Stijn Niessen

Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus : a clue for endocrine disruption in humans?

It was recently hypothesized that pets may serve as sentinels to explore human exposure to organohalogenated chemicals (OHCs) via indoor environments and adverse health effects. The current study investigates OHCs contamination in domestic cats suffering from diabetes mellitus (DM), particularly DM induced by acromegaly and a form of DM akin to human type 2 DM (T2DM). Plasma from three groups of domestic cats was analyzed: acromegaly induced DM, T2DM and age matched control cats without DM. Analytes targeted included organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs), together with their hydroxylated (HO-) metabolites. Similar PCB profiles were measured in cat plasma compared to humans, while the PBDE profile (dominated by BDE-99 (48%-55%) and BDE-47 (19%-25%)), the PCB and PBDE metabolite profiles were different in cat plasma than found in humans. Significantly higher OHC concentrations were recorded in plasma of acromegalic cats compared to the other two groups. Group differences in the PCBs/HO-PCBs ratios suggest that acromegalic cats have a lower capacity to metabolize persistent OHCs, like PCBs, than diabetic cats or cats without an endocrinopathy. As pituitary tumorigenesis in animals can be induced by estrogens, and PCBs may act as xenoestrogens, further investigation into whether there could be a causative link with the induction of feline acromegaly is warranted. Interestingly, BDE-47/BDE-99 ratios in cats were similar to the ratios in house dust. The results of this study suggest that domestic cats may represent a good model to assess human exposure to chemicals present in indoor dust.

Validation and application of a radioimmunoassay for ovine growth hormone in the diagnosis of acromegaly in cats

The validity of an ovine growth hormone (ogh) assay for the detection of feline growth hormone (fgh) was demonstrated by the parallel displacement of radiolabelled ogh by standard concentrations of ogh and serial dilutions of pooled fgh-rich serum. The minimum detectable limit of the assay was 1·67 μg/l. The mean (sd) basal fasting fgh level in 19 non-acromegalic, non-diabetic cats aged two to 16 years was 4·01 (1·38) μg/l (range 1·87 to 6·33); 19 acromegalic cats had significantly higher fgh levels (range 8·45 to 33·2 μg/l). There were no significant differences in the fgh levels measured when aprotinin was added to the samples or when plain serum and serum gel separation tubes were used for blood collection, but the fgh levels were significantly higher when the samples were collected into edta. There were also no significant differences between the concentrations of fgh measured in samples in which the separation of the serum and storage had been delayed by 24 hours, or in samples that had been stored for up to four weeks at −20°C.

Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus

When confronted with a diabetic cat in clinical practice, it is tempting to assume it has a form of diabetes mellitus akin to human type 2 diabetes mellitus (diabetes). For most diabetic cats examined, this will indeed be justified. Nevertheless, a significant proportion have other specific types of diabetes with distinctly different etiologies. This article discusses the concept of other specific types of feline diabetes caused by endocrinopathies, and more specifically feline hypersomatotropism, acromegaly, and hyperadrenocorticism, including relevance, presentation, diagnosis, and therapy.

Systematic review of feline diabetic remission: Separating fact from opinion

It is increasingly recognised that diabetic remission is possible in the cat. This systematic review, following Cochrane Collaboration (CC) guidelines, critically appraises the level of evidence on factors influencing remission rate and factors predicting remission. A systematic online, bibliographic search and reference list examination was conducted. A level of evidence was assigned to each identified article by five internists using the Newcastle-Ottawa Scale for follow-up, cohort, case-series and case-control studies, the CCs risk of bias tool for trials and the Cochrane Effective Practice and Organisation of Care Group risk of bias criteria for before and after trials. Twenty-two studies were included in the review, assessing influence of pharmaceutical intervention (n = 14) and diet (n = 4), as well as diagnostic tests (n = 9) and feline patient characteristics (n = 5) as predictors of remission. The current level of evidence was found to be moderate to poor. Common sources of bias included lack of randomisation and blinding among trials, and many studies were affected by small sample size. Failure to provide criteria for the diagnosis of diabetes, or diabetic remission, and poor control of confounding factors were frequent causes of poor study design. Addressing these factors would significantly strengthen future research and ultimately allow meta-analyses to provide an excellent level of evidence. No single factor predicts remission and successful remission has been documented with a variety of insulin types and protocols. Dietary carbohydrate reduction might be beneficial, but requires further study. A lack of well-designed trials prevents reliable remission rate comparison. Factors associated with remission resemble those in human medicine and support the hypothesis that reversal of glucotoxicity is a major underlying mechanism for feline diabetic remission.

