5. Pituitary Dependent (PDH)
Overproduction of ACTH = Increased cortisol
Majority of HAC dogs (85%)
Mainly small breeds
Middle aged – older (7-9yrs)
6. PDH
Radiotherapy
Progression of disease : can form a
pituitary macroadenoma
Neurological signs
Median survival time = 662-900 days (tx
with trilostane)
7. Adrenal Dependent
Tumour of the Adrenal cortex produces
excessive cortisol
Less common (15%)
Large breeds
Older dogs (11yrs)
Median survival time = 353 days
8. ADH
50% benign and 50% malignant
Surgery: Adrenalectomy
Progression of disease:
Malignancy is a possibility in 50% of these
cases
9. Study
Involved 57 dogs from both first opinion
(32 dogs) and referral hospitals (25
dogs)
All diagnosed with HAC
Age Range = 4 – 17 years old
Weight range = 2.3 - 38.5kg
11. What tests were used to diagnose HAC?
Were the patients differentiated into
PDH or ADH?
And if so, How were they differentiated?
12. Diagnostic tests
Cannot use basal cortisol
Non-adrenal illness (NAI) can cause a high
circulating cortisol level
Pulsatile action of ACTH
Therefore diagnosis of HAC based on
other tests
13. Tests performed
ACTH LDDST 17-OH Urine Cortisol:Creatinine
ACTH Stimulation Test
LDDST
17-OH Progesterone
Urine Cortisol:Creatinine
14. ACTH stimulation test
HAC = exaggerated response
Post ACTH cortisol >600nmol/l
Sensitivity = 57-83%
Specificity = 59-93%
15. ACTH Stimulation Test
ACTH Stim was performed on 45 dogs
in the study
31 recorded as a positive result
Positive Post ACTH ranged from 618-
1443 (mean 926)
Negative Post ACTH ranged from 218-
651 (median 427)
16. LDDST
HAC response: either no suppression or
suppression and then escape at 8h
8 hour >40nmol/l
Sensitivity: 85-100%
Specificity: 44-73%
17. LDDST performed in 20 dogs in study
Of these 14 produced positive result
19. Urine cortisol:creatinine
Cortisol excreted in urine – reflection of
cortisol release
Very sensitive (92%)
Non-specific (21%)
Used in one case in the study as ACTH,
LDDST and 17-OH were all negative but
clinical signs strongly suggested HAC.
23. Differentiated
54% were differentiated
PDH = 25 cases (89%)
ADH = 3 cases (11%)
29% cases in 1st opinion practice
90% cases in referral hospital
24. Ultrasound
PDH = Bilateral adrenomegaly
ADH = Mass on adrenal gland
Ultrasound of adrenals performed in
24/53 dogs in study
95% of referral cases had adrenal
ultrasound
15% of first opinion cases
25. Endogenous ACTH
PDH = high ACTH (>28pg/ml)
ADH = low ACTH (<5pg/ml)
Used in 5 cases
All in referral centres
Used alone in 2 of these
Rest were used in conjunction with
ultrasound
26. LDDST
Suppression at 4hours and then escape
suggest PDH
No suppression – either ADH or PDH
Suggestive results were used to
differentiate alone in 7 cases
6 in First opinion
1 in Referral
Used in conjunction with ultrasound and
endogenous ACTH
27. MRI
Used to diagnose PDH or following PDH
diagnosis for planning of radiotherapy
Used in one case in the study as
showed neuro signs and was diagnosed
with a macroadenoma
28. Conclusions
ACTH was the most popular test of
choice for diagnosing HAC
LDDST suggested as test of choice
Higher Sensitivity
Confusion over interpretation
30. Only 54% of dogs were differentiated
Simple test that can be performed in first
opinion practice
31. Case Example - Sammy
Diagnosed in first opinion practice with
HAC and was not differentiated
The year following diagnosis
More PUPD
Dx: diabetes insipidus. Responded to tx
6 months later represented for PUPD,
weight loss and lethargy
Believed to be due to an over suppression
(Addisons) therefore decreased dose of
trilostane
2 months later – presented for lying in
lateral recumbency and head banging
32.
