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Selecting The Best Treatment Option For A Dog With Cushing’S Syndrome

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Spontaneous hypercortisolism or Cushing's syndrome is a common endocrinopathy in dogs. Pituitary-dependent and adrenal-dependent hypercortisolism each require specific treatment and diagnostic imaging is very helpful in choosing the treatment that is appropriate. The aims and expectations of the treatment need to be established beforehand and discussed with the owner to avoid unexpected disappointments. The clinical signs of pituitary-dependent hypercortisolism caused by a pituitary microadenoma can be managed with the adrenocorticostatic drug trilostane, but the drug will not affect the pituitary tumor. Hypophysectomy is therefore preferred in those dogs that have an enlarged pituitary but are in good clinical condition and have a long life-expectancy. Inoperable pituitary tumors can be treated by radiotherapy. The best treatment in dogs with cortisol-secreting adrenocortical tumors is adrenalectomy. If surgery is not possible, because of vascular invasion or metastatic spread, mitotane is recommended. Treatment with trilostane can be considered but is only palliative: it does not affect the adrenocortical tumor.
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Acta Veterinaria-Beograd 2015, 65 (1), 1-19
UDK: 636.7.09:616.453-008.84-08
DOI: 10.1515/acve-2015-0001
Review article
Corresponding author: e-mail: S.Galac@uu.nl
SELECTING THE BEST TREATMENT OPTION
FOR A DOG WITH CUSHING`S SYNDROME
GALAC Sara
Dept. of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University,
Utrecht, The Netherlands
(Received 28th January; Accepted 17th February 2015)
Spontaneous hypercortisolism or Cushings syndrome is a common endocrinopathy
in dogs. Pituitary-dependent and adrenal-dependent hypercortisolism each require
specic treatment and diagnostic imaging is very helpful in choosing the treatment
that is appropriate. The aims and expectations of the treatment need to be established
beforehand and discussed with the owner to avoid unexpected disappointments.
The clinical signs of pituitary-dependent hypercortisolism caused by a pituitary
microadenoma can be managed with the adrenocorticostatic drug trilostane, but the
drug will not affect the pituitary tumor. Hypophysectomy is therefore preferred in those
dogs that have an enlarged pituitary but are in good clinical condition and have a long
life-expectancy. Inoperable pituitary tumors can be treated by radiotherapy. The best
treatment in dogs with cortisol-secreting adrenocortical tumors is adrenalectomy. If
surgery is not possible, because of vascular invasion or metastatic spread, mitotane is
recommended. Treatment with trilostane can be considered but is only palliative: it does
not affect the adrenocortical tumor.
Key words: hypophysectomy, adrenalectomy, trilostane, mitotane, dogs
INTRODUCTION
Spontaneous hypercortisolism or Cushing’s syndrome is characterized by physical and
biochemical changes resulting from chronic exposure to elevated concentrations of
circulating glucocorticoid. About 80-85% of cases of hypercortisolism in dogs are
adrenocorticotropin (ACTH)-dependent, most often the result of excessive secretion
of ACTH by a pituitary corticotroph adenoma. In the remaining cases hypercortisolism
is ACTH-independent, the result of excessive secretion of glucocorticoids by an
adrenocortical tumor (AT) [1]. The ectopic ACTH secretion syndrome and ACTH-
independent or primary bilateral adrenal hyperplasia are both rare in dogs [2,3].
The pituitary lesions producing excess ACTH range from small nests of
hyperplastic corticotrophs (or melanotrophs) to micro- or macroadenomas. Pituitary
macroadenomas can eventually invade surrounding tissues such as the cavernous sinus,
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
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dura mater, brain, and rarely the sphenoid bone. These are called invasive adenomas,
to distinguish them from pituitary tumors with extracranial metastasis, which are a rare
in dogs [4].
Cortisol-secreting ATs can be divided into adenomas and carcinomas, but histological
differentiation is not always straightforward. Histological markers of adrenocortical
carcinoma include vascular invasion, intracapsular growth, and atypical nuclei [5].
However, the most reliable indicator of malignancy at present is metastasis.
Establishing the diagnosis of hypercortisolism
Cushing’s syndrome is a disease of middle-aged and older dogs. There is no gender
predilection. It occurs in all breeds, with a slight predilection for small breeds such as
the Dachshund and the Miniature Poodle. Many of the clinical signs can be related to
the biochemical effects of glucocorticoids, namely, gluconeogenesis and lipogenesis at
the expense of protein (Figure 1). In dogs, the cardinal physical features are centripetal
Figure 1. A dog with hyperocrtiosolism at the time of diagnosis (a) and during trilostane
therapy (b)
Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
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obesity, alopecia, and atrophy of muscles and skin. Abdominal palpation may reveal
hepatomegaly [1]. Polyuria and polyphagia are also prominent features. The polyuria is
known to be due to impaired osmoregulation of vasopressin release and interference
by the glucocorticoid excess with the action of vasopressin in the kidney.
