How would you manage this case?
Veterinary Medicine is pleased to present this interactive veterinary case example written for educational purposes only by Jennifer L. Garcia, DVM, DACVIM. Dr. Garcia is a veterinary internal medicine specialist at Sugar Land Veterinary Specialists in Houston, Texas.
Ivy is a 6-year-old female spayed Jack Russell terrier mix.
Ivy’s owners think Ivy has been drinking more water than usual and, as a result, having accidents in the house. Twice in the last week they have also woken up in the morning to find that Ivy has gotten into the kitchen cupboards. The first night, they found she had opened and eaten half a bag of uncooked rice; the second time she had eaten all the shortening in a can. They are concerned because she seems extremely ravenous for her own food, is begging for food more than usual, and is eating any food she can get her paws on. They also have noticed that Ivy has gained weight in the last month. She is not experiencing vomiting, diarrhea, coughing, sneezing, or other clinical signs.
Ivy has historically been healthy, is current on vaccinations, and receives monthly flea, tick, and heartworm preventives. She is not receiving any other medications at this time. However, on further questioning, the owners report that their other dog has a history of skin allergies and they think Ivy may have them, too, so when Ivy scratches more than usual, they give her some of their other dog’s prednisone. One week ago, Ivy received 5 mg prednisone once a day for three days, and her pruritus resolved.
Physical examination findings
• Ivy is bright, alert, and responsive
• Temperature = 100.9 F (38.8 C), pulse = 110 beats/min, respiration = 46 breaths/min
• Weight = 18 lb (8.2 kg) – she has gained 2 lb since her last visit about eight months ago
• Body condition score = 6/9
• You note mild abdominal distention and cranial organomegaly, but no discomfort or fluid wave is palpable.
• The rest of her physical examination findings are normal.
Based on the history and physical examination findings, your problem list for Ivy includes:
• Polydipsia with suspected polyuria (PU/PD)
• Mild abdominal distention and cranial organomegaly
You recommend starting with baseline laboratory tests (complete blood count, serum chemistry profile, and urinalysis) to look for metabolic or endocrine problems or lower urinary tract issues that would explain her clinical signs.
Here are Ivy’s test results:
Complete blood count
|Patient values||Reference range|
|Platelet count (103/µl)||400||170-400|
Serum chemistry profile
|Patient values||Reference range|
Urinalysis (collected by cystocentesis)
|Patient values||Reference range|
|Urine specific gravity||1.005||1.015-1.050|
Based on these test results as well as Ivy’s clinical signs, which option would be the most logical next step for Ivy?
Because Ivy has a stress leukogram, elevated ALP, hyposthenuria (consistent with her history of increased water intake), and polyphagia, you talk to the owners about screening her for hyperadrenocorticism.
True or False: Adding a urine cortisol to creatinine ratio (UCCR) to Ivy’s urinalysis would be the best and fastest way to diagnose hyperadrenocorticism.
From the American College of Veterinary Internal Medicine consensus statement on the diagnosis of spontaneous hyperadrenocorticism (available here), you know that a low-dose dexamethasone (LDDS) test is the screening test of choice, so you schedule Ivy for this test the next day. Because you are concerned about the possibility of hyperadrenocorticism, you also recommend a urine bacterial culture to look for an occult urinary tract infection (UTI). Fortunately, the owners agree.
The results of Ivy’s LDDS test:
• Baseline serum cortisol concentration: 5.2 µg/dl (normal = 1-6.5 µg/dl)
• (An intravenous injection of 0.01 to 0.015 mg/kg dexamethasone sodium phosphate was administered.)
• 4-hour serum cortisol concentration: 4.3 µg/dl (normal < 1.5 µg/dl)
• 8-hour serum cortisol concentration: 6.3 µg/dl (normal <1.5 µg/dl)
The results of Ivy’s urine bacterial culture and sensitivity profile:
Organism: Escherichia coli > 100,000 cfu/ml
|Antibiotic (µg/ml)||Minimum inhibitory concentration||Interpretation||Reference range|
Based on these results, what is the most appropriate next step for Ivy?
b. The LDDS test results indicate hyperadrenocorticism and Ivy has a UTI, so you prescribe trilostane and an antibiotic and recommend an ACTH stimulation test to monitor response to treatment in one week.
e. You prescribe an antibiotic to treat the UTI and tell the owners that you are concerned that Ivy’s recent treatment with prednisone may be causing the elevated cortisol concentrations, so you recommend that the LDDS test be repeated in three weeks to rule out iatrogenic hyperadrenocorticism.
