Pathogenesis and diagnosis of equine Cushing's disease (Proceedings)
Aug 01, 2009
CVC IN KANSAS CITY PROCEEDINGS
In humans and dogs, Cushing's disease is most commonly attributed to a corticotroph adenoma in the pars distalis of the pituitary gland. These adenomas are thought to arise spontaneously. In contrast, Cushing's disease in horses is almost exclusively attributed to hyperplasia or adenoma formation in the pars intermedia that appears to be due to loss of hypothalamic innervation. Abnormal pars intermedia tissue in horses contains markedly reduced amounts of dopamine, about 10% that of normal pars intermedia tissue, consistent with a specific loss of hypothalamic dopaminergic innervation. Recent evidence suggests that this loss of dopaminergic innervation is due to oxidant-induced injury to hypothalamic tissue. Thus, a risk factor for affected horses may be reduced anti-oxidant defense mechanisms in neural tissue. Further, insoluble aggregates of the neural protein α-synuclein have been found in dopaminergic nerve terminals of PPID-affected horses. These protein aggregates are also found in humans with Parkinson's disease suggesting that the two neurodegenerative disorders may share a similar pathogenesis. However, the population of neurons affected in horses, as compared to humans, appears to be different leading to the difference in clinical signs observed in each species.Abnormal pars intermedia cells produce excessive amounts of pro-opiomelanocortin (POMC) and a number of POMC-derived peptides including adrenocoticotropin (ACTH). Also unlike Cushing's disease in humans and dogs, adrenocortical hyperplasia accompanying equine Cushing's disease is relatively uncommon, occurring in ~20% of affected horses. These differences in location and pathophysiology between human, canine, and equine pituitary adenomas have lead several authors to suggest that the disease in horses should not be called equine Cushing's disease; rather, pituitary pars intermedia dysfunction (PPID) has been advanced as a more appropriate descriptor.
The classic clinical sign of PPID in horses is hirsutism, a long and curly hair coat that fails to shed. In some affected horses, coat color changes have also been observed (Figure 2, left). The pathogenesis of hirsutism, which is characterized by arrest of hair follicles in telogen, remains unknown. Hyperhidrosis is also observed in up to two-thirds of horses with PIPD, most commonly over the neck and shoulders, and has been attributed to a thermoregulatory response to the long hair coat. Weight loss and lethargy, or poor performance, are also commonly observed in horses with PPID. In addition to true weight loss, protein catabolism due to increased cortisol activity leads to loss of muscle mass. This is most notable in advanced cases as a loss of epaxial and rump musculature. Despite weight loss, appetite in affected horses is normal or even increased (polyphagia). However, dental abnormalities, leading to painful mastication and quidding, may compromise feed intake and contribute to weight loss in some horses. Combined with, or often preceding, loss of muscle mass is deposition of fat along the crest of the neck, over the tail head, and in the sheath of male horses. Another area where abnormal fat deposition may occur is above and behind the eyes (supraorbital area, Figure 2, center). Horses with PPID have also been described as overly docile and more tolerant of pain than normal horses. The latter signs have been attributed to increased plasma and cerebrospinal fluid concentrations of β-endorphin that are 60- and more than 100-fold greater, respectively, in horses with PPID than in normal horses.
Other signs that have been reported in horses with PPID include persistent lactation and infertility. Central nervous system (CNS) dysfunction, including ataxia, blindness, and seizure-like activity, are occasionally observed in equids with PPID. A major complication of hypercortisolism in affected human patients is osteoporosis. Although occurrence of this complication has not been investigated in horses, it is interesting to note that euthanasia of horses with PPID has been reported due to development of pelvic, pedal bone, mandibular, and multiple rib fractures.