PPID (Equine Cushing’s Disease) or Equine Metabolic Syndrome: Which One Does My Horse Have?

It is challenging to determine whether a horse is suffering from PPID (also known as Equine Cushing’s Disease), EMS (Equine Metabolic Syndrome) or both disorders concurrently. Both conditions share commonalities which may complicate recognition and diagnosis. However, determining which disorder a horse is suffering from is essential for treatment and management success.
EMSvsPPID_2_blog_pic
FIRST, WHAT IS PPID?

Pituitary Pars Intermedia Dysfunction (PPID), also known as Equine Cushing’s Disease, is the most common endocrine disorder in horses. An estimated 21% of horses and ponies over the age of 15 are affected by this disease, and this prevalence increases each year of age.1 PPID is the now the preferred scientific name as it specifies the exact area of the pituitary gland affected. Although the pathogenesis of disease is different from that of humans and dogs with Cushing’s, the term Equine Cushing’s Disease is still commonly used.

PPID is a chronic progressive disease. PPID causes multiple health problems for the horse, including laminitis and recurrent infections. With a growing geriatric equine population, many owners are becoming more aware of PPID and seeking better information on diagnosis and management.

HOW DOES PPID OCCUR?

The pituitary gland is located at the base of the brain. The equine pituitary is divided into 3 regions: the pars distalis (anterior pituitary), the pars intermedia (intermediate lobe), and the pars tuberalis (posterior pituitary.) The pituitary gland secretes many hormones responsible for maintenance of essential bodily functions including growth, metabolism, reproduction, and lactation. As PPID horses age, dopamine-secreting neurons that innervate and control the intermediate lobe degenerate at a faster rate. The exact cause of this degeneration is poorly understood, similar to human Parkinson’s disease, but is thought to result from oxidative damage.2   When degeneration of neurons occurs, control to the intermediate lobe is lost. As this happens, the intermediate lobe becomes much more active, increasing secretion of hormones such as α-MSH, β-endorphin, CLIP, but now also ACTH, which is not normally produced in significant amounts from this region. Elevated ACTH from the intermediate lobe acts on the adrenal glands to produce excessive cortisol (a stress hormone) which, along with multiple other secreted hormones, results in the individual clinical signs of PPID. Over time, horses may develop classic pituitary tumors, known as “adenomas,” which, in advanced disease, can compress adjacent structures resulting in neurological signs.

WHAT DOES PPID LOOK LIKE?

Most horses affected with PPID are between 15-21 years of age, although horses as young as 4 have been reported in the literature. Ponies and Morgans are overrepresented, but all light horse breeds may be affected.3  Horses with a history of Equine Metabolic Syndrome are thought to be at higher risk.4 PPID-affected horses show a wide variety of nonspecific clinical signs which worsen over time.

Early signs of PPID may include:

  • Abnormal haircoat (delayed shedding compared to herdmates, dull, thicker haircoat, change in hair color, presence of longer, lighter hairs along the jaw, neck, elbow, lower legs)
  • A shift in metabolism from an “easy keeper” to more lean body condition
  • Regional fat deposits, i.e. “cresty neck”
  • Poor performance, attitude/behavioral changes, i.e. “dullness, lack of energy”
  • Subfertility, reproductive problems
  • Unexplained laminitis episodes,“foot soreness”

Advanced signs of PPID may include:

  • Generalized long, curly, dull haircoat that fails to shed despite changes in season
  • Muscle wasting with regional fat deposits,  “pot-bellied appearance”
  • Increased thirst and urination
  • Recurrent infections, i.e. white line disease, hoof abscesses, sinusitis
  • Inappropriate sweating (not sweating or increased sweating)
  • Chronic laminitis
  • Neurologic deficits/blindness

