Fat, foundered horses: What is equine metabolic syndrome? (Proceedings)

Middle-aged obesity (body condition score 7-9 on a scale of 1 to 9) accompanied by insidious-onset laminitis is a syndrome that has been recognized by equine practitioners for decades. Equine metabolic syndrome (EMS) is a recently coined name that has gained acceptance to describe this condition. Clinical signs of laminitis commonly develop while horses are grazing spring pasture but can also occur at other times of the year and in horses without pasture access. Affected horses tend to be aged between 10-to-20 years and there does not appear to be a sex predilection. Occasionally, the syndrome can occur in younger animals that have been overfed. Pony breeds, domesticated Spanish mustangs, Peruvian Pasos, Paso Finos, Andalusians, European Warmbloods, American Saddlebreds, Arabians, and Morgan horses are more commonly affected than Thoroughbreds, Standardbreds, and Quarter Horses. This breed disparity is supportive of a genetic predisposition. In the past, this syndrome was commonly attributed to hypothyroidism or pituitary pars intermedia dysfunction (PPID or classic equine Cushing's disease); however, most affected horses do not manifest additional clinical signs or endocrinologic test results to support these conditions. It is now recognized that insulin resistance is the primary endocrinopathy induced by obesity in EMS-affected horses. However, a number of additional metabolic and endocrinologic alterations can occur in affected equids making the pathophysiology of EMS an increasingly complex subject. Finally, a subgroup of EMS-affected equids may only have abnormal fatty deposits (e.g., a cresty neck or fat deposits behind the shoulders, over the tail head, and in the sheath of male horses) without generalized obesity and these patients are often more challenging to manage than those with generalized obesity.

Prevalence of laminitis and obesity in horses

Laminitis is a devastating clinical problem for horses and their owners. In fact, data collected in the 2000 USDA-NAHMS study revealed that laminitis was reported on 13% of horse operations. Further, the leading cause of laminitis was reported to be grazing lush pasture (Figure 1). Similarly, in the United Kingdom more than 8,000 cases of laminitis are estimated to occur annually, representing 7% of the equine population, and more than 60% of cases were classified as pasture-associated disease. In both reports, pasture-associated laminitis had a peak incidence in May, followed by October and November.

Figure 1. Causes of laminitis reported in the 2000 USDA NAHMS study; note that grazing lush pasture was the most common reported cause with a peak incidence in May.

Also, as horses have transitioned from beasts of burden to recreational companions, the physical condition of many horses has paralleled that of their human counterparts: they have been overfed and become more sedentary. As a consequence, obesity is becoming a significant problem in the equine species. In a recently studied cohort of horses aged 4-20 years in Virginia, 19% of 300 horses were classified as obese, defined as a body condition score (BCS) of 7.5 or greater on a scale of 1 through 9.

Pathophysiology

The cause of obesity is fairly straightforward: caloric intake exceeding daily caloric requirement. Clearly, there is also a genetic predisposition towards development of obesity that has been referred to as having "thrifty genes". Unfortunately, obesity has a number of metabolic consequences including insulin resistance (IR), hyperglycemia, altered tissue-level cortisol activity, increased leptin concentrations, altered lipid metabolism with hypertriglyceridemia, increased expression of inflammatory cytokines, and hypertension. In horses, the most obvious clinical sign that results from these metabolic alterations is laminitis. EMS appears to have some parallels to the human metabolic syndrome - a syndrome of IR and visceral adiposity (deposition of omental fat) that is recognized to affect an increasing number of middle-aged people. In affected humans, cardiovascular disease, hypertension, dyslipidemias, and type II diabetes (insulin resistant diabetes) are the common sequelae.

In horses, EMS is usually not recognized (or perhaps acknowledged) until insidious-onset laminitis develops in overweight horses that have no obvious risk factors for laminitis (e.g., grain overload, colic or diarrhea with endotoxemia, pleuropneumonia, or retained placenta). Hindsight often reveals that affected horses have had a decrease in exercise program (e.g., the primary rider goes away to college) while nutritional restriction was not implemented. Many horses are initially tested for hypothyroidism and serum thyroxine (T4) concentrations may be near or below the lower end of the reference range in affected equids. However, when the hypothalamic-pituitary-thyroid axis is tested dynamically by administration of thyrotropin-releasing hormone, thyroid gland function has consistently been normal. Similarly, horses older than 15 years of age are commonly suspected of having PPID but overnight dexamethasone suppression test results are normal and hirsutism is not a typical clinical sign. Elevated fasting insulin concentrations (>42 uU/ml or >300 pmol/L) may be found in some, but not all, EMS-affected equids. As an example, in the same cohort of Virginia horses described above, 10% were found to have fasting hyperinsulinemia. Although obese horses were more likely to have hyperinsulinemia than those with a BCS ≤6, not all obese horses had an elevated insulin concentration. However, when dynamic testing of tissue sensitivity to insulin is pursued (several methods are available), IR is found to be a consistent feature of this syndrome.

