VetCpd

Adrenal Disease Notes

Sophie Keyte BVMS (Hons) MVetMed (Dist) DipACVIM MRCVS
Sophie.keyte@bristol.ac.uk


Canine Hyperadrenocorticism – Cushing’s Syndrome

Summary
• Hyperadrenocorticism occurs due to excessive production of cortisol as a consequence of pituitary
(most common) or adrenal tumours
• Common clinical signs: PUPD, pot-belly, polyphagia, panting, dermatologic, lethargy.
• Compatible clinical and haematological/biochemical abnormalities (steroid leukogram, ↑ALKP) should
be present before further testing is performed. Can be a difficult diagnosis to confirm – no test is
perfect.
• Screening tests
o to rule out disease: LDDST or UCCR
o in unwell patient: ACTH stimulation test
• Discriminatory tests (PD-HAC vs AD-HAC)
o Endogenous ACTH; HDDST; Imaging
• Treatment
o Trilostane the only licensed drug – close monitoring required
o consider referral for surgery for Hypophysectomy or adrenal tumours
o radiation
• Prognosis – reasonable if well managed. Beware medical complications.


Canine hyperadrenocorticism is classified as pituitary dependent (PD-HAC), adrenal dependent (AD-HAC), or
iatrogenic (due to administration of glucocorticoids). The adrenal gland is responsible for production of various
hormones: mineralocorticoids (zona glomerulosa); glucocorticoids and sex hormones (z. fasciculata and z.
reticularis); and catecholamines (medulla). Cushing’s syndrome is the clinical consequence of chronic excessive
cortisol secretion.

Regulation of glucocorticoid release

CRH Hypothalamus
Stimulation
Negative feedback

ACTH Anterior pituitary gland

Adrenal glands

Cortisol

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Diagram of steroid biosynthesis
Cholesterol Pregnenolone

17α hydroxypregnenolone Dehydroepiandrosterone

3βhydroxysteroid
dehydrogenase 3βhydroxysteroid 3βhydroxysteroid
dehydrogenase dehydrogenase

Progesterone 17α hydroxyprogesterone Androstenedione

11-deoxycorticosterone 11 deoxycortisol 21 deoxycortisol

Testosterone
Corticosterone

Oestradiol
Aldosterone Cortisol

Pathophysiology
• Pituitary-dependent disease (PD-HAC) is most common, particularly in small breeds of dogs, accounting
for approximately 85% of cases. Excessive production of ACTH results in bilateral adrenal hyperplasia and
stimulation of excessive cortisol production, with loss of negative feedback control. Adenoma of the pars
distalis is the most common histological finding (in dogs). In the majority of dogs the tumours are small
(<1cm) and don’t cause CNS signs; however about 10-20% of cases have macroadenomas (>1cm) which
have the potential to cause neurological signs.

• Adrenal-dependent disease (AD-HAC) is less common, accounting for 15-20% of Cushing’s cases.
Adenomas and carcinomas occur with similar frequency. Carcinomas are often bigger and may invade
surrounding structures such as the vena cava or kidney. AD-HAC results in excessive, autonomous
production of cortisol from the neoplastic adrenal gland, which suppresses ACTH production. Lack of
ACTH results in atrophy of the contralateral adrenal gland.

• Iatrogenic hyperadrenocorticism occurs as a result of excessive administration of exogenous
glucocorticoids, often given to control allergic or immune-mediated disorders. Suppression of
endogenous CRH and ACTH production results in bilateral adrenal atrophy.

Clinical features
Median age 10 years (has been reported as young as 1 year old). Clinical signs are caused by the effects of excessive
circulating levels of cortisol. Dogs usually present bright and alert and medically stable, but with a mixture of the
following signs noted by the owner:
• PUPD (>80%)
• Pot-bellied appearance (54%)
o due to redistribution of fat, muscle weakness and hepatomegaly
• Dermatological changes (50%)
o Endocrine alopecia (bilaterally symmetrical, non-pruritic)
o Calcinosis cutis
o Hyperpigmentation
• Polyphagia (44%)
• Exercise intolerance (28%)
• Panting (18%)

Less commonly
• Neurologic signs (pituitary macroadenomas)
o Stupor, ataxia, aimless wandering, circling, pacing

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 • Medical complications
o Pulmonary thromboembolism
o Diabetes mellitus
o Urinary tract infections (may not be symptomatic due to anti-inflammatory effects of cortisol)
o Urinary calculi
o Systemic hypertension
o Pancreatitis
o Glomerulopathy and proteinuria

Diagnosis

Diagnosis of HAC depends on demonstration of either:

(1) increased cortisol production or
(2) decreased sensitivity of the hypothalamic-pituitary-adrenal axis to negative feedback by glucocorticoids.

