Download FELINE ACROMEGALY Acromegaly was once described as a rare

FELINE ACROMEGALY
Acromegaly was once described as a rare disease in cats but that observation is no longer the case. In fact
the journey of acromegaly could be summarized as a “rarely diagnosed freak of nature disease with an
extreme phenotype to a relatively common explanation for diabetes mellitus seen in general practice”.
GENERAL DESCRIPTION
The cause of feline acromegaly is chronic hypersecretion of growth hormone (GH) by a functional
adenoma of the pituitary gland. This syndrome is characterized by insulin-resistant diabetes mellitus and
progressive overgrowth of soft tissue, membranous bone, and viscera. Acromegaly develops in middleaged to older cats without an obvious breed predilection although there is a strong male sex predilection
(approximately 70% of cats are male).
The earliest clinical signs of feline acromegaly include progressive polyuria, polydipsia, and polyphagia,
all of which are associated with poorly controlled or insulin-resistant diabetes mellitus. Additional clinical
findings may occur weeks to months after development of diabetes; these include enlargement of one or
more organs (i.e., heart, liver, kidneys, spleen, and tongue), progressive increase in body size and weight,
disproportionate enlargement and thickening of the head and paws, prognathia of the lower jaw,
nephropathy associated with renal failure, degenerative arthropathy, and central nervous signs caused by
enlargement of the pituitary tumor.
UPDATE ON PREVALANCE
In 2007, initial studies by Niessen et al in the UK proposed that feline acromegaly was a relatively
common cause of diabetes mellitus with a reported prevalence rate of ~ 30%. Since that time, two further
studies have been conducted. One study was performed among first opinion veterinarians in Switzerland
and the Netherlands. Participants were asked to provide blood samples from diabetic cats treated with
insulin for at least 4 weeks. Of the 225 cats entered into this study, 17.8% had a serum IGF-1
concentration > 1000 ng/ml which was considered suggestive of acromegaly. This new data confirmed
that acromegaly likely represents a frequently encountered underlying etiology for diabetes mellitus in
cats seen in primary practice. The data also suggested the potential for geographical differences.
The second new prevalence study represented an extension of the 2007 Niessen et al study and is by far
the largest screening study conducted to date. Fructosamine determination in diabetic cats was offered at
no cost to first opinion veterinary practices throughout the UK. Spare serum was used to measure IGF-1
levels, and if found to be > 1000 ng/ml, a free contrast-enhanced pituitary computed tomography (CT)
was offered. In total, 1222 diabetic cat samples were submitted whereby IGF-1 measurement suggested
possible acromegaly (>1000 ng/dl) in 323 cats (26.4%). CT confirmed acromegaly in approximately 90%
of patients with IGF-1 values > 1000 ng/ml, once again making the point that serum IGF-1 elevations at
this level are reasonably specific for establishing the presence of hypersomatotropism (HS).
The scientific debate about the exact prevalance of feline acromegaly is currently ongoing and remains
interesting. Differences might relate to the use of different IGF-1 assays, recruitment methods, and
geographical influences. Nevertheless, from a clinical point of view, the outcome of such a debate will
not change the overall message from all these studies conducted in the last decade – feline acromegaly
should be considered as a relatively common cause of diabetes mellitus in the cat.
UPDATE ON POSSIBLE CAUSES OF FELINE ACROMEGALY
As with many endocrine cancers the exact cause of human and feline acromegaly remains to be
determined. Nevertheless, work is currently ongoing to help understand the triggers for pituitary
oncogenesis in both species.
Organohalogenated contaminants (OHCs) have been implicated in pituitary oncogenesis in rodent
models. OHCs include organochlorine pesticides, industrial chemicals such as polychlorinated biphenyls
(PCBs) and brominated flame retardants (BFRs) such as polybrominated diphenyl ethers (PBDEs). Both
cats and humans are exposed to such chemicals through a multitude of routes including food and water
contamination mainly through dust ingestion; this is especially relevant in light of cats’ grooming
behavior. It has therefore been hypothesized that companion animals may serve as sentinals to assess the
relationships between human exposure to chemicals via indoor environments and adverse health effects.
Such a comparison can be drawn to feline hyperthyroidism where a similar link has been suggested
between its emergence and presence of OHCs in domestic materials and/or food.
In a recent study, plasma levels of OHCs were compared between elderly cats without an identifiable
endocrinopathy, cats with primary diabetes mellitus, and cats with secondary diabetes mellitus as a
consequence of acromegaly. Significantly higher levels of OHCs, particularly the PBDE levels (the
brominated flame retardants), were observed in the cats with acromegaly. Additional analysis of the
metabolites of these chemicals suggested that acromegalic cats may have a lower capacity to metabolize
these chemicals. Because PCBs have been linked to pituitary growth hormone adenomas in humans, it has
been hypothesized that a causal relationship may exist between excess OHCs and their metabolites and
pituitary oncogenesis in the cat.
