This month, Equine Veterinary Education and Equine Veterinary Journal have combined forces to create a free online collection of our recent articles on equine endocrinology. This initiative has been made possible with the support of the British Equine Veterinary Association Trust, and we are extremely grateful to Professor Nick Frank and Professor Philip Johnson, who have served as guest editors for this collection.
Equine endocrinology is a fast-moving field; in an introductory editorial, Philip Johnson, writing with Professor Sojka-Kritchevsky, reflects on the pace of progress that has generated a vast number of publications in the last decade (Sojka-Kritchevsky and Johnson 2014). The online collection encompasses a comprehensive range of topics within the field of endocrinology and includes authoritative review articles on insulin dysregulation (Frank and Tadros 2014), glucocorticoids and laminitis (Cornelisse and Robinson 2013) and paraneoplastic syndromes (Axiak and Johnson 2012).
Pituitary pars intermedia dysfunction (PPID) (McGowan et al. 2013aa) and equine metabolic syndrome (Frank and Tadros 2014) are both associated with insulin dysregulation and are now recognised as important and common problems in equine medicine that affect the health and well-being of many horses and ponies globally. Both become extremely significant due to their link with recurrent laminitis, which raises their impact in terms of both morbidity and mortality (Tadros and Frank 2011). The exact mechanisms that link insulin, glucocorticoids, lipid metabolism and inflammation, endothelial function and the laminae remain to be clarified (Sojka-Kritchevsky and Johnson 2014), but the online collection highlights several studies that represent important pieces of this jigsaw (Tóth et al. 2010; Venugopal et al. 2011; Borer-Weir et al. 2013; Burns et al. 2013; Gauff et al. 2013; Dunkel et al. 2014).
Current best practice for management of equine metabolic syndrome is outlined by Professors Nick Frank and Ray Geor in this month's issue of Equine Veterinary Education (Frank and Geor 2014). The first goal of management is to induce weight loss, and helpful and explicit guidelines for designing diets for obese equids are provided. There is little doubt that exercise together with dietary management (Hudson et al. 2012) can reduce the clinical signs and indices of inflammation in equine metabolic syndrome (Hudson et al. 2012; Menzies-Gow et al. 2013; Frank and Geor 2014); however, further studies are needed to quantify the efficacy of these management changes on long-term outcomes.
In cases that are refractory to this approach, metformin (Rendle et al. 2013) or levothyroxine (Frank and Geor 2014) may be helpful. However, questions remain regarding the most effective medication, if any, for management of insulin dysregulation. It seems reasonable to postulate that removal or control of the underlying causes will be more rational than simply treating the effects, and it is essential that horse-owners understand that with sufficient effort on their part, equine obesity can be tackled (Owers and Chubbock 2013).
The online collection includes several studies addressing the diagnosis of PPID, and in particular, the value of plasma adrenocorticotropic hormone (ACTH) when interpreted with seasonally adjusted reference ranges is discussed by several authors (Copas and Durham 2012; McGowan et al. 2013bb; Rendle et al. 2014); this is advocated by Professors Frank and Geor as the most readily accessible test for monitoring PPID cases in a field setting, although the thyroid-releasing hormone stimulation test is more sensitive and therefore has advantages in confirmation of diagnosis (Frank and Geor 2014).
There are some significant problems emerging with the way that horse-owners interpret the information that can be gleaned from screening horses for PPID with the plasma ACTH assay. Perusal of the extremely popular and highly influential Horse and Hound forum in the UK (http://www.horseandhound.co.uk/forums/) on 21 October 2013 reveals some interesting strands on this topic. In a query entitled ‘Cushings, how high could a false positive be?’ a horse owner outlines her concern as follows:
Had vet out for routine stuff the other day and decided to get a mare tested for Cushings purely because it was free and she is in her 20's. She doesn't show any outward signs of Cushings. The result came back 119. Could this be a false positive or a natural spike or is it too high to be false?
In reply, another forum user describes some typical clinical signs of PPID, but nevertheless encourages treatment in the absence of any other clinical evidence of a problem, offering the following in response:
ACTH levels are naturally higher at this time of year for normal horses but for Cushings horses the levels go quite a bit higher. Some horses hardly show any signs of Cushings and the first sign can be an attack of laminitis…when mine was first diagnosed she had a thick coat which didn't [sic] shed properly and fat pads above her eyes and quarters, her level was 172…so your [sic] may be at the beginning of Cushings and it may be worth putting her on the medication to control it and then getting her tested again to see if it has made a difference. Unfortunately the medication is quite pricey but you may find she only needs a low dose.
Pituitary pars intermedia dysfunction is a neurodegenerative disorder, and current knowledge on its pathogenesis is discussed in detail by Professors Sojka-Kritchevsky and Johnson in their introduction to the online collection published in this month's issue of Equine Veterinary Journal (Sojka-Kritchevsky and Johnson 2014). The odds of developing clinical signs associated with PPID increase by approximately 20% per year in horses over 15 years of age. The prevalence of clinical signs in a group of Australian horses was 21.5% (McGowan et al. 2013aa). The prevalence of clinical signs in horses younger than 15 years of age has not been reported but, while there is little doubt that clinical PPID can occur in younger horses, it seems reasonable to speculate that the prevalence is lower than 20%. The studies on use of plasma ACTH assays for diagnosis of PPID suggest that the sensitivity and specificity are very satisfactory in autumn, but only around 80% in other seasons. Studies on the sensitivity and specificity of plasma ACTH as a diagnostic test for PPID are hampered by the lack of a readily available ‘best’ or ‘gold standard’ test for the condition.
So, where does prevalence come in? Sensitivity and specificity are indicators that relate directly to the test under scrutiny, while for calculation of positive and negative predictive values, prevalence is included in the denominator. In the study by McGowan et al. during autumn the positive predictive value (in other words, the proportion of positive test results that truly are positive) was only 75%, while in spring, summer and winter the positive predictive value fell to around 45% (McGowan et al. 2013bb), indicating that 3 of 4 horses with positive test results in autumn were affected, but in the other seasons, when a ‘positive’ result was obtained, slightly more horses did not have the disease than did. The population from which those estimates were derived was restricted to horses ≥15 years old. The positive and negative predictive values fall as prevalence decreases, and a test useful for diagnosis is not necessarily appropriate for screening apparently healthy populations for subclinical disease. Horse-owners are increasingly aware of PPID and want to screen their horses because the concept of early diagnosis and treatment is attractive. However, studies are urgently required to provide the evidence on which to base screening programmes. Overdiagnosis leads to overtreatment, and treating animals unnecessarily creates unnecessary concern for their owners as well as inappropriate financial investment in drug therapy. In addition, the risk of untoward effects of drug treatment must always be considered; pergolide was removed from the market for human use in the USA in 2007 because of a perceived increase in the risk of valvular heart disease.
Pergolide has emerged as the drug of first choice for treatment of PPID, and it has the advantage that it is licensed for use in the horse in many regions (Frank and Geor 2014). While the early introduction of medication may avert the spectre of laminitis, clinicians should be aware that, at present, there are no randomised controlled trials comparing pergolide with alternatives. Furthermore, there have been no long-term studies to show that horses that are treated with low-dose pergolide before the onset of clinical signs of PPID have better outcomes, including a reduced incidence of developing laminitis, than horses in which treatment is delayed until clinical signs become apparent. Perhaps the next decade will provide the evidence base that is needed to provide robust guidelines on this and other medications?