The American College of Veterinary Internal Medicine has published a consensus statement on the diagnosis of HAC
in dogs, and there are many excellent reviews on this topic (Behrend and others 2013; Kooistra, H.S., Galac, S., 2010;
Melian, C. and others 2004).

STEP 1: Clinical signs and positive screening tests

History and clinical signs

• It is essential that some compatible historical and clinical features are present before pursuing a diagnosis of
hyperadrenocorticism. No test is 100% accurate and false positives will increase dramatically in a poorly
selected patient population.

Haematology
• Screening test
• Stress leukogram (mature neutrophilia, monocytosis, eosinopenia, lymphopenia)
• Mild erythrocytosis
• Thrombocytosis

Biochemistry
• Screening test
• Increased alkaline phosphatase (steroid-induced isoenzyme) (85-95% cases, can be up to 10X RI)
• Increased alanine aminotransferase (mild-moderate only)
• Increased fasting bile acids (up to 30% cases)
• Hypercholesterolaemia, hypertriglyceridemia (lipaemia) (>50% cases)
• Hyperglycaemia (mild unless concurrent diabetes mellitus)
• Be aware cPLI is increased in dogs with HAC – interpret with caution
• Serum total thyroxine (TT4) and free T4 (fT4) concentrations are commonly decreased in dogs with HAC–
interpret with caution.

Urinalysis
• Important in evaluation of any PUPD case
• USG 1.001-1.030 (most <1.020)
• Urinary tract infection (NB sediment often unremarkable – important to culture) (40-50% cases)
• Proteinuria (UPC not usually >6)
• Glycosuria if diabetic

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Tests of the pituitary-adrenocortical axis
These should only be performed in the presence of strong clinical suspicion with suggestive history, clinical signs,
and haematological/biochemical findings. Treatment of HAC is expensive and there is little point pursuing a specific
diagnosis if treatment will not be an option; save any finances that are available to treat any associated
complications e.g. UTI. There is no ideal test to confirm HAC. Dogs with non-adrenal illness can have false positives,
and dogs with HAC can have false negative results. A combination of tests may be required for the disease to be
diagnosed with confidence; ideally at least two positive screening tests. If more than one test is negative then the
patient is highly unlikely to have HAC.

a) Screening tests
• Urinary cortisol: creatinine ratio (UCCR)
o High sensitivity but poor specificity i.e. false positives are common – useful to help exclude HAC
o Should be performed on 2 consecutive morning free-catch urine obtained by the owner at home, at
least 48h after stress event (e.g. visit to vet), to minimise effects of stress
o In some countries, UCCR is measured pre and post administration of oral dexamethasone at home,
as a form of dexamethasone suppression test. This is a useful option for dogs that get very stressed
in the hospital or are difficult to blood sample. Protocol available from Cambridge Specialist
Laboratory Services.

• ACTH stimulation test – a test of adrenal reserve

o Rapid, simple, safe screening test
o Measure serum cortisol before and 1 hour following administration of exogenous ACTH I/V
o Abnormal response – post ACTH cortisol >600nmol/l (exact cut-off varies with lab)
o 57-95% sensitive for HAC overall; about 80% sensitive for PD-HAC and about 60% sensitive for AD-
HAC; false negative therefore quite common. Specificity about 90% - false positives do occur but
rarely if case selection appropriate. Useful to support diagnosis (although beware false negatives) or
in patients with other disease (fewer false positives than LDDST).
o Doesn’t distinguish between pituitary and adrenal dependent disease
o Only test that diagnoses iatrogenic hyperadrenocorticism (flat-line response)
o Often used to monitor response to treatment





Hyperadrenocorticism – post ACTH cortisol >600nmol/l


Cortisol Normal dog
concentration

Iatrogenic disease

Time

• Low-dose dexamethasone suppression test (LDDST) – test of intact negative feedback
o Measure serum cortisol before and 3 and 8 hours following I/V administration of a low dose
(0.01mg/kg) of dexamethasone
o Avoid feeding during the test
o Good sensitivity (85-100%), but poor specificity (44-73%) – false positives common in dogs with non-
adrenal illness. Therefore, useful to exclude HAC – if LDDST normal, HAC is unlikely.
o In normal dogs, prolonged suppression of cortisol production occurs due to reduced ACTH
production

