Diagnose

Hva er den beste testen for å diagnostisere Cushings syndrom?

Ideelt sett er det best å velge en test som både er svært spesifikk og svært sensitiv når man tester for en sykdom. I praksis er en test med høy sensitivitet god til å finne dyr med sykdommen og vil derfor gi få falske negative resultater. En test med høy spesifisitet gir et positivt resultat hos dyr som virkelig har sykdommen, og vil derfor gi få falske positiver.
 
Men ingen av testene for Cushings har både høy følsomhet og høy spesifisitet – alle er et kompromiss mellom de to. Dette betyr at de diagnostiske testene vi har for hyperkortisolisme hos hunder ofte må brukes i kombinasjon for å være sikre på diagnosen.
 
(Merk: Prosentverdiene som er oppgitt for sensitivitet og spesifisitet nedenfor, skal betraktes som omtrentlige og er representative for flere undersøkelser om dette emnet. Forfatteren henviser leseren til 2019 Bennaim et al review for ytterligere informasjon).

ACTH stimuleringstest (ACTHST):
 
Høy spesifisitet (90 %), moderat sensitivitet (85 % PDH og 50 % ADH)
Falske positive er mindre vanlig. Falske negative er ganske vanlig.

Suppresjonstest med lavdose deksametason (LDDST):

Moderat spesifisitet (70 %), høy sensitivitet (95 %).
Falske positive er ganske vanlig. Falske negative er mindre vanlige.

Urinkortisol: Kreatinin-ratio (UCCR):

Dårlig spesifisitet (20 %), høy sensitivitet (97 %).
Falske positive er vanlig. Falske negative er mindre vanlige.
 
Når du tolker noen av disse testene, er det verdt å vurdere den positive og negative prediktive verdien. Positiv prediktiv verdi (PPV) er andelen av hunder med en positiv test som virkelig har Cushings. Negativ prediktiv verdi (NPV) er andelen av hunder med en negativ test som ikke har sykdommen.
De positive og negative prediktive verdiene tar både testen og populasjonen som testes med i beregningen. Hvis du bruker en test i to populasjoner med forskjellig sykdomsprevalens, vil de prediktive verdiene være forskjellige. Derfor varierer PPV og NPV avhengig av hvor ofte du tester.
 
Når du tolker noen av disse testene, er det verdt å vurdere den positive og negative prediktive verdien. Positiv prediktiv verdi (PPV) er andelen av hunder med en positiv test som virkelig har Cushings. Negativ prediktiv verdi (NPV) er andelen av hunder med en negativ test som ikke har sykdommen.
De positive og negative prediktive verdiene tar både testen og populasjonen som testes med i beregningen. Hvis du bruker en test i to populasjoner med forskjellig sykdomsprevalens, vil de prediktive verdiene være forskjellige. Derfor varierer PPV og NPV avhengig av hvor ofte du tester.

Hvis vi skulle teste nesten alle pasienter vi ser (en populasjon med lav prevalens – 5 %)


I dette scenarioet, hvis vi bruker LDDST, kan vi være 100 % sikre på at et negativt resultat virkelig er negativt. Mens bare 16 % av de positive resultatene vil faktisk ha Cushings.

  • Hvis vi var mer kritiske til pasientene vi tester vi (en populasjon med høy forekomst – 90 %)

I dette scenarioet, hvis vi bruker LDDST, vil 62 % av de negative resultatene virkelig være negative og 97 % av de positive resultatene vil ha Cushings.
 
Konklusjon
 
ACVIM Consensus Statement panel 2012 (Behrend et al. 2013) regnes som en lavdose deksametason-suppresjonstest (LDDST) som den foretrukne screeningtesten med mindre det er mistanke om iatrogen Cushings. På grunn av den lavere følsomheten til ACTH-stimuleringstesten er den diagnostiske nytten som screeningtest dårligere ved naturlig forekommende Cushings syndrom enn LDDST.
Det er imidlertid også viktig å ta hensyn til andre faktorer ved valg av diagnostisk test, inkludert testtilgjengelighet, kostnader og samtidig sykdom hos pasienten. Og like viktig er det å forbedre det potensielle utfallet av testen ved å sikre en høy grad av mistanke om sykdom før det gjennomføres bekreftende testing.

