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The Laminitis Site

Managing horses with PPID - Marian Little & Dianne McFarlane

2/27/2014

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Notes of the TheHorse.com Ask the Vet Live webinar
Managing Horses with PPID with Dr Marian Little and Dr Dianne McFarlane
on 27 February 2014
Sponsored by Boehringer Ingelheim. 
​
 
Background:
Dr McFarlane (M) – 12 years studying PPID, understanding causes, diagnosis and treatment protocol.  Wanted to know how best to care for older horses.
Dr Little (L) – vet with BI since 2007, lost 2 horses to PPID.
 
L:  PPID – most common endocrine disorder of aging horses, prevalence 15-30 % of horses over 15, this is probably an under-estimate.  Chronic degeneration of dopamine secreting neurons leads to loss of dopamine controlling effect to pituitary, which leads to enlargement of the intermediate lobe and increased secretion of hormones.
Early clinical signs – changes in behaviour, loss of topline, secondary infections, haircoat changes, late shedding.
Later signs: “woolly mammoth”, leaner body condition.  Some get PU/PD, sweating abnormalities, abnormal fat deposits, laminitis related to insulin.
TLS: laminitis, especially in the autumn, is often the first sign of PPID that is noticed.
 
Q.  What’s the difference between IR and PPID?
M: 1/3-1/2 horses with PPID will also have dysregulation of insulin, i.e. insulin resistance.  They will have high insulin concentrations (tests: resting insulin or Oral Sugar Test), and high insulin causes laminitis, so these horses are at high risk of laminitis.  1/2-2/3 of horses with PPID are not at risk of laminitis.  Both conditions can happen together – insulin dysregulation (EMS) and PPID in the same horse, with these horses we need to be very cautious of how they are fed, particularly whether they have grass, as there is a high risk of laminitis.  But if insulin is normal PPID horses can have grass and as these horses are often thinner, they are likely to need feeding to maintain weight rather than lose weight
 
Q.  How effective is Pergolide as a treatment of PPID, can it be used on a seasonal basis?
L:  In the 1980s research suggested horses with PPID have an 8 fold decrease in dopamine in the pituitary gland, since then pergolide has been considered the treatment of choice.  There are over 25 published references from the past 30 years describing pergolide’s usefulness in improving clinical signs and test results.
Most recent being the 2009 study for FDA approval of Prascend - 76% of 113 horses with PPID were deemed treatment successes http://thelaminitissite.myfastforum.org/about14.html.
Most common side effect is inappetence - 30% of horses in Prascend study had loss of appetite, only 2 required dose reduction and both returned to a normal dose within the first month.
Recommended starting dose is 2 mg/kg bodyweight so 1 mg/1000 lbs, horses should be monitored and dose adjusted appropriately to control both clinical signs and test results.
No data on the intermittent use of pergolide, but given knowledge of Prascend and the disease, she would be skeptical we can just treat in the autumn and expect adequate control throughout the rest of the year.
TLS: From the Equine Endocrinology Group’s Recommendations for the Diagnosis and Treatment of PPID: It is therefore recommended that PRASCEND be introduced gradually by giving partial doses for the first four days or by administering half the dose morning and evening. 
http://sites.tufts.edu/equineendogroup/files/2013/11/EEG-recommendations_-downloadable-final.pdf
   
Q.  How does Pergolide work?
M: Pergolide is a dopamine agonist – acts similar to dopamine – PPID is the result of a loss of dopamine in the pituitary, pergolide replaces lost dopamine and reduces hormones being produced, when hormones return to normal concentration, clinical signs resolve.
 
Q.  Pergolide was banned from human market because risk of heart problems, is it ok for horses?
L:  Some humans taking ~ 3 mg pergolide for Parkinson’s disease developed fibrosis of heart valves.  This is not an issue in horses, likely due to differences in dosing with regard to dose in proportion to body weight, also there are differences in heart muscle receptors that are stimulated and some other minor differences between humans and horses.  In pergolide research carried out in horses to date there have been no issues noted with cardiac abnormalities.  The FDA 6 month Prascend target animal safety study evaluated 32 horses at elevated doses of Prascend, no cardiac abnormalities were observed clinically or at necropsy.
 