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 o Suppression is defined as
• Cortisol <40nmol/l at 3 and 8 hours post dexamethasone, and
• Cortisol <50% basal at 3 hours post dexamethasone, and
• Cortisol <50% basal at 8 hours post dexamethasone
o 8-hour sample useful to confirm HAC (i.e. >40nmol/l); 3 or 4-hour sample useful to help discriminate
between PD-HAC and AD-HAC
o Although used as a screening test, can also be useful to discriminate between PD-HAC and AD-HAC
• Most dogs with PD-HAC will suppress at 3 hours but escape at 8 hours
• 40% of dogs with PD-HAC and all dogs with AD-HAC will fail to suppress

AD-HAC; PD-

HAC



Cortisol PD-HAC
concentration




Normal dog


Time
0 hr 3 hr 8 hr

• 17-Hydroxyprogesterone assay
o may be considered in equivocal cases – some cases may have increased concentrations
o can use samples previously submitted for ACTH stimulation test – contact laboratory

ACVIM consensus statement summary: http://onlinelibrary.wiley.com/doi/10.1111/jvim.12192/epdf

Summary of test characteristics

Test Sensitivity Specificity

ACTH stimulation test 57 - 95% 59 – 93%

Low-dose dexamethasone suppression test (LDDST) 85 – 100% 44 – 73%

Urine cortisol: creatinine ratio (UCCR) 99% 20 – 77%

STEP 2: Differentiation

b) Tests to differentiate PD-HAC from AD-HAC
• Endogenous ACTH
o Very useful test
o Considered the most accurate stand-alone differentiating test
o Special sampling requirements; contact laboratory for details
o 60% of dogs with AT have undetectable ACTH concentrations
o 85% of dogs with PDH have ACTH concentrations >45pg/ml

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 o Concentrations between 10 and 45pg/ml are unhelpful - causes of results in “grey area” may include
pulsatile release of ACTH or sample degradation
• High-dose dexamethasone suppression test (HDDST)
o Similar to LDDST but 0.1mg/kg dexamethasone
o Regardless of dose, AD-HAC will not suppress
o 15% of PD-HAC will still fail to suppress even with high-dose dexamethasone
• Imaging
o Not usually necessary for diagnosis of HAC, but useful to differentiate PD-HAC from AD-HAC –
requires experienced personnel. Width of adrenal gland is most significant measurement. Adrenal
glands MAY be normal.
o Abdominal radiographs commonly show pot-belly, hepatomegaly, urinary bladder distension, +/-
calcification of adrenal glands, adrenal masses
o Thoracic radiographs commonly show calcification of trachea and bronchi
o Ultrasound – the presence of bilaterally normal-sized or enlarged adrenals in a dog diagnosed with
hyperadrenocorticism is highly suggestive of PD-HAC. AD-HAC is usually identified by an adrenal
mass; the contralateral gland is usually small and difficult to identify.
o CT and MRI may be used to evaluate the pituitary gland or the adrenal glands. Over 90% of dogs
have a detectable pituitary tumour.
o It is the authors recommendation that pituitary imaging is offered to every diagnosed case of PD-
HAC

Treatment of PD-HAC
It is not always possible to confirm a diagnosis of HAC with complete certainty. However, treatment should only be
initiated in cases where there is a high index of suspicion, based on history, clinical signs, haematology/biochemistry
and specific testing. Inappropriate treatment can be dangerous. HAC is a progressive disorder and, in equivocal
cases, it is sensible to withhold treatment, monitor and re-evaluate at a later date if necessary.

What is your target?

