UPDATES IN PPID DIAGNOSIS
Diagnostics for PPID should be conducted in the face of history and clinical signs consistent with disease. Routine CBC may reveal
a relative neutrophilia and lymphopenia. Chemistry is usually unremarkable with exception of hyperglycemia present in diabetes
mellitus. Hypertriglyceridemia may also occur.
2
Diagnosis of PPID can be challenging in early stages, as no gold standard exists for
detection of early disease. Horses with early PPID may test negative due to inability of certain tests to detect subtle pituitary changes.
There have been a variety of tests suggested historically for PPID diagnosis. Long thought to be the diagnostic “gold standard,” the
Overnight Dexamethasone Suppression Test (ODST) has not proven superior in sensitivity or specificity. Diagnosis of PPID currently
focuses on one screening test, Resting plasma ACTH concentration, and one evocative test, Thyrotropin-releasing hormone (TRH)
stimulation measuring ACTH. Resting ACTH can be interpreted year-round and is easy to perform in the field as a single blood draw.
Resting ACTH is primarily recommended when obvious clinical signs are present (moderate-advanced PPID). TRH stimulation (1.0 mg
TRH IV) measuring ACTH at 0 and 10 minutes is currently advocated as a more sensitive test for detection of early PPID, when subtle
clinical signs may exist.
5
TRH stimulation may also be used when resting ACTH is equivocal, or to confirm a positive or negative result.
TRH is available as protirelin or synthetic TRH, and is now available commercially to practitioners.
Both tests are affected by normal hormonal processes that occur in the fall, when the body is triggered to prepare for winter. Both
normal and PPID horses experience the seasonal rise in ACTH and other hormones, generally August-October, with PPID horses
exhibiting a more profound hormonal rise. Thus, for resting ACTH, positive test results obtained in the fall should be interpreted
carefully utilizing laboratory seasonally-adjusted reference ranges. As laboratory ACTH assays vary significantly, it is also important to
standardize sampling times, be consistent with the laboratory used, and confirm the laboratory’s familiarity with equine endocrine
samples and updated testing recommendations.
6
Currently, TRH stimulation measuring ACTH can only be performed December-
June as seasonally-adjusted reference ranges have not been established for this test. Test results should be interpreted alongside
clinical signs. It is recommended that prior to initiating medical treatment, baseline test results (day 0) be obtained via either test in
order to accurately judge clinical response to drug. Follow-up testing at 30 days is recommended with dose titration (if necessary)
and the horse placed on a 6-month recheck schedule with one appointment occurring August-October.
2
This protocol ensures
assessment of the horse during the seasonal rise in ACTH, and ensures treatment is adequate during this time.
Detection of early PPID remains difficult, although this is the time period in which medical intervention can be most satisfying. In
horses with negative or equivocal test results, tests should be repeated in six months or alternatively, the TRH stimulation test used. If
test results remain negative in the presence of clinical signs, a 6-month treatment trial with pergolide (Prascend®) can be considered.
In advanced disease, the most accurate diagnostic “test” is the observation of generalized hypertrichosis. This classic haircoat abnormalty
provides high specificity for an abnormally functioning pituitary, although with end-stage disease, medical treatment is palliative.
COMPLICATING FACTORS
Hyperinsulinemia and insulin resistance/IR now collectively referred to as insulin dysregulation
2
is a common finding in
approximately 30% of horses with PPID.
1
Insulin resistance/IR is defined as decreased tissue response to insulin,
or
decreased uptake
of insulin. In IR, the pancreas continues to secrete
more
insulin to compensate for the decreased tissue response, thus blood insulin
levels will be elevated when IR occurs (hyperinsulinemia). As the condition worsens, the pancreas can fail to secrete enough insulin,
which may lead to a true uncompensated diabetic state. The concern with insulin dysregulation is with decreased tissue response
to insulin, laminar tissues can be deprived of proper nutrients. Hyperinsulinemia has been shown to precipitate laminitis in horses
and ponies and PPID must be controlled before it exacerbates underlying insulin dysregulation.
2
Insulin dysregulation occurs in a
minority of horses with PPID, but is a defining component of Equine Metabolic Syndrome (EMS).
It is important to note that horses can exhibit concurrent history and clinical signs consistent with both EMS and PPID. It is highly
recommended that when screening for PPID, insulin parameters be evaluated, and when screening for EMS, diagnostics for PPID be
included. As the relationship between EMS and PPID is emerging, a complete diagnostic evaluation should include comprehensive
testing parameters for both. Proper nutritional management of the PPID horse must include knowledge of insulin status (i.e.
presence of insulin dysregulation), and hence laminitis risk. Fasting insulin is easily performed and may be combined with resting
ACTH, however fasting insulin is limited by low sensitivity compared to the dynamic Oral Sugar Test (OST). The oral sugar test is
now considered the first choice for evaluation of insulin status. A panel consisting of OST, leptin and triglycerides may be helpful for
a thorough assessment of the PPID horse.