Apart from environmental factors, the role of genetic factors in the role of feline acromegaly is also being
currently investigated. A particular gene of interest is the aryl hydrocarbon receptor interacting protein
(AIP) gene. Previously, human adenomas were widely considered to be monoclonal in origin – a single
cell acquired somatic mutation was responsible for tumor growth. However, more recently, mutations of
the AIP gene has been associated with up to 40% of spontaneous somatotropinomas in humans (49
sequence variations have been identified). Human AIP mutation positive acromegalics are known to
develop growth hormone secreting tumors at a younger age and have a larger tumor size than other
acromegalics. In addition, AIP gene positive somatotropinomas are known to cause more extreme GH
secretion compared to non-AIP mutated somatotropinomas and respond less well to medical management.
Of interest, is that AIP mutations are linked to faulty metabolism and accumulation of OHCs.
The research group at the Royal Veterinary College (RVC) in London has now sequenced the feline AIP
gene and is currently screening for AIP mutations in cats coming through the RVC Acromegalic Cat
Clinic. This work is designed to shine light on the role of AIP-gene alterations in feline acromegaly. To
date, approximately 25% of the cats diagnosed with acromegaly are positive for the AIP gene.
UPDATE ON THE EXPECTED PHENOTYPE
The largest case assessment to date included 323 cats with suspected acromegaly. Of these cats, 70%
were neutered males with a mean age of 11.3 years (range: 4-19 years), and most were DSH cats (87%),
although a variety of breeds were affected including Maine Coon Cats (2%).
An interesting aspect of this study was that clinicians were asked to indicate whether they suspected
acromegaly at the time of submission of the blood sample for fructosamine quantification. Of all the
submitting clinicians, only 24% strongly suspected acromegaly in the cases where the IGF-1 level was
subsequently shown to be > 1000 ng/ml. This study confirmed earlier observations from the Niessen at al
2007 study that suggested historical and phenotypical clues are rarely convincingly present, and validates
the controversial practice of screening newly diabetic cats for the presence of hypersomatotropism. It also
suggests it is more appropriate to use the term hypersomatotropism (HS), and not acromegaly, the latter
indicating a syndrome which includes phenotypical changes which do not appear consistently.
When looking at a cat with HS in more detail and with more advanced imaging methods, more subtle
clues can be spotted giving away the possible presence of this endocrinopathy. Apart from the presence of
a pituitary tumor on CT imaging of the cranium in the majority of cats, assessing 3-dimentional surface
rendered CT images, cats with HS have significantly thicker skull bones, and thicker skin and subcutis
than unaffected cats. In addition, the nasopharynx was found to be narrower in cats with HS than in
control cats which may explain the relatively high incidence of respiratory stridor (53%). Nevertheless, all
these changes would be difficult to spot with the naked eye, which is similar to the experience with
human acromegaly. In summary, the presence of physical changes might increase the clinical suspicion of
HS, although their absence does not rule out HS in the diabetic cat.
UPDATE ON DIAGNOSTIC TOOLS
Serum IGF-I determinations: In man, determination of circulating concentrations of the polypeptide
hormone, insulin-like growth factor-1 (IGF-1), is a very useful diagnostic test for acromegaly, as well as a
test proven to have many advantages over measuring basal GH concentrations alone. In contrast to the
highly pulsatile and fluctuating circulating GH concentrations, serum IGF-1 values remain relatively
constant throughout the day due to the peptide’s long-half life. The basis for use of IGF-1 as a diagnostic
test for acromegaly is that circulating GH activates the hepatic and peripheral tissue production of IGF-1,
which is responsible for many of the actions normally attributable to GH itself. In fact, other than diabetes
mellitus, most of the clinical features of acromegaly are not the result of a direct catabolic effect of GH
excess, but rather, result from an indirect anabolic effect of GH excess mediated through the production
of the IGF-1 (e.g., overgrowth of soft tissue, bony enlargement, and organomegaly). Therefore,
circulating IGF-1 levels serve as a biomarker for assessing the peripheral biological effect of GH
hypersecretion, which, at least in human patients, tend to correlate better with the severity of the
acromegalic state than does random circulating GH determinations.
For most veterinarians serum IGF-1 assessment is the most feasible and accessible means for screening
for HS in the diabetic cat, especially since GH assays remain difficult to access commercially, despite
their potential value. However, because hepatic IGF-1 production is dependent on the presence of
sufficient portal insulin, it can be deficient in newly diagnosed diabetic cats, resulting in false negative
results. Additionally, false positive results have been reported in non-acromegalic diabetic cats. And
finally, differences in performance of IGF-1 assays exist. Because of these short-comings, alternative, or
additional diagnostic tests for HS, as well as to evaluate the success of treatment are therefore desirable.
