Hyperadrenocorticism is characterized by chronically elevated circulating concentrations of the steroid hormones produced by the adrenal cortex and is a common endocrine disorder in dogs.1,2 Current treatments for dogs with PDH include a group of clinically evaluated drugs, only some of which effectively control the disorder.3–22 Two medications that are commonly used to treat dogs with PDH are mitotane (o,p'-DDD [1,1-dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl) ethane]) and trilostane.3–16 Ketoconazole, cyproheptadine, aminoglutethimide, and L-deprenyl are used for treatment, but studies17–22 in which the effectiveness of these drugs has been evaluated are limited and incomplete.
The imidazole derivative ketoconazole is often used as an antifungal agent in dogs.1,2,17,19 Ketoconazole also inhibits synthesis of steroid hormones by the gonads and adrenal glands by interfering with the activities of cytochrome P-450–dependent enzymes in the adrenal cortex.2,17,23,24 Among the drugs used to treat dogs with hyperadrenocorticism, ketoconazole is the only one legally available for veterinary use in Taiwan. The purpose of the study reported here was to evaluate the effects of ketoconazole in the treatment of dogs with PDH.
Materials and Methods
Case selection—Medical records of dogs in which PDH was diagnosed at the National Taiwan University Veterinary Hospital from 1994 through 2007 were reviewed.
Medical records review—Data obtained from the records included breed, sex, body weight, age at diagnosis, clinical signs, serum activities of ALP and ALT, findings of abdominal ultrasonographic evaluations, results of ACTH stimulation tests (before and after ketoconazole treatment), dosage of ketoconazole, clinical response, and survival time.
Inclusion criteria were evidence of clinical signs consistent with a diagnosis of PDH (eg, polydipsia, polyuria, polyphagia, decreased activity, panting, a potbellied appearance, and dermatologic problems), results of routine serum biochemical analyses that were consistent with a diagnosis of PDH (ie, elevated activities of hepatic enzymes), and results of ACTH stimulation tests and abdominal ultrasonographic evaluations that were consistent with a diagnosis of PDH. Dogs with inconclusive results of ACTH stimulation tests were excluded from the study. To rule out the possibility of hyperadrenocorticism attributable to an adrenal tumor, dogs were excluded when abdominal ultrasonography revealed adrenal glands with a nodular (or mass) appearance and hyperechoic foci.
All included dogs were required to have had an ACTH stimulation test with synthetic ACTHa (0.25 mg, IM) prior to treatment with ketoconazole. Blood samples for detection of serum cortisol concentrations were collected via cephalic venipuncture immediately before and 1 hour after synthetic ACTH was injected.1,2 Serum cortisol concentrations were measured by use of a validated radioimmunoassay.b
Ketoconazole treatment—Ketoconazolec was administered PO at a dosage of 5 to 25 mg/kg (2.3 to 11.4 mg/lb) every 12 hours for the remaining lifetime of each dog. During treatment, clinical signs of PDH were recorded periodically every 2 to 16 weeks. Any adverse effects of ketoconazole treatment were also recorded. Adrenal gland function was reevaluated by means of an ACTH simulation test administered 1 to 5 months after commencement of ketoconazole treatment, the timing of which was influenced by the condition of the dog and the compliance of the owner.
Statistical analysis—Comparisons of pretreatment and posttreatment serum cortisol concentrations and ALP and ALT activities were performed by means of repeated-measures ANOVAs. Associations between serum cortisol concentration after treatment with ketoconazole and improvement of polydipsia, polyuria, and exercise endurance as well as the detection of adverse reactions to ketoconazole were evaluated by means of ANOVA. A Kaplan-Meier survival curve was plotted. Data for dogs that were alive at the conclusion of the study were censored. Variables that might have influenced survival time were analyzed by use of a Cox proportional hazard model. Such variables included sex and age at diagnosis; serum ALP and ALT activities; serum cortisol concentrations after ACTH stimulation and prior to treatment with ketoconazole; improvement in polydipsia, polyuria, and exercise endurance after treatment; improvement of serum ALP and ALT activities after treatment; improvement of serum cortisol concentration after ACTH stimulation and after treatment; and adverse reactions attributed to ketoconazole. All statistical analyses were performed by means of commercially available software.d Continuous data are presented as mean ± SD. Statistical significance was set at P ≤ 0.05.
