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3/10/2016
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Update on Canine
Hyperadrenocorticism (HAC) Management and Treatment
Kathy Engler, DVM, DABVP
Dechra Veterinary Products
1-866-933-2472
Hyperadrenocorticism (HAC)
• Pathophysiology
• Clinical signs
• Diagnostics & Differentiation
• Treatment/Monitoring
• Cases & common ?’s
Pathophysiology
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Adrenal Glands Cortex
• Glucocorticoids – (cortisol / corticosterone)
• Mineralocorticoids – (aldosterone)
• Androgens – (precursors of sex hormones)
Medulla
• Catecholamines – (adrenaline/noradrenaline)
Hypothalamic-Pituitary-Adrenal Axis
Normal Positive feedback
Negative feedback
BILATERAL
HYPERPLASIA
PDH
CONTRALATERAL
ATROPHY
ADH
Etiology of HAC
• Pituitary dependent (80-85%)
• Adrenal dependent (15-20%)
• Iatrogenic
• Food induced
• Atypical
Macroadenoma in the pituitary gland
From: BSAVA Manual of Canine & Feline
Endocrinology 3rd edition, 2004. Chapter 15
‘Canine Hyperadrenocorticism’ by Michael Herrtage
Liver neoplasia secondary to a malignant adrenal
tumor
Photo courtesy of Dr Reto Neiger
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Atypical HAC
• Clinical Signs
• Normal UCCR, ACTH stim
& LDDS
• Sex Hormone evaluation
• May respond to tx for
HAC
Clinical Signs
Cortisol has more diverse effects on
the body than any other hormone Liver
– Increased gluconeogenesis
– Increased glycogen stores
– Induction of certain enzymes
Muscle
– Increased protein catabolism leads to muscle wasting and weakness
Bone
– Osteopenia associated with increased protein catabolism and neg. calcium balance
Skin
– Increased protein catabolism – thin skin, poor wound healing and poor scar formation
– Possible calcium deposition
Adipose Tissue
– Increased lipolysis
– Redistribution of fat deposits
Blood
– Decreases in circulating lymphocytes
– Decreases in circulating eosinophils
– Increase in circulating neutrophils
Immune System
– Diminished inflammatory response
– Reduced immune response
Kidney/Urinary
– Increased GFR and interference with vasopressin release or action (polyuria)
– Increased calcium excretion
CNS
– Euphoria, depression, other
behavioral changes
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Hyperadrenocorticism (HAC)
Quality of life issue for both dog
and owner
• Chronic & progressive
• Not immediately life-threatening
• Owners often confuse signs with aging
Treating a patient with Cushing’s
can restore their quality of life.
HAC Signalment
• Middle age to older – Typically > 6 yr
• Male = Female
• Many breeds: – Poodles, Dachshunds, various Terrier breeds, G.
Shepherd, Labrador commonly represented
– Boxer and Boston Terrier ↑ risk (Feldman, Nelson 3rd ed. p 265)
Hyperadrenocorticism
is a CLINICAL
diagnosis
What you hear…
• Excessive thirst and urination
• Robust appetite
• Hair coat changes
• Panting
• Weakness
• Infections
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… and what you see
• Thin hair coat
• Poor growth following clipping
• Thin skin
• Comedones
Princess • 13-year-old, 9 pound, female (c), Maltese
• Hx of pedal pruritus summer/fall responsive to antibiotic/corticosteroid tx
• Developed facial pruritus – not responsive to tx
• PE: hair coat diffusely thin, pot-bellied appearance, ventral abdominal skin moderately striated w/ reduced elasticity, and numerous papules, pustules and epidermal collarettes over entire body.
• Skin scrape: Demodex canis
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…and other common findings
• Hypertension
• Hyperproteinuria
• Hypercoagulability
– Risk for pulmonary thromboembolism (PTE)
Clinical Signs HAC unlikely to
have: • Poor appetite
• Vomiting and/or diarrhea
• Coughing, sneezing
• Pain
• Seizures
• Bleeding
• Pancreatitis – VERY RARE!