Suppresjonstesten med lavdose deksametason måler resistensen i hypofyse-binyreaksen til suppresjon ved deksametason. Følgende protokoll er utarbeidet av Dechra i sammen med spesialiserte laboratorier, men hvis du har spørsmål, anbefaler vi at du sjekker denne protokollen med ditt vanlige laboratorium før du utfører testen.

  1. Ta en basal blodprøve (1-2 ml) og merk dette røret som «pre Dex». Egnede prøvetyper på de fleste laboratorier inkluderer separert heparinisert plasma eller serum, eller sentrifugerte serumgelrør.
  2. Injiser 0,01 mg/kg til 0,015 mg/kg deksametason I.V. umiddelbart. Det er antydet at bruk av 0,015 mg/kg deksametason kan bidra til å redusere sjansen for falske positive resultater. Volumet av deksametason som skal administreres i ml = (kroppsvekt (kg) x dose (mg/kg)) / konsentrasjon av deksametasonoppløsning (mg/ml). Injeksjonsvolumer er små for denne testen, og i noen tilfeller kan det være nyttig å foreta en 1:10 fortynning av deksametason før administrering.
  3. Ta ytterligere to blodprøver, 3-4 timer og 8 timer etter injeksjon av deksametason. Merk tidspunktene for prøvene tydelig på rørene (f.eks. '8 timer etter').
  4. Send inn rør og forespørselskjema til laboratoriet.

Suppresjonstesten med lavdose deksametason måler resistensen i hypofyse-binyreaksen til suppresjon med deksametason og tolkes i to trinn:

  • For det første fastslås tilstedeværelse eller fravær av Cushings syndrom ved å undersøke resultatet etter 8 timer. En 8 timers kortisolverdi større enn 40 nmol/l anses generelt å representere et «positivt» resultat
     

Hos en hund med ADH utskiller vanligvis binyretumoren kortisol autonomt og ACTH-produksjonen er allerede undertrykt, og dermed undertrykkes ikke kortisolproduksjonen som svar på administrering av deksametason.

  • Det andre trinnet gjelder kun i de positive tilfellene og når man ser etter tegn på kortisolhemming. I opptil 60 % av PDH-tilfellene vil det være en markert undertrykkelse av kortisol (til < 50 % av baseline-verdien) etter enten 3 timer eller 8 timer, noe som gjør det mulig å skille mellom de to typene hyperkortisolisme.

ACTH-stimuleringstesten er et mål på adrenokortikal reserve. Følgende protokoll er utarbeidet av Dechra i kombinasjon med spesialiserte laboratorier og ved bruk av ACVIMs konsensusuttalelse fra 2012 om diagnostisering av spontan Cushings hos hund (Behrend et al, 2013). Men hvis du har spørsmål, anbefaler vi at du sjekker denne protokollen med ditt vanlige laboratorium før du utfører testen.

  1. Ta en basal blodprøve (1-2 ml) og merk dette røret som «pre ACTH». Egnede prøvetyper ved de fleste laboratorier inkluderer separert heparinisert plasma eller serum, eller sentrifugerte serum-gel-rør
  2. Injiser umiddelbart 5 μg/kg syntetisk ACTH IV.
  3. Ta en ny blodprøve (1-2 ml) én time etter injeksjon av syntetisk ACTH. Merk røret som «post ACTH»
  4. Send inn rør og forespørselsskjema til laboratoriet
     

Videoen nedenfor viser hvordan en normalt sunn hund skal reagere på ACTHST. Som du ser stimulerer den syntetiske ACTH binyrene til å produsere mer kortisol, og deretter bør nivåene øke i sirkulasjonen. En normal økning antas å være til ca 300 – 400 nmol/l. Et positivt testresultat er vanligvis definert som 1 time kortisol  >600 nmol/l, hos hunder med kompatible kliniske tegn og ingen holdepunkter for samtidig ikke-binyresykdom.

ACTH-stimuleringstesten vil identifisere ca. 85 % av tilfellene av hypofyseavhengig hyperkortisolisme.

