Downloaded from http://veterinaryrecord.bmj.com/ on May 28, 2015 - Published by group.bmj.com
Paper
Paper Prognostic factors for survival in dogs with pituitary-dependent hypercortisolism treated with trilostane F. Fracassi, S. Corradini, D. Floriano, A. Boari, G. Aste, M. Pietra, P. F. Bergamini, F. Dondi Pituitary-dependent hypercortisolism (PDH) is one of the most frequent endocrinopathies in dogs, but prognostic factors are largely unknown. The aim of this retrospective case series study was to determine the prognostic value of different clinical and clinicopathological variables evaluated in dogs newly diagnosed with PDH that were subsequently treated with trilostane. Medical records from one referral centre were evaluated. Eighty-five dogs with PDH were included. The median survival time was 852 days (range 2–3210 days); 60/85 (70 per cent) and 25/85 (29 per cent) dogs survived more than one and three years, respectively. In multivariable model analysis the length of survival of older dogs (HR 1.24, 95% CI 1.09 to 1.40) and dogs with higher serum phosphate concentrations (HR 1.35, 95% CI 1.01 to 1.81) was shorter. Serum phosphate concentrations were above the reference range in 37/85 (44 per cent) of animals. Clinical signs, liver enzymes, serum cortisol concentrations of the endocrine tests, proteinuria, systolic hypertension, the presence of concomitant disorders, and the frequency of trilostane administration were not associated with survival time. Hyperphosphataemia is a common finding in dogs with newly diagnosed PDH and represents a negative prognostic factor.
Introduction
Spontaneously occurring hypercortisolism (HC), or Cushing’s syndrome, is defined as the combination of physical and biochemical changes that result from chronic and pathologically high concentrations of circulating glucocorticoids. In most cases HC is due to inappropriate secretion of adrenocorticotropic hormone (ACTH) from the hypophysis (pituitary dependent-hypercortisolism (PDH)) or is caused by a primary adrenal disorder (adrenal-dependent hypercortisolism (ADH)). PDH accounts for 85 per cent of HC cases (Feldman 1983). An excess of glucocorticoids causes various clinical signs, which are reviewed elsewhere (Feldman and Nelson 2004). The majority of clinical signs have a considerable impact on the animal’s quality of life; this condition is therefore usually treated and there are no studies on the causes of death in a large series of untreated cases. PDH is most commonly treated medically, although surgical options have been published (Hanson and others 2005). The destruction of the adrenal cortex with mitotane (o,p’DDD) has long been the medical treatment of choice for PDH in dogs. Trilostane
(4,5-epoxy-17-hydroxy-3-oxoandrostan-2-carbonitrile), a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase, has gained increasing acceptance in the treatment of dogs with PDH, and its efficacy has been reported in several studies (Neiger and others 2002, Ruckstuhl and others 2002). Although the pathophysiological features, clinical aspects, diagnostic procedures and treatment options for dogs with PDH have been extensively reported, only a few studies (Neiger and others 2002, Barker and others 2005, Perez-Alenza and others 2006, Clemente and others 2007, Hanson and others 2007) have mentioned the life expectancy and/or prognostic factors of the disease in dogs treated with trilostane. Precise data about the outcome and prognostic factors of PDH in dogs would help to characterise the disease better. Therefore, the aim of the present study was to determine the survival time and the prognostic value for survival of different variables retrieved from the history, signalment, physical examination and laboratory evaluations in a population of dogs newly diagnosed with PDH that were subsequently treated with trilostane.
Veterinary Record (2014)
Materials and methods
F. Fracassi, DVM, PhD, DECVIM-CA, S. Corradini, DVM, D. Floriano, DVM, M. Pietra, DVM, P. F. Bergamini, DVM, F. Dondi, DVM, PhD, Department of Veterinary Medical Sciences, University of Bologna, Ozzano dellEmilia, Italy A. Boari, DVM,
doi: 10.1136/vr.102546 G. Aste, DVM, PhD, Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy E-mail for correspondence: [email protected] Provenance Not commissioned; externally peer reviewed Accepted August 11, 2014
Inclusion criteria
The medical records of all dogs with spontaneous HC admitted to the Department of Veterinary Medical Sciences, University of Bologna, Italy, between March 2003 and October 2013 were evaluated. Dogs were included in the study if they had newly diagnosed PDH, had not been treated for HC, were subsequently treated with trilostane, and had follow-up examinations until death or until the last re-evaluation for which records were evaluable. Dogs were excluded if, at diagnosis, the owner declined a complete diagnostic work-up or if the dogs had previously been treated by referring veterinarians. Dogs with ADH were also excluded. January 10, 2015 | Veterinary Record
Downloaded from http://veterinaryrecord.bmj.com/ on May 28, 2015 - Published by group.bmj.com
Paper Dogs were included in the study when clinical and laboratory findings were consistent with HC, the low dose dexamethasone suppression test (LDDST) and/or the ACTH stimulation test were positive for HC, a treatment with trilostane was subsequently carried out, and no other treatments for HC had previously been administered. A diagnosis of PDH or ADH was based on the ultrasonographic appearance of the adrenal glands, the results of the LDDST, and concentrations of endogenous ACTH (Behrend and others 2013).
