CUSHINGS DISEASE - Equine Pituitary Gland Hyperplasia (EPGH)
RANVET an Australian veterinary product manufacturer is currently seeking cases of EPGH to be included in a treatment study. They intend to register a pergolide syrup for horses. This would make treatment less expensive and more convenient. They require cases where horses are being treated or could be treated with pergolide. Then they will supply pergolide syrup at reasonable cost for ongoing treatment. The sooner they get enough cases, the sooner the product will be available.
Please contact Dr. Graham Best on 1800 727 217 or http://www.ranvet.com.au
Laminitis Seminars 2008 will cover in detail cushings disease and equine metabolic syndrome. The dates are the 1st and 15th of June - click here for details.
CUSHINGS DISEASE - Equine Pituitary Gland Hyperplasia (EPGH)
Cushings disease describes a similar group of diseases in several species including, humans, dogs and horses. Equine Cushings is slightly unusual in that the primary problem is usually enlargement of the pituitary gland (found at the base of the brain) due to hyperplasia or adenoma (hypertrophy). The pars intermedia of this gland is poorly vascularised and relies on neuro transmitters from the hypothalamus to control secretion. The main neurotransmitter is DOPAMINE which has an inhibitory role. A loss of inhibition by dopamine is responsible for excess pars intermedia activity. This is the beginning of a hormonal chain of events that results in Equine Cushings Syndrome. Up to 10% of aged horses can be affected. Older horses are susceptible to the loss of dopamine and recent research suggests that this may be due to oxidative damage. (Antioxidants should be part of the cushings/laminitic horse's diet.) This is not a form of cancer. However spontaneous adenoma (benign tumor) may also occur and this may account for young horses that develop the syndrome. The end result in all cases is an excess of hormones produced without sensitivity to negative feedback from the end organ to say that too much is being produced. The effect is hypercortisolaemia (excess circulating cortisol).
The pituitary gland is situated at the base of the brain and makes many vital hormones including adrenocorticotropic hormone (ACTH), which functions to stimulate the cortex of the adrenal glands found close to the kidneys, to produce corticosteroids including cortisone and cortisol. Cortisol is the principal glucocorticoid. Cortisone is a glucocorticoid with significant mineralocorticoid activity used as an antiinflammatory and for adrenal replacement therapy. Corticosteroids raise low glucose levels and help regulation of the blood glucose level in an antagonistic role to insulin. Insulin responds to high glucose levels and sends excess glucose into storage. Cortisone levels naturally increase during times of stress. Therefore, an excess of this hormone will result in mobilisation of stored energy from tissues e.g., protein and fat. Lipids from fat are converted to glucose raising blood glucose levels, and a breakdown of connective tissue occurs as a result of the excessive antiinflammatory effects leading to the pot belly and weakness associated with advanced disease.
In EPGH excess ACTH leads to excess corticosteroids from the adrenal gland and the long-term effects of Equine Cushings Disease (EPGH) include decreased immunity, weakness, pot belly, unusual distribution of fat over the tail base, sides and even above the eyes, weight loss despite a covering of fat, increased appetite, thirst and urination, a long shaggy coat (most advanced cases) that does not shed easily in summer, browning of the coat colour and laminitic episodes or chronic laminitis that is difficult to resolve. Pneumonia and other infections due to the effects of excess cortisol on the immune system are advanced signs. Autumn may be the time when many cases become worse due to the effects of decreasing day length on hormonal systems.
As cortisol levels increase insulin levels must then increase in an attempt to keep glucose within the normal range. A chronic unregulated elevation of insulin is diabetes. When the insulin and cortisol levels are tested in horses with EPGH they are often significantly outside the normal range despite blood glucose levels being normal. Usually the horse or pony is aged 15 or over when signs are noticed. Many cases are never diagnosed or treated. Treatment is effective in many cases and at least 2 options are available and can be used in conjunction with each other or singly.