33. Limitations of Study
Assumptions of correct diagnosis
History availability
Information on diagnosis
Absent values for Post ACTH/8hr
LDDST
Assumptions of ultrasound
measurements made by first opinion
vets
34. Important to differentiate
Not being done as often in first opinion
practice as in referral hospitals
Endogenous ACTH – very simple
35. References
Gould S.M, Baines E.A, Mannion P.A, Evans H and Herrtage M.E. (2001)
Use of endogenous ACTH concentration and adrenal ultrasonography to
distinguish the cause of canine hyperadreocorticism. Journal of Small
Animal Practice 42, 113-121
Behrend et al. (2012) Diagnosis of Spontaneous Canine
Hyperadrenocorticism:ACVIM Consensus Statement (Small Animal). J Vet
Intern Med 2013;27:1292–1304
Mooney C.T, Peterson M.E (2012) BSAVA Manual of Canine and Feline
Endocrinology 4th ed.
Helm et al. (2011) A Comparison of Factors that Influence Survival in Dogs
with Adrenal-Dependent Hyperadrenocorticism Treated with Mitotane or
Trilostane. J Vet Intern Med 2011;25:251–260.
Chapman, P.S. et al (2003) Evaluation of the basal and post
adrenocorticotrophic hormone serum concentrations of 17-
hydroxyprogesterone for the diagnosis of hyperadrenocorticism in dogs.
Veterinary Record 153, 77-775
Smiley L.E, Peterson M.E (1993) Evaluation of a urine cortisol:creatinine
ratio as a screening test for hyperadrenocorticism in dogs. JVIM 7, 163-8
Ramsey I, Ristic J (2007) Diagnosis of canine hyperadrenocorticism. In
Practice 2007;29:446-454
HAC is a common endocrine condtition in dogs in the UK that results in an overproduction of cortisol
The most commonly seen clinical signs are PUPD, Polyphagia, alopecia and abdominal distension
Corticotrophen releasing hormone is released from the hypothalamus which acts on the anterior pituitary gland to release ACTH.
ACTH stimulates the secretion of cortisol from the adrenal cortex. This then acts in negative feedback loop.
ACTH is released in pulses meaning that both ACTH and cortisol levels fluctuate throughout the day in the normal dog.
In Cushing’s there is either overproduction of ACTH from the pituitary gland or an overproduction of cortisol from the adrenal cortex.
In PDH there is an overproduction of ACTH from the anterior pituitary gland which then acts on the adrenal cortex to release more cortisol and causes bilateral adrenal enlargement.
The negative feedback loop from the excess cortisol is not responsive in these dogs and so ACTH keeps being produced
PDH is more common accounting for around 80-85% of dogs with Cushings
Small breeds of dogs are more likely to develop PDH
Mean age of onset tends to middle aged (7-9 years old)
Trilostane and Mitotane can be used to treat both PDH and ADH
An Additional treatment option for PDH is the use of radiotherapy.
PDH can progress to cause a pituitary macroadenoma or this can be present on initial presentation
Pituitary macroadenoma occurs in 10-15% of PDH cases
Can cause neurological signs such as decreased mentation, inappetance and ataxia.
Median Survial Time of 662-900 days (based on a study looking at dogs treated with trilostane)
Most often results from a cortisol secreting tumour on one of the adrenal glands. The cortisol production is not associated with the ACTH production.
ADH is less common than PDH and accounts for the remaining 15% of patients
ADH tends to affect larger breeds of dogs and these dogs tend to have a slightly later age of onset (mean age 11yrs)
As
Around 50% of ADH lesions are malignant - further investigations should be done to look for metastasis (thoracic radiographs, abdo ultrasound).
Also these dogs may not show evidence of metastasis now but might do in later life.
Adrenal gland width >4 cm is highly correlated with malignancy. Invasion into the vena cava or adjacent tissues can be detected by ultrasonography, but CT92 and MRI are more sensitive techniques to identify vascular invasion and detect metastases. Therefore, abdominal ultrasonography ideally should be followed by CT or MRI before adrenalectomy.
So again ADH can be treated with trilostane or mitotane.
Another treatment option is to go for surgery to perform an adrenalectomy.
However this needs to be performed by experienced surgeons and will need intensive care following surgery.
As some of these cases are malignant – it is important to carry out investigations prior to surgery.
This surgery is not without risk and even in referral hospitals this surgery still has a perioperative mortality rate between 20-30%.
If surgery is successful the median survival time is just less than 2 years (although some of the dogs lived as long as 4 years)
20 Cross-breeds and 27 Pedigrees of varying breeds. Mostly small breeds.
Cannot use a basal cortisol to diagnose HAC.
This is because any form of non-adrenal illness has the potential to cause cortisol release as a stress response.
As well as this the pulsatile release of ACTH means that a HAC patient could present with cortisol within the reference range.