The biochemical diagnosis of hypercortisolism depends on the demonstration of
two characteristics: increased production of cortisol and decreased sensitivity to
glucocorticoid feedback [6]. The diagnostic approach has been reviewed recently in
a consensus statement by leading veterinary endocrinologists [7]. It has been agreed
that in dogs with clinical signs of hypercortisolism, the diagnosis should be conrmed
by tests of cortisol secretion and integrity of the feedback system. The low-dose
dexamethasone suppression test (LDDST) is the most recommended test for this
purpose. Measurement of plasma cortisol at 4 and 8 hours after dexamethasone
administration is recommended to differentiate between pituitary- and adrenal-
dependent hypercortisolism [8]. Measurement of the urinary corticoid to creatinine
ratio is a convenient test for hypercortisolism, if performed at home to avoid the
inuence of stress [9]. Urinary corticoid excretion represents an integrated measure
of corticoid production over an interval (usually one night), smoothing the effects of
short-term uctuations in plasma cortisol concentration. As it can be easily combined
with the HDDST, the two forms of hypercortisolism can be differentiated in one test,
but its reliability depends on the availability of a trustworthy assay [10]. The ACTH
stimulation test, which has been used in the diagnosis of spontaneous hypercortisolism
in dogs for quite some time, is no longer recommended [7]. In principle it is a test of
adrenocortical reserve capacity, used to diagnose primary and secondary adrenocortical
insufciency. It can thus be used to diagnose iatrogenic hypercortisolism, which via
feedback suppression results in secondary adrenocortical insufciency [11]. In addition,
this test is now often used to monitor treatment with trilostane [12]. Measurement of
plasma ACTH concentration is useful to differentiate between the adrenal- and pituitary-
dependent forms of hypercortisolism, but not for other diagnostic purposes [6]. Plasma
ACTH concentration is expected to be low or undetectable in adrenal hypercortisolism
but in cases of pituitary tumor it may be elevated or within the normal range, because of
the pulsatile secretion pattern of ACTH.
Diagnostic imaging of the pituitary and adrenal glands
Diagnostic imaging of the pituitary and adrenals is of great value in determining
the best treatment and for objectively evaluating the prognosis. The pituitary can be
visualized by computed tomography (CT, Figure 2) or nuclear magnetic resonance
imaging (MRI) [13,14]. In healthy dogs, the pituitary gland is 6 to 10 mm in length,
5 to/9 mm in width, and 4 to/6 mm in height [15]. The size of the pituitary can be
evaluated by means of the ratio between its height and the area of the brain (P/B
ratio), measured on a CT image through the center of the pituitary: a P/B ratio greater
than 0.31 indicates pituitary enlargement [16,17].
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
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Macroadenomas of the pituitary are easily detected on contrast-enhanced CT images
because they alter the size and shape of the gland, but a normal appearance does
not exclude the possible presence of a microadenoma. The classication of pituitary
adenomas in humans as microadenomas (0.10 mm) and macroadenomas (10 mm)
is not useful in dogs, where adenomas between 6 and 10 mm in height enlarge the
gland and therefore cannot be classied as microadenomas. Direct visualization of the
pituitary adenoma is only possible when the imaging characteristics of the adenoma
are different from those of the surrounding normal pituitary tissue. The enhancement
pattern of the neurohypophysis during dynamic contrast enhanced CT has been called
the ‘pituitary ush’. The displacement, distortion, or disappearance of the pituitary
‘ush sign’ in the early phase of dynamic CT examinations can be used to identify both
micro- and macroadenomas in dogs [18].
The adrenal glands can also be visualized by CT [19-21], but ultrasonography is less
expensive, requires less time, and does not require anesthesia, and so it is often used
rst (Figure 3) [22,23]. Attention has been given to the symmetry, size, shape, and
echogenicity of adrenal glands. Bilateral enlargement of the adrenal glands is expected
in PDH, while a cortisol-secreting AT usually presents as a unilateral adrenal mass with
atrophy of the contralateral adrenal. Determining the size of the adrenals has been
controversial. An adrenal diameter greater than 7 mm has been reported to signify
hyperplasia, with a sensitivity of 77% and specicity of 80% [23]. Recently, Choi and
coauthors [24] reported that in dogs weighing less than 10 kg a diameter greater than
6 mm indicates PDH, with a sensitivity of 75% and a specicity 94%. The structure
of the adrenal may be more important than its size. In hyperplastic adrenal glands
the normal shape is preserved and the sonographic appearance is homogeneous
[25]. Contrast-enhanced ultrasonography is a relatively new approach in evaluating
Figure 2. Mildly (a) and severely (b) enlarged pituitary gland in two dogs with pituitary-
dependent hypercortisolism visualized by computer tomography. An arrow pints to the
pituitary gland
Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
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adrenal glands [26-28]. During this procedure, the contrast agent is administered IV
and time-intensity curves are generated for the adrenal cortex, adrenal medulla, and
ipsilateral renal artery of both adrenal glands. Contrast-enhanced ultrasonography is
able to detect vascular changes induced by hypercortisolism. In normal dogs, contrast
enhancement distribution in the adrenals is homogeneous and in the washout phase
there is a gradual and homogeneous decrease in enhancement [26]. In dogs with PDH,
there is a rapid, chaotic, and simultaneous contrast enhancement in both the cortex
and medulla [28]. In addition, the peak contrast intensity in both the cortex and the
medulla was twice as high in dogs with PDH compared with that of healthy controls.