Step 1. Research. the information in this site is the tip of the iceberg and only relates to my experience with this disease. If you are going to test a horse for this condition gather as much information for yourself and your vet and then you will make better choices. The following is a guide only.
If your veterinarian suspects this disease it is worth testing to try and confirm if this is the case. Several different tests are available. However, I have had good results by testing the level of insulin. If normal, but the horse has symptoms, you may be one of the 30% that tests negative despite having the disease, and another test may be required. I like to combine insulin, cortisol/or ACTH and glucose as my tests. This gives me a start. Your vet will discuss all the options with you. Please note; all the horses I have suspected to have the disease and then blood tested, have so far tested positive for high insulin or insulin and cortisol despite some having only mild symptoms. I also have to take finacial restraints into account and whether I am going to conduct a treatment trial regardless of test results.
Other tests include Basal ACTH level and comparison of morning and evening cortisol levels. There should be at least a 30% decrease in levels in the evening in normal horses. Cortisol alone is not considered reliable due to its widely varing level over time. Low dose Dex test, TRH test and other tests are available.
Feed roughage eg. some hay etc. in the evening prior and then you must organise to test first thing the next morning. You must not feed the horse. You should not feed or move any other horses as this may upset the horse to be tested. Ideally a very calm and comfortable horse with no current pain or problem will give the most accurate blood result. I organise to collect blood first thing in the morning so that the owner can then feed up as normal once the blood has been taken. Use the correct tubes, keep it chilled and get it to the lab promptly.
Step 2. If your horse has the symptoms of this disease and tests confirm this, you may wish to begin treatment. The options include.
- Pergolide mesylate (PERMAX) is a human product used to treat Parkinson's disease. It is available through your veterinarian who will write a prescription which can be filled by a pharmacist at the chemist shop. The small tablets are given crushed in feed or whole in an apple or bread and jam, or "whatever" your horse likes. Please refer to the boxed information on RANVET's pergolide syrup at the start of this section.
- The alternative therapy is a herb called Vitex agnus cactus which is usually called Chaste Tree Berry. This is available in Australia, USA and the UK and is given in feed once or twice per day. Other herbal preparations of Vitex agnus cactus are available from Hilton Herbs in the UK but are not available in Australia. Refer to the page of recommended links for Austral Herbs in Australia.
- After 6 weeks of treatment retest insulin and cortisone levels to see if they have changed. If blood insulin/cortisol levels are unchanged or increased, the dose of medication or herb needs to be increased and the animal retested in a further 6 weeks. If a significant improvement has occurred then it is possible to reduce the medication or herb. Then retest again in 6 weeks.
- Once a maintenance dose of medication or herb has been established, the interval between tests can be extended to 3 - 6 months so that the correct maintenance dose is maintained to stabilise the symptoms. Many cases are managed on a minimum daily dose for years.
- Other treatments are currently being trialed.
- A low energy, high roughage diet with balanced minerals and supplementation with antioxidants form part of ongoing management. Obesity should be avoided. Refer to the laminitis diet from the home page or at the end of the laminitis section of this site for further information on feeding.
Recommended web sites
Hilton herbs - refer to recommended web sites and links for more detail.
Austral herbs - refer to recommended web sites and links for more detail
Prognosis
Many ponies and horses are diagnosed only when they have developed very severe symptoms, or are not diagnosed because people think that the changes in the way the animal looks are associated with old age, or that laminitis is due to other reasons. Life expectancy depends on the age of the horse or pony when treatment commences and the response to the medication or herb. Some go well and some do not. The more debilitated and advanced cases have a poorer prognosis than those cases where symptoms are detected and treatment commences early in the disease process. No treatment will result in ill-health and a shortened life expectancy.
