Diagnosis of hyperadrenocorticism (cushing’s syndrome) in dogs. which tests are best?. in: proceedings of the 65° congresso internazionale scivac - rimini, italy, 2009

65th SCIVAC International Congress
May 28-30, 2010 - Rimini, Italy
Reprinted in IVIS with the permission of the Congress Organizers
Reprinted in IVIS with the permission of SCIVAC Close window to return to IVIS www.ivis.org 62° Congresso Internazionale Multisala SCIVAC Diagnosis of hyperadrenocorticism
(cushing’s syndrome) in dogs. which tests are best?
Edward C. Feldman
DVM, Dipl ACVIM (Internal Medicine), California, USA calcification (calcinosis cutis), clitoral hypertrophy, and easybruisability are much less common. There is, however, Dogs chronically exposed to excess cortisol usually devel- remarkable variation in the number and severity of abnor- op a classic combination of clinical signs, some of which malities noted. These dogs may have a single dominant sign may be dramatic. These common signs include polydipsia, polyuria, polyphagia, abdominal enlargement, alopecia,pyoderma, panting, muscle weakness, thin skin, and lethar-gy. It must be remembered, however, that not all dogs with SENSITIVITY AND SPECIFICITY
hyperadrenocorticism develop the same signs. From this (WHICH TEST IS BEST?)
long list of potential signs (plus others), most dogs exhibitseveral (but not all) of these problems. Hyperadrenocorti- Sensitivity of a particular test refers to the number of cism is a clinical disorder, and animals afflicted with this patients with a condition whose test results are abnormal.
disease must have at least some clinical signs or the diagno- Specificity of a particular test refers to the number of sis must be questioned. Clinical signs result from the com- patients that do not have a condition but their test results are bined gluconeogenic, lipolytic, protein catabolic, antiinflam- positive for that condition. Medicine would be much easier matory, and immunosuppressive effects of glucocorticoids.
if our tests were 100% sensitive and 100% specific. Since Typically, the course of the disease is insidious and this is never the situation, the most commonly asked ques- slowly progressive. Owners usually report observing some tion regarding naturally occurring hyperadrenocorticism is: alterations typical of hyperadrenocorticism in their pet for “which test is best?” There is no doubt that the most specif- 6 months to as long as 6 years before they seek veterinary ic and sensitive tests for this condition are history and phys- attention for their animal, since these changes are quite ical examination. Therefore, all test interpretations must be gradual in onset and are often believed to be a result of done in the context of these two parameters. simple “aging.” Commonly, only after signs become intol-erable to the client or after abnormalities are pointed out bypeople who see a pet infrequently (therefore objectively “ROUTINE” DATA BASE
noting obvious changes that have developed so slowly theowners do not observe them) that professional opinion is Any dog suspected of having hyperadrenocorticism from sought. The most common reasons that owners give for the history and physical examination should be thoroughly finally seeking veterinary help are usually evaluated before specific endocrine testing is undertaken.
polydipsia/polyuria, polyphagia, lethargy, panting, and/or These initial tests should include clinicopathologic studies hair coat changes. It should be pointed out that dogs with (complete blood count [CBC]; urinalysis with culture; and a Cushing’s syndrome do not have vomiting, diarrhea, serum chemistry profile). In addition to blood and urine test- anorexia, weight loss, or other signs that would cause many ing, abdominal ultrasonography (preferred over radiogra- phy) should be completed. Finding a large percentage ofabnormalities on initial screening tests that are consistentwith hyperadrenocorticism further allows the veterinarian to PHYSICAL EXAMINATION
establish a diagnosis that was initially based on history andphysical examination. Typical abnormalities include dramat- The physical examination on a typical “Cushing’s” dog ic increases in serum alkaline phosphatase activity, mild-to- reveals an animal that is stable, hydrated, has good mucous moderate increases in ALT and serum cholesterol, low-nor- membrane color and is not in distress. Veterinarians will mal or low BUN, urine specific gravity <1.020 on a sample usually observe, during the physical examination, many of caught by the owner at home, and bacteriuria. The more the signs seen by owners. Among these abnormalities are expensive and sophisticated studies needed to “confirm” a abdominal enlargement (truncal obesity), panting, bilateral- diagnosis and localize the cause of Cushing’s syndrome can ly symmetrical alopecia, skin infections, and comedones.