Computed tomographic signs of acromegaly in 68 diabetic cats with hypersomatotropism

In order to describe the signs of acromegaly in cats, a case-control study was done based on computed tomography (CT) scans of the heads of 68 cats with hypersomatotropism and 36 control cats. All cats with a diagnosis of hypersomatotropism had diabetes mellitus, serum insulin-like growth factor-1 >1000 ng/ml and a pituitary mass. Measurements of bones and soft tissues were done by two independent observers without knowledge of the diagnosis. Pituitary masses were identified in CT images of 64 (94%) cats with hypersomatotropism. Analysis of variance found a moderate effect of gender on the size of bones and a large effect of hypersomatotropism on the size of bones and thickness of soft tissues. In cats with hypersomatotropism the frontal and parietal bones were, on average, 0.8 mm thicker (P <0.001); the distance between the zygomatic arches was, on average, 5.4 mm greater (P <0.001); and the mandibular rami were, on average, 1.1 mm thicker (P <0.001) than in control cats. The skin and subcutis dorsal to the frontal bone were, on average, 0.4 mm thicker (P = 0.001); lateral to the zygomatic arch were, on average, 0.7 mm thicker (P <0.001); and ventral to the mandibular rami were, on average, 1.1 mm thicker (P = 0.002) in cats with hypersomatotropism than in control cats. The cross-sectional area of the nasopharynx was, on average, 11.1 mm2 smaller in cats with hypersomatotropism than in control cats (P = 0.02). Prognathia inferior and signs of temporomandibular joint malformation were both observed more frequently in cats with hypersomatotropism than in control cats (P = 0.03). Overall, differences between affected and unaffected cats were small. Recognising feline acromegaly on the basis of facial features is difficult.

Pasireotide for the Medical Management of Feline Hypersomatotropism.

Background Feline hypersomatotropism (HST) is a cause of diabetes mellitus in cats. Pasireotide is a novel multireceptor ligand somatostatin analog that improves biochemical control of humans with HST. Hypothesis/Objectives Pasireotide improves biochemical control of HST and diabetes mellitus in cats. Animals Hypersomatotropism was diagnosed in diabetic cats with serum insulin‐like growth factor‐1 (IGF‐1) concentration >1,000 ng/mL by radioimmunoassay and pituitary enlargement. Methods Insulin‐like growth factor 1 was measured and glycemic control assessed using a 12‐hour blood glucose curve on days 1 and 5. On days 2, 3, and 4, cats received 0.03 mg/kg pasireotide SC q12h. IGF‐1, insulin dose, and estimated insulin sensitivity (product of the area under the blood glucose curve [BGC] and insulin dose) were compared pre‐ and post treatment. Paired t‐tests or Wilcoxon signed rank tests were employed for comparison where appropriate; a linear mixed model was created to compare BGC results. Results Insulin‐like growth factor 1 decreased in all 12 cats that completed the study (median [range] day 1: 2,000 ng/mL [1,051–2,000] and day 5: 1,105 ng/mL [380–1,727], P = .002, Wilcoxon signed rank test). Insulin dose was lower on day 5 than on day 1 (mean reduction 1.3 [0–2.7] units/kg/injection, P = .003, paired t‐test). The product of insulin dose and area under the BGC was lower on day 5 than day 1 (difference of means: 1,912; SD, 1523; u × mg/dL × hours, P = .001; paired t‐test). No clinically relevant adverse effects were encountered. Conclusions Short‐acting pasireotide rapidly decreased IGF‐1 in cats with HST and insulin‐dependent diabetes. The decrease in IGF‐1 was associated with increased insulin sensitivity.

X‐RAY ATTENUATION OF THE LIVER AND KIDNEY IN CATS CONSIDERED AT VARYING RISK OF HEPATIC LIPIDOSIS

X-ray attenuation of the liver has been measured using computed tomography (CT) and reported to decrease in cats with experimentally induced hepatic lipidosis. To assess the clinical utility of this technique, medical records and noncontrast CT scans of a series of cats were retrospectively reviewed. A total of 112 cats met inclusion criteria and were stratified into three hepatic lipidosis risk groups. Group 1 cats were considered low-risk based on no history of inappetence or weight loss, and normal serum chemistry values; Group 2 cats were considered intermediate risk based on weight loss, serum hepatic enzymes above normal limits, or reasonably controlled diabetes mellitus; and Group 3 cats were considered high risk based on poorly controlled diabetes mellitus due to hypersomatotropism. Mean CT attenuation values (Hounsfield units, HU) were measured using regions of interest placed within the liver and cranial pole of the right kidney. Hepatic and renal attenuation were weakly positively correlated with each other (r = 0.2, P = 0.03) and weakly negatively correlated with body weight (r = -0.21, P = 0.05, and r = -0.34, P = 0.001, respectively). Mean (SD) hepatic and renal cortical attenuation values were 70.7 (8.7) HU and 49.6 (9.2) HU for Group 1 cats, 71.4 (7.9) HU and 48.6 (9.1) HU for Group 2, and 68.9 (7.6) HU and 47.6 (7.2) HU for Group 3. There were no significant differences in hepatic or renal attenuation among groups. Findings indicated that CT measures of X-ray attenuation in the liver and kidney may not be accurate predictors of naturally occurring hepatic lipidosis in cats.

