Mitotane (o, DDD) resistance in a dog with pituitary-dependent hyperadrenocorticism and phaeochromocytoma

A dog was presented with a 2 year history of polyuria and polydipsia due to pituitary-dependent hyperadrenocorticism. A low-dose dexamethasone suppression test and measurement of plasma ACTH concentration confirmed the diagnosis. Treatment was instituted with mitotane at 44 mg/kg/day and then 88 mg/kg/d without complete resolution of signs. The dog collapsed with signs consistent with liver disease and was euthanased. Necropsy revealed a phaeochromocytoma of the left adrenal medulla with extensive metastases to the liver. A chromophobe adenoma of the pars intermedia of the pituitary was found.     

Non-dexamethasone-suppressible, pituitary-dependent hyperadrenocorticism in a dog

A 5-year-old female dog with hyperadrenocorticism was determined to have pituitary-dependent hyperadrenocorticism even though plasma cortisol concentrations were not suppressed after high-dosage dexamethasone administration. The diagnosis was based on a supranormal response of plasma cortisol to ACTH administration and a lack of suppression of plasma cortisol concentration after administration of 0.1 mg of dexamethasone/kg. Although a higher dosage of dexamethasone (1 mg/kg) did not cause suppression of plasma cortisol, plasma ACTH concentrations in the dog were increased above those in clinically normal dogs, supporting a diagnosis of pituitary-dependent hyperadrenocorticism. During treatment with mitotane, the dog became unconscious and died. Necropsy revealed a pituitary tumor that had compressed and displaced the hypothalamus. Although high-dosage dexamethasone suppression tests often are useful in the differential diagnosis of hyperadrenocorticism, a lack of suppression of plasma cortisol does not necessarily exclude pituitary-dependent hyperadrenocorticism.     

Hyperadrenocorticism in a dog due to ectopic secretion of adrenocorticotropic hormone

Spontaneous hyperadrenocorticism in dogs is known to be the result of excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland or excessive autonomous glucocorticoid secretion by an adrenocortical tumor. Here, we report on an 8-year-old German shepherd dog in which ACTH-dependent hyperadrenocorticism was a result of ectopic ACTH secretion and could be related to an abdominal neuroendocrine tumor. Hyperadrenocorticism was diagnosed on the basis of the history, clinical signs, and elevated urinary corticoid/creatinine ratios (UCCRs; 236 and 350 x 10(-6); reference range < 10 x 10(-6)). The UCCR remained elevated (226 x 10(-6)) after three oral doses of dexamethasone (0.1 mg/kg body weight) at 8-h intervals. Ultrasonography revealed two equivalently enlarged adrenal glands, consistent with adrenocortical hyperplasia. Plasma ACTH concentration was clearly elevated (159 and 188 ng/l; reference range 5-85 ng/l). Computed tomography (CT) revealed that the pituitary was not enlarged. These findings were interpreted as indicating dexamethasone-resistant pituitary-dependent hyperadrenocorticism. Transsphenoidal hypophysectomy was performed but within 2 weeks after surgery, there was exacerbation of the clinical signs of hyperadrenocorticism. Plasma ACTH concentration (281 ng/l) and UCCRs (1518 and 2176 x 10(-6)) were even higher than before surgery. Histological examination of the pituitary gland revealed no neoplasia. Stimulation of the pituitary with corticotropin-releasing hormone did not affect plasma ACTH and cortisol concentrations. Treatment with trilostane was started and restored normocorticism. CT of the pituitary fossa, 10 months after hypophysectomy, revealed an empty sella. Hence, it was presumed that there was ectopic secretion of ACTH. CT of the abdomen revealed a mass in the region of the pancreas and a few nodules in the liver. Partial pancreatectomy with adjacent lymph node extirpation was performed and the liver nodules were biopsied. Histological examination revealed a metastasized neuroendocrine tumor. Abdominal surgery was not curative and medical treatment with trilostane was continued. At 18 months after the abdominal surgery, the dog is still in good condition. In conclusion, the combination of (1) severe dexamethasone-resistant hyperadrenocorticism with elevated circulating ACTH levels, (2) definitive demonstration of the absence of pituitary neoplasia, and (3) an abdominal neuroendocrine tumor allowed the diagnosis of ectopic ACTH secretion.     

Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism

OBJECTIVE: To evaluate the efficacy of trilostane in treating dogs with pituitary-dependent hyperadrenocorticism. DESIGN: Prospective clinical trial using client-owned dogs with pituitary-dependent hyperadrenocorticism treated at University Veterinary Centre, Sydney from September 1999 to July 2001. PROCEDURE: Thirty dogs with pituitary-dependent hyperadrenocorticism treated with trilostane, a competitive inhibitor of 3beta-HSD, were monitored at days 10, 30 and 90 then 3-monthly by clinical examination, tetracosactrin stimulation testing, urinary corticoid:creatinine ratio measurement and by client questionnaire. RESULTS: Twenty-nine of 30 dogs were successfully treated with trilostane (median dose 16.7 mg/kg; range 5.3 to 50 mg/kg, administered once daily); one responded favourably but died of unrelated disease before full control was achieved. CONCLUSION: Trilostane administration controlled pituitary-dependent hyperadrenocorticism in these dogs. It was safe, effective and free of side-effects at the doses used. Most dogs were initially quite sensitive to the drug for 10 to 30 days, then required higher doses until a prolonged phase of stable dose requirements occurred. Urinary corticoid:creatinine ratio was useful in assessing duration of drug effect. Some dogs treated for more than 2 years required reduction or temporary cessation of drug because of iatrogenic hypoadrenocorticism.     

Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism

Trilostane is considered an efficacious and safe medication for canine pituitary-dependent hyperadrenocorticism (PDH). Its recommended frequency of administration is once daily. In this prospective study, the efficacy, toxicity, and long-term outcome of trilostane administered twice daily per os were evaluated in 44 dogs with PDH. Mean initial dose was 3.1 mg/kg q 12 hours, and mean final dose was 3.2 mg/kg q 12 hours. The final total daily dose was lower than previously reported for once-daily administration. The mean survival time for affected dogs was 930 days.     

Thrombosis of the portal vein in a miniature schnauzer

A miniature schnauzer with a history of apathy, anorexia and jaundice was presented to the Utrecht University Clinic for Companion Animals. Abnormal laboratory findings included highly increased levels of total bile acids and alkaline phosphatase, and hyponatraemia. Abdominal ultrasonography revealed that the right side of the liver was enlarged and the left side was small, together with a thrombus in the portal vein. Biopsies from the right side of the liver demonstrated subacute to chronic active hepatitis, for which the dog was treated with prednisolone (1 mg/kg/day for four weeks). No improvement was observed and the owner requested euthanasia. At necropsy the left lobes of the liver were found to be small and firm, while the right lobes were large and soft. There were two thrombi in the portal vein. Microscopic examination revealed chronic active hepatitis and cirrhosis.     

Pituitary tumor size, neurologic signs, and relation to endocrine test results in dogs with pituitary-dependent hyperadrenocorticism: 43 cases (1980-1990).