Signs of PPID may be attributed to the normal ageing process, but it is important to recognize that this disease develops very slowly over time, making early detection difficult. Owners should record when their ageing horse sheds its winter haircoat and compare this time with herdmates to detect delayed shedding. Subtle alterations in length, color, texture, or thickness of hair may indicate early PPID. Chronic, recurrent infections (white line disease, hoof abscesses, sinus infections, skin infections, etc.) that fail to respond appropriately to treatment may occur in PPID due to immunosuppression. The diagnosis of PPID may be missed altogether due to focus on the primary problem (infection) and lack of other overt signs of PPID. Another indicator common to both PPID and EMS may be subtle foot soreness. Foot soreness may be difficult to recognize unless the horse is examined on a hard surface. Subtle foot soreness without an inciting cause can indicate the presence of chronic laminitis, which can become debilitating. The presence of a generalized long, curly, dull haircoat (known as “generalized hypertrichosis”) that fails to shed is easily recognized and considered pathgnomonic for PPID. However, the presence of this “wooly mammoth” haircoat is considered advanced disease. Ideally, detection and treatment of PPID should begin long before this “classic” sign is observed.

COMPLICATING FACTORS?

High blood insulin (hyperinsulinemia) and insulin resistance/IR now collectively referred to as insulin dysregulation3 is a common finding in approximately 30% of horses with PPID.1 Insulin is a hormone produced by the pancreas in response to elevated blood sugar (glucose) which occurs after a meal. Insulin works within the body to mediate absorption of glucose into tissues such as liver, adipose, and skeletal muscle. 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. As the condition worsens, the pancreas can fail to secrete enough insulin, which may lead to a true diabetic state. The concern with insulin dysregulation is that with decreased tissue response to insulin, tissues can be deprived of proper nutrients. Tissues within the hoof are extremely sensitive to changes in nutrient supply, and horses with a history of insulin dysregulation usually suffer from laminitis. Insulin dysregulation occurs in a minority of horses with PPID, but is a defining component of Equine Metabolic Syndrome.

WHAT ABOUT EQUINE METABOLIC SYNDROME?

Insulin dysregulation is associated with another condition, Equine Metabolic Syndrome (EMS.) Horses with EMS are generally <15 years of age, and as in PPID, ponies and Morgans are overrepresented.3 EMS horses tend to exhibit “thrifty genes,” are historically “easy keepers” and able to maintain body condition on very few calories. EMS is currently characterized by three components:

  • Obesity or regional fat deposits, “cresty neck”
  • Laminitis (historical or current)
  • Insulin dysregulation

WHAT DOES EMS LOOK LIKE?

Horses with Equine Metabolic Syndrome are predominantly overweight, and exhibit areas of abnormal fat accumulation, particularly in the neck crest, hindquarters, and sheath. Sheath fat deposits may be so profound as to impinge lymphatics and cause some horses to “stock up.” Horses with EMS usually have a history of obesity since a young age with owners relaying, “Doc, he’s always been this way.” Although several breeds may be genetically prone to obesity, (ponies, Morgans, Paso Finos, Arabs, Mustangs, and others) many horses can develop this condition when overfed grain, grazed on improved pasture, with minimal exercise. Less commonly, there is a “lean” body type with EMS horses, and these horses are thought to be in transition to PPID.

Horses with a history of EMS may develop PPID at a younger age, and it has been proposed that Equine Metabolic Syndrome may be a “risk factor” for development of PPID. Horses in transition from EMS to PPID exhibit a change in body mass from obese to lean, have increased caloric needs, a worsening of insulin dysregulation, and may exhibit severe laminitis for the first time. Horses that develop PPID with concurrent insulin dysregulation (as occurs in those with a history of EMS) exhibit a poorer prognosis and are difficult to manage. The treatment for EMS is primarily diet and exercise with the goal of improving insulin parameters.  It has been suggested that proper management of the horse with EMS can perhaps delay the onset of PPID, althought this has not been proven. Prevention of obesity in high-risk breeds and maintenance of horses in a lean, healthy body condition (BCS 4-5) should be encouraged to avoid this condition.

HOW ARE THESE DISORDERS DIAGNOSED?

