How I manage endocrine cases (Proceedings)

Thyroid Function

• ↑ mitochondrial number and size
• ↑activity of Na,K-ATPase

• 15% to 40% of your Basal Energy

• Increased energy expenditure of the cell

• ↑protein synthesis and catabolism

• ↑ heat production

• Stimulate basal metabolic rate

Thyroid Function in the Fetus/Neonate

• ↑ mental activity and neural development

• ↑ lung maturation

• ↑ gastrointestinal function

• ↑ cardiovascular function

• ↑ growth and maturation of the skeletal system

Hypothyroidism

Primary

Secondary / Tertiary

• Problem with conversion of T4 to T3 in peripheral tissues

• TSH

• TRH

"False" (Non-thyroidal Illness)

Hyperthyroidism

Factors Affecting Thyroid Levels

Physiologic/pathologic influences

• NSAID administration

• Decrease levels for 2 weeks!

• Corticosteroid administration

• High energy or protein diets

• > 30% of Diet Concentrate levels will decrease

• > 50% then levels decrease to very low levels

• High zinc or copper diets

• Food deprivation

• High intensity exercise

• Non-thyroidal illness syndrome

What DVM's associate with low thyroid levels

• Anhidrosis

• Alopecia

• Chronic Laminitis

• Infertility

• Obesity

• Orthopedic disease

• Congenital hypothyroidism/dysmaturity syndrome

Thyroidectomized horses

• Retarded growth

• Increased sensitivity to cold

• Edema of lower legs

• Decreased feed consumption

• Weight loss

• Decreased Cardiac Output

• Increased blood/plasma volume

Non Thyroidal Illness

• Low thyroid levels to help decrease metabolic rate

• Conservation of lean mass

• Decreased conversion of T4→T3

DIAGNOSTICS

• Rule out other diseases

• Sick euthyroid

• Free T4/T3 and Total T4/T3

• Free T4 either by Dialysis or Diasorin two

• IF fT4 and fT3 are normal→ Not hypothyroid

• Even IF Total T4 and T3 are low

• If fT4 and fT3 are low then:

• Repeat test / Rule Out Sick euthyroid

• Perform TRH stimulation test

• TRH Stimulation Test

• No sterile medical preparation available

• 1mg IV Horse

• 0.5 mg IV Pony

• Pre-Sample

• Post Sample 2 hours Post

• Look for peak in T3

• Response to Treatment

Treatments

• Thyro-L

• Highest MRD 0.08 mg/kg

• Minimal Increases of T4 Levels

• Double MRD

• 100% increase in T4 levels

• Treat for 4-6 weeks and re-test if OK

• Decrease to MRD

• Routinely do PE and hormone levels every 2-4 months

Pituitary Pars Intermedia Dysfunction (PPID)

• Pituitary Gland

• Pars distalis (Anterior Lobe)

• Somatotrophs: growth hormone

• Lactotrophs: prolactin

• Thyrotrophs: Thyroid Stimulating Hormone

• Gonadotrophs: FSH, LH (or ICSH)

• Corticotrophs: prohormone proopiomelanocortin (POMC) cleaved to ACTH & LPH

• Pars intermedia (Intermediate Lobe)

• Melanotropes: Melanocyte Stimulating Hormone

• POMC→ β-Endorphin,ACTH and α – MSH

• ACTH= 2% of Posttranslation

• Pathogenesis (McFarlane 2006)

• Oxidative damage in the Hypothalmus

• Dopamine metabolism produces free radicals

• Loss of dopaminergic innervation to the PI

• Increased levels of ACTH, α – MSH , β-Endorphin

• α – MSH and β-Endorphin

• Six fold increase in the steroidogenic properties of ACTH

• Increased ACTH

• Increased Cortisol Concentrations

• Loss of Circadian Cortisol Concentrations

• Melanotropes

• Insensitive to glucocorticoid feedback

• Corticotrophs are SENSITIVE to feedback

• Breed Predilection

• Morgan and Pony Breeds

• Can occur in any breed

Clinical Signs

• Hirsutism

• Most common clinical sign

• Pathogenesis?

• Polyuria/Polydipsia

• Hyperhidrosis

• Chronic Laminitis

• Any older horse (> 13 yrs of age) that develops insidious onset of laminitis should be evaluated for PPID

• Chronic Infections

• Exercise Intolerance

Diagnostics

• Hirsutism

• Over the fence diagnosis

• Most accurate way to assess PPID

• So why do testing on these animals?