Hunder med PDH har bilateralt forstørrede binyrer. Med større adrenokortikal masse kan man forvente en overdreven respons på ACTH
 
ACTHST vil også identifisere >50 % av tilfellene av binyreavhengig hyperkortisolisme, siden de fleste hunder med ADH også vil vise overdreven respons på ACTH.
 
Hos noen hunder, spesielt med ADH, kan det imidlertid forekomme atrofi av normalt binyrevev og/eller tumoren kan være ufølsom for ACTH. I disse tilfellene, som vist i denne videoen, kan vi se en «flat linjet, middels» kortisolrespons. Dette forklarer hvorfor ACTHST er mindre følsom for ADH enn PDH.


Siden følsomheten til testen er mindre enn ideell, spesielt for hunder med ADH, bør man ikke utelukke en diagnose av Cushings på grunnlag av et normalt ACTH-stimuleringstestresultat hvis det er tilstrekkelig klinisk mistanke.

ACTH-stimuleringstesten vil identifisere ca. 85 % av tilfellene av PDH og >50 % av tilfellene av ADH.
 
Derfor er følsomheten til testen mindre enn ideell, spesielt hos ADH, og noen hunder som faktisk har hyperkortisolisme vil ha normale resultater på ACTH-stimuleringstest. Derfor bør man ikke utelukke en diagnose av Cushings på grunnlag av et normalt ACTH-stimuleringstestresultat hvis det er tilstrekkelig klinisk mistanke.
 
I slike tilfeller anbefales det å foreta en LDDST for å prøve å finne en riktig diagnose. Alternativt, hvis de kliniske tegnene tillater det, kan pasienten overvåkes klinisk og ACTHST gjentas om 4-6 uker.

ACTHST er den eneste diagnostiske testen som gjør at vi kan skille mellom iatrogent og spontant forekommende Cushings syndrom. Kronisk administrering av eksogene glukokortikoidholdige behandlinger, inkludert perorale og injiserbare glukokortikoid-legemidler, topiske øredråper og hudpreparater, vil forårsake suppresjon av hypotalamus, hypofyse-binyreaksen. Dette vil i sin tur gi en subnormal respons på ACTHST.
 
Følgende video illustrerer dette:

Det er svært ønskelig å skille mellom hypofyseavhengig hyperkortisolisme og binyreavhengig hyperkortisolisme for å kunne gi en mer nøyaktig prognose og muliggjøre at hele spekteret av mulige behandlinger diskuteres med hundeeieren.
 
Diskriminerende tester som er tilgjengelige for å skille mellom PDH og ADH omfatter måling av endogen ACTH, lav- og høydose deksametason-undertrykkelsestester, ultrasonografi og avansert avbildning som MR og CT.

Administration

No, as the Vetoryl SPC states ‘Do not divide or open capsules’

Emptying the capsule, or dividing its contents, increases the risk of ingestion of trilostane by the human user. This is to be avoided due to the potential adverse effects of trilostane on human health.

Trilostane may decrease testosterone synthesis and has anti-progesterone properties. Trilostane has shown teratogenic and embryotoxic effects in animal studies. Trilostane could therefore be harmful to women who are pregnant or trying to become pregnant.

The contents of the capsules may also cause skin and eye irritation and sensitisation.

Also, you cannot be sure that by dividing the capsules you are accurately dividing the quantity of the active ingredient

Monitoring

It is vitally important that every monitoring appointment for Vetoryl treated patients uses clinical observations alongside biochemical assessment to decide on the next action for the patient.

Dechra provide a number of tools to aid in the clinical assessment of the patient including the Cushing’s Clinical Score and the CushQOL questionnaire. More information on these can be found in the FAQ section ‘Consultation Support’ below.

If, after clinical assessment, the dog is deemed to be ‘unwell’ (e.g. vomiting/diarrhoea, abdominal pain, off their food), Vetoryl must be stopped, serum electrolytes analysed and an ACTH stimulation test performed using Cosacthen®. The results of the ACTH stimulation test can then help you decide if the dog is unwell due to iatrogenic hypocortisolism (pre- and post-ACTH cortisol <40 nmol/l) or due to another reason (post-ACTH cortisol >40 nmol/l). 