• Renal failure – VERY UNUSUAL
Feldman,Nelson: Canine and Feline
Endocrinology and Reproduction
Diagnostic/Differentiation tests
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Clinical Pathology
Chemistry
+/- Hyperglycemia
ALKP, Cholesterol, Triglycerides
+/- Hyperphosphatemia
Stress Leukogram Neutrophilia
Monocytosis
Lymphopenia
Eosinopenia
Urine Analysis Low USG <1.020
+/- Glucosuria
Proteinuria
UTI-usually silent
↑ HCT, platelets
Diagnosing Cushing’s
All available diagnostic tests have weaknesses
• UCCR (Urine Cortisol:Creatinine Ratio)
• LDDS (Low dose dexamethasone suppression)
• ACTH stimulation test
UCCR
• Highly sensitive
– Negative r/o’s HAC
• Poor specificity
– Stress
– Other dz
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LDDS
• High sensitivity
• False + >
56% of cases
• 10% of PDH
dogs normal
results
• Low specificity 0
50
100
150
200
250
0 2 4 6 8 10
Pla
sm
a c
ort
iso
l (n
mo
l/l)
Time (hours post dexamethasone)
LDDS Test
?PDH/ ADH
PDH
Normal
HY
PE
RA
DR
EN
OC
OR
TIC
ISM
Normal
• Is patient’s negative
feedback intact?
ACTH Stimulation
• Low sensitivity
• 20-30% false
negatives
• High specificity
• Iatrogenic HAC
Princess
• CBC – WNL
• Serum chemistry:
– Alk Phos 1456 IU/L (12 – 118 IU/L)
– GGT 62 IU/L (1 – 12 IU/L)
• Total T4: 0.8 µg/dl (1 – 4 µg/dl)
– Free T4 & TSH concentrations WNL
ACTH Stim: pre – 2.7 µg/dl & post 47.3 µg/dl
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PDH vs ADH
• Low Dose Dex
60% of + Patients
• Imaging • Radiography
• Ultrasound
• CT/MRI
• Endogenous
ACTH Contact Lab
• High Dose Dex
Princess
• Abdominal ultrasound:
– Bilaterally enlarged adrenal glands w/ no evidence of
an adrenal tumor
Treatment/Monitoring
ACTH Stimulation
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Why treat Cushing’s?
• Risk of chronic skin infections
• Risk of chronic urinary/kidney infections
• Risk of developing diabetes secondary to
hypercortisolemia
• Chance of resolving hypertension—present in 75%
of HAC cases1
• Chance of resolving proteinuria—present in 50% of
HAC cases1
Most important reason--Improve the quality of life of the
pet and pet owner, and decrease the likelihood of
euthanasia due to annoying clinical signs
1 Dr Mark Peterson veterinary endocrine blog http://endocrinevet.blogspot.com
Treatment Options
Surgical • Adrenalectomy
• Hypophysectomy
Medical • Vetoryl® Capsules (trilostane)
• Anipryl® (selegiline)
• Lysodren® (mitotane)
• Ketaconozole
Radiation
VETORYL® Capsules (trilostane)
Available in 5 mg, 10 mg, 30 mg,
60 mg and 120 mg capsules
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VETORYL Capsules
Vetoryl® (trilostane) reversibly inhibits 3ß-
hydroxysteroid dehydrogenase
Vetoryl® (trilostane) reversibly inhibits
3ß-hydroxysteroid dehydrogenase
Cortisol levels following
VETORYL Administration
0
10
20
30
40
50
60
70
80
0 4 8 12 16 20 24
Hours post-pill
Me
an
se
rum
co
rtis
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)
VETORYL Capsules
• 1-3 mg/lb (2.2-6.7 mg/kg)
• Start LOW
• Round DOWN
• Administer SID
• Administer w/ Food
• 3 X absorption
NO Induction Period
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Initial Monitoring • 10-14 days!