Pituitary neoplasm was identified in 43 dogs with pituitary-dependent hyperadrenocorticism via necropsy (n = 33), diagnostic imaging with computerized tomography or magnetic resonance imaging (n = 5), or diagnostic imaging and necropsy (n = 5). All dogs had clinical signs and clinicopathologic test results typical of hyperadrenocorticism. Thirty-seven dogs had grossly visible pituitary tumors, and 6 dogs had microscopic pituitary tumors. Fifteen dogs had developed neurologic signs typical of those resulting from an enlarging pituitary mass. Twenty-three dogs had pituitary tumors greater than or equal to 1 cm in diameter. Provocative testing of the pituitary-adrenocortical axis was performed on all dogs. Dogs with grossly visible pituitary tumors and dogs with neurologic signs had significantly (P less than 0.05) higher mean plasma endogenous ACTH concentrations, compared with values from dogs with microscopic tumors and dogs without neurologic signs, respectively. Dogs with grossly visible pituitary tumors and dogs with tumors greater than or equal to 1 cm in diameter had significantly (P less than 0.05) lower adrenocortical responsiveness to exogenous ACTH, compared with dogs with microscopic pituitary tumors and dogs with tumors less than 1 cm in diameter, respectively. Despite these differences, there was overlap between test results among dogs. On the basis of endocrine test results, it would appear difficult to distinguish dogs with pituitary-dependent hyperadrenocorticism and large pituitary tumors from those with pituitary-dependent hyperadrenocorticism and microscopic pituitary tumors prior to onset of neurologic signs.     

Diseases of the adrenal cortex of dogs and cats

Of cases of hyperadrenocorticism in small animals 80-85% are the result of adrenocortical hyperplasia. Middle-aged or older Poodles, Dachshunds, Boston Terriers and Boxers are most commonly affected, and cats rarely. Clinical signs include polydipsia, polyuria, alopecia, abdominal distension, lethargy, weakness, hepatomegaly, calcinosis cutis, testicular atrophy and anestrus. Hematologic and biochemical changes may include neutrophilia, lymphopenia, monocytosis, eosinopenia, increased blood levels of alkaline phosphatase, SGPT, cholesterol, Na and glucose, and decreased K and T4 levels. The high-dosage dexamethasone suppression test helps differentiate pituitary-dependent hyperadrenocorticism from that caused by adrenal tumors. The low-dosage dexamethasone suppression test, determination of plasma ACTH levels, and ACTH response test are additional diagnostic aids in the diagnosis of Cushing's disease. Medical treatment involves oral use of mitotane (o,p'-DDD) at 50 mg/kg/day for 7 days and prednisone or prednisolone at 0.05 mg/kg/day. Hypophysectomy has been used with only 5% mortality in cases of pituitary-dependent hyperadrenocorticism. Adrenalectomy is indicated in cases of adrenal neoplasia.     

Prevalence of pituitary tumors among diabetic cats with insulin resistance

OBJECTIVE: To determine prevalence of pituitary tumors, detectable by means of computed tomography or magnetic resonance imaging, in cats with insulin resistance suspected to have acromegaly or hyperadrenocorticism versus cats with well-controlled diabetes mellitus. DESIGN: Case series. ANIMALS: 16 cats with insulin resistance that were also suspected to have acromegaly (n = 12) or pituitary-dependent hyperadrenocorticism (4) and 8 cats with well-controlled diabetes mellitus. PROCEDURE: Computed tomography was performed on all 16 cats with insulin resistance and 2 cats in which diabetes mellitus was well-controlled. The remaining 6 cats in which diabetes mellitus was well-controlled underwent magnetic resonance imaging. Images were obtained before and immediately after i.v. administration of contrast medium. RESULTS: Computed tomography revealed a mass in the region of the pituitary gland in all 16 cats with insulin resistance. Maximum width of the masses ranged from 4.4 to 12.7 mm; maximum height ranged from 3.1 to 12.6 mm. Results of computed tomography performed on 2 cats with well-controlled diabetes and magnetic resonance imaging performed on the remaining 6 cats were considered normal. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cats with insulin resistance suspected to have acromegaly or pituitary-dependent hyperadrenocorticism are likely to have a pituitary mass detectable by means of computed tomography or magnetic resonance imaging.     