Results
Records of 568 dogs with clinical signs of PDH and results of ACTH stimulation tests consistent with hyperadrenocorticism were screened. Only 178 of these records included results from an ACTH stimulation reevaluation; however, 67 dogs lacked ultrasonographic evidence of PDH, and 63 dogs had only 1 ACTH stimulation test after ketoconazole treatment. Therefore, only 48 dogs were included in the study.
Breeds of the 48 included dogs were Maltese Terrier (n = 9), mixed breed (9), Pomeranian (6), Toy Poodle (6), Shih Tzu (4), Miniature Dachshund (3), Miniature Pinscher (3), Yorkshire Terrier (2), Beagle (1), Chihuahua (1), Japanese Spitz (1), Miniature Schnauzer (1), Pekinese (1), and Pug (1). Dogs ranged in age from 5 to 14 years (mean ± SD, 9.8 ± 2.3 years; median, 10 years). There were 17 sexually intact males, 13 sexually intact females, 10 spayed females, and 8 castrated males. No sex predilection for PDH was evident. Owners of the 13 sexually intact female dogs were advised to have the dogs spayed to reduce the risk of diabetes mellitus or improve control of blood sugar concentrations in dogs with concurrent diabetes mellitus.
The most common clinical signs of PDH recorded upon initial admission to the hospital were polydipsia (n = 45 [94%]), polyuria (44 [92%]), polyphagia (42 [88%]), poor activity and panting (41 [85%]), a potbellied appearance (38 [79%]), and dermatologic problems (36 [75%]). Thirty-seven (77%) dogs had cardiac murmurs at the initial admission; subsequent manifestations of heart failure developed in 40 (83%) dogs. Eleven (23%) dogs had concurrent diabetes mellitus, and 2 (4%) had demodicosis.
Adrenal gland function before ketoconazole treatment—In response to ACTH stimulation tests performed at admission, all 48 dogs had serum cortisol concentrations that exceeded the upper reference limit (reference range, 0.5 to 3.0 μg/dL). Mean serum cortisol concentration before ACTH administration was 4.3 ± 2.1 μg/dL (median, 3.5 μg/dL); that for after ACTH administration was 28.4 ± 11.5 μg/dL (median, 24.2 μg/dL; value for diagnosis of hyperadrenocorticism, > 16 μg/dL; Figure 1).
Activities of hepatic enzymes before ketoconazole treatment—Serum ALP and ALT activities were above reference ranges (21 to 219 U/L and 20 to 123 U/L, respectively) in 43 (90%) and 29 (60%) dogs, respectively. Mean serum ALP activity was 2,076 ± 1,780 U/L (median, 2,089 U/L), and mean serum ALT activity was 366 ± 615 U/L (median, 171 U/L).
Effects of ketoconazole treatment on clinical signs—Median dose of ketoconazole was 12.5 mg/kg (5.7 mg/lb), PO, every 12 hours. Evidence of clinical improvement following initiation of treatment with ketoconazole was detected in 43 of 48 (90%) dogs. Improvement generally became evident within 2 months after the start of treatment. Specifically, 40 of 44 (91%) dogs had alleviation of polyuria, 38 of 42 (90%) had alleviation of polyphagia, 40 of 45 (90%) had alleviation of polydipsia, 29 of 41 (71%) had improved exercise endurance and reduced panting, 17 of 36 (47%) had fewer dermatologic problems, and 9 of 38 (24%) dogs had a reduction in potbellied appearance.