• Assess Clinical Signs
• 4-6 hrs Post-Pill (w/ Food)
• ACTH stim,
Chem/Electrolytes
0
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40
50
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80
0 4 8 12 16 20 24
Hours post-pill
Mean
seru
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)
Initial Monitoring
• ACTH Stim Target range = 1.45 -9.1 µg/dL
• Goal is to unmask oversuppression • Or any impending potential for it
• Do NOT increase dose yet
• Cortisol levels will continue to drop with time
• If cortisol is < 1.45 µg/dL or low normal
• the dose
Long-Term Monitoring
• Clinical Signs
• ACTH stim, Chem panel with electrolytes • +/- CBC
• 4 and 12 weeks
• From initiation of therapy
• Q3 Months • Once dose established
• Dose Adjustments • Repeat stim 10-14 days later
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What to expect with Success!
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
TreatmentDay 14
TreatmentDay 28
TreatmentDay 42
TreatmentDay 84
% Improved Clinical Signs
Activity (N=33)
Appetite (N=57)
Panting (N=47)
Thirst (N=76)
Urination (N=74)
Princess
• Initial ACTH stimulation: – pre – 2.7 µg/dl & post 47.3 µg/dl
• Started 10 mg VETORYL capsule SID AM w/ food
• 14 day re-check: – Clinically improving
– ACTH stim 2.7 µg/dl & post 10.3 µg/dl (1.45 – 9.1 µg/dl)
• Continued current dose – (ACTH stim at 4 weeks and 3 months WNL)
• Day 45 – Demodex counts decreased significantly
• Day 90 – skin scrape negative & new hair growth evident w/ minimal pruritus
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Princess
• 5-months after initiating treatment….
• Represented w/ facial crusting and pruritus after owners had been out of town (stayed w/ relatives)
• Discovered VETORYL Capsules discontinued for 30 days before examination
• Skin scraping positive for demodicosis and superficial bacterial infection
• Treatment reinitiated
Moral of the story…
• Client compliance key
– Easy to become complacent w/ medication
administration for chronic dz
• Once pet looking better and acting normal…
– Client communication key
• Client literature
• Follow-up calls/emails from veterinary team
Cases & Common ?’s
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Q: Should I put my patient on once
daily or twice daily Vetoryl?
A: Default to once daily…
Case 1
• 25 pound Beagle
• 30 mg Vetoryl® SID for 2 wks
• ACTH stim (1.45-9.1 µg/dL)
pre 6.7
post 18.0
• Why this result?
Owner Compliance?
Is Vetoryl being given at night?
Was Vetoryl given that morning?
Was Vetoryl given with food?
Are clinical signs improving?
Owner able to medicate?
How are they medicating
the dog?
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Case 1
• 25 pound Beagle
• 30 mg Vetoryl® SID for 2 wks
• ACTH stim (1.45-9.1 µg/dL)
pre 6.7
post 18.0
• What did the owner report?
• Would you change the dosage?
Case 2
• 35 pound mix breed
• 30 mg Vetoryl SID for 8 weeks
• PU/PD, panting in the evening only
• Otherwise owner happy
• ACTH (1.45-9.1 µg/dL)
pre 2.5 µg/dL
post 7.0 µg/dL
• What do you think?
Case 2
• 35 pound mix breed
• 30 mg Vetoryl SID for 8 weeks
• PU/PD, panting in the evening only
• Otherwise owner happy
• ACTH (1.45-9.1 µg/dL)
pre 2.5 µg/dL
post 7.0 µg/dL
30 mg A.M.; 10 mg P.M.
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Case 3
• 62 pound, male castrated, Weimaraner – R adrenal 2.5 cm mass (ultrasound)
• Started 60 mg Vetoryl SID
• 2 weeks recheck: – Still PU/PD
– Frequent nocturia & accidents
• ACTH stim (1.45-9.1 µg/dL)
pre 1.8 µg/dL
post 4.2 µg/dL
• What do you think?
Case 3
• 62 pound, male castrated, Weimaraner
– R adrenal 2.5 cm mass (ultrasound)
• New Treatment Plan:
– Split current Vetoryl dose
30 mg PO BID
• Recheck in 2 weeks
VETORYL CAPSULE- How can
SID work?
0
10
20
30
40
50
60
70
80
0 4 8 12 16 20 24
Hours post-pill
Me
an
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)
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How might SID fail?