Q.  Are minis/ponies dosed the same as horses?
L:  2 mcg/kg bodyweight so ~ 0.5 mg for a pony is the recommended starting dose, watch for inappetance.  Ponies can be worse in terms of clinical signs, progression of disease and insulin dysregulation than horses.
 http://www.noahcompendium.co.uk/?id=-447753

Q.  25 year old gelding diagnosed with PPID last year because he was sweating when other horses weren’t, being treated with Prascend.  His winter coat is longer than other horses but not excessively long and it does shed out almost completely.  What signs would indicate that his dose needs to be increased?
M:  Sweating excessively can be an early sign of PPID and may happen before haircoat abnormalities.  Diagnosis of PPID should take into account clinical signs and blood tests, worsening of either can indicate that the dose of Prascend needs to be increased.
 
Q.  What % of ponies have PPID/EMS, and how many are diagnosed at a young age?
M:  By the time they are in their 30s, prevelence of PPID in ponies may be 50% (guess!).  Ponies are more at risk of insulin dysregulation, particularly if fat – they are bred to be thrifty – therefore at risk of having both conditions, need to watch feet because of risk of laminitis.
 
Q.  Horse had elevated cortisol levels, started on Prascend, when should he be retested?
L:  By cortisol presumably this means post-DST cortisol, as resting cortisol is not recommended as a diagnostic test.  Retest 30 days after starting treatment with Prascend, then every 6 months, with one test in autumn seasonal rise.
In the USA the upper end of the dose range is 4 mcg/kg (10 mcg/kg in the UK).  Some members of the Equine Endocrinology Group recommend a higher, more flexible dose before considering dual treatment but this is an extra label recommendation (i.e. not recommended on the Prascend data sheet).
With an advanced case, it may not be possible to get hormones into the normal reference range even though clinical signs are responding well – either try raising the dose to see if test results will come down into the normal range or stick with the dose as long as it is controlling clinical signs.
In earlier/milder cases best to adapt dose to try to get both hormones within normal range and achieve improvement in clinical signs.
Best not to overly focus on reaching a particular target for blood results, but focus on achieving a significant improvement in clinical signs and when possible a significant improvement in test results as well.
TLS strongly advises against using the dexamethasone suppression test.
http://sites.tufts.edu/equineendogroup/files/2013/11/EEG-recommendations_-downloadable-final.pdf
 
Q.  Will a horse with PPID need Prascend for rest of its life?
M:  Yes.  At the moment we tend to diagnose horses once they have fairly significant disease.  Perhaps in future if recognised early and we understand more about dopaminergic neurons we may be able to change this.  But once dopamine neurons have been lost we need to keep replacing dopamine for life.  Dr Schott has found that many horses do not need increased doses but can be maintained on a consistent dose for a long time and do well.
 
Q.  PPID horse got loose manure on and off all winter when on liquid compound of pergolide, this year he is on Prascend, she increased the dose for the seasonal rise and reduced it in December, and he immediately got loose manure again.  What are the possible causes?
M: PPID causes a decreased ability to deal with infection and parasites.  Study looked at horses with PPID and they had higher fecal egg counts (FECs), so check FEC to check for worms and use strategic worming in consultation with vet.  At the higher dose, the immune system was probably working better, therefore parasite burden should be investigated.
Also there may be problems with efficacy using compounded pergolide.
TLS: also consider any diet changes in December, e.g. starting hay – stalky hay has anecodotally been reported as causing diarrhoea.  We sometimes see diarrhoea in horses on too high a dose of pergolide – when the dose is reduced, the diarrhoea disappears, with no increase in PPID clinical signs –
 http://www.noahcompendium.co.uk/?id=-447754

Q.  How important is owner’s relationship with their vet?
M:  Important to have vet involved with PPID horse, lot of complexity in diagnosis and treatment, owner info is critical, keep good records – e.g. when coat sheds, feet, appetite, BCS, weight tape – to notice problems early.  Schedule routine checks with vet.  Have to keep on top of PPID.
 
Q.  16 year old gelding, ACTH normal but muscle loss, long curly coat, reoccuring laminitis despite controlled diet and exercise.  Vet suggested starting on Prascend – is it a good idea to treat without a positive blood test?
M:  There’s a good clinical indication that this horse has PPID.  If you suspect a horse has PPID, it almost always does have it, as test results often only become positive later in disease.  The TRH stimulation of ACTH may be more effective at picking up early PPID.  This horse is likely to benefit from Prascend.
TLS: insulin dysregulation should be tested in all cases of laminitis.
 
