Endocrinopathic Laminitis

Melody Anne de Laat and Cathy McGowan

Endocrinopathic laminitis is a common debilitating cause of lameness in horses and ponies associated with endocrine disor­ders, most notably equine pituitary pars intermedia dysfunction (PPID) and equine metabolic syndrome (EMS).

This important shift in our understanding of laminitis has allowed a wealth of new research into endocrinopathic laminitis and improved our understanding of the pathophysiology, diagnosis, treatment, and prevention of this highly prevalent form of laminitis.

Epidemiology

Endocrinopathic laminitis occurs worldwide, and it has been reported to be the most common form of laminitis^8,9; however, a full epidemiologic understanding has been hampered by poor case definitions of laminitis, especially in distinguishing endocrinopathic causes.¹⁰ The true frequency of endocrinopathic laminitis across the whole population is unknown, but it can be as high as 34% in EMS-susceptible breed groups¹¹ and 82% in retrospective case series of PPID.¹² A more robust cohort study from the United Kingdom reported 9.9% ponies and cobs 7 years of age or older, excluding PPID and without a history of laminitis developing laminitis during a 3-year period.¹³ Endocrinopathic laminitis does appear to recur with reasonable frequency, with the recurrence rate reported to range between 33% and 70% depending on the timeframe studied.^14,15 The data indicate a seasonal influence on disease occurrence, with a tendency for more new cases to occur in spring and summer when consumption of pasture high in nonstructural carbohydrates is more likely.^15,16 Even though not studied specifically for endocrinopathic laminitis, increasing age and breed have been proposed as risk factors for laminitis, while it is unclear whether a sex predisposition exists.^17-19 There are no direct data to support a genetic origin for the disease beyond the proposed genetic predisposition to underlying endocrinopathies, such as EMS/ID.²⁰ More simply, some studies have investigated an association between height and laminitis incidence, with the hypothesis that ponies are at greater risk of disease than horses, but the data are inconclusive.¹⁶

More recently, a focus on metabolic and endocrine param­eters has resulted in the identification of some clear risk factors for endocrinopathic laminitis. Increased basal and dynamic serum insulin concentrations have been correlated with an increased risk of laminitis occurrence.^13,21-23 In addition, hyperleptinemia and hypoadiponectinemia increase the risk of laminitis.^13,22 Morphometric data are also supportive in some breeds, with increased BCS (≥7∕9) and CNS (≥4∕5) in combina­tion with basal insulin (> 32 μIU∕mL) or leptin (>7.3 ng∕mL) being associated with an increased risk of pasture-associated laminitis.²² Horses and ponies with PPID have an increased risk of both ID and laminitis.

Clinical Signs

Endocrinopathic laminitis typically results in lameness in all four limbs, which can vary from mild or even subclinical to severe debilitating pain. The degree of lameness was graded by Obel in 1948²⁵ using a simple but effective scale of 1 to 4. Although this grade was developed using laminitis associated with systemic inflammatory conditions (starch overload and retained placenta; SIRS-associated), it is still relevant 60 years later for endocrinopathic laminitis.²⁵ Supportive findings such as typical gait, weight shifting, increased or bounding digital pulses, and pain on hoof testers may be found.²⁶ The hyperinsulinemic model confirmed clinical suspicion that endocrinopathic lami­nitis is slower in onset than SIRS-associated laminitis. Ponies and horses subjected to hyperinsulinemia developed laminitis slowly in all four limbs, with the onset of lameness associated with laminitis (Obel grade 2) by approximately 48 hours.^6,7

It is also important to recognize that endocrinopathic laminitis can occur in the absence of pain. Experimentally, evidence of histologic lesions of laminitis was detected as early as 6 hours post exposure to hyperinsulinemia, ²⁷ and in response to much lower circulating concentrations of endogenous insulin than in the hyperinsulinemic model,²⁸ which supports the contention of lamellar lesions and laminitis occurring before or without lameness. In a study of naturally occurring laminitis it was noted that hoof capsular changes such as divergent rings occurred in all histologically confirmed laminitis cases, but gross pathological changes did not correspond to the duration of lameness.²⁹ Divergent rings could extend the full length of the hoof wall in horses with a short history of lameness, which based on the growth rate of the hoof wall confirmed the occurrence of a preclinical stage in some horses.²⁹

Histology

The hyperinsulinemic model has also facilitated more in-depth study of the pathologic lesions associated with laminitis.

