Hyperadrenocorticism In Cats (Cushing’s Syndrome)

Chapter 7 HYPERADRENOCORTICISM IN CATS (CUSHING’S SYNDROME)
















In 1932, Dr. Harvey Cushing authored a report in which he described a group of people with a disorder that he suggested was “the result of pituitary basophilism.” Subsequent study of the clinical, biochemical, and histologic features of these individuals indicate that each had been afflicted with a syndrome resulting from chronic exposure to excesses in circulating cortisol concentrations. The eponym Cushing’s syndrome is an “umbrella” term referring to this condition (hyperadrenocorticism) in people and, more recently, in animals. Chronic cortisol excess may occur secondary to iatrogenic cortisol administration, or it may occur with naturally occurring disease. Thus a pathophysiologic classification of causes for Cushing’s syndrome includes several different conditions. In addition to the iatrogenic condition, the naturally occurring disorder can be caused by a pituitary tumor secreting excess ACTH with subsequent adrenocortical hyperplasia and excess adrenocortical cortisol secretion. The other common naturally occurring condition in animals is that caused by an autonomously functioning, cortisol-secreting, adrenocortical tumor. As discussed later, adrenocortical tumors possess the ability to synthesize steroid hormones other than cortisol. Such cortisol-secreting tumors have been documented in cats together with two additional syndromes (progesterone and aldosterone excess).


ACTH-secreting pituitary tumors have been demonstrated to be the result of an aberrant single cell line that autonomously secretes ACTH in excess, which in turn causes chronic cortisol excess and adrenocortical hyperplasia. This is a relatively uncommon but well-described disease in humans. Autonomous cortisol-secreting primary adrenocortical tumors are also well described in humans, cause cortisol excesses, and occur less frequently than the pituitary-dependent disease. Iatrogenic cortisol excess due to chronic administration of ACTH does not occur, but chronic administration of glucocorticoids is a common cause of Cushing’s syndrome. Other forms of this syndrome have been described, but these are rare and of little importance in veterinary medicine.


Veterinary medicine, especially canine and feline veterinary medicine, has received support from studies describing conditions, diagnoses, and management of diseases acquired by human beings. Thus studies by physicians have been of great benefit to veterinarians. Human beings are the animal model most frequently studied by veterinarians. In many situations, what has been learned about people is then applied to dogs. Often, what has been learned and applied to dogs is then applied to cats. In some situations, illnesses in cats may be analogous to conditions in dogs, whereas other illnesses may be analogous to the conditions in people. Some feline diseases, of course, are unique. With respect to hyperadrenocorticism (Cushing’s syndrome), there are more similarities when comparing cats with people than there are when comparing cats with dogs. One of the more obvious comparisons involves the incidence of hyperadrenocorticism. In dogs this endocrine disorder is surprisingly common, whereas in people and cats it is quite uncommon.


We assume that the underlying physiologic causes for hyperadrenocorticism are similar in people, dogs, and cats. Thus the reader interested in applied physiology and in mechanisms of disease is encouraged to review the appropriate sections in Chapter 6. The focus of this chapter is a review of the clinical condition of hyperadrenocorticism in cats. To aid in this discussion, information from the records of 46 cats diagnosed as having naturally occurring hyperadrenocorticism at our hospital were added to the information from an additional 24 cats described in the literature (Immink et al, 1992; Daley et al, 1993; Goossens et al, 1995; Watson and Herrtage, 1998; Moore et al, 2000a; Meij et al, 2001), for a total of 70 cats with hyperadrenocorticism. This literature includes only those reports published since 1992. We chose reports from this time period in order to be sure that valid and currently available assays were used in the assessment of each cat and that current concepts in diagnosis and treatment were used. Before 1990, only a few cats with this disease were mentioned in the literature (Meijer et al, 1978; Peterson and Steele, 1986; Zerbe et al, 1987; Nelson et al, 1998). Furthermore, in the reports we arbitrarily used, we set the following selection criteria: each cat must have had some clinical signs associated with Cushing’s syndrome, each diagnosis must have been confirmed with appropriate screening test results, and each cat must have had advanced imaging (computed tomography [CT] or magnetic resonance imaging [MRI] scans) confirmation or histologic confirmation of the diagnosis. Reports that did not meet these inclusion criteria were not used.




ETIOLOGY



Iatrogenic Cushing’s Syndrome


Among the major differences regarding Cushing’s syndrome when comparing species is the relative frequency of iatrogenic disease. Iatrogenic Cushing’s syndrome is extremely common among people and dogs. By comparison, iatrogenic Cushing’s syndrome in cats is rare. This can be explained, in part, by what appears to be a relative “insensitivity” to the negative or deleterious side effects of chronic glucocorticoid administration in cats. We are aware of only three cats described in recent literature within the past 10 years with iatrogenic Cushing’s syndrome. By contrast, the number of people and dogs reported in the literature to have had iatrogenic Cushing’s syndrome is considerable.