Q.  How should you prioritise testing when finances are tight?
L:  Depends what clinical signs the horse has, in more advanced cases where the horse has overt signs e.g. long shaggy haircoat, muscle loss, PU/PD, diagnostic tests may be less important as the clinical signs indicate PPID, treatment with pergolide would be warranted.  Diagnostic testing may be more critical earlier in the disease if clinical signs are subtle, e.g. recurrent infection, change in behaviour which aren’t obviously PPID.  Start with diagnostic test then follow up test to monitor treatment, then ideally follow up rechecks.
TLS: NB be aware that tests in early stages of PPID may give false negative results.
 
Q.  22 year old Morgan mare diagnosed with PPID in 2012, doing fairly well on pergolide.  Concerned mare isn’t drinking enough which seems to cause dry manure and bouts of colic.  Before starting pergolide the mare drank 5 gallons/day, now only 2 gallons/day.  Can pergolide reduce thirst too much? 
M:  PPID horses can have PU/PD, but 5 gallons is not excessive so no reason to think this horse had PU/PD before treatment.  Dr McFarlane has never seen pergolide reduce drinking other than correcting PU/PD.  Pergolide does not reduce thirst.  Is horse eating the same as it was before?
 
Q.  Is there a difference between pergolide products in terms of effectiveness?
M:  Research looked at some of the different compounded drugs compared to manufactured pergolide.  Pergolide is extremely hard to compound, if compounding companies do not have all the right equipment they will end up with a product that is not consistent so you might not be giving your horse the dose you think you are.  Pergolide is very unstable, it can degrade quickly, liquid forms degrade as it is sensitive to light and temp.  When peroglide is correctly manufactured and packaged it is stable.  2 investigators have done 3 studies that have shown that the compounded drug is not stable.  TLS: see under Pergolide http://www.thelaminitissite.org/p-q.html.
L:  Recent unpublished data: 21 additional compounded pergolide forumulations were looked at at North Carolina State University, “out of those 21 common compounded formulations from major pharmacies at day 0 of the 6 month study only 4 of those compounds met the plus or minus 10% of labelled concentration, which is what would be acceptable.  And in fact, 1 of those 4 there was absolutely no pergolide detectable during that 6 month time frame” (*this needs clarification – see end of notes).  Plenty of data demonstrating the potency and stability issues with compounded pergolide.
M: Compounded drugs are not under regulatory control, don’t know that what it says on label is what’s in drug.  Manufactured drug is guaranteed to contain what it says on the label.
L/M: 4 out of 21 that were plus or minus 10% at day 0 before chance to degrade.
Prascend is a 1 mg tablet packed in a nitrogen sealed blister pack.
 
Q.  How should Prascend be given?
L:  Prascend should be given as soon as it is taken out of the blister pack.  Can be fed by hand, or dissolved in a bit of water.  If the horse has insulin issues, use low sugar treats to give Prascend, e.g. sugar free pancake syrup.  If no problem with insulin, put tablet in e.g. apple, carrot, apple sauce, grape.  Find something horse likes to insert tablet in, may have to try something new every few weeks.  Horses may go off feed if given with pergolide, so may need to give tablet at different time.
TLS: carrot on an as fed basis has less than 7% combined sugar/starch and a small amount should be safe to feed to any horse, insulin dysregulation or not: http://www.thelaminitissite.org/2/post/2013/03/who-said-stop-the-carrots.html.
 
Q.  Are there any issues regarding vaccinating and worming for horses with PPID?
M:  Vaccinate as any aged horse, depending on exposures to pathogens.  PPID horses respond less rigourously to flu.  Ongoing studies about how PPID horses respond to vaccines.  FECs are important for PPID horses, as they can be high egg shedders, and worm strategically according to results, in consultation with your vet.
 
Q.  Horse was diagnosed with PPID and had laminitis in spring 2013, can he be exercised as normal now?
M:  The consideration regarding exercise is the laminitis.  Horses with PPID can continue to work, and if one of the majority of horses that doesn’t have insulin problems and risk of laminitis, there shouldn’t be any concerns.  Need to be sure the horse isn’t over-exercised if still any pain or inflammation in the feet.  If the laminitis has been resolved and managed then horse should be able to return to exercise.  Feet are limiting factor, work with vet and farrier to do corrective trimming and/or shoeing, take radiographs and be sure feet are resolved before doing much in the way of exercise.
TLS: a horse with active laminitis or founder should not be exercised at all and kept confined until the active laminitis has resolved and the feet have been realigned.
 