Effects of ketoconazole treatment on adrenal gland function—The first reevaluation of adrenal gland function was carried out 3 months (median) after treatment with ketoconazole began. At that time, the mean serum cortisol concentration before the ACTH stimulation test was performed was 1.4 ± 1.3 μg/dL (median, 1.1 μg/dL), and the mean serum cortisol concentration after ACTH was administered was 10.0 ± 8.2 μg/dL (median, 7.7 μg/dL). Reduced excretion of cortisol by the adrenal glands was evident in all 48 dogs. After ACTH was administered, serum cortisol concentrations decreased to values within the therapeutic range (ie, < 10 μg/dL) in 33 (69%) dogs.
A second reevaluation of adrenal gland function was performed in 48 dogs at 5 months (median) after the first reevaluation (Figure 1). At that time, the mean serum cortisol concentration before the ACTH stimulation test was performed was 1.2 ± 1.2 μg/dL (median, 0.9 μg/dL), and the mean serum cortisol concentration after ACTH was administered was 9.7 ± 5.6 μg/dL (median, 8.2 μg/dL). Reduced excretion of cortisol by the adrenal glands was evident in all 48 dogs. In 33 (69%) dogs, serum cortisol concentration after the ACTH stimulation test decreased to a value within the therapeutic range (< 10 μg/dL). Treatment with ketoconazole significantly decreased serum cortisol concentrations measured before (P < 0.001) and after (P = 0.002) ACTH was administered.
Effects of ketoconazole treatment on activities of hepatic enzymes—Treatment of dogs with ketoconazole resulted in a significant (P < 0.001) decrease in serum ALP activity in 38 of 43 (88%) dogs to 455 ± 713 U/L (median, 169 U/L), compared with the mean pretreatment value. Of the 43 dogs, 23 (53%) had ALP activities that were reduced to within the reference range. Similarly, treatment resulted in a significant (P = 0.003) decrease in serum ALT activity in 23 of 29 (79%) dogs to 129 ± 117 U/L (median, 100 U/L). Reductions in serum ALT activity to within the reference range were evident in 15 of the 29 (52%) dogs. Improvements in polyuria, polydipsia, exercise intolerance, and serum ALT and ALP activities were not associated with posttreatment serum cortisol concentration measured after the ACTH stimulation test.
Adverse effects of ketoconazole treatment—The most common adverse effects of ketoconazole treatment in the 48 dogs were anorexia (n = 32 [67%]), vomiting (14 [29%]), and diarrhea (5 [10%]). The adverse reactions were transient in most dogs and could be resolved by administering ketoconazole with food or temporarily reducing the dosage by 25% for 1 to 2 days. Generally, these adverse effects were tolerated by the dogs and considered acceptable by their owners.
Markedly increased serum ALT activities (> 1,000 U/L) were evident in only 3 (6%) dogs (a neutered male Maltese, a spayed female Shih Tzu, and a neutered male Shih Tzu) at dosages of ketoconazole that exceeded 7.5 mg/kg (3.4 mg/lb) every 12 hours. Ultrasonographic examination of these 3 dogs revealed hepatic abnormalities, characterized by nodular heteroechogenicity near the end of the dogs' lives. These abnormal findings had not been detected via ultrasonography performed at the time that PDH was diagnosed. The suggestion of liver biopsy was declined by the owners of these dogs. In the affected dogs, the high serum ALT activity decreased and remained within the reference range when the dosage of ketoconazole was maintained in the range of 5 to 7.5 mg/kg every 12 hours.
After treatment with ketoconazole, 3 (6%) dogs had a serum cortisol concentration before ACTH stimulation testing that was lower than the reference range and a value after ACTH was administered that was within the reference range. The lowest serum cortisol concentration after ACTH was administered was 2.1 μg/dL, and this result was for a dog that had been treated with the highest dosage of ketoconazole (22 mg/kg [10 mg/ lb], q 12 h) for nearly 37 months. Results of follow-up ACTH stimulation tests and assessments of clinical signs indicated that iatrogenic hypoadrenocorticism did not develop in that dog.
