Feline Acromegaly
Tanya Schoeman BVSc(Hons)MMedVet(Med) Dipl ECVIM-CA
Cape Animal Medical Centre, 78 Rosmead Avenue, Kenilworth, Cape Town
Abstract
Feline acromegaly is more common in cats than once thought. This article
emphasises the importance of being open to this diagnosis, particularly in
diabetic cats. Some cats do not demonstrate the physical changes associated
with this disease. Although these changes remain important disease markers,
they are not required to pursue the diagnosis of acromegaly. In addition,
acromegaly can cause significantly diminished quality of life from insulin
resistance and poorly regulated DM, as well as concurrent problems (eg,
congestive heart failure).
Definition
Hypersomatotropism represents the excess production of growth hormone
(GH). Most cases of feline acromegaly are caused by a functional benign
pituitary tumour originating from the acidophilic cells in the pars distalis of the
anterior pituitary. In addition rare cases of pituitary hyperplasia have been
reported. This is in contrast to the situation in dogs, where it occurs as a
consequence of dioestrus-induced GH production by the mammary gland.
Acromegaly refers to a clinical syndrome as a result of the
hypersomatotropism, which includes the physical changes that occur in the
patient when exposed to the excess GH over a longer period of time.
However, these classical acromegalic features take time to appear and are
therefore not consistently present in our feline patients. Technically it is
therefore better to use the term hypersomatotropism (overactivity of
somatotrophs or GH producing cells), which might or might not result in the
complete syndrome of acromegaly. Admittedly, both terms are however often
used interchangeably, with acromegaly being the more popular term.
Significance
Acromegaly was previously thought to be rare and therefore usually featured
only infrequently or sparsely during the basic training of veterinarians. This
has changed very recently in light of studies revealing that its prevalence
amongst diabetic cats is higher than expected. Since that time, screening
diabetic cats for acromegaly or hypersomatotropism has increased and it has
become evident that it is a rather common cause for diabetic cats to become
diabetic in the first place, as well as being difficult to control once diabetes
mellitus (DM) has occurred. Prevalence of acromegaly amongst diabetic cats
in North America and the UK was found to be around 1 in 4 diabetic cats seen
in primary practice. The disease is therefore likely currently under diagnosed.
The prevalence amongst non-diabetic cats is currently unknown although
these cats would be expected to become diabetic in the long run. On the
basis of this high prevalence and the significant clinical implications of missing
the diagnosis, it is important for veterinarians to at least consider offering to
screen diabetic cats for this disease.
Pathogenesis and clinical signs
Although many of the physical changes associated with acromegaly take
several months to (more often) years to appear, diabetes mellitus will be one
of the very first (or often only) things to be noticed. The youngest cat
described to date was 6 years of age, although the average age of an
acromegalic cat is approximately 11 years. Like regular diabetic cats,
acromegalic cats are more often male than female. Body condition can range
from normal to being overweight and an average body weight of 5.8kg was
found in a large cohort of acromegalic cats. This is of particular interest, since
typical diabetic cats with poorly controlled DM would show weight loss.
Therefore gaining weight despite suboptimal glucose control should alert
clinicians on the possible presence of hypersomatotropism.
Most described cats have been domestic short hair cats, although a range of
other breeds has also been known to suffer from the disease. The insulin
requirements of an acromegalic cat will ultimately likely be higher than an
average non-acromegalic diabetic. In fact, some acromegalic cats need an
extraordinarily high insulin dose and still show a poor response to therapy. A
group of 59 acromegalics was found to be treated with an average of 7 iu BID,
but with some cats receiving as much as 35 iu BID. The reason for the insulin
resistance observed in these patients relate to the excess GH that has a
range of anabolic and catabolic effects on a cat. One of the most noticeable
effects of excess GH is that it decreases insulin sensitivity through a postreceptor defect in insulin action at the level of target tissues and through this
mechanism will cause the, often insulin-resistant, DM. Polyuria and polydipsia
are often reported due to uncontrolled diabetes mellitus, as well as
polyphagia. Interestingly, the polyphagia can be reported to be extreme,
possibly related to both the indirect effect of uncontrolled diabetes,
compounded by the direct effects of GH on appetite. In fact, the polyphagia
can be so extreme that owners perceive it to be one of the main, or even the
main quality of life affecting signs.