Further studies are needed to determine whether reference ranges for clinically normal
dogs and dogs with PDH can be determined and applied in clinical settings. This
approach may be promising in the diagnosis of bilateral adrenocortical tumor as well
as in differentiating between tumor and adrenocortical hyperplasia [27]. Especially
differentiation between bilateral cortisol-secreting ATs and hyperplastic adrenals is
challenging [29,30]. Bilateral ATs are not very common and it is a heterogeneous
echographic appearance, reecting necrosis and hemorrhage in the adrenals, which
may suggest tumor rather than hyperplasia. Asymmetry of the adrenal glands is a
typical ultrasonographic nding with a unilateral cortisol-secreting AT. In addition
to the size and structure of an AT, its expansion into the blood vessels and possible
metastasis to the liver are also evaluated. If nodular structures are revealed in the liver,
ultrasound-guided needle aspiration biopsy can be performed. Radiographs or a CT
scan of the thorax should be made to determine whether there are metastases in the
lungs.
TREATMENT
The goal of treatment of hypercortisolism is to eliminate the cause. Depending on
the etiology, this may be achieved by transsphenoidal hypophysectomy, adrenalectomy,
radiotherapy, or medical treatment with trilostane or o,p’-DDD (mitotane).
Figure 3. Cortisol-secreting adrenocortical tumor visualized by ultrasonography (a) and
computer tomography (b). A nodular change in the cranial pool of the adrenal (arrow) and
atrophic caudal part of the adrenal gland (hole arrow) are noted. Computer tomography
demonstrated a heterogenous structure of the adrenocortical tumor
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
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Pituitary-dependent hypercortisolism
Surgical treatment
Ideally, the treatment of canine PDH should be removal of the ACTH-producing
adenoma [1]. Otherwise, the tumor may continue to grow and eventually lead to
neurological signs associated with an intracranial mass. However, hypophysectomy
requires the joint efforts of a neurosurgeon, an endocrinologist, a radiologist, and
an intensivist and it is therefore not available in most cases [31]. A CT scan of the
pituitary is a surgical prerequisite for localization of the gland in relation to the
anatomical landmarks and for assessment of pituitary size [13]. In the hands of a
skilled neurosurgeon, microsurgical transsphenoidal hypophysectomy has proved
to be a safe and effective treatment for Cushing’s disease in dogs [32,33]. Following
hypophysectomy, hormone replacement therapy consists of lifelong administration
of cortisone acetate and thyroxine. Desmopressin, a synthetic vasopressin analogue,
is needed temporarily because in dogs removal of the pituitary adenoma by
hypophysectomy also removes the pars nervosa, via which the antidiuretic hormone
arginine vasopressin, secreted by the hypothalamic paraventricular and supraoptic
nuclei, reaches the systemic circulation [34]. Hypophysectomy thus results in transient
central diabetes insipidus (CDI) for up to 2 months, after which desmopressin can be
gradually withdrawn. However, in about 10% of cases, the CDI remains permanently
[33].
The major complications of hypophysectomy are postoperative mortality,
hypernatremia due to acute vasopressin deciency, prolonged central diabetes
insipidus, keratoconjunctivitis sicca (KCS), and residual or recurrent hypercortisolism
[34]. Postoperative mortality and severe hypernatremia have been reduced over the
years as a result of better intensive care facilities and the learning curve of the critical
care specialist [35]. Frequent sodium measurements in the postoperative period and
adjustments in uid therapy are key to prevent life-threatening changes in osmolality.
Patient selection has also contributed to the decrease in postoperative mortality.
Dogs in poor clinical condition due to hypercortisolism are now treated with the
adrenocorticostatic drug trilostane until their clinical condition improves sufciently
for surgery. KCS can be a severe complication after transsphenoidal hypophysectomy
if left untreated. Routine postoperative use of the Schirmer tear test (STT) and
immediate ophthalmologic treatment prevent the development of lesions in the
cornea. There is no correlation between pituitary size and development of KCS. Its
development after hypophysectomy has been ascribed to direct (traumatic) or indirect
(ischemic) neuropraxia of the major petrosal nerves, resulting in a secretomotoric
decit in the lacrimal glands, but this has not yet been proved and the pathogenesis
remains uncertain. Most dogs recover completely but in few tear production remains
low for life. The STT should be performed on the rst day after hypophysectomy, for
early detection and treatment prevents the development of severe KCS.
Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
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The 10-year follow-up ndings after hypophysectomy in 150 dogs with PDH showed
that it is effective, especially in the long term, with remission for up to seven years
[32]. With increasing pituitary size the survival and disease-free periods decrease and
the incidence of central diabetes insipidus increases. The recurrence rate of 25%
compares favorably with that after nonselective adrenocortical destruction with
mitotane [36]. Hence transsphenoidal hypophysectomy can be expected to have the
best outcome as the primary treatment in dogs with nonenlarged or only moderately
enlarged pituitaries [33]. The recurrence rate increases with longer follow-up intervals
after initially successful surgery. This may be because normal corticotrophs present in
the sella turcica after surgery tend to remain functional (much more so than the other
cell types) and maintain normocorticism, while residual adenoma cells are insensitive
to feedback control and eventually cause recurrence of hypercortisolism.
In dogs with larger pituitary tumors and tumor extension rostrally or caudally over
the dorsum sellae, transsphenoidal debulking surgery may be only palliative and
radiotherapy might be preferred.