Several studies on laboratory cats experimentally treated with glucocorticoids have been published. Those treated for a 4-week period had few abnormalities on physical examination and no consistent hematologic or biochemical changes (Scott et al, 1979; Scott et al, 1982). When treated for 9 weeks or longer, some cats exhibited polydipsia, polyuria, polyphagia, abdominal enlargement, thin skin, and curling of their ear tips. Some of these cats also developed liver enlargement, muscle wasting, ecchymoses, and skin fragility (Scott et al, 1982). They also tended to develop mild hyperglycemia, mild hypercholesterolemia, glycogen accumulation in hepatocytes, and a vacuolar hepatopathy. Cataracts developed in some laboratory cats treated with topical glucocorticoids (Brightman, 1982; Zhan et al, 1992). The muscle weakness associated with glucocorticoid administration tends to be most pronounced in the muscles with fast twitch fibers (Robinson and Clamann, 1988).


Three privately owned cats have been described that had iatrogenic chronic glucocorticoid excesses. The cats had received steroids for stomatitis, feline infectious peritonitis (FIP), and pruritus (Green et al, 1995; Schaer and Ginn, 1999; Ferasin, 2001). At the time of final presentation, one of the three cats was extremely ill as a result of FIP. Among the common features noted in these cats after chronic glucocorticoid exposure were abdominal enlargement, muscle wasting, poor hair coats, and skin fragility. The skin fragility included easy bruisability, skin tears, and thin skin. Two cats had increases in liver enzymes and hepatic vacuolar hepatopathy thought to be similar to those seen in dogs. The most important information derived from these three reports is the realization that iatrogenic Cushing’s syndrome in cats is uncommon. In addition, some features seen in cats chronically treated with exogenous steroids are not seen in cats with naturally occurring Cushing’s syndrome.



Naturally Occurring Feline Cushing’s Syndrome (FCS)


The causes of naturally occurring feline Cushing’s syndrome (FCS) are similar to those recognized in human beings and dogs. It has been suggested that resistance to glucocorticoid-induced side effects, likely to exist in cats, may help explain the relative low rate of naturally occurring disease diagnosis as compared with the incidence of the naturally occurring syndrome in dogs. In other words, if excess glucocorticoids cause few clinical signs in cats, how would the diagnosis ever be suspected in the first place? However, the incidence of the naturally occurring disease in cats (assessed nonscientifically) appears to be similar to the incidence of the syndrome in human beings; yet people are sensitive to the effects of glucocorticoids. Therefore it is our suspicion that naturally occurring FCS is simply less common among cats as compared with dogs.


Regardless, the majority of cats (˜80%) with naturally occurring FCS have pituitary-dependent hyperadrenocorticism (PDH) and a minority (˜20%) have adrenal tumor–dependent hyperadrenocorticism (ATH). Cats with PDH have autonomous secretion of ACTH synthesized by a pituitary adenoma, although several cats with a pituitary carcinoma have been diagnosed. About 50% of pituitary tumors are microscopic in size; the remaining tumors are large enough to be visualized with a CT scan or MRI scan, or they are grossly visible at necropsy or surgery (usually greater than 3 to 4 mm in greatest diameter). Approximately 50% of cats with an autonomously functioning adrenocortical tumor have had an adenoma, and 50% have had a carcinoma.



SIGNALMENT (AGE, SEX, BREED)


Hyperadrenocorticism is a disease of middle-aged and older cats. As can be seen in Table 7-1, the mean age of 39 cats diagnosed as having PDH was 10.7 years with a range of 5 to 16 years. The mean age among 12 cats with a functioning adrenocortical tumor was 12 years, with a range of 8 to 15 years. The mean age for all 51 cats was just under 11 years. Among these same 51 cats, there were 25 males and 26 females. Almost all cats that have been diagnosed as having naturally occurring FCS have been neutered. A variety of breeds are included among the cats diagnosed with hyperadrenocorticism. As seen in Table 7-2, the most commonly afflicted breed is the domestic short-haired cat (31 of 51 cats; 61%), and if domestic long-haired cats are added to that group, 38 of the 51 cats (75%) are represented. Cats representing various other breeds have been diagnosed with FCS.