Outcome—Clinical improvement was evident in 43 of 48 (90%) dogs with PDH after treatment with ketoconazole, and 33 (69%) had a serum cortisol concentration after ACTH was administered that had decreased to a value within the reference range. Forty (83%) dogs were stable in terms of clinical status, activities of hepatic enzymes, and results of ACTH stimulation tests while being maintained on a constant dosage throughout the rest of their lives. The dosage was adjusted within a narrow range (2 mg/kg [0.9 mg/lb], q 12 h) in some dogs as needed on the basis of clinical signs, results of ACTH stimulation tests, and adverse reactions. Of the 48 treated dogs, 7 were still alive at the conclusion of the study, and data regarding these dogs were censored from the survival analysis. Mean survival time after time of diagnosis was 26.9 months (range, 2 to 61 months; median, 25 months; 95% confidence interval, 24.3 to 34.5 months; Figure 2).
Results of the Cox proportional hazard model indicated that survival time was significantly (P < 0.001) negatively associated with age at diagnosis of PDH (hazard ratio, 1.49; 95% confidence interval, 1.17 to 1.91). Survival time was not affected by sex, nor was it affected by values for serum cortisol concentration after ACTH administration or serum ALP and ALT activities. Survival time was not associated with improvements in polydipsia, polyuria, or exercise endurance; reduction in serum cortisol concentration as measured after ACTH administration; or reductions in serum activities of ALP or ALT after treatment with ketoconazole. Furthermore, there was no evidence of an association between the probability of adverse effects of ketoconazole and survival time.
Causes of death were not attributable to PDH in 26 dogs and included heart failure (n = 8), respiratory disorder (5), diabetes mellitus (3), neoplasia (liver, spleen, or urinary bladder; 3), renal failure (2), automobile accident (1), babesiosis (1), esophageal retention of foreign body (1), pancreatitis (1), surgical complication (cataracts; 1). Causes of death possibly attributable to PDH (advanced age [cognitive dysfunction or progressive myotonia]) were reported for 2 dogs. Causes of death attributable to PDH or PDH treatment included rapid deterioration in clinical signs (disrupted response to treatment; 2), neurologic disorder (ataxia, blindness, or deafness; 2), and advanced stage of PDH at time of admission and diagnosis (decubital ulcers with sepsis and severe myotonia; 1). Owners were generally reluctant to submit their dogs for euthanasia and postmortem examination. Therefore, the cause of death was not determined for 8 (20%) dogs.
Concurrent disorders in dogs with PDH—Clinical signs associated with heart failure developed in 40 (83%) dogs during the study period. Diagnosis of heart failure was made on the basis of findings of thoracic radiography, electrocardiography, and echocardiography. Survival time was not influenced by the coexistence of heart failure.
Most dogs with concurrent diabetes mellitus were originally referred to the hospital for evaluation of diabetes rather than PDH. The dose and type of insulin prescribed were not changed before or after treatment with ketoconazole. Clinical signs of diabetes in all diabetic dogs improved, including reduced polyuria, reduced polydipsia, better exercise endurance, and less day-to-day variation in blood glucose concentrations.
Discussion
The present study revealed that, as a result of treatment with ketoconazole, most (89.6%) dogs had improvements in clinical signs and serum biochemical values, with limited adverse effects. These findings suggested that ketoconazole is a safe and effective option for treating dogs with PDH. As in other studies,3,4,11,16 the dogs in our study were predominantly small-breed dogs. The overrepresentation of Maltese Terriers, Pomeranians, and Toy Poodles in our study probably reflected the popularity of small-breed dogs in the region in which the study was conducted rather than a breedspecific predisposition to PDH. The age distribution of dogs was also similar to that in other studies,3,4,12,14 with most dogs being middle- to advanced-aged. The prevalence of diabetes mellitus in the dogs in our study (23%) was greater than that reported for other studies1,4,9,11,12 (0% to 10%).