Although they share multiple commonalities such as breed, fat deposits, insulin dysregulation, and laminitis, it is important to differentiate between EMS and PPID. Diagnosis of PPID can be challenging in early stages, as no gold standard exists for detection of early disease. Some horses in early stages of disease may test “negative” due to inability of these tests to detect subtle pituitary changes over time. There have been a variety of tests suggested for diagnosis of PPID. As of this writing, a screening field diagnosis of PPID focuses on one Tier 1 test:  Resting ACTH.  Resting ACTH can be interpreted all year, and does not have the perceived risk of exacerbating laminitis. A Tier 2 test, TRH Stimulation Test measuring ACTH, may be used when the first test is inconclusive, or to confirm a positive or negative result. TRH measuring ACTH is proving much more sensitive in detection of earlier PPID, and may become a first line test in coming months.5 TRH is not a Tier 1 test currently as TRH is costly, making ACTH more economical for routine use. (Visit www.prascend.com for supplemental information on testing published in 2011.)

Tier 1/Tier 2 tests are affected by normal hormonal processes that increase in the Fall, when the body is triggered to prepare for winter. Both normal and PPID horses experience the Fall increase in pituitary hormone activity, generally August-October, with PPID horses exhibiting a more profound hormonal rise. Therefore, positive tests results obtained in the fall should be interpreted carefully and laboratory seasonally-adjusted reference ranges used. Also, laboratory assays vary, so it is important to standardize sampling times and be consistent with the lab used. The convenience of performing certain tests in the field, time of year, sample handling, and cost are all factors that may influence the choice of one diagnostic test over another. Discuss these tests with your veterinarian and determine which is best for your horse.

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 “grey area” test results, tests should be repeated in 6 months or alternatively, another Tier 1 or Tier 2 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 a long, curly haircoat that fails to shed. The presence of this classic “wooly mammoth” haircoat remains the most sensitive indicator of an abnormally functioning pituitary, although with advanced disease, medical treatment is palliative.

Diagnosis of Equine Metabolic Syndrome relies on a history of obesity, laminitis, and diagnostic testing for insulin dysregulation. Veterinarians may choose to measure insulin under short-term fasting conditions, although this is an insensitive measure of detection of insulin dysregulation. A more recent test is the Oral Sugar Test (OST) or “Karo Syrup test,” which mimics a horse’s normal response to grazing excess sugars from pasture grass.6 Horses with insulin dysregulation may demonstrate a normal fasting insulin but have a profoundly abnormal result on the OST, making the OST a much more sensitive test for detection of insulin dysregulation. Other parameters that may be evaluated in the EMS horse are leptin and triglycerides. Leptin, a measure of pathologic fat (similar to omental fat in people), may indicate a horse predisposed to or has a problem with obesity. Triglycerides should be monitored in any obese horse or pony managed by strict dietary restriction. A combination of these parameters should be used to assess if a horse truly suffers from insulin dysregulation.4

It is important to note that horses can exhibit concurrent history and clinical signs consistent with both EMS and PPID. It is recommended that when screening for PPID, insulin parameters should also be evaluated, and when screening for EMS, diagnostics for PPID should also be conducted. As the relationship between EMS and PPID is emerging, a complete diagnostic evaluation should include testing parameters for both.

HOW IS PPID TREATED?

PPID is a chronic, lifelong condition for which there is no cure. Treatment of PPID focuses on administration of pergolide (FDA-approved Prascend®) and attention to other significant issues which may impact the horse’s health, such as laminitis, dental disease, and maintenance of proper diet. Pergolide is considered the gold standard for treatment of PPID. Pergolide, a dopamine agonist, acts to restore control to the intermediate lobe, down-regulating its activity, and decreasing the production of detrimental hormones. 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 one study, initial concentrations in all formulations were highly variable, with many having concentrations well below the label claim. In the same study, a high degree of variation was observed in concentrations “between two containers of same product ordered from same pharmacy on the same date.”7 In September 2011, FDA-approved pergolide became available, under the trade name Prascend® (www.prascend.com.) Prascend® is now the treatment of choice for PPID.8 Owners should expect significant improvement in their horse’s clinical signs and test results when properly controlled with pergolide. However, similar to human Parkinsons, it should be expected that PPID will progress over time. Some horses with advanced PPID can be managed with higher doses of pergolide, with the addition of cyproheptadine, a serotonin antagonist.  Pergolide has not been definitively shown to improve insulin parameters, therefore management of laminitis due to insulin dysregulation should be primarily addressed with diet, excercise, +/- medical therapies (see below.)  Two recent studies do demonstrate a beneficial effect of pergolide on measured insulin parameters and body weight, although this remains a subject of ongoing investigation.9,10 Although PPID is primarily managed medically, body clipping, farrier care, regular deworming, and routine dentistry are also important. Additional water should be provided if the horse drinks and urinates excessively.