be recommended to the client if the dog is still believed to Hyperpigmentation, testicular atrophy, and hepatomegaly have this condition. Initial data base results not only ensure are commonly identified on physical examination. Ectopic that the veterinarian is pursing the correct diagnosis but also Proceedings of the International SCIVAC Congress 2009 Reprinted in IVIS with the permission of SCIVAC Close window to return to IVIS www.ivis.org 62° Congresso Internazionale Multisala SCIVAC might alert the clinician to any concomitant medical prob- by these 3 criteria. A dog with Cushing’s that fails to meet lems. These problems may be common for hyperadrenocor- any of these 3 criteria could have either PDH or ACT. How- ticism (urinary tract infection) or unexpected (renal failure), ever, if it has 2 relatively equal sized adrenals on abdominal but in any case may require specific therapy.
ultrasonography, it most likely has PDH.
ACTH Stimulation
“SCREENING” TESTS
(NO LONGER RECOMMENDED)
The ACTH stimulation test has been popular for decades Background
in veterinary medicine. It is simple to complete and takes After establishing a presumptive diagnosis of canine little time. The other significant feature regarding results of hyperadrenocorticism from a review of owner observations, an ACTH stimulation test is that this is the only study physical examination, and laboratory data base, one usually which reliably demonstrates the effect of o,p’ DDD on the proceeds to attempt “confirmation” of the diagnosis. When adrenal cortex. Thus, some veterinarians want results of an necessary, and if possible, an attempt can also be made to ACTH stimulation test, prior to initiating o,p’ DDD thera- determine whether the pet has pituitary dependent hypera- py, because the results are used as “baseline” information drenocorticism (PDH) or an adrenocortical tumor (ACT).
to objectively monitor effects of o,p’ DDD. Regardless of Choosing a screening test for Cushing’s syndrome is impor- the protocol chosen, it must be appreciated that 20-30% of tant because that test result may determine whether or not a dogs with Cushing’s syndrome have test results within the dog is treated. Routinely used screening tests include ACTH reference range (in our laboratory: post ACTH plasma cor- stimulation, low dose dexamethasone, and the urine cortisol: tisol concentrations of 6 to 17 µg/dl). An additional 20 - creatinine ratio. The decision to treat a dog for Cushing’s 30% of dogs with Cushing’s have test results described as syndrome should never be based solely on laboratory infor- “borderline” (plasma cortisol concentrations >17 but <22 mation. Cushing’s syndrome is a clinical disorder with clin- µg/dl). Therefore, the test is not considered sensitive but is ical signs. If a dog has no clinical signs of Cushing’s syn- relatively specific, i.e., those dogs with plasma cortisol drome, treatment is not recommended. This concept gains concentrations >22 µg/dl frequently have Cushing’s. How- importance when it is understood that no screening test is ever, specificity of an exaggerated response to ACTH is correct all of the time, i.e., as previously stated, sensitivity also not perfect. Therefore, test results should never be and specificity is never 100%. Some dogs with non-adrenal interpreted without knowing results of history, physical disease and many with polyuria and polydipsia due to a con- examination, and routine data base testing. There are no dition other than Cushing’s syndrome can have false positive features of ACTH stimulation test result that allow dis- screening test results for hyperadrenocorticism. Because crimination between PDH and ACT. As ACTH has become false positive test results have been observed with any com- more and more expensive, this test is losing popularity.