The mean dosage of ketoconazole used in the present study was lower than that of other studies,2,17,18 and only 2 dogs received > 20 mg/kg (8.9 mg/lb) every 12 hours. Results of other studies23,24 have suggested that treatment of dogs with ketoconazole at a moderate dosage (eg, 15 mg/kg [6.8 mg/lb], PO, q 24 h) may result in inconsistent suppression of overstimulated adrenal glands, whereas a higher dosage (eg, 30 mg/kg [13.6 mg/lb], PO, q 12 h) may result in better suppression, particularly when compared with effects of a low dose of ketoconazole (eg, 10 mg/kg [4.5 mg/lb], q 12 to 24 h). However, in contrast to results of other research,1 the present findings suggested that such a high dose can cause more adverse than beneficial effects. Moreover, it has been our experience that owners' compliance can be affected by the onset of adverse effects such as anorexia in their dog. Thus, administration of ketoconazole was limited to a dosage that did not induce adverse effects.
Adrenal gland function was analyzed by means of the ACTH stimulation test because it is the only tool that differentiates spontaneous from iatrogenic hyperadrenocorticism,1,2 the latter of which is common in the region in which the study was conducted. Although ACTH stimulation tests are more time-consuming and expensive to perform than determinations of urine cortisol-to-creatinine ratios,6 the ACTH stimulation test is a more reliable indicator of the effectiveness of treatment in dogs with PDH.5,6 It is also considered the most reliable test for identifying hypoadrenocorticism resulting from medication overdose in dogs with PDH.1,2 In the present study, serum cortisol concentrations in all 48 dogs with PDH decreased substantially after ketoconazole treatment both before and after ACTH administration and values for after testing were within the reference range in 69% of the dogs. Restoration of serum cortisol concentration after ACTH administration to within the reference range occurs in 11% to 83% of mitotane-treated dogs and 33% to 100% of trilostanetreated dogs.8,11–16
In the study reported here, consistent suppression of adrenal gland function was evident in 2 follow-up ACTH stimulation tests, with the earliest effect being evident after 1 month of treatment with ketoconazole. A lack of compliance and the financial burden on owners prevented performance of ACTH stimulation tests on a monthly basis for all dogs. Similarly, the time at which reevaluations of the ACTH stimulation test were performed varied widely among the dogs.
Clinical signs of PDH improved in 90% of dogs treated with ketoconazole in the present study, which is a success rate that is notably higher than that reported previously (50% of dogs)18 and is comparable to that in studies4,8,9,11–16 in which the effects of mitotane or trilostane were examined (range of clinical improvement, 70% to 100%). Initial amelioration of clinical signs was evident during the first 2 weeks to 2 months after treatment with ketoconazole was initiated. Decreased panting and improved activity levels were evident in 71% of the dogs in the present study; these changes were appreciated by the owners.
Similar to findings of another study,1 most (90%) dogs in the present study had high serum ALP activities; fewer dogs (60%) had high serum ALT activities. Treatment with ketoconazole resulted in significantly lower serum ALP and ALT activities in 88% and 79% of these dogs, respectively. Moreover, treatment with ketoconazole restored serum ALP and ALT activities to within reference ranges in 53% and 52% of these dogs, respectively, during the course of treatment. In dogs with PDH, decreased serum ALP activity reportedly results from treatment with trilostane.12,15 Treatment with trilostane also reduces serum ALT activity in dogs with PDH.12
In human patients, the risk of severe hepatic injury caused by treatment with ketoconazole is 1 in 15,000.25 In addition, 10% to 15% of human patients are susceptible to developing a high serum ALT activity while receiving ketoconazole; however, this situation usually resolves after discontinuation of ketoconazole.25 Although the potential for hepatotoxicity with ketoconazole is commonly mentioned in the veterinary literature, confirmed cases of ketoconazole-induced liver damage are rarely reported.1,2,17,18 A serum ALT activity higher than the upper reference limit is characteristic of approximately 8% to 20% of dogs treated with ketoconazole.24,26 Approximately 79% of the dogs in our study had decreased ALT activity after treatment with a mean dosage of 12 to 13 mg/kg (5.4 to 5.9 mg/lb) every 12 hours. These findings suggested that ketoconazole should be considered a safe option in terms of risk of hepatotoxicity for managing PDH in dogs.