Medical treatment
Selective [37] or nonselective [36] destruction of the adrenal cortex with o,p’-
DDD (mitotane) has long been the medical treatment of choice for PDH in
dogs. Selective treatment aim at selective destruction of the zona fasciculata (ZF)
and zona reticularis (ZR), sparing the zona glomerulosa (ZG). However, in 5-6%
of dogs in which this is attempted, the ZG is also destroyed to such an extent that
iatrogenic hypoadrenocorticism develops. On the other hand, in more than half of
the cases in which selective destruction is the aim, there are one or more relapses of
hypercortisolism during treatment. In order to avoid these complications, a treatment
schedule aimed at complete destruction of the adrenal cortices and substitution for
the induced hypoadrenocorticism was developed [38]. This nonselective destruction
has been reported to result in fewer recurrences than does selective destruction [36].
Now o,p’-DDD is no longer used for treatment of PDH, but rather for treatment
of inoperable and/or metastasized AT, with the intention of destroying all AT cells,
including metastases [39]. In some countries, the use of o,p’-DDD requires specic
authorization from the veterinary medicines directorate [12]. It should therefore be
used only when trilostane has proved to be ineffective or cannot be used for other
reasons, such as when specic side effects or other disorders preclude its use.
A decade ago, trilostane was introduced as a safe and effective alternative to
o,p’-DDD in dogs with PDH [40].Trilostane is a competitive inhibitor of
hydroxysteroid dehydrogenase (HSD3B), an enzyme that is essential in the synthesis
of cortisol, aldosterone (ALD), and androstenedione (Figure 4) [12]. In dogs with
PDH, treatment with trilostane has the potential to signicantly decrease basal and
ACTH-stimulated plasma cortisol concentration. This results in loss of negative
feedback and thus increased plasma ACTH concentration [41,42]. Consistent with
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
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its competitive inhibitory effect on HSD3B, trilostane also causes an insignicant
decrease in plasma ALD concentration in dogs with PDH, although ALD usually
remains within the reference range [43,44]. A result, there is a signicant increase in
plasma renin activity (PRA), which compensates for the decline in ALD. It has been
Figure 4. Major pathways of adrenocortical steroid biosynthesisin canine adrenal gland cortex..
StAR = steroidogenic acute regulatory protein, CYP11A = cholesterol side-chain cleavage
enzyme, HSD3B2 = 3b-hydroxysteroid dehydrogenase, CYP17 = 17a-hydroxylase, CYP21 =
21-hydroxylase, CYP11B1 = 11b-hydroxylase, 17βHSD = 17β-hydroxysteroid dehydrogenaase.
Cellular location of enzymes (mitochondria or smooth endoplasmic reticulum) is depicted
Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
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concluded that trilostane not only affects the pituitary-adrenocortical axis but also the
renin-ALD axis [42].
Trilostane is absorbed rapidly from the gastrointestinal tract. Administration with food
signicantly increases the rate and extent of absorption. There is marked variation in
the optimal dose and to avoid adverse effects due to overdosage, treatment is started at
a relatively low oral dose of 2 mg/kg body weight once daily [1,12]. This frequency of
administration seems to be sufcient to control the clinical signs of hypercortisolism,
despite the fact that the effect of trilostane on basal and ACTH-stimulated cortisol is
considerably less than 24 hours in most cases [45].
The effectiveness of trilostane therapy is judged by 1) resolution of the clinical signs
associated with glucocorticoid excess and 2) the results of an ACTH stimulation test
[40]. Within about a week on an appropriate dose of trilostane, there is a clear reduction
in polydipsia, polyuria, and polyphagia, although notable improvement in the skin
and coat, reduction of central obesity, and increased physical activity requires 3 to 6
months of adequate doses [46]. The purpose of performing an ACTH stimulation test
in a dog on trilostane therapy is to determine whether there is sufcient adrenocortical
reserve at the time of maximal effect of trilostane, which is about 2-3 hours after
administration [45]. Despite its widespread use, the ACTH stimulation test has never
been validated for use during trilostane therapy. The author’s currently recommended
target ranges for the post-ACTH cortisol concentration are presented in Table 1 and are
based on the ACTH stimulation test started 2-4 hours after trilostane administration.
Table 1. Adjustments of trilostane dose by ACTH stimulation test performed
2-3 h after dosing
Clinical manifestation Post-ACTH plasma
cortisol concentration Action
Major clinical signs have
ceased 40-150 nmol/l The dose is left unchanged
Clinical signs of
hypercortisolism have not
decreased or ceased
40-150 nmol/l Slightly increase the dose or rather divide
in two portions
No effect in clinical signs >150 nmol/l Increase the daily dose by 1 mg/kg
Major clinical signs have
ceased >150 nmol/l
Do not change the dose, but monitor the
dog closely for the recurrence of signs of
hypercortisolism
Major clinical signs have
ceased and the dog is in
good clinical condition
< 40 nmol/l
Trilostane dosage is decreased by 50% and
the dog is monitored closely for signs of
hypocortisolism
Sings suggested
of adrenocortical
insufciency, such as
lethargy and anorexia
< 40 nmol/l Stop the treatment and administer
intravenous uids and glucocorticoids
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
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Trilostane is generally well tolerated at the recommended dose and with appropriate
monitoring. Overdosage results in cortisol deciency and sometimes even
mineralocorticoid deciency [47,48]. The most common clinical signs are inappetence,
weakness, diarrhea, weight loss, and abdominal pain. If they appear, trilostane must be
stopped immediately. Recovery is usually rapid but trilostane will still be required to
control the clinical signs of hypercortisolism [42]. Hence the dose is reduced by 50%
and monitoring is continued.