Q.  Can chaste berry be given in addition to Prascend/at all?
M: Chaste berry is a herb with reportedly similar dopaminergic-type properties to pergolide.  In herbal supplements we don’t know the amount of active substance (if any) from year to year, or forumulation to formulation.  Dr Beech used chaste berry extract for horses with PPID and found no improvement, then found improvement when same horses were treated with manufactured pergolide.  Don’t use, use only Prascend.
TLS: See Vitex agnus castus http://www.thelaminitissite.org/u-v-w-x-y-z.html.
 
Q.  Numerous supplements/homeopathic treatments claim to help horses with PPID – do any work?
M:  Very little research has been done, the ones tested have shown no improvement.  Nothing can be recommended that has any science behind it to suggest that it is helpful.
 
Q.  28 mare that’s been on Prascend for 18 months, no recurrence of laminitis and a more normal haircoat.  Started shedding in February but seems thin, can’t eat hay as bad teeth.  On grass and concentrate mix, what else can she feed?
L:  Start with thorough dental exam, every 6 months.  Ensure good deworming programme.  For diet, as she’s had laminitis she probably has insulin dysregulation so have to be careful with feed.  If she can’t eat hay, make sure she is fed at least 2% of her bodyweight/day, recommend vegetable oil for calories ½ cup to 1 cup/day, rinsed and soaked unmolassed beet pulp for nutrients, fibre and water (to help prevent colic in horses with poor teeth), flax seed for EFAs and calories, and commercial supplements for weight gain, in addition to her concentrate mix.
 
Q.  Is flaxseed (linseed in UK) good for PPID?
L:  Excellent for equine diet – rich in protein, good for muscle wasting; omega 3 fatty acids; seed holds water so may help prevent colic; in humans may improve immune response, may be added benefit.
 
Q. Will PPID horses have improved FECs when treated with pergolide?
M:  This is an area that needs to be studied.  In theory it should, as Prascend improves immune function, but haven’t done FECs pre and post Prascend.
 
Q.  Any supplements PPID horses should not have?
M:  Can’t think of anything that would be contra-indicated in a typical supplement.
 
Q.  28 PPID gelding on pergolide and Thyro-L, never fully sheds, clipped in summer and autumn, can coat be made normal?
L: Haircoat should improve with adequate treatment, retest to ensure on proper dose, make sure actually getting dose!  Check correct deworming programme, parasites can affect haircoat.  Focus on diet, ensure balanced and supplying adequate protein, vitamins and minerals.  Use Prascend not compounded pergolide.
 
Q.  What is the life expectency for a horse with PPID with/without medication?   
M: Horses with PPID can live a long time and have a high quality of life if well managed and able to avoid infectious diseases and laminitis if they  have insulin dysregulation.  If PPID well controlled with pergolide and good management, no reason they can’t live a long quality life, possibly into their 40s (Dr McFarlane knew a 45 year old with PPID) – PPID is not necessarily going to shorten life expectency.
Important that owners are proactive at recognising problems (e.g. infections and laminitis) before they become well established.    

 
Q.  Can a horse with PPID feel discomfort because of the increased size of the pituitary gland?
M:  No indication that PPID horses have head pain.  The hormones that are increased with PPID are anti-inflammatory and analgesic so PPID horses tend to feel good!
 
Q.  Can PPID affect eyesight?
M:  There are a few reports, but no direct link proven.  90% of old horses have eye lesions, old horses will have vision problems, not just PPID horses.  Corneal ulcers heal slower with PPID.
 
Q.  Should pergolide be given at the same time each day?
L:  Give when most convenient, no recommendation for either morning or evening.
 
Q.  Is an increase in tendon & ligament injuries seen with PPID?
M:  No indication that PPID causes more problems with tendons and ligaments.  However reports have been received of horses that have been lethargic due to PPID starting treatment and feeling too good,  and injuring themselves when they are turned out!  So rehab horses, warm up well before exercise – they may feel a lot younger than their body is!
 
Final thoughts.
L: Most important thing for owners to do is to be proactive – learn early signs of PPID, help vet with diagnosis, the earlier we recognise and manage PPID, better quality of life our horses will have.
M: PPID horses still have a lot to give, fabulous that owners are learning about PPID and taking care of these older horses.
 
www.thehorse.com/PPID  - 10 articles about PPID
 
 
TLS:
*We’ve listened to this over and over – best sense we can make is that the FDA standard for potency is that there should be no more than a +/- 10% difference between the active ingredient actually in a drug and the active ingredient declared on the label.
So we are guessing that 4 out of the 21 compounded formulations looked at were found to have a difference of more than 10% between the actual amount of pergolide and the quantity on the label when they were first analysed (at day 0), and that 1 of these 4 had no pergolide detectable at all during the 6 months.
 
