PPID

Question 1

At what age, type and breed is equine cushings prevelant in?

Answer 1

Prevalence: 15-30% in horses >15y.o.

Age: >7y.o. BUT avg 19-21 years of age

Typically a condition of older horses

Diagnosis in <15y.o. interpreted cautiously

Gender: no gender predilection

Breed: Ponies appear predisposed

Question 2

What are the clinical signs of PPID (out in bold the most common)?

Answer 2

• Weight loss/Muscle wastage (up to 88%)
• PU/PD (up to 76%) not always obvious if animals pasture fed.
• Hirsutism (long, curly haircoat) (55-80%)
• Quieter demeanour/lethargy/increased docility
• Poor performance (The owner what do they mean by poor performance)
• Regional adiposity (supraorbital)
• Potbellied appearance
• Chronic laminitis
• Recurring infections (skin, respiratory, dental)
• Hyperglycaemia
• Hyperhidrosis/anhydrosis (less common)
• Neurologic: blindness/seizures/narcolepsy (if adenoma presses on parts of brain, blindness= pressing on optic nerve)
• Absent reproductive cycle/infertility

Question 3

What does this image show?

Answer 3

PPID

• Hirsutism (picture taken in california pony still with winter coat though)
• Potbellied appearance
• Abnormal fat depots
• Muscle loss

Question 4

Describe the generic appearance of a cushings horse?

Answer 4

Question 5

Label the pituitary gland?

Answer 5

Question 6

What is the pathogenesis of PPID?

Answer 6

Pituitary Gland

Pars Distalis produces normally most of ACTH in response to stress:

• Pain, illness
• Excitement, travelling, exercise
• Veterinary procedures
• etc

Pars Intermedia produces normally very small amounts of ACTH

Pars Intermedia becomes hyperplastic/neoplastic, biologically active cells

Lack of dopaminergic inhibition of pituitary PI

ACTH mediated adrenal gland stimulation pituitary hyperadrenocorticism.

Other POMC hormones synthesised:

• α-MSH
• β-endorphins
• Lipotrophins

Question 7

What is the normal physiology of the Pars intermedia in the absence of PPID?

Answer 7

• Pars Intermedia is in a state of tonic inhibition
• Inhibited by dopamine released from dopaminergic neurons that extend down from the hypothalamus
• Dopamine interacts with D2 receptors on melanotrophs and inhibits their activity

Question 8

Illustrate the pathogenesis of PPID?

Answer 8

• Of the 3 hypothalamic tracts involved in Dopamine production, the periventricular tract is the main one implicated the activity of the pars intermedia
• Dopamine acts on D2-receptors on melanotropes in the Pars intermedia and this results in reduction of POMC mRNA expression and POMC-derived hormone release

Question 9

What are POMCs cleaved to?

Answer 9

Question 10

Why is EMS a risk factor for PPID?

Answer 10

• Obesity and insulin resistance associated with low-grade inflammation and pro-oxidative state
• Increased oxidative degeneration of dopaminergic neurons
• PPID developing at an earlier age in horses with EMS
• Key point: Insulin dysregulation exacerbated by the development of PPID

Question 11

What causes the weightloss that is seen in PPID?

Answer 11

Question 12

What causes the PU/PD seen in the PPID?

Answer 12

• Neurogenic diabetes insipidus (decreased ADH production) is likely the result of compression of the pars nervosa by the adenomas in the pars intermedia which results in decrease production and secretion of ADH
• Glucocorticoids increase GFR
• Hyperglycaemia -> osmotic diuresis -

Question 14

What causes the hirsutism seen in PPID?

Answer 14

Question 15

What leads to the lethargy associated with PPID?

Answer 15

Make animal more relaxed and quiet

Question 16

What leads to the increased risk of laminits associated with PPID?

Answer 16

Question 17

What causes the increased susceptibility of disease associated with PPID?

Answer 17

More foot abscesses than normal.

Treat the cushings to get on top of the infections.

Dermatophilus: rainscald

Question 18

What causes the poor fertility associated with PPID?

Answer 18

Question 19

What causes the hyperhidrosis associated with PPID?

Answer 19

Question 20

How can PPID be confirmed?

Answer 20

Clinical

• History
• Clinical Signs

Laboratory tests

• Haematology/biochemistry
• Resting ACTH concentration (best test at present)
• TRH Stimulation Test

Question 21

What would be seen on haemotology/biochemistry for a equid with PPID?

Answer 21

Haematology/biochemisty

• Anaemia
• Neutrophilia/lymphopaenia (stress leukogram because of the cortisol production)
• High insulin
• Hyperglycaemia
• Hyperlipaemia
• High liver enzymes
• Glucosuria

RESTING PLASMA CORTISOL NOT DIAGNOSTIC FOR PPID IN HORSES

Question 22

What is a resting ACTH test?

Answer 22

Submit EDTA plasma sample (purple top)

• Ideally separate quickly and refrigerate within 3h of collection
• Degenerates at room temperature (10-20% daily at room temp)
• Submit chilled

Affected horses have high concentrations

Normally see a seasonal increase in ACTH in Aug, Sept, and Oct (autumn) season specific range that the lab will give you

Positive if > 29 pg/mL

> 47 pg/mL in Aug, Sept, Oct

Gray area 19-40pg/ml in Non-autumn months – repeat testing later

Assay dependent values in

Cost: Approximately £30-40

If sample not refrigerated potential for false negative results

Freezing full blood could give false positive result

Low sensitivity in early PPID

Stress can cause false positive results due to cortisol response to pain.

Question 24

What is the TRH stimulation test?