The histology of naturally occurring endocrinopathic laminitis is similar to the hyperinsulinemic model and shows a range of lesions with overall stretching and lengthening of primary and secondary lamellae. Abaxially (underneath the hoof wall) there is apoptosis, lamellar fusion and hyperplasia, and keratinization that may lead to tearing and separation. Axially (adjacent to P3) there is tapering of the primary and secondary lamellae in variable amounts.²⁹ In both experimental hyperinsulinemia and in naturally occurring endocrinopathic laminitis, the lesion is not basement membrane driven as has been proposed from research in SIRS-associated models. Early cellular changes are associated with limited and localized basement membrane damage likely to be associated with the cytoskeletal disruption within the epithelial cells.⁸

Pathophysiology

Considerable research effort has been invested in exploring the pathogenesis of endocrinopathic laminitis. While significant progress has been made, certain elements of the pathophysiology remain elusive, with uncertainty surrounding exactly which pathways engender the demise of the lamellar structure during laminitis onset. What is clear is that in cases of ID, whether from PPID or EMS, hyperinsulinemia is a catalytic factor for lamellar failure.^6,7,29,32 However, precisely how insulin drives the lamellar lesions to induce clinical laminitis remains unclear.

Early studies focused on impaired lamellar metabolism and potential interference with glucose supply during the initia­tion of lamellar separation.^34,35 Current consensus is that the lamellae are an insulin-independent tissue, with a profusion of the glucose transporter 1 (GLUT1).^36,37 Further, the lamellae do not appear to be rich in GLUT4, which is the principal insulin-dependent transporter and predominates in insulin­sensitive tissues such as striated muscle and adipose tissue.^36,37 GLUT1 does not rely on insulin to drive glucose uptake and predominates in highly metabolic tissues such as the brain and epithelium, where interruptions to glucose supply would be problematic.³⁸ As such, the lamellae appear well equipped to meet their metabolic demands.

Once it was shown that failure of glucose uptake was an unlikely catalyst for lamellar failure, investigations into the potential involvement of glucose toxicity, oxidative stress, and lamellar glycation were undertaken.³⁹ Despite these processes being evident in the pathophysiology of type 2 diabetes mellitus sequelae,⁴⁰ data demonstrated that glycoxidative processes were only upregulated after the onset of lamellar pathology³⁹ and therefore this hypothesis was not supported.

Despite obesity, which is often associated with EMS, being a proinflammatory state, there is little evidence to support a major role for inflammation in endocrinopathic laminitis pathophysiology. Histologic studies of both naturally occurring and experimentally induced laminitis have demonstrated minimal leukocyte infiltration, unlike the marked inflammation in SIRS-associated laminitis.³¹ Further, gene and protein studies of the lamellae have not reached a consensus that proinflam­matory cytokines are key instigators of endocrinopathic laminitis pathophysiology.^41,42 Lastly, an active role for matrix metal­loproteinases (enzymes secreted by leukocytes that degrade the extracellular matrix) in the onset of endocrinopathic laminitis has not been supported,⁴³ unlike in other forms of the disease.⁴⁴

Similarly, the role of blood flow in the inception of endo- crinopathic lamellar pathology is unclear.

An ischemic or hypoxic pathogenesis for laminitis also makes physiologic sense and is supported by the knowledge that persistent weight bearing on one limb, which may reduce blood flow to the foot, can induce the disease.⁴⁸ While investigations in vivo of lamellar ischemia have not been attempted, data from isolated, perfused vessel studies suggest that experimental preincubation with insulin may drive intracellular signaling away from the metabolic pathway, with aberrant vessel contrac­tion observed in response to insulin in the lamellae.^49-50 The same effect was seen where vessels had been collected from horses with naturally occurring endocrinopathic laminitis.⁵¹ However, ischemic lesions have not been observed histologi- 272930

cally^,29^, and how ischemia may contribute to the pathogenesis of endocrinopathic laminitis remains unclear.