monly used screening test, the definitive diagnosis of Cush- ACTH gel is effective and synthetic ACTH can be given at ing’s syndrome should never be solely on screening test 0.05 mg/kg (IV or IM) instead of using .25 mg (one vial) results, especially in dogs without classical clinical signs or per dog. Excess cortrosyn can be frozen while maintaining in those with known non-adrenal disease. In our experience, potency for about 6 months. In our opinion, the lack of sen- the most sensitive, specific, and reliable screening tests for sitivity of the ACTH stimulation test makes it a test that the hyperadrenocorticism in dogs are history and physical profession should abandon. The situations in which ACTH examination. The most sensitive, specific, and reliable hos- stimulation testing would be indicated include monitoring pital study is the low dose dexamethasone test.
therapy for naturally occurring hyperadrenocorticism, toaid in the diagnosis of iatrogenic Cushing’s syndrome, and Low Dose Dexamethasone Test (LDDS)
as the “gold standard for the diagnosis of naturally occur- The protocol utilized for this test is obtaining plasma sam- ples for cortisol before and 4 and 8 hours after I.V. adminis-tration of 0.01 mg/kg dexamethasone. The 8-hour plasma Urine Cortisol: Creatinine Ratio (UC:CR)
cortisol is used as a screening test for hyperadrenocorticism, The urine UC:CR ratio is easily performed (simply have with concentrations >1.4 µg/d1 being consistent with (not the owner collect and deliver urine to the hospital and sub- confirming) the diagnosis of Cushing’s syndrome. This test mit it to the laboratory) and, therefore, it is usually less is relatively sensitive and specific, but not perfect. Approxi- expensive than other screening tests. Most dogs (~97%) with mately 90% of dogs with Cushing’s syndrome have an 8 naturally occurring Cushing’s syndrome have an abnormal hour post-dexamethasone plasma cortisol concentration result (the test is sensitive) but a significant percentage of >1.4 µg/dl and another 6 to 8% have values of 0.9 – 1.3 dogs with polyuria / polydipsia due to other conditions and µg/dl. The results of a low dose test can also aid in discrim- those with non-endocrine illness also have abnormal results inating PDH from ACT, using 3 criteria: 1) an 8 hour plas- (the test is not specific). It has be suggested that the UC:CR ma cortisol >1.4 µg/dl but <50% of the basal value; 2) a 4 be routinely performed only on urine collected by an owner hour plasma cortisol concentration <1.0 µg/dl; and 3) a 4 at home, rather than having it collected in-hospital. Since hour plasma cortisol concentration <50% of the basal value.
this protocol eliminates travel or hospital stress from altering If a dog has Cushing’s and it meets any of these 3 criteria, it test results, it seems reasonable to follow this concept. We do most likely has PDH. Approximately 65% of dogs with nat- not utilize this test with the same degree of confidence with urally occurring PDH demonstrate suppression, as defined which we use the low dose dexamethasone screening test.
Proceedings of the International SCIVAC Congress 2009 Reprinted in IVIS with the permission of SCIVAC Close window to return to IVIS www.ivis.org 62° Congresso Internazionale Multisala SCIVAC However, a normal result is quite uncommon in a dog with monly utilized when other discrimination test results pro- Cushing’s syndrome while an abnormal result could be used to prompt further testing. Therefore, this test can be used asa prompt to recommend abdominal ultrasonography and a High Dose Dexamethasone Suppression
low dose dexamethasone test to an owner.