TABLE 7-1 AGE AT TIME OF HYPERADRENOCORTICISM DIAGNOSIS IN CATS (51 CATS)*



























































Age (Years) Pituitary Dependent Number of Cats Adrenocortical Tumor Number of Cats
5 1
6 5
7 2
8 3 1
9 3 2
10 4
11 4 1
12 5 3
13 3 1
14 4 2
15 2 2
16 3
Mean 10.7 years 12 years

* Mean age of all 51 cats was 10.9 years




DURATION OF CLINICAL SIGNS, CHIEF COMPLAINT, AND GENERAL HISTORY




Owner Chief Complaints


It may be of interest to separate “owner chief complaints” from general “owner observations.” The chief complaint is the primary reason that an owner seeks veterinary assistance. It should be obvious that an owners’ primary concern does not always match the primary concern that a veterinarian may have after completion of an owner history. Certainly a veterinarian’s major concern may be much different after completion of a thorough physical examination.


The chief complaints noted in records from 48 cats with FCS included “difficult to regulate diabetes mellitus” in 26 cats (54%). Most commonly, diabetes mellitus was classified as difficult to regulate when owners felt that their pet had persistence of polyuria, polydipsia, and/or polyphagia despite administration of insulin (Table 7-4). Less frequently, owners believed their cats’ diabetes mellitus was poorly controlled if their pet lost weight, failed to gain weight, remained lethargic, or had poor grooming habits. It was not always obvious from the records whether or not an owner believed that any of these problems was directly due to inadequate control of diabetes mellitus. Often, insulin dose and type had been altered numerous times by the primary care veterinarian in an effort to gain control of the diabetes mellitus prior to referral.


TABLE 7-4 CHIEF COMPLAINTS BY OWNERS OF CATS ULTIMATELY DIAGNOSED AS HAVING HYPERADRENOCORTICISM (48 CATS – TOTAL; 37 OF THESE 48 CATS HAD DIABETES MELLITUS AND 11 DID NOT HAVE DIABETES MELLITUS)



















































Complaint Pituitary Dependent (36 Cats) Adrenocortical Tumor (12 Cats)
Resistant diabetes mellitus (PD/PU/PP)* 22 4


6 2
Fragile (torn) skin 3 3
Weight loss 2
Lethargy 2 2
Alopecia/failure to regrow hair 2 2
Diarrhea 2
Weakness 1
Vomiting 1
Abdominal enlargement 1 1
Not grooming 1

* PD, polydipsia; PU, polyuria; PP, polyphagia.


Of the 48 cats in this evaluation, 37 had diabetes mellitus. Eleven of the 37 diabetic cats were believed to be well controlled with insulin. Of the 11 nondiabetic cats, 8 were believed to have polyuria and polydipsia (PU/PD); this problem was established as the owners’ chief complaint. Other chief complaints varied and were relatively less common (see Table 7-4). Among the uncommon primary owner concerns were fragile (torn) skin in six cats (12%), lethargy in four cats, and alopecia or failure to regrow hair that had been previously shaved in four cats.



Owner Observations




SUMMARY OF OBSERVATIONS.

Owner observations were available from 62 cats diagnosed as having FCS (Table 7-5). The most common concerns noted in the histories obtained from these owners was PU/PD in 51 cats (82%), polyphagia in 42 cats (68%), weight loss or failure to gain weight in 32 cats (52%), and lethargy or reports of “sleeps more” in 29 cats (47%). Concerns about skin problems were noted 61 times. These concerns ranged from the extremely worrisome fragile or torn skin noted in six cats, to a failure to grow hair after it had been shaved (usually for venipuncture or abdominal ultrasonography examination). There were also concerns over grooming excessively or not enough and concerns about a hair coat that had become unusually coarse. Multiple skin problems were noted in some cats, whereas others had none. The owners of 21 cats with PDH (from the total of 50, or 42%) and the owners of 3 cats with ATH (from the total of 12, or 25%) did not observe any problem relative to the skin or hair coat. Similar owner observations in cats with PDH as compared with those with ATH underscores the final common denominator of disease in these cats, that is, chronic exposure to excesses in circulating cortisol.



It has been suggested that clinical signs of hyperadrenocorticism are not commonly detected by owners or veterinarians until cats with FCS develop diabetes mellitus. The results of this review suggest that this is true for a majority of afflicted cats. However, some of the signs in these cats did precede development of diabetes mellitus, and other cats never developed diabetes. Thus a suspicion of FCS may result from a history and physical examination in nondiabetic cats. Such abnormalities as thin skin, skin fragility, “potbelly” appearance, muscle atrophy, weakness, PU/PD, and various hair coat disorders might lead to the diagnosis of FCS in nondiabetic cats.