Medical records review
Data obtained at the time of diagnosis from the medical records comprised breed, gender, bodyweight, age, history, physical examination findings, systolic blood pressure, routine haematology, biochemistry profile, urinalysis including urinary protein:creatinine ratio (UPC), ACTH stimulation test, LDDST, endogenous ACTH concentration, and abdominal ultrasonography. Any concurrent disease diagnosed at initial evaluation and the trilostane treatment dose and regimen (every 24 hours or every 12 hours) were recorded. Date of death or survival of all cases were recorded and entered into the database which was closed on October 15, 2013 before analysis. When necessary, owners and/or referral veterinarians were contacted.
Diagnostic procedures
An ACTH stimulation test and LDDST were performed by injecting intravenous tetracosactide esacetate (Synacthen, Novartis, Origgio, Italy) and dexamethasone (Dexadreson, Intervet, Peschiera Borromeo, Italy), respectively, as previously described (Feldman and Nelson 2004). Blood samples for the determination of endogenous ACTH concentrations were collected from the jugular vein or cephalic vein into EDTA-coated plastic tubes placed on ice. The samples were immediately centrifuged at 4°C, 500g for eight minutes, and plasma was immediately transferred to plastic tubes and stored at −80°C until analysis. Serum cortisol and plasma ACTH concentrations were determined using kits (Immulite cortisol and Immulite ACTH, Diagnostic Product Corporation, Los Angeles, California, USA) that have previously been validated for use in dogs (Singh and others 1997, ScottMoncrieff and others 2003). The reference intervals reported in the present study were obtained from a population of healthy adult dogs (>1 year) of different breeds as described in the Clinical and Laboratory Standards Institute (CLSI) guidelines (Horowitz 2010). Systemic blood pressure measurement was determined by means of either an oscillometric device (BP-88 Next, Colin Corporation, Japan or petMAP graphic, Ramsey Medical, Inc, Tampa, Florida, USA) or by Doppler ultrasonic transducer (Minidop ES-100VX, Hadeco, Japan). The choice of method depended on the dog’s bodyweight: Doppler was employed in dogs
Paper
Paper Prognostic factors for survival in dogs with pituitary-dependent hypercortisolism treated with trilostane F. Fracassi, S. Corradini, D. Floriano, A. Boari, G. Aste, M. Pietra, P. F. Bergamini, F. Dondi Pituitary-dependent hypercortisolism (PDH) is one of the most frequent endocrinopathies in dogs, but prognostic factors are largely unknown. The aim of this retrospective case series study was to determine the prognostic value of different clinical and clinicopathological variables evaluated in dogs newly diagnosed with PDH that were subsequently treated with trilostane. Medical records from one referral centre were evaluated. Eighty-five dogs with PDH were included. The median survival time was 852 days (range 2–3210 days); 60/85 (70 per cent) and 25/85 (29 per cent) dogs survived more than one and three years, respectively. In multivariable model analysis the length of survival of older dogs (HR 1.24, 95% CI 1.09 to 1.40) and dogs with higher serum phosphate concentrations (HR 1.35, 95% CI 1.01 to 1.81) was shorter. Serum phosphate concentrations were above the reference range in 37/85 (44 per cent) of animals. Clinical signs, liver enzymes, serum cortisol concentrations of the endocrine tests, proteinuria, systolic hypertension, the presence of concomitant disorders, and the frequency of trilostane administration were not associated with survival time. Hyperphosphataemia is a common finding in dogs with newly diagnosed PDH and represents a negative prognostic factor.
