Proceedings of the 16th Italian Association of Equine Veterinarians Congress

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1 Close this window to return to IVIS Proceedings of the 16th Italian Association of Equine Veterinarians Congress Carrara, Italy January 29-31, 2010 Next SIVE Meeting: Feb. 4-6, 2011 Montesilvano, Pescara, Italy Reprinted in the IVIS website with the permission of the Italian Association of Equine Veterinarians SIVE

Diagnosis and treatment of metabolic syndromes Thomas Divers DVM, DACVIM, DACVECC Cornell University, Ithaca NY, USA DIAGNOSIS Endocrine testing to confirm a diagnosis of equine metabolic syndrome

2 Diagnosis and treatment of metabolic syndromes Thomas Divers DVM, DACVIM, DACVECC Cornell University, Ithaca NY, USA DIAGNOSIS Endocrine testing to confirm a diagnosis of equine metabolic syndrome (EMS) or equine Cushing s disease (ECD) is important for: (1) early preclinical diagnosis in hopes of avoiding laminitis and other complications associated with these metabolic disorders, (2) early confirmation of clinical disease, and (3) monitoring response to treatments. METABOLIC SYNDROME Horses and ponies with either phenotypic and/or genetic predisposition for EMS should be routinely tested for the disorder at least once per year. An age to begin testing is unknown, but I would suggest that in breeds with a known pre-disposition testing begin as early as 3 years of age. The simplest test is to measure A.M. plasma insulin in a horse/pony that has been fed a low starch/sugar diet for 12 hrs or more. If the amount of starch and sugar in the feed is unknown, a grass hay soaked in hot water for 30 minutes to remove some sugar, and then drained, could be used. Insulin values greater than µu/ml, depending upon the assay being performed, should be considered suspicious of EMS. The higher the value, the greater the suspicion index for EMS. When testing horses eating rapid growth or stressed pasture, normal values may be as high as µu/ml. This will, of course, depend upon the combination of starches and sugars (the non-structural carbohydrates - NSC) in the grass. Horses that have been fed grain can be tested 6 hours after the last grain feeding but results are not as predictive as overnight feed withholding. A phenotype typical of EMS (cresty neck, fat pads of the tuber ischii and prepuce of males) and insulin levels greater than 20 µu/ml, for all practical purposes, is considered diagnostic for EMS. Conversion factor for laboratories using pmol/l is 1 µiu/ml: 6.945: pmol/l. Slightly more sensitive testing can be performed by testing the glucose:insulin ratio (values < 10 should be considered abnormal) but, because most horses with EMS maintain glucose within normal range when fed only low NSC forage, the change in insulin is the primary determinant of any ratio changes. This is different from ECD where the blood glucose may be persistently high in approximately 20% of cases. When a single insulin value is used as the diagnostic test of EMS, we must be careful not to over interpret a borderline value, such as 15 µu/ml, because not only do we need to consider different diets, but also inter-laboratory variation. Most veterinary laboratories have recently switched from a DSL assay to a Linco assay; the Linco assay may give results up to 10% higher than the DSL assay. In contrast, labs that are still using a DPC assay may normally produce results that are much lower than seen with other testing methods. Triglyceride values > 56 mg/dl in normally fed ponies was an indicator of EMS in one study. Triglyceride values may vary between labs, so this number should not be considered absolute. A triglyceride value that might be supportive of EMS in horses has, to my knowledge, not been established. Other tests that can be used to diagnose EMS are compu- 69