EXPLANATIONS FOR THE HISTORY AND PHYSICAL EXAMINATION ABNORMALITIES



Polyuria and Polydipsia


Polyuria and polydipsia (PU/PD), polyphagia, and weight loss are the cardinal signs of diabetes mellitus. Since a majority of cats with FCS also have diabetes mellitus (usually a result of excess cortisol causing insulin resistance), the explanation for signs such as PU/PD in diabetic cats is straightforward. However, some FCS cats with these clinical signs were not diabetic. Polyuria and polydipsia are extremely common clinical signs in dogs with excess circulating cortisol concentrations. Since it is not common for dogs with hyperadrenocorticism to have concomitant diabetes mellitus, it is thought that dogs have PU/PD secondary to central or nephrogenic diabetes insipidus caused by excess circulating cortisol. Despite being common in dogs (the single most common owner concern), PU/PD occurs uncommonly in human beings with naturally occurring or iatrogenic cortisol excess. This side effect is also not considered common in cats; however, the diabetes insipidus explanation remains a possibility in those cats that do not have glycosuria.


Eight of 11 nondiabetic cats were thought to have PU/PD by their owners. Confounding the issue is the realization that a huge majority of dogs with hyperadrenocorticism have randomly obtained urine samples with a specific gravity less than 1.024 and concomitant serum urea nitrogen or creatinine concentrations within or below the reference range. By contrast, only a small percentage of the urine samples obtained from 58 cats with FCS (50 with PDH and 8 with ATH) had a specific gravity less than 1.024 (5 cats, or 9%). Each of those five cats had an increase in their serum urea nitrogen, creatinine, or both. Thus the observation of PU/PD is noted almost exclusively in cats that had glycosuria or renal disease. It is also possible that some of these cats do have transient insulin resistance, glycosuria, and secondary PU/PD. This hyperglycemia and glycosuria may not be demonstrable at the time that in-hospital testing is carried out.


Polyphagia is common in nondiabetic dogs with hyperadrenocorticism. However, it is not a well-understood effect of excess circulating cortisol concentrations and is not a typical cortisol-induced problem in people or cats.




Weakness, Lethargy, Pot Belly, and Bruising


Explanations for these clinical signs can be directly related to the physiologic effects of cortisol. Cortisol is protein-catabolic and therefore causes the breakdown of muscle. Muscle wasting results in weakness, which may be obvious to owners. Alternatively, weakness may appear to an owner to be lethargy or an increase in the amount of time spent sleeping. Furthermore, some cats with FCS have a plantigrade posture, which is often related to the neuropathy associated with diabetes mellitus in cats. Chronic cortisol excess is also well recognized to cause a redistribution of fat from areas throughout the body with specific increases in abdominal (mesenteric) fat deposition. This classic abnormality is common in human beings, dogs, and cats. The increase in abdominal fat content coupled with muscle wasting results in the pot belly appearance that is classic of Cushing’s syndrome in all species. A pot belly is the clinical consequence of increased weight of abdominal content pressing down upon weakened abdominal musculature (see Fig. 7-1, A and B).


Cortisol also causes a relative decrease in the ability to heal because of blood vessel friability and a decrease in fibrous response to injury. Loss of subcutaneous fat (mobilized to the abdomen), friability of blood vessels that are more superficial because of loss of fat protection, and decreases in normal healing properties increase the predisposition to bruising in these cats. In many cats, bruising after venipuncture or clipping of hair can be dramatic.




Dermatologic Abnormalities


Bilateral symmetric nonpruritic alopecia is a classic and common feature of Cushing’s syndrome in dogs but not a typical abnormality in cats. The alopecia that most FCS cat owners observe is due to a failure to regrow hair that has been shaved by veterinarians or hair lost as a result of normal or excessive grooming (Fig. 7-2, A and B). It is difficult to know whether “excessive” grooming is truly an abnormality. Are these cats grooming normally but causing hair loss, thereby also causing owner concern? Or are they licking themselves more than normal? The failure to regrow lost hair is most likely secondary to atrophy of the hair follicles. This atrophy disrupts the hair shaft attachment to the follicle. Any new hair that does grow tends to be brittle, sparse, and fine.



Thin skin (Fig. 7-3, A and B), poor wound healing, and susceptibility to infection are typical sequelae to chronic excesses in circulating cortisol. Suppression of the immune system in individuals with Cushing’s syndrome exaggerates these problems. Skin fragility is not typical of canine Cushing’s syndrome but is well recognized in afflicted people and is well described but not common in cats (Fig. 7-4, A and B; see Tables 7-5 and 7-6). These dermatologic abnormalities are serious and can result in life-threatening overwhelming sepsis. Thin skin is an expression of the catabolic effects of cortisol.





