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Journal of Feline Medicine and Surgery (2017) 19, 933–947
CLINICAL REVIEW
PECULIARITIES OF FELINE HYPERADRENOCORTICISM Update on diagnosis and treatment Lara A Boland and Vanessa R Barrs
Introduction
While the term ‘hyperadrenocorticism’ (HAC) refers to overproduction of any adrenocortical hormone, in veterinary medicine it is typically used to describe hypercortisolism (Cushing’s syndrome). HAC may also occur secondarily to pituitary or adrenal tumours that secrete other hormones with glucocorticoid-like activity; for example, alphamelanocyte-stimulating hormone (α-MSH), progesterone, oestradiol, testosterone, androstenedione and 17α-hydroxyprogesterone. This review discusses the signalment, history, clinical findings, diagnosis, treatment and prognosis for cats with spontaneous HAC (hypercortisolism), iatrogenic HAC and adrenal sex steroid-producing tumours. For information on hyperaldosteronism (not covered here), readers are referred to an earlier review by Djajadiningrat-Laanen et al.1 Normal physiology
Adrenocorticotropic hormone (ACTH) is secreted by the pars distalis of the anterior lobe of the pituitary gland. ACTH is derived from pro-opiomelanocortin, which is processed to pro-ACTH and subsequently cleaved to ACTH by the prohormone convertase 1.2 ACTH is also produced by the pars intermedia, but most is cleaved by melanotropic cells to α-MSH and to corticotropin-like intermediate lobe peptide by proconvertase 2.3,4 Cortisol and androgens are secreted by the zona fasciculata and reticularis of the adrenal cortex, while the zona glomerulosa secretes mineralocorticoids.
Aetiopathogenesis
In contrast to canine HAC, HAC in cats is a relatively uncommon endocrine disorder, with a little over 180 cases reported in the veterinary literature.2–40 A large UK study estimated the prevalence of HAC in UK dogs attending primary care practices to be 0.28%.41 Approximately 80% of feline cases are pituitarydependent hyperadrenocorticism (PDH). Carcinomas comprise a minority of cases overall, since at least 90% of PDH cases and 50–60% of adrenal-dependent hyperadrenocorticism (ADH) cases are caused by adenomas.2–40 Lara A Boland BVSc, MANZCVS, DipECVIM-CA Valentine Charlton Cat Centre, Sydney School of Veterinary Science, Faculty of Science, University of Sydney, NSW, Australia Vanessa R Barrs* BVSc, PhD, MVetClinStud, MANZCVS, FANZCVS (Feline), GradCertEd Valentine Charlton Cat Centre, Sydney School of Veterinary Science, Faculty of Science, and Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, NSW, 2006, Australia *Corresponding author: [email protected]
DOI: 10.1177/1098612X17723245 © The Author(s) 2017
Practical relevance: Hyperadrenocorticism (HAC) is a relatively uncommon endocrinopathy of older cats, with a mean age at diagnosis of 10 years. In addition to pituitarydependent and adrenal-dependent hypercortisolism, clinical signs of HAC can result from adrenal sex steroid-producing tumours. Clinical challenges: While HAC in cats has many similarities to canine HAC, there are key differences in presentation, diagnosis and response to therapy. Most, but not all, cats with HAC have concurrent diabetes mellitus, which is often insulin resistant. Up to a third of cats with HAC have extreme skin fragility and are at high risk of debilitating iatrogenic skin tears during diagnostic or therapeutic interventions. Infections of the skin and nail beds, and urinary, respiratory and gastrointestinal tract, secondary to cortisol-induced immune suppression, are also common. Cats respond differently to dogs to adrenal function tests including adrenocorticotropic hormone (ACTH) stimulation and dexamethasone suppression tests; a 10-fold higher dose of dexamethasone is recommended in cats to screen for HAC. Curative treatment options include adrenalectomy or transsphenoidal hypophysectomy. Radiation or medical treatment may improve clinical signs. The response to mitotane therapy is poor. While trilostane is the medical treatment of choice based on retrospective studies, investigations into the pharmacokinetics of this drug in cats are lacking. Global importance: Feline HAC occurs worldwide and is not associated with any purebreed predisposition. Although uncommon, adrenal sex steroid-producing tumours have a higher prevalence in cats than in dogs. Evidence base: The information in this review is drawn from over 180 reported cases of feline HAC. Reports investigating clinical presentation, clinicopathological findings and treatment outcomes are observational, retrospective multiple case series (EBM grade III) or single case reports (EBM grade IV). While most endocrine testing studies for diagnosis are cohort controlled analytical studies (EBM grade III), prospective, randomised, placebo-controlled studies have been performed (EBM grade I).