What is insulin resistance? Simply stated, IR is the metabolic state in which a greater amount of insulin is required to exert the expected physiological effect of glucose uptake by peripheral tissues. IR is most easily documented by detection of hyperinsulinemia after an overnight fast (or at least 6 hours after a grain meal). Unfortunately, because insulin release is a dynamic physiologic response to feeding, fasting serum insulin concentration is not always elevated in horses with the metabolic syndrome. However, increases in serum glucose and insulin concentrations in response to administration of a bolus of glucose are typically exaggerated in horses with insulin resistance (Figure 2). A relatively simple test for IR is an intravenous glucose tolerance test (IVGTT). In the IVGTT, blood glucose concentration is measured before and for 3-6 hours after administration of an intravenous bolus of glucose (0.1-0.3 g/kg). In the normal state, blood glucose and insulin concentrations should return to baseline within 1 to 2 hours. Glucose intolerance (another name for IR) is present when blood glucose and insulin concentrations remain elevated for more than 3 hours after glucose administration.

Figure 2. Andalusian mare with EMS and mild laminitis at initial evaluation (2004, 14-years-old, left picture) with a BCS of 8/9 and weight of 1250 lbs and at reevaluation 2 years later after a 160 pound weight loss (2006, 16-years-old, right picture) to a BCS of 6/9; a glucose tolerance test (0.3 g/kg IV) was performed at both times and revealed greater increases in both glucose (left graph) and insulin (right graph) in 2004 (lines with squares) as compared to 2006 (lines with circles); however, it is important to note that fasting insulin concentrations were not remarkably different at these two times emphasizing the limitation of using fasting insulin concentration alone for documentation of insulin resistance.

It is also recognized that both endogenous and exogenous corticosteroids can alter uptake and release of glucose and fatty acids by hepatic, adipose, and muscle tissue. Syndromes of cortisol excess, such as PPID, can also lead to decreased tissue uptake of glucose and IR, sometimes manifested by hyperinsulinemia. With EMS, serum cortisol concentration is not elevated (and is often nearer the lower end of the reference range) and results of overnight dexamethasone suppression tests are normal. However, cortisol activity at the tissue level is largely regulated by the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-β-HSD1). This enzyme has both oxo-reductase and dehydrogenase activities. Dehydrogenase activity of this enzyme converts active cortisol to inactive cortisone. In contrast, oxo-reductase activity of this enzyme results in greater conversion of inactive cortisone to active cortisol in the tissues, thereby magnifying the effects of circulating glucocorticoids on target tissues. As has been recently found in people, some horses are likely genetically predisposed to developing EMS due to tissue-specific dysregulation of 11-β-HSD1. Because the alteration in cortisol metabolism occurs at the tissue level, rather than through the hypothalamic-pituitary-adrenal axis, the terms "Cushing's disease of the omentum" and "peripheral Cushing's syndrome" were early descriptors used for the metabolic syndrome.

A number of further metabolic alterations can accompany both human and equine metabolic syndrome. However, obesity is the primary problem that sets off the cascade of metabolic abnormalities. In humans, excess fat can either be deposited centrally (android or apple-shaped individuals) or around the hips (gynoid or pear-shaped individuals). The former are typically insulin resistant and may have hyperinsulinemia while the latter typically are not insulin resistant. One mechanism that appears to contribute to IR in android individuals is excess fat storage in liver and skeletal muscle, perhaps because adipocytes in other areas of the body are less effective in taking up and storing fat. Excess fat in liver and muscle tissue has been demonstrated to inhibit glucose uptake by these tissues. Decreased glucose uptake subsequently leads to increased insulin release and hyperinsulinemia. With either advancing age or inheritance of "thrifty genes", mitochondrial density and function in skeletal muscle is also reduced. Lower mitochondrial oxidation of fat can also lead to excess fat in skeletal muscle.

