapid and non-invasive method to diagnose hyperadrenocorticism."
July 2012: Texas A&M researchers find compounded trilostane may be defective. In a July 2012 report, a team of researchers from Texas A&M University (Audrey K. Cook, Cornelia D. Nieuwoudt, and Susan L. Longhofer) evaluated 96 batches of compounded trilostane products from eight pharmacies. They found a wide variablity in actual drug content, compared to the labels' claims. They determined that the defective products may compromise effective management of patients being treated for hyperadrenocorticism.
Ocular manifestations of hyperlipoproteinaemia. S. M. Crispin. J.Small Animal Prac.;Oct. 1993;34(10):500-506. Quote: "The ocular manifestations of hyperlipoproteinaemia include visible lipaemia of ocular blood vessels, corneal opacities, lipaemic aqueous and gross infiltration of the globe itself which is easiest to observe in the peripheral cornea and uveal tract. Both primary and secondary hyperlipoproteinaemia may produce ocular signs and the ocular appearance can be characteristic of the underlying lipoprotein disorder. ... Crystalline stromal dystrophy in a Cavalier King Charles spaniel with secondary hyperlipoproteinaemia associated with Cushing’s syndome. ... Crystalline stromal dystrophy [due to] Hyperlipoproteinaemmia (raised HDL, LDL, and VLDL) [is an] ocular manifestation [of the] clinical disorder Cushing's syndrome especially in the Cavalier King Charles Spaniel.
Control of Canine Genetic Diseases. Padgett, G.A., Howell Book House 1998, pp. 198-199, 222.
A Comparison of the Survival Times of Dogs Treated with Mitotaneor Trilostane for Pituitary-Dependent Hyperadrenocorticism. E.N. Barker, S. Campbell, A.J. Tebb, R. Neiger, M.E. Herrtage, S.W.J. Reid, and I.K. Ramsey. J Vet Intern Med; 2005;19:810–815. Quote: "The survival times of 148 dogs [including 6 cavalier King Charles spaniels] treated for pituitary-dependent hyperadrenocorticism were studied using clinical records from 3UK veterinary centers between 1998 and 2003. Of these animals, 123 (83.1%) were treated with trilostane, while 25 (16.9%) weretreated with mitotane. Treatment groups were compared using t-tests and analysis of variance (or their nonparametric equivalents)and chi-square tests. Survival data were analyzed using Kaplan-Meier survival plots and Cox proportional hazard methods. Therewas no signiﬁcant difference between the population attributes from each center or between treatment groups. The median survival time for animals treated with trilostane was 662 days (range 8–1,971) and for mitotane it was 708 days (range 33–1,399). There were no signiﬁcant differences between the survival times for animals treated with trilostane and those treated with mitotane. In the multivariable model (including drug, center, breed group, weight, diagnostic group, and age at diagnosis), only age at diagnosis and weight were signiﬁcantly negatively associated with survival. Importantly, there was no signiﬁcant effect of drug choice on survival."
Diagnosis and Management of Hypoadrenocorticism. Michael E. Herrtage. 2008. Quote: "Mitotane-induced hypoadrenocorticism: breed incidence: higher in Scottish terrier, Cavalier King Charles spaniel, Cocker spaniel, Springer spaniel, and Yorkshire terrier. Age range: range 4 - 10 years; mean 8.4 years."
Use of Computed Tomography Adrenal Gland Measurement for Differentiating ACTH Dependence from ACTH Independence in 64 Dogs with Hyperadenocorticism. M.I. Rodríguez Piñeiro, P. de Fornel-Thibaud, G. Benchekroun, F. Garnier, C. Maurey-Guenec, F. Delisle, D. Rosenberg. J Vet Int Med Sept 2011; 25(5):1066-1074. Quote: "The measurement of adrenal gland size on computed tomography (CT) scan has been proposed for the etiological diagnosis of hyperadrenocorticism (HAC) in dogs. Symmetric adrenal glands are considered to provide evidence for ACTH-dependent hyperadrenocorticism (ADHAC), whereas asymmetry suggests ACTH-independent hyperadrenocorticism (AIHAC). However, there are currently no validated criteria for such differentiation. Objective: The aim of this retrospective study was to compare various adrenal CT scan measurements and the derived ratios in ADHAC and AIHAC cases, and to validate criteria for distinguishing between these conditions in a large cohort of dogs. Results: An overlap was systematically observed between the AIHAC and ADHAC groups for all measurements tested. Overlaps also were observed for ratios tested. For the maximum adrenal diameter ratio derived from reformatted images (rADR), only 1/18 AIHAC dogs had a rADR within the range for ADHAC. For a threshold of 2.08, the 95% confidence intervals for estimated sensitivity and specificity extended from 0.815 to 1.000 and from 0.885 to 0.999, respectively, for AIHAC diagnosis. Conclusion and Clinical Importance: Measurements from cross-sectional or reformatted CT scans are of little use for determining the origin of HAC. However, rADR appears to distinguish accurately between ADHAC and AIHAC, with a rADR > 2.08 highly suggestive of AIHAC."