Perhaps the most promising line of research for uncovering the exact pathophysiology lies in understanding how aberrant intracellular signaling in the epithelial cells, especially the shift away from the metabolic pathway as has been shown in the vasculature, may be driving their demise. Insulin is a growth factor and may still exert its effect directly on the tissue, such as by signaling through, or upregulating, other receptors. Insulin can bind to insulin-like growth factor 1 (IGF-1) and hybrid insulin/IGF-1 receptors,⁵² and these are both possible targets, especially considering that IGF-1 receptors have been identified on lamellar epithelial cells, and that they are differentially expressed during experimental laminitis.^33,53 Insulin may also regulate the expression of other growth factor receptors in the lamellae, such as the epidermal growth factor receptor,⁵⁴ with signaling achieved by a variety of local or circulating ligands. Activation of all of these receptors can trigger common intracel­lular signaling pathways that cause cellular damage via cyto- skeletal disruption, leading to the well-defined initial lesion of lamellar and cellular stretching.^8,55

Management, Prognosis, and Prevention Endocrinopathic laminitis remains difficult to manage. However, better understanding of the cause, and in particular the relation­ship with ID, has allowed a focus on monitoring and manage­ment of the underlying problem to reduce recurrence in the future.⁵⁶ Further, pathologic understanding of the lesion and the potential for a subclinical phase leading to divergent hoof rings or other hoof capsular changes as an early warning²⁹ has meant that prevention before lameness is more achievable in some cases.

Laminitis management strategies focus on pain relief and remediation of gross hoof defects¹⁵ (also see Laminitis section in Chapter 38). Pain relief can often be achieved with nonsteroidal antiinflammatory drugs (NSAIDs), although in severe cases opioids or multimodal analgesia may be necessary. More recently, there has been increased interest in targeting neuropathic pain with gabapentin, although the potentially low oral bioavailability of this drug may limit its efficacy.^57,58 Restriction of movement in severe cases is important, and provision of deep bedding is recommended.⁵⁹ Additional pain relief can be achieved with hoof supports, such as moldable pads that are designed to cushion the palmar hoof surface and ease the breakover. Farriery is also recommended to reform hoof biomechanics, and specialist ongoing hoof care is often required.⁵⁹

Treatment of the underlying endocrinopathy is also central to management, as a reduction in hyperinsulinemia is crucial for reducing the risk of recurrence. The prognosis for endo­crinopathic laminitis is variable. Severe, intractable cases carry a poor prognosis, and euthanasia is often the only humane option in these animals. Milder cases with a clear underlying endocrinopathy that can be addressed and the absence of marked displacement of the distal phalanx carry a fair prognosis if appropriately and promptly managed.

Prevention of endocrinopathic laminitis should be the key focus, and identification of hoof capsular changes indicative of laminitis on clinical examination²⁶ should prompt appropriate endocrinologic testing. The goal should be to identify animals at particular risk of this form of Iaminitis in the preclinical phase and instigate strategies to reduce the likelihood of disease onset. Studies have indicated that hyperinsulinemia indicative of ID is the strongest predictor of disease.^{3,4,9,11,13,29} The predic­tive power of insulin concentration is also apparent in animals with PPID^21,32 and has been supported more recently by the finding that an abnormal oral glucose test result was predictive of laminitis risk.²³ Combining tests for insulin, leptin, adipo- nectin, and morphometry may support a diagnosis of ID, but further research in this area is required.

In conclusion, the paradigm shift in our recognition and understanding of endocrinopathic laminitis has greatly improved our ability to appropriately focus management and prevention on the underlying endocrinopathy. More research will help pinpoint risk factors, improve diagnostic tests, and improve treatments for the underlying endocrinopathies, and as these are developed, so too the toolkit for preventing laminitis will grow.