Obstructed portal venous flow and portal vein thrombus in a dog

A young adult Doberman Pinscher had clinical signs and laboratory data consistent with the copper-associated hepatopathy commonly found in Doberman Pinschers. Hepatic biopsy and hepatic copper analysis did not support this diagnosis. Furthermore, changes seen in the hepatic biopsy specimen did not explain the acquired portosystemic shunting or the portal hypertension that the dog had. A mesentery venoportagram revealed markedly delayed filling of one portal vein, and necropsy revealed a small thrombus partially occluding that hepatic vein. It was not determined whether obstructed portal venous flow caused the portal vein thrombus or vice versa; however, it was theorized that the portal vein thrombus, once formed, contributed to further portal hypertension and/or delayed portal vein filling.     

Familial canine pituitary-dependent hyperadrenocorticism in wirehaired Dachshunds

Canine pituitary hyperadrenocorticism (Cushing's disease) caused by neoplasia of the corticotrope cells is one of the most common endocrine diseases especially in smaller dog breeds. Cushing's disease was diagnosed in eleven wire-haired Dachshunds and for further six wire-haired Dachshunds Cushing's disease was suspected on the basis of clinical signs. A joined pedigree could be ascertained for all these 17 dogs. Eleven of these dogs were so closely related to each other, that they were summarized in four nucleus families. Two fullsiblings were examined by means of clinical, laboratory diagnostic and morphological methods. The main lesions consisted of atrophic dermatosis with alopecia, increase of activity of liver enzymes in plasma and bilateral adrenocortical hyperplasia and therefore corresponded to the typical signs of a secondary hyperadrenocorticism. A rather unusual finding was the pituitary carcinoma in one of these dogs. Similarly to human patients affected by hyperadrenocorticism, real-time PCR analysis showed a 2.9-fold increase of expression of the canine MDR1 gene in the liver of one affected wirehaired Dachshund. This study documents the first familial occurrence of pituitary-dependent hyperadrenocorticism in wirehaired Dachshunds, the overexpression of the MDR1 gene in the dog and the third case of familial hyperadrenocorticism in dogs ever described.     

Pituitary-dependent hyperadrenocorticism in a cat

Pituitary-dependent hyperadrenocorticism was diagnosed in a 9-year-old, male castrated cat that had polyuria, polyphagia, pendulous abdomen, truncal hair loss, congestive heart failure, and insulin-resistant diabetes mellitus. Results of pituitary-adrenal function testing revealed inadequate serum cortisol suppression following dexamethasone administration, exaggerated serum cortisol responses after exogenous ACTH stimulation, and high plasma ACTH concentrations. The pathologic findings of bilateral adrenocortical hyperplasia and a pituitary adenoma that immunostained well for ACTH-related peptides confirmed pituitary-dependent hyperadrenocorticism.     

Urinary excretion of glucocorticoids in the diagnosis of hyperadrenocorticism in cats

In dogs and humans, the measurement of urinary corticoid excretion has become a standard screening test for the diagnosis of hyperadrenocorticism. Mainly because the urinary excretion of cortisol was considered to be very low in cats, its measurement was not used in the diagnosis of hyperadrenocorticism in this species. We therefore studied the urinary excretion of [³H]cortisol and measured the corticoid/creatinine (C/C) ratio in healthy cats and in cats with hyperadrenocorticism in order to evaluate the applicability of this measurement in the diagnosis of feline hyperadrenocorticism. The median urinary excretion of intravenously administered [³H]cortisol was 1.85% (measured as excreted ³H; range, 1.56 to 1.99; n = 4). High-performance liquid chromatography analysis showed a small peak of cortisol and a large peak consisting primarily of conjugates of cortisol and/or its metabolites. The 2.5 and 97.5 percentiles of the urinary C/C ratio in healthy cats were 2 × 10⁻⁶ to 36 × 10⁻⁶ (n = 42). The C/C ratio was significantly higher in six cats with pituitary-dependent hyperadrenocorticism (median, 122 × 10⁻⁶; range 51 × 10⁻⁶; to 272 × 10⁻⁶). The administration of a high dose of dexamethasone (0.1 mg/kg thrice daily per os) led to marked suppression of the C/C ratio in healthy cats (median suppression of the average of the C/C ratio of the first two consecutive days was 92%; range, 74 to 96%; (n = 12), as well as in five cats with pituitary-dependent hyperadrenocorticism. Our results demonstrate that despite the low urinary excretion of injected [³H]cortisol, urinary corticoid concentrations in cats can be measured by radioimmunoassay and that the urinary C/C ratio is a sensitive test in the diagnosis of hyperadrenocorticism in the cat.     