Only 3 of 45 dogs had an exaggerated increase in serum ALT activity when the dosage of ketoconazole exceeded 7.5 mg/kg every 12 hours. These instances may have been idiosyncratic reactions,24 although ultrasonographic abnormalities in the liver, characterized by nodular heteroechogenicity, developed during the last 3 to 6 months of the dogs' lives. These abnormal findings were not detected at the time PDH was diagnosed nor during the subsequent years of seemingly effective treatment with ketoconazole that preceded the dogs' senescence.
The most common adverse effects of ketoconazole treatment in the study reported here were anorexia, vomiting, and diarrhea, at least 1 of which was evident in 67% of dogs during the study period. This percentage was higher than that reported for dogs with PDH in other studies1,2,17–19 (0% to 25%). Anorexia and vomiting appeared to be resolved by administration of ketoconazole with food or a temporary reduction in dose by 25% for 1 to 2 days. Anorexia, vomiting, lethargy, and diarrhea were reported in 8% to 64% of dogs with PDH that were treated with mitotane4,8,9,11,25,27 and in 0% to 18% of dogs with PDH that were treated with trilostane.12,15,16 Adverse neurologic effects were also evident in 5% of mitotane-treated dogs.9
The ACTH stimulation test and sodium-to-potassium ratio are often used to detect hypoadrenocorticism secondary to treatment with mitotane or trilostane. In view of the fact that ketoconazole has not been reported to affect mineralocorticoid activity, even at a dosage of 20 mg/kg every 12 hours,28 the sodium-to-potassium ratio may not be appropriate for detecting secondary hypoadrenocorticism in dogs treated with ketoconazole. Iatrogenic hypoadrenocorticism was not detected in our study but has been reported for 0% to 20% of dogs treated with mitotane or trilostane.4,7,8,11,14–16 Adrenal necrosis in 1 trilostane-treated dog was also reported.29
The median survival time of dogs treated with ketoconazole in this study (25 months) compares favorably with that of dogs treated with mitotane or trilostane (14 to 30 months and 18 to 31 months, respectively) in other studies.3,7,8,11,12,16 Similar to findings in dogs treated with mitotane or trilostane,3 survival time was significantly associated with age at diagnosis and serum cortisol concentration after ACTH stimulation after ketoconazole treatment. In our study, cause of death could be attributed to PDH in only 12% of dogs. Development of major organ failure may be more strongly associated with advanced age at diagnosis rather than PDH or PDH treatment.
A limitation of the present study was the lack of histologic evaluation of the adrenal glands. Unfortunately, owners were reluctant to consent to a postmortem examination of their dog. Additional research is needed to evaluate the effects of long-term treatment with ketoconazole on the adrenal glands. The results of our study suggested that ketoconazole should be considered a safe and effective option for treating dogs with PDH.
ABBREVIATIONS
ALP | Alkaline phosphatase |
ALT | Alanine aminotransferase |
PDH | Pituitary-dependent hyperadrenocorticism |
Cortrosyn, Organon, Oss, The Netherlands.
Coat-A-Count Cortisol, Diagnostic Products Corp, Los Angeles, Calif.
Nizoral, Janssen Pharmaceutica, Beerse, Belgium.
SPSS, version 13.0, SSPS Inc, Chicago, Ill.
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