The South African Veterinary Association



Hyperadrenocorticism/ Cushing’s syndrome – Diagnosis and Therapy March 2020Dave MillerJohannesburg Specialist Veterinary Centre Introduction:Cushing’s syndrome or Hyperadrenocorticism is a slow onset and progressive insidious disease process. Testing for hyperadrenocorticism in a dog is done because they [are nearly always healthy, happy dogs that] have?clinical signs of the disease?(at least some of the signs) e.g., abdominal enlargement, panting, muscle weakness, thin skin, lethargy, polyphagia, polyuria/polydipsia (PU/PD) for months to even years before the owners recognize a problem and seek veterinary help. Or you see the dog another reason and inform them their dog probably has Cushing’s syndrome. Approximately 75-85% of our dogs with Cushing's have pituitary Cushing's, and only 15-25% have an adrenal tumour.Typical Signalment:In a large retrospective study of almost 600 dogs, Cushing’s was more frequent in females. Neutering was associated with a minor, but significant, increase in the odds of hyperadrenocorticism [HAC]. HAC was the presumed to be the eventual cause of death of 25?9% of affected dogs despite therapy. When aetiology was specified, pituitary-dependent hyperadrenocorticism at 73?4%, was more common than functional adrenocortical tumour 25?8%. Of the select comorbidities investigated, dogs with HAC were at increased risk for concurrent diabetes mellitus, urinary tract infection, urolithiasis, hypertension, gall bladder mucocoele and thromboembolic disease. Another study of 60 plus dogs found:- owners' presenting complaints- increased urination and/or water intake, 71%- polyphagia, 35%- enlarged abdomen, 32%- dermatological signs, 13%- exercise intolerance, 11%- prevalence of clinical signs- polydipsia, 90%- polyuria, 90%- polyphagia, 70%- abdominal enlargement, 61%- excessive panting, 61%- testicular atrophy, not reported here but had been previously- anestrus, 50%- alopecia, 43%- lethargy, 39%- muscle weakness, 34%- nocturia, 30%- hyperpigmentation, 29%- muscle atrophy, 28%- recurrent pyoderma, 23%- comedones, 19%- recurrent urinary tract infection, 16%- calcinosis cutis, 8%- facial nerve paralysis, 5%- suspected ligament rupture, 3%- anorexia, 2%- pseudomyotonia, 1%? ? ?Knowing the above, many syndromes have signs overlapping with Cushing’s syndrome, so how will I know when I should be testing for Cushing’s syndrome or not?I have made a section of questions and answers to try guide one through this decision-making process.Question 1: Who should NOT be tested for Cushing’s?Testing is NOT recommended if the only abnormality is an increased serum alkaline phosphatase (AlKP) concentration and the dog is otherwise apparently healthy. Check with owner re any other symptoms of Cushing's. Most of the time they're going to say no, and so don’t test for HAC, especially if the AlKP has been elevated on the previous lab work and it's just rising over time. It's really common in geriatric dogs to have nodular hyperplasia in the liver. It doesn't seem to have any clinical consequences and it causes a high AlKP. It's very unusual in other primary liver disease that just AlKP is elevated. With chronic active hepatitis, copper storage disease [worrisome diseases], almost always the alanine transaminase (ALT) is up, and usually it's higher than the AlKP. When the ALT is higher than the alkaline phosphatase we worry about real liver disease. Gallbladder mucocele’s are at their most worrisome when ALT rises.ALSO - Don’t test if you just see truncal alopecia only? That's a different dog than the one we usually see in internal medicine. That's the dermatology case. Some of those dogs do just have Cushing's and other signs will come with time.?It is difficult enough to interpret endocrine tests in dogs with clinical signs of the disease; if they have no clinical signs, and all of the endocrine tests can be difficult to interpret because of false positive and false negative results, then you won’t be any the wiser!.Do NOT test a dog for hyperadrenocorticism if the dog is sick (e.g., vomiting, anorexia, weight loss, etc). Many non-specific illnesses and other systemic diseases will produce false positive results with the endocrine tests. Remember, the diagnosis of hyperadrenocorticism is not an emergency diagnosis.Do not check for Cushing’s in a sick or newly diagnosed diabetic, do your best to get it stabile first as test give a high percentage false positive results.It is therefore always good to ask oneself, if the test results would indicate Cushing’s, would I then feel confident to start treating. If the answer is "no", it is probably best not to test for it in the first place.Exceptions to this rule, worried owner who just wants an answer, they can't sleep at night because this alkaline phosphatase hasn't been explained or you performed an ultrasound examination and found a unilateral