This means other tests must be performed
5 cases no information on what tests were used to diagnose
On the patients with information available – the tests that were performed were: ACTH Stim, LDDST, 17-OH and Urine Cortisol Creatinine
Measure basal cortisol and then inject synthetic ACTH and then measure serum cortisol levels an hour later
In the normal dog this should stimulate the production of more cortisol
Patient with Cushings will show an exaggerated response. >600nmol/l considered a positive
The sensitivy of this tests varies from 57-83% and is more sensitive in PDH cases (80-83%)
ADH sensitivity 57-63%
Specificity 59-93%
Need to recheck!
The ACTH is a very popular test and was the most popular test performed in this study being performed on 45 of the dogs included.
Of these 45 dogs – 31 of them produced a result the vet considered diagnostic (however a further 3 dogs also had a result over 600nmol/l but the vet did not consider diagnostic and so other test were performed)
Most labs have a cut off of anything over 600 is suggestive of hyperadrenocoricism
Positive post ACTH values ranged from 618-1443 in the group of dogs included in the study with the median positive value being 874.
Some dogs in the study did produce a negative ACTH results or a result that the vet thought warranted another test to confirm HAC.
These values ranged from 218-651 with the median result being 472.
There is an overlap in what is considered a definitve positive and what others thought was a negative result.
Measure at either 3 or 4 hours depending on what lab it is being sent to.
A normal response would be that the Low dose of dexamethasone causes suppression of ACTH secretion and therefore causes a suppression of the cortisol that will stay suppressed at both the 4 hour and 8 hour measurement.
Diagnosis of HAC is based on the 8 hour cortisol.
If >40nmol/l positive for Cushings
This test has a higher sensitivty than the ACTH stim test and has been reported to be 85-100% sensitive
However it has a lower specificty than the ACTH
Second most popular test and used as the follow up to negative ACTH stimulation tests
17-OH Progesterone used much less commonly than the other tests
It is a precursor for cortisol
Tested for in the same sort of method as an ACTH Stim test but 17-OH progesterone is measured instead of cortisol
Serum 17-OH progesterone increases in response to ACTH in HAC patients (and in atypical HAC – where has yielded a negative result for ACTH Stim and LDDST but still showing signs of Cushings). However, this has been shown to increase in dogs with non-adrenal illness.
Sensitivity and Specificity debated depending on cut off values – 8.5nmol/l specificty of 70%
Paper looked at cut off values –
4.5nmol/l = 90% sensitivity but only 40% specificity
16.7nmol/l = 47% sensitivity but a 90% specificty
Cortisol and its metabolites are excreted in urine and so are a reflection of cortisol release over the last few hours.
Very sensitive – therefore can be used a screening test. If it is negative then the dog is very unlikely to have HAC
A positive result however, does not confirm a diagnosis and so the specificity of this test is quite low
Morning sample taken at home to minimise stress
Interestingly the one dog that had this performed produced a negative result and the diagnosis of HAC was only made after a trilostane trial resolved the clinical signs
Comparing to creatinine will correct differences due to concentration
Dog should be at home so subjected to as little stress as possible>10x10^-6 in dogs with HAC
The first test of choice in the majority of the dogs included in this study was the ACTH followed by LDDST.
49 dogs info for diagnosis
41 ACTH
8 LDDST
In 84% of the patients had an ACTH Stim test performed first and the other 16% had a LDDST stim test performed first
Tests that confirmed diagnosis –
Majority of dogs were diagnosed on the basis of an ACTH Stim test
Followed by LDDST
1 dog diagnosed from 17-OH after negative ACTH and LDDST
1 dog diagnosed on basis of trilostane therapy after ACTH, LDDST, 17-OH and Urine cortsiol:creatinine were all negative.
In this study out of 52 dogs that information was available for only 28 of the cases were differentiated into either pituitary or adrenal dependent.
Of these 89% of the cases were pituitary dependent and the other 11% were adrenal.
This is fairly similar to published figures of 85% and 15%
Ultrasound is now readily available however using ultrasound to differentitate cases of HAC requires locating and assessing both adrenal glands and therefore may need a more experienced ultrasonographer.
ADH: In one study the Diameter of adrenal mass varied 12.9-96.8mm
Of the 53 dogs in this study an ultrasound exam was performed on 29 of them however for 5 of these casese the ultrasound did not include an adrenal check and was used for checking for concurrent disease.