• Monitor response to treatment

• Unfortunately does not occur until later on in the disease process

• Endocrine Testing

• Some are controversial

• Dexamethasone Suppression Test

• Look for Suppression of endogenous Cortisol

• After giving 2mg/100 pounds of Dexamethasone IM

• Give late afternoon (4pm or 5pm)

• Take 2nd sample between 10am and noon

• < 1µg/dl by 19 hours

Dexamethasone Suppression Test

• Do not like to do in hospital setting

• Seasonal Variation

• September to December(Donaldson JVIM 2005)

• Hypothalamic pituitary axis is very active

• Metabolically prepare for the winter?

• Decreased availability of food during the winter

• Increased weight gain/ Fat deposition

• Accurate with early disease?

ACTH Plasma Levels

• Looking for Elevations greater than the reference range for you lab

• ELEVATION: Supportive of PPID

• Magnitude DOES NOT EQUAL Severity

• Single Sample Test!

• Sample Handling

• Needs to be cooled

• Protein can degrade if warm

• Seasonal Variation (Donaldson JVIM 2005)

• Sept-Dec

Diurnal Cortisol Level

• Promoted by BET laboratory

• NO DATA provided by Peer Review

• Too much variability

• I DO NOT ADVOCATE THIS TEST

Dexamethasone and TRH Stimulation

• Time Consuming

• Accuracy 81%

• Histological Findings on 42 Horses

• DST 71%

• Good test for earlier stages of the disease?

Dexamethasone and TRH Stimulation

• FIRST

• Give Dexamethasone 2mg/100 pounds IM

• Suppresses Cortisol to "base line" level

• Similar between PPID and normal horses

• SECOND

• 3 hours later give 1mg TRH IV

• Samples

• Time 0 : Before TRH is given

• 30 Minutes after TRH is given

• 66% increase of Cortisol is suggestive of PPID

• 24 hours after TRH

• Lack of suppression of cortisol

• < 1µg/dl

Fasting Insulin Testing (Dr. Schott)

• Insulin Resistance

• Long term Prognosis = GUARDED

TRIAL and ERROR

• "Early PPID"

• Vague clinical signs

• Poor performance

• Tender Feet

• Diagnostic Dilemma

Treatments

• MANAGEMENT

• Foot Care

• Clip Hair

• Nutritional Consult?

• Equine Senior Feeds

• High fiber feeding

• Frequent fecal egg counts

• Intermittent antibiotic administration

• Medical

• Will early intervention prolong my horse's life?

• NO DATA EXISTS

• Does it need to be continuous or intermittent?

• Long term longitudinal studies would be needed

• My horse is in a Fescue Field, do I need to tx?

• May contain alkaloids that are dopamine-mimetic agents

• I still would Tx if clinical signs are persistent

• PERGOLIDE

• FIRST ROUND CHOICE (Donaldson JVIM 2002)

• Best treatment response from 3 independent studies

• SID

• 2-6µg/kg PO SID (1mg for 500kg horse)

• Anorexia?

• Decrease dose to 0.5 mg orally for 1-2 weeks and then increase to 1mg

• NO PK studies! In horses or humans!!

• Compounding vs Non Compounding

Treatments

• PERGOLIDE

• Response: 30-60 days

• Give at least 6 weeks

• Retest in 90 days

• DST

• Per Schott : Only 30% will show normalization

• ACTH

• Cyproheptadine

• Anti-serotonin

• Serotonin = Secretagogue of ACTH

• Anti-histamine

• 0.3 mg/kg PO BID

• POOR CLINICAL RESPONSE

• Combined with Pergolide

• Will work for some cases

• Vitamin E

• Antioxidant

• 5,000 to 10,000 IU Orally SID

Equine Metabolic Syndrome

• Criteria

• Insulin Resistance

• Prior or current laminitis

• Subclinical laminitis

• Obesity

• Regional Adiposity

• Pre Laminitic Metabolic Syndrome (Dr. Geor)

• Genetic Factors

• "Thrifty" genes →Easy Keeper

• Survival through periods of harshness

• Natural selection/survival of the fittest

• IR and Pro-inflammatory state before harsh winter

• Ossabaw Island Pigs

• Spanish Colonists

• Environmental Factors

• NSC in the pasture

• Over feeding → Iatrogenic

• INSULIN

• Released from the pancreas and helps drive glucose into the cells

• Major sites for insulin mediated glucose uptake (GLUT 4 transport proteins)

• Skeletal Muscle

• Adipose Tissue

• INSULIN Resistance

• Failure of the Skeletal muscle or Adipose Tissue to respond appropriately to insulin

• Compensated Insulin Resistance (Common)

• Example: Insulin has 1/2 of its normal effect→ Pancreas will respond→ MORE INSULIN

• Normal "Net Effect"

• Uncompensated Insulin Resistance (Uncommon)

• Pancreas "fails"

• Glucose levels start to rise

• Diabetes Mellitus : Rarely noted (Advanced PPID?)