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PDH results from autonomous secretion of ACTH by tumours arising from corticotroph cells of the pars distalis (more commonly) or pars intermedia. This stimulates excessive production of cortisol from the adrenal cortex and causes cortical hyperplasia. ADH is usually secondary to autonomous cortisol production by tumours arising from the adrenal cortex.
Clinical signs
Commonly reportSignalment ed clinical signs and physical examHAC is a disease of ination findings, older cats, with a mean collated from age of approximately reports of 167 cats 10 years. The majority with naturally of reported cases are occurring HAC domestic breed cats published between (85%) and neutered; 1973 and 2015, are slightly more (54%) are listed in Table 1. male than female.3,5–37 Clinical signs are typically present for several months before presentation to a veterinarian, although time to presentation ranges from weeks to more than a year.2,5,6,11–19,22–33,35,36,38–40 Clinical signs overlap with other diseases (eg, diabetes mellitus), and early signs may be subtle. Whether hypercortisolism can cause secondary central or nephrogenic diabetes insipidus in cats has not been established.35 Polydipsia and polyuria may result from comorbidities; for example, diabetes mellitus, chronic kidney disease (CKD) or hyperthyroidism. Polyphagia has been reported in non-diabetic cats with HAC.9,10,19,42 Table 1
Clinical signs of HAC often overlap with those of diabetes mellitus. Diabetes mellitus occurs in almost 80% of cats with HAC.
Clinical signs and physical examination findings collated from reports of 167 cats with hyperadrenocorticism*
Clinical sign
Percentage of cases
Polydipsia and polyuria
81
Abdominal enlargement (‘pot-belly’)
61
Polyphagia
60
Skin atrophy
59
Muscle wasting
47
Weight loss
47
Lethargy
41
Alopecia
37
Skin fragility (skin tears)
32
Unkempt hair coat
30
Weakness/plantigrade stance
18
Hepatomegaly
13
Weight gain
12
*References 2,5,6,11-19,22,33,35,36,38–40
934
The majority (80%) of feline HAC cases are due to PDH. Adenomas account for at least 90% of PDH cases and 50–60% of ADH cases.
HAC causes skin atrophy and reduced skin elasticity, resulting in prominent subcutaneous veins and fragile, thin, papery skin (Figure 1). Comedones, a common feature of canine HAC, can sometimes be detected on ventral abdominal skin (Figure 1). Skin tears following minor trauma, routine handling or even grooming are common complications (Figure 2). Footpad excoriations can also occur. Extreme care should be taken when handling cats with suspected HAC to avoid iatrogenic trauma. Alopecia is typically bilaterally symmetrical, may involve the thoracic, ventral abdominal, flank and limb regions, and may be patchy or generalised. An ‘unkempt’ haircoat may result from growth of brittle and sparse hair, skin scaling and seborrhoea. Failure of hair regrowth after clipping is common (Figures 1–4).9,18,35,42 Hypercortisolism also leads to blood vessel friability and reduced fibrous response to injury which, in turn, can produce excessive bruising, delayed wound healing and reduced ligament and tendon strength.3,35,37 Weight loss from concurrent diabetes mellitus is common. Muscle wasting, due to increased
JFMS CLINICAL PRACTICE
b
a
c
Figure 1 Nine-year-old female neutered Devon Rex cat with diabetes mellitus and pituitarydependent hyperadrenocorticism (PDH). The cat had abdominal distension (‘pot-belly’), alopecia of the ventral abdomen with comedones (a and b), and bilaterally symmetrical alopecia of the pelvic limbs with thin, papery skin and excoriations (c)
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a
c
b
Figure 2 (a) This 9-year-old male neutered British Blue cat with PDH had extreme skin fragility and tore a large piece of skin as it squeezed between two bars of a security grill. (b) Nail bed infection and (c) fragile skin from the head that was inadvertently torn loose during grooming in the same cat
Figure 3 Seven-year-old male neutered Burmese cat with PDH.18 Four months after clipping for an abdominal ultrasound examination to investigate the cause of its hypertensive retinopathy, the cat re-presented with severe polydipsia and polyuria. The hair on the ventral abdomen had not regrown (a), and the skin was thin and papery with prominent subcutaneous vessels (b)
b
a
protein catabolism, is generalised or involves the lumbar musculature and contributes to weight loss. Although common, weight loss may not be apparent to owners because of abdominal distension (‘pot-belly’) resulting from hepatomegaly, abdominal fat deposition and abdominal muscle wasting (Figure 4). Depending on the balance of these factors, cats with HAC occasionally gain, rather than lose, weight.9
Approximately one-third of cats with HAC have skin fragility. Extreme care should be taken during handling and restraint to avoid iatrogenic trauma.