Therefore an ultrasound was used to aid differentiation in 24/53 cases
Ultrasound was used as the only way to differentiate in 14/53 cases
And was used in conjunction with other tests in 5 cases
Performed in both first opinion and referral hospitals
This is a simple blood test that measures the endogenous ACTH levels. It is widely available (sent to an external lab) although it is relatively expensive
Mentioned earlier that a single basal cortisol could not be used to diagnose cushings due to the fluctuations of ACTH secretion in a normal animal.
However, endogenous ACTH can be used to separate PDH from ADH but not to diagnose
In PDH the circulating ACTH will be high (>28) as there is oversecretion of ACTH
But in ADH due to the negative feedback from the excessive levels of cortisol, ACTH will be low (<5). This is 100% sensitive for ADH and 95% specific.
LLDST – suppression at 3-4h and then an escape suggest PDH.
No suppression = either PDH or ADH
Suggestive results were used to differentiate in alone in 7 cases in the study (mostly first opinion practice)
Other used endogenous ACTH or ultrasound
Some suggested that advanced imaging such as MRI should be performed at time of diagnosis of PDH as can then consider other optins for treatment
MRI performed at another referral centre.
Because radiation therapy or hypophysectomy is required for their treatment and both are more effective with smaller tumors and in the absence of neurological abnormalities, the Panel recommends that pituitary imaging be considered for all dogs at the time of PDH diagnosis.
LLDST test of choice unless suspect iatrogenic Cushing’s as it has a greater sensitivity.
As there is a shortage of Synacthen at the moment then this does seem a more feasible option. However the LDDST does require a full day of hospitalisation.
Confusion over interpretation in both the ACTH Stim and LDDST
Some of the vets in first opinion performed an ACTH Stim and got a post of just over 600 and counted this as a borderline test however between 400-600 is normally considered non-diagnostic by external labs but over 600 is considered diagnostic for HAC
There was also 2 LDDST performed that were positive but were not included as a positive result.
UCCR most sensitive
Followed by LDDST
17-OH
Least Sensitive = ACTH
From this sample of cases only 52% were differentiated in to either PDH or ADH.
Differentiating ideally relies on Ultrasound of the adrenal glands and an Endogenous ACTH.
The endogenous ACTH is a simple blood test this can very easily be done in first opinion practice however it is reasonably expensive (£128)
Ultrasound is a method that is widely available as most practices will have an ultrasounds machine however Ultrasound of the adrenal glands relies on the ultrasonographers ability to visualise and assess the adrenal glands and so does potentially limit the availability of this option.
A case that illustrates the importance of differenitation is a case that was seen here in 2014
Sammy was a 8 year old Male Neutered Lurcher who was diagnosed with HAC in a first opinion vets but he was not differentiated in to either PDH or ADH. TREATED WITH TRILOSTANE
The year following his diagnosis Sammy represented to his vets for significant PUPD and after investigation was diagnosed with Diabetes Insipidus which responded well to treatment
However 6 months later, he represented again for further PUPD, weight loss and lethargy. Thought to be due to an oversppression causing an iatrogenic Addisons and therefore the vets decreased the dose of trilostane.
2 months after this Sammy then presented at GUVS as an emergency as he was lying in lateral recumbency and head banging.
He was seen by GUVS and had an ultrasound which showed bilateral adrenomegaly and then had an MRI.
This is Sammy’s MRI which shows a large pituitary macroadenoma
This pituitary macroadenoma had most likely been the cause of the HAC and then the subsequent Diabetes Insipidus
Had Sammy had a diagnosis of PDH when first diagnosed then it would have been easier for the vets to understand the progression of the disease and the reason for his deterioration.
Sammy went for radiation therapy following his diagnosis. Pituitary macroadenoma respond better to this treatment when they are small in size and when there is no neurological signs and therefore he could have had treatment for this about 18 months previous to when he was first started on treatment.
We assume all of the dogs in this study were correctly diagnosed and did indeed have HAC
Access to history from some dogs was not available
Some of these histories contained no information on how diagnosed
And some of the histories did provide which test was performed but the specific values of the post ACTH and 8HR LDDST were absent
Assumption that the vets ultrasound interpretation was correct for example Vets that reported bilateral adrenal enlargement there was no measurements included in the history
Differentiation not being done as often in first opinion practice as in referral centres.
Since it is important to differentiate this is something that first opinion practices should try to do more in the future.
Ultrasound does rely on technique and experience and therefore limits availability in first opinion
However, Endogenous ACTH, is a simple blood sample that all vets can readily perform.
The limitation of this is ordering the kit to send the sample to the lab.
Vets in first opinion may not be aware of the test and its availability.
Offered to owners more