ROUTINE CLINICAL PATHOLOGY (CBC, SERUM BIOCHEMISTRY, URINALYSIS)


Small animal (canine and feline) veterinarians are familiar with Cushing’s syndrome. For the most part, this familiarity can be explained by the numerous indications for using corticosteroids in treating various canine conditions. Since glucocorticoids are commonly used, veterinarians are well aware of their attributes and side effects. These side effects also comprise the clinical signs and laboratory abnormalities that are associated with both iatrogenic and naturally occurring Cushing’s syndrome in dogs. Therefore veterinary clinicians expect dogs with Cushing’s syndrome to have PU/PD, isosthenuria/hyposthenuria, low-normal or low BUN, and low-normal serum creatinine concentrations. It is also assumed that affected dogs will have increases in serum alkaline phosphatase activities, serum cholesterol concentrations, and serum alanine aminotransferase activities. In fact, most veterinarians would be surprised if a steroid-treated dog or a dog with naturally occurring Cushing’s syndrome failed to exhibit many, if not all, of these changes. Remember, the “final common denominator” for naturally occurring Cushing’s syndrome is the same as the iatrogenic syndrome, that is, chronic exposure to excesses in circulating glucocorticoids. With these changes in mind, we can state with confidence that, with regard to Cushing’s syndrome, cats are not small dogs. The differences encountered when comparing the condition in these two species are at least equal to their similarities.



Complete Blood Count (CBC)


Complete blood count (CBC) results from 45 cats with naturally occurring hyperadrenocorticism can be found in Table 7-7. The most important feature of these results is the lack of consistent abnormalities. That is, none of the results seem “classic.” A majority of afflicted cats had a “stress leukogram” (neutrophilia and reduction in lymphocyte and eosinophil percentages). Of the 45 cats, 24 (53%) had a neutrophil percentage of >86%, 25 (56%) had a lymphocyte percentage of <5%, and 26 (58%) had an eosinophil percentage of <2% of the total white cell count. As can be seen, therefore, stress leukograms were identified, but this was not a consistent feature of the CBC results. No cat was leukopenic, one was thrombocytopenic, and four were anemic. Of the four anemic cats, only one had a hematocrit below 24% (that result was 16%).




Serum Biochemistry and Urinalysis




LIVER ENZYMES.

The introduction to this section discusses the common routine biochemical test result abnormalities from dogs with naturally occurring or iatrogenic Cushing’s syndrome. The results from cats with this endocrine disorder are strikingly different (Table 7-8). Although dramatic increases in serum alkaline phosphatase (SAP) activities (average >1,000 IU/L) are the most common biochemical abnormality in dogs, only 3 of 43 cats (7%) with naturally occurring Cushing’s syndrome had an increase in serum alkaline phosphatase activity. Another common abnormality in dogs with Cushing’s syndrome is mild to moderate increase in serum alanine aminotransferase (ALT) activity. This abnormality is identified in more than 50% of dogs, but occurred in only 12 of 43 cats (28%). Several of the cats with increases in ALT activity had significant hepatopathies that were not related to their Cushing’s syndrome. Dogs with iatrogenic or naturally occurring excesses in serum cortisol concentration commonly develop “steroid hepatopathy,” as well as significant circulating concentrations of the “steroid-induced” isoenzyme of SAP. Neither of these typical canine features of Cushing’s syndrome is believed to occur in cats or human beings. However, “steroid hepatopathy” that included liver enlargement and a vacuolar appearance to hepatocytes has been occasionally described in cats with FCS.





BUN, SERUM CREATININE, URINE SPECIFIC GRAVITY.

Perhaps one of the more consistent group of abnormalities seen in dogs that have Cushing’s syndrome are those related to polyuria and polydipsia. A tremendous majority of these dogs have urine specific gravities <1.020 (especially on samples obtained by owners from dogs in their home environment), many are <1.014 and about 30% are <1.008. In other words, polyuria in this population of dogs is common and represents a frequent owner concern. Polyuria is one of the two most common reasons that owners seek veterinary care for their dog (the other is alopecia). If not resolved, polyuria is a frequent reason for owners to elect euthanasia. In addition to the PU/PD and the previously discussed isosthenuria/hyposthenuria in dogs with Cushing’s syndrome are low-normal-to-low BUN and serum creatinine concentrations. These are classic features of canine Cushing’s syndrome. Emphasizing this concept, increases in BUN or creatinine not only are rare in dogs with Cushing’s syndrome but are a serious indication for avoiding treatment. Appetite in such dogs may be dependent on cortisol excess, and the concern in treating such dogs for Cushing’s syndrome is unmasking both renal failure and its clinical signs (including poor appetite).


