This is the presentation given by Dr. Nielsen on Equine Metabolic Syndrome (insulin resistance) and Cushing's disease for the Functional Hoof Conference 2014 in Australia.
About a decade ago I was blessed with a few horses who changed my career path dramatically. One was an overweight cresty sweaty Missouri Foxtrotter who drank and peed a lot, one was a Tennessee Walking Horse colt with soles so thin they literally split open at the end of his first long dry summer, and another was a Walker whose toes shot out in front of him while in shoes. All of these horses taught me valuable lessons and turned me into a hoof junkie. The opportunity to regularly trim most of the horses I treat has been, and continues to be, an invaluable learning experience.
The Foxtrotter, along with countless horses I'd meet in the coming years, taught me about Equine Metabolic Syndrome and Cushing's, the two most common causes of laminitis. I hope to pass along that knowledge to you in my presentation.
Laminitis is caused by disease far from the hoof. We can do the most perfect trim/shoe job and it may not mean a thing if we don't address the underlying cause. In some cases the cause is never identified and in others the initiating cause is a one time event that once gone leaves us with nothing to do but focus on the damaged hooves. These can be the most difficult cases of all.
Equine metabolic syndrome (EMS) and Cushing's disease (PPID) are two very different diseases with different causes and different treatments, yet they can be present simultaneously. They are the "endocrinopathic laminitis" cases, and fortunately for the horse they are slower in onset, more preventable, and more likely to have a good outcome than other causes of laminitis such as sepsis caused by colic or infections like pneumonia or retained placenta, or support limb laminitis (remember Barbaro?). The latter are usually sudden catastrophic events that once resolved leave the horse with relatively more serious and permanent hoof damage.
Horses, ponies and donkeys with EMS have an underlying genetic predisposition for abnormal insulin responses to feeding, producing dangerously elevated blood insulin levels toxic to laminae. The syndrome itself has been defined as comprising three key features - obesity ( regional and/or generalized), insulin resistance, and laminitis - although it is now known that obesity is not necessarily present in all cases. Insulin normally is released in response to food intake and as blood glucose levels rise, insulin output from the pancreas also rises and drives glucose from the blood into the cells of muscle, brain and organs. It also enhances fat deposition in adipose tissue. In EMS the cells don't respond as well to insulin (insulin resistance) but perhaps more importantly the pancreas produces excessive amounts of insulin especially when feeds high in non-structural carbohydrates and perhaps amino acids are consumed. This hyperinsulinemia has been shown experimentally to induce laminitis both in ponies, who tend to be more insulin resistant than horses, as well as insulin sensitive Standardbred horses (Asplin et al 2007; de Laat et al 2010).
Equine Cushing's disease, or pituitary pars intermedia dysfunction (PPID) is caused by excessive production of certain hormones from the intermediate lobe of the pituitary gland as a result of degeneration of inhibitory neurons extending from the hypothalamus to cells of this lobe. These hypothalamic neurons normally produce dopamine, a neurotransmitter that controls the output of the intermediate lobe. As the neurons from the hypothalamus degenerate, the decreased dopamine secretion allows the pars intermedia to produce more ACTH, beta-endorphins, MSH and CLIP than normal. The excessive levels of these hormones cause the many varied clinical signs of PPID. The cells of the PI increase in size and number, resulting in enlargement of the pituitary's intermediate lobe
Many field clinicians have suspected based on anecdotal evidence that EMS horses may be predisposed to PPID, and research is beginning to support this suspicion. In addition, EMS horses may develop PPID at an earlier age than non-EMS equines. PPID likely exacerbates hyperinsulinemia. Therefore, even though EMS and PPID have different causes, they both are linked to hyperinsulinemia, which results in the laminitis so often seen in these syndromes.
Many EMS horses, ponies and donkeys can be diagnosed simply by their appearance: fat deposits in the neck ("cresty neck"), supraorbital fossae, tailhead, shoulder areas, or generalized obesity; often they have both regional as well as general obesity. However, EMS horses can be normal weight and have normal BCS (body condition score). This is important to remember.
Breeds most predisposed to EMS include but are not limited to: Morgans, ponies (Shetland, Welsh, Connemara, Australian, New Forest, Dartmoor, Exmoor, Cob types), mustangs, Arabians, Andalusians, Tennessee Walkers, Missouri Foxtrotters, Peruvian Paso, Paso Fino, Saddlebred, Fjord, Icelandic, Kentucky Mountain Saddle Horse, Rocky Mountain, Paint, QH. Typically the age of diagnosis is around 5 to 10 years in my experience, but can be as early as 3.
Some EMS horses, particularly early cases, may not have fasting hyperinsulinemia but they do have it in response to feeding. Other EMS horses have both fasting as well as postprandial hyperinsulinemia; these can be diagnosed with a simple blood draw. The former cases are more likely to be diagnosed with an oral sugar test. The horse is given 0.15ml/kg corn syrup (75ml/500 kg) in the morning after fasting from midnight before. Blood is drawn at either 60 and 90 minutes or once at 75 minutes, and both insulin and glucose are assessed. Cut-offs are a work in progress but guidelines are as follows: insulin < 45 microU/ml = normal; 45-60 = equivocal; >60 = abnormal.