Generalised weakness and/or a plantigrade hindlimb stance are less common signs in feline HAC. Where present, contributing factors may include peripheral diabetic neuropathy, muscle wasting and hypokalaemia. Uncommon clinical signs include gastrointestinal signs (eg, inappetence, vomiting and diarrhoea), systemic hypertension, neurological signs from a pituitary macroadenoma, or a palpable adrenal mass.8–10,13,15,16,18,19,28,31,33,35,39
b
Figure 4 Nine-year-old male neutered domestic shorthair cat with adrenal-dependent hyperadrenocorticism (ADH). Note the ventral abdominal alopecia and skin excoriations resulting from thin skin (a,b). The cat had a ‘pot-bellied’ appearance on physical examination (a) and abdominal distension on a lateral abdominal radiograph (c). In cats with hyperadrenocorticism (HAC), these signs result from hepatomegaly, abdominal fat deposition and abdominal muscle wasting
a
c
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Concurrent disease Diabetes mellitus due to insulin resistance from hypercortisolism is a common comorbidity (reported in 77% [145/188] of cats with HAC), and is often insulin resistant.2,3,5–40,42,43 However, insulin resistance is not as severe as that encountered in hypersomatotropism (acromegaly). Also, in cats with diabetes mellitus and HAC, weight loss is more common than weight gain (47% vs 12%, Table 1), while weight gain is a common feature of acromegaly in cats. Bacterial or fungal infections, secondary to a b hypercortisolism-induced immunosuppression, are common – reported in 31% (37/121) of Figure 5 Cats with HAC may be presented by their owners for secondary infections. (a) A 9-year-old British Blue cat with PDH (same cat as in Figure 2), presented with left cases.3,5–19,23–25,27,28,31–33,36–39,42,44 These include exophthalmos, third-eyelid prolapse and fever, secondary to an odontogenic retrobulbar urinary tract, respiratory tract and oral cavity abscess. (b) A 9-year-old male neutered domestic shorthair cat with ADH (same cat as in Figure 4), presented by its owner for lameness due to a hindlimb paronychia infections, subcutaneous abscesses and paronychia (painful, swollen nail beds, purulent in older cats: CKD, pancreatitis, cardiac disease, neoplasia and exudate and loss of nails) (Figure 5). hyperthyroidism.5,10–12,19,22,24,26,35,39 Multiple endocrine neoplasia Other, less common concurrent diseases include those found type-I-like syndrome was reported in two diabetic cats with PDH Cats with insulin-resistant diabetes and multiple invasive pancreatic beta cell carcinomas as well as cell hyperplasia.33 One also mellitus and concurrent HAC often show thyroid C-cell and parathyroid chief had a hepatocellular carcinoma.33 Rarely, concurrent functional pituitary or adrenal adenomas weight loss, while those with acromegaly have been reported, with excess production of growth hormone, often show weight gain. aldosterone or catecholamines.23,26,27,32
Diagnostic tests Clinical pathology Haematological findings in cats with HAC may be unremarkable or may reveal components of a ‘stress’ leucogram (mildto-moderate mature neutrophilia, lymphopenia, eosinopenia and/or monocytoTable 2
Abnormalities in serum biochemistry collated from reports of 138 cats with HAC*
Biochemical abnormality
Percentage of cases
Hyperglycaemia
84
Hypercholesterolaemia
34
Mild-to-moderate increase in urea
30
Mild-to-moderate increase in ALT activity
30
Hyperglobulinaemia
21
Mild-to-moderate increase in ALP activity 17 Increased creatinine
13
Hypokalaemia
10
Increased total protein
7
Hyperphosphataemia
7
Hypertriglyceridaemia
7
Hypernatraemia