The HDDS test is relatively easy to perform (plasma 17-HydroxyProgesterone (17OHP) Testing
obtained before and 4 or 8 hours after I.V. administration of The use of 17OHP has been recommended as a screening 0.1 mg/kg dexamethasone), readily available and inexpen- test for dogs with “atypical Cushing’s syndrome”. The defi- sive. If a dog has Cushing’s syndrome and the plasma corti- nition of “atypical” is a dog with clinical signs and routine sol, 8 hours post dex, is <50% of the basal value, the dog has laboratory testing consistent with hyperadrenocorticism but PDH. However, our experience with the LDDS and abdom- with normal low dose dexamethasone screening test results, inal ultrasonography has limited the need and use of HDDS.
normal ACTH stimulation test results, and normal urine cor- Approximately 75% of dogs with PDH demonstrate sup- tisol: creatinine ratio test results. Human beings, dogs and cats with adrenocortical tumors have been reported in which Realizing that approximately 65% of PDH dogs demon- the primary hormone secreted by such tumors has been strate “suppression” consistent with PDH on the LDDS lim- 17OHP. Adrenocortical tumors have long been known to its the value of this test by only identifying an additional synthesize and secrete a myriad of steroids and it is not sur- prising to learn that some primarily produce steroids otherthan cortisol. Such dogs and cats, in our experience, do not Abdominal Ultrasonography
have “normal” screening tests results, but their results may In dogs suspected as having hyperadrenocorticism, abdominal ultrasonography serves three major functions.
It is extremely rare for a dog or cat with PDH to produce First, it is part of the “routine data base” utilized to evaluate only 17OHP. Further, the recommendation regarding use of the abdomen for any unexpected abnormalities (urinary cal- this hormone involves assaying 17OHP after ACTH stimu- culi, masses, etc.). Second, the study is used to evaluate the lation. Our recommendation would be repeating a low dose size and shape of the adrenals. If the adrenal glands appear dexamethasone test if results are <0.9 µg/dl at the 8-hour to be bilaterally normal sized or large in a dog or cat other- sample, since the most common explanation for such a wise diagnosed as having Cushing’s, this is considered result would be administration of 0.1 instead of 0.01 mg/kg strong evidence of adrenal hyperplasia due to pituitary dependent disease (PDH). If one, large, irregular and/or If one is convinced that a dog has naturally occurring invasive adrenal is visualized and the opposite is small or not hyperadrenocorticism, and if that dog persistently has a non- seen, adrenal tumor must be suspected. Some dogs with diagnostic low dose dexamethasone test result, use of ACTH ACT have one adrenal that appears to be a “mass” and the stimulation and assessment of 17OHP can be considered.
other may be normal or enlarged. One must consider the This is an extremely unusual situation, however. possibility of PDH with irregular adrenals or PDH in a dogthat also has a pheochromocytoma. Third, if an adrenaltumor is identified, ultrasound is an excellent screening test DISCRIMINATION TESTS
to identify hepatic or other organ metastasis, compression ofadjacent tissues by a tumor, or tumor invasion into the vena Low Dose Dexamethasone Test
cava or other vascular structures. It must be emphasized that interpretation of abdominal ultrasonography is completelyoperator dependent. Radiologists at our school routinely Endogenous ACTH
visualize both adrenals in healthy dogs and cats. The only This test is relatively difficult to perform because the limitations to successfully visualizing the adrenals are: 1) plasma must be handled with care, the test is not routinely the pet’s willingness to remain still and 2) air in the intestin- available, and it is expensive. Having used this test for al tract. Neither of these problems is common and both more than 30 years, we have found it to be highly specific adrenals are usually visualized. In dogs and cats with PDH, and sensitive (normals: 10 to 100 pg/ml; PDH: 45 to 450 both adrenals are also routinely visualized. The adrenals in pg/ml; ACT: results are undetectable). There is some over- PDH are usually described as relatively equal in size.
lap in results, however. Most specifically, some dogs with Approximately 50% of dogs with PDH have adrenals that PDH and some with ACT have results that range from 10 – appear to be “normal” in size and about 50% have adrenal 45 pg/ml. Our experience with the LDDS and abdominal glands that appear to be enlarged. Adrenal size is best deter- ultrasonography has limited the need for assaying the mined using the width of the left adrenal (7.5 mm represents endogenous ACTH concentration. This test is most com- Proceedings of the International SCIVAC Congress 2009

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