Another-but life-threatening-side effect of trilostane is adrenocortical necrosis
[47]. Its etiology is uncertain but thought to be related to increased basal ACTH
concentration [49]. Trilostane therapy causes basal ACTH concentration to increase as
a physiologic reaction to the lowering of the plasma cortisol concentration [42]. This
in turn leads to the increase in size of the adrenal glands that is observed in many dogs
treated with trilostane. Paradoxically, even short periods of highly elevated ACTH
levels can result in focal necrosis and hemorrhage in the adrenal glands in humans.
Presumably, elevated ACTH levels in dogs with PDH could also lead eventually
to adrenocortical necrosis [42]. There have been several case reports of dogs with
adrenal necrosis in which the severity of the lesions may have been related to the
high doses of trilostane used and the long duration of treatment [47,48]. Dogs with
suspected adrenocortical necrosis are presented as emergencies and deserve prompt
corticosteroid substitution and supportive therapy with uid, an antiemetic, and an
analgesic. Usually, glucocorticoid supplementation must be continued after the dog is
discharged.
ACTH concentration also increases in normal dogs treated with trilostane. This is
associated with an increase in pituitary size (as assessed by MRI) and histological
evidence of pituitary corticotroph hyperplasia and bilateral adrenocortical hyperplasia
[50]. It seems reasonable to assume that trilostane could result in an increase in size
of pituitary tumors, but no evidence for this has been reported. Nevertheless, at this
institution a control CT scan is obtained 12 months after initiation of therapy when
trilostane is used in a dog with a pituitary microadenoma. This objective evaluation of
the size of the pituitary tumor enables surgical intervention to be undertaken in time,
if needed.
In order to diminish the likelihood of side effects and possibly improve effectiveness,
the use of a lower dose of trilostane and twice-daily administration has been introduced.
There have been two reports of a better clinical response to twice daily administration,
with no difference in adverse effects [51,52].
In most veterinary institutions trilostane administration is started once daily, the main
considerations being the relatively high cost of the drug and owner compliance. The
administration is increased to twice daily if the clinical response is unsatisfactory
and an ACTH stimulation test reveals mild adrenocortical reserve. Whether the drug
should be administered once or twice daily is still uncertain. Long-term studies using
even very low doses have demonstrated good clinical responses [53,54].
Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
11
In dogs with hypercortisolism and concurrent diabetes mellitus (DM), trilostane should
be administered at the same time as insulin. Hence, in most diabetics it is started twice
daily [12]. It has been suggested that twice-daily administration of trilostane might
also be benecial in dogs with hypercortisolism and severe proteinuria, but this has
not been investigated.
The median survival time for dogs with PDH treated with trilostane once daily (662
days), is similar to that for dogs with PDH undergoing selective adrenocorticolysis with
o,p’-DDD (798 days) [55]. The median survival time for dogs with PDH treated with
trilostane twice daily (900 days) is comparable to that for dogs with PDH undergoing
nonselective adrenocorticolysis with o,p’-DDD (720 days) [56]. In these studies no
attempt was made to relate the size of the pituitary tumor to the survival time.
Pituitary irradiation therapy
Radiation therapy is considered to be the treatment of choice for pituitary macrotumors
with suprasellar extension. Megavoltage irradiation from a lineal accelerator or cobalt
60 source is required to penetrate to the depth of the pituitary without injuring
overlying soft tissues [57-59]. Radiotherapy is effective in reducing the size of such
pituitary tumors, but with a quite variable delay, from 1 to 16 months. The reduction
in size is gradual in onset but can continue for a year or more after completion of the
therapy [59]. The improvement in clinical signs of hypercortisolism is associated with
reduced pituitary ACTH secretion and may not be evident until a few months after
therapy. Hence, treatment with trilostane is advocated until this occurs.
Radiotherapy is only available in a few veterinary institutions. Most treatment protocols
involve irradiation for 4 weeks on alternate days and since anesthesia is required, the
anesthetic risk must be evaluated carefully before recommending this approach [58,59].
Data on the efcacy of pituitary irradiation in veterinary medicine are scarce. The best
results are to be expected in dogs with pituitary macrotumors without neurological
signs. If neurological signs are present, they may increase with the gradual decrease in
pituitary size after radiotherapy, and this is usually decisive for euthanasia. Kent et al.
[60], reported a signicant correlation between the relative size of the tumor and the
severity of neurological signs and between the relative size of the tumor and remission
of neurological signs.
Adrenal-dependent hypercortisolism
Surgery
The treatment of choice for unilateral ACT is adrenalectomy, because successful
removal eliminates both the tumor and the associated clinical signs of glucocorticoid
excess, without the need for lifelong medication. Because of the atrophy of the cortex
of the nontumorous contralateral adrenal gland, due to the longstanding glucocorticoid
excess, glucocorticoid substitution is needed temporarily [1]. Substitution is started at
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
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the time of anesthesia and is continued for 6 to 8 weeks after surgery. The dose of
glucocorticoid is decreased gradually to facilitate progressively increasing feedback
stimulation of pituitary ACTH secretion.