Hyperadrenocorticism explains Ivy’s clinical signs and laboratory test results. In about 65% of cases, the 4-hour cortisol concentration suppresses to ≤ 50% of baseline, which supports a diagnosis of pituitary-dependent hyperadrenocorticism. Because Ivy’s 4-hour cortisol concentration did not suppress ≤ 50% of baseline, we still don’t know whether she has pituitary or adrenal disease.
Finding that Ivy has a UTI is not surprising because patients with immunosuppressive diseases such as Cushing’s or diabetes may have infection even in the face of normal urine sediment results. Bacteriuria and pyuria may also be absent in patients with dilute urine. You prescribe amoxicillin (20 mg/kg orally twice daily for seven days).
You also discuss with Ivy’s owners the different types of hyperadrenocorticism and why it is important to know whether she has pituitary- or adrenal-dependent hyperadrenocorticism.
Differentiating tests for hyperadrenocorticism
• Can be used to look for bilateral symmetrically enlarged adrenal glands
• Can identify the presence of metastatic or invasive adrenal disease
• Very operator dependent
• May not be available in all situations
|High-dose dexamethasone suppression test||
• Similar procedure and sample handling as that of an LDDS test
• Suppression at 4- or 8-hour to ≤ 50% of baseline confirms pituitary-dependent hyperadrenocorticism
|• Lack of suppression still does not confirm adrenal-dependent disease|
|Endogenous ACTH concentration||
• Only a single blood sample is required
• Most accurate differentiating test
• Requires proper blood sample collection, cooling, and processing, and shipment of frozen plasma
• Sensitivity varies with the assay used
After discussion with the owners, you decide to pursue an abdominal ultrasonographic examination as a differentiating test for Ivy.
Ivy’s abdominal ultrasonographic examination results:
The liver appears enlarged and is hyperechoic throughout. No discrete masses or nodules are noted. Both adrenal glands are symmetrically enlarged and measure > 9 mm at their widest aspect. A small amount of positionally dependent hyperechoic fluid is present in the gallbladder. The kidneys, urinary bladder, pancreas, intestinal tract, and spleen appear normal.
Based on the finding of bilaterally enlarged adrenal glands, you determine that Ivy has pituitary-dependent hyperadrenocorticism.
What would your recommendation have been if you received this ultrasonographic report instead? (There is more than one correct answer.)
The cranial pole of the right adrenal gland appears enlarged and irregularly shaped, measuring 12 mm at its widest aspect. The left adrenal gland is normal in size and appearance. The liver appears enlarged and is hyperechoic throughout. The rest of the abdominal examination is normal.
d. The report supports a diagnosis of adrenal-dependent hyperadrenocorticism, so you recommend a fine-needle aspirate of the enlarged pole of the right adrenal gland to look for evidence of neoplasia.
Please match the following drugs to their mechanism of action:
|a. Trilostane||1. Adrenal cytotoxic agent that causes necrosis of the zonas fasciculata and reticularis|
|b. Mitotane||2. Inhibits cytochrome p450 systems|
|c. Selegiline||3. Competitive inhibitor of 3-beta hydroxysteroid dehydrogenase, one of the enzymes required for cortisol synthesis|
|d. Ketoconazole||4. Inhibits monamine oxidase-B (MAO-B) to increase dopamine concentrations|
You decide to start giving Ivy trilostane at a dosage of 1.2 mg/kg (one 10-mg capsule) orally twice a day. While the package insert for this drug states a starting dose of 2.2 to 6.7 mg/kg once a day, recent research suggests that a lower starting dose given twice daily is a safer and still effective starting point.1,2
You instruct Ivy’s owners to give the medication with food and watch carefully for any decrease in appetite or any vomiting, diarrhea, or lethargy and to call you if there are any problems. You also send home prednisone and instruct them to give Ivy 2.5 mg (a physiologic prednisone dose is 0.2 to 0.25 mg/kg once a day) if they note any of those signs. You also schedule a recheck visit in 10 to 14 days.
For the recheck, you tell the owners to give the trilostane with food at the usual time in the morning and then bring Ivy in so an ACTH stimulation test can be done four to six hours after trilostane administration (per the label). Because trilostane works by blocking cortisol production, the timing of the test is important so you can evaluate the cortisol concentrations when the drug is at its peak effect. You will also repeat a urinalysis and culture at the recheck.
The owners return 10 days later and report that Ivy is doing well. She is still drinking a lot of water but it seems less than before. She also seems to be eating a closer to normal amount of food and hasn’t been caught stealing food. She has also completed her amoxicillin treatment.
You confirm the time of Ivy’s morning trilostane dose then perform an ACTH (5 µg/kg cosyntropin given intravenously) stimulation test.