Introduction
Spontaneously occurring hypercortisolism (HC), or Cushing’s syndrome, is defined as the combination of physical and biochemical changes that result from chronic and pathologically high concentrations of circulating glucocorticoids. In most cases HC is due to inappropriate secretion of adrenocorticotropic hormone (ACTH) from the hypophysis (pituitary dependent-hypercortisolism (PDH)) or is caused by a primary adrenal disorder (adrenal-dependent hypercortisolism (ADH)). PDH accounts for 85 per cent of HC cases (Feldman 1983). An excess of glucocorticoids causes various clinical signs, which are reviewed elsewhere (Feldman and Nelson 2004). The majority of clinical signs have a considerable impact on the animal’s quality of life; this condition is therefore usually treated and there are no studies on the causes of death in a large series of untreated cases. PDH is most commonly treated medically, although surgical options have been published (Hanson and others 2005). The destruction of the adrenal cortex with mitotane (o,p’DDD) has long been the medical treatment of choice for PDH in dogs. Trilostane
(4,5-epoxy-17-hydroxy-3-oxoandrostan-2-carbonitrile), a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase, has gained increasing acceptance in the treatment of dogs with PDH, and its efficacy has been reported in several studies (Neiger and others 2002, Ruckstuhl and others 2002). Although the pathophysiological features, clinical aspects, diagnostic procedures and treatment options for dogs with PDH have been extensively reported, only a few studies (Neiger and others 2002, Barker and others 2005, Perez-Alenza and others 2006, Clemente and others 2007, Hanson and others 2007) have mentioned the life expectancy and/or prognostic factors of the disease in dogs treated with trilostane. Precise data about the outcome and prognostic factors of PDH in dogs would help to characterise the disease better. Therefore, the aim of the present study was to determine the survival time and the prognostic value for survival of different variables retrieved from the history, signalment, physical examination and laboratory evaluations in a population of dogs newly diagnosed with PDH that were subsequently treated with trilostane.
Veterinary Record (2014)
Materials and methods
F. Fracassi, DVM, PhD, DECVIM-CA, S. Corradini, DVM, D. Floriano, DVM, M. Pietra, DVM, P. F. Bergamini, DVM, F. Dondi, DVM, PhD, Department of Veterinary Medical Sciences, University of Bologna, Ozzano dellEmilia, Italy A. Boari, DVM,
doi: 10.1136/vr.102546 G. Aste, DVM, PhD, Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy E-mail for correspondence: [email protected] Provenance Not commissioned; externally peer reviewed Accepted August 11, 2014
Inclusion criteria
The medical records of all dogs with spontaneous HC admitted to the Department of Veterinary Medical Sciences, University of Bologna, Italy, between March 2003 and October 2013 were evaluated. Dogs were included in the study if they had newly diagnosed PDH, had not been treated for HC, were subsequently treated with trilostane, and had follow-up examinations until death or until the last re-evaluation for which records were evaluable. Dogs were excluded if, at diagnosis, the owner declined a complete diagnostic work-up or if the dogs had previously been treated by referring veterinarians. Dogs with ADH were also excluded. January 10, 2015 | Veterinary Record
Downloaded from http://veterinaryrecord.bmj.com/ on May 28, 2015 - Published by group.bmj.com
Paper Dogs were included in the study when clinical and laboratory findings were consistent with HC, the low dose dexamethasone suppression test (LDDST) and/or the ACTH stimulation test were positive for HC, a treatment with trilostane was subsequently carried out, and no other treatments for HC had previously been administered. A diagnosis of PDH or ADH was based on the ultrasonographic appearance of the adrenal glands, the results of the LDDST, and concentrations of endogenous ACTH (Behrend and others 2013).
Medical records review
Data obtained at the time of diagnosis from the medical records comprised breed, gender, bodyweight, age, history, physical examination findings, systolic blood pressure, routine haematology, biochemistry profile, urinalysis including urinary protein:creatinine ratio (UPC), ACTH stimulation test, LDDST, endogenous ACTH concentration, and abdominal ultrasonography. Any concurrent disease diagnosed at initial evaluation and the trilostane treatment dose and regimen (every 24 hours or every 12 hours) were recorded. Date of death or survival of all cases were recorded and entered into the database which was closed on October 15, 2013 before analysis. When necessary, owners and/or referral veterinarians were contacted.
Diagnostic procedures
An ACTH stimulation test and LDDST were performed by injecting intravenous tetracosactide esacetate (Synacthen, Novartis, Origgio, Italy) and dexamethasone (Dexadreson, Intervet, Peschiera Borromeo, Italy), respectively, as previously described (Feldman and Nelson 2004). Blood samples for the determination of endogenous ACTH concentrations were collected from the jugular vein or cephalic vein into EDTA-coated plastic tubes placed on ice. The samples were immediately centrifuged at 4°C, 500g for eight minutes, and plasma was immediately transferred to plastic tubes and stored at −80°C until analysis. Serum cortisol and plasma ACTH concentrations were determined using kits (Immulite cortisol and Immulite ACTH, Diagnostic Product Corporation, Los Angeles, California, USA) that have previously been validated for use in dogs (Singh and others 1997, ScottMoncrieff and others 2003). The reference intervals reported in the present study were obtained from a population of healthy adult dogs (>1 year) of different breeds as described in the Clinical and Laboratory Standards Institute (CLSI) guidelines (Horowitz 2010). Systemic blood pressure measurement was determined by means of either an oscillometric device (BP-88 Next, Colin Corporation, Japan or petMAP graphic, Ramsey Medical, Inc, Tampa, Florida, USA) or by Doppler ultrasonic transducer (Minidop ES-100VX, Hadeco, Japan). The choice of method depended on the dog’s bodyweight: Doppler was employed in dogs