3 tation of proxies for insulin sensitivity and pancreatic beta-cell response, or the more laborious frequently sampled intravenous glucose tolerance test, combined glucose-insulin testing or euglycemic hyperinsulinemia clamp testing which may be the most sensitive test of the group. These tests have recently been reviewed. It is possible that these tests could be affected by season of the year (undocumented). Seasonal variations in plasma leptins occur in mares and higher leptin concentrations are associated with an increased insulin response (up to 4x) in response to intravenous glucose. Seasonal variations to several tests would not be surprising because adrenocorticotropic hormone (ACTH) and, to a lesser degree, the dexamethasone suppression test, both of which are used to test for ECD, are known to have seasonal variation. Plasma leptin in addition to fasting insulin would have advantages in diagnosis since leptin concentration are more stable than insulin immediately following a meal. Thyroid testing is probably of little benefit in horses with either EMS or ECD. Mares with high body scores and high leptin routinely have high T 3 but low thyroxine. Management changes, exercise, and reduced NSC diets may lead to improvement in obesity and/or insulin sensitivity tests. Monitoring EMS with repeated laboratory testing, body condition scores, and clinical findings is recommended. Horses with clinically-active laminitis may be difficult to test due to release of endogenous cortisol and catecholamines and their antagonistic effect on insulin sensitivity. Once the laminitis is in a quiescent stage, testing can be performed. ECD can be diagnosed by several laboratory tests. The clinical finding of hirsutism is considered the gold standard and laboratory testing in those cases would be purely for the purpose of monitoring response to treatments. Hyperglycemia does occur in a significant percentage of ECD patients and, in older horses/ponies, the finding of hyperglycemia in a non-painful, unexcited, healthy animal that has not been fed a sweet feed within 4 hours should be considered highly suspicious for ECD. The screening test I prefer for ECD is single sample ACTH (EDTA tube, plasma placed in plastic and frozen within 4 hours) measurement. While there are both false negatives and false positives, predictive value of the test in my hands has been good, although not great. ACTH should not be relied upon as a diagnostic test between the last week of August and the first week of November in the Northern states (would likely vary by geographic region). Overnight dexamethasone suppression test can also be used and may have a higher predictive value for ECD than ACTH, but two visits to the patient (late afternoon at time of dexamethasone administration and 18 hours later) might be needed. Failure to suppress cortisol < 1 µg/ml is considered diagnostic for ECD. This test also loses some accuracy during the September to November months. I have minimal reservations about administering one dose of dexamethasone (0.04 mg/kg) to even chronically laminitic horses/ponies if needed to diagnose ECD. Worsening of the laminitis after the dexamethasone administration is rare, but may occur. Another test used by some veterinarians, but lacking published information, is diurnal variation in cortisol (requires two samples). ACTH and cortisol response following administration of thyrotropin releasing hormone (TRH) has also been used as a diagnostic test for ECD, but the test is more expensive and requires multiple samples. The TRH cost is approximately $35 for 1 mg of a chemical grade TRH, which may cause some transient, albeit mild, adverse reactions following intravenous administration. A combined dexamethasone suppression-trh stimulation test has been described as a valid diagnostic test but I have rarely, if ever, felt compelled to use the test. Likewise, urine cortisol:creatinine ratio has been reported to be useful in the diagnosis of ECD, but is rarely used in the U.S. Testing for ECD during September to November can be difficult and domperidone response (3.3 mg/kg PO of domperidone causes a 2-fold or greater increase in ACTH 4 hours later in ECD horses) might prove to be a valuable test during this time, but needs further validation. Testing ACTH alone during the fall can still be 70

4 helpful if the values are either normal (< 35 pg/ml, negative for ECD), or very high (> 250 pg/ml ponies or > 150 pg/ml horses, supportive of ECD) during these months. Plasma insulin should not be relied upon to diagnose ECD, but I do recommend measuring it as it can be both a prognostic indicator and be used along with changes in ACTH and clinical signs as an indicator of response to therapy. A domperidone stimulation test has been proposed but it s value in diagnosing ECD remains undetermined. If both EMS and ECD are being considered as possible diagnoses in the same horse (which does occur), testing with combine baseline insulin, ACTH and dexamethasone suppression test might be the easiest way to test for both diseases, although this is unconfirmed. If cortisol is suppressed (< 1ug/ml), but either insulin baseline is high or insulin is increased 4X or more 18 hrs following dexamethasone administration, EMS might be suspected. TREATMENT AND PREVENTION Prevention of endocrine related laminitis has the greatest chance of success if: (1) an early diagnosis of endocrinopathy is made and (2) appropriate treatments, monitoring of treatments and important management changes are made. Proven medical treatment for equine metabolic syndrome (EMS) include Metformin and thyroxine. Metformin (Fortamet ) 15 mg/kg P.O. q 12 hr therapy has been shown, in one study to improve insulin sensitivity. Trilostane (0.5 mg/kg p.o.) is used by some veterinarians and there is a single abstract indicating improvement in horses with EMS when treated with Trilostane. Currently, dietary management (lower carbohydrates) and increased exercise resulting in appropriate weight loss and improved insulin sensitivity provide the best long term chance of preventing laminitis in EMS. Early recognition of EMS in the prelaminitis (PL) stage is important to prevent any structural damage to the hoof and the cascading pathology that can follow the initial laminitic episode which may prevent adequate exercise and cause persistent pain, both of which may further diminish insulin sensitivity. Exercise should be increased in obese horses/ponies with the primary intention of improving insulin sensitivity and secondarily decreasing excess body weight. Exercise can improve insulin sensitivity without a change in diet, BCS, or body weight. It has been shown in horses that improved insulin sensitivity can begin after only a few days of exercise. The amount of increase in exercise will depend on how sedentary the horse/pony is currently, body condition score, musculoskeletal health, etc. Although some obese horses may never develop EMS, they should all be considered EMS candidates, especially those with unusual fat deposits and/or those with suspected genetic predisposition. All soluble carbohydrates in the form of grain feeding and treats should be removed from the diet of horses/ponies diagnosed with EMS. If the patient is a pregnant horse/pony, any high carbohydrate concentrate may need to be gradually replaced with a higher fat concentrate to prevent negative energy balance and hyperlipemia. In many cases, hay will become the entire diet of horses with EMS. The hay should be routinely tested, mixing samples from several bales from the same field if possible; hay fed to EMS horses/ponies should have a nonstructural carbohydrate (NSC) content of < 12%. Some forage analysis labs will not provide NSC content, but will provide water soluble carbohydrate (WSC) and starch percentages. This is similar to the NSC, and when added together, should also be below 12%. Mixed grass hay harvested in the summer prior to seed head formation will usually meet this criterion as will some cuttings of alfalfa. The hay should be fed at approximately 1½% B.W. When we are unsure of the NSC content of hay being fed to EMS patients in our hospital, we may soak the hay in hot water for 30 minutes prior to feeding to remove some of the sugars in the hay. This can be done on a farm where EMS horses exist and when hay analysis has not been performed. Pelleted hay with low NSC content and timothy cubes are commercially available and promoted as alternative feeds for horses 71