Adrenalectomy can be performed in dogs via a ventral midline celiotomy, with
paracostal extension of the incision when needed, or via a paracostal approach [61-
63]. The choice remains controversial. While the midline approach allows complete
exploration of the abdomen and direct examination of both adrenal glands, the
paracostal approach affords better surgical access to the ipsilateral adrenal with less
trauma to the liver, pancreas, and spleen, and less risk of wound dehiscence.
Regardless of the surgical approach, adrenalectomy has a perioperative mortality of
about 20% [62,64]. This is explained in part by the relatively high risk of postoperative
complications such as renal failure, pneumonia, pancreatitis, and pulmonary
thromboembolism, but it also reects the difculty of the surgical procedure per se.
In dogs with hypercortisolism access to the adrenals is usually hindered by central
obesity and hepatomegaly. Furthermore, ATs are friable, lie in close proximity to the
vena cava, and tend to invade blood vessels. As for hypophysectomy [35], the skill of
the surgeon and of the rest of the team affects the outcome. Postoperative intensive
care facilities are essential and hence surgery should be undertaken only in referral
centers. At some institutions, treatment with trilostane prior to surgery is advocated,
but it is not known whether this improves survival.
In the recent years, laparoscopic adrenalectomy has gained in popularity [65,66]. Its
potential advantages over open techniques include reduced manipulation of other
abdominal organs, an excellent view of abdominal structures, decreased surgical
wound complications, and improved postoperative comfort. While ATs up to 5 cm in
diameter do not pose a problem for laparoscopic removal, if ingrowth in the blood
vessels is suspected, the open technique is preferred. Pelaes et al. (2008) reported
creating a small window in the adrenal capsule to aspirate necrotic content and thus
reduce the risk of rupture of the AT and escape of neoplastic cells during surgery
[65]. Although the clinical consequences of capsule rupture and leakage of AT cells
remain unclear, it is probably better to avoid this complication by delicate dissection,
initial sealing, and perhaps the use of a retrieval bag [66].
The median survival time after adrenalectomy is about 2 years, although some dogs
survive more than 4 years [64].
Medical treatment
The adrenocorticolytic drug mitotane (o,p’-DDD) has been the mainstay of medical
treatment for inoperable ACTs and/or metastases. While cortisol excess can be treated
successfully by selective destruction of the adrenal cortex, the aim of mitotane therapy
in cortisol-secreting ATs is complete destruction of the adrenocortical tumor tissue [1].
Mitotane is administered in a dose of 50-75 mg/kg body weight per day. It is given
daily for the rst 5 days, then on alternate days for an additional 20 days. Substitution
Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
13
with cortisone acetate, udrocortisone acetate, and salt is started on the third day.
The dose of cortisone begins at twice the usual replacement dose and is reduced to
0.5 to 1 mg/kg per day at the end of the 25 days of mitotane therapy. The doses of
udrocortisone (0.0125-0025 mg/kg per day) and salt (0.1 mg/kg per day) are adjusted
by measurements of plasma sodium and potassium concentrations. After the 25 days
of mitotane administration, the magnitude of destruction of the AT is evaluated by
measurement of the UCCR. The evening doses cortisone and udrocortisone are
omitted prior to the morning urine collection for the UCCR. Complete destruction
of the AT results in a very low UCCR. In order to prevent recurrence, mitotane is
administered once weekly for at least 6 months, or even lifelong.
The chemotherapy with mitotane produces side effects, such as vomiting, poor appetite
or anorexia, and sometimes ataxia [39]. The owner is instructed to stop giving mitotane
if any of these occur, but to continue the substitution therapy. If for any reason the
dog cannot take or retain the tablets two times in succession, injectable medications
should be started. If side effects are ignored and the substitution therapy is refused,
the dog can develop a hypoadrenocorticoid (Addisonian) crisis. Owner compliance
is essential for successful chemotherapy with mitotane. The injectable glucocorticoid
and mineralocorticoid are provided to the owner for use if necessary [36].
If there is metastasis of a functional AT or if neither adrenalectomy nor adrenocortical
destruction with mitotane is an option, trilostane therapy can be used as a palliative
treatment [67, 68]. Although the manufacturer’s recommended dose of trilostane
does not differentiate between treatment of pituitary and adrenal hypercortisolism,
experience has shown that ATs are more sensitive to trilostane than are hyperplastic
adrenal glands. At this institution, the starting dose of trilostane used in dogs with AT
is 1 mg/kg body weight is. Monitoring of trilostane therapy consist of evaluation of
clinical signs and the ACTH stimulation test, as in trilostane therapy for PHD [1,12].
The median survival time in dogs with ATs treated with mitotane were 10 and 15.6
months and in those treated with trilostane it was 14 months [69,70]. In both studies
mitotane was used in a protocol for selective destruction to resolve the clinical signs
and not for complete destruction of the AT and metastases. It is thus not surprising
that the survival times for mitotane and trilostane were similar. However, in both
studies survival of animals with metastases was signicantly shorter than in those
without. This supports the use of the protocol to attempt complete destruction with
mitotane and continuing weekly administration.
CONCLUSION
Both pituitary-dependent and adrenal-dependent hypercortisolism can be treated
either surgically or medically and pituitary macrotumors can be treated by radiotherapy.