More about the stability and potency of pergolide in compounded products under pergolide: http://www.thelaminitissite.org/p-q.html
 
 
Interesting that lots of reference was made to horses being diagnosed later, i.e. in their teens, and a 13 year old horse was described as being young for diagnosis.  However in the UK we are seeing horses being diagnosed younger than this – is this a result of the free testing campaigns by Talk About Laminitis picking up early cases of PPID at a younger age?
 
 
Disclaimer: No responsibility is taken for the accuracy of these notes.
The Horse Ask the Vet Live session is available on-line: http://www.thehorse.com/ask-the-vet/33389/managing-horses-with-ppid-equine-cushings

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Is it PPID or is it EMS?

2/26/2014

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Is it PPID or is it EMS – Diagnosing Equine Endocrine Disease 
Dr Dianne McFarlane – Oklahoma State University - www.thehorse.com - 31 January 2014

These notes are based on this presentation but are not intended to be an accurate representation – no responsibility is taken for their accuracy.
There are two common equine endocrine diseases:
Equine Pituitary Pars Intermedia Dysfunction – PPID
Equine Metabolic Syndrome – EMS

PPID 

Pathophysiology of PPID (i.e. what goes wrong)

The equine pituitary gland is suspended from the hypothalamus (towards the bottom of the brain) by the infundibular stalk.  It has 4 lobes:

Pars tuberalis – a thin band of tissue around the infundibular stalk;
Pars nervosa – secretes oxytocin and ADH (vasopressin);
Pars distalis (anterior lobe) - secretes many hormones including reproductive hormones: FSH, LH, GH, TSH, Prolactin, ACTH;
Pars intermedia.

The pars intermedia is made up of melanotrope endocrine cells.  Hormone production is reduced when dopamine, released by periventricular dopaminergic neurons which originate in the hypothalamus, interacts with D2 dopamine receptors on the melanotropes of the pars intermedia.
Picture
The pars intermedia produces a peptide called POMC.  Two enzymes, PC1 and PC2, cut the POMC into smaller hormones including alpha-MSH, CLIP and beta-endorphin. 

In a normal horse, hardly any ACTH is made in the pars intermedia – it comes from the corticotrope cells of the pars distalis where POMC is cleaved into ACTH by PC1.  PPID horses produce ACTH in both the pars distalis and the pars intermedia.

PPID is a dopaminergic neurodegenerative disease – the dopamine producing neurons are lost, and with less dopamine to inhibit hormone production, the pars intermedia releases massively increased amounts of alpha-MSH, beta-endorphin and CLIP, and also ACTH.  This leads to hypertrophy (increase in cell size) and hyperplasia (increase in cell number), causing the pars intermedia and therefore the pituitary gland to increase in size – a normal pituitary gland weighs around 2 grams, in a horse with advanced PPID the pituitary gland can weigh more than 10 grams.

If the missing dopamine is replaced with a dopamine agonist, e.g. pergolide, hormone abnormalities and clinical signs of PPID are reduced.

Clinical signs of PPID 

A collection of clinical signs can be seen in horses with PPID, some early and others later as the disease progresses.

Early:
Muscle loss
Lethargy/docile – horse becomes more mellow, perhaps nicer (due to increased beta-endorphin)
Infertility in breeding horses
Secondary infections e.g. sinusitis, abscesses

Late:
Abnormal haircoat – including regional abnormalities like long hair on the legs, long tufts on chin and belly which may shed, and hypertrichosis (failure to shed).
Profound weight loss – loss of all fat, not just muscle
Pot belly – due to loss of muscle tone
Abnormal sweating/thermoregulation - hyperhydrosis (increased sweating) or anhydrosis (lack of normal sweating in hot conditions).      
Picture
Some but not all horses with PPID will also have the potential for laminitis, hyperinsulinaemia, abnormal fat deposits, PU/PD (excessive drinking and urination), exercise intolerance, infertility, abnormal sweating  – they have PPID and EMS.   Some experts believe that not all horses with PPID are at risk from laminitis – only a subset of horses with PPID are at risk from laminitis (therefore insulin dysregulation should be measured in all horses with PPID to assess laminitis risk).