HOW IS EMS MANAGED?

Equine Metabolic Syndrome should be managed via strict diet and exercise. Obese horses must cut calories and increase their activity level. In the face of active laminitis, exercise should be delayed until laminitis is controlled. Most obese horses with EMS will respond with weight loss and improvement in insulin parameters when calorie restricted, i.e. removed from pasture grass and fed no or very little grain, kept in a small paddock or dry-lot, and treats/supplements minimized or eliminated. Grazing muzzles are very helpful in horses that cannot be removed from grass pasture, although some will go through an intial 2-3 day “sulking” period which can disconcert some owners. (Horses will also remove muzzles from one another, or attempt to self-remove them, so muzzles must be checked daily.) Horses removed from pasture do quite well on a measured diet of hay +/- a vitamin /mineral supplement, or a ration balancer for added protein, and switching to this basic diet in the case of the obese, overfed horse will readily result in weight loss. In the obese EMS horse, medical therapies should never be used as a subsititue for diet and exercise (below). In short, when it comes to obesity and insulin dysregulation, there is no easy answer. “Diet and Exercise” is still the most effective recommendation for obesity-associated problems in horses and humans alike.

EMS horses in lean body condition (in transition to PPID) need calories and may benefit from commercial low carbohydrate feeds, molasses-free beet pulp, with possible addition of corn or cocosoya oil for added fat without worsening of insulin levels.  In these and refractory cases, where efforts at management have been properly instituted and weight loss is not occurring, insulin parameters not improving, or laminitis remains uncontrolled, medical therapies can be considered. Medical therapies include levothyroxine, to increase metabolic rate, and Metformin (Glucophage®), to increase insulin sensitivity. A new resveratrol supplement, Metabarol™, may also prove helpful in controlling insulin levels.11 Though EMS may be a risk factor for PPID, at the time of this writing, daily pergolide would not be routinely recommended for control of obesity and insulin dysregulation. Skilled farriery is also paramount to management of the laminitic EMS horse.

TAKE HOME:

The determination of whether a horse is suffering from EMS or PPID, or both disorders concurrent, is imperative to a positive outcome. With awareness of subtle clinical signs, owners and veterinarians can work together as a team to identify the correct diagnosis. And by intervening earlier with treatment and control strategies, we can provide our horses with the optimal chance at longer, healthier, more productive lives.

AUTHOR:

Marian G. Little, DVM, Field Equine Professional Services, Boehringer Ingelheim, Paris, KY

Email: Marian.little@boehringer-ingelheim.com

REFERENCES:

1McGowan TW, Pinchbeck GP, McGowan CM. Prevalence, risk factors and clinical signs predictive for equine pituitary pars intermedia dysfunction in aged horses. Equine Vet J 2013;45:74-79.

2McFarlane D, Cribb AE. Systemic and pituitary pars intermedia antioxidant capacity associated with pars intermedia oxidative stress and dysfunction in horses. Am J Vet Res 2005;66:2065-2072.

3Frank N. Pituitary Pars Intermedia Dysfunction. Current Therapy 2013. Pending publication.

4Geor R. Oral Presentation. Equine Endocrine Summit, Boston, MA, 2012.

5Goodale L, Hermida P, Oench SD, Frank N. Assessment of Compounded Thyrotropin eleasing Hormone for Diagnosis of Pituitary Pars Intermedia Dysfunction. ACVIM Abstract, 2013.