Serum procollagen propeptide. Since feline HS is associated with tissue growth, serum procollagen
type III procollagen propeptide (PIIIP), a peripheral indicator of collagen turnover, was recently shown to
be a useful indicator of growth hormone activity in the cat. Median PIIIP activity was five times higher in
HS-induced diabetic cats compared to cats with primary diabetes mellitus. There was also a significant
correlation between serum IGF-1 and PIIIP. Given that PIIIP is not dependent on portal insulin
availability, this parameter could prove useful, perhaps as part of a panel, to increase the possibility of
reliably diagnosing feline HS without the explicit need for intra-cranial imaging.
Serum Ghrelin. Ghrelin is a peptide that is a growth hormone secretagogue that stimulates appetite. It
has been shown to be down-regulated in humans with HS, while it increases following successful therapy.
Serum ghrelin was shown to be significantly higher in control cats compared to cats with HS-induced
diabetes mellitus. Disappointingly, the latter group had similar concentrations as those cats with regular
diabetes mellitus, rendering this test not useful in the initial diagnostic phase. However, it was shown that
serum ghrelin levels increased significantly in cats with HS-induced diabetes post-radiotherapy, while
IGF-1 levels were not significantly altered. This suggests a possible role for serum ghrelin as a marker of
treatment effect.
Computed tomography beyond the pituitary gland. Although intra-cranial imaging is most often used
to prove or disprove the presence of pituitary enlargement, CT or MRI has a role beyond mere assessment
of pituitary morphology. As previously mentioned, useful hints of HS can be found when looking for the
presence or absence of prognathia inferior, presence of TMJ malformation, increased thickness of the
calvarium bone, subcutis, and skin. However, relying on these changes is not without its problems such as
the disease’s gradually progressive nature and individual/breed variations in head conformation.
UPDATE ON MOST EFFECTIVE TREATMENT MODALITIES
Hypophysectomy. With increasing experience of using hypophysectomy to definitively treat feline HS,
this procedure constitutes the gold-standard treatment option provided there is no contraindication.
Contraindications can include excessive tumor size, significant co-morbidities that prevent safe anesthesia
and post-operative recovery (eg, significant renal or cardiovascular disease), or an owner that is
completely risk-averse. The initial financial commitment is another obstacle, although it is important to
realize that a year of ineffective insulin treatment or radiotherapy could have similar cost implications. At
the RVC Hypophysectomy Clinic in London, approximately 80% of the cases will enter diabetic
remission within 1 month after surgery. The peri- and post-operative mortality rate is currently 15%,
which is acceptable to most owners given the paucity of equally effective treatment modalities. Postoperatively, the cats are treated with a low dose of hydrocortisone and L-thyroxine for life and DDAVP,
which can be discontinued in most (80%) cats.
Medical management. Medical treatment options remain desirable although somatostatin (sst) analogs
and dopamine agonists have thus far proven largely ineffective. Pasireotide (SOM230), a novel multireceptor ligand sst receptor analog with high-binding affinity for sst receptor subtypes 1,2,3 and 5 has
been shown to suppress GH and IGF-1 in diabetic cats with HS. All eight cats treated with BID injections
of a short-acting preparation showed a significant decrease in IGF-1, average 12-hour blood glucose
determinations, and insulin requirements. Unfortunately the cost of the short-acting form of this drug
(Signifor, Novartis, Basel, Switzerland) is considerable. A long-acting release (LAR) formulation has also
been recently developed and has been recently marketed for humans. This once monthly formulation was
tested for 6 months in 12 diabetic cats with HS; a significant decrease in IGF-1, insulin dose and
fructosamine was noted. A quarter of the cats went into diabetic remission, although 5 cats were retracted
from the study because of the lack of sufficient effect or mild adverse reactions (particularly diarrhea).
Update on radiotherapy. Radiotherapy was initially touted to be the best therapy for feline HS,
however, even with the advent of stereotactictical or gamma-knife radiotherapy, this treatment modality
does not rival the results of hypophysectomy. The effect of radiotherapy remains unpredictable in terms
of whether it will occur at all, when it will occur, to what extent it will make a difference in insulin
requirements, and how long will it last. Lack of response in terms of normalizing IGF-1 levels casts
further doubt over its efficacy even in those cases with reduced insulin requirements. However,
radiotherapy still serves a valuable purpose, especially in cases where there is a large pituitary tumor or
other contraindications for hypophysectomy.
References available upon request