TARGET
ADRENAL PITUITARY

Medical Mitotane Selegiline
Trilostane Pasireotide
Ketoconazole Cabergoline
Others (under investigation) Retinoic acid
Gefitinib
Radiation therapy


Surgical Bilateral adrenalectomy Hypophysectomy

Medical treatment

• Trilostane (Vetoryl®; Dechra)
o Licensed for dogs in the UK
o Available as 5mg (directly from Dechra), 10, 30, 60 and 120mg capsules
o Give just prior to or with food to enhance absorption

o Mechanism of action: Competitive inhibition of 3β-hydroxysteroid-dehydrogenase enzyme in the
adrenal gland (essential for cortisol synthesis). (See steroid biosynthesis diagram above)

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 o Initial dose: currently licensed for once daily dosing with a starting dose of 2.2-6.7mg/kg PO. The
trilostane dose required to treat each individual patient varies greatly and therefore frequent
monitoring and dose adjustments are required. Limited availability of capsule leads to challenging
dosing in smaller dogs. Clinical experience suggests that trilostane doses towards the lower end of
the reference interval are often sufficient and would recommend that if once daily doing is
undertaken a starting dose of 1-2mg/kg PO SID is used. Although this may lead to more gradual
control of clinical signs in some dogs it reduces the risk of overdosing and associated serious and
potentially life-threatening complications.
o Studies have also shown that as patient body weight increases the required trilostane dose
decreases (Feldman 2011; Feldman and Kass 2012), further supporting lower starting doses,
particularly in some cases.
o No dose changes should be made within the first 2 weeks of treatment due to the risk of subsequent
overdosing.

o Frequency of administration: short-duration of action with plasma cortisol suppression lasting <20
hours. Therefore, several studies have investigated twice daily, lower dosing of trilostane (Arenas
and others 2013; Cho and others 2013; Feldman 2011; Vaughan and others 2008). In the above
studies twice daily, lower dosing of trilostane (0.2-1mg/kg PO BID) was shown to be effective,
associated with fewer side effects and more rapid improvement in clinical signs compared to once
daily dosing (likely due to more consistent cortisol suppression over 24hours). In addition, the total
trilostane dose administered over 24 hours required to achieve good control was lower on twice
daily dosing compared to once daily. This may have cost implications for owners, particularly those
with larger dogs.
o Recommended twice daily administration starting dose: 0.5-1mg/kg PO BID
o Some patients already receiving once daily trilostane have seemingly appropriate biochemical
monitoring but continued clinical signs of uncontrolled PD-HAC e.g. polydipsia/polyuria. In such
cases a pre-trilostane urine specific gravity (U.S.G) and ACTH stimulation test should be performed. If
pre-trilostane U.S.G is <1.020 (and glucose negative) alongside a pre-trilostane post-ACTH
stimulation test serum cortisol concentration >41nmol/l and <152nmol/l then the frequency of
trilostane administration should be increased as short duration of action is likely. As an alternative, a
pre-trilostane urine cortisol: creatinine ratio could be performed.
o Although twice daily dosing may not be possible (on a practical basis i.e. tableting or capsule size
availability) or necessary to enable good control for every patient consideration of starting on low
dose twice daily would be particularly recommended in patients where consistent control of
hypercortisolemia is even more essential e.g. those with concurrent diabetes mellitus, other
complications of uncontrolled PDH such as hypertension.

o Efficacy: > 80% dogs with HAC improve; most effective for PD-HAC but may work for AD-HAC
o PUPD resolves in 60% by 10 days and by a further 30% by 4 weeks; generally improved hair growth
in 3 months
o The presence of an underlying enteropathy can affect response to medications and this should be
considered in a patient not responding as expected to medical therapy.
o HAC is associated with cholestatic disease. PD-HAC dogs with cholestatic disease require higher
trilostane dosages than do those without cholestatic lesions. (Kim and others 2017)
o Despite frequent improvement in clinical signs poor long-term outcome is reported with trilostane
therapy alone: 30% 3 – year survival (Fracassi and others 2015).

o Side effects
Despite overall good drug tolerance but some serious side effects are reported. These include:
• Lethargy
• Vomiting and diarrhoea
• Hyperkalemia
• Overdosing and subsequent iatrogenic adrenal insufficiency
• Acute adrenocortical necrosis (due to ACTH hypersecretion)

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 • More rapid pituitary tumour growth with subsequent progression of neurological signs (circling,
head pressing, seizures etc.), possibly due to ACTH hypersecretion.
• Recrudescence of previously suppressed immune-mediated, inflammatory or neoplastic
processes.

