Equine metabolic syndrome--identifying horses at risk and diagnosis (Proceedings)

Equine Metabolic Syndrome (EMS) is the term used to describe a characteristic collection of clinical signs and clinicopathologic changes in horses. Affected animals typically are obese with increased condition score overall and increased adiposity over the topline including increased thickness of the neck (cresty neck), and fat over the tailhead. Laminitis, both chronic and acute, is common and is the clinical sign most often brought to the attention of practitioners.

Mares with EMS may be either infertile or problem breeders with altered ovarian activity. Hyperinsulinemia with normal blood glucose concentrations (insulin resistance) is the primary clinical pathologic finding. Other laboratory findings include hypertriglyceridemia, increased serum concentrations of leptin, increased systemic markers of inflammation, and arterial hypertension. Previously, this cluster of clinical signs in horses has been referred to as hypothyroidism, peripheral Cushing's disease, pre-laminitic syndrome, or Syndrome X.  Equine Metabolic Syndrome replaces these earlier terms.

Etiology/pathogenesis

Equine metabolic syndrome is limited to equids. It has been describe in horses, donkeys, and ponies. EMS is most common in horses between the ages of 5 and 16 years of age. The breeds that appear to be most commonly affected include ponies, Saddlebreds, Tennessee Walking Horses, Paso Fino, Morgans, Mustang, and Quarter Horses. Thoroughbreds and Standardbreds infrequently suffer from EMS. There is not a recognized sex predilection.

The common denominator behind many of the signs associated with EMS appears to be increased adiposity, insulin resistance, and hyperinsulinemia. The underlying reason why some horses develop EMS and others do not is not known. There appears to be a genetic disposition both within and between breeds. It has been hypothesized that affected animals possess a “thrifty” gene that enabled their ancestors to survive in very harsh environments. This increased efficiency of energy metabolism became maladaptive in modern environments with plentiful, nutrient-dense feedstuffs.

Adipocytes in the omental fat are particularly active as endocrine and paracrine tissues. They elaborate leptin and other adipokines as well as tumor necrosis factor and other inflammatory mediators. The elaboration of inflammatory mediators by omental fat cells may result in a vicious cycle of increasing adipocyte inflammation as more and more inflammatory cells are attracted to adipose tissue as a result of these increased inflammatory mediator concentrations. 

There is also increased corticosteroid elaboration in the omental fat of horses with EMS. This may lead to a chronic low-grade inflammatory state in horses with EMS, which in turn may lead to vascular injury. Increased fat stores in the omentum and liver may also predispose to insulin resistance due to downregulation of insulin receptors.

Insulin has vasoregulatory actions and increased insulin concentrations can decrease nitric oxide production and promote vasoconstriction.  Altered glucose and insulin levels may also lead to alterations in both epidermal cell function and glucose uptake by epidermal laminar cells.  These effects, in turn, predispose horses with EMS to develop laminitis.

Horses with EMS respond to high-carbohydrate meals with an exaggerated increase in insulin and a very slow return to baseline values. This indicates a resistance to the peripheral effects of insulin and an inability to metabolize carbohydrate normally.        

Clinical signs and lesions

There is no clinical picture that is pathognomonic for insulin resistance, and it is important for clinicians to recognize that horses may exhibit all the phenotypic characteristics of EMS with normal responses to evocative testing. These horses would be the equivalent of the “healthy obese” person.  In most instances, these animals are obese due to excess calorie intake, and not due to any underlying metabolic alteration. Affected horses typically are obese with a body condition score over 6 out of 9. At times they are normal weight. This is particularly true if the horse's feed intake is reduced due to laminitis pain. Even if the overall condition score is not extremely elevated, there is increased fat deposition in the nuchal ligament area of the neck, leading to a “cresty” appearance. Fat deposition over the ribs and over the topline to the tailhead is also common. Geldings may have increased fat deposition in the prepuce, while mares may have increased fat deposition around the mammary gland.

Laminitis is a common finding in horses with EMS, and often the only reason owners request veterinary intervention. Many owners do not recognize high condition scores as a problem, and some believe their horses look best when they can be assessed at condition scores of 7 or 8 out of 9. Even when the owner believes the horse is suffering from its first bout of laminitis, there is often evidence of prior episodes, such as abnormal hoof growth rings and radiographic evidence of pedal osteitis. Laminitis may occur secondary to ingestion of feeds high in soluble carbohydrates, in the form of lush pasture or high-carbohydrate hays and supplements, but often the animal becomes painful with no obvious predisposing factor.

Because of the association between laminitis and endocrine disturbances, any horse under the age of 15 that develops unexplained laminitis should be tested for EMS. If the horse is older than 15 years, it should also be tested for pituitary pars intermedia dysfunction (PPID, equine Cushing's disease) as well as for insulin resistance. Affected horses may not lose weight without extreme feed restriction, and owners commonly report that horses with EMS remain obese even when they are fed minimal amounts. Obesity is often exacerbated by the fact that laminitis limits the amount of exercise that many horses with EMS can tolerate. Horses with EMS have what is perceived as increased appetites, with owners mentioning that they will eat continuously as long as feed is available.

On post-mortem examination, horses with EMS often have large amounts of abdominal fat when compared to normal equids. In addition, increased general adiposity is often documented.  The pituitary gland is normal in horses with EMS, which is the key difference between the insulin resistance of EMS and that associated with pituitary pars intermedia dysfunction (PPID).