Where any dog becomes unwell whilst receiving any veterinary medicinal product, it is important to report the event to the local body responsible for veterinary pharmacovigilance, even if you are confident the adverse event is not linked to administration of the medicine itself. You can do this directly to your local authority, or alternatively you can provide us with the case details so that we may record the case and forward to local authorities on your behalf. Please use the contact us section of this site. 

For dogs which are not considered clinically unwell, either the ACTH stimulation test or pre-Vetoryl Cortisol (PVC) can be used to monitor cortisol long term. Further information can be found within the treatment & monitoring section of the site.

Since the Pre-Vetoryl Cortisol test does not feature on the Vetoryl Summary of Product Characteristics, informed owner consent for ‘off-label’ monitoring should be obtained.

There is no evidence to suggest that Vetoryl is hepatotoxic

Alkaline phosphatase (ALKP) and alanine aminotransferase (ALT) levels should decrease in dogs on Vetoryl treatment, but may not return to the reference range. In Dechra’s 6 month clinical trial ALT concentrations had decreased significantly by 9-12 days and by 6 months 92% of dogs had levels within the normal range. ALKP concentrations decreased significantly by 4 weeks but at 6 months 58% of dogs still had levels greater than the reference range. 

If liver enzymes are increasing in a dog on Vetoryl treatment this could be due to:

-    Inadequate control of hypercortisolism for the entire 24 hour period 

-    Progression of primary hepatic disease possibly as a result of ‘unmasking’ of an underlying inflammatory hepatopathy due to a reduction in endogenous corticosteroid levels. Vetoryl is contraindicated in primary hepatic disease.

-    Concurrent administration of other medications that may cause an increase in liver enzymes

Further investigations into these possibilities should be undertaken in order to determine the cause of hepatic enzyme increase.

Where any dog experiences an unwanted or unexpected event whilst receiving any veterinary medicinal product, it is important to report the event to the local body responsible for veterinary pharmacovigilance, even if you are confident the adverse event is not linked to administration of the medicine itself. You can do this directly to your local authority, or alternatively you can provide us with the case details so that we may record the case and forward to local authorities on your behalf. Please use the contact us section of this site. 

There is no evidence to suggest that Vetoryl is nephrotoxic.

Urea and creatinine levels can be slightly below the reference range at the time of diagnosis of Cushing’s due to continual urinary loss as a result of glucocorticoid-induced diuresis (cortisol is thought to interfere with antidiuretic hormone (ADH) release or effect, causing polyuria and polydipsia). Therefore, when treatment with Vetoryl is started, urea and creatinine? levels may increase slightly but should remain within the reference range in a dog with normal renal function.

An increase in serum urea and creatinine above the reference range may be pre-renal, renal or post-renal. Determination of the origin of the azotaemia will allow the best next steps for the patient to be identified.  

Vetoryl can potentially induce an iatrogenic hypoadrenocorticism, which induces a pre-renal increase in urea and creatinine due to hypovolaemia. Expected changes to electrolytes include hyperkalaemia and hyponatraemia. Urine specific gravity in these cases may be high.

An azotaemia unaccompanied by hyperkalaemia is more likely to be a primary renal azotaemia. In these cases urine specific gravity should be isosthenuric (1.008-1.012). The Vetoryl datasheet states: “Subclinical renal dysfunction may be unmasked by treatment with the product” and this occurs due a reduction in glucocorticoid-induced diuresis. It is not uncommon for dogs to have both Cushing’s and renal dysfunction. This may simply reflect the fact that both diseases are more common in older dogs. In addition, systemic hypertension occurs in a large percentage of dogs with hypercortisolism. Hypertension may lead to glomerular damage and glomerulosclerosis.

It should be noted that Vetoryl is contra-indicated in dogs with renal insufficiency.

The reason for this is that extrapolation from studies in other species suggest that trilostane is likely to be renally excreted in dogs. Renal insufficiency may impair the excretion of trilostane, leading to increased serum concentrations of trilostane and its active metabolites, which could precipitate adrenal over-suppression.

Further investigations into these possibilities should be undertaken in order to determine the cause of azotaemia. 