Screening diabetic cats for hypersomatotropism: performance of an enzyme-linked immunosorbent assay for insulin-like growth factor 1

Screening diabetic cats for feline hypersomatotropism (HS) is currently dependent on using a radioimmunoassay (RIA) for measurement of growth hormone or insulin-like growth factor 1 (IGF-1), both of which require radioactivity, are costly and have limited availability. Performance of an enzyme-linked immunosorbent assay (ELISA) using anti-human IGF-1 antibodies was assessed. Total IGF-1 was determined in diabetic cat samples across a wide range of IGF-concentrations using a previously validated RIA (serum: 92 cats; plasma: 31 cats). Repeat IGF-1 measurement was then performed using the ELISA-system. Mean IGF-1 recovery after serial dilution proved satisfactory with a correlation coefficient of 0.96 (serum) and 0.97 (plasma). Appropriate precision was established [intra-assay coefficient of variation (CV) 9.5 ± 2% (serum) and 13.6 ± 7% (plasma); inter-assay CV 11.4 ± 4% (serum) and 7.6 ± 6% (plasma)] and significant effect of hyperlipidaemia, haemoglobinaemia, bilirubinaemia and storage was excluded, with the exception of an increase in serum IGF-1 when left at room temperature for more than 24 h. ELISA concentrations correlated significantly with RIA concentrations (serum Pearson r2: 0.75; plasma: 0.83, P <0.001). Receiver operating characteristics analysis showed an area under the curve of 0.99 (serum) and 0.96 (plasma), and indicated high diagnostic accuracy for categorising a diabetic cat correctly as suspicious for HS at a serum IGF-1 cut-off of 997 ng/ml (sensitivity, 100%; specificity, 88.1%). The current study is the first to validate an easy-to-use and economical IGF-1 ELISA for the screening for HS among diabetic cats, which is important given the suspected significant prevalence of HS-induced diabetes mellitus.

Quality-of-life assessment: honouring our oath in practice and research.

There is a significant chance that before reading this article you have been involved in a conversation about the quality-of-life (QoL) of a companion animal. This conversation might have led to a certain treatment decision, a non-treatment decision or even a decision to perform euthanasia. However, were you certain about what you meant by the term “quality-of-life” when these words were used in conversation with the pet owner? Were you certain that the owner had an equal or at least similar understanding of the concept of QoL of their pet? Were you certain that the advised course of action would indeed lead to the best achievable QoL outcome? As clinicians we frequently talk about QoL, but what is it and how do we determine it? Surely, it is subjective or are there also objective areas and is it truly quantifiable? These are essential questions, which are directly connected to our veterinary oath to act in the interest of the health and welfare of the animals under our care. Oddly enough, investigation of these fundamental questions has so far been underrepresented in mainstream companion animal research. Instead, studies on novel treatment modalities or emerging diseases have vastly outnumbered studies on qualifying and/or quantifying companion animal QoL, both in (apparent) health and in disease. In the majority of studies, it is often automatically assumed that new or more advanced treatment options are de facto beneficial and in the interest of the companion animal’s and therefore also the owner’s QoL. Additionally, treatment impact has traditionally been measured using only quantifiable or “sterile parameters” such as survival rates or duration, or improvement in laboratory or physical parameters (e.g. body weight, heart rate, lymph node size, appetite). Treatment impact measurement in terms of QoL changes is rarely attempted. The lack of structured assessment of QoL could easily lead to incorrect assumptions. Several good examples of how it is possible to make the wrong QoL assumptions can be found within human medicine, where QoL has by now been structurally assessed for several decades and where it is logically seen as an outcome in its own right (McMillan and others 2004). Sugarbaker and others (1982) assessed QoL in human patients undergoing treatment for limb sarcoma. The authors hypothesised that limb-sparing surgery followed by radiation therapy would result in better QoL than after amputation, assuming that patients would prefer to keep both their legs. However, the hypothesis was convincingly rejected. Using a range of validated and specific QoL tools, patients undergoing amputation had a better QoL, in terms of psychosocial impact, function, economic impact, mobility, sexual function and pain. The second interesting conclusion was that the mere process of explicitly asking patients about their QoL exerted a positive impact on their health related QoL. It is likely that similar incorrect assumptions are currently being made within veterinary medicine; although to date remain largely unchallenged. For instance, an anxious cat that suddenly requires daily oral medication might experience a reduction of the impact of the disease on QoL, but this might be off-set by the negative impact of the daily conflict between owner and cat when administering that same medication. Home blood glucose monitoring might well be indicated to obtain better control over a patient’s diabetes mellitus, but does it automatically lead to improved QoL in every individual patient? In veterinary research, it therefore seems sensible to routinely include qualitative and quantitative QoL parameters in the original study design whenever a disease is being described and especially when an intervention is being studied. Unfortunately, there is much work to be done to equalise with the standards in human medicine because of a current lack of sufficient veterinary specific QoL measurement tools. The reason for the latter is obvious: as frontline clinicians we are forced to, and therefore used to, making an assessment of something seemingly unquantifiable, such as QoL, whereas as scientists we tend to avoid unquantifiable parameters in general. It is possible that veterinary researchers have failed veterinary clinicians by not producing the data and tools to address QoL questions directly. So how are appropriate QoL measurement tools designed? A quick glance at QoL research in human medicine shows us that in general two categories of tools can be identified. Firstly there is a body of generic health tools, which globally assess QoL, and, secondly there are specific health tools (Kirkley and Griffin 2003). A veterinary version of this first category features in an article by Yeates and David (2011) in this issue of JSAP. The advantages of such generic instruments include the fact that they can be used in virtually any animal with any disease and tend to be easy and quick to use. These tools also allow comparisons across species and diseases. The main disadvantage is that they may not detect the specific aspects of QoL that are relevant for a specific disease or treatment. The second category of specific health tools overcome that limitation and allow a more detailed and specific quantification of the impact of a disease and/or treatment on the patient’s QoL. The tools are often specific for the disease (e.g. diabetes mellitus), or the organ system involved (e.g. limb), or a specific population (e.g. young) or a specific function (e.g. mobility) (Kirkley and Griffin 2003, McMillan and others 2004). Such tools are therefore most useful in the ill patient. The author and colleagues have designed a veterinary tool of this category for the specific assessment of QoL of diabetic cats and their owners (Niessen and others 2010). There is of course something different about the animal patients we deal with, which significantly complicates matters in QoL assessment. Firstly our patients cannot themselves contribute to the QoL tools. Secondly, apart from the QoL of the pet, the interactions between the QoL of the owner and the pet should not be ignored. This is especially important when owners are required to be heavily involved in the care of an ill pet. The more intense such care is, in terms of time, financial outlay or emotional commitment, the more important it is for us as

