DEVELOPMENTS IN DIAGNOSIS AND TREATMENT OF CUSHING S DISEASE

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1 Vet Times The website for the veterinary profession DEVELOPMENTS IN DIAGNOSIS AND TREATMENT OF CUSHING S DISEASE Author : Jo Ireland Categories : Vets Date : May 28, 2012 Jo Ireland reports on the webinar given by Andy Durham, on this endocrine disorder EQUINE Cushing s disease, also known as pituitary pars intermedia dysfunction (PPID), is the most common endocrine disorder in older equids. Research studies have led to improvements in the accuracy of diagnostic testing for PPID, and awareness is increasing, in both the equine veterinary profession and horse owners, of the welfare benefits of early diagnosis. A live CPD webinar presented by equine internal medicine specialist Andy Durham was hosted by Boehringer Ingelheim Vetmedica to high-light the importance of endocrinopathic laminitis and developments in diagnostic testing for PPID. The webinar used voting technology to allow the live audience of 127 veterinary surgeons to actively participate throughout the presentation. Using a combination of best evidence from the latest research and practical pointers from his extensive experience in practice, Andy Durham presented a comprehensive and informative discussion about diagnosing and treating PPID. Pasture-associated laminitis Pasture-associated laminitis is the most common form reported by horse owners, and, until recently, even within the veterinary profession, laminitis was frequently considered to be primarily a spring affliction associated with the ingestion of lush pasture. 1 / 7

2 Traditional experimental models of laminitis, including starch and fructan overload models, induced disruption of the mucosal barrier in the colon and caecum, resulting in systemic absorption of toxins that triggered laminitis. It was proposed that naturally occurring cases of laminitis could be caused by consuming excessive amounts of fructans found in spring grass, resulting in dysfermentation and acidosis in the hindgut. To induce laminitis experimentally in a 300kg pony, the amount of fructans or starch required would be a bolus administration of 1.5kg to 3kg 1-3. During normal grazing, the fructan intake for a 300kg pony would range from 5g to 450g per hour, depending on appetite, grass type and environmental factors. Therefore, the quantities of fructans and simple sugars ingested by grazing animals are far lower than that required to damage the mucosal barrier and would not result in significant absorption of toxins from the hindgut. However, fructan or other sugars ingested at a rate of 50g to 75g per hour cause marked hyperinsulinaemia 4-5, which is highly likely to further increase the risk of laminitis in animals with an underlying endocrinopathy. These figures strengthen the hypothesis that, rather than gastrointestinal dysfunction, endocrinopathies are the underlying cause of pastureassociated laminitis. Endocrinopathic laminitis Clinical signs of PPID have been well documented and include hirsutism or more subtle hair coat abnormalities, laminitis, lethargy, weight loss and altered fat distribution, epaxial muscle wastage, polyuria and polydipsia, excessive or patchy sweating and increased susceptibility to infection 6. While recurrent infections, such as solar abscesses or sinusitis, may be problematic, laminitis is the major health concern in cases of PPID and represents the most common reason for euthanasia. The other primary cause of endocrinopathic laminitis is equine metabolic syndrome (EMS), highlighted by the findings of two studies where approximately 90 per cent of laminitis cases had one of these underlying endocrine disorders 7-8. Together with these research advances, the clinical observation that laminitis rarely occurs in young, fit, non-obese, non-native horses without signs indicative of an endocrinopathy, has resulted in a revolution regarding our understanding of laminitis in the UK equine population. Hyperinsulinaemia, which is a characteristic feature of EMS and is also found in a considerable proportion of PPID cases, has been shown to cause laminitis in horses and ponies 9, 10. Serum insulin concentration is an important prognostic indicator for both PPID and laminitis While the role of insulin in EMS-associated laminitis is now recognised, historical beliefs surrounding PPID may have obscured the association between insulin and laminitis. The increased risk of laminitis with PPID was previously considered to result from high basal cortisol concentrations in affected animals. However, there is little evidence to support a causative role of cortisol in laminitis and in fact cortisol has little diagnostic value in PPID cases, as many have normal levels. Therefore, it is now considered that insulin is very relevant to the mechanisms underlying laminitis in PPID as well as in EMS cases, and may help to explain why some animals with PPID are more susceptible to 2 / 7