Laminitis, which is poorly responsive to other treatments is a sign of Equine Pituitary Gland Hyperplasia (EPGH). Laminitis is the second most common cause of death of horses after colic. Treatment of the primary disease is always an essential factor in control of laminitic symptoms and prevention of further damage to the feet. When the cortisol level is controlled the insulin responsiveness of the hoof lamellae is restored. Hypothyroidism is also anecdotally associated with an increased risk of laminitis. Therefore, if you have an older horse with recurring moderately severe laminitis it should be tested for Cushings disease, and possibly hypothyroidism, and if necessary treated. Not all horses with EPGH develop laminitis, or a long coat. If they have any 3 of the symptoms, and are 15 years or older, it should be included in the differential diagnosis list, and tests performed to prove that it is, or is not, the underlying cause of the symptoms your horse has.
Genetics, Body Type and Laminitis
In my experience certain breeds, families and body types (phenotype) are much more predisposed than others to developing laminitis on certain farms at certain times. I can almost predict the ponies or horses that will have a problem. A couple of little studies of my own revealed a high risk to females in comparison to males and that some ponies are innately resistant to the disease. Then I read an article in Equus magazine by Dr. David Kronfeld of the Middleburg Agricultural Research and Extension Center in the USA. A study of 160 related ponies into risk factors for laminitis indicates that metabolic changes in the body associated with obesity and pregnancy combined with genetics and pasture changes resulting in insulin resistance contribute to laminitis. Blood tests taken when all the ponies were healthy revealed that those who had previously developed laminitis showed elevated levels of triglycerides (fats) and increased insulin and insulin compensation. Of this group 11/13 later developed laminitis. Genetically a link was also present with a dominant mode of inheritance that was partially suppressed in males. This genetic predisposition may have given a survival advantage in very harsh conditions in which ponies evolved but creates disaster when overloaded with rich feed. During the time of the study (spring) pasture testing revealed a two fold increase in starches and sugars known to increase the risk of laminitis. Plasma cortisol was also studied and this stress hormone has been previously linked to hyperlipemic laminitic syndrome.
Pre Laminitic Metabolic Syndrome (PLMS) is a set of risk factors that can be identified in healthy ponies. Fat tissue plays a role by producing hormones that hamper the action of insulin which is trying to get glucose from the blood into cells for energy production. In other cases insulin resistance causes the animal to get fat. This process is yet to be fully understood. The body fat of insulin resistant horses forms in patterns e.g., hard, thick, cresty neck, spongy fat on the shoulders, tail base and in the sheath of males and over the eyes. In my experience these animals are at risk of developing laminitis with any slight increase in energy in the ration. I can now see the pattern of elevated insulin, cortisol and triglycerides in hypercortisolaemia (Cushing's like syndrome), hyperlipemia and laminitis. These three diseases are all fatal in severe form.
Relevant conclusions from Dr. Kronfeld's study were:
- A genetic connection and dominant mode of inheritance for pasture laminitis with partial suppression in males.
- A phenotype e.g., refined head, cresty neck, rounded body (the show pony type) with a distinctive metabolic profile.
- Characterization of a pre laminitic metabolic syndrome in apparently healthy ponies and exaggerated compensated then decompensated insulin resistance during laminitis.
- Evidence of association between the onset of laminitis and increased pasture starch content due to rapid growth of clover (the trigger factor for at risk ponies or horses).
The researchers offered the following advice:
- Blood test ponies and horses at risk of Pre Laminitic Metabolic Syndrome.
- Test for elevations of triglycerides and insulin. This is most relevant to overweight animals related to those with laminitis.
- I suggest that cortisol or ACTH should also be included if you are blood testing.
- If your animal is healthy but shows signs of PLMS it is time to act to change the metabolic profile and improve insulin sensitivity.
- Begin daily exercise, a controlled weight reduction program, eliminate large grain or molasses based feeds and begin administering antioxidants and omega 3 and 6 fatty acids.
- Sample your pasture grasses and test your ponies when nutrient levels are high. Feed seedless grass hay and consult your veterinarian for further advice.
Suggested reading.