Interestingly, it is becoming clear that adipocytes are not simply repositories of stored energy. Adipocytes also produce hormones (adipokines) that may exert actions throughout the body. One of these hormones is leptin and recent research has found an association between obesity and elevated serum leptin concentrations in horses. Another of these hormones is resistin – it is named for the fact that it plays a substantial role in IR. It remains to be seen what roles these hormones play in development of EMS. Of interest, obese horses can either have low (1-5 ng/ml) or high (10-50 ng/ml) resting plasma leptin concentrations. Horses with high leptin concentrations also had a greater insulin response to glucose infusion (during an IVGTT). Despite the fact that obesity is an important risk factor for human metabolic syndrome, it has also been recognized that not all obese people develop the clinical problems clustered under the metabolic syndrome. This again reflects the importance of genetic predisposition. Perhaps a high vs. a low resting leptin concentration in horses is another risk factor, in combination with obesity, for development of laminitis in EMS. Adipocytes also produce a family of adiponectins, peptide hormones that actually enhance insulin action. It is currently speculated that higher circulating concentrations of these peptides may be a protective factor against development of the complications of obesity. Clearly, the pathophysiology of IR with obesity is complex and incompletely understood at this time

Finally, insulin has a broader range of actions than simply enhancing tissue glucose uptake. Specifically, insulin can act as a pro-inflammatory agent stimulating inflammatory mediator production (e.g., tumor necrosis factor-a, interleukin-6, and others) and alterations in hemodynamics (vasoconstriction and hypertension). A recent study in ponies also demonstrated that laminitis can be experimentally induced within 24-48 hours of starting an intravenous infusion of insulin (that produced supraphysiologic blood insulin concentrations). Further, endothelial cells are particularly susceptible to the effects of excess insulin and glucose. Specifically, there is a reduction in endothelial-derived nitric oxide (NO) activity and increased expression of endothelin-1 (ET-1). The combination of reduced NO and enhanced ET-1 production leads to an increased state of vasospasticity because NO and ET-1 represent the two most potent endothelium-derived vasorelaxing and vasocontracting factors, respectively. The role of these hemodynamic changes on the development of laminitis in obese horses is currently unknown but it is becoming increasingly evident that the traditional "vascular hypothesis" and more recently described "metabolic hypothesis" for development of laminitis are not mutually exclusive.

Diagnosis

So how does knowledge of this complex and incompletely understood pathophysiology help an equine practitioner evaluating the overweight, foundered horse? They are perhaps not a lot further ahead than they were a few years ago because no drugs have been developed to effectively treat EMS. Further, we are not a whole lot better at treating or predicting the outcome of horses with acute laminitis. However, knowledge is useful as it allows principles to be followed in the evaluation of horses with EMS and, more importantly, it fosters increased emphasis on prevention of laminitis in at risk horses.

At present, diagnosis of EMS is based on physical characteristics, specifically obesity and/or regional fat deposits with or without laminitis. Further support for EMS can be demonstrated by measurement of fasting hyperinsulinemia and mildly elevated plasma triglyceride concentrations. Of interest, some clinicians have recently suggested that the upper limit of the reference range for insulin in healthy horses should be reduced to ≈30 uU/ml or 200 pmol/L. Ideally, blood samples should be collected in the morning after an overnight fast or, at a minimum, 6 hours after meal feeding (even hay feeding can cause a mild increase in insulin in horses). It is also important to remember that medications can sometimes alter blood glucose and insulin concentrations (i.e., α-2-agonist such as xylazine or detomidine). Thus, blood samples should be collected before sedation that may be needed for farrier work or other diagnostic procedures. Unfortunately, EMS-affected horses do not consistently manifest hyperinsulinemia. In those cases in which further evidence to support EMS is needed (e.g., for clients that refuse to believe that their overweight horse may be at risk for laminitis), an IVGTT can be pursued.

Development of a "metabolic profile" that would include physical measurements (e.g., body weight, body condition score, neck circumference to assess "crestiness", and others) and laboratory values (e.g., insulin, glucose, triglycerides, leptin, adiponectin, and others) that would allow risk assessment for development of laminitis in overweight horses is a goal of several research groups. Unfortunately, such a profile may take years to develop due to our limited understanding of EMS pathophysiology. Ideally, our goal should be to identify at risk horses prior to onset of laminitis in order to implement diet changes and an exercise program. Thus, this author strongly advocates assessment of obesity by performing a body condition score during annual or semiannual preventive health care visits. When BCS is 6 or greater, diet should be evaluated (concentrate feeds discontinued and pasture access limited or a grazing muzzle used) and an exercise program should be initiated. In addition, hoof conformation should be regularly assessed with an emphasis on looking for early changes indicative of chronic laminitis. If changes are noted, lateral foot radiographs should also be pursued. Lastly, a good veterinarian-client relationship is critical for diet and exercise recommendations to be practically implemented by owners.

Supplemental readings available on request to the author