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Alexandre B. Le Roux Unit of Diagnostic Imaging, The Animal Medical Center, 510 E 62nd St, New York, NY 10065.

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Jennifer M. Hickey Unit of Diagnostic Imaging, The Animal Medical Center, 510 E 62nd St, New York, NY 10065.

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Peter G. Noel Unit of Diagnostic Imaging, The Animal Medical Center, 510 E 62nd St, New York, NY 10065.

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History

An 11-year-old 15-kg (33-lb) spayed female Labrador Retriever-Poodle mix was evaluated because of an acute onset of vomiting, inappetence, and signs of abdominal pain. The dog had a 1-year history of hypothyroidism that was currently treated with levothyroxine (0.02 mg/kg [0.009 mg/lb], PO, q 12 h). The dog also had hyperadrenocorticism that had been treated with trilostane (4 mg/kg [1.8 mg/lb], PO, q 24 h) for the past 5 months.

On physical examination, the dog was febrile (39.7°C [103.5°F]), mildly dehydrated, and tachycardic. Abdominal palpation revealed a tense abdomen and organomegaly in the cranial portion of the abdomen. A CBC revealed a mild stress leukogram (ie, neutrophilia, lymphopenia, eosinopenia, and monocytosis) without other abnormalities. Serum biochemical analysis revealed mild hyperphosphoremia (6.6 mg/dL; reference range, 2.5 to 6.1 mg/dL), minimally decreased Na-to-K ratio (27; reference range, 28 to 37]), mildly increased liver enzyme (alanine transaminase, 140 U/L [reference range, 18 to 121 U/L]; aspartate transaminase, 75 U/L [reference range, 16 to 55 U/L]; and alkaline phosphatase, 252 U/L [reference range, 5 to 160 U/L]) activities, increased creatine kinase (486 U/L; reference range, 10 to 200 U/L) activity, and mild hypoglycemia (55 mg/dL; reference range, 63 to 114 mg/dL). No abnormalities were detected on urinalysis. Abdominal ultrasonography was performed for further assessment (Figure 1).

Figure 1—
Figure 1—

Longitudinal B-mode ultrasonographic views of the left (A) and right (B) adrenal glands of an 11-year-old 15-kg (33-1b) spayed female Labrador Retriever-Poodle mix that was evaluated because of an acute onset of vomiting, inappetence, and signs of abdominal pain. Images were obtained transabdominally with a 4- to 8-MHz microconvex transducer.

Citation: Journal of the American Veterinary Medical Association 249, 12; 10.2460/javma.249.12.1353

Determine whether additional imaging studies are required, or make your diagnosis from Figure 1—then turn the page →

Diagnostic Imaging Findings and Interpretation

Both adrenal glands are irregularly enlarged, with their caudal pole measuring approximately 1.2 cm in thickness on the left adrenal gland and 1.4 cm on the right adrenal gland (Figure 2). The adrenal gland parenchyma is heterogeneously hypoechoic with intraparenchymal hyperechoic foci, and the surrounding retroperitoneal fat is focally hyperechoic and hyperattenuating, with a scant amount of anechoic fluid dissecting through the retroperitoneal fat.

Figure 2—
Figure 2—

Same ultrasonographic images as in Figure 1. Notice the irregular enlargement of both adrenal glands, with the left adrenal gland (A) caudal pole measuring approximately 1.2 cm in thickness and the right adrenal gland (B) measuring 1.4 cm. The adrenal gland parenchyma is heterogeneously hypoechoic with intraparenchymal hyperechoic foci, and the surrounding retroperitoneal fat is focally hyperechoic and hyperattenuating (arrowheads), with a scant amount of anechoic fluid dissecting through the retroperitoneal fat (asterisk). The liver can be observed cranial to the right adrenal gland.

Citation: Journal of the American Veterinary Medical Association 249, 12; 10.2460/javma.249.12.1353

On further ultrasonographic evaluation, a small broad-based intraluminal echogenic thrombus partially obstructed the lumen of the caudal vena cava (Figure 3) at the level of the adrenal glands, with lack of blood flow within the right phrenicoabdominal vein. The liver was diffusely hyperechoic and mildly enlarged, with several small (< 1 cm in diameter) hypoechoic and hyperechoic nodules, none of which was deforming the hepatic capsule. No other abnormalities were detected.