3 laminitis than others. Diagnosing PPID In PPID, age-related dopaminergic neurodegeneration results in loss of dopaminergic inhibition leading to overproduction and elevated circulating levels a number of pro-opiomelanocortin (POMC)-derived peptides, including adrenocorticotrophic hormone (ACTH). Several endocrine tests have been employed in the diagnosis of PPID, of which the overnight dexamethasone suppression test (ODST) and plasma ACTH are the most frequently used. Reviewing previous studies showed the ODST has an accuracy of approximately 88 per cent 13, 15, which compares favourably to the 90 per cent accuracy reported for ACTH 15, 16. However, concern regarding the administration of exogenous glucocorticoids to laminitis-prone animals, from both veterinary surgeons and horse owners, together with the requirement for two procedures 18 to 24 hours apart and relative expense, mean the ODST is now performed far less frequently than ACTH. Although widely used, some potential issues regarding ACTH assays have been proposed. Stress and pain, as may be expected to occur with an acute episode of laminitis, are often thought to result in elevations of ACTH. This concern is not necessarily supported by research findings, where neither isolation distress nor mild moderate pain or illness were shown to affect ACTH levels Severe pain or illness does however affect ACTH; therefore this should be considered when using this diagnostic test in very severe cases of laminitis. Protocols for sample handling have previously been complicated by concerns regarding the labile nature of ACTH. Data from the Liphook Equine Hospital s laboratory demonstrate that contrary to popular belief, ACTH degrades relatively slowly in EDTA plasma. In fact, even at room temperature, the average reduction in ACTH values after two days of storage was only 30 per cent and the largest fall in any tested sample was 52 per cent. Based on these data, there appears to be no additional advantage of freezing plasma samples prior to laboratory submission, and ACTH is stable provided the sample is chilled within three hours and transported to the laboratory using a chill pack. Seasonal changes in the equine hypothalamic-pituitary axis are now well documented, and earlier research suggested a high risk of false positive PPID diagnostic test results during the autumn. However, recently published findings show that while normal horses have increased ACTH levels in the autumn, the magnitude of this increase is far greater in PPID cases 20. In fact, the diagnostic power of ACTH assays is greatest during the autumn, as there is a more pronounced difference between diseased and healthy animals. As ACTH levels are significantly higher in the autumn compared to all other times of year, the development of seasonally adjusted reference ranges has ensured there should no longer be concern over the accuracy of testing for PPID at that time. 3 / 7

4 It has been suggested that rather than constantly elevated secretions, ACTH is released in a pulsatile manner from the affected pituitary pars intermedia, and, therefore, that measuring ACTH from a single time point may potentially reduce sensitivity. However, little available data is available pertaining to pulsatile release of ACTH, and as such Liphook Equine Hospital laboratory would welcome the submission of two samples taken 10 minutes apart for a trial period. Preliminary evaluation of the paired samples they have received to date have not revealed any major differences that would affect the diagnostic value of a single sample assay in the vast majority of cases. Alternative diagnostic tests Although both the ODST and ACTH assay have excellent diagnostic value and relatively high accuracy, in a small proportion of cases, these tests will produce results that are close to the reference range or at odds with our clinical diagnosis. While not yet widely available, using a dynamic test assessing ACTH response to the administration of TRH 15, may prove to be a very useful diagnostic test, particularly where conventional tests yield equivocal results. Though more expensive, studies suggest that highest sensitivity and specificity are obtained where post-trh blood samples are collected at 10 or 30 minutes, meaning that this test would be practical for use in the field setting. Medical grade TRH is no longer available in this country, but a pure freeze-dried product is available from European companies, which can be used under the cascade system, following completion of the appropriate VMD treatment authorisation. Treating and monitoring PPID Pergolide is the only licensed treatment available for PPID, and although widely used for years, no consensus exists in published data regarding dosage regimes. Previous studies have used treatment doses between 0.85µg/kg bodyweight twice daily and 10µg/kg bodyweight administered once daily, and voting by the webinar audience indicated that most vets would select an initial dose of between 1.7µg/kg to 3.3µg/kg. A starting dose of approximately 2µg/kg would be recommended regardless of ACTH levels prior to treatment, and using higher doses initially may increase the risk of potential adverse effects such as inappetence. Cases of PPID represent a wide spectrum of disease and pergolide dose should be adjusted for individuals if required based on clinical improvement and the results of further laboratory testing. Results of repeat samples submitted to Liphook s laboratory showed that while ACTH may not return to normal levels, in most cases there is a significant reduction following treatment with pergolide. Reduction in ACTH appears to occur relatively rapidly, with approximately 50 per cent of cases responding within the first week on pergolide and the vast majority demonstrating decreased ACTH after a month of treatment. Based on these data, ACTH assays represent a useful monitoring tool in the management of PPID cases. 4 / 7