Diagnosis of PPID 

Early stage PPID can be hard to diagnose – blood tests are often negative early in the condition, and clinical signs can overlap with normal aging.  However, it is worth pursuing a positive test result to provide a useful guide for response to treatment.

A diagnosis of PPID should only be made if there are clinical signs of PPID, based on examination and a complete history – owners should regularly record weight, body condition score, dates of shedding/haircoat changes, how often feet need trimming, signs of laminitis and PPID such as hoof rings, to help the vet reach a diagnosis.

A long haircoat is highly suggestive of PPID in an older horse but it is not an absolute diagnosis – e.g. malnutrition can cause haircoat changes and false positive blood results.  Concurrent disease can also affect clinical signs and blood results.

Diagnostic tests for PPID 

Resting plasma ACTH concentration is now the most common test - the vet collects blood into a purple topped tube (EDTA).  Equine ACTH is not particularly unstable and as long as it is kept cool it can be separated up to 12 hours later, and then kept chilled or frozen until it is tested.

There are 2 methods for measuring ACTH:
Chemiluminescent (CIA) - Immulite as used by Cornell and Liphook
Radioimmunoassay (RIA)
Reference ranges are different between CIA and RIA (and potentially between different RIA assays) – seasonally adjusted reference ranges specific to the testing lab must be used, and results may not be comparable between labs.

There is no way of telling whether the ACTH measured came from the pars intermedia or the pars distalis - ACTH may increase with other diseases or stress.

(TLS comment: more than one ACTH sample will increase diagnostic accuracy as ACTH concentrations can fluctuate significantly).

The dexamethasone suppression test (DST) is no longer recommended – there is a risk of causing/exacerbating laminitis, it requires 2 vet visits, it cannot be used in the autumn, and it may only detect advanced PPID cases.
Picture
Dr McFarlane compared ACTH, alpha-MSH, dexamethasone suppression test (DST) cortisol and resting cortisol to pituitary gland cell changes and haircoat changes in 120 older horses, using the pituitary grading scale published by Miller:

Miller MA, Pardo ID, Jackson LP, Moore GE, Sojka JE
Correlation of Pituitary Histomorphometry with Adrenocorticotrophic Hormone Response to Domperidone Administration in the Diagnosis of Equine Pituitary Pars Intermedia Dysfunction
Vet Pathol 45:26–38 (2008)

Findings:
                                    Sensitivity (true positives)            Specificity (true negatives)
Alpha-MSH                             63%                                         90%
ACTH                                      71%                                         81%
DST                                         65%                                         98%

All 3 tests identified advanced (grade 5) PPID.
All 3 tests were poor at identifying early PPID.
ACTH had a weaker correlation with pars intermedia enlargement than Alpha-MSH or DST.
Alpha-MSH had 2/48 false positives, ACTH had 13/48 false positives.
ACTH may be from the pars intermedia or the pars distalis, and may increase with other diseases or stress.
Resting cortisol is not predictive of PPID (this has been known for a long time).

A better test was needed.

Since around 2011 the TRH stimulation of ACTH has been used to diagnose PPID, and further research is being carried out on this test. 

The vet collects a blood sample to measure resting ACTH, then injects 1 mg of the hormone TRH intravenously and collects blood to measure ACTH 10 and/or 30 mins after giving the TRH.

Currently suggested reference ranges are:
PPID if ACTH > 36 pg/ml (using Immulite CIA) at 0 or 30 minutes
PPID if ACTH > 110 pg/ml at 10 minutes
However these reference ranges are likely to change as more data is collected (normal horses have tested above these ranges), and reference ranges have not been established for the autumn seasonal rise.

Sensitivity (true positives) 88-95%, specificity (true negatives) 71-91% so the TRH stimulation of ACTH appears more diagnostic than resting ACTH.

TRH stimulates pars intermedia activity – however, increased activity does not necessarily mean dysfunction, increased activity could be appropriate and not due to lack of dopaminergic inhibition.

Autumn natural stimulation of ACTH 

The pars intermedia becomes more active in the autumn in all horses, with increased hormone output and histological changes.  It isn’t known exactly why this happens, but it may help the horse prepare for winter by changing metabolism and stimulating hair coat growth, as is seen in other species.

