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Paradigm shifts in understanding equine laminitis

Authors:
  • AnimalStrategies, LLC
  • University of Helsinki, Finland, Faculty of Veterinary Medicine

Abstract

Laminitis, one of the most debilitating conditions of all equids, is now known to be the result of several systemic disease entities. This finding, together with other recent developments in the field of laminitis research, have provoked a rethink of our clinical and research strategies for this condition. First, laminitis is now considered to be a clinical syndrome associated with systemic disease (endocrine disease, sepsis or systemic inflammatory response syndrome, SIRS) or altered weight bearing rather than being a discrete disease entity. Next, laminitis associated with endocrine disease (endocrinopathic laminitis) is now believed to be the predominant form in animals presenting (primarily) for lameness. Third, the designation of laminitis as a primary and severe basement membrane pathology now requires revision. Instead, current data now proposes a variable subclinical phase associated with gross changes in the hoof capsule, with stretching and elongation of the lamellar cells an early and key event in the pathophysiology. These findings have fuelled new mechanistic hypotheses and research directions that will be discussed, together with their implications for future clinical management.
E Article: Paradigm shifts in understanding equine laminitis
This paper is open access just use https://doi.org/10.1016/j.tvjl.2017.11.011
... Hyperinsulinemia associated with pituitary pars intermedia dysfunction (PPID) and/or equine metabolic syndrome (EMS) is well documented to put horses at high risk of laminitis (Patterson-Kane et al., 2018;de Laat et al., 2019). Diet control, restricting intake of simple sugar and starch, is the cornerstone of therapy for hyperinsulinemia (Johnson et al., 2004;Morgan et al., 2016;Kellon, 2017). ...
... Hyperinsulinemia (HI) with EMS or as a complication of PPID is the leading cause of laminitis (Patterson-Kane et al., 2018;de Laat et al., 2010). Many horses are laminitic at the time of diagnosis. ...
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Background: Hyperinsulinemia associated with pituitary pars intermedia dysfunction (PPID) and/or equine metabolic syndrome is well documented to put horses at high risk of laminitis. While dietary control of simple sugars and starch is the most effective therapy to control hyperinsulinemia, some horses fail to respond. Case descriptions: Ten horses with hyperinsulinemia refractory to diet control, metformin, levothyroxine, and pergolide (if diagnosed with PPID) were treated with sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana®). Nine horses were hyperglycemic (>5.5 mmol/l) or had a history of hyperglycemia. Before instituting therapy, renal function was assessed by determining serum creatinine and blood urea nitrogen concentrations. Canagliflozin was administered orally once a day, with food. Dipstick urinalysis was performed every 2 weeks to confirm glucosuria and screen for proteinuria. Owners were also instructed regarding clinical signs consistent with urinary tract infection. All horses responded with a substantial decrease in serum insulin concentrations to normal or near normal values. Laminitis pain resolved in all cases, with regression of fat deposits. Owner satisfaction with outcomes was 100%. Conclusion: Once daily administration of the SGLT2 inhibitor canagliflozin corrected hyperglycemia, reduced insulin to normal or near normal levels, and was 100% effective in reversing or reducing abnormal fat pads and eliminating laminitis pain in horses with refractory hyperinsulinemia and laminitis. The core aspects of therapy-diet control, exercise when possible, and adequate treatment of PPID-must also be maintained if using canagliflozin. Canagliflozin should be reserved for refractory cases. Further controlled trials to investigate canagliflozin pharmacokinetics, pharmacodynamics, efficacy, and safety are needed.
... Positive staining for both TUNEL and caspase-3 indicate apoptosis as the primary cause of cell death in this region 15 . Less extensive apoptosis has been reported in hyperinsulinaemia-associated laminitis [16][17][18] where it is considered a secondary event 19 and apoptosis is rarely observed in acute sepsis-associated laminitis 13,20 . Although apoptosis was a feature of naturally-occurring acute laminitis (of unspecified cause) in one study, TUNEL positive cells adjacent to the PEL axes were identified as parabasal keratinocytes (caspase-3 negative) that were likely undergoing cornification 13 , whereas the extensive caspase-3 positive staining adjacent to the PEL axes in the current study confirms apoptosis in this region. ...
Article
Background: Surgical stabilisation of the distal phalanx (DP) is a potential therapeutic strategy for severe acute laminitis. Objective: To evaluate the effects of locking compression plate (LCP) fixation of the DP to the dorsal hoof wall. Study design: Ex vivo and in vivo experiments. Methods: A T-shaped LCP was applied to one limb per pair in six pairs of cadaver forelimbs subjected to a combination of thermally induced lamellar failure and vertical load to simulate severe acute laminitis. Standard radiographic measurements were used to compare DP displacement. The LCP was then applied to one forefoot in 12 healthy Standardbred horses either standing (n = 6) or under general anaesthesia (n = 6). Lameness was evaluated daily, then horses were euthanised (day 8) and lamellar tissue analysed using light microscopy, histomorphometery and molecular markers of apoptosis. Results: In the cadaver limb model, LCP fixation prevented the significant changes in hoof-distal phalanx distance, coronary extensor process distance and sole depth that characterised DP displacement in untreated limbs (p < 0.05). Application of the construct in vivo was well tolerated with minimal lameness (10/12 horses were sound at the trot on day 8); however, histology revealed dorsal lamellar pathology consistent with laminitis, but with extensive keratinocyte apoptosis. Adjacent to the LCP, caspase-3 positive cell counts were approximately 20-fold higher than control (p < 0.001). Main limitations: Pathology was evaluated at a single time point. Microvascular perfusion was not evaluated. Conclusions: Rigid fixation of the DP to the hoof capsule was achieved with the LCP construct in a cadaver limb laminitis model. In live horses, LCP fixation caused regional lamellar pathology with extensive apoptosis, likely due to disturbed lamellar microvascular perfusion and/or mechanostasis. Understanding these mechanisms is critical for refinement of the technique in order to avoid iatrogenic lamellar damage.