5 A practical approach would be obtaining a follow-up ACTH level one month after starting pergolide treatment, with subsequent dose alterations introduced slowly based on these results. Once ACTH levels appear controlled, regular monitoring at three to 12 month intervals is indicated. Pergolide dose should be titrated to the lowest effective dose in each case, but as PPID is a slowly progressive disease it is possible some individuals may require increased medication over time. Equine geriatric medicine continues to increase in importance, and this webinar provided valuable information for everyone working in equine practice. Following his presentation, Andy answered questions submitted online by the audience, adding to the discussion of diagnostic testing for PPID in the practice setting. As the proportion of geriatric horses in our equine population increases, inevitably so will the number of PPID and endocrinopathic laminitis cases we treat. Andy highlighted the need to diagnose the underlying endocrinopathy in laminitis cases, and while the focus tends to be on EMS in younger animals, it is important to consider also testing for PPID, as the distinction between the two may not be clear and it is increasingly recognised that both conditions can occur concurrently. The practical advice about treatment and monitoring will aid practitioners in the successful management of PPID cases. This, in turn, should improve the quality of service we offer to owners, who often have a very strong bond with their elderly horse and are keen to provide the best possible care. The CPD webinar is available by visiting References 1. French K R and Pollitt C C (2004). Equine laminitis: loss of hemidesmosomes in hoof secondary epidermal lamellae correlates to dose in an oligofructose induction model: an ultrastructural study, Equine Vet J 36: Crawford C, Sepulveda M F, Elliott J, Harris P A and Bailey S R (2007). Dietary fructan carbohydrate increases amine production in the equine large intestine: implications for pasture-associated laminitis, J Anim Sci 85: 2,949-2, Tóth F, Frank N, Chameroy K A and Bostont R C (2009). Effects of endotoxaemia and carbohydrate overload on glucose and insulin dynamics and the development of laminitis in horses, Equine Vet J 41: Bailey S R, Menzies-Gow N J, Harris P A, Habershon-Butcher J L, Crawford C, Berhane Y, Boston R C and Elliott J (2007). Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis, J Am Vet Med Assoc 231: Frank N, Elliott, S B, Chameroy K A, Tóth F, Chumbler N S, McClamroch R (2010). Association of season and pasture grazing with blood hormone and metabolite concentrations in horses with presumed pituitary pars intermedia dysfunction, J Vet Intern Med 24:1,167-1, McCue P M (2002). Equine Cushing s disease, Vet Clinics Equine Pract 18: Donaldson M T, Jorgensen A J and Beech J (2004). Evaluation of suspected pituitary 5 / 7

6 pars intermedia dysfunction in horses with laminitis, J Am Vet Med Assoc 224: 1,123-1, Karikoski N P, Horn I, McGowan T W and McGowan C M (2011). The prevalence of endocrinopathic laminitis among horses presented for laminitis at a first-opinion/referral equine hospital, Domest Anim Endocrinol 41: Asplin K E, Sillence M N, Pollitt C C and McGowan C M (2007). Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies, Vet J 174: de Laat M A, McGowan C M, Sillence M N and Pollitt C C (2010). Equine laminitis: induced by 48h hyperinsulinaemia in Standardbred horses, Equine Vet J 42: Walsh D M, McGowan C M, McGowan T W, Lamb S V, Schanbacher B J and Place N J (2009). Correlation of plasma insulin concentration with laminitis score in a field study of equine cushing s disease and equine metabolic syndrome, J Equine Vet Sci 29: McGowan C M, Frost R, Pfeiffer, D U and Neiger R (2004). Serum insulin concentrations in horses with equine Cushing s syndrome: response to a cortisol inhibitor and prognostic value, Equine Vet J 36: Dybdal N O, Hargreaves K M, Madigan J E, Gribble D H, Kennedy P C and Stabenfeldt G H (1994). Diagnostic testing for pituitary pars intermedia dysfunction in horses, J Am Vet Med Assoc 204: Frank N, Andrews F M, Sommardahl C S, Eiler H, Rohrbach B W and Donnell R L (2006). Evaluation of the combined dexamethasone suppression/thyrotropin-releasing hormone stimulation test for detection of pars intermedia pituitary adenomas in horses, Vet Intern Med 20: Beech J, Boston R, Lindborg S and Russell G E (2007). Adrenocorticotropin concentration following administration of thyrotropin-releasing hormone in healthy horses and those with pituitary pars intermedia dysfunction and pituitary gland hyperplasia, J Am Vet Med Assoc 231: van der Kolk J H, Wensing, T, Kalsbeek H C and Breukink H J (1995). Laboratory diagnosis of equine pituitary pars intermedia adenoma, Domest Anim Endocrinol 12: Alexander S L, Irvine C H, Livesey J H and Donald R A (1988). Effect of isolation stress on concentrations of arginine vasopressin, alpha-melanocyte-stimulating hormone and ACTH in the pituitary venous effluent of the normal horse, J Endocrinol 116: Couëtil L, Paradis M R and Knoll J (1996). Plasma adrenocorticotropin concentration in healthy horses and in horses with clinical signs of hyperadrenocorticism, J Vet Intern Med 10: Towns T J, Stewart A J, Hackett E, Zhong Q, Munsterman, A Wooldridge A A, Funk R A and Hewes C A (2010). Cortisol and ACTH concentrations in ill horses throughout 6 days of hospitalisation, Proceedings IVECCS 16: A Copas V E N and Durham A E (2011). Circannual variation in plasma adrenocorticotropic hormone concentrations in the UK in normal horses and ponies, and those with pituitary pars intermedia dysfunction, Equine Vet J doi: /j x. 21. McFarlane D, Beech J and Cribb A (2006). Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with 6 / 7

7 Powered by TCPDF ( pituitary pars intermedia dysfunction and equine pars intermedia explants, Domest Anim Endocrinol 30: Beech J, Boston R and Lindborg S (2011). Comparison of cortisol and ACTH responses after administration of thyrotropin releasing hormone in normal horses and those with pituitary pars intermedia dysfunction, J Vet Intern Med 25: 1,431-1, / 7