The difference between PPID and normal horse resting ACTH is greatest in the autumn, making this the best time to test.
Picture
Courtesy of Liphook Equine Hospital
Copas VEN, Durham AE
Circannual variation in plasma adrenocorticotropic hormone concentrations in the UK in normal horses and ponies, and those with pituitary pars intermedia dysfunction 
Equine Veterinary Journal Vol 44, Issue 4, pages 440–443, July 2012

EMS 

EMS is not a disease, it is a cluster of risk factors which indicate that a horse is at greater risk of developing endocrinopathic laminitis.

Frank N, Geor RJ, Bailey SR, Durham AE, Johnson PJ
Equine Metabolic Syndrome - ACVIM Consensus Statement
J Vet Intern Med 2010;24:467–475

The 2010 ACVIM Consensus Statement described the EMS phenotype as including:
  • General (obesity = body condition score (BCS) of 7 to 9 on the 9 point scale) or regional adiposity (crest of neck, tailhead, shoulder, sheath/mammory glands),
  • Hyperinsulinaemia/abnormal insulin response,
  • Predisposition to laminitis.

Plus horses may be described as “easy keepers” or “thrifty”, mares may have abnormal reproductive seasons, blood tests for lipids and leptin may show abnormalities.  Some breeds appear to be more predisposed to EMS than others.

Insulin Dysfunction - Insulin Resistance v Hyperinsulinaemia

Insulin resistance is when the body produces insulin, but the insulin sensitive tissue (primarily muscle) does not respond normally to that insulin, which prevents glucose in the blood from entering the tissue normally.
Insulin resistance is at the level of the tissue (muscle).

Over time, insulin resistance causes the horse to “compensate” by making more insulin to ensure that glucose does enter the tissue – this is compensatory hyperinsulinaemia .

However, chronic hyperglycaemia and hyperinsulinaemia may be the primary problem, and can lead to tissue insulin resistance.

Why is this important?

It is hyperinsulinaemia (high concentrations of insulin), not insulin resistance, that is the risk factor for endocrinopathic laminitis, and this has implications for both testing and treatment.

For example, if the primary problem is at the level of the pancreas, not the level of the tissue, and a drug is given that causes improvement at the tissue level, the health of that animal may not be improved.
Picture
When a normal horse eats, glucose is absorbed into the blood stream and insulin is released to enable that glucose to enter insulin sensitive tissue – blood levels of both glucose and insulin rise after a meal and then drop back down (dotted lines above).

When an EMS horse eats, glucose is absorbed into the blood stream and insulin is released, but if the horse has a problem at the level of the insulin sensitive tissue, the glucose doesn’t enter the tissue efficiently, so the pancreas compensates by making more insulin – blood levels of both glucose and insulin increase and take longer to drop back down (solid lines above).

If a horse has greater than normal absorption of glucose or greater than normal release of insulin from the pancreas, over time the horse can develop insulin resistance at the level of the tissue - a dynamic oral test will pick up dysfunction at every level.

Diagnosis of insulin dysregulation

The fasting blood insulin concentration is the easiest test to carry out and involves taking a single sample of blood after the horse has been fasted for at least 6 hours.

An above normal result (20 µIU/ml is often used as the cut-off but see below) is diagnostic of hyperinsulinaemia.  The test has a high false negative rate (around 2/3 of horses with insulin dysregulation have normal fasting insulin), so a normal test result does not rule out EMS, and a dynamic test should follow a normal fasting insulin test for any horse suspected of having insulin dysregulation.

Glucose may be normal or above normal.

Reference ranges for insulin may be breed specific, therefore a cut-off of 20 µIU/ml may not be appropriate for all breeds.

Reference ranges for insulin are laboratory specific, therefore a cut-off of 20 µIU/ml may not be appropriate for all labs (different assays, e.g. RIA v CIA, may produce different results meaning that results cannot be compared).

Dr McFarlane suggests that PPID horses with insulin resistance more commonly have abnormal fasting insulin results than horses with EMS only.

The most appropriate dynamic test is the oral sugar test (OST) – this mimics natural conditions, testing at the level of the GI tract, pancreas and tissue, not just at the level of the tissue.

The horse is fasted for at least 6 hours, then given 0.15 ml/kg bodyweight (so 75 ml for a 500 kg horse) Karo Light syrup by mouth (either syringed directly in to the mouth or in a small low sugar feed).  Blood is collected 60 and 90 minutes later and both insulin and glucose are measured.