4
*References 5,6,11–15,17–19,22–26,29–36,38–40 ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase
936
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Figure 6 Lithium heparin blood sample from the cat pictured in Figure 1. This was grossly lipaemic despite fasting, due to hypercholesterolaemia, which occurs in approximately one-third of cats with HAC
sis).5,6,8–13,15,16,21,22,24,25,35,37,38 A mild-to-moderate anaemia is occasionally present.10,19,35 Serum biochemical abnormalities are usually nonspecific; Table 2 summarises biochemistry data collated from reports of 138 cats with naturally occurring HAC published between 1975 and 2015 where laboratory findings were documented. Although hyperglycaemia secondary to concurrent diabetes mellitus is common, it is important to note that some cats will have transient diabetes mellitus or ‘stress’ hyperglycaemia.35 In contrast to dogs with HAC, elevations in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) are much less frequent in affected cats. Since cats lack a glucocorticoid-induced isoenzyme of ALP, increases in ALP activity occur secondarily to diabetes mellitus or other concurrent diseases. Hypercholesterolaemia is common, but not as frequent as in canine HAC (Figure 6). Total thyroxine is usually within the reference interval; however, some cats may have decreased concentrations secondary to nonthyroidal illness.5,7,10,19,23,35 Feline immunodeficiency virus and feline leukaemia virus testing is usually negative.5,7,17,26,38 Urinalysis has typically revealed glucosuria in cats with concurrent diabetes mellitus. Unlike dogs, the majority of cats with HAC have a urine specific gravity (USG) of >1.020. However, USG may range from isosthenuria
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to well concentrated and is influenced by comorbidities such as CKD or hyperthyroidism. Glucosuria may also cause a mild artefactual increase in USG. Proteinuria (not quantitated) has been reported in some cats.6–8,10,13,15,17–19,22–25,31,32,35,37 Endocrine testing Endocrine testing should be performed to support the initial diagnosis in cats suspected to have HAC. Signalment, history, clinical signs and laboratory findings suggestive of HAC will increase the positive predictive value of endocrine testing.
Urine cortisol to creatinine ratio The urine cortisol to creatinine ratio (UCCR) can be used as an initial screening test. Similar to its use in the investigation of canine HAC, this test has high sensitivity but low specificity for diagnosis of HAC in cats.42 It is used as a rule-out test due to the high predictive value of a negative result. UCCR values will increase with stress (eg, hospitalisation) and illness, and home-collected urine samples should be submitted for analysis several days after a veterinary visit.45,46 UCCR values also show day-to-day variation and so a minimum of two morning urine samples collected on consecutive days is advised. UCCR results do not vary with age, gender, neuter status or breed, but hyperthyroid cats have significantly higher values.42,45–47 The median UCCR was 13–16 x 10-6 for home-collected urine samples from 87 healthy cats in two reports.42,47 Thirteen cats with HAC had median UCCR values of 80–122 x 10–6 (note reference ranges are laboratory specific).3,42 Low dose dexamethasone suppression test Dexamethasone suppression tests are used to assess the appropriateness of the physiological negative feedback response to exogenous glucocorticoid administration. In healthy ani-
The UCCR is used as a rule-out test for HAC due to the high predictive value of a negative result.
