PPID

• PPID, equine pituitary Pars intermedia dysfunction, affects horses older than 15 years old and has no sex predilection or breed predisposition. It can also occur in donkeys.
• The pituitary gland sits ventral to the hypothalamus and is formed of 4 key sections

  • The pars distalis, pars intermedia and pars tuberalis and pars nervosa (aka posterior pituitary)
  • The pars intermedia is the focus

  A) intermedia

  
• Normally only a small amount of ACTH makes it to the peripheral circulation which then goes to the adrenal gland for glucocorticoid stimulation (most of it goes to produce beta endorphin, alpha-MSH and CLIP). In the pars intermedia (of the pituitary gland) TRH is stimulatory and increases the amount of POMC and therefore ACTH produced. Dopamine is inhibitory and reduces the amount of POMC and therefore reduces ACTH produced and therefore reduces glucocorticoids
• fill in the blanks

  A) POMC

  B) ACTH

  C) CLIP

  D) Glucocorticoids

  
• In PPID you get an increased size of pars intermedia (which is associated with the adenoma formation) which leads to an increased activity of pars intermedia (PI) and can cause compression of other structures e.g., hypothalamus and optic chiasm. Upon histology, you will see oxidative damage as well as accumulation of α-synuclein and lipofuscin.
• Rather than being a typical neoplasia this is actually a neurodegenerative disease due to a loss of inhibitory dopamine input from the hypothalamus. This leads to hyperplasia, adenoma formation and overproduction of POMC and POMC derived peptides including ACTH (and then an increase in glucocorticoids).

  • This explains why age is a risk factor and why onset is slow and insidious.
  • Neurons degrades with age and this takes time.
• in the horse, you see an increase in ACTH with a variable increase in cortisol and a low level of adrenocortical hyperplasia.
• Early clinical signs include…

  • Muscle atrophy (especially the epaxial muscles which run along the sides of the spine) and pendulous abdomen (likely due to a lack of musculature holding the abdomen in causing a pot-bellied appearance)
  • Hair abnormalities
  • More hair in anagen phase may be due to an increased α-MSH. This leads to abnormal hair shedding which leads to long curly hair coats. Hypertrichosis is pathognomonic
  • Lethargy / quiet / poor performing
  • Due to increased B-endorphins which causes a mild sedative effect.
  • Regional adiposity
  • Due to increased α-MSH because it affects appetite.
• Later clinical signs include…

  • Laminitis
  • PPID exacerbates insulin dysfunction which predisposes the horses to laminitis.
  • This is often the presenting complaint!
  • Recurrent infections due to immune dysfunction e.g., sinusitis, skin, foot abscess, bronchopneumonia and increased parasite burden
  • This is likely because α-MSH affects neutrophil function meaning they are not as effective in horses with PPID.
  • PUPD
  • Compression of pars nervosa (due to the increase in size of the pars intermedia) leads to a decreased ADH causing the PUPD.
• urther uncommon clinical signs include…

  • Hyperhidrosis
  • This leads to anhidrosis due to sweat gland exhaustion
  • Pseudo-lactation due to a lack of dopaminergic control
  • Suspensory ligament breakdown due to collagen disruption causing a dropped fetlock
  • Blindness due to compression of the optic chiasm
  • Keratitis due to decreased corneal sensation. These often present as recurrent non-healing ulcers
  • Low fertility and irregular cycling due to adenoma compression which affects the reproductive hormones.
• A key diagnostic method for PPID is baseline ACTH, to perform you need…

  • EDTA blood tube is used to collect blood
  • Ice packs or refrigerated in the car
  • Centrifugation within 4h: plasma separation

  This is less sensitive in the early stages so you can get false positives. If performing on a high suspicion based on clinical signs, then you are more likely to correctly identify positives.