adrenal mass and you want to know if it's making cortisol. This is important when you're doing an adrenalectomy because as soon as you remove a cortisol-secreting adrenal mass, they are going to be acutely Addisonian.Question 2: The dog has clinical signs of cushings – Now can I test?If the dog has any or all the clinical signs of HAC, testing is required. Dachshunds are way over-represented, and Yorkies and Boston Terriers are a close 2nd with Min. Schnauzers 3rd. They have slack abdominal muscles, they're kind of bony on the top, they're not always obese but they're in a funny shape. They have a big liver and the classic signs – the polyuria/polydipsia (PU/PD), the polyphagia, the panting, and the poor coat and they are exercise intolerant.However, it is necessary first to ensure that the dog is NOT being exposed to exogenous glucocorticoids, including topical glucocorticoids in the eyes, ears or on the skin. Check with the owner that they are not applying topical glucocorticoids to their OWN skin - in some cases dogs ingest glucocorticoids by licking steroid-containing cream off the owner's skin. Ask the owner to bring in all and any medications that the patient is receiving (including OTC preparations) and anything that the owner or owner's family might be using, to verify that no glucocorticoids are in any of these medications.Next, obtain a routine database (CBC, chemistry screen, UA and urine culture) before any endocrine testing is undertaken. Finding the expected clinical pathology changes in a suspected case of Cushing’s helps confirm what the initial history and physical exam suggested. Typical abnormalities seen with Cushing’s are that AlKP is probably the most consistently elevated, but it's not in about 10-20% of cases. The ALT is almost always elevated, usually in the 100 to 400 range, but it's not more elevated than the ALKP. If ALT is more raised then AlKP, think mucocoele or bacterial hepatitis or cholecystitis. It could also be that it's unrelated like chronic active hepatitis, neoplasia in the liver, and copper storage disease.Urinalysis - dilute urine, Proteinuria, evidence of infection, they don't have glucose in their urine when they have Cushing's. It can be hyposthenuric which is less than 1.008. It can be isosthenuric which is 1.008 to 1.012. It can be above that – 1.012 but usually it's less than 1.025 or so. Protein in the urine ranges between 50 to 75%Usually a stress leukogram with raised platelets in the top normal rangePotassium is not really increased. It's an artefact because when raised levels of platelets clot, they release a lot of potassium.Question 3: WHICH TEST - ACTH vs. LDDST.Both tests can be used, both have pros and cons.Synacthen – 250ug/ml – Section 21 – Equity Pharmaceuticals (012) 3451747[Section 21 – Catherine – pervetS21@.za]The ACTH Stimulation Test:ACTH Pro’s:Only takes 1 hour Synacthen – split the vial into little aliquots in plastic syringes, then freeze [ in back part of your freezer so constant temp]Send the cortisol samples to a commercial lab, do not run the cortisol samples in house. We test naive cases at 5ug/kg with a max dose of 250 ug intra muscularWhen monitoring dogs on lysodren therapy, test at 1ug/kg I.M.When testing dogs on Trilostane we DO NOT perform an ACTH but rather a Trilostane response test.?ACTH - Fewer false positive results than a LDDST. The ACTH stimulation test can be used in situations where a 'sick' dog requires testing. Note that testing a dog that is anorectic, vomiting, losing weight, etc. is contraindicated; however, testing a dog with, as best controlled as you can, diabetes or stable heart disease can be performed. It is considered the screening test of choice in this situation (but can still produce false positive results on occasion).?The only screening test that will show exposure to exogenous steroids (iatrogenic Cushing’s), although a good history usually identifies these cases. ACTH Cons??More false negative results than a LDDST. Approximately 20-30% of dogs with cushings will have ACTH stimulation test results within the reference range. An additional 20-30% of dogs with hyperadrenocorticism will have "borderline" test results. The test is notorious for producing false negative results in dogs with cortisol-secreting adrenal tumours (AT), but dogs with PDH (pituitary-dependent hyperadrenocorticism) also frequently have normal stimulation tests.A positive ACTH stimulation test doesn't tell you whether the dog has PDH or AT, so additional testing is necessary - it is a true screening test.Summary ACTH - There are more false negatives than the low dose. This is its primary disadvantage – you're going to miss a lot of cases. Literature summaries show – 20 to 30% of dogs with Cushing's have an ACTH stim that is normal. Another 20 to 30% will have borderline results. That leaves 20 to 30% that are going to test positive, clearly positive on the ACTH