In order to determine the best treatment, factors such as the patient’s age, concurrent
diseases, and general health should be considered. Diagnostic imaging is very helpful in
Acta Veterinaria-Beograd 2015, 65 (1), 1-19
14
the process of decision making. Dogs with PHD caused by a pituitary microadenoma
can be treated with the adrenocorticostatic drug trilostane. Hypophysectomy is not
necessary, since the main problem is cortisol excess and not a pituitary mass. In young
dogs with hypercortisolism a pituitary scan is recommended after 12 months of
trilostane administration, to evaluate the size of the pituitary and determine whether
surgical intervention is needed. In dogs with an enlarged pituitary, medical treatment
will control the clinical signs of hypercortisolism, but not the growth of the tumor,
and therefore hypophysectomy is preferred. Lifelong substitution with cortisone
and thyroxine will be required. Pituitary macrotumors can be managed surgically by
debulking or by radiotherapy.
Because unilateral ATs can be malignant, adrenalectomy is the best treatment
option. Administration of cortisone acetate is required following surgery, because
the contralateral adrenal cortex is atrophic as a result of feedback suppression of
pituitary ACTH secretion, but this is reversed within two months. Adrenalectomy, like
hypophysectomy, requires special facilities and a team consisting of an experienced
surgeon, endocrinologist, radiologist, anesthesiologist, and critical care specialist.
The medical treatment of hypercortisolism aims at the suppression of cortisol
secretion and control of the clinical signs. Trilostane has become the most commonly
used drug. It has been shown to be safe and effective, but its dosage needs to be
controlled on a regular basis and its long-term effects are not yet known. The major
indication for medical treatment with trilostane is PDH, but it can also be used in
adrenal-dependent hypercortisolism when surgery is not possible due to the presence
of metastasis or for other reasons. Mitotane is still available for use in dogs with
inoperable, cortisol-secreting AT. A complete destruction protocol is used for this
purpose and may be followed by once-weekly administration in order to suppress the
growth of the AT.
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Galac: Selecting the best treatment option for a dog with Cushing`s syndrome
19
IZBOR NAJBOLJE TERAPIJE KOD CUSHING-OVOG SINDROMA
PASA
GALAC Sara
Spontani hiperkorticizam (Cushingov sindrom) je česta endokrinopatija kod pasa. Hip-
erkorticizam zavisan kako od funkcije nadbubrežne žlezde tako i od funkcije hipoze,
zahteva specičnu terapiju, pri čemu je imidžing dijagnostika veoma korisna za izbor
pravilne terapije. Da bi se izbegli nesporazumi, ciljevi i očekivanja tretmana treba da se
uspostave i prodiskutuju sa vlasnikom pre primene terapije. Klinički simptomi hipoza
zavisnog hiperkorticizma koji je posledica mikroadenoma hipoze, mogu se kontroli-
sati adrenokortikosteroidom trilostanom. Međutim, ovaj lek neće uticati na sam tumor.
Iz tog razloga preporučuje se hipozektomija kod pasa kod kojih je uvećana hipoza,
a koji su u dobrom zdravstvenom stanju i kod kojih se očekuje da požive duži vremen-
ski period. Neoperativni tumori hipoze mogu da se tretiraju radioterapijom. Najbolja
terapija pasa sa adrenokortikalnim tumorima koji utiču na sekreciju kortizola, sastoji se
iz adrenalektomije. U slučaju da hirurški zahvat nije moguć ukoliko je tumor zahvatio
krvne sudove ili zbog metastatskog širenja tumora, preporučuje se primena mitotana.
Treba uzeti u obzir terapiju trilostanom,ali se u ovom slučaju radi samo o palijativnoj
terapiji: nema uticaja na adrenokortikalni tumor.
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Trilostane is the drug of choice to treat pituitary-dependent hyperadrenocorticism (PDH) in dogs, but there is still controversy about which protocol best controls the clinical signs and results of adrenal functioning test. To compare the efficacy of twice daily (BID) versus once daily (SID) trilostane administration and to compare the safety of both protocols in the treatment of dogs with PDH. Thirty-two client-owned dogs diagnosed with PDH between 2008 and 2010 and treated with trilostane either BID or SID. In this prospective randomized study, 2 trilostane protocols were evaluated on the basis of the owner's perception of clinical signs, on the results of laboratory tests, and on the results of the ACTH stimulation test in dogs with PDH. Dogs were followed up for a period of 1 year. During the study, more dogs in the BID group had complete clinical recovery than in the SID group. However, there was no significant difference in the mean post-ACTH cortisol concentration between groups. Basal cortisol concentration at 6 months was higher in animals treated SID compared with animals treated BID. Mean total daily doses of trilostane used to control PDH, as well as adverse effects observed in the course of the study, in both groups were not statistically different. Adverse effects were mild using either protocol of treatment. Using trilostane BID might increase the number of dogs with a good clinical response compared with using trilostane SID.
