“Peripheral Cushing’s Syndrome” (“Metabolic Syndrome”)
– what exactly is it?

The name - Over the last three or four years there has been increasing conversation and discussion about a condition with the rather confusing name of “Peripheral Cushing’s Syndrome” or, even worse, “Peripheral Cushing’s Disease”. The condition has come into our awareness following a considerable amount of fascinating investigation and research performed primarily by Philip Johnson (University of Missouri) who now refers to the condition by the name of the analogous human condition which is “Metabolic Syndrome”. This name reflects the diverse pathophysiological and endocrine effects of the condition. Horses with Metabolic Syndrome have some clinical similarities (plus many differences) with Cushing’s Disease, but as people and horses with Metabolic Syndrome have no abnormalities of either their pituitary or adrenal glands it is really unnecessarily confusing to refer to the condition as either Peripheral Cushing’s Syndrome or Disease.

The cause - At the root of the problem in cases of Metabolic Syndrome is the discovery that omental adipose cells are by no means simply fat storage organs. They are now recognised to be very endocrinologically active and genuinely constitute an endocrine organ in their own right. This is a function not shared to the same extent by fat cells at other locations around the body hence the human association between “apple-shaped people” with metabolic syndrome rather than “pear-shaped people”. Among the numerous products of omental adipocytes is 11b hydroxysteroid dehydrogenase 1 (11b-HSD1). This enzyme resynthesises cortisol from its inactive metabolite, cortisone, and hence serves to regenerate and potentiate circulating endogenous glucocorticoid activity. Hence the omental adipocytes serve as an endogenous cortisol generator. Interestingly Philip Johnson has also suggested that 11b-HSD1 may also be upregulated within the laminae of horses and ponies affected by metabolic syndrome which may have even more relevance towards a propensity towards laminitis.

Among its many metabolic effects, increased circulating levels of cortisol cause hyperglycaemia and also inhibit the uptake of glucose into cells such as muscle due to antagonism of insulin. This has 2 main detectable consequences. Firstly, a resting hyperglycaemia is common and, secondly, further increased insulin secretion from the pancreas results in response to the persistent hyperglycaemia. Glucotoxicity is a term that has been coined to describe the deleterious systemic effects of persistent hyperglycaemia. The most serious of these, in humans, is probably effects on the vasculature resulting in hypertension and in horses and ponies perhaps this is a significant contributor to laminitis. In humans the chronic insulin resistance resulting from cortisol antagonism eventually results in pancreatic b-cell exhaustion and failure to synthesise insulin resulting in insulin-dependent diabetes mellitus. In horses it seems that the pancreas does not become exhausted and generally speaking persistently elevated levels of insulin as well as glucose are seen which may reflect insulin-independent diabetes mellitus .

The clinical picture - Although many affected horses and ponies are significantly overweight this is not invariably the case. Horses and ponies with metabolic syndrome tend to be “good doers” and fairly resistant to getting weight off. Clinical or subclinical laminitis is a common feature in many of these cases. Where clear clinical laminitis is not evident there are often distinct changes to be seen in the hooves such as laminitic rings or expansion of the white line which suggests laminitis has indeed occurred despite the absence of apparent previous clinical signs of foot pain (described as a ‘laminopathy’). Some cases may become pot-bellied, perhaps polydipsic, acyclic and generally lethargic and may share many features common in true Cushing’s disease cases. The latter sign along with weight gain has led to confusion over the possible involvement of hypothyroidism – which does not seem to be the case.

The diagnosis - There is no definitive diagnostic test available for metabolic syndrome. Diagnostically a key feature of metabolic syndrome is that there is no problem with the horse’s pituitary-adrenal-axis. Therefore the tests that we might use to diagnose true Cushing’s Disease in horses such as the overnight dexamethasone suppression test, the TRH stimulation test, ACTH stimulation test or resting ACTH concentration should all have normal results. Another useful rule of thumb is that true Cushing’s disease is very rare in horses under 15 years of age and so suggestive signs in this younger age group are most probably explained by metabolic syndrome rather than Cushing’s disease. Other applicable tests include resting insulin concentration and urinary cortisol to creatinine ratios although there is considerable overlap in results between true Cushing’s disease cases, metabolic syndrome and indeed some normal horses. Resting insulin is probably the commonest screening test used. For interpretation it is imperative that blood is taken following a minimum 5 hour fast and that the subject is neither significantly stressed or in pain at the time. Consequently there is no clear and unequivocal test available that will diagnose metabolic syndrome beyond doubt although the results of the tests above in conjunction with suggestive clinical signs should allow us to make a reasonably confident diagnosis.

The treatment - There are several ways to treat and manage cases with suspected metabolic syndrome. Undoubtedly the most effective and logical treatment is to undertake a gradual process of fittening and weight loss. Fit horses and ponies (even if they are still overweight) have a far greater sensitivity to insulin which largely helps to ameliorate the clinical problems. Clearly weight loss in conjunction with this will also carry tremendous benefits and will eventually remove the causal problem, that is, excessive omental adiposity. Other treatments which may be considered are those aimed at reducing adrenal glucocorticoid synthesis which may act to reduce the substrate available for the omental adipocytes to regenerate cortisol. Such drugs include aminoglutethamide, metyrapone and trilostane and all have been used with varying degrees of anecdotal success. Feed supplements containing manganese have been suggested to improve insulin sensitivity although controlled trials of such products do not support their usefulness.

I am sure that we all see cases that share the features described above on a reasonably regular basis. These cases are not rare and a cynic might suggest that metabolic syndrome is purely a clever way of describing what we have all known for years - that is that many fat ponies and horses are prone to laminitis and have great difficulty in losing weight. It also follows that when they have successfully lost weight and become fitter they no longer have a problem – which should not come as much of a surprise to any of us! The presence of any genuine benefit of pharmacologic agents in addition to fittening and slimming remains to be firmly established.