Where any dog experiences an unwanted or unexpected event whilst receiving any veterinary medicinal product, it is important to report the event to the local body responsible for veterinary pharmacovigilance, even if you are confident the adverse event is not linked to administration of the medicine itself. You can do this directly to your local authority, or alternatively you can provide us with the case details so that we may record the case and forward to local authorities on your behalf. Please use the contact us section of this site. 

Potassium levels may increase slightly in dogs on Vetoryl treatment, but should remain within reference range. 
 
Some dogs on Vetoryl treatment can have a mild, isolated rise in potassium – the reason for this is uncertain. Therefore, if the dog is clinically well, has normal sodium levels, normal cortisol levels, and the potassium is only mildly elevated then this would not be a cause for undue concern, though clearly it is important to continue to regularly monitor the animal.  

Clinical symptoms of hyperkalaemia are often not displayed unless plasma potassium exceeds 7.5 mEq/L (Maggiore, 2017). However, substantial variation occurs because factors such as the plasma calcium concentration and acid base status can modify the toxicity of hyperkalaemia. Clinical signs that are directly referable to hyperkalaemia include varying degrees of muscular weakness and disturbances in cardiac conduction.

In a study by Wenger (et al 2004) of dogs with PDH treated with trilostane, elevations in potassium concentrations were observed up to a maximum level of 6.2 mmol/l. Using this study as a reference, a persistent hyperkalaemia above this value could therefore raise suspicion of underlying disease which may require further investigation.

If an animal has a persistent hyperkalaemia, and the hyperkalaemia is at a level where there could be adverse consequences, aldosterone levels can be checked pre- and post-ACTH. However, note that in the Wenger (et al 2004) study, there was no correlation between potassium and aldosterone concentrations detected at any of the follow-up evaluations. It would be very rare for an animal to have a normal cortisol level but a low aldosterone level.

- If an animal is hyperkalaemic and the cortisol (+/- aldosterone) monitoring level is low, this may indicate adrenal oversupression, and Vetoryl should be stopped for 7 days. 

- If an animal is hyperkalaemic, the cortisol measurement is normal but the post-ACTH aldosterone level is low, then the Vetoryl dose can be reduced. However, this may result in unacceptable clinical signs of Cushing’s if cortisol levels are inadequately controlled. An alternative treatment for Cushing’s could be considered.

- If an animal is hyperkalaemic and the cortisol and aldosterone measurements are normal, then this could be an idiosyncratic reaction to Vetoryl. If the hyperkalaemia is persistent and is at a level that is causing clinical concern, then Vetoryl should be stopped. An alternative treatment for the Cushing’s should be considered.

There can be other reasons for elevations in potassium, including sampling errors, increased intake of potassium or decreased clearance. Consideration should also be given to this when assessing  hyperkalaemia in these patients.

Where any dog experiences an unwanted or unexpected event whilst receiving any veterinary medicinal product, it is important to report the event to the local body responsible for veterinary pharmacovigilance, even if you are confident the adverse event is not linked to administration of the medicine itself. You can do this directly to your local authority, or alternatively you can provide us with the case details so that we may record the case and forward to local authorities on your behalf. Please use the contact us section of this site. 

Where any patient becomes unwell whilst receiving Vetoryl therapy the following action is recommended:

  1. Stop Vetoryl treatment 
  2. Undertake an ACTH stimulation test alongside measurement of electrolytes
  3. Treat symptomatically as required
    • If post ACTH cortisol is < 40 nmol/l: dexamethasone to treat hypocortisolaemia, IV 0.9% NaCl to resolve dehydration & hyperkalaemia; alternatively hydrocortisone CRI and IV 0.9% NaCl
    • If post ACTH cortisol is > 40 nmol/l: hypocortisolism is unlikely, investigate other causes 
  4. Report as a possible adverse event – even where the post ACTH stimulation cortisol returns within normal reference limits. 

If you suspect that an adverse event has occurred whilst your patient is receiving Vetoryl this should be reported directly to Dechra or your local regulatory authority. 

An adverse event is defined as ‘any observation in animals, whether or not considered to be product-related, that is unfavourable and unintended and that occurs after any use of veterinary medicine. This is particularly important for dogs that are considered unwell. 