A review of the serum biochemical data presented in Table 7-8 from cats with naturally occurring FCS demonstrates remarkable differences in test results as compared with those from dogs that have Cushing’s syndrome. None of the 43 cats had a BUN concentration below the reference range, and only 1 of the 43 had a serum creatinine concentration below the reference range. Only 1 of 43 cats had a randomly obtained urine specific gravity <1.020. That cat had both isosthenuria and renal failure. Furthermore, 23 of the 43 cats (53%) had abnormally increased BUN concentrations at the time of diagnosis, and 14 of those 23 cats (14 of the total 43 = 32%) also had abnormally increased serum creatinine concentrations. Thus it is likely that the polyuria and polydipsia recognized in most cats with FCS is either due to diabetes mellitus, chronic renal failure, or a combination of both conditions.


There have been descriptions of cats with FCS that have PU/PD but no clinical or laboratory evidence supporting concurrent renal failure or diabetes mellitus. The number of such cats is unknown, but the concept is that hypercortisolemia does occasionally cause PU/PD in some cats. On the one hand, it is possible that this does occur. On the other hand, we remain suspicious that some of these cats may have periodic hyperglycemia leading to episodic glycosuria and, thereby, episodic secondary polyuria. Stress-induced hyperglycemia is one explanation for hyperglycemia noted in some nondiabetic cats. This stress-induced condition interferes with our ability to distinguish those cats with persistent euglycemia except at times of stress from those with periodic physiologic hyperglycemia due to their hypercortisolemia. Even use of glycosylated hemoglobin or fructosamine concentrations would not consistently identify cats with periodic hyperglycemia. There is no evidence, however, to suggest that any cat with FCS has a physiologic syndrome similar to the diabetes insipidus–like condition that occurs commonly in dogs with Cushing’s syndrome, since such a situation would cause dilute urine. Cats with FCS rarely have dilute urine.








HYPERGLYCEMIA.

Of the 43 cats with FCS whose laboratory data were included in Table 7-8, 35 were hyperglycemic at the time that blood was obtained for the chemistry profile. Twenty-six of the 35 hyperglycemic cats were diabetic, and 25 of the 26 were being treated with insulin and had received insulin that day. Since cats with FCS are commonly believed to be insulin-resistant, the finding of hyperglycemia would be expected in some of these cats. Resistance is not an acceptable explanation for all these hyperglycemic cats, however. An additional reason for the hyperglycemia could be inadequate control of the diabetes (with numerous causes ranging from owner error to FCS). Another possible explanation is that blood was obtained before or after the period of insulin effectiveness. Finally, any of these cats may have had stress-induced hyperglycemia in addition to their diabetes mellitus.


Nine of the 35 hyperglycemic cats were not diabetic. How many of the nine cats had simple stress-induced hyperglycemia at the time that blood was obtained? Of equal interest, how many of the nine hyperglycemic cats had some degree of glucose intolerance that had not been recognized as representing diabetes mellitus? The answers to these questions are unknown, but it is likely that at least some cats in this population fit into one of these two categories.



DIABETES MELLITUS.

Diabetes mellitus is among the more common conditions diagnosed in small animal practice, and it is, along with hyperthyroidism, one of the two most frequently diagnosed endocrine disorders in cats. In contrast, the diagnosis of feline hyperadrenocorticism, or FCS, is considered uncommon-to-rare. We cannot state that FCS is diagnosed only in diabetic cats with insulin resistance. To the contrary, FCS is diagnosed in nondiabetic as well as diabetic cats. It seems easier to suspect FCS in an insulin-resistant cat, however, than in a cat that is simply lethargic or pot-bellied. However, clinical signs of thin skin, skin fragility, alopecia, failure to regrow hair after it has been clipped, or PU/PD are also problems that could reasonably be explained should the cat be confirmed to have FCS.


One problem facing the veterinary practitioner is determining which poorly controlled diabetic cats are truly insulin-resistant and which of those truly insulin-resistant cats have FCS. Many of our diabetic cats have stress-induced hyperglycemia when examined at veterinary hospitals. Most of our poorly controlled diabetic cats have problems that can be traced to one or more of many potential owner errors. Although monitoring serum glycosylated hemoglobin or fructosamine concentrations may aid in identification of such cats, these tests are not perfect.


An additional group of poorly controlled diabetic cats are given insulin that has an extremely brief duration of action; these cats continue to exhibit clinical signs and have frequent hyperglycemia, since it is more likely to detect hyperglycemia than euglycemia at any given time of day in such cats. Another category of causes for poor control, or insulin resistance, in a diabetic cat includes many concurrent conditions that interfere with insulin action. These include pancreatitis, other nonseptic inflammatory conditions, infections, and other disorders (such as neoplasia and heart disease). Finally, problems such as acromegaly, anti-insulin antibodies, and hyperadrenocorticism are uncommon but popular conditions to diagnose.