5 with EMS or ECD. It should be noted that some cool season grass hays will be higher in NSC than some alfalfa hays. Time of year, stage of growth, time of day the hay is cut, fertilization and environmental factors all affect NSC content. Pasture turnout with other horses can be used and may be the simplest way to both reduce carbohydrates and increase exercise (assuming there is adequate room and stimulus to exercise), but there are many aspects of pasture turn out that must be considered. During times of dynamic growth, especially spring, seed maturation or stressed drought or frost grass conditions, a grazing muzzle would be required to prevent over consumption of high NSC grasses. Grazing muzzles only work if they remain on the horse and accidental removal of the muzzle could be devastating for horses/ponies with EMS. Grasses are generally the greatest risk in the spring or fall and at any other times where rapid changes in growth are expected. Pasture is best avoided during these times. Although NSC of grass is lowest at night, intermittent grazing can be risky as the horse/pony may engorge on the pasture. Grazing during moderate growth periods in the summer is probably acceptable for some EMS horses/ponies and may even have some advantages over total dry lot confinement by supplying some essential nutrients and anti-oxidants that may not be available in commercial feeds and stored hays. If the horse/pony becomes too thin over the ribs, soaked plain beet pulp, soybean or corn oil and/or rice bran can be added to the diet. It is especially important to not make dramatic changes in the diet of pregnant horses/ponies to avoid hyperlipemia! Some horses have such efficient thrifty genes that high body condition scores (BCS>7) are maintained in spite of conscientious exercise and nutrition programs; for those horses daily thyroxine (0.1 mg/kg) is often used. Many times, thyroxine treatment is begun as soon as the diagnosis of EMS is made and concurrent with changes in nutrition and exercise programs. Chromium (1 mg/100 lbs) has been recommended in hopes of improving insulin sensitivity but there is limited scientific support for this in horses. Although horses with EMS have not been documented to be hypertensive in one study, as in the human metabolic syndrome, some veterinarians recommend 30 mg/kg of magnesium oxide (MgO) daily in hopes of decreasing blood pressure. I have not routinely recommend chromium, cinnamon, curry, magnesium or L- carnitine for either EMS or equine Cushing s syndrome (ECS), although the products seem safe and I have no medical opposition to their use. I do recommend vitamin E, beta carotene, some green forage and a balanced mineral mix for EMS and ECD horses/ponies. The vitamin E and beta carotene are extremely important if the animal has no access to green forage. Monitoring response to treatments and management changes in EMS should include: baseline serum insulin testing (withhold feed for hours) at least twice a year but not in the fall, body condition scoring in early spring and late fall and hoof wall examination and radiographs if needed. Blood for insulin would ideally be collected in the early morning each time as there could be some diurnal and seasonal variation in serum insulin in horses with endocrinopathies. The diagnostic or monitoring value of serum leptin is yet to be determined in EMD suspect horses but it in combination with insulin may be the best testing practice. There may be some over-lap between EMS and ECD and as a consideration, EMS horses > 8 years of age should be tested for ECD. Pergolide is a moderately effective treatment for ECD and should be recommended for all equines diagnosed with the disease. That being said, some owners may waive treatment because of expense. Monitoring the clinical condition and re-testing blood glucose, baseline insulin, and adrenocorticotropic hormone (ACTH) should be performed after 4 weeks of therapy and once or twice yearly, thereafter. Ideally, testing would be performed at the same time of day and same months each year and not during a time of rapidly decreasing sunlight, e.g., fall. If the plasma ACTH concentration is extremely high, there may be large fluctuations in hour to hour sampling and ACTH changes in those horses following 72