Dechra is happy to process this report as part of our commitment to pharmacovigilance and to the safe and effective use of veterinary medicines. Please contact us to do this.

Pre-Vetoryl Cortisol

Prior to consultation:

  • Owners should be encouraged to keep good records at home.  An easy way to ensure this is to direct owner’s to our dedicated website https://www.canine-cushings.co.uk/ where they are able to download a logbook. 
  • The consultation itself should be arranged at the time of, or up to 2 hours after, the dog’s normal Vetoryl dosing time (i.e. If the dog is normally dosed at 8 am, the consultation should be arranged between 8 am and 10 am – but the blood sample must be collected before that day’s dose has been administered).
  • NB – If a patient is receiving Vetoryl twice daily, and is being monitored prior to the evening dose, then this is the dose that should not have been administered before sampling. The morning dose can be given as per the patient’s regular routine.

During the consultation:

  • Questions regarding the clinical signs of Cushing’s should be asked alongside questions which are designed to highlight signs of oversupression or concurrent disease.

For more information please see the FAQ ‘What is the Cushing’s Clinical Score?’ and ‘What is the CushQoL-pet?" in FAQ section - Consultation Support.

  • 1 to 2 ml of blood should be collected in a heparin or serum tube for measurement of cortisol.
  • We recommend that this sample is sent to an external laboratory participating in an external quality assurance scheme (e.g. ESVE- or SCE- programmes) and preferably that uses a Siemens IMMULITE® – or a method that has been validated against this machine. 

After the consultation:

  • Using all information collected, the clinical status of the patient should be determined. The patient will fall into one of three categories, and this determines result interpretation.
    • Clinically well but with signs of Cushing’s
    • Clinically well without signs of Cushing’s
    • Clinically unwell
  • We advise that you then use the following flowchart to aid in interpretation of the results:

 

Since the Pre-Vetoryl Cortisol test does not feature on the Vetoryl Summary of Product Characteristics, informed owner consent for ‘off-label’ monitoring should be obtained.

In this situation, the PVC Flowchart recommends to:

  • Re-evaluate case (reassess history and consider Pre-Vetoryl ACTH stimulation test. Contact Dechra Technical Services for further information) AND/OR
  • Consider lower dose (use combinations of capsule sizes to decrease the once or twice daily dose)

In this context, ‘re-evaluate case’ means carefully questioning the owner and examining the dog to see if there are any signs consistent with adrenal over-suppression. Questions around lethargy, inappetence and vomiting should be specifically asked to ensure there are no subtle signs of iatrogenic hypocortisolism which the owner has not volunteered. If the owner has kept good home records this process will be much easier. 

If the dog does genuinely appear to be well, then a Pre-Vetoryl ACTH stimulation test can be run. 

If the post-ACTH cortisol is normal (40-200 nmol/l) then the Vetoryl dose could be left unchanged, as these results indicate that (at least at the pre-capsule time) the dog has sufficient adrenal reserve to respond to stressful situations. 

However, a post-ACTH cortisol at the low end of this 40-200 nmol/l range at 24 hours post-capsule, and certainly any dog with a post stimulatory cortisol of <40 nmol/l, would be potentially concerning as it would indicate minimal adrenal recovery at the time the next dose is due. A dose reduction could be a sensible option to reduce the risk of adrenal over-suppression.

In this situation, the PVC Flowchart recommends to:

  • Re-evaluate case (contact Dechra Technical Services if further support is required) AND/OR
  • Consider dividing the current dose equally between morning and evening doses. If already dosing twice daily then consider a small dose increase (use combinations of capsule sizes to increase the twice daily dose)

In this context, ‘re-evaluate case’ means carefully questioning the owner and examining the dog to see if there are any signs consistent with Cushing’s syndrome. Questions around thirst, urination and appetite should be specifically asked to ensure there are no subtle signs of Cushing’s which the owner has not volunteered. If the owner has kept good home records this process will be much easier. It is worth bearing in mind that it would be unusual for a dog to have persistently elevated circulating cortisol without showing signs associated with this.

Another explanation for an elevated PVC without symptoms of Cushing’s is that the patient was particularly stressed or anxious at the time the sample was taken. 