Article
This report offers a consensus opinion on the diagnosis of spontaneous canine hyperadrenocorticism. The possibility that a patient has hyperadrenocorticism is based on the history and physical examination. Endocrine tests should be performed only when clinical signs consistent with HAC are present. None of the biochemical screening or differentiating tests for hyperadrenocorticism are perfect. Imaging can also play a role. Awareness of hyperadrenocorticism has heightened over time. Thus, case presentation is more subtle. Due to the changes in manifestations as well as test technology the Panel believes that references ranges should be reestablished. The role of cortisol precursors and sex hormones in causing a syndrome of occult hyperadrenocorticism remains unclear.
Article
To report a technique for, and short-term outcome of unilateral laparoscopic adrenalectomy in dogs positioned in sternal recumbency without abdominal support. Experimental and prospective clinical study. Healthy dogs (n = 5) and dogs with unilateral adrenal gland tumor (n = 9). Anesthetized dogs were positioned in sternal recumbency with 2 cushions placed under the dog to elevate the chest and pelvic area so that the abdomen was not in contact with the surgical table allowing gravitational displacement of the abdominal viscera. Three 5-mm portals were located in the paralumbar fossa. Adrenal glands were carefully dissected and surrounding tissues sealed and cut using a vessel-sealing device. A retrieval bag or part of a surgical glove finger was used to remove the adrenal gland from the abdomen. Surgical time and complications were recorded, and short-term outcome assessed. Adrenal glands in normal dogs and unilateral adrenal tumors (8 left, 1 right) not involving the caudal vena cava in affected dogs were successfully removed laparoscopically. There were no major intraoperative complications. Of the dogs with adrenal tumors, 1 dog died within 24 hours of surgery from unrelated causes. Eight dogs recovered within 1 day and were discharged within 72 hours. Surgical times ranged from 42 to 117 minutes and were significantly shorter than those reported previously. Positioning anesthetized dogs in sternal recumbency with the abdomen suspended to facilitate gravitational displacement of the abdominal viscera improves access to, and visibility of, the adrenal gland for laparoscopic removal.
Article
A noninvasive method for quantifying adrenal gland vascular patterns could be helpful for improving detection of adrenal gland disease in dogs. The purpose of this retrospective study was to compare the contrast-enhanced ultrasound (CEUS) characteristics of adrenal glands in 18 dogs with pituitary-dependent hyperadrenocorticism (PDH) vs. four clinically healthy dogs. Each dog received a bolus of the contrast agent (SonoVue®, 0.03 ml/kg of body weight) into the cephalic vein, immediately followed by a 5 ml saline flush. Dynamic contrast enhancement was analyzed using time-intensity curves in two regions of interest drawn manually in the caudal part of the adrenal cortex and medulla, respectively. In healthy dogs, contrast enhancement distribution was homogeneous and exhibited increased intensity from the medulla to the cortex. In the washout phase, there was a gradual and homogeneous decrease of enhancement of the adrenal gland. For all dogs with PDH, there was rapid, chaotic, and simultaneous contrast enhancement in both the medulla and cortex. Three distinct perfusion patterns were observed. Peak perfusion intensity was approximately twice as high (P < 0.05) in dogs with PDH compared with that of healthy dogs (28.90 ± 10.36 vs. 48.47 ± 15.28, respectively). In dogs with PDH, adrenal blood flow and blood volume values were approximately two- to fourfold (P < 0.05) greater than those of controls. Findings from the present study support the use of CEUS as a clinical tool for characterizing canine adrenal gland disease based on changes in vascular patterns.
Article
Physical and emotional stresses are known to increase the production and secretion of glucocorticoids by the adrenal cortex in both humans and experimental animals. The urinary corticoid: creatinine (C:C) ratio is increasingly used as a measure of adrenocortical function. In this study we investigated whether a visit to a veterinary practice for vaccination, a visit to a referral clinic for orthopedic examination, or hospitalization in a referral clinic for 1.5 days resulted in increases of the urinary C: C ratio in pet dogs. In experiment 1, owners collected voided urine samples from 19 healthy pet dogs at specified times before and after taking the dogs to a veterinary practice for yearly vaccination. In experiment 2, 12 pet dogs were evaluated in a similar way before and after an orthopedic examination at a referral clinic. In experiment 3, 9 healthy pet dogs were hospitalized for 1.5 days and urine samples were collected before, during, and after this stay. Basal urinary C:C ratios in all experiments ranged from 0.8 to 8.3 × 10-6. In experiment 1, the urinary C:C ratio after the visit to the veterinary practice ranged from 0.9 to 22.0 × 10-6. Six dogs had a significantly increased urinary C:C ratio (responders), but in 5 of these dogs the ratio was ≤10 × 10-6 In experiment 2. 8 of 12 dogs responded significantly with urinary C:C ratios ranging from 3.1 to 27.0 × 10-6. In experiment 3, 8 of 9 dogs had significantly increased urinary C:C ratios, ranging from 2.4 to 24.0 × 10-6, in some or all urine samples collected during hospitalization. In 4 dogs urinary C:C ratios 12 hours after hospitalization were still significantly higher than the initial values. Thus, a visit to a veterinary practice, an orthopedic examination in a referral clinic, and hospitalization can be considered stressful conditions for dogs. A large variation occurs in response, and in individual dogs the increases in urinary C:C ratios can exceed the cutoff level for the diagnosis of hyperadrenocorticism. Therefore, urine samples for measurement of the C: C ratio in the diagnosis of hyperadrenocorticism should be collected in the dog's home environment, to avoid the influence of stress on glucocorticoid secretion.