7
The author wishes to thank the Equine Endocrinology Group for providing updates to
diagnostic recommendations.
/
MANAGEMENT OF PPID
PPID is a chronic, lifelong condition for which there is no cure. Treatment of PPID focuses on administration of pergolide and
attention to concurrent issues impacting the horse’s health, such as laminitis, dental disease and maintenance of proper diet.
Pergolide is the gold standard for treatment of PPID. Pergolide, an ergot alkaloid dopamine receptor agonist, binds to D2 receptors of
melanotrophs of the intermediate lobe, inhibiting the production of excessive POMC hormones, namely αMSH and ACTH. Until 2011,
only compounded pergolide was available. Compounded pergolide products have been shown to be highly susceptible to light and
temperature, and have also been associated with rapid declines in stability over time. In a 2010 study, initial concentrations of all 14
formulations were highly variable, with many well below the label claim. In the same study, a high degree of variation was observed
“between two containers of same product ordered from same pharmacy on the same date.”
8
Unpublished 2012 data on 21 additional
compounded pergolide formulations supports previous findings.
9
In September 2011, the FDA approved an equine pergolide
formulation, Prascend® (
. Prascend® is now the standard of care for PPID with a starting dose of 2 µg/kg PO
q24hrs (0.5 mg for 250-kg pony; 1.0 mg for 500-kg horse).
10
Diagnostic testing should be performed prior to starting treatment (day
0). The test used to diagnose PPID (resting ACTH or TRH stimulation) should be rechecked after 30 days to assess treatment response,
and a minimum of 60 days required before evaluation of improvement in clinical signs. Photographs taken at initiation of treatment
and at 6-month intervals are recommended to document physical changes and provide motivation for clients to continue long-term
treatment. In refractory PPID where daily pergolide dose has reached 6 µg/kg/day (3mg for 500-kg horse), horses may require the
addition of cyproheptadine (Periactin®) a serotonin antagonist, at a dose of 0.25 mg/kg PO q12h or 0.5 mg/kg PO q24hrs.
2, 11
It should
be expected that like Parkinson’s disease, PPID will progress over time. At the time of this writing, pergolide has not been definitively
shown to improve insulin parameters, thus management of laminitis due to insulin dysregulation should be primarily addressed
with diet, exercise, +/- medical therapies. Although PPID is primarily managed medically, nutrition, body clipping, farrier care, regular
deworming and routine dentistry are important. Additional water should be provided if the horse drinks and urinates excessively.
Twice yearly re-assessment of haircoat, body condition and endocrine test results is recommended for ongoing monitoring of
disease progression.
AUTHOR
Marian G. Little,
DVM, Field Equine Professional Services, Boehringer Ingelheim, Paris, Kentucky.
REFERENCES
1
McGowanTW, Pinchbeck GP, McGowan CM. Prevalence, risk factors and clinical signs predictive for equine pituitary pars intermedia dysfunction in aged horses. EquineVet J 2012;45:74-79.
2
Frank N. Pituitary pars intermedia dysfunction. CurrentTherapy 2013.
3
McFarlane D, Cribb AE. Systemic and pituitary pars intermedia antioxidant capacity associated with pars intermedia oxidative stress and dysfunction in horses. Am JVet Res 2005;66:2065-2072.
4
Innera M, et al.Veterinary Dermatology. In press. 2013.
5
Goodale L, Hermida P, Oench SD, Frank N. Assessment of compounded thyrotropin releasing hormone for diagnosis of pituitary pars intermedia dysfunction. ACVIM abstract, 2013.
6
Schott HC, et al. Comparison of assay kits for measurement of plasma Adrenocorticotropin Concentration. ACVIM abstract, Seattle,WA. 2013.
7
Frank N. Oral sugar test used to diagnose insulin resistance in horses. AAEP Proceedings 2012; 58: 576.
8
Stanley SD, Knych HD. DVM, Ph.D. Comparison of pharmaceutical equivalence for compounded preparations of pergolide mesylate. AAEP Proceedings 2012; 56: 274-276.
9
Davidson G, Davis J. Potency and stability of compounded pergolide formulations for use in the horse. Unpublished. 2012.
10
PRASCEND® (pergolide mesylate) [Freedom of Information Summary]. St. Joseph, MO: Boehringer IngelheimVetmedica, Inc.; 2011.
11
Schott HC. Medical management of PPID. 2012.
Pituitary Pars Intermedia Dysfunction (PPID) continued