Once you are happy that the result is a true indication of elevated circulating cortisol, then the recommended next step would be to move to BID dosing. This should be achieved by increasing the total daily dose by up to 50% and dividing into equal morning and evening doses. If the patient is already receiving Vetoryl twice daily, the recommendation would be to make a small increase to the total daily dose. In either case you should re-evaluate the patient after 28 days.

Provided the PVC value is > 40 nmol/l then a change in dose or dose frequency is recommended. 

Where symptoms are not adequately controlled for the entire 24 hour dosing period, then a move to BID dosing should be considered. by dividing the current dose equally to form morning and evening doses.

Alternatively, where once daily dosing is preferable, or where the patient is already receiving Vetoryl twice daily, an increase in the overall dose should be considered. 

ACTH Stimulation Test

At 4 - 6 hours post-capsule, the aim should be to achieve a post-ACTH cortisol value of >40 nmol/l and <200 nmol/l.

However, it is important to remember that biochemical control should always be matched with clinical control.  It may be the case that a dog is showing no clinical signs of Cushing’s syndrome but has a slightly higher post-ACTH cortisol value (<250 nmol/l).

In this situation, a dose increase would not be required if the clinical signs were well controlled. Therefore, cortisol values should always be interpreted alongside the clinical picture.

Although a post stimulatory cortisol of >200 nmol/l  is higher than we would ultimately like the cortisol to be for a dog on Vetoryl therapy, we do not generally advise a dose increase at 10 days.

Experience suggests that there is likely to be a further reduction in the post-ACTH cortisol at the 28 day test, even if the dose is not increased. Also, we do not want cortisol levels to fall too rapidly. If they do, the animal may suffer from cortisol withdrawal syndrome. Signs of cortisol withdrawal syndrome include weakness, lethargy, anorexia, vomiting and diarrhoea. It should be distinguished from hypoadrenocorticism (Addison’s disease) by an ACTH stimulation test and evaluation of serum electrolytes.

The action to be taken would be dependent on both the clinical signs the dog is displaying and the value of the post stimulatory cortisol. 

Good history taking is essential to determine exactly when the clinical signs are being displayed. This can give an indication as to whether the overall dose of Vetoryl is too low, or whether the effect of Vetoryl is not persisting for the entire 24 hour dosing period.

Where the post stimulatory cortisol is > 120 nmol/l and the preference is to maintain once daily dosing a small increase in the overall dose could be considered. 

Alternatively consideration could be given to moving to twice daily dosing. This can be achieved by taking the total daily dose and dividing equally into morning and evening doses. 

Where a patient is clinically well but there is no response to an ACTH stimulation test our recommendation would be to stop Vetoryl treatment for at least 7 days.

Once the clinical signs of Cushing’s return, Vetoryl can be restarted at a lower dose. The patient should then be rechecked after 10 days (as per SPC recommendations). 

Alternatively, consideration could be given to measuring pre-Vetoryl cortisol (PVC). If the PVC is between 40 and 138 +/- 15% nmol/l then the current dose could be maintained.

In general, this is not something to be concerned about. The pre-ACTH cortisol may be higher than the post-ACTH cortisol if the animal was stressed at the time of blood sampling. 

Any decisions regarding dosage adjustments should be made based on the post-ACTH cortisol.

Consultation Support

Assessment of serum cortisol concentrations alone is unreliable for the monitoring of Cushing’s, therefore paying particular attention to the clinical signs is vital to achieving treatment success. 

To do this, excellent owner communication is vital to truly understand how a dog is doing on Vetoryl. Motivating an owner to take control of their dog’s condition right from the point of diagnosis is of benefit to everyone involved in the dog’s care. Explaining the need for good record keeping at home and providing the tools to enable consistent and effective monitoring can help get owners on board.

As such, Dechra has worked alongside the Royal Veterinary College, London to create the ‘Cushing’s Clinical Score’. This comprises of a series of questions, to be completed by the owner, which can provide you with the information you need in order to determine the true clinical status of your patient. 

The questions cover four factors:

  1. Drinking and urination
  2. Appetite
  3. Demeanour
  4. Appearance 

In addition to covering clinical information, the aim is that by using one standardised form throughout the practice, the same questions are asked in the same way for every monitoring consult – ensuring consistency for the patient and owner and improving consult efficiency. 

