1. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences CUSHING’S DISEASE and OTHER METABOLIC DISEASES Nicholas Frank, DVM, PhD, DACVIM Assistant Professor Large Animal Internal Medicine

2. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Laminitis and Hormonal Disorders LAMINITIS “Founder” OBESITY Cushing’s Disease Too much grain Colic Diarrhea Lush pasture

3. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

4. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

6. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences LAMINITIS & CUSHING’S DISEASE Possible cause if 10 to 20 years old Likely cause if over 20 years old Estimated that more than 70% of horses over 20 years of age have Cushing’s disease

7. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences What To Look For: Body Condition Too FAT in places –Cresty neck –Fat pads at tail head –Bulging fat pads above eyes And too THIN in places –Ridge along back or swayed back –Ribs showing –Losing leg muscle mass Rounded abdomen (pot-bellied)

8. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

9. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

10. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

11. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences What To Look For: Hair Coat Long hair in places –Back of legs Curlier hair –Neck or sides Takes longer to shed out –Patches of long hair in early summer Long curly hair coat that never sheds

12. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

13. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences What To Look For: Lethargy Mellowing with age? Doesn’t want to be ridden

14. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences What To Look For: Infections More prone to sole abscesses White line disease Gets every respiratory disease that comes through the barn Tooth root abscesses Sinus infections

15. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences What To Look For: Drinking/Urinating Seems to drink more water than before (filling up buckets more often) Stall is wetter than before Stall smells worse than before

16. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Other Associated Conditions Osteoporosis Delayed wound healing Central nervous system dysfunction Persistent lactation Infertility Hindlimb suspensory breakdown

17. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Cortisol Is the “stress hormone” FIGHT or FLIGHT Released from adrenal glands (near to kidneys) Acts to provide fuel for flight (glucose) Reduces inflammation

18. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Cortisol and Laminitis Reduces blood supply by constricting arteries Weakens attachments Impairs ability to repair damage Alters glucose delivery to hoof cells

19. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

20. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Pituitary Gland Tumor Microadenoma if < 1 cm in size Macroadenoma if > 1 cm in size

21. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Pituitary Gland Hormones ACTH – tells adrenal glands to release cortisol TSH – stimulates release of thyroid hormones LH and FSH – sex hormones (normal cycle) Growth hormone – normal growth Prolactin – milk production Oxytocin – milk let down ADH – concentrate urine

22. CRH ACTH CORTISOL CUSHING’S

23. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Routine Laboratory Testing Elevated blood glucose levels Shift in white blood cell pattern Insulin concentrations are sometimes high (tolerance test recommended) –Seen with other conditions –Higher in ponies and obese horses –Vary with time and diet

24. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Serum Cortisol Resting cortisol is NOT helpful Loss of daily rhythm Usually higher in morning hours Lower in afternoon and evening Cushing’s diagnosed if less than 30% difference between morning and evening samples

25. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

26. Cortisol Rhythm as a Diagnostic Test UT Research 2003: Four healthy mares assessed every 2 weeks for 8 weeks

27. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Plasma ACTH Cushing’s disease if plasma ACTH concentration is above 10 pmol/L (45 pg/ml) Suspect Cushing’s if above 7.5 pmol/L (35 pg/ml) Advantage: one-time sampling Disadvantage: grey area in normal/abnormal Can be used to assess treatment

28. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Dexamethasone Suppression Test Measure blood cortisol before injection Inject 0.04 mg/kg dexamethasone Measure blood cortisol 24 hours later Suppression to below 10ng/ml is normal You should be aware that, in very rare cases, injecting dexamethasone may cause an episode of laminitis

29. CRH ACTH CORTISOL DEXAMETHASONE Time 24h 10 HEALTHY

30. CRH ACTH CORTISOL Time 24h 10 DEXAMETHASONE CUSHING’S

31. TRH Response Test: Inject TRH and then measure cortisol over 60 minutes Cushing’s TRH Healthy

32. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Cyproheptadine Site of action:Brain Mechanism:Decreases chemicals that speed up the pituitary Dose:Variable (look at response) Response:More active Milder bouts of laminitis, Sheds out Negatives:Only at high doses (drowsy or wobbly)

33. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Pergolide Site of action:Brain Mechanism:Increases chemicals that slow down the pituitary Dose:Variable (look at response) Response:Same as cyproheptadine Negatives:Only at high doses Go off feed, colic

34. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Hypothyroidism Peripheral Cushing’s Metabolic Syndrome Diabetes

35. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Obesity

36. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

37. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Diet-Induced Obesity A horse’s diet contains little fat (< 5%) and should contain limited soluble carbohydrate Human high fat/high cholesterol diet (American diet contains 40% fat)

38. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Obesity-Associated Laminitis Affects delivery of glucose to cells of hoof (insulin resistance) Diabetes-like changes in blood vessels Increases inflammation Lowers ability to respond to changes –More affected by switch to lush pasture –Consistent foot care is more important

39. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences

40. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Hypothyroidism Previously associated with obesity, lethargy, poor performance, laminitis, rhabdomyolysis, and infertility Deficiency of biologically active thyroid hormone

41. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Effects of Hypothyroidism (>12 months) Edema Skin abnormalities Not lethargic Not obese No cresty necks No laminitis No muscle disease

42. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Diagnosis: Routine Measures Serum total T 3 concentration (UT) Serum total T 4 concentration (UT) Free hormones (MSU) Problems –Low when any other disease is present –Low if on phenylbutazone –Low in obese horses –Low in horses with Cushing’s disease

43. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Getting More Reliable Information 1.Measure another hormone called TSH –Currently only available for research –Real hypothyroidism (experimental) High serum TSH concentrations –Other types of hypothyroidism Low serum TSH concentrations 2.Perform a TRH response test

44. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Treating Obesity-Associated Laminitis Reduce caloric intake –Discontinue grain –Limit access to pasture (avoid very green grass) –Feed hay Increase exercise (often limited by laminitis) Supplements

45. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Levothyroxine (Thyro-L®) Type: Synthetic T4 (12mg per tsp) Action:Supplies additional hormone Dose:Commonly use 1-2 tsp/d 80 tsp/lb $20-25/lb $0.25-1.25/d Response:More active. Laminitis? T4 levels to high-normal range Negatives:No TSH monitoring available. Changes in heart muscle

46. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences SUPPLEMENTS Thyro-L® (Lloyd, Inc. funded study) Reduces weight Improves insulin sensitivity (short-term) Magnesium Dietary Ca:Mg increased to 2:1 Mg deficiency is risk factor for type 2 diabetes Chromium tripicolinate Lowers insulin concentrations (ponies)

47. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Chasteberry (Vitex agnes castus) Hormonize Actions against insulin and prolactin Advanced Protection Formula (APF) Contains Siberian ginseng (and chasteberry?) LaminaSaver® “Restaurex™ is the active ingredient found exclusively in Figuerola Laboratories' LaminaSaver®. Restaurex™ major role it to support the body's ability to enhance new cell regeneration during founder/laminitis.” www.figuerola-labs.com

48. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences University of Tennessee Obesity Research (UT Fat Camp) http://www.vet.utk.edu/cemr Began Summer 2003 Six obese horses examined to date Comparing obese and normal weight horses –Less than 15 years old –Calorie-restricted diets –More prone to laminitis –Do not have Cushing’s disease –Insulin resistant

49. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences Questions

50. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences ACTH Synthesis in the Pituitary Gland ACTH αMSHCLIP γMSH βLPH β endorphin γLPH PROHORMONE

51. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences ACTH αMSHCLIP γMSH βLPH β endorphin γLPH ACTH and CLIP Laminitis Increased drinking and urinating Infections (sole abscesses)

52. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences ACTH αMSHCLIP γMSH βLPH β endorphin γLPH MSH: Melanocyte stimulating hormone Long curly haircoat Not shedding properly

53. University of Tennessee College of Veterinary Medicine Department of Large Animal Clinical Sciences ACTH αMSHCLIP γMSH βLPH β endorphin γLPH β endorphin Lethargy More pain tolerance