CUSHING’S DISEASE and OTHER METABOLIC DISEASES

1. CUSHING’S DISEASE and OTHER METABOLIC DISEASES Nicholas Frank, DVM, PhD, DACVIM Assistant Professor Large Animal Internal Medicine

2. Laminitis and Hormonal Disorders Too much grain Colic Diarrhea Lush pasture Cushing’s Disease LAMINITIS “Founder” OBESITY

6. 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. 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)

11. 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

13. What To Look For: Lethargy • Mellowing with age? • Doesn’t want to be ridden

14. 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. 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. Other Associated Conditions • Osteoporosis • Delayed wound healing • Central nervous system dysfunction • Persistent lactation • Infertility • Hindlimb suspensory breakdown

17. 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. Cortisol and Laminitis • Reduces blood supply by constricting arteries • Weakens attachments • Impairs ability to repair damage • Alters glucose delivery to hoof cells

20. Pituitary Gland Tumor Microadenoma if < 1 cm in size Macroadenoma if > 1 cm in size

21. 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. CUSHING’S CRH ACTH CORTISOL

23. 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. 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

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

27. 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. 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. HEALTHY CRH ACTH DEXAMETHASONE CORTISOL 10 Time 24h

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

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

32. 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. 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. HypothyroidismPeripheral Cushing’sMetabolic SyndromeDiabetes

35. Obesity

37. 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. 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

40. Hypothyroidism • Previously associated with obesity, lethargy, poor performance, laminitis, rhabdomyolysis, and infertility • Deficiency of biologically active thyroid hormone

41. Effects of Hypothyroidism (>12 months) Edema Skin abnormalities Not lethargic Not obese No cresty necks No laminitis No muscle disease

42. Diagnosis: Routine Measures • Serum total T3 concentration (UT) • Serum total T4 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. Getting More Reliable Information • Measure another hormone called TSH • Currently only available for research • Real hypothyroidism (experimental) High serum TSH concentrations • Other types ofhypothyroidism Low serum TSH concentrations • Perform a TRH response test

44. 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. 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. 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. 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 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. Questions

50. ACTHSynthesis in the Pituitary Gland PROHORMONE γMSH ACTH βLPH αMSH CLIP γLPH β endorphin