Kronfeld. D., PASTURE LAMINITIS BREAKTHROUGH, EQUUS 342, April 2006, pp. 47 - 63.
THE ROLE OF GLUCOSE IN LAMINITIS, Medical Front, EQUUS 341.
www.EquusMagazine.com
Normal reference ranges for insulin and glucose (variation between laboratories)
normal reference range for equine insulin 4.0 - 7.1 mu/L or
normal reference range for equine insulin 10 - 30 uU/ml
normal reference range for equine glucose 3.4 - 7.7 mmol/L
normal reference range for equine triglycerides
normal reference range for equine cortisol 83 - 360 nmol/L
normal reference range for equine triglycerides 0.1 - 0.9 mmol/L
Cushings Case Histories
| Name of horse or pony |
Age |
Diagnosis |
Retest |
Current status |
Name
|
Age |
Diagnosis |
Retest |
Current status |
Footy: was investigated for EPGH at his owners request because he seemed to urinate a lot and she felt he had a slightly abnormal coat for a show horse in summer. He had blood collected at the clinic and I warned that this would affect the results because he had a float trip and there is the usual excitement. Due to the inconclusive result (pathologists comments follow) he was retested at 9.00 am after a normal night at home, before he was hungry or any horses were moved about. The results indicated no abnormality.
Pathologists comments: "Resting normal insulin (5 - 36 micro U/ml should be interpreted with great care. many horses with Cushings disease are indeed found to have elevated resting insulin concentrations due to cortisol induced antagonism of insulin and also the pro-secretory effect of CLIP (one of the pituitary derived products in ECD cases). However, diet and stress also have profound effects on insulin secretion and these should be carefully considered. A hard feed will elevate insulin levels for up to 5 hours. insulin levels as high as 250 uU/ml may also be seen in non Cushings horses with painful conditions such as colic and it is likely the pain of laminitis could have a similar effect. Thus insulin is not a suitable test for ECD horses with active laminar pain and also is best measured first thing in the morning before feeding". This horse had no signs of laminitis and testing in the morning at the property delivered a normal result.
| Name Horse gelding T |
Age |
Diagnosis |
Retest 17/3/2005 |
Current status After increasing medication and an excellent response T was euthanased due to severe lameness in one foot secondary to chronic laminitis. |
T: After several years with severe lameness secondary to laminitis and Cushings symptoms including an extremely long, shaggy coat in winter, Trojan was diagnosed in March 2005. After 6 weeks of treatment a blood test revealed a further 1 mU/L increase in insulin and the dose of Pergolide was increased. Trojan improved noticeably within days. However, he eventually succumbed to severe lameness in one foot despite expensive hoof reconstruction and therapeutic shoeing, which had initially resulted in great improvement. Mid way through the treatment period Trojan was off all pain relief and cantered for the first time in years. When wet weather set in he had significant lameness in his most affected front foot which did not respond to therapy, and after 10 days of treatment and high doses of phenylbutazone the owners chose to euthanase him to end his suffering.
| Name Horse Mare Jess |
Age 22 |
Diagnosis |
Retest |
Current status |
Jess: A much loved and still ridden Appaloosa mare, with severe chronic laminitic changes to the feet and only mild observable changes to the hair coat and skin. Lameness prompted the owner to contact me, and after much discussion a blood test indicated the mare was strongly positive for EPGH. Treatment with Pergolide was combined with Vitex agnus cactus dried herb and the mare was returning to soundness quickly. At the 6 week retest, the insulin level had returned within the normal reference range (from 113 down to 22.2 in 6 weeks). Treatment for the laminitic changes to the feet are continuing and the mare is now ridden gently. Her overall health and coat have improved.