6Frank N. Oral Sugar Test Used to Diagnose Insuline Resistance in Horses. AAEP Proceedings 2012; 58: 576.

7Stanley SD,Knych HD. DVM, Ph.D. Comparison of Pharmaceutical Equivalence for Compounded Preparations of Pergolide Mesylate. AAEP Proceedings 2012; 56: 274-276.

8PRASCEND® (pergolide mesylate) [Freedom of Information Summary]. St. Joseph, MO: Boehringer Ingelheim Vetmedica, Inc.; 2011.

9Durham A, Campbell J. Changes in Resting Serum Insulin Concentrations Following Pergolide Treatment in Horses with PPID. Equine Endocrinology SIG. ACVIM, Seattle, WA. 2013.

10McFarlane D, Banse HE. Response of Serum Insulin, Oral Sugar Testing and Body Weight in Horses Treated with Prascend.® Equine Endocrinology SIG. ACVIM, Seattle, WA, 2013.

11Lawless P. Personal Communication. www.Equithrive.com

Defining Equine Metabolic Syndrome (EMS)

What is Equine Metabolic Syndrome (EMS)?  EMS was first recognized as a problematic health condition of the obese, “easy keeper” or “good doer” type horse in 2002 by Dr P.J. Johnson.  A major advance came in 2010 when a Consensus Statement of the American College of Veterinary Internal Medicine (ACVIM) panel of experts (Veterinarians, Clinicians and Researchers) formally recognized EMS as a clinical syndrome of the horse and provided the veterinary community with information characterizing and defining EMS horses.  The challenge remains in continuing to educate veterinarians and horse owners about the seriousness of the EMS condition.  Thus, our goal is to help everyone better understand and bring awareness to the condition of EMS.

Link: ACVIM Consensus Statement on EMS

While statistics disclosing the percentage of horses suffering from EMS are scarce, one needs only to peruse the popular equine press to locate a myriad of articles on the subject of “obesity” and/or “EMS” to find ample evidence that EMS is a major concern for the horse population.  While not all obese horses are going to be EMS, obesity is observed in the majority of cases. Unfortunately, EMS is a complex disorder with many unknowns remaining to be answered.  To date, there are no epidemiology studies of EMS.  Although, anecdotal evidence suggests that middle aged horses (5 to 15 yrs) are mostly affected and that certain breeds may be predisposed to EMS, such as some pony breeds (Welsh and Shetland) and horse breeds (Morgans, Paso Finos, Arabians, Spanish Mustangs, Quarter Horses and Arabians).

The 3 main criteria for classifying a horse as EMS are as follows:

1) Increased “general” or “regional” adiposity.  General obesity is observed in the majority of EMS horses, but some affected horses will have a leaner overall body condition and regional adiposity or fat accumulation, while others are normal in appearance. Regional adiposity involves fat accumulation on the top of the neck (“cresty neck” appearance) and/or in “fat pads” close to the tail head, behind the shoulder or in the mammary gland region.

Areas of Fat Accumulation with Regional Adiposity

Areas of Fat Accumulation with Regional Adiposity

2) Insulin Resistance (IR) or decreased insulin sensitivity can be simply defined as a failure of insulin to stimulate glucose uptake by metabolically active tissues (muscle, fat and liver) when nutrients are abundant after feeding. Glucose is not readily transported into the cells in animals with insulin resistance. To compensate for insulin resistance, the pancreas of IR animals typically produces and secretes larger amounts of insulin to promote entry of glucose into cells. The high levels of blood insulin associated with insulin resistance is a condition known as hyperinsulinemia which can contribute to increased risk of laminitis or “founder.”

3) A predisposition toward developing Laminitis. Laminitis or “founder” is a devastating condition of the hoof that involves the breakdown of the hoof lamellar interface that connects the coffin bone to the hoof wall. Laminitis results from chronic inflammation and reduced blood flow to the lamellar interface and can lead to euthanasia.  Laminitis in EMS horses may be clinical or subclinical and occurs in the absence of grain overload, colic, colitis, retained placenta or infectious/sepsis.