mals, hypothalamic secretion of corticotropinreleasing hormone is suppressed for at least 24 h, thereby suppressing pituitary ACTH secretion and adrenal cortisol secretion. The low dose dexamethasone suppression test (LDDST) is arguably the best initial screening test for HAC due to its high sensitivity. However, when using the same protocol as for dogs (0.01 mg/kg IV and serum cortisol measurements at 0, 4 and 8 h), 10–20% of healthy cats will fail to demonstrate suppression.5,19,34,48–50 Thus, to increase test specificity, the LDDST protocol in cats involves administration of a 10-fold higher dose of dexamethasone (0.1 mg/kg IV), with serum cortisol measurements at 0, 4 and 8 h.5,7,51 Using this protocol, 4 and 8 h serum cortisol levels in healthy cats will be suppressed to
Journal of Feline Medicine and Surgery (2017) 19, 933–947
CLINICAL REVIEW
PECULIARITIES OF FELINE HYPERADRENOCORTICISM Update on diagnosis and treatment Lara A Boland and Vanessa R Barrs
Introduction
While the term ‘hyperadrenocorticism’ (HAC) refers to overproduction of any adrenocortical hormone, in veterinary medicine it is typically used to describe hypercortisolism (Cushing’s syndrome). HAC may also occur secondarily to pituitary or adrenal tumours that secrete other hormones with glucocorticoid-like activity; for example, alphamelanocyte-stimulating hormone (α-MSH), progesterone, oestradiol, testosterone, androstenedione and 17α-hydroxyprogesterone. This review discusses the signalment, history, clinical findings, diagnosis, treatment and prognosis for cats with spontaneous HAC (hypercortisolism), iatrogenic HAC and adrenal sex steroid-producing tumours. For information on hyperaldosteronism (not covered here), readers are referred to an earlier review by Djajadiningrat-Laanen et al.1 Normal physiology
Adrenocorticotropic hormone (ACTH) is secreted by the pars distalis of the anterior lobe of the pituitary gland. ACTH is derived from pro-opiomelanocortin, which is processed to pro-ACTH and subsequently cleaved to ACTH by the prohormone convertase 1.2 ACTH is also produced by the pars intermedia, but most is cleaved by melanotropic cells to α-MSH and to corticotropin-like intermediate lobe peptide by proconvertase 2.3,4 Cortisol and androgens are secreted by the zona fasciculata and reticularis of the adrenal cortex, while the zona glomerulosa secretes mineralocorticoids.
Aetiopathogenesis
In contrast to canine HAC, HAC in cats is a relatively uncommon endocrine disorder, with a little over 180 cases reported in the veterinary literature.2–40 A large UK study estimated the prevalence of HAC in UK dogs attending primary care practices to be 0.28%.41 Approximately 80% of feline cases are pituitarydependent hyperadrenocorticism (PDH). Carcinomas comprise a minority of cases overall, since at least 90% of PDH cases and 50–60% of adrenal-dependent hyperadrenocorticism (ADH) cases are caused by adenomas.2–40 Lara A Boland BVSc, MANZCVS, DipECVIM-CA Valentine Charlton Cat Centre, Sydney School of Veterinary Science, Faculty of Science, University of Sydney, NSW, Australia Vanessa R Barrs* BVSc, PhD, MVetClinStud, MANZCVS, FANZCVS (Feline), GradCertEd Valentine Charlton Cat Centre, Sydney School of Veterinary Science, Faculty of Science, and Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, NSW, 2006, Australia *Corresponding author: [email protected]
DOI: 10.1177/1098612X17723245 © The Author(s) 2017
Practical relevance: Hyperadrenocorticism (HAC) is a relatively uncommon endocrinopathy of older cats, with a mean age at diagnosis of 10 years. In addition to pituitarydependent and adrenal-dependent hypercortisolism, clinical signs of HAC can result from adrenal sex steroid-producing tumours. Clinical challenges: While HAC in cats has many similarities to canine HAC, there are key differences in presentation, diagnosis and response to therapy. Most, but not all, cats with HAC have concurrent diabetes mellitus, which is often insulin resistant. Up to a third of cats with HAC have extreme skin fragility and are at high risk of debilitating iatrogenic skin tears during diagnostic or therapeutic interventions. Infections of the skin and nail beds, and urinary, respiratory and gastrointestinal tract, secondary to cortisol-induced immune suppression, are also common. Cats respond differently to dogs to adrenal function tests including adrenocorticotropic hormone (ACTH) stimulation and dexamethasone suppression tests; a 10-fold higher dose of dexamethasone is recommended in cats to screen for HAC. Curative treatment options include adrenalectomy or transsphenoidal hypophysectomy. Radiation or medical treatment may improve clinical signs. The response to mitotane therapy is poor. While trilostane is the medical treatment of choice based on retrospective studies, investigations into the pharmacokinetics of this drug in cats are lacking. Global importance: Feline HAC occurs worldwide and is not associated with any purebreed predisposition. Although uncommon, adrenal sex steroid-producing tumours have a higher prevalence in cats than in dogs. Evidence base: The information in this review is drawn from over 180 reported cases of feline HAC. Reports investigating clinical presentation, clinicopathological findings and treatment outcomes are observational, retrospective multiple case series (EBM grade III) or single case reports (EBM grade IV). While most endocrine testing studies for diagnosis are cohort controlled analytical studies (EBM grade III), prospective, randomised, placebo-controlled studies have been performed (EBM grade I).