0
10
20
30
40
50
60
70
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0 4 8 12 16 20 24
Hours post-pill
Me
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Adjusting VETORYL Capsules
Consider BID dosing if…
• Clinical signs evening/during the night, but
controlled during day
• Clinical signs NOT improving
BUT post-ACTH is < 9.1 µg/dL
• The patient is diabetic
Diabetic Patients
• Often Concurrent
• Difficulty Regulating
• LDDS & ACTH +
• Vetoryl BID
• ↓ Insulin by 50%
• Monitor!!!
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1-3 mg/lb SID or BID
SID to BID Options
• 60 mg SID → 30 mg BID
• 60 mg SID → 60 mg AM, 10 mg PM
Q: What do I do if a dog on Vetoryl
has increased potassium but no
other problems?
A: Consider all causes…
Reasons for Hyperkalemia
1. Suppression of aldosterone – Unlikely, but can occur
– No action needed if < 6 mmol/L • Decrease dose if higher
2. Concurrent drug use – ACE inhibitors
– Spironolactone (contraindicated) – Potassium citrate administration
3. Thrombocytosis – Common in dog w/ HAC
• Often > 600,000/µl
– K+ released during sampling
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Case 4
• 50 pound mixed breed dog
• 60 mg once a day for 2 wks
• ACTH stim post-cortisol = 1.5 µg/dl (1.45-
9.1)
• Do you adjust the dose?
• If so, how?
• What else should you
know?
Adrenal Hormone Deficiencies Weakness, Lethargy, Anorexia, Vomiting
Glucocorticoid
• Cramping
• Hypoglycemia
• Wt. Loss
• 7-10 days
“Cortisol Withdrawal
Syndrome”
Mineralocorticoid
• Diarrhea
• Collapse
• Shock
“Addisonian Crisis”
Differentiation Electrolytes & ACTH Stim
STOP Vetoryl!!!!
Wait ~ 7 Days
Lower Vetoryl Dose
Cortisol Withdrawal
Supportive Care IV Fluids
Glucocorticoids
Mineralocorticoids
Wait for HAC
signs to return
Repeat ACTH stim
Addisonian Crisis
STOP Vetoryl!!!!
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Case 4
• 50 pound mixed breed dog
• 60 mg once a day for 2 wks
• ACTH stim post-cortisol = 1.5 µg/dl
• Electrolytes were NORMAL
Stop Vetoryl, wait 7-10
days, repeat bloodwork,
lower dose
Q: What do you do if the patient has
acceptable ACTH stim results but an
elevated or increasing ALP?
A: Don’t worry…but US the liver.
ALP Activity • Do not expect the ALP to return to normal
– Persistent vacuolar change in most dogs
– Cortisol readily drives this process
• Monitor ALT activity
– Hepatocellular injury
– Modest increases much more important
• Consider ultrasonography
– Liver mass
– GB mucocele
• Related to HAC
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Case 5
• 12 yr old F(s) 18 pound Bichon Frise
• Hx of GB mucocele, elevated BP, PU/PD,
urinary accidents and elevated liver enzymes for
6 months not responding to therapy
– Denamarin, ursodiol, benazepril
• ACTH stim:
– pre 3.4 µg/dl and post 28.2 µg/dl
• Started 10 mg Vetoryl SID
Case 5
• 12 yr old F(s) 18 pound Bichon Frise
• Started 10 mg Vetoryl SID
• 2 days later patient vomited, anorexic
• Vetoryl discontinued
• Day 3 - trembling seen and patient painful
• Ultrasound – GB rupture w/ diffuse bile peritontitis
Take home points…
• Need to weigh risk of surgery
– Compromised healing
– Increased risk of PTE
– Increased risk of post op infection
• May be best to tx surgically before initiating tx of
HAC in some cases
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Q: What factors should be considered
if a dog is not responding to Vetoryl?
A: Define the problem…
Poor response to Vetoryl means…
1. Post ACTH stim cortisol > 9.1 µg/dl
– Check source – FDA approved vs. compounded
• ACTH gel & trilostane
– Given with food
– Increase dose gradually
– Small dogs need more
Vetoryl® (trilostane) Capsules
vs. compounded trilostane
Compounded
• Not FDA approved
• Variability in
dissolution and
content
• No tech support
• Liability – VET!