GH induces the production of a peptide called insulin-like growth factor-1
(IGF-1), predominantly by the liver. Acromegalic cats will therefore also have
excess circulatory IGF-1, which has additional anabolic effects. As a result,
after long-term exposure to excess GH and IGF-1, patients can suffer from
excessive tissue growth and deformations of internal and/or external organs,
which may include broad facial features, big (so-called ‘clubbed’) paws,
cranial abdominal organomegaly and prognathia inferior (protrusion of the
mandible). Some cats will show the classic enlargement of extremities, body
size, jaw, tongue, and forehead that is characteristic of acromegaly in people.
Gross necropsy findings in acromegalic cats may include a large expansile
pituitary mass, hypertrophic cardiomyopathy with marked left ventricular and
septal hypertrophy (early) or dilated cardiomyopathy (late), hepatomegaly,
renomegaly, degenerative joint disease, lumbar vertebral spondylosis,
adrenocortical hyperplasia, and (most commonly) diffuse enlargement of the
pancreas with multifocal nodular hyperplasia.
Neurological signs (blindness, seizures, circling) due to a gradually expanding
pituitary tumour can rarely occur. This is however uncommon as the tumours
tend to be benign and slow growing.
Auscultation may reveal a systolic cardiac murmur or gallop rhythm or
respiratory changes due to congestive heart failure or referred upper
respiratory stridor (due to an increase in oropharyngeal tissue and thickening
of the soft palate). Hypertension is an irregular finding. The question whether
cardiovascular complications are genuinely more common in acromegalic cats
compared to age matched controls is still under investigation.
It has been shown that when a more proactive approach is chosen and one
screens for acromegaly amongst diabetic cats, a large proportion of cases will
in fact look like any other regular diabetic cat. Clinical management of their
diabetes will usually however prove more difficult.
Diagnosis
1. Clinical picture
No one single test proves without doubt that acromegaly is present.
Suspicious clinical signs include polyuria, polydipsia, polyphagia, weight gain,
upper respiratory stridor, broad facial features, prognathia, organomegaly and
clubbed paws. Particular attention should be paid to the presence of signs not
typically seen in a regular diabetic, including weight gain despite lack of
control and presence of insulin resistance. However, since these clinical signs
are not consistently present, one could argue that a screening test for
acromegaly should be run in every diabetic feline. Acromegaly should
definitely be considered in any diabetic cat with insulin resistance (requiring a
dose of >1.5 IU/kg).
2. Endocrine testing
Feline growth hormone (fGH; serum and plasma) and IGF-1 (serum) have
been shown to be useful screening tests, although both false positive and
false negative results have been reported when using either test. A suggested
growth hormone cutoff value of 10 ng/mL was shown to result in an
acceptable specificity of 95% and sensitivity of 84% when using the fGH
assay recently developed at the Royal Veterinary College in London. Feline
GH also appeared relatively stable, allowing overnight transport of
unseparated samples. Unfortunately fGH determination is currently not
commercially available (although this should change soon).
Documenting an elevated IGF-1 concentration (>1000 ng/ml) is useful as a
screening test, but it merely tells us that further confirmatory testing is
required. If the IGF-1 is normal, yet the animal clinically still fits the picture of
acromegaly, it will be wise to repeat the IGF-1 measurement after 6-8 weeks.
It is important to note that hepatic IGF-1 production is dependent on presence
of insulin in the portal circulation, as hepatic IGF-1-production is induced via
stimulation of insulin-dependent hepatic GH-receptors. This means that in
some diabetic cats that have beta-cell dysfunction and therefore
hypoinsulinemia, IGF-1 will be lower and presence of acromegaly can be
masked when using IGF-1 as a screening test. When we re-test the IGF-1
after 6-8 weeks of exogenous insulin therapy the true IGF-1 value will be
detected which might prove higher. Combining IGF-1 and fGH determination
should significantly increase diagnostic accuracy, although we have to await
the commercialisation of a GH assay.
Given the potential for both false positives and false negatives with either GH
or IGF-1 assessment and the need for confirmatory intracranial imaging,
research is currently ongoing to evaluate alternative biomarkers for feline
hypersomatotropism. Because hypersomatotropism is associated with tissue
growth, serum type III procollagen propeptide (PIIIP), a peripheral indicator
of collagen turnover, has recently been shown to be elevated in cats with
hypersomatotropism. A PIIIP concentration greater than 8 ng/mL was shown
to be 100% specific for a diagnosis of hypersomatotropism, with a sensitivity
of 75%.