o Monitoring: Repeat examinations are advised after 1, 3, 6, 13 weeks, 6 months and 12 months after
starting therapy; followed by approximately every 3-6 months.
o The most reported method of monitoring response to therapy is improvement in clinical signs and a
post-pill ACTH stimulation test. It is essential that the ACTH stimulation test is performed at the
same time following pill administration on each re-examination to ensure directly comparable
results. It is recommended to perform the ACTH stimulation test 2- 4 hours post-trilostane pill
(approximate timing of trough cortisol concentrations); as the goal is to detect overdosing. At these
times, a post-pill ACTH serum cortisol concentration of 41-152nmol/l is considered appropriate. If a
dog on trilostane is clinically well with adequate control of clinical signs but the post-ACTH serum
cortisol concentration 3-6 hours post trilostane is <40nmol/l re-testing at 9-12 hours post trilostane
can be performed. A study by Midence et al documented that in these cases of likely subclinical
hypoadrenocorticism a post-ACTH serum cortisol concentration 9-12 hours post trilostane >55nmol/l
demonstrates that no dose change is required as no dogs with these results developed clinical signs
or consequence of hypoadrenocorticism within 88 days of follow-up (Midence and others 2015).
o It is important to recognize that the ACTH stimulation test has not been validated for monitoring
response to trilostane therapy so therefore has its limitations, it is also affected by concurrent
disease.
o Studies and clinical experience demonstrate overall poor correlation of ACTH stimulation test results
to clinical response (Macfarlane and others 2016). Therefore, perhaps the use of the ACTH
stimulation test is limited to detection of overdosing and iatrogenic hypoadrenocorticism rather
than dose adjustments in an otherwise well dog on trilostane treatment. As such alternative
monitoring tools are being assessed.
o Measurement of pre-trilostane cortisol concentration in conjunction with clinical status of the
patient (defined as well or unwell status and degree of control of clinical signs) has shown the most
promise (Macfarlane and others 2016) although in itself is also not perfect. See also Dechra support
sheet (attached to course information).
o In any unwell patient trilostane should be stopped while the underlying cause (which may be
iatrogenic hypoadrenocorticism) is investigated, initially a haematology, biochemistry and
electrolytes should be performed in these cases.


The ACTH stimulation test remains the gold-standard for assessing adrenocortical reserve and should be used in sick
patients on trilostane to investigate the possibility of hypoadrenocorticism or where subclinical hypoadrenocorticism
is suspected.

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 ADVANTAGES DISADVANTAGES
Experience in use Life-long - cost
Readily available/licensed Leaves pituitary tumour untreated
No need for referral Theory of expansion of pituitary mass
Cost effective Side effects can occur; some are life-threatening
Easy to administer – with food Iatrogenic hypoadrenocorticism
Overdosing
Adrenocortical necrosis
Non-invasive Frequent monitoring and dose adjustments are required, which is time-
consuming, costly and can be frustrating for owners.
Effective in controlling CS >80% ACTH stimulation test not a validated monitoring tool
Reversible (usually) Poor correlation between clinical signs and ACTH stim
Cortisol suppression lasts <20 hours; BID dosing?
30-40% cases require dose adjustments
Accurate dosing difficult in small dogs (capsule size)
Low long-term survival rate MST 600-900d; 3yr survival 30%


Alternative medical management

Pituitary-target

1. Selegiline (L-deprenyl)
o monoamine oxidase B inhibitor- increases dopamine concentrations within the brain
o reported to be effective in 20-30% of PDH dogs with pars intermedia involvement (Peterson 2001).
o few reported side effects
o only really used where the cost of monitoring prohibits the use of other medications.

2. Pasireotide (SOM230, Signifor® (Novartis)
o targets multiple somatostatin receptors (SSTRs) including SSTR2 and 5; which are expressed on the
pituitary gland of dogs with PD-HAC
o inhibits ACTH secretion and thus reduces cortisol secretion
o One study of twice daily subcutaneous injection documented decreased ACTH concentrations, urine
cortisol: creatinine ratios and pituitary adenoma size in dogs treated with pasireotide (Castillo and
others 2011).

3. Cabergoline
o dopamine D2 receptor agonist that inhibits ACTH secretion.
o A study in 40 dogs with PDH given weekly cabergoline documented that approximately 40% of cases
had decreased ACTH concentrations, urine cortisol: creatinine ratios and pituitary adenoma size
(Castillo and others 2008).
o In people cabergoline is also recognised for its antineoplastic effects.

4. Retinoic acid
o inhibits ACTH secretion by affecting control of the ACTH precursor proopinomelanocortin (POMC).
o also inhibits corticotroph proliferation
o Once daily administration demonstrated control of cortisol and ACTH hypersecretion, tumour size
and clinical signs in dogs with PDH (Castillo and others 2006).