Diagnosis/differential diagnosis

Diagnostic testing for EMS concentrates on documenting insulin resistance while ruling out PPID. It must be stressed that the presence of obesity and the cresty neck phenotype is not sufficient to make a diagnosis, but can be present in any overweight horse. Breeds such as the Friesian, Andalusian, and Paso Fino have a cresty neck phenotype, and most animals of those breeds have prominent necks without abnormal glucose metabolism.

A careful dietary history is essential, as is a careful physical examination. Establishing baseline body condition score and neck circumference will enable owners and practitioners to assess the degree of overcondition. Neck circumference can be followed over time to document the horse's response to treatment. Even if there is not a history of laminitis, careful examination of the feet, including obtaining lateral images of P3, is indicated.

Because many conditions including diet, pain, and stress can affect blood glucose and insulin levels, diagnostic testing should be performed in a controlled manner in a low stress environment.  If a horse is suffering from laminitis, diagnostic testing should be delayed until the feet have stabilized and are relatively pain-free.

Laboratory testing

Blood glucose concentrations are in the normal range or only slightly elevated with EMS. If persistent hyperglycemia is documented, PPID should be strongly suspected.  Because of the many factors that influence blood glucose and thus insulin levels, one-time blood insulin is the least reliable means of diagnosing insulin resistance. Insulin should be determined after the horse has been fasted overnight or has access to only grass hay low in soluble carbohydrate. If those conditions are met, a blood insulin concentration over 20µU/mL is suggestive of insulin resistance.

The best way to document insulin resistance is to evaluate the horse's ability to handle an increased glucose load or to respond to exogenous insulin. Because of the large number of blood samples required and the fact that change from baseline values as opposed to absolute glucose values is of interest, using a hand-held glucometer is sufficient for determining blood glucose values when performing these tests.

The “gold standard” method to diagnose insulin resistance is via the use of the euglycemic clamp method. This requires a sophisticated technical set-up, and is not practical for use in a diagnostic setting. The frequently sampled glucose response test may be the next-best method. Again, due to the numerous samples that must be collected and then modeled with computer modeling software, this is not practical for practitioners. There are other methods that are not quite as precise, but are adequate in most instances. In the field, assessing insulin resistance can be done via oral or intravenous glucose tolerance testing or a combined glucose-insulin response test and an insulin response test. 

The oral glucose tolerance test results can be altered by delayed gastric emptying or poor gastrointestinal absorption and is thus is the test most prone to false positives. In field situations, however, measuring the horse's reaction to an oral glucose load can be used to document insulin resistance. The combined glucose-insulin test provides a great deal of information in a short period of time, and is the diagnostic test recommended in the recently published ACVIM consensus statement on EMS. The insulin tolerance test is the fastest to perform and requires only 3 blood samples and one dose of insulin to accomplish.

Oral glucose tolerance test

1 g/kg dextrose as a 20% solution is given via a nasogastric tube after collection of a baseline glucose sample.  Serial blood glucose measurements are taken at half-hour intervals for 3 hours. Blood glucose is expected to return to baseline before 2.5 hours and no later than 3 hours after glucose administration.

Intravenous glucose tolerance test

 0.5 g/kg dextrose as a 50% solution is given as a bolus intravenously after a baseline blood glucose determination. Serial blood glucose measurements are taken at half-hour intervals for 3 hours. Blood glucose is expected to return to baseline before 2.5 hours and no later than 3 hours after glucose administration.

Combined glucose-insulin test

A baseline blood sample is collected for glucose and insulin determination. Fifty percent dextrose at a dose of 150 mg/kg body weight is then given IV immediately followed by 0.10 units/kg regular insulin IV  Blood glucose concentrations are determined at the following times: 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, 120, 135, and 150 minutes post-infusion. Blood is also collected for insulin determination at 45 minutes post-infusion.  Blood glucose returns to baseline and blood insulin concentrations should be less than 100 µU/ml within 45 minutes in normal horses. Despite the fact that a single blood test at 45 minutes is often sufficient to make a diagnosis of EMS, generating the entire curve by measuring all time points allows one to compare sequential testing periods to assess response to therapy.

Insulin response test

A baseline blood sample is collected for glucose determination. A dose of 0.1U/kg regular insulin is given IV, and blood collected for glucose determination 15 and 30 minutes later. In normal horses, the blood glucose will decrease to 50% baseline or less in 30 minutes. Insulin-resistant horses experience either no decrease in blood glucose or only a small decrease in which the blood glucose concentrations never get less than 60% baseline. Giving 100 ml 50% dextrose IV or PO or corn syrup PO immediately following the final glucose measurement can be done in order to bring glucose concentrations up to normal quickly.

The use of surrogate tests that ultimately are evaluating the ratio between insulin and glucose such as the QUICKI and HOMA-IS is sometimes advocated, but these test's correlation with evocative testing has not been reported and appears to be poor. Using a glucose/insulin ratio should be considered a screening test at best. An abnormal result indicates the need for a glucose or insulin challenge test.

Tests for PPID such as endogenous ACTH concentrations, the dexamethasone suppression test, domperidone response test, and thyroid releasing hormone (TRH) response test are normal in horses with EMS.