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PDH results from autonomous secretion of ACTH by tumours arising from corticotroph cells of the pars distalis (more commonly) or pars intermedia. This stimulates excessive production of cortisol from the adrenal cortex and causes cortical hyperplasia. ADH is usually secondary to autonomous cortisol production by tumours arising from the adrenal cortex.
Clinical signs
Commonly reportSignalment ed clinical signs and physical examHAC is a disease of ination findings, older cats, with a mean collated from age of approximately reports of 167 cats 10 years. The majority with naturally of reported cases are occurring HAC domestic breed cats published between (85%) and neutered; 1973 and 2015, are slightly more (54%) are listed in Table 1. male than female.3,5–37 Clinical signs are typically present for several months before presentation to a veterinarian, although time to presentation ranges from weeks to more than a year.2,5,6,11–19,22–33,35,36,38–40 Clinical signs overlap with other diseases (eg, diabetes mellitus), and early signs may be subtle. Whether hypercortisolism can cause secondary central or nephrogenic diabetes insipidus in cats has not been established.35 Polydipsia and polyuria may result from comorbidities; for example, diabetes mellitus, chronic kidney disease (CKD) or hyperthyroidism. Polyphagia has been reported in non-diabetic cats with HAC.9,10,19,42 Table 1
Clinical signs of HAC often overlap with those of diabetes mellitus. Diabetes mellitus occurs in almost 80% of cats with HAC.
Clinical signs and physical examination findings collated from reports of 167 cats with hyperadrenocorticism*
Clinical sign
Percentage of cases
Polydipsia and polyuria
81
Abdominal enlargement (‘pot-belly’)
61
Polyphagia
60
Skin atrophy
59
Muscle wasting
47
Weight loss
47
Lethargy
41
Alopecia
37
Skin fragility (skin tears)
32
Unkempt hair coat
30
Weakness/plantigrade stance
18
Hepatomegaly
13
Weight gain
12
*References 2,5,6,11-19,22,33,35,36,38–40
934
The majority (80%) of feline HAC cases are due to PDH. Adenomas account for at least 90% of PDH cases and 50–60% of ADH cases.
HAC causes skin atrophy and reduced skin elasticity, resulting in prominent subcutaneous veins and fragile, thin, papery skin (Figure 1). Comedones, a common feature of canine HAC, can sometimes be detected on ventral abdominal skin (Figure 1). Skin tears following minor trauma, routine handling or even grooming are common complications (Figure 2). Footpad excoriations can also occur. Extreme care should be taken when handling cats with suspected HAC to avoid iatrogenic trauma. Alopecia is typically bilaterally symmetrical, may involve the thoracic, ventral abdominal, flank and limb regions, and may be patchy or generalised. An ‘unkempt’ haircoat may result from growth of brittle and sparse hair, skin scaling and seborrhoea. Failure of hair regrowth after clipping is common (Figures 1–4).9,18,35,42 Hypercortisolism also leads to blood vessel friability and reduced fibrous response to injury which, in turn, can produce excessive bruising, delayed wound healing and reduced ligament and tendon strength.3,35,37 Weight loss from concurrent diabetes mellitus is common. Muscle wasting, due to increased
JFMS CLINICAL PRACTICE
b
a
c
Figure 1 Nine-year-old female neutered Devon Rex cat with diabetes mellitus and pituitarydependent hyperadrenocorticism (PDH). The cat had abdominal distension (‘pot-belly’), alopecia of the ventral abdomen with comedones (a and b), and bilaterally symmetrical alopecia of the pelvic limbs with thin, papery skin and excoriations (c)
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a
c
b
Figure 2 (a) This 9-year-old male neutered British Blue cat with PDH had extreme skin fragility and tore a large piece of skin as it squeezed between two bars of a security grill. (b) Nail bed infection and (c) fragile skin from the head that was inadvertently torn loose during grooming in the same cat
Figure 3 Seven-year-old male neutered Burmese cat with PDH.18 Four months after clipping for an abdominal ultrasound examination to investigate the cause of its hypertensive retinopathy, the cat re-presented with severe polydipsia and polyuria. The hair on the ventral abdomen had not regrown (a), and the skin was thin and papery with prominent subcutaneous vessels (b)
b
a
protein catabolism, is generalised or involves the lumbar musculature and contributes to weight loss. Although common, weight loss may not be apparent to owners because of abdominal distension (‘pot-belly’) resulting from hepatomegaly, abdominal fat deposition and abdominal muscle wasting (Figure 4). Depending on the balance of these factors, cats with HAC occasionally gain, rather than lose, weight.9
Approximately one-third of cats with HAC have skin fragility. Extreme care should be taken during handling and restraint to avoid iatrogenic trauma.