In a full-blown case of EMS, a simple single blood draw about 2 hours after the horse's normal hay meal is sufficient in my experience. Fasting isn't necessary or desirable in my opinion since we may miss cases. Ratio of glucose to insulin is not accurate. Insulin >20 microU/ml in a fasted animal is diagnostic. There are various ranges in the literature for "normal" insulin levels. I think one has to use and become familiar with their own lab's numbers. For example, the lab I use states normal is 0-65 microUnits/ml, and does not require fasting. I have found that a "well-controlled" EMS horse does typically fall below 65 even when fed hay prior to sampling, and clearly non-EMS horses will usually be below 30 postprandial.
One of the biggest reasons for lack of success with these cases is inadequate follow up. I can't stress enough how crucial it is to monitor insulin levels both short and long term. We need to be sure that our therapy is working both to prevent the horse from relapsing or preferably to prevent laminitis in the first place, as well as to know whether diet and exercise are sufficient therapies in our EMS animals. If diet and exercise and weight loss are not bringing the insulin levels down then we need to use medications such as metformin and/or thyroxine. When I have an EMS case that is severely overweight and has a very high insulin, over 150 - 200 microU/ml, I will start the horse on both of these medications at the time of diagnosis.
EMS equines should be fed a diet of tested low NSC (non-structural carbohydrate) grass hay or alternatively soaked hay. Hay analyses should include either NSC (the definition of which can vary between labs) or WSC (water-soluble carbs), ESC (ethanol-soluble carbs), and starch. WSC includes ESC by definition, so in reality we only need WSC plus starch. Some lay people use ESC plus starch, ignoring WSC, but this is not correct and will leave horses at risk because it does not take into account the fructan component of the true NSC total. Know the protein content of the hay as well because excess protein = excess calories.
With obese horses, weight loss is imperative; if a horse remains overweight we will lose the laminitis battle regardless of other treatments. Metformin and thyroxine are not substitutes for weight loss; they are adjunctive treatments for the short term. Dividing feedings into 3 or 4 smaller portions or using "slow feeders" can help with leveling out insulin levels.
Exercise is the other side of the coin and is very helpful for weight loss and weight control in most EMS horses. However I am not a fan of forcing exercise in the acute laminitis case; allowing plenty of room and motivation for voluntary movement seems adequate for these cases and I don't force exercise until nearly sound. I do believe it is crucial to provide whatever foot protection seems to make the horse the most comfortable to encourage voluntary movement as well as for humane reasons.
EMS horses are not hypothyroid and testing thyroid hormone levels is unnecessary and inaccurate. Thyroxine powder has been shown to increase insulin sensitivity as well as to promote weight loss. Horses do not have to be kept on it indefinitely; I recommend weaning off once the horse has reached an appropriate weight and BCS.
Metformin has been used for treating Type 2 diabetes in humans for decades. Although studies have seemed to conflict regarding pharmacokinetics and efficacy in horses, most authors do use it and feel it helps decrease insulin levels. Current recommended dosage is to give 30 mg/kg 30-60 minutes before feeding 2-3 times per day. Although I have not seen this, one author states that the only side effect seen is occasional mouth irritation upon initiation (Frank AAEP 2013).
Certainly prevention is far preferable to treating after the fact, and insulin-induced laminitis IS preventable. Maintaining horses and ponies in lean body condition through proper feeding and exercise will, in the vast majority of EMS predisposed horses, prevent laminitis. Maintaining insulin levels below 100 microU/ml in these animals is key in my experience.
Personally I don't believe EMS-prone horses and ponies should be on pasture at all but if that is not possible then owners can use grazing muzzles and become knowledgeable about when grass is likely to accumulate WSCs and starch. The best source for pasture management and grazing guidelines in my opinion is Katy Watts (www.safergrass.org)
Obviously trimmers and farriers cannot run blood tests on their clients' equines but we do have the foot as a very good indicator of what insulin levels are doing. One of the earliest changes I have seen in EMS horses whose insulins have become too high after being under control is in heel growth. One may see the heels "pop up" after 6 weeks of growth. Likewise, one of the best most obvious short-term indicators of properly controlled insulin levels is normalized heel growth.
Clinical signs of PPID include: long and/or curly coat that does not shed out normally; winter coat that appears earlier than normal; laminitis; excessive drinking and urination; lethargy; weight loss especially muscle loss along topline; pot belly; abnormal sweating (focal or generalized); insulin resistance and associated physical appearance, clinical signs and lab work; decreased immunity - chronic and/or recurrent infections such as hoof abscesses, intestinal parasites, sinusitis, tooth root, respiratory, skin; seizures, blindness, ataxia, other neurological signs; increased appetite; slow healing wounds; corneal or mouth ulcers, change in coat color, lightening of coat color; lactation without foaling. Most horses affected with PPID will have one or two of these, occasionally more, never all, and in some cases none. Laminitis may be the only sign, and often the first sign, which makes prevention difficult. Any horse with unexplained laminitis should be a suspect for PPID. Some authors now feel that the only PPID cases who will develop laminitis are those with hyperinsulinemia. For years this has been my impression.