stim.If you find an adrenal mass - cortisol-secreting adrenal tumours, [the big dogs are over-represented with an adrenal tumour], I would not run an ACTH stim as your screening test in those dogs.NOTE:Dexamethasone isn't measured on the cortisol assay, so you can give that if you're seeing a dog that you think might have Addison's and you want to give them a steroid but you also want to do the ACTH stim that dayLow-Dose Dexamethasone Suppression Test [LDDST]LDDST – Very small amount of Dexamethasone needed in small dogs, using a 1ml syringe, fill the rest of the syringe with saline right before you inject that entire syringe full. 0.01–0.015 mg/kg dexamethasone intravenouslyLDDST Pro’s:Fewer false negative test results than the ACTH stimulation test - approximately 90% of dogs with hyperadrenocorticism will have an 8-hour post-Dexamethasone cortisol concentration > 38 (another 6-8% have borderline values, i.e. > 27 but < 38)Identifies the underlying cause of the disease in 50% of the cases. The LDDST will not only confirm hyperadrenocorticism (e.g., 8-hour post-Dexamethasone cortisol is > 37), but can often differentiate between PDH and AT, avoiding additional testing.How you look at a LLDST is that you look at the 8-hour result first and see if it's above or below your cut off for your lab about 38.6 nanomoles per litre (nmol/L) If Above = Cushing’s, If below = notThe 3 criteria for diagnosing PDH on the LDDS include:?If the 8 hour cortisol value is > 38.6 nmol/L but <50% of the resting cortisol value?If the 4-hour cortisol value is <27 nanomoles per litre nmol/L?If the 4-hour cortisol concentration is <50% of the resting cortisol valueNote that if the above criteria are NOT met to diagnose PDH, the dog could have either PDH or AT. Further testing is necessary to find out (e.g. Abdominal ultrasound, high-dose dexamethasone suppression test [HDDST] or endogenous ACTH).LDDST Cons:?Takes 8 hours to run the testMore false positives if the dog is systemically ill or on exogenous steroids (so avoid testing dogs that are systemically ill or on steroids)Don't do anything stressful to the dog while the dog is there. This is not the time to get the nail trim done, to take x-rays, to express the anal glands, or to do any other thing to this dog. Don't do a cystocentesis. Don't do anything to stress the dog during any endocrine test for Cushing's.?NOTE:Dogs on phenobarbital look a lot like a dog with Cushing's. They are PU/PD, they are polyphagic, they have an increased alkaline phosphatase AND it can also cause false positives on the LDDST (U/S the adrenals to see if need other tests or change meds and retest a month later).HDDST – we do not run these:Well, it will confirm pituitary Cushing's if you get a 4-hour sample that's less than the cut off value and if you see suppression on the high-dose dex, either the 4 or the 8-hour value are less than 50% of the resting value and/or the 4-hour sample is less than the lab cut off value, then that confirms pituitary Cushing's. About 75% of the dogs with pituitary Cushing's has one of these patterns of suppression. Again, 25% of the dogs with PDH don't suppress on the high dose. That still doesn't mean they have an adrenal tumour. It just means you've wasted time and money with this high dose, and you still could have either an adrenal tumour or Pituitary Cushing's. That’s why we do u/s scans of these cases.Question 4: If the LDDST is generally a better (screening) test, when should the ACTH stimulation test be used?Its cheaper, its faster, its easier!!!The most common use of the ACTH stimulation test is in a suspect patient that has a systemic illness like diabetes mellitus to avoid the false positives of the LDDST. It’s used with monitoring the response to therapy (Lysodren), To document iatrogenic hyperadrenocorticism, or to diagnose Addison's disease. Contrary to popular belief, it is not necessary to run an ACTH stimulation test prior to treatment for hyperadrenocorticism i.e. there is no need for a 'baseline' ACTH stimulation test prior to treatment with either Trilostane or Lysodren. It is not important what the cortisol concentrations are prior to therapy if Cushing’s is proven.Question 5: When should Cushing’s be treated?Once a definitive diagnosis of Cushing’s has been made, a decision needs to be made regarding treatment, which is a life-long commitment for the clinician and the owner. We do NOT recommend treating Cushing’s if the dog does not yet exhibit clinical signs of disease (i.e., the diagnosis was prompted exclusively by biochemical abnormalities, such as a high ALKP), or exhibits signs that are not yet bothering the owner or the veterinarian. Hyperadrenocorticism is a slowly progressive disease that unfolds over many months-years, so it may be a long time before the dog needs to be treated. Instead, provide a client info. sheet with instructions to look for clinical signs that