Pharmaceutical Evaluation of Compounded Trilostane Products. Audrey K. Cook, Cornelia D. Nieuwoudt, and Susan L. Longhofer. J Am Anim Hosp Assoc. Jul/Aug 2012;48(4):228-233. Quote: "Compounded trilostane capsules (15 mg, 45 mg, or 100 mg) were purchased from eight pharmacies and assayed for content and dissolution characteristics. Capsules made in-house containing either inert material or 15 mg of the licensed product and proprietary capsules (30 mg and 60 mg) served as controls. Findings were compared with regulatory specifications for the licensed product. Altogether, 96 batches of compounded trilostane and 16 control batches underwent analysis. In total, 36 of 96 (38%) compounded batches were below the acceptance criteria for content. The average percentage label claim (% LC) for each batch ranged from 39% to 152.6% (mean, 97.0%). The range of average % LC for the controls was 96.1–99.6% (mean, 97.7%). The variance in content of the purchased compounded products was substantially greater than for the controls (234.65 versus 1.27; P<0.0001). All control batches exceeded the acceptance criteria for dissolution, but 19 of 96 batches (20%) of purchased compounded products did not. Mean percent dissolution for the purchased compounded products was lower than for controls (75.96% versus 85.12%; P=0.013). These findings indicate that trilostane content of compounded capsules may vary from the prescribed strength, and dissolution characteristics may not match those of the licensed product. The use of compounded trilostane products may therefore negatively impact the management of dogs with hyperadrenocorticism."
Applied Dermatology: Old or New? A Comparison of Mitotane and Trilostane for the Management of Hyperadrenocorticism. Joel D. Griffies. Compendium. May 2013; 35(5). Quote: "Hyperadrenocorticism (HAC) is a common endocrinopathy in dogs. With better recognition of the disease, more cases are being presented to clinicians for management. Mitotane, a 3- to 4-decade-old therapy, remains a viable and useful option for management of this disease. Thorough education and understanding of the drug are important, however, as the learning curve of how to manage its effects can be significant. Trilostane, a newer option for management of HAC, offers a simplified protocol and, often, smoother and faster control of the disease. ... Both mitotane and trilostane are useful tools in the management of an often insidious chronic disease. While both have pros and cons, the clinician’s comfort level, experience, and understanding of each drug are probably the most important features in deciding which to choose. With proper drug therapy, patient follow-up, and client communication, successful management of HAC can result in significantly improved quality of life for the patient and the owner."
Drug Interactions in Polypharmacy. Lauren A. Trepanier. Clinician's Brief. June 2013:23-26.
Measurement of cortisol in dog hair: a noninvasive tool for the diagnosis of hypercortisolism. Claudia Ouschan, Alexandra Kuchar, Erich Möst. Vet.Dermatology. August 2013;24(4):428-e94. Summary: "As the hormones are known to be present in hair, at least in humans, Ouschan reasoned that measuring glucocorticoid concentrations in dog hair might represent a way of diagnosing Cushing’s disease without causing the animals unnecessary distress. She thus compared the levels of cortisol, corticosterone and cortisone in the hair of twelve dogs with hyperadrenocorticism and ten healthy dogs. The results were striking: all three hormones were found at far higher levels in the hair of dogs with Cushing’s disease than in the control group, with the increase in cortisol particularly pronounced. The importance of the finding is clear. As Ouschan says, 'we have shown that the level of cortisol in dogs’ hair is much higher when the animals have hyperadrenocorticism. Measuring cortisol in hair is so much easier and less painful to the animal than other tests for the disease and we think it has real promise for use as a rapid and non-invasive method to diagnose hyperadrenocorticism.'"