Ivy’s test results:
• Baseline serum cortisol concentration: 3.3 µg /dl
• One-hour post-ACTH serum cortisol concentration: 12.5 µg /dl
• Ivy’s urine bacterial culture result is negative.
What are your recommendations for Ivy based on these test findings?
a. Because Ivy's clinical signs reveal mild improvement, and although the trilostane package insert states to increase the dose if the ACTH stimulation test results reveal a post-ACTH serum cortisol concentration > 9.1 µg/dl, you decide to continue the current dose of trilostane and schedule a recheck in one month.
b. While she seems to be responding well clinically, her clinical signs are still present and her post-ACTH cortisol concentrations are above the goal range of 5.4 to 9.1 µg/dl, so you opt to increase her trilostane to 20 mg twice a day and plan on rechecking her again in two weeks.
c. Since her post-ACTH cortisol concentrations are still above the range of 5.4 to 9.1 µg/dl and her clinical signs have not resolved, you decide to switch Ivy to once a day therapy at a higher dose—30 mg once a day.
You explain to Ivy’s owners that this initial ACTH stimulation test was done to check whether her trilostane dose needed to be reduced. Even though her test results are above the treatment reference range, she is improving clinically so the plan is to continue on the current dose, keep monitoring her clinical signs, and recheck her ACTH stimulation test results in a month.
The owners return about six weeks later and report that Ivy is still drinking more than usual and her appetite has been about the same. She has received trilostane as recommended (10 mg twice a day with food), and her last dose was 4.5 hours ago. Her physical examination findings are normal, but she has gained 1.3 kg; her current weight is 9.5 kg.
The results of a serum chemistry profile are normal except for an alkaline phosphatase activity of 1,200 IU/L (reference range 5 to 131 IU/L).
Ivy’s ACTH stimulation test results:
Baseline serum cortisol concentration: 2.3 µg/dl
One-hour post-ACTH stimulation cortisol concentration: 10.2 µg/dl
What do you recommend for Ivy at this time?
b. Because Ivy’s clinical signs are still present, her post-ACTH stimulation cortisol concentration is still > 9.1 µg/dl, and she has now been receiving this trilostane dose for about two months, you decide to increase the dose.
c. Because Ivy’s clinical signs are still present, her post-ACTH stimulation cortisol concentration is still > 9.1 µg/dl, and she has now been receiving this trilostane dose for about two months, you decide to discontinue trilostane and start mitotane treatment instead.
At this time, you feel the best course of action is to increase Ivy’s trilostane dose by about 50%. In order to administer a new dose of 15 mg every 12 hours, the drug will need to be compounded because the next capsule size available is 30
-mg. Once Ivy begins this dose, you recommend another ACTH stimulation test in two weeks.
The owners return in two weeks and report that Ivy is doing great. Her water intake is back to normal, and she is acting like herself again. The results of her ACTH stimulation test at this visit are:
Baseline serum cortisol concentration: 1.5 µg/dl
One-hour post-ACTH stimulation cortisol concentration: 6.2 µg/dl
Ivy’s clinical signs have resolved and her ACTH stimulation test results are within the target treatment range, so you recommend another recheck in three months. You explain to Ivy’s owners that if Ivy continues to do well, she will need to be re-evaluated with a physical examination and an ACTH stimulation test and serum chemistry profile every three months for the rest of her life. Routine bacterial cultures of her urine should also be considered starting with her next recheck because silent infection will continue to be a health concern.
Because management of hyperadrenocorticism with the frequent recheck veterinary visits required can become costly for pet owners, once Ivy is doing well clinically you could consider evaluating only a resting serum cortisol concentration to assess disease control. For example, if the resting cortisol concentration is between 1.3 and either 2.9 µg/dl or ≤ 50% of the pretreatment baseline cortisol concentration and her clinical signs are controlled, then you can consider continuing the same trilostane dose.4 There are instances, however, where these results can be misleading and the patient may be receiving too much trilostane, which may not be reflected in a single cortisol value. Consider the individual patient and their clinical signs before deciding whether a resting cortisol concentration alone may be sufficient.
Good job, doc!
1. Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2011;238(11):1441-1451.
2. Cho KD, Kang JH, Chang D, et al. Efficacy of low- and high-dose trilostane treatment in dogs (< 5 kg) with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2013;27(1):91-98.
3. Alenza DP, Arenas C, Lopez ML, et al. Long-term efficacy of trilostane administered twice daily in dogs with pituitary-dependent hyperadrenocorticism. J Am Anim Hosp Assoc 2006;42(4):269-276.
4. Cook AK, Bond KG: Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. J Am Vet Med Assoc 2010;237(7):801-805.