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The diagnostic minefields of PPID and EMS

How to choose the best diagnostic tests for equine pituitary pars intermedia dysfunction and equine metabolic syndrome

24 June 2018, at 3:06pm

Equine pituitary pars intermedia dysfunction (PPID) and equine metabolic syndrome (EMS) are two clinically relevant metabolic diseases seen in the equine population. Both diseases can have profound effects on the health of horses and therefore warrant diagnosis and ongoing treatment. There are numerous tests available for both diseases, making it difficult to know which is the best to undertake and how to advise the owner based on the results.

Clinical signs associated with PPID can include: hypertrichosis, delayed coat shedding, changes in body conformation/ regional adiposity, laminitis and PU/PD, among many others

Overview of the conditions 

PPID is a neurodegenerative disease that is progressive due to the loss of dopaminergic input to the pituitary leading to an overproduction of pars intermedia-derived hormones, including adrenocorticotrophic hormone (ACTH). Many other hormones are produced, but ACTH is the most tested and clinically validated.

Clinical signs associated with PPID can include: hypertrichosis, delayed coat shedding, changes in body conformation/regional adiposity, laminitis and PU/PD, among many others. It is frequently seen in the ageing population, with 21 percent of horses over 15 years having endocrinological changes consistent with PPID (McGowan, 2013), but it has also been documented on post-mortem in a 7-year-old horse. 

Equine metabolic syndrome has been described as the presentation of insulin dysregulation, a predisposition to laminitis (or ongoing laminitis) and a phenotype of obesity (Frank, 2010). Hyperinsulinaemia has been associated with laminitis with the suspected pathology being secondary to changes in the vasculature (Asplin, 2007). Therefore, diagnosis can allow for appropriate recommendations to be made to reduce the insulin dysregulation and subsequent risk of laminitis. 

PPID testing 

Basal ACTH concentration in plasma is the most easily accessible test available, but is not without its drawbacks. The cut-off values have been debated; there are various viewpoints as to where the exact cut-off should be. 

At Liphook Equine Hospital, we have a reference range that changes weekly based on over 30,000 samples that have been run through our lab thanks to the Talk About Laminitis scheme. This allows us to very accurately guide clinicians on the appropriate treatment course and clinical relevance of each result. It should be noted that treatment with pergolide should always be based on the presence of clinical signs and age as well as the exact value on the test. 

If the basal ACTH result is borderline or within a grey area proposed by the Equine Endocrinology Group (30 to 50 pg/ml in the non-autumn months and 50 to 100pg/ml in the autumn period), further testing with a thyrotropin-releasing hormone (TRH) stimulation test should be undertaken. 

Although reference ranges are available for the autumn period, there is some question as to their sensitivity and specificity. As such, it may be more appropriate to run a basal ACTH during the autumn period due to its high sensitivity and specificity. The TRH stimulation is affected by feeding, so horses should not be given supplementary food for approximately four hours prior to the test. Repeat testing, whether it is a basal ACTH or a TRH stimulation, is essential once pergolide treatment has been initiated. Most horses will have responded maximally within one month following initiation of pergolide, but a few outliers can take longer. If repeat samples are taken early and the results do not reflect complete endocrinological control, the test can be repeated one to two months later to ensure that there are no ongoing reductions in ACTH at the dose being given. It should also be noted that repeat tests should be interpreted alongside the reference range for that time of year. In autumn, it can appear as though the absolute ACTH value has increased, but it may fall within the reference range in an endocrinologically controlled horse.

EMS testing 

There are multiple tests available for insulin dysregulation, each with its own strengths and weaknesses. 

A resting, or even fasting, insulin can be run and when positive (>20µIU/ml), it likely indicates insulin dysregulation. Note, however, that there are lots of false negatives, so this is likely the least appropriate diagnostic modality for EMS.

High molecular weight adiponectin is a hormone produced by metabolically active fat. In non-insulin dysregulated horses, this value is high, leading to increased insulin sensitivity in peripheral tissue. When it is low there is an increased risk of insulin resistance. Although not a direct marker of EMS, it is highly correlated with the risk of laminitis associated with insulin dysregulation. The biggest advantage of this test is that it can be taken throughout the day with no need to starve the horse. Monitoring the values, as with dynamic insulin testing, can be disappointing if excellent weight loss is not achieved. Retesting should only be undertaken once good weight loss has been achieved. 

Dynamic glucose/insulin testing can be performed in one of two ways: either 1g/kg dextrose or glucose powder can be added to feed and a blood sample taken two hours later for glucose and insulin (the former to confirm adequate absorption of glucose has been achieved); or, 45ml/100kg BW of Karo-light corn syrup syringed into the mouth (gentle warming makes this much easier) with samples taken for glucose and insulin at between 60 and 90 minutes. The higher dose of 45ml/100kg compared with previously advised 15ml/100kg has a higher sensitivity and specificity and is therefore recommended. 

The final test available is the two-step insulin tolerance test. This is the only test that directly assesses the sensitivity of the insulin receptors. It involves basal blood glucose being taken followed by the administration of 0.1IU/kg of soluble insulin IV with a blood sample taken 30 minutes later for glucose testing. Insulin sensitive horses should have a reduction in glucose of greater than 50 percent, while insulin resistant horses will not (Bertin, 2013). 

Horses should not be fasted prior to this test as fasting will lead to a decreased response to the administration of insulin. When performing this test, it is advisable to have access to IV glucose (50 percent) in case of a hypoglycaemic incident, although this is very rare. Normal advice is to feed the horse following the second blood sample. 

Once a diagnosis of EMS has been made, the owner should be advised on how to minimise the inherent increased risk of laminitis. The primary treatment is to ensure an appropriate diet is undertaken; the use of scales to weigh food is essential, alongside exercise if the horse is not currently suffering from laminitis. Metformin can be added to decrease the absorption of glucose and so reduce the insulin peak, but it should be used as an adjunctive therapy rather than a curative one. 

Testing for PPID and especially EMS is complicated by the number of tests available and the different ways of interpreting the results. No single test will always be the most appropriate; they should be chosen based on clinical knowledge and the case being presented.

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References
Author Year Title
Asplin, K. E., Sillence, M. N., Pollitt, C. C., McGowan, C. M. 2007 Veterinary Journal, 174
Bertin, F. R. and Sojka-Kritchevsky, J. E. 2013 Domestic Animal Endocrinology, 44
Frank, N., Geor, R. J., Bailey, S. R., Durham, A. E. and Johnson, P. J. 2010 Journal of Veterinary Internal Medicine, 24
McGowan, T. W., Pinchbeck, G. P., and McGowan, C. M. 2013 Equine Veterinary Journal, 45