Evaluation of Hair Cortisol in the Diagnosis of Hypercortisolism in Dogs. S. Corradini, P.A. Accorsi, A. Boari, V. Beghelli, M. Mattioli, P. Famigli-Bergamini, F. Fracassi. J.Vet.Int.Med. July 2013. Quote: "Background: Measurement of hair cortisol is a noninvasive technique used for several purposes in humans and in animals. Objectives: To measure hair cortisol concentrations (HCC) in dogs with spontaneous hypercortisolism (HC) and determine whether it can represent a useful diagnostic test for this syndrome. Animals: Twenty-two dogs with spontaneous HC before treatment, 28 sick control dogs (SCD), and 40 healthy dogs. Methods: In this prospective, observational clinical study, the HCC was measured by an RIA assay after extraction in HC dogs, in dogs with other chronic diseases, and in healthy dogs. The diagnostic accuracy of HCC was evaluated by subjecting data from dogs with HC and dogs with other chronic diseases to receiver operating characteristic (ROC) curve analysis. Results: Median (range) cortisol concentration in dogs with HC was 4.53 pg/mg (0.32–74.62 pg/mg) and was significantly higher than in SCD (1.49 pg/mg, 0.13–14.19 pg/mg) and healthy dogs (1.28 pg/mg, 0.34–5.38 pg/mg). Within the 3 groups, there was a large overlap of HCC. The area under the ROC curve was 0.80 (95% CI: 0.67–0.92). A cut-off value of HCC of 1.93 pg/mg revealed 91% sensitivity and 61% specificity to diagnose HC. Conclusions and Clinical Importance: Hair cortisol concentrations are higher in dogs with HC compared to SCD and healthy dogs. It is a noninvasive technique that should be further investigated as a possible diagnostic procedure for the diagnosis of HC in dogs."
Diagnosis of Spontaneous Canine Hyperadrenocorticism: 2012 ACVIM Consensus Statement (Small Animal). E.N. Behrend, H.S. Kooistra, R. Nelson, C.E. Reusch and J.C. Scott-Moncrieff. J.Vet.Int.Med. Nov. 2013;27(6):1292-1304. Quote: "This report offers a consensus opinion on the diagnosis of spontaneous canine hyperadrenocorticism. The possibility that a patient has hyperadrenocorticism is based on the history and physical examination. Endocrine tests should be performed only when clinical signs consistent with HAC are present. None of the biochemical screening or differentiating tests for hyperadrenocorticism are perfect. Imaging can also play a role. Awareness of hyperadrenocorticism has heightened over time. Thus, case presentation is more subtle. Due to the changes in manifestations as well as test technology the Panel believes that references ranges should be reestablished. The role of cortisol precursors and sex hormones in causing a syndrome of occult hyperadrenocorticism remains unclear."
Inoculation of dogs with a recombinant ACTH vaccine. Robert J. Kemppainen. Am.J.Vet.Research. Dec. 2013;74(12):1499-1505. Quote: "Objective: To determine whether inoculation of healthy dogs with a recombinant peptide containing 3 copies of ACTH would result in the production of antibodies against ACTH and whether this would affect pituitary-adrenocortical function. Animals: 8 healthy dogs. Procedures: A recombinant peptide consisting of 3 copies of ACTH fused to a T-helper cell epitope was produced in Escherichia coli. The protein was inoculated into 4 dogs at 4-week intervals (total of 3 inoculations/dog). Four control dogs received inoculations of PBS solution mixed with adjuvant. Blood samples were collected for determination of antibody titers against ACTH and for measurement of basal and ACTH-stimulated plasma cortisol concentrations. Results: Inoculation with the ACTH vaccine resulted in production of anti-ACTH antibodies in all 4 dogs. Titers were initially high but declined by 15 weeks after the initial inoculation. Basal cortisol concentrations were unaffected by inoculation with the ACTH vaccine. Plasma cortisol concentrations in response to ACTH stimulation were reduced at 12 weeks, but not at 15 weeks, after the first inoculation. Conclusions and Clinical Relevance: Inoculation of dogs with a recombinant ACTH vaccine resulted in the production of antibodies against the hormone. Anti-ACTH titers were initially high but were not sustained. The only detectable endocrine effect in treated dogs was a reduction in cortisol concentration in response to ACTH stimulation in 2 of 4 dogs at 12 weeks after the first inoculation. The effect of vaccine administration on the pituitary-adrenal system was subtle and transient."
Canine Cushing’s Syndrome: Some Old but Everything New. Mark E. Peterson. The Animal Endocrine Clinic;NAVC. 2014.
Trilostane for the Treatment of Hyperadrenocorticism: Things Learned Over the Past 10 Years. Doug Brum. MSPCA-Angell. September 2014. Quote: "It is extremely common for serum potassium levels to be elevated when using Trilostane. In fact, you should expect mild to moderate elevations. Given its mechanism of action, this should not be surprising. Trilostane should be used with caution with anti-aldosterone drugs (e.g. ACE inhibitors, spironolactone). Occasionally, one will need to change to a different medication if the potassium rises too high."