Serum ghrelin, an endogenous ligand of the GH secretagogue receptor and
therefore susceptible to negative feedback in a state of hypersomatotropism,
has thus far not been found useful in differentiating diabetes from
hypersomatotropism-induced diabetes, despite such suggestions in human
hypersomatotropism.
The glucose suppression test (measuring GH before and after administration
of glucose) is a gold standard test in the diagnosis of human hypersomatotropism, although little evidence in favour of its use in feline
hypersomatotropism has as yet been published.
3. Intra-cranial imaging
After having detected an elevated IGF-1 and/or fGH in a diabetic cat
hypersomatotropism becomes a genuine possibility and confirmatory testing
is indicated. Intracranial imaging (with contrast enhancement) has been
proven useful in confirming the presence of hypersomatotropism, with MRI
probably more sensitive than CT.
If a structural pituitary abnormality is documented, this provides further
circumstantial evidence for the presence of hypersomatotropism, especially
if there are concurrent increases in frontal bone thickness and/or evidence of
soft tissue accumulation in the nasal cavity, sinuses and pharynx.
However, the demonstration of a pituitary tumour as such does not provide
differentiation from a non-functional pituitary tumour or pituitary dependent
hyperadrenocorticism (PDH), especially because pituitary tumours are a
relatively common type of brain tumour in the cat.
Cases with a negative CT and/or MRI have also been documented, with the
diagnosis eventually being confirmed on post mortem examination. Cases
with subtle (microscopic) acidophilic hyperplasia or microadenoma, instead
of obvious (macroscopic) adenoma, might more likely show negative
intracranial imaging.
In conclusion, pituitary imaging is too expensive and too invasive (sedation or
anaesthesia needed) to be considered suitable as a screening test, and is
ideally used as an attempt to confirm the disease or for preradiation or presurgical planning. Refinement of our hormonal assessment methods and
increasing availability of assays probably constitutes the best way to improve
the diagnosis of hypersomatotropism.
Differential diagnosis
Since hyperadrenocorticism can also cause insulin-resistant diabetes mellitus,
weight gain despite uncontrolled diabetes mellitus (although weight loss is
more common with hyperadrenocorticism) and adrenomegaly and can also be
associated with a pituitary tumour on CT or MRI, potential exists for
misdiagnosis. Differentiation will be made extra difficult in light of all pituitaryadrenal function tests being vulnerable to rendering false positives in ill and
stressed animals. Interestingly, urine cortisol:creatinine ratios will often be
elevated in acromegalic cats as well. The differentiation will usually be
possible though through paying attention to specific clinical differences
between the two endocrinopathies; acromegaly: broad facial features, clubbed
paws, arthropathy, prognathia inferior, particularly severe insulin resistance;
hyperadrenocorticism: frail skin, fur changes, bruising, less severe insulin
resistance). Additionally, fGH and IGF-1 results are expected to be different.
In some cases a low-dose dexamethasone suppression test (LDDST; often
preferred over an ACTH stimulation test in cats) helps deciding if
hyperadrenocorticism is likely.
Treatment
The main aim of treatment is to improve the quality of life of the patient. As
such, different pet-owner combinations may require a different treatment
option.
Treatment options for hypersomatotropism consist of medical treatment,
surgical options, radiotherapy or palliative treatment. When definitive
treatment is instituted, clinicians and owners need to be vigilant for rapid
changes in insulin demands should the treatment prove effective. Iatrogenic
hypoglycemia is frequently encountered and home blood glucose
measurement should be considered.
Medical treatment
In contrast to the situation in human hypersomatotropism, medical treatment
options aimed at inhibiting the pituitary have not proven very successful in the
cat thus far. Previously tested dopamine agonists and somatostatin
analogues, including long-acting formulations such as lanreotide and
sandostatin, have not resulted in detectable clinical improvement.
Nevertheless, a novel somatostatin analogue Pasireotide (Novartis) has
been tested recently in a phase 2 clinical trial and found to be effective,
leading to insulin dose reduction in all cats, decreases in IGF-1 and even
diabetic remission in 25% of cases when using a once monthly preparation.
However,
somatostatin treatment was also associated with gastro-intestinal side effects
in a significant number of cats, including diarrhoea, rendering this not a
miracle solution, especially when considering its considerable expense and
the fact that the pituitary tumour is left in place.