5. Gefitinib (EGFR antagonist)
o epidermal growth factor receptor (EGFR) antagonist; which suppresses POMC expression and thus
ACTH secretion.
o Studies are underway in investigating this potential treatment modality.

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• Radiation therapy
o Radiation oncology referral centres only
o Fractionated external bean radiation therapy targets the pituitary mass itself with several radiation
fractions being administered under general anaesthesia.
o Tolerance is good with reported evidence of reduction in tumour size and improvement in clinical
signs, including neurological abnormalities.
o However, reduction in secretion of ACTH is variable so most dogs continue to require concurrent
medical management with trilostane (Goossens and others 1998; Kent and others 2007)
o Clinical improvement can have a delayed onset; which can impact on a dog’s quality of life.
o Radiotherapy improves survival in patients with pituitary masses, and the response to radiotherapy
and survival following treatment is negatively correlated with the ratio of tumour size to brain height
o Valid treatment option, especially for large macroadenomas.
o Mean survival time of 25 months in dogs with mild neurologic signs reported.

Adrenal-target

1. Mitotane (Lysodren®)
o Leads to progressive, selective destruction (necrosis) of the adrenal cortex (adrenocorticolytic)
o Also inhibits 11β hydroxylase and desmolase in the adrenal gland, reducing steroid synthesis
o Depending on the protocol used the adrenal cortex can be completely or partially destroyed.
o More than 80% of dogs with PDH have a good to excellent response; which is similar to trilostane
(Barker and others 2005).
o High frequency of relapse during treatment is reported in additional to risks of iatrogenic adrenal
insufficiency and drug intolerance.
o Only available with a Special Treatment Authority from the Veterinary Medicines Directorate
o Side-effects common (approx. 40% cases)
• Gastric irritation and vomiting
• Hypocortisolaemia - Lethargy, anorexia, vomiting, diarrhoea, weakness
• Hypoaldosteronism - Hyperkalaemia, hyponatraemia, lethargy, weakness, cardiac
abnormalities, hypovolaemia, hypotension
• increased growth of pituitary macroadenoma - neurological signs? Unproven risk

2. Ketoconazole
o inhibits synthesis of adrenocortical steroids (via cytochrome P450 enzyme and 11β hydroxylase
inhibition)
o can be used as an alternative to trilostane, or as an additional medication to reduce the dose of
trilostane required
o expensive and hepatotoxicity can occur.

3. Metayrapone
o inhibits adrenal steroidogenesis pathway through inhibition of 11β-hydroxylase enzyme.


Surgical treatment
• Transphenoidal hypophysectomy
o Complete surgical removal of the pituitary gland accessed via the soft palate
o Referral centres only
o only available potential curative treatment option for dogs with PDH
o around 75% of canine patients experience long-term cure (Hanson and others 2005)
o surgical debulking can also provide relief from space-occupying lesion effects of
macroadenomas, and can improve the sight of individuals who have optic nerve compression
o Good long-term outcome is reported: 70% 3 – year survival

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 o increasing pituitary tumour size associated with higher the mortality and incidence of residual
disease and relapse (van Rijn and others 2016)
o large upfront cost (approximately £3000-4000) but associated with less expensive long-term
management
o after surgery patients need life-long hormonal supplementation with glucocorticoids and
thyroxine, transient diabetes insipidus means that DDAVP administration can often be
discontinued.

• Bilateral adrenalectomy
o Referral centres only but more widely available than hypophysectomy
o consideration where the primary tumour cannot be identified (rare cases of ectopic ACTH
producing tissue), unsuitable cases for PD-HAC or where owner declines hypophysectomy in
favour of another surgical procedure
o following surgery patients will need life-long glucocorticoid and mineralocorticoid
supplementation, and to be monitored in a similar manner to a patient with naturally occurring
hypoadrenocorticism
o However, hypoadrenocorticism is more easily managed than hyperadrenocorticism, rendering
this still an attractive alternative
o There are case reports of bilateral adrenalectomy in dogs, but to the authors knowledge a large
case-series has not been reported.
.