Pasireotide Long-Acting Release Treatment for Diabetic Cats with Underlying Hypersomatotropism

Background Long‐term medical management of hypersomatotropism (HS) in cats has proved unrewarding. Pasireotide, a novel somatostatin analogue, decreases serum insulin‐like growth factor 1 (IGF‐1) and improves insulin sensitivity in cats with HS when administered as a short‐acting preparation. Objectives Assess once‐monthly administration of long‐acting pasireotide (pasireotide LAR) for treatment of cats with HS. Animals Fourteen cats with HS, diagnosed based on diabetes mellitus, pituitary enlargement, and serum IGF‐1 > 1000 ng/mL. Methods Uncontrolled, prospective cohort study. Cats received pasireotide LAR (6–8 mg/kg SC) once monthly for 6 months. Fructosamine and IGF‐1 concentrations, and 12‐hour blood glucose curves (BGCs) were assessed at baseline and then monthly. Product of fructosamine concentration and insulin dose was calculated as an indicator of insulin resistance (Insulin Resistance Index). Linear mixed‐effects modeling assessed for significant change in fructosamine, IGF‐1, mean blood glucose (MBG) of BGCs, insulin dose (U/kg) and Insulin Resistance Index. Results Eight cats completed the trial. Three cats entered diabetic remission. Median IGF‐1 (baseline: 1962 ng/mL [range 1051–2000 ng/mL]; month 6: 1253 ng/mL [524–1987 ng/mL]; P < .001) and median Insulin Resistance Index (baseline: 812 μmolU/L kg [173–3565 μmolU/L kg]; month 6: 135 μmolU/L kg [0–443 μmolU/L kg]; P = .001) decreased significantly. No significant change was found in mean fructosamine (baseline: 494 ± 127 μmol/L; month 6: 319 ± 113.3 μmol/L; P = .07) or MBG (baseline: 347.7 ± 111.0 mg/dL; month 6: 319.5 ± 113.3 mg/dL; P = .11), despite a significant decrease in median insulin dose (baseline: 1.5 [0.4–5.2] U/kg; 6 months: 0.3 [0.0–1.4] U/kg; P < .001). Adverse events included diarrhea (n = 11), hypoglycemia (n = 5), and worsening polyphagia (n = 2). Conclusions and Clinical Importance Pasireotide LAR is the first drug to show potential as a long‐term management option for cats with HS.