(Stijn Niessen, DVM, PhD, DipECVIM, personal communication, 2012).
Surgical treatment
Hypophysectomy is the treatment of choice in many human acromegaly
sufferers as well as many of our feline patients. It will result in instant near
complete removal of the pituitary tumour, as well as fast and complete
normalisation of GH levels with a high chance of achieving diabetic remission.
After decades of this procedure being available only in the Netherlands,
transphenoidal hypophysectomy has in recent years become available also in
the United Kingdom (London), United States (California), and Japan. Analog
to the situation in human medicine, success rates are strongly correlated with
the experience of the surgeon, as well as the availability of high-quality
intensive postoperative care. Post-operatively the cats should be managed
with once daily oral prednisolone (0.1 mg/kg/d) or hydrocortisone (0.5
mg/kg/d) and thyroid hormone supplementation. A minority also needs daily
DDAVP administration (ADH replacement) in an ocular preparation. The
induced diabetes insipidus seems only temporary in nature in most patients,
whereas secondary hypocortisolism and secondary hypothyroidism require
lifelong supplementation.
Glucose concentrations must be very closely monitored, because severe
clinical hypoglycemia can ensue in patients as soon as the first week after
surgery. A number of cases have been published; all showing diabetic
remission rates within 4 weeks after surgery. This further substantiates that
early diagnosis and subsequent immediate and effective intervention
increases the chance for complete diabetic remission hugely, given that
sufficient beta-cell function will still be present.
On the basis of these results, hypophysectomy has become the treatment of
choice for feline acromegaly, unless the tumor is rather large or there are
specific reasons for the procedure to be too dangerous in a particular patient.
Radiation therapy
The primary aim of the radiotherapy is to reduce GH production to levels that
are no longer clinically significant whilst at the same time reducing the size of
the tumour. Unfortunately radiotherapy is actually better at reducing the size
of the tumour than normalising excess hormone secretion. Nevertheless, it
can lead to improved control of the diabetes mellitus and even diabetic
remission in a proportion of patients. A significant disadvantage is the fact that
the treatment’s effect is impossible to predict in terms of degree (no response,
partial response, complete response), time of onset (within weeks, after a
year or never) and duration (temporary or permanent). Other disadvantages
with most protocols include the need for several anaesthetics with associated
risks and associated hospitalisations and costs, therefore making it unsuitable
for a significant proportion of owners and pets.
Palliative treatment
Risk-averse owners might opt for the most conservative route. This route
ignores the underlying disease mechanism and focuses on gaining more
control of the diabetes mellitus and treating possible co-morbidities.
Twice daily or sometimes even more frequent long-acting insulin injections
might help reduce the levels of polyuria and polydipsia in some cases.
However, obtaining good glycemic control often proves impossible using this
approach and high doses of insulin will be needed. Nevertheless, if more
definitive treatment options are not available or declined, it remains an option
to explore. Finding the appropriate insulin dose is an empirical process;
dosage increases are implemented until satisfactory clinical improvement is
achieved according to improvement in fructosamine, a series of blood glucose
curves and clinical signs associated with the diabetes mellitus. Sometimes
more intense insulin therapy is required to bring the diabetes under control.
This could include the use of more intense subcutaneous insulin regimes
including using combinations of long-acting insulin twice daily and short-acting
insulin preparations (soluble insulin) at the time of each meal, as well as
feeding four to five times daily to limit blood glucose undulations.
Treating complications and co-morbidities
No matter which treatment modality is chosen, acromegaly-associated
complications and co-morbidities need to be attended to in order to ensure a
maximal quality of life. Analgesia should be provided to all cats in case of
arthropathies, while angiotensin converting enzyme (ACE)-inhibitor, diuretic
treatment and regular veterinary assessments are required if heart failure
occurs.
Prognosis
When left unattended, quality of life will be negatively affected in a chronic
and slowly progressive fashion in feline hypersomatotropism. Traditionally a
guarded to poor prognosis has been suggested, but advances in the
treatment of feline hypersomatotropism, especially in terms of increased
availability of hypophysectomy and identification of effective somatostatins,
will likely lead to modification of expected life expectancy and life quality
expectations. When effective treatment is initiated early enough, an improved
quality of life and even diabetic remission can be achieved.
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