warrant treatmentDo routine check-ups 4- 6 monthly and monitor for the insidious damage that Cushing’s can cause by physical examinations and urine testing to r/o UTI and check BP and urine protein levels [maybe]..Question 6a: What clinical signs usually concern owners sufficiently to warrant starting treatment?Most owners become concerned when their pet displays signs of inappropriate urination, or nocturnal pollakiuria (owner must get up in the middle to take dog out). Exercise intolerance, occasionally, skin problems, such as coat changes. Alopecia alone is generally insufficient to warrant instituting treatment; however, recurrent pyoderma,?Malassezia?dermatitis, demodicosis, ringworm, etc. warrant intervention.Question 6b: What clinical signs usually concern veterinarians sufficiently to warrant starting treatment?Even if the owner is still not concerned, we start therapy if:?Recurrent infections (primarily UTI, but could be recurrent skin infections).Severe Cushing’s-related hypertension (that is refractory to amlodipine treatment).Progressive proteinuria (a UPC in the 1.0 – 3.0 -5.0 range). Culture the urine first (via cystocentesis) even if the sediment is quiet, as the urine is dilute, and the dog is immunosuppressed so often no neutrophils) before running a UPC. Note that the UPC would rarely be >5.0 – 8.0 due to Cushing’s, therefore, hypoalbuminemia will not develop. We are still not 100% sure whether treatment for Cushing’s will reverse proteinuria. Poor wound healingSevere muscle mass loss, severe weakness, signs of glucocorticoid myositisQuestion 7: If treatment is not yet indicated, what do I do?Educate the owner about what clinical signs are likely to warrant instituting therapy. Perform routine physical examinations every 4-6 months. Monitor blood pressure, urine culture (via cystocentesis) and degree of proteinuria (UPC after the urine culture is negative) during these visits.Question 8: Is there no other damage that hyperadrenocorticism could cause while we're waiting to treat?Rarely, a dog will develop diabetes mellitus because of untreated hyperadrenocorticism, or will rupture cranial cruciate ligament(s). The risk of treating outweighs the risk of complications. Warn the owners that rarely, very unwanted complications develop from not treating hyperadrenocorticism immediately, but because these are so rare, we don't over-treat lots of dogs to prevent this in a few'. Gallbladder mucocoele’s, commonly associate with Cushing’s syndrome is neither prevented not cured when we institute therapy.Possible exceptions to this - Miniature Schnauzer’s with Cushing’s, are more prone to developing diabetes mellitus But the tendency toward diabetes mellitus is better controlled by screening for hyperlipidaemia (cholesterol and triglyceride levels after a 12 hour fast) and controlling it with the necessary manoeuvres (low fat diet +/- drug therapy) to try to avoid the “smoldering” pancreatitis that leads to the high incidence of diabetes mellitus.Other uncommon complications of hyperadrenocorticism include:?CNS signs secondary to a pituitary macroadenoma?Pulmonary thromboembolismHowever, these can occur regardless of the control of hyperadrenocorticism. Therefore, they do not factor into the decision about instituting treatment.Question 9: And Ultrasound to differentiate Adrenal from Pituitary Cushing’s?Best Discriminating Tests for AD vs PDH = abdominal ultrasound. BUT sometimes it's confusing because you'll see asymmetry of the adrenal glands, like they're both enlarged but one is larger. That can happen sometimes in pituitary Cushing's if they're not too asymmetrical, but it could also happen in dogs that have both. We sometimes find that dogs can have pituitary Cushing's and an adrenal tumour, or they can have a pheochromocytoma tumour of the medulla rather than the cortex plus pituitary Cushing's.About 20% of the dogs with pituitary Cushing's have normal adrenals on ultrasound, but Cushing's almost always has hepatomegaly on ultrasound and grossly it looks like steroid hepatopathy. If one sees a dog with normal adrenal glands that you think has Cushing's, it is reassuring to see hepatomegalyQuestion 10: How do we TreatTrilostane2 mg/kg once-a-day (in the AM, with food) is the advised starting dose BUT dogs >25 kg may need lower doses on a per kilogram basis Exceptions:In the listed specific cases below - 1 mg/kg twice daily (each dose with food from the start in …..Diabetic dogs (we want to influence the insulin requirement the same in the AM and PM)Dogs with calcinosis cutisDogs whose owners are close to euthanasia unless the urination in the house stops immediatelyTrilostane overdose causes glucocorticoid insufficiency, which responds to temporary halt in the trilostane (if the cortisol levels are really low) then restarting at a new lower dose, or just adjusting the dose downward if the cortisol levels aren't flatline. Rarely