Pneumothorax secondary to pulmonary thromboembolism in a dog

Objective – To describe a case of spontaneous pneumothorax secondary to pulmonary thromboembolism possibly associated with pituitary dependent hyperadrenocorticism.
Case Summary – A 7-year-old spayed female Collie weighing 26 kg was referred for evaluation of spontaneous pneumothorax. An exploratory thoracotomy was performed and revealed 2 lung lobes to be diffusely hemorrhagic and they were resected. Histologic examination of multiple sections documented diffuse thromboembolism. A 2–3 cm thrombus was visualized distal to the bifurcation of the pulmonary artery during an echocardiographic examination postoperatively. The dog was discharged to the owner after recovery from surgery. The thrombus had resolved at the 4-week recheck examination. Diagnosis of pituitary dependent hyperadrenocorticism was confirmed based on follow-up endocrine testing.
New or Unique Information Provided – This is the first report of pulmonary thromboembolism causing spontaneous pneumothorax in the dog.     

Comparison of mitotane treatment for adrenal tumor versus pituitary-dependent hyperadrenocorticism in dogs.

The purpose of this study was to determine the sensitivity of dogs with hyperadrenocorticism to treatment with the adrenocorticolytic agent mitotane. Specifically, we looked for differences in response to treatment using this drug in dogs with adrenocortical tumors (adrenal tumor hyperadrenocorticism, ATH) vs those with pituitary-dependent hyperadrenocorticism (PDH). For inclusion in this study, each dog must have had clinical signs, data base laboratory abnormalities, and endocrine screening test results consistent with the diagnosis of hyperadrenocorticism. Further, each dog had to have been treated for at least 6 months with mitotane and have histologic evidence for adrenocortical or pituitary neoplasia (all dogs were necropsied). Thirteen dogs with ATH (8 carcinomas, 5 adenomas) were identified. The ages and body weights of these 13 dogs were computer-matched to 13 dogs with PDH. All dogs were initially treated with approximately 50 mg of mitotane/kg/d of body weight. Reexaminations were performed after 7, 30, 90, and 180 days of treatment. Individual dosages varied widely after the initial 5 to 12 days of treatment. The mean (+/- SD) dose of mitotane (mg/kg/d) for the first 7 days of treatment was 47.5 +/- 9.4 for dogs with ATH vs 45.7 +/- 11.9 for dogs with PDH. The mean plasma cortisol concentrations 1 hour after ACTH administration at the 7-day recheck were significantly higher in dogs with ATH (502 +/- 386 nmol/L) than in dogs with PDH (88 +/- 94 nmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)     

Severe systemic hypertension in a cat with pituitary-dependent hyperadrenocorticism

A seven-year-old Burmese cat was presented with sudden onset blindness. On physical examination, the cat had bilateral retinal detachment and severe systemic hypertension. Further clinical investigations revealed pituitary-dependent hyperadrenocorticism. Antihypertensive therapy was discontinued when the hypertension resolved after bilateral adrenalectomy. Systolic blood pressure remained normal until 19 months post-operatively when systemic hypertension recurred and was attributed to chronic kidney disease. The cat was euthanased 47 months after initial presentation. A pituitary adenoma was identified at post-mortem examination. This case illustrates that systemic hypertension can occur secondary to hyperadrenocorticism in the cat.     