Insulin > 60 µIU/ml at 60 or 90 minutes is diagnostic of hyperinsulinaemia.
Insulin between 45-60 µIU/ml at 60 or 90 minutes is equivocal and further testing should be considered.
Insulin below 45 µIU/ml at 60 or 90 minutes is considered normal.
Glucose > 125 mg/dl at 60 or 90 minutes is considered an excessive glucose response.

(For more details see the Equine Endocrinology Group Recommendations for the diagnosis and treatment of PPID).

The combined glucose insulin tolerance test (CGITT) and insulin tolerance test (ITT) measure insulin resistance at the level of the tissue only (NB the ITT may risk causing hypoglycaemia).

However, EMS is a very frustrating condition and the current tests are not that good.  Vets are seeing horses they strongly suspect have insulin dysregulation but are having trouble getting the test results to prove it.
Dr McFarlane looked at horses that appeared to be hyperinsulinaemic, all had a BCS of 8 or 9 and two thirds of them had foundered, but she could not get half of these horses to test positive.

She suggests if there is a clinical indication of a “thrifty” horse then it’s best to consider that it has EMS and treat appropriately.

The purpose of trying to diagnose EMS is to prevent laminitis.

Endocrinopathic laminitis

Endocrine disease (obesity/EMS, PPID) is the most common cause of laminitis, and may be triggered by diet, particularly when grasses are highest in NSC.

Endocrinopathic laminitis can be insidious and may be mistaken for other conditions - radiographic and hoof growth changes may precede clinical symptoms.

Endocrinopathic laminitis was once believed to be the result of excessive cortisol, but there is now strong evidence that it is caused by serum insulin concentration (hyperinsulinaemia), as horses receiving a continuous infusion of insulin consistently develop laminitis.

Endocrine laminitis has different histological characteristics to SIRS laminitis (laminitis secondary to endotoxaemia e.g. colitis, retained placenta).  With endocrine laminitis, the secondary epidermal laminae (SEL) become longer and narrower before clinical signs of laminitis are seen, and there is a general absence of inflammation (compared to SIRS laminitis).  It is currently thought that excessive insulin binds to and activates insulin growth factor–1 (IGF-1) receptors on the laminae causing cell division and elongation of the SEL, making them structurally unsound and causing laminitis.

Potential new drugs for the treatment and/or prevention of endocrinopathic laminitis may target this area.

EMS and PPID Summary 

EMS and PPID are not mutually exclusive – a horse can have EMS and PPID.
Clinical signs common to EMS and PPID include laminitis, hyperinsulinaemia, abnormal fat deposits, PU/PD, abnormal sweating, exercise intolerance, infertility.

EMS by definition is hyperinsulinaemia or an excessive insulin response to a meal stimulus (which increases the risk of laminitis).
PPID by definition is an overly active pars intermedia.

Horses with EMS may be at greater risk of developing PPID as they get older – horses with EMS should be monitored and tested for PPID.
There appears to be a transitional period between the diseases during which horses have both EMS and PPID at the same time.  These horses often have higher insulin concentrations and potentially a greater risk of laminitis, therefore treatment should be instigated as early as possible.

It isn’t yet known whether EMS and PPID are causitively linked – i.e. whether having EMS causes PPID.

In Dr McFarlane’s experience, a horse with PPID that has never had laminitis and has normal insulin is not at greater risk of developing laminitis than any other horse.

Equine endocrine diseases are progressive and difficult to diagnose in the early stages – there will always be a grey zone for testing in the early stages of a progressive disease.  Retest horses that are suspected of having EMS/PPID if they have negative results, and/or instigate treatment.

History and clinical signs are essential for early diagnosis – a diagnosis should not be made on the basis of diagnostic test results if there are no clinical signs.

Tests can be carried out in any season as long as results are interpreted correctly, and autumn is the best time to test for PPID using resting ACTH.

Insulin/insulin dynamics should be measured in all equine endocrine cases (PPID as well as EMS) as insulin dysfunction is predictive of laminitis risk.

Use resting ACTH concentration or TRH stimulation of ACTH for PPID diagnosis.
Use fasting insulin or the oral sugar test to assess risk of laminitis (for both EMS and PPID).

Believe clinical impressions, retest or treat cases that are suspicious – people are better at diagnosing PPID (and EMS) than current blood tests are at confirming it.  However, always get blood tests done too to monitor disease progression/efficacy of treatment.

The goal is to recognise these diseases early to avoid clinical signs, especially laminitis – early intervention may keep horses healthy for longer.

Download these notes in pdf format

Watch Dianne McFarlane's presentation at www.thehorse.com
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