We encourage veterinarians having difficulty controlling diabetes in any cat to prioritize the potential explanations for difficult control. The top of this priority list should be the fact that in-hospital testing may not reflect what is happening in the home environment. Owner history is the single most important monitoring tool in the long-term management of diabetes in cats, and if the owner is satisfied with the cat’s response to therapy, in-hospital test results should not supersede this opinion unless hypoglycemia is documented. In-hospital stress-induced hyperglycemia is common, and this differential diagnosis should not be limited to “mean” (or obviously stressed) cats.


Next, veterinarians must consider all the potential owner errors that commonly take place. These errors include, but are not restricted to, using the incorrect insulin, mixing the insulin improperly, drawing insulin into the syringe incorrectly, using incorrect syringes, using out-dated insulin, and practicing improper administration techniques. Every time a diabetic cat is evaluated in the hospital, owners should be watched as they handle and administer their insulin. Once these potential problems have been dismissed, the veterinarian should consider the possibility that the insulin being used is either too weak (such as sometimes occurs with ultralente or PZI insulins) or too potent (which sometimes occurs with NPH or lente insulins) for the cat being evaluated. Additionally, one should consider the possibility that a concurrent disorder exists and may be interfering with insulin sensitivity. This could include any infection (urinary tract and skin infections are only two of the numerous potential infections that may or may not be obvious) or any source of inflammation (pancreatitis is just one of numerous potential inflammatory conditions that may or may not be obvious). Additional conditions that could cause insulin resistance include neoplasias, heart disease, and others. Last among the considerations of causes for insulin resistance should be anti-insulin antibodies, progesterone excess, acromegaly, and FCS.




ENDOCRINE SCREENING TESTS


Several endocrine tests are used for distinguishing cats that may have naturally occurring FCS from cats that do not have the disease. Those tests most commonly employed are the ACTH stimulation test, the low-dose dexamethasone screening test (LDDST), and the urine cortisol-to-creatinine ratio (UC:CR). Each of these tests has advantages and disadvantages. It is important to remember that no test is perfect. This concept gains significance when it is appreciated that cats with Cushing’s syndrome do not have a good prognosis. Because of this poor prognosis, owners of cats diagnosed with FCS may elect to euthanize their pet rather than pursue therapy. Furthermore, the most effective treatment options appear to be pituitary surgery, adrenal surgery, or pituitary irradiation. Each of these therapeutic modalities is rather expensive, and special facilities and/or training are required, limiting availability. Neither surgery nor radiation therapy is a benign treatment. Thus it is recommended that the diagnosis of FCS be reserved for cats with clinical signs as well as endocrine test results consistent with the diagnosis.



Urine Cortisol-to-Creatinine Ratio (UC:CR)




BACKGROUND.

The urine cortisol-to-creatinine ratio (UC:CR) has been recommended as a screening test to aid in separating patients with Cushing’s syndrome from those without the condition. A thorough explanation of the test and the indications for its use are provided in Chapter 6. In summary, the “gold standard” screening test for Cushing’s syndrome in human beings has been to assess total cortisol excreted in urine over a 24-hour period. Repeating this test several times further ensures validity of results. Cortisol excreted in urine reflects that secreted by the adrenal glands over time and negates concern of minute-to-minute pulsatile fluctuations in plasma concentrations. It is considered a reliable test for understanding whether the adrenal glands are producing normal or excessive quantities of cortisol.


The use of a randomly collected single urine sample, assessing it for cortisol concentration, and then creating a ratio of that cortisol to urine creatinine (UC:CR) is a short-cut to the more cumbersome 24-hour collection procedure. Although the UC:CR is much easier for patients and physicians, most physicians continue to use the 24-hour protocol. The UC:CR has been well studied in dogs. It is highly recommended by some veterinary endocrinologists but not by others because the test has both positive and negative traits. Those who recommend the UC:CR test usually point to several attributes: it is inexpensive, easy to perform and interpret, and sensitive (there is a high predictive value of a negative test result). Virtually all veterinarians who have critically evaluated the UC:CR in dogs with naturally occurring Cushing’s syndrome agree that it is highly sensitive. In other words, a tremendous percentage (in the range of 97% to 99%) of dogs with the disease have an abnormal test result. Therefore if one is suspicious of Cushing’s syndrome in a dog and the UC:CR test result is abnormal, there is a possibility that the dog has Cushing’s syndrome.


However, the problem that others note with the UC:CR is that finding an abnormal result is not specific for dogs with Cushing’s syndrome. For example, the UC:CR result is frequently abnormal in dogs with polyuria and polydipsia of any cause, such as those with diabetes mellitus, diabetes insipidus, renal failure, hypercalcemia, pyometra, and liver failure. Therefore, results of the UC:CR test may be consistent with a diagnosis of Cushing’s syndrome in animals that do not have the disease.