  • Sensitivity 93%, specificity 88% in autumn
  • Sensitivity 60%, specificity 87% at other times
• Another diagnostic test includes the TRH stimulation test, to perform you need to,

  • Collect a baseline
  • Inject 0.5mg (<250kg) or 1mg (>250kg) IV TRH
  • Collect the second sample 10 min later (+/-30min later)
  • Handle samples as for baseline ACTH (chilled EDTA blood)

  This is more accurate in horses with a lower clinical suspicion than baseline ACTH as the effects of stress, pain and illness are reduced so you are more likely to get a correct positive than a false positive.
• There is significant seasonality with hormone production from the PI. The output of the PI increases with shorter day length therefore plasma concentrations of the hormones produced by the PI are greatest in the autumn (Aug-Oct)

  • This has clinical relevance as it alters the ranges depending on the season for our diagnostic tests which measure blood ACTH and we see more variation in results in the autumn. Hence a negative test in the autumn is more likely to be a true result so is the best time of year to test
• when is the best time of year to test?

  autumn
• It is important to consider the following when testing for PPID…

  • Stress, excitement, trailering: transient increase in ACTH
  • ACTH should not be collected within 30 minutes of trailering or if the horse is visibly excited
  • Pain
  • Low to moderate pain has no effect but severe pain can affect the results
  • Active laminitic horses cannot be tested so you need to postpone until severe pain is controlled. Alternatively use the TSH test in these cases.
  • Sedation (xylazine/detomidine+/-butorphanol)
  • Only immediately (within 5-10 minutes) after sedation
  • Do not test during 24-48 hours after sedation
• The main treatment is pergolide (licensed) administered at an initial dose of 1 micrograms/kilograms
• Other treatments are available but they are all off-license. When treating it is also important to consider…

  • Concurrent diseases e.g. EMS in 33% of cases
  • Laminitis management (soaked hay, pain relief and deep soft bedding)
  • Treatment of any secondary infections
• Once the appropriate dose is established recheck the baseline ACTH every 6-12 months, this is due to it being a degenerative disease so is likely to get worse.

  • Re-testing can be fit in with vaccinations so doesn’t cost the owner too much

  It is important to treat these horses as it can greatly improve their welfare and for incentive for the owner it can reduce laminitis episodes).
• fill in the blanks

  A) ACTH

  B) 6

  C) 4

  D) 6

  
• PPID occurs due to the gradual loss of dopaminergic neurones in the hypothalamus of the brain, leading to a decline in dopamine production.
• Clinical trials show that pergolide promotes normal hair growth and alleviates muscle wasting in affected horses. This drug also helps to increase energy levels and improves body condition in horses with PPID.
• Common symptoms of PPID are...

  • Hirsutism
  • Delayed shedding
  • Pot belly
  • Weight loss
  • Muscle wasting & loss of topline
  • Excessive thirst and urination
  • Frequent infections (compromised immunity)
  • Excessive sweating
  • Sinusitis
  • Tooth loosening
  • Tendon and ligament weakening
• Laminitis is a condition that can develop secondary to PPID. This painful inflammatory condition is characterized by damage to the laminae of the hoof.
• Pergolide should not be given to horses on dopamine antagonist medications, such as acepromazine, sulpiride, domperidone or perphenazine, because these drugs have opposing effects on dopamine receptors. 
• Horses may appear dull, depressed or lethargic after starting pergolide treatment. This impact on mood may be explained by changes in dopamine signalling in the brain. Side effects typically disappear within 1 to 4 weeks.
• Cyproheptadine hydrochloride is a serotonin agonist and is considered less effective than pergolide for treating PPID.
• Trilostane is a synthetic steroid that inhibits an enzyme (3-beta hydroxysteroid dehydrogenase) that plays an important role in cortisol production. It shows promise as a treatment for insulin resistance in PPID and may help minimize clinical signs, especially laminitis. However, other hormones increased in PPID can also influence insulin resistance and may not be affected by trilostane.
• Bromocriptine is a dopamine receptor agonist that has a similar mechanism of action to pergolide but is difficult to obtain and less convenient. Due to its low oral bioavailability, it is often administered multiple times a day via subcutaneous injection. In the EU, it is given orally twice a day.
• While diet alone cannot treat PPID, a forage-based diet that provides sufficient vitamins and minerals can help support the overall health of horses with this condition. These horses benefit from a diet that is low in sugars and starches, also known as hydrolyzable carbohydrates (HC). Avoid feeding energy-dense grains to reduce the risk of metabolic dysfunction and laminitis.
• regarding management advise...

  • maintaining a goof BCS
  • increase exercise when there are no laminitis flares
  • provide pain relief, good farriery and deep bending during laminitic episodes
  • regular density to combat any lose teeth and promote eating