Answer 24

TRH stimulates ACTH release from the Pars-Intermedia

More sensitive to pick-up early PPID cases – use to detect suspected cases with borderline resting ACTH

• Inject 1.0 mg thyrotropin-releasing hormone (TRH) intravenously at time = 0
• Collect blood at 0 + 10mins ±30mins
• Positive if ACTH >35pg/mL at time 0 or >110pg/mL at 10 minutes

Avoid testing August to October

Sensitivity: 77%

Specificity: 82%

(DST less sensitive but more specific)

No correlation between TRH-st, resting ACTH and DST

Question 25

What is the Dexamethasone suppression test (DST)?

Answer 25

Dexamethasone suppression test (DST) Last thing you want to do is give dex to a horse with laminitis as it turns into cortisol! **\*Rarely used now – historical value\*** * Inject 0.04 mg/kg dexamethasone IV or IM (20 mg for a 500-kg horse) * Measure cortisol at 19 or 24h (£33.50) * Normal response: * Suppresses below 27 nmol/L (=10 ng/mL; 1.0 μg/dL) * PPID if fails to suppress (\>27nmol/L) * Sensitivity: 65% (or less) Specificity:76-100% Somewhat insensitive as seems to identify only cases with obvious clinical signs – resting ACTH more suitable in these cases High false positive rate from July to October!!

Question 26

What is the combined DST/TRH stimulation test?

Answer 26

TRH stimulates ACTH release from the Pars-Intermedia More sensitive to pick-up early PPID cases * Dexamethasone: 40µg/kg, IV @8-10am * TRH: 1.0mg IV 3.5h after Dexamethasone * Collect blood at 0, 3h (before TRH), 3.5h, 24h * **Cortisol** concentration PPID: Greater than 27nmol/L @24h OR greater than 66% increase between 3h and 3.5h (so after TRH) NORMAL:\<27nmol/L @24h AND \<66% increase at 3 vs 3.5h Sensitivity:88% Specificity:76% More samples required more time consuming, more expensive

Question 27

what are the targets for dopamine treatment?

Answer 27

**Dopamine and Serotonin** Loss of dopaminergic neurons with aging Lower dopamine levels allow growth of neoplastic cells and increased activity Dopamine is an INHIBITORY neurotransmitter Interacts with dopamine (D2) receptors on the melanotrophs of the pars intermedia. In contrast, serotonin acts as an excitatory neurotransmitter **Dopamine agonists** * Pergolide * Bromocriptine **Serotonine antagonists** * Cyproheptadine

Question 28

How should pergolide (prascend) be used?

Answer 28

* Starting dose of 2 µg/kg SID (1x1mg tab for 500kg horse) * Recheck ACTH after 4 weeks * Lifelong treatment * Severe cases might not return to range but ACTH concentration should decrease considerably or clinical signs should improve * Clinical improvement within 4-6 weeks * If no improvement increase dose gradually: * 1µg/kg increases every 3-4weeks * Up to 10µg/kg (5mg/day) * Periodic assessment and increase dosage if: * ACTH increases * Lack of clinical improvement/deterioration * Some become anorexic * Reduce dose by 1µg/kg * Split dose to BID * Generally a transient phenomenon * Rarely also lethargy, colic and diarrhea

Question 29

How should Cyproheptadine (periactin) be used?

Answer 29

* Start at 0.25mg/kg PO SID for 4-8 weeks * Increase to 0.25mg/kg PO BID for 4 weeks if no clinical improvement * But Pergolide should be used first to comply with cascade * Rare side effects: sedation, dry mucous membranes, tachycardia

Question 30

How is Vitex agnus-castus (herbal product) thought to work?

Answer 30

* Supposed to stimulate dopamine receptor activity * Blinded study found no positive effect

Question 31

What is Trilostane (used in dogs not recommended for equids)?

Answer 31

Some subjective clinical improvement Older studies found no improvement of DST Currently not reccommended

Question 32

Outline general management of clinical signs?

Answer 32

Diet: adequate caloric intake vs restrictionConsider Insulin sensitivity status Free choice hay (2%BWT) Oil to supplement calories (1-2 cups daily) Laminitis: NSAIDs + Farriery Antimicrobials ±Vit E supplementations (preventing oxidative damage) Frequent dental examinations If PU/PD: plenty of access to water Monitor FWEC (faecel worm egg count)

Question 33

Name the particulars of pergolide (prascend)?

Answer 33

* Treatment of equine Cushing’s disease * Initial dose: 1mg total q24h by mouth * Maximum: 5mg total/day (Source: N: Frank) * 1mg tablets; pack of 60 for £70; pack of 160 for £140 * Dopamine receptor agonist; replaces dopamine inhibition of melantrophs * Can see anorexia when treatment initiated, so gradually introduce * First expect to see improvement in attitude (brighter), then improved PU/PD, and then increased muscle mass and better haircoat shedding * Monitor use with plasma ACTH concentration or TRH stimulation test results * Approximate cost to client per month for a 500-kg horse: £1 per day; £30 to 45/mo

Question 35

Name the particulars of Cyproheptadine?

Answer 35

* Periactin * Treatment of Equine Cushing’s disease * 0.25mg/kg q24h by mouth for 2 weeks * Increase to q12h * 125mg for 500kg horse * Source 1: Periactin: 4mg x 30 = £1.23 wholesale * Source 2: Periactin: 4mg: 4p/tablet wholesale; 7p/tablet retail * Cyproheptadine frequently is combined with pergolide to treat PPID. * Cyproheptadine blocks serotonin, a brain chemical that stimulates POMC production. Often works for a while then loses its effectiveness * Serotonin (excitatory neurotransmitter) antagonist * Can cause Drowsiness and ataxia * “First expect to see improvement in attitude (brighter), then improved PU/PD, and then increased muscle mass and better haircoat shedding” * Monitor with Plasma ACTH concentration or TRH stimulation test results