Hyperthyroidism due to an intrathoracic tumour in a dog with test results suggesting hyperadrenocorticism

The elevated urinary corticoid/creatinine ratios of an 11-year-old Jack Russell terrier with polyuria were suppressible in a high-dose dexamethasone suppression test, which was suggestive of pituitary-dependent hyperadrenocorticism. The absence of physical and routine-laboratory changes compatible with hyperadrenocorticism and the relatively high plasma thyroxine concentration were the impetus for additional studies of thyroid and adrenocortical functions. A high plasma thyroxine concentration (62 nmol/l; 5.0 microg/100 ml) suggested the presence of hyperthyroidism. Radiography, (99m)TcO(4) (-) scintigraphy, ultrasonography, computed tomography and cytology revealed a hyperfunctioning intrathoracic thyroid tumour. In the low-dose dexamethasone suppression test, the plasma cortisol concentration exceeded the reference value of 40 nmol/l (1.4 microg/100 ml) at eight hours after dexamethasone administration (0.01 mg/kg intravenously), a test result compatible with hyperadrenocorticism. In conclusion, this report represents the first case of a dog with an autonomously hyperfunctioning thyroid tumour in the thorax. The elevated urinary corticoid excretion and the positive low-dose dexamethasone suppression test may be explained by alterations in cortisol metabolism, the stress of the hyperthyroid state or both.     

Cushing's disease complicated with thrombosis in a dog

Thrombosis is a potential complication of hyperadrenocorticism (HAC) in dogs. An 8-year-old male Beagle diagnosed with pituitary-dependent HAC had complicated with thrombosis in the caudal vena cava and abdominal aorta, which was treated by hypophysectomy and antithrombotic therapy. After hypophysectomy, hypercortisolemia disappeared and the general condition was also significantly improved. Ultrasonography after hypophysectomy revealed that the thrombus remained in the abdominal aorta, but the thrombus in the caudal vena cava had disappeared. However 692 days after the hypophysectomy, the dog had an acute onset of dyspnea and died. Postmortem examination revealed the presence of thrombi in the abdominal aorta and the pulmonary artery. Observations from this case show that HAC dogs must be attention to thrombosis.     

Gastric adenocarcinoma in a horse with portal vein metastasis and thrombosis: a novel cause of hepatic encephalopathy

A 17-year-old Quarter horse mare was referred to Cornell University for postmortem examination after 72 hours of encephalopathy that consisted of depression, mania, and blindness. A plasma sample and cerebral spinal fluid demonstrated hyperammonemia. Gross necropsy examination findings included the following: mild icterus, a transmural mass in the glandular portion of the gastric fundus, multiple masses throughout the liver, and a large tumor thrombus in the portal vein. Microscopically, the gastric mass, hepatic masses, and portal vein thrombus were composed of similar neoplastic epithelial cells that formed variably sized acini and branching cords separated by a dense desmoplastic stroma. Throughout the cerebral frontal cortex were numerous Alzheimer type II astrocytes. Hepatic encephalopathy was caused by gastric adenocarcinoma, with metastasis to the liver and the portal vein. The clinical and pathologic lesions from this unique case, as well as hyperammonemia and portal vein thrombosis in the pathogenesis of hepatic encephalopathy, are discussed.     

Cortisol concentrations following stimulation of healthy and adrenopathic dogs with two doses of tetracosactrin

A prospective study was undertaken to compare intravenous tetracosactrin at doses of 5 microg/kg and 250 microg for diagnosing hyperadrenocorticism in dogs. Both healthy dogs and dogs with pituitary-dependent hyperadrenocorticism were evaluated with the two doses of the drug, and serum cortisol concentrations were compared at 60 minutes post-stimulation. Some of the dogs had additional samples taken at 90 and 120 minutes. For four dogs with hyperadrenocorticism, timed samples were also obtained at 150, 180 and 240 minutes post-injection. Cortisol concentrations 60 minutes after stimulation with either 5 microg/kg or 250 microg intravenous tetracosactrin were similar for both healthy dogs and dogs with hyperadrenocorticism. The lower dose can therefore be used for diagnosing hyperadrenocorticism in dogs.