PUBLISHED DATA.

In the initial study evaluating the UC:CR in cats, it was suggested that there was a paradox in comparing reference ranges for dogs versus those for cats because of relative rates of urinary cortisol excretion when comparing the two species. The paradox is related to the relatively high reference UC:CR range in cats versus their low urinary excretion of administered radiolabeled cortisol. Healthy dogs excrete larger amounts of cortisol into urine than do healthy cats. It was suggested that the higher UC:CR in healthy cats, despite their lower overall excretion, may be explained by a higher glomerular filtration rate and/or a lower renal reabsorption of free cortisol. Thus the ratio between unaltered cortisol to conjugates and metabolites of cortisol in urine would be higher in cats than dogs (Goossens et al, 1995).


It is also wise to review the concerns that many veterinary clinical researchers have regarding specificity of UC:CR testing when it is used as the sole diagnostic aid for confirming Cushing’s syndrome in cats. The results from one study indicate that health status of cats affects UC:CR (Henry et al, 1996). Test results in healthy cats were not affected by age, gender, or neuter status. Ill cats have higher UC:CR values than healthy cats, implying that specificity may be a problem (as in dogs). The UC:CR from 16 ill cats were evaluated. Three cats had test results consistent with hyperadrenocorticism (≥3.6 × 10−5), and another seven had results in the range we would consider “borderline” (i.e., between 1.0 and 3.6 × 10−5. Thus 10 of 16 ill cats had UC:CR results that could be considered consistent with a diagnosis of hyperadrenocorticism. However, although the study demonstrated that sick cats had significantly higher UC:CR results than healthy cats, it did not include any results from cats with naturally occurring Cushing’s syndrome, negating direct comparison of data from each of the three groups in question (healthy, ill, and FCS cats; Henry et al, 1996).


We are not aware of any additional studies evaluating specificity of the UC:CR in cats. Thus it is premature to suggest that the test should not be used. To the contrary, we do recommend use of the test, especially if owners can bring urine samples from home (perhaps using small quantities of litter or nonabsorbable litter to make urine easier to collect). Home-collected urine negates concern of spurious results due to the stress associated with in-hospital urine collection. Also, there is less concern about UC:CR results from ill cats than results from cats confirmed as not having hyperadrenocorticism but having some clinical signs suggestive of the disease. It is this group of cats that must be evaluated before concrete suggestions are made regarding use of the UC:CR.



TEST INTERPRETATION.

Two studies have been published suggesting reference ranges for feline UC:CR. The reference range from the first report was <3.6 × 10−5 (Goossens et al, 1995), and from the second report it was <2.8 × 10−5 (Henry et al, 1996). If the initial reference range for cats (<3.6 × 10−5) is used, it should be remembered that this value is slightly higher than that for dogs (<1.0 or <1.3 × 10−5). It seems prudent to suggest, from the information published in these two reports coupled with our experience, that a UC:CR value ≥3.6 × 10−5 in a cat with clinical signs consistent with hyperadrenocorticism (FCS) is consistent with that diagnosis. We also recommend that UC:CR values between 1.3 and 3.6 × 10−5 in cats with appropriate clinical signs be considered “borderline.” It is possible for a cat with test results in this range to have naturally occurring hyperadrenocorticism.



RESULTS.

As can be seen from the data presented in Tables 7-9 and 7-10, we were able to collate UC:CR data from a total of 37 cats that had confirmation of their naturally occurring hyperadrenocorticism. Twenty-four of the cats were from our series, and 13 were from cats from the literature with well-documented FCS (Goossens et al, 1995 [6 cats]; Meij et al, 2001 [7 cats]). Of these 37 cats, 29 had PDH and 8 had functioning adrenocortical tumor hyperadrenocorticism (ATH). Twenty-nine of the total of 37 cats (78%; 24 from the PDH group and 5 from the ATH group) had results above the reference range of 3.6 × 10−5. An additional 7 cats (19%) had results in the borderline range (4 from the PDH group and 3 from the ATH group). This now accounts for results from all 8 cats with ATH and for 28 of the 29 cats with PDH. Borderline values were defined as those above the approximate canine reference range (<1.3 × 10−5) but lower than the higher range established for cats in the previously mentioned study (<3.6 × 10−5). Only one cat had a UC:CR test result that was considered normal (that cat had PDH). Thus the UC:CR appears to be a sensitive test for confirming the diagnosis of Cushing’s syndrome in cats, with a sensitivity approaching that demonstrated for dogs. We have not evaluated the specificity of the UC:CR but suspect that it may have similar problems to those noted in dogs.


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Jul 10, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Hyperadrenocorticism In Cats (Cushing’s Syndrome)

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