Name |
Age 20 |
Diagnosis |
Retest |
Current status |
Pony M: This older pony-cross mare is improving in health after her owner visited the vet clinic describing her horse as pot bellied and exercise intolerant. The symptoms were suggestive of EPGH despite the owner saying the hair coat was normal and the horse appeared well. Blood tests revealed a high level of insulin and treatment with Pergolide commenced. Research into the use of Vitex agnus cactus prompted the inclusion of this herb in the daily treatment program, and at the 6 week recheck of insulin levels a significant improvement was noted. Therefore, the dose of Pergolide was halved and the Vitex agnus cactus continued at the same dose. The goal is to recheck at 6 weeks and if necessary further reduce or eliminate the Pergolide while continuing with herbal therapy.
Name Pony |
Age 23 |
Diagnosis |
Retest |
Current status Euthanased due to respiratory infection and old age. |
Mare M: After a long career in a riding academy this mare was diagnosed in an advanced stage of the disease. The owner of this mare was intending to contribute to this topic by treating the mare with Vitex agnus cactus only rather than combine it with Pergolide, or use Pergolide only. Before it was possible to commence treatment the mare contracted a respiratory infection and due to her advanced age and poor general health the owner made the difficult decision to end her suffering.
Name |
Age |
Diagnosis |
Retest |
Current status |
Jorge: A longer than 2 year history of laminitis with long periods of being sound in between. Jorge was going well but after a mild dose of laminitis followed by a severe foot trim he continued to get worse. Jorge was shod and was much improved but then continued to decline again. Diet, environment and feet were well managed and pain relief did not bring about a change in the symptoms. Blood testing revealed the laminitic metabolic profile and Jorge has been treated with pergolide to try and resolve the laminitis. He is also on a diet plan to lose 30 kg, to increase his exercise and to get him out of his current insulin resistance. So far so good. March 2007 still sound and being exercised. On low dose pergolide & vitex agnus cactus.
Name |
Age |
Diagnosis |
Retest Nov Mal insulin 200/ml & sound again |
Current status |
Summer C: Has been slowly developing EPGH symptoms with laminitis. We are in drought conditions at the time of writing so the chance of carbohydrate overload in these cases is zero. The mare has front shoes and was worsening despite pain relief. She is improving on pergolide. Plan - retest and adjust dose rate if needed.
Pathologists comments: Cortisol - A single random cortisol result may be of limited diagnostic value due to the variable secretion of both ACTH and cortisol. Dynamic testing i.e. the overnight Dexamethasone suppression test, is recommended to assess for EPGH or Cushings-like disease. Please contact the lab if you require a protocol for this disease. (Do you think that was a hint). I don't do dex tests in these cases as more corticosteroid is likely to be detrimental to the laminitis and could tip the patient over the edge. I do a treatment trial instead. March 2007. Did this mare's feet myself which led to improvement, I blood tested normal. Reshod November 2007, going very well increased dose of pergolide to 1mg daily but mare did shed her winter coat and her laminitis is now controlled. March 2008 summer was enthanased due to complications from a tooth root abcess, foot abcess and a tight bandage. My condolences to her family that tried very hard to save her. However she is no longer suffering from her chronic laminitic feet.
Name Todi
|
Age 25 |
Diagnosis Tests performed |
Retest Pergolide |
Current status Euthanased by owner due to ongoing difficulty of treatment and the harsh winter conditions where this horse lived. 1/12/07. |
Todi: Todi had her last foal at 22 without complication. She survived 2 bouts of colic and 2 rattlesnake bites and enjoyed good health all her life with only a few bouts of laminitis. To her owners distress in the last few years she began to lose weight with chronic laminitis and abscesses associated with her teeth despite regular dentistry. The weight loss became severe and through www.farriervet.com I corresponded with Jean in the USA about this horse and advised that after tests by her local vet which indicated Cushing’s disease, that Pergolide should help. Jean was naturally very anxious about using this drug as she has a holistic philosophy (as do I). Jean reported a postive response to treatment and I know that seeing her horse respond well makes it easier for Jean to continue treating Todi. At the time I considered the treatment palliative and for quality of life not quantity. However I am happy to say that at the last e-mail Todi was shedding her coat and doing well despite a very harsh winter. She was eating as much as she could and had regained some weight.