Treatment of AD-HAC

Medical treatment
o Success has been reported with trilostane, mitotane and ketoconazole (similar protocols to PDH)
although in general more resistant to therapy

Surgical treatment
o Adrenalectomy is considered the treatment of choice for AT unless metastatic lesions are present,
the tumour is invading surrounding tissues or the dog is a particularly poor anaesthetic risk
o Should not be attempted by inexperienced personnel
o The bigger the tumour the greater the chance of post-surgical complications
o Complications include haemorrhage, hypertension, acute hypocortisolaemia, hypoaldosteronism
and wound breakdown
o REFER!!
o Mean survival following successful surgery is 36 months; dogs with metastatic disease usually
die/euthanased within 12 months

General treatment complications
• Reducing cortisol concentrations can unmask other underlying diseases e.g. osteoarthritis, atopy
• Reducing cortisol concentrations can cause pituitary lesions to expand causing rapidly progressive
neurological signs

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Key points


o Following a diagnosis of Cushing’s disease pituitary and adrenal-dependent disease should be
differentiated from each other, as treatment options vary.
o Early discussion of all options with owners and consideration of patient (age, temperament)
is paramount to help identify the best treatment option for that individual.
o Trilostane remains an effective medical treatment option for PD-HAC with most dogs having
improved clinical signs within the first 3-6 months of treatment.
o Low dose twice daily dosing of trilostane should be considered, especially in some patients
i.e. those with concurrent diabetes mellitus, other complications of uncontrolled PD-HAC and
those dogs with improved biochemical monitoring but continued clinical signs of disease (e.g.
PUPD).
o Surgical intervention is the only treatment modality to offer potential disease cure. But
patients undergoing transphenoidal hypophysectomy or bilateral adrenalectomy require
lifelong management of hypoadrenocorticism.
o Radiation therapy is a good treatment option for those experiencing neurological
consequences of PD-HAC. However, alone it does not lead to good hormonal control.




Feline Hyperadrenocorticism – Cushing’s Syndrome; hypercortisolism


Hyperadrenocorticism does occur in cats, although less commonly than in dogs. PD-HAC is more common than AD-
HAC. Particular features in cats include high frequency of insulin-resistant diabetes mellitus (DM), cachexia, and
dermal/epidermal atrophy which leads to “fragile skin syndrome”. Skin may slough during routine handling. The
main differential for this spectrum of signs is hyperprogesteronism from progesterone-secreting adrenal tumours.
Significant increases in ALP are rare as cats do not have a steroid-induced isoenzyme; and liver enzymes are rarely
>3x upper reference limit. Urine abnormalities are rare; apart from glycosuria. Over 80% cats with HAC are
hyperglycemic at the time of diagnosis. Various different protocols are quoted for screening and diagnostic tests of
the pituitary-adrenal axis – generally a high dose dexamethasone suppression test (0.1mg/kg IV c.f. low dose in dogs)
and ACTH stimulation test with post sample at 60 or 90 minutes after injection are recommended (post-ACTH
cortisol concentration >400ng/ml is suggestive; contact labs for further information).

Treatment is difficult. Adrenalectomy is treatment of choice for adrenal masses. A reliable medical treatment for
PD-HAC has not been established in cats, although success has been reported with trilostane. Hypophysectomy and
bilateral adrenalectomy has been described. The prognosis is worse than in dogs and reported as guarded to poor;
especially with poorly controlled concurrent DM.

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References

ARENAS, C., MELIAN, C. & PEREZ-ALENZA, M. D. (2013) Evaluation of 2 Trilostane Protocols for the Treatment of
Canine Pituitary-Dependent Hyperadrenocorticism: Twice Daily versus Once Daily. Journal of veterinary internal
medicine 27, 1478-1485
BARKER, E. N., CAMPBELL, S., TEBB, A. J., NEIGER, R., HERRTAGE, M. E., REID, S. W. & RAMSEY, I. K. (2005) A comparison
of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism. J Vet
Intern Med 19, 810-815
BEHREND, E. N., KOOISTRA, H. S., NELSON, R., REUSCH, C. E. & SCOTT-MONCRIEFF, J. C. (2013) Diagnosis of
spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med 27,
1292-1304
CASTILLO, V., GIACOMINI, D., PAEZ-PEREDA, M., STALLA, J., LABEUR, M., THEODOROPOULOU, M., HOLSBOER, F.,
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VAUGHAN, M. A., FELDMAN, E. C., HOAR, B. R. & NELSON, R. W. (2008) Evaluation of twice-daily, low-dose trilostane
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