Figure 3—
Figure 3—

Transverse B-mode ultrasonographic view (A) and longitudinal color-flow Doppler ultrasonographic view (B) of the adrenal glands of the dog in Figure 1. A—Similar to findings in images of Figure 2, bilateral enlargement of the adrenal glands is noted, with surrounding retroperitonitis (asterisks). A faint, intraluminal, echogenic thrombus can be seen in the lumen of the caudal vena cava (long arrowhead). B—Notice the partial abdominal vena cava luminal occlusion by the thrombus on color Doppler evaluation. LA = Left adrenal gland. RA = Right adrenal gland.

Citation: Journal of the American Veterinary Medical Association 249, 12; 10.2460/javma.249.12.1353

Although bilateral adrenomegaly is expected secondary to trilostane treatment,1 the ultrasonographic features reported following uncomplicated trilostane treatment of dogs with hyperadrenocorticism differed from the ultrasonographic findings in the patient of the present report. Because of the ultrasonographic findings and history of the patient, a presumptive diagnosis of bilateral adrenal gland necrosis secondary to treatment with trilostane was made, with associated focal retroperitonitis and nonocclusive caudal vena cava thrombosis. Other considerations, such as bilateral adrenal gland neoplastic infiltration (possibly metastatic or multicentric because of the bilateral feature of the lesions) or infectious disease (either fungal or bacterial), could not be completely ruled out but were considered unlikely because of the acute clinical signs at the time of initial evaluation, hematologic findings, and lack of other ultrasonographic findings.

Treatment and Outcome

An ACTH stimulation test was performed. Serum cortisol concentrations before (0.4 μg/dL; reference range, 2 to 6 μg/dL) and after (0.3 μg/dL; reference range, 6 to 18 μg/dL) ACTH stimulation were low. A post-ACTH stimulation serum cortisol concentration of < 2 μg/dL in the dog was consistent with iatrogenic hypoadrenocorticism caused by an idiosyncratic reaction to trilostane treatment that resulted in acute adrenal gland necrosis.2,3

The dog was treated with IV fluids, pain medication, gastroprotectants, and antiemetics. The dog also received glucocorticoids (dexamethasone, 0.13 mg/kg [0.06 mg/lb], IV, q 24 h; and then prednisone, 1 mg/kg [0.45 mg/lb] PO, q 24 h) and a mineralocorticoid (desoxycorticosterone pivalate, 2.2 mg/kg [1 mg/lb], IM, q 30 d). Trilostane administration was discontinued, and levothyroxine treatment was continued. Prophylactic anticoagulant medication was also initiated to prevent progression of the caudal vena cava thrombus and potential formation of additional clots.

The dog's clinical condition improved dramatically following initiation of the medical treatment, with resolved anorexia, vomiting, and signs of abdominal pain, and the dog was discharged from the hospital after 3 days. On follow-up with the referring veterinarian 1 month later, the dog did not have any recurrence of clinical signs, which further supported the presumptive diagnosis of bilateral adrenal gland necrosis secondary to treatment of hyperadrenocorticism with trilostane.

Comments

Trilostane is an orally administered, reversible, short-acting competitive inhibitor of 3β-hydroxysteroid dehydrogenase. It is used successfully in the treatment of pituitary dependent hyperadrenocorticism in dogs.4 Trilostane blocks the production of adrenal gland steroids, mainly affecting cortisol production, with lesser effects on aldosterone synthesis.4 In contrast to mitotane, which decreases adrenal gland size through controlled destruction of adrenal gland tissue leading to a decrease in cortisol production, trilostane treatment does not normally induce adrenal gland parenchymal destruction and has actually been reported to induce increased adrenal gland thickness and length on ultrasonographic examination, increased conspicuity of the corticomedullary definition, and even adrenal gland distortion in some cases.1 In contrast, the adrenal gland parenchyma of the dog of the present report was heterogeneous, without increased corticomedullary conspicuity, and severe focal retroperitonitis was observed around both adrenal glands, which has not been reported with uncomplicated trilostane treatment.1

Despite the lack of histologic evaluation, the parenchymal changes observed ultrasonographically in the dog of the present report were considered most likely consistent with adrenal gland necrosis and hemorrhage, which are histologic changes reported from trilostane administration.2,5 A recent experimental study5 performed on rats concluded that these histologic findings are secondary to ACTH hypersecretion, causing adrenal gland degeneration in a dose-dependent manner, rather than a direct action of trilostane or its metabolites on the adrenal gland parenchyma, as previously hypothetized.3,5 Various degrees of severity have been reported histologically for these parenchymal changes, which may be related to the blood concentration of endogenous ACTH reached following trilostane administration, the duration of treatment, and potential prior mitotane treatment.3,5 As for the dog of the present report, in some instances, these changes are severe enough to induce hypoadrenocorticism.2,6 Finally, the presence of the nonobstructive caudal vena cava thrombus in the dog of the present report was considered secondary to focal periadrenal gland inflammation triggering venous thrombus formation resulting from the regional vascular wall inflammation within the adjacent vessels (eg, phrenicoabdominal vein and caudal vena cava), rather than secondary to a hypercoagulable state.