Generalised weakness and/or a plantigrade hindlimb stance are less common signs in feline HAC. Where present, contributing factors may include peripheral diabetic neuropathy, muscle wasting and hypokalaemia. Uncommon clinical signs include gastrointestinal signs (eg, inappetence, vomiting and diarrhoea), systemic hypertension, neurological signs from a pituitary macroadenoma, or a palpable adrenal mass.8–10,13,15,16,18,19,28,31,33,35,39
b
Figure 4 Nine-year-old male neutered domestic shorthair cat with adrenal-dependent hyperadrenocorticism (ADH). Note the ventral abdominal alopecia and skin excoriations resulting from thin skin (a,b). The cat had a ‘pot-bellied’ appearance on physical examination (a) and abdominal distension on a lateral abdominal radiograph (c). In cats with hyperadrenocorticism (HAC), these signs result from hepatomegaly, abdominal fat deposition and abdominal muscle wasting
a
c
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Concurrent disease Diabetes mellitus due to insulin resistance from hypercortisolism is a common comorbidity (reported in 77% [145/188] of cats with HAC), and is often insulin resistant.2,3,5–40,42,43 However, insulin resistance is not as severe as that encountered in hypersomatotropism (acromegaly). Also, in cats with diabetes mellitus and HAC, weight loss is more common than weight gain (47% vs 12%, Table 1), while weight gain is a common feature of acromegaly in cats. Bacterial or fungal infections, secondary to a b hypercortisolism-induced immunosuppression, are common – reported in 31% (37/121) of Figure 5 Cats with HAC may be presented by their owners for secondary infections. (a) A 9-year-old British Blue cat with PDH (same cat as in Figure 2), presented with left cases.3,5–19,23–25,27,28,31–33,36–39,42,44 These include exophthalmos, third-eyelid prolapse and fever, secondary to an odontogenic retrobulbar urinary tract, respiratory tract and oral cavity abscess. (b) A 9-year-old male neutered domestic shorthair cat with ADH (same cat as in Figure 4), presented by its owner for lameness due to a hindlimb paronychia infections, subcutaneous abscesses and paronychia (painful, swollen nail beds, purulent in older cats: CKD, pancreatitis, cardiac disease, neoplasia and exudate and loss of nails) (Figure 5). hyperthyroidism.5,10–12,19,22,24,26,35,39 Multiple endocrine neoplasia Other, less common concurrent diseases include those found type-I-like syndrome was reported in two diabetic cats with PDH Cats with insulin-resistant diabetes and multiple invasive pancreatic beta cell carcinomas as well as cell hyperplasia.33 One also mellitus and concurrent HAC often show thyroid C-cell and parathyroid chief had a hepatocellular carcinoma.33 Rarely, concurrent functional pituitary or adrenal adenomas weight loss, while those with acromegaly have been reported, with excess production of growth hormone, often show weight gain. aldosterone or catecholamines.23,26,27,32
Diagnostic tests Clinical pathology Haematological findings in cats with HAC may be unremarkable or may reveal components of a ‘stress’ leucogram (mildto-moderate mature neutrophilia, lymphopenia, eosinopenia and/or monocytoTable 2
Abnormalities in serum biochemistry collated from reports of 138 cats with HAC*
Biochemical abnormality
Percentage of cases
Hyperglycaemia
84
Hypercholesterolaemia
34
Mild-to-moderate increase in urea
30
Mild-to-moderate increase in ALT activity
30
Hyperglobulinaemia
21
Mild-to-moderate increase in ALP activity 17 Increased creatinine
13
Hypokalaemia
10
Increased total protein
7
Hyperphosphataemia
7
Hypertriglyceridaemia
7
Hypernatraemia
4
*References 5,6,11–15,17–19,22–26,29–36,38–40 ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase
936
JFMS CLINICAL PRACTICE
Figure 6 Lithium heparin blood sample from the cat pictured in Figure 1. This was grossly lipaemic despite fasting, due to hypercholesterolaemia, which occurs in approximately one-third of cats with HAC