Vetoryl® Capsules
• FDA approved
• Consistent
dissolution
• Confidence in content
of capsule
• Tech support
• Liability – using
approved product
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Vetoryl® (trilostane) Capsules
vs. compounded trilostane Cook, Audrey K., BVM&S, et al, Pharmaceutical Evaluation of Compounded Trilostane Products." Journal of the American
Animal Hospital Association 48.4 (2012): 228-33.
Study published in 2012, evaluated 96 batches of compounded trilostane
• 38% of compounded batches were below the acceptance criteria for content.
• Average % label claim for each batch ranged from 39% to 152.6%
• 20% (19 of 96 batches) of compounded batches failed to meet dissolution criteria
Vetoryl® (trilostane) Capsules
vs. compounded trilostane Cook, Audrey K., BVM&S, et al, Pharmaceutical Evaluation of Compounded Trilostane Products." Journal of the American Animal Hospital Association 48.4 (2012): 228-33.
Study published in 2012, evaluated 96 batches of compounded trilostane
• 38% of compounded batches were below the acceptance criteria for content.
• Average % label claim for each batch ranged from 39% to 152.6%
• 20% (19 of 96 batches) of compounded batches failed to meet dissolution criteria
“On the basis of these
findings, compounded
trilostane products should
be used with caution as
they may jeopardize the
management of dogs with
HAC and potentially
impact patient safety”
Poor response to Vetoryl means…
2. Signs of HAC but acceptable cortisols
– Increase frequency of administration
3. Severe polydipsia
– Pyelonephritis
– Diabetes mellitus
– Diabetes insipidus
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Rare Neuro Signs - PDH
• May occur during TX
• NEURO Signs • Tumor compression
• Removal of anti-inflammatory effects of cortisol
• Not a direct side effect
• MACROADENOMAS • Concurrent CENTRAL DIABETES
INSIPIDUS
dullness, depression,
disorientation, loss of learned
behavior, anorexia, aimless
wandering or pacing, head
pressing, circling, ataxia,
blindness, seizures,
anisocoria
Things to know about…
• Corticosteroid-Responsive Underlying disease • Osteoarthritis
• Allergic Skin Disease
• Cautions –ACE Inhibitors
• Contraindications –K+ Sparing Diuretics
And finally…
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Side Effects • The most common side effects reported were:
– Anorexia
– Lethargy/depression
– Vomiting, diarrhea
– Elevated liver enzymes
– Elevated potassium with or without elevated sodium
– Elevated BUN
– Decreased Na/K ratio
– Hypoadrenocorticism
– Weakness
– Elevated creatinine
– Shaking
– Renal insufficiency
– In some cases, death has been reported as an outcome of these adverse events.
Contraindications
• Hypersensitivity
• Primary hepatic or renal
• Pregnant or nursing
• Breeding animals
• Caution in animals less than 3kg
• Do not divide or open capsules
Adrenal Necrosis “Supports the hypothesis that adrenal lesions
seen in trilostane-treated dogs with PDHAC
are caused by elevated ACTH levels and not by
trilostane per se.”
• RARE Side Effect
• Lysodren
• Monitor!
Burkhardt, WA, et al. Domestic Animal
Endocrinology (2011) pp. 155-164
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Multiple support
materials available
from Dechra
• Algorithms
• Technical
brochure
• Client brochure
Vetoryl Key Points
• Get the diagnosis RIGHT; don’t treat if asymptomatic
• Start @ the low end of the dose range, SID, WITH food
• NEVER miss early monitoring (10-14d)
• Change dosage based on clinical signs and blood work at 30+ day testing
• Over-suppression and glucocorticoid withdrawal most common consequences
• Beware of long-term changes in dose requirements
Additional Resources
• Vetoryl (trilostane) Capsule package insert
• Dechra Technical Services Team: 866-933-2472
• Dechra online CE: www.DechraCE.com
• Dechra technical brochures
• Dr. Mark Peterson blog:
http://endocrinevet.blogspot.com
• Dechra Field Sales Managers
• Website: www.dechra-us.com
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Beau and Cody