In conclusion, clinicians should be aware of this rare adverse effect of trilostane treatment, which leads to severe adrenal gland necrosis and hemorrhage and potentially induces hypoadrenocorticism.

References

  • 1. Mantis P, Lamb CR, Witt AL, et al. Changes in ultrasonographic appearance of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Vet Radiol Ultrasound 2003; 44: 682685.

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  • 2. Chapman PS, Kelly DF, Archer J, et al. Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. J Small Anim Pract 2004; 45: 307310.

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  • 3. Reusch CE, Sieber-Ruckstuhl N, Wenger M, et al. Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet Rec 2007; 160: 219224.

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  • 4. Wenger M, Sieber-Ruckstuhl NS, Muller C, et al. Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2004; 65: 12451250.

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    • Search Google Scholar
    • Export Citation
  • 5. Burkhardt WA, Guscetti F, Boretti FS, et al. Adrenocorticotropic hormone, but not trilostane, causes severe adrenal hemorrhage, vacuolization, and apoptosis in rats. Domest Anim Endocrinol 2011; 40: 155164.

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    • Search Google Scholar
    • Export Citation
  • 6. Ramsey IK, Richardson J, Lenard Z, et al. Persistent isolated hypocortisolism following brief treatment with trilostane. Aust Vet J 2008; 86: 491495.

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    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Longitudinal B-mode ultrasonographic views of the left (A) and right (B) adrenal glands of an 11-year-old 15-kg (33-1b) spayed female Labrador Retriever-Poodle mix that was evaluated because of an acute onset of vomiting, inappetence, and signs of abdominal pain. Images were obtained transabdominally with a 4- to 8-MHz microconvex transducer.

  • Figure 2—

    Same ultrasonographic images as in Figure 1. Notice the irregular enlargement of both adrenal glands, with the left adrenal gland (A) caudal pole measuring approximately 1.2 cm in thickness and the right adrenal gland (B) measuring 1.4 cm. The adrenal gland parenchyma is heterogeneously hypoechoic with intraparenchymal hyperechoic foci, and the surrounding retroperitoneal fat is focally hyperechoic and hyperattenuating (arrowheads), with a scant amount of anechoic fluid dissecting through the retroperitoneal fat (asterisk). The liver can be observed cranial to the right adrenal gland.

  • Figure 3—

    Transverse B-mode ultrasonographic view (A) and longitudinal color-flow Doppler ultrasonographic view (B) of the adrenal glands of the dog in Figure 1. A—Similar to findings in images of Figure 2, bilateral enlargement of the adrenal glands is noted, with surrounding retroperitonitis (asterisks). A faint, intraluminal, echogenic thrombus can be seen in the lumen of the caudal vena cava (long arrowhead). B—Notice the partial abdominal vena cava luminal occlusion by the thrombus on color Doppler evaluation. LA = Left adrenal gland. RA = Right adrenal gland.

  • 1. Mantis P, Lamb CR, Witt AL, et al. Changes in ultrasonographic appearance of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Vet Radiol Ultrasound 2003; 44: 682685.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Chapman PS, Kelly DF, Archer J, et al. Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. J Small Anim Pract 2004; 45: 307310.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Reusch CE, Sieber-Ruckstuhl N, Wenger M, et al. Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet Rec 2007; 160: 219224.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Wenger M, Sieber-Ruckstuhl NS, Muller C, et al. Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2004; 65: 12451250.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Burkhardt WA, Guscetti F, Boretti FS, et al. Adrenocorticotropic hormone, but not trilostane, causes severe adrenal hemorrhage, vacuolization, and apoptosis in rats. Domest Anim Endocrinol 2011; 40: 155164.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Ramsey IK, Richardson J, Lenard Z, et al. Persistent isolated hypocortisolism following brief treatment with trilostane. Aust Vet J 2008; 86: 491495.

    • Crossref
    • Search Google Scholar
    • Export Citation

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