• Not all obese horses have an endocrine disorder

• Mismanaged(Feeding)

• Feeding grain

• Stalled without turnout

• Overestimated significance of "work"

• Owner is "at fault"

• Too much energy in ration = fat

• Genetically Predisposed

• Middle Aged Obese Horses

• Pony's

• Morgans

• Paso Finos

• Saddlebreds

• Norwegian fjords

• Tennessee Walkers

• Arabs

• QH

• Typical Signs

• Laminitis

• Obesity

• Infertility

• Confused with Cushings

• Confused with "hypothyroidism"

Fat acts like a GLAND

• Adipokines (> 100 described)

• Reistin

• Leptin

• Obese horses noted elevations

• "Leptin Resistance"

• IL-6

• TNF alpha

• Oxidative stress → Cushing's?

• Cortisol

Omental Adipocytes → Special

• Produce numerous "hormones"

• 11β-hydroxysteroid dehydrogenase-1

• Converts Cortisone→Cortisol (Locally)

• Adipogenesis→IR

• Net activity is greater during obesity

• Glucocorticoids tend to provoke MORE adipocytes to express MORE 11β-HSD-1

Insulin Resistance

• Interference with insulin action at targets

• Enhanced stimulation for pancreatic insulin production (hyperinsulinemia)

• Insufficient glucose delivery to target cells

• Too much glucose for cells that do not depend on insulin (endothelial cells)

Insulin Resistance

• CAUSES

• Genetic variance

• Glucocorticoids

• Obesity →adipokines

• Stress

• Inflammation (cytokines)

• Dietary factors

• Mineral/micronutrient imbalances

• Supplements (glycosaminoglycans) (Dr. Messer)

Consequences

• Laminitis

• PPID →Oxidative Stress

• Thyroid Function

• Incr. Cortisol will Decr TSH production

• Chronic Inflammatory State→ Ox. Stress

• Rhabdomyolysis???

• Muscle cells and Glucose uptake

• OCD/Osteoarthritis

Insulin Resistance And Laminitis

• Endothelium is an organ with a mass equivalent to that of the liver

• Subjected to high levels of glucose

• Glucotoxicity → Oxidative stress

Insulin Resistance : What we learned

• Glucotoxic endotheliopathy

• Vasospasticity

• Oxidative stress

• Pro-inflammatory effects

• Impaired capillary recruitment

• MMP-9 expression

• Glucose starvation/deprivation

DIAGNOSTICS

• FASTING INSULIN

• Take off food 12 hours

• Measure Insulin Levels > 30 µU/mlSuggestive

• NEED TO REDUCE STRESS!

• Stress can induce insulin resistance

• Grass Hay If needed to quiet horse

• Minimal Glycemic Index

• Combined Glucose-Insulin Test

• Dynamic Test

• Detect Early Cases?

• 150 mg/kg 50% dextrose Drip

• Give 0.1 units/kg of regular Insulin

• After dextrose (immediate)

• BETTER HAVE EMERGENCY DOSE OF GLUCOSE

• Combined Glucose-Insulin Test

• Spike of Glucose

• Back to base line by 45 minutes

• Take Glucose Levels

• Pre-Sample

• 1,5,25,35,45 Minutes

TREATMENT

• Diet Changes

• Remove Concentrates

• Reduce access to lush pasture

• Morning grazing

• DO NOT GRAZE AFTER FROST

• 5,000 – 10,000 IU Vitamin E?

• CONSULT A NUTRITIONIST

• Magnesium Oxide

• Shown to be effective in rats and humans

• NOT SHOWN TO BE EFFECTIVE IN THE HORSE

• Chromium

• No Data to say it is efficacious?

• APF and Metformin?

TREATMENT

• Thro-L

• 4 teaspoons 1x daily for 1-2 months and then try to decrease

• Use as a metabolic Stimulant (Some clients have used it for 6-8 months)

• Can use oats to mix in (Low glycemic index)

TREATMENT

• Podiatry