6 initiation of pergolide therapy should be interpreted with caution. Regular and appropriately timed monitoring is important for regulating the dose of pergolide and making appropriate nutritional changes. Increases in properly timed/collected serum insulin may indicate a need for increased pergolide treatment and/or changes in dietary management. Several herbal products have been touted as effective treatments for equine cushing s disease but to my knowledge none have been proven to be efficacious. Dietary changes for ECD are similar to EMS, except dramatic restriction of soluble carbohydrates might not be possible, especially in older horses/ponies with dental problems or abnormally low body condition scores. Many horses/ponies with ECD also have heaves, which may prevent the feeding of hays (or even pasture in the Southeast U.S.). Furthermore, dental problems are common in ECD horses/ponies requiring feeding of complete pellets and oils in many cases. Anti-oxidants, both vitamin C and E, should be fed to horses/ponies with ECD. In addition to the medical, nutritional and exercise management needs for EMS and ECD, proper and routine hoof care should be provided; the routine hoof care is particularly important in ECD. Lastly, it is very important that horses with ECD and/or EMS be maintained on an excellent preventative medicine program, e.g., deworming, vaccination and dental. Any intestinal disorder such as colic, diarrhea or choke, and any systemic illness could provide trigger factors that initiate laminitis. REFERENCES Bailey SR, Habershon-Butcher JL, Ransom KJ, Elliott J, Menzies-Gow NJ. Hypertension and insulin resistance in a mixed-breed population of ponies predisposed to laminitis. Am J Vet Res Jan; 69(1): Carter RA, Treiber KH, Geor RJ, Douglass L, Harris PA.Prediction of incipient pasture-associated laminitis from hyperinsulinaemia, hyperleptinaemia and generalised and localised obesity in a cohort of ponies. Equine Vet J Feb;41(2): Donaldson MT, LaMonte BH, Morresey P, Smith G, Beech J. Treatment with pergolide or cyproheptadine of pituitary pars intermedia dysfunction (equine Cushing s disease). J Vet Intern Med Nov-Dec;16(6): Donaldson MT, McDonnell SM, Schanbacher BJ, Lamb SV, McFarlane D, Beech J. Variation in plasma adrenocorticotropic hormone concentration and dexamethasone suppression test results with season, age, and sex in healthy ponies and horses. J Vet Intern Med Mar-Apr; 19(2): Durham AE, Rendle DI, Newton JE. The effect of metformin on measurements of insulin sensitivity and beta cell response in 18 horses and ponies with insulin resistance. Equine Vet J Jul;40(5): Frank N, Elliott SB, Boston RC. Effects of long-term oral administration of levothyroxine sodium on glucose dynamics in healthy adult horses. Am J Vet Res Jan;69(1): Geor R, Frank N. Metabolic syndrome-from human organ disease to laminar failure in equids. Vet Immunol Immunopathol Jun 15;129(3-4): Kronfeld DS, Treiber KH, Hess TM, Splan RK, Byrd BM, Staniar WB, White NW. Metabolic syndrome in healthy ponies facilitates nutritional countermeasures against pasture laminitis. J Nutr Jul; 136(7 Suppl):2090S-2093S. McFarlane D, Cribb AE. Systemic and pituitary pars intermedia antioxidant capacity associated with pars intermedia oxidative stress and dysfunction in horses. Am J Vet Res Dec;66(12): McFarlane D, Holbrook TC. Cytokine dysregulation in aged horses and horses with pituitary pars intermedia dysfunction. J Vet Intern Med Mar-Apr; 22(2): McGowan CM, Frost R, Pfeiffer DU, Neiger R. Serum insulin concentrations in horses with equine Cushing s syndrome: response to a cortisol inhibitor and prognostic value. Equine Vet J Apr;36(3): Miller MA, Pardo ID, Jackson LP, Moore GE, Sojka JE. Correlation of pituitary histomorphometry with adrenocorticotrophic hormone response to domperidone administration in the diagnosis of equine pituitary pars intermedia dysfunction. Vet Pathol Jan;45(1): Perkins GA, Lamb S, Erb HN, Schanbacher B, Nydam DV, Divers TJ.Plasma adrenocorticotropin (ACTH) concentrations and clinical response in horses treated for equine Cushing s disease with cyproheptadine or pergolide. Equine Vet J Nov; 34(7):

Nutrition for the Metabolic/Cushingoid Horse. Ocean State Equine Associates 2205 Providence Pike North Smithfield, RI 02896

Nutrition for the Metabolic/Cushingoid Horse Ocean State Equine Associates 2205 Providence Pike North Smithfield, RI 02896 Goals What are PPID and EMS? What is their link to IR? How is IR linked to laminitis?