Click here to download a copy of the Cushing’s Clinical Score to use in your practice.

Click here to hear Professor Stijn Niessen’s overview of the Cushing’s Clinical Score.  

Once an owner has completed the Cushing’s Clinical Score form, a numerical value for the clinical status of the patient will be gained. Lower values indicate better clinical control.

When interpreting the Cushing’s Clinical Score, there isn’t a ‘cut off’ value, or a set score change, which indicates action is required. This is because the score shouldn’t be interpreted as a one off number- but should be monitored over time, in the individual patient.

Each dog will have their own starting score which we would take as their baseline. With treatment we would expect this to reduce (ideally down to 0), and providing the score is reducing or remaining at a constant low level (at which you and owner are happy that the maximum possible clinical improvement has been made) then the dog is doing well.

If, however, the score slowly starts to increase over time, or there is a sudden increase during a routine check-up, this would then warrant further investigation and possible dose adjustment. 

The overall aim of treatment with Vetoryl is to improve the quality-of-life of dogs and, as a result, their owners. Recent research highlighted that it is not just the clinical signs of Cushing’s that impacts on a dog’s quality-of-life. Consideration of specific treatment needs for individual patients as well as their owners are important to optimise the quality-of-life for dogs with Cushing’s.

The scientifically validated CushQoL-pet (Schofield et al, 2019) is a questionnaire which has been developed for completion by pet owners to help assess quality-of-life within your monitoring consultations. It is recommended to complete this at least every three months to facilitate communication and to work with the owner to decide the next steps of their dog’s management.

Click here to download the CushQoL-pet questionnaire for use in your Vetoryl monitoring consultations. 

Once an owner has completed the CushQoL form, a numerical value will be generated based upon the response. 

This number should then be divided by 57 to provide the CushQoL-pet score.

Scores nearest to 0 indicate the best possible quality-of-life, whereas scores nearest to 1 indicate the worst possible quality-of-life.

The CushQoL-pet score is useful as it enables you to determine trends in quality-of-life over time:

Interaction with other medicine

The possibility of interactions between Vetoryl and other veterinary medicinal products has not been specifically studied. Given that hyperadrenocorticism tends to occur in older dogs, many will be receiving concurrent medication. In clinical studies, no interactions were observed.

Although there is no overt contraindication for use of Vetoryl alongside potassium sparing diuretics, the Vetoryl SPC does state that: The risk of hyperkalaemia developing should be considered if trilostane is used in conjunction with potassium-sparing diuretics. This is because both drugs have an anti-aldosterone effect

Vetoryl inhibits aldosterone production by competitive inhibition of the enzyme 3 beta-hydroxysteroid dehydrogenase in the adrenal cortex. Potassium-sparing diuretics competitively inhibit the action of aldosterone, preventing sodium resorption and promoting potassium retention in the distal tubules of the nephrons in the kidney.

Therefore a risk vs benefit analysis for the individual patient should be carried out before commencing concurrent therapy. 

The possibility of interactions between Vetoryl and other veterinary medicinal products has not been specifically studied. Given that hyperadrenocorticism tends to occur in older dogs, many will be receiving concurrent medication. 

Although there is no overt contraindication for use of Vetoryl alongside ACE-inhibitors the Vetoryl SPC does state that: The risk of hyperkalaemia developing should be considered if trilostane is used in conjunction with ACE inhibitors and there have been a few reports of deaths (including sudden death) in dogs when treated concurrently with trilostane and an ACE inhibitor.

Both Vetoryl and ACE-I have an anti-aldosterone effect. 

Vetoryl inhibits aldosterone production by competitive inhibition of the enzyme 3 beta-hydroxysteroid dehydrogenase in the adrenal cortex. ACE inhibitors inhibit angiotensin converting  enzyme (ACE) thus preventing the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates secretion of aldosterone by the adrenal cortex; hence aldosterone secretion is reduced in animals treated with ACE inhibitors.

Therefore a risk vs benefit analysis for the individual patient should be carried out before commencing concurrent therapy. 

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