it causes adrenal necrosis (irreversible), which results in both glucocorticoid and mineralocorticoid insufficiency; this is not only associated overdosing of the drug but appears to result from very high endogenous ACTH levels, which damage the adrenal cortexQuestion 11: How do we monitor therapyUsing Clinical signsDose adjustments are often needed and are based on clinical signs and if unsure a pre and post trilostane cortisol test. The accuracy of baseline cortisol alone to predict the adrenal reserve in dogs being treated with trilostane for HAC has not been consistent. If the dog is normal as regards clinical signs the dose if correctIf signs of PUPD, polyphagia etc continue, the dose is to lowSigns of overdose like decreased appetite, vomiting, diarrhoea, listlessness or normalization of water intake can occur insidiously or overnight. Then with time, in overdose, suddenly these overdosed dogs become old dogs with no zest for life. It may take 30 days for the full effect of trilostane to manifest, so the dose should not be increased after the 2week check-up visit.Using Pre Trilostane levels - ?target range of 40 to 138 nmol/l, the pre-trilostane cortisol concentrations were better than the post-ACTH cortisol concentrations at discriminating between dogs whose HAC was well controlled and those that were under-controlled with a?sensitivity of 55.4% and a specificity of 86.5%.?Pre-trilostane monitoring may be better able to identify over-suppression when the result is <40 nmol/l, Post-trilostane (pre-ACTH) cortisol was also able to discriminate between dogs whose HAC was well controlled and those that were under-controlled; however, it was not able to distinguish between those dogs that were well controlled and those that were over-suppressed.Using aTrilostane Response testing:See separate spread sheetQuestion 12: Life expectancy A 2019 Vet Record publication found:81.7 per cent of cases died with a median survival time from first diagnosis of 510 days (95%?CI 412 to 618 days). Trilostane was used in 94.1 per cent of cases. Question 12: Adrenal Tumours and Adrenal size on ultrasound examination.Adrenal tumours that we see at u/s, so that's 15% of our cases, half are benign and half are malignant, so that's 7.5% of the dogs you see have a benign adrenal tumour and 7.5% have a malignant adrenal tumour. But remember, up to 70% of adrenal tumours are non-secretary and we call them Incidentaloma’s. So if owners say - yeah, we would never do that adrenalectomy, just make a note of it in the record so that they can't yell at you later if the dog has a malignant tumour that you didn't diagnose.Do u/s as long as you understand that big adrenals don't mean a diagnosis of Cushing's, it's fine to look. In a broader PU/PD workup instead of the more focused Cushing's workup, and you wanted to see a whole lot of things, the kidneys, liver, and the adrenals. Cushing's, if you see big adrenals or one big adrenal, hepatomegaly, and gross changes that look like steroid hepatopathy. Adrenalectomy is the treatment of choice for non-metastatic FAT.?Due to atrophy of the contralateral adrenal cortex, prednisolone is typically administered (1 mg/kg) immediately postoperatively; this dose is gradually tapered over 8–12 weeks to eventual alternate-day therapy. The steroids are then discontinued for 2–3 days prior to performing an ACTH stimulation test to evaluate the function of the remaining adrenal gland. Question 13: What is Atypical Cushing’s?What is it? Who knows? It's been advocated that it is an elevation in the sex hormones without the cortisol elevations causing symptoms of Cushing's. One study evaluated the 17-hydroxyprogesterone and the estradiol level for the diagnosis of typical and the results were inconclusive. There was an ACVIM consensus statement put out probably 2015 ish. The consensus of experts is that they did not believe that sex hormones cause occult hyperadrenocorticism.Then there is also food-stimulated Cushing's where they have expression of their gastrointestinal peptide (GIP) receptors. They have more receptors on their adrenals than usual, and the adrenals secrete cortisol after they take in food. They don't test positive for Cushing's when they're fasting or not eating, but if you test them right after they eat, we can find positive tests. What's been described is to do a urine cortisol-creatinine ratio before and four hours after a meal and see if it rises by at least 50%. Diagnosis of Hyperadrenocorticism in Dogs: Pathways and Pitfalls, February 9, 2020 Sherri Wilson, DVM, DACVIMCanine hyperadrenocorticism associations with signalment, selected comorbidities and mortality within North American veterinary teaching hospitals. J Small Anim Pract. 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Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS ................
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