Name |
Age |
Diagnosis |
Retest |
Current status Much improved and on half the dose of pergolide. |
E;Why: laminitic for greater than 5 months with diet, environment and feet well managed. Suspected metabolic cause of laminitis and this is the first pony that I have tried pergolide on that did not present as classic Cushing's disease. The results have been good and this case prompted me to treat the other young ponies listed here with laminitis.
Pathologists comments 6/10/'06: "Insulin - the published reference ranges are in the region up 35 uU/ml so this indicates insulin resistance. Cortisol - In normal horses the range is above 55 nmol/L approximately, Dexamethasone suppression test recommended to investigate further". Started a treatment trial instead. Result excellent, reduced medication after the first retest and is now on minimal daily dose and has lost weight and increase exercise.
Name |
Age |
Diagnosis |
Retest Normal. |
Current status |
Maybelle: A much loved, very old and shaggy mini that had survived colic surgery once was put down after developing colic again. She had chronic laminitis, however she improved with farriery and a diet change including supplements. It would have been interesting to see if pergolide would have helped her.
Name |
Age |
Diagnosis |
Retest 1st/Feb/2007 Glucose 5.5mmol Cortisol 71nmol/L insulin 8uU/ml |
Current status Significant improvement. Has improved dramatically is off all medication except pergolide and is moving freely around the farm. 1/12/07. |
Tango: A beautiful show pony with a 3 year intermittent history of laminitis. For the past 4 months he has been deteriorating. My fist meeting was in December '06 and he was so severely laminitic that he could not bear to stand up. After an initial investigation into his laminitis I suspected a metabolic cause but he was deteriorating so fast in our summer weather that I was not sure we would save him. Breed and phenotype (how he looks) he is the classic candidate for laminitic metabolic syndrome.
 |
This photo of Tango is before treatment. He had severe laminitis, shuffling from foot to foot. After 6 weeks treatment his blood tests were normal and he is much improved. |
I feel that hyperlipemia was part of his problem and that if his owners hadn't given him 24 hour a day care, hosing his feet and loving him through he would not have survived this long. Now at 4 weeks he is out most of the day, going for walks and getting his spark back. He has a long way to go and I am reluctant to change anything too soon. I will re blood test him before touching his feet, we will also begin to reduce his medications including anti-ulcer meds and pain relief which is now at a very low dose. The owner is keeping a diary and I hope to present this case to other vets.
In early February 2007 Tango has been retested. At this time he was clinically dramatically improved, off all pain relief, standing comfortably and moving comfortably despite the dramatic crisis line below the coronary band that you would expect to see with such a severe case of laminitis. His blood results for cortisol, insulin and glucose were normal. We have reduced the dose of pergolide to 750 micrograms per day and the owner intends to also begin feeding Vitex Agnus Cactus with the plan to eventually get Tango off pergolide if possible. He will be on the laminits diet with antioxidants and other management changes for life. The family have set a goal to take him to a show in August this year even if he is only an observer. Tango has a lot of living left to do. I strongly feel that if he hadn't been treated with pergolide he would have been euthanased before Christmas '06.
I have recently tested a few more ponies and the histories and results are similar to those above. When I have enough cases I hope to use this information as part of a small study into pergolide as a treatment for laminitis for those cases that have metabolic laminitic syndrome.
2008 - Tango and Jorge are both for the first time unrugged, unfed, out in the paddock, doing it tough and both ponies are sound and healthy. They are loved, but it has taken a long time to convince the owners that less is more. When the weather turns really cold they will be supplemented. Tango is the best he has been for 18 months.
Suggested Links
http://www.horsechannel.com/horse-health/equine-cushings-disease-24321.aspx
http://www.laminitis.org/cushings.html
http://www.laminitis.org/Trilostane.html