It is absolutely crucial for everyone to understand that many PPID horses have normal haircoats. Those cases that do develop abnormal haircoats do so later in the disease process. Horses as young as 7 years have been diagnosed and in one study the average age was 15.5. We need to look for it earlier to catch it earlier. Early signs can be very subtle and non-specific such as decreased performance, activity, or a very subtle loss of topline muscle.
Because of the association of PPID and EMS, which we don't fully understand yet, we should be testing all EMS horses for PPID, at least when they reach 9 or 10, and retest regularly. Likewise, all PPID cases should have their insulins and glucoses checked on a regular basis even if they don't look like the "typical" EMS horse.
We also know now that late PPID cases can develop diabetes mellitus.
The aforementioned hair coat abnormalities, if present, are diagnostic for PPID. Still, we should evaluate a resting ACTH, or a TRH stimulation. These are the only two diagnostic tests currently recommended. The dexamethasone suppression test is no longer recommended, and cortisol has never been shown to be an acceptable test for PPID.
ACTH is easy as it is a one time blood draw, however it requires special handling of the sample and some labs require tubes containing aprotinin. False negatives are possible, especially in early cases. There is seasonal variation in this hormone even in normal horses - in late summer/early fall levels tend to rise. Cut-off values are as follows: November - July >35 pg/ml horse; > 20 pg/ml ponies. August - November: >100 = strong +; 50 - 100 = weak + (one should consider clinical signs in theses cases to guide treatment decision) (Frank 2013 AAEP)
Traditionally vets have been advised not to test in fall but recommendations have reversed because PPID horses can have a much higher level of ACTH during this time. Values greater than 80 - 100 pg/ml are strongly indicative. It must be emphasized a normal ACTH does not rule out PPID. Early cases are more likely to be in the normal range and now the TRH stimulation is thought to be the most sensitive test for PPID available at present (Frank AAEP 2013). This test requires injection of synthetic TRH (protirelin) followed by a blood draw at either 10 or 30 minutes post injection. This test should be performed only from November through July because normal versus abnormal ranges have not been established yet during late summer into fall.
For a 30 minute blood draw: >75 pg/ml = strong +; 35-75 = weak + (consider signs to guide treatment). For the 10 minute draw: >100 pg/ml = strong +; 85-100 = weak +; negative if <85.
PPID is not curable. Treatment is aimed at preventing or controlling adverse clinical signs with the goal of providing a better quality of life and to make the horse feel better overall. The aim is also to prevent or minimize the occurence of life-threatening complications such as laminitis and severe infections.
Pergolide has been well-established as the most effective treatment for PPID, with response rates of 70-80%. The mechanism is via enhanced dopamine production and/or action so as to decrease the pituitary's excessive hormone production. The starting dose for the average horse is 1 mg per day; however, in most cases the dose will need to be increased eventually. The most common mistake vets make is not dosing high enough. The average dose is 3 mg daily therefore some may require more than 3. Some horses need a higher dose in late summer or fall than during the rest of the year. Dose should be based on both clinical signs as well as blood results. In the US the only FDA- approved form of pergolide is Prascend.
The most common side effects of pergolide in the horse are lethargy or anorexia upon initiation, but many if not most have no side effects at all. The drug can be started at a much lower dose and gradually increased or if side effects do occur at full dose then discontinue for a couple days and restart at a lower dose. The few pharmacokinetic studies evaluating pergolide in equines have conflicting results so at this time once daily dosing is recommended. However I have treated some horses with twice daily dosing.
Cyproheptadine is less effective but may have synergistic effects when administered with pergolide. Some authors recommend adding it if a dose of 5 mg pergolide has been reached with no success in ameliorating clinical signs or lowering ACTH levels. Dose is 0.25 mg/kg twice daily. Chasteberry extract has little to no efficacy.
Dental care is very important to prevent tooth root abscesses and sinus infections, which can be very difficult to treat if the PPID is not under control. Likewise these horses may need more frequent dewormings. PPID cases have been shown to have higher fecal egg counts and shorter reappearance periods after deworming.
Horses with only PPID and normal insulin levels do not need a low carb diet especially if they are severely underweight. That doesn't mean we need to feed high sugar feeds since there are many options for increasing calorie intake without increasing sugar intake; for example one can feed unmolassed soaked beet pulp shreds, corn oil, or one of the complete feeds that are low carb. Alfalfa is acceptable in these cases also.
Not all cases of PPID respond to medication regardless of the drug used. Although PPID is a progressive disease, many horses live years on medication and eventually die of other causes. It must be emphasized that the most common mistakes made with treatment are underdosing and not following up regularly. PPID exacerbates high insulin levels and it is crucial to control insulin. Horses and ponies with both EMS and PPID must have the corresponding treatments for both diseases.