sis).5,6,8–13,15,16,21,22,24,25,35,37,38 A mild-to-moderate anaemia is occasionally present.10,19,35 Serum biochemical abnormalities are usually nonspecific; Table 2 summarises biochemistry data collated from reports of 138 cats with naturally occurring HAC published between 1975 and 2015 where laboratory findings were documented. Although hyperglycaemia secondary to concurrent diabetes mellitus is common, it is important to note that some cats will have transient diabetes mellitus or ‘stress’ hyperglycaemia.35 In contrast to dogs with HAC, elevations in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) are much less frequent in affected cats. Since cats lack a glucocorticoid-induced isoenzyme of ALP, increases in ALP activity occur secondarily to diabetes mellitus or other concurrent diseases. Hypercholesterolaemia is common, but not as frequent as in canine HAC (Figure 6). Total thyroxine is usually within the reference interval; however, some cats may have decreased concentrations secondary to nonthyroidal illness.5,7,10,19,23,35 Feline immunodeficiency virus and feline leukaemia virus testing is usually negative.5,7,17,26,38 Urinalysis has typically revealed glucosuria in cats with concurrent diabetes mellitus. Unlike dogs, the majority of cats with HAC have a urine specific gravity (USG) of >1.020. However, USG may range from isosthenuria
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to well concentrated and is influenced by comorbidities such as CKD or hyperthyroidism. Glucosuria may also cause a mild artefactual increase in USG. Proteinuria (not quantitated) has been reported in some cats.6–8,10,13,15,17–19,22–25,31,32,35,37 Endocrine testing Endocrine testing should be performed to support the initial diagnosis in cats suspected to have HAC. Signalment, history, clinical signs and laboratory findings suggestive of HAC will increase the positive predictive value of endocrine testing.
Urine cortisol to creatinine ratio The urine cortisol to creatinine ratio (UCCR) can be used as an initial screening test. Similar to its use in the investigation of canine HAC, this test has high sensitivity but low specificity for diagnosis of HAC in cats.42 It is used as a rule-out test due to the high predictive value of a negative result. UCCR values will increase with stress (eg, hospitalisation) and illness, and home-collected urine samples should be submitted for analysis several days after a veterinary visit.45,46 UCCR values also show day-to-day variation and so a minimum of two morning urine samples collected on consecutive days is advised. UCCR results do not vary with age, gender, neuter status or breed, but hyperthyroid cats have significantly higher values.42,45–47 The median UCCR was 13–16 x 10-6 for home-collected urine samples from 87 healthy cats in two reports.42,47 Thirteen cats with HAC had median UCCR values of 80–122 x 10–6 (note reference ranges are laboratory specific).3,42 Low dose dexamethasone suppression test Dexamethasone suppression tests are used to assess the appropriateness of the physiological negative feedback response to exogenous glucocorticoid administration. In healthy ani-
The UCCR is used as a rule-out test for HAC due to the high predictive value of a negative result.
mals, hypothalamic secretion of corticotropinreleasing hormone is suppressed for at least 24 h, thereby suppressing pituitary ACTH secretion and adrenal cortisol secretion. The low dose dexamethasone suppression test (LDDST) is arguably the best initial screening test for HAC due to its high sensitivity. However, when using the same protocol as for dogs (0.01 mg/kg IV and serum cortisol measurements at 0, 4 and 8 h), 10–20% of healthy cats will fail to demonstrate suppression.5,19,34,48–50 Thus, to increase test specificity, the LDDST protocol in cats involves administration of a 10-fold higher dose of dexamethasone (0.1 mg/kg IV), with serum cortisol measurements at 0, 4 and 8 h.5,7,51 Using this protocol, 4 and 8 h serum cortisol levels in healthy cats will be suppressed to