... It is frequently necessary to euthanize suffering animals, and those that survive are left useless, proving a great economic and social impact of laminitis on the horse breeding industry. Wijnberg et al. (2013) demonstrated that BoNT-A reduced the activity of deep digital flexor muscle (DDFM) in horses, and the other authors (Patterson-Kanea et al., 2018) hypothesized that reducing the activity of a DDFM might play a role in the treatment of laminitis without inducing the gait asymmetry and subsequent risk of tenotomy. This study was conducted with the same experimental design as the study by Wijnberg et al. (2013). ...
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... Although there are many reasons for developing laminitis, the most common cause in highly developed countries is endocrinopathic issues: 89% of horses with laminitis admitted to hospital in Finland suffered from this condition [16]. Endocrinopathic laminitis develops very slowly, and the affected horses stay in subclinical laminitis for a long period before the acute phase [17]. ...
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Obesity is a common problem in horses. The associations between obesity and equine metabolic syndrome (EMS) and between EMS and laminitis are known. However, there is a lack of data on whether obesity itself can affect hoof lamellae. Forelimbs and blood from 12 draft horses (six obese and six lean) from a slaughterhouse were acquired. To exclude laminitis and EMS horses, insulin concentration was measured, and hooves were radiographed. Histological evaluation was performed. The shape of the primary and secondary epidermal lamellae (PEL and SEL) was evaluated, and the length of the keratinized and total primary epidermal lamellae was measured (KPEL and TEL). All horses showed pathological changes in lamellae. In the lean group, the changes were longer SELs, more proliferated and separated PDLs, and less standard PDLs. In the obese group, the changes were a lower number of club-shaped and standard SELs and significantly more tapered SELs. No difference in the shape of PELs and the length of KPELs was noticed. The research did not confirm the effects of obesity on lamellar failure. The measurements taken indicate that the lamellae are much longer compared to other research studies; this could indicate that the length of the PEL depends on the hoof size.
... Laminitis manifests as a painful condition of the equine hoof, secondary to certain systemic diseases, most commonly the endocrinopathies (equine metabolic syndrome (EMS) and pituitary pars intermedia dysfunction), or excessive weight bearing (Patterson-Kane et al., 2018). Endothelial dysfunction may play a role in laminitis pathophysiology. ...
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Hoof lamellar pathology in horses with PPID has not been described previously. To describe the histomorphometry and pathological lesions in hoof lamellar tissue of animals that had PPID with or without concurrent laminitis, with reference to age-matched controls. We hypothesised that lamellar lesions consistent with laminitis would be associated with PPID, even in animals without current or historical laminitis. Prospective case-control study. Mid-dorsal hoof histological sections were obtained post-mortem from the forelimbs of 16 PPID-affected animals either with (n = 6) or without laminitis (n = 10) and 10 age- and breed-matched controls. Sections were examined by a blinded veterinary pathologist. The length and width of 10 primary epidermal lamellae (PEL) were measured using image analysis software. The morphology and pathology of PEL and secondary epidermal lamellae (SEL) were then typed or graded in axial, middle and abaxial regions. Fasting serum insulin, plasma ACTH and blood glucose concentration were measured from blood samples taken prior to euthanasia. All animals with PPID and laminitis had fasting hyperinsulinaemia (median 74.1 mIU/L, IQR 49.9-349.5 mIU/L) whereas PPID animals without laminitis had serum insulin concentrations below the upper limit of the reference range (<20 mIU/L). Lamellar pathology in PPID animals with laminitis was variable in severity and unrelated to the reported duration of laminitis (range 2 months-5 years). Most lesions were located abaxially within the lamellar tissue and included increased length and width of the lamellae, chronic abnormal keratinisation, interlamellar epidermal bridging and cell death with more acute lamellar tearing in some cases. The lamellae of PPID animals without laminitis were normal referent to the relevant control group. Whether PPID and hyperinsulinaemia have a causal inter-relationship or not, it may only be the hyperinsulinemia that is associated with lamellar morphological alteration and pathology consistent with laminitis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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The electronic patient records of all equine patients of Rossdales Equine Practice between January 1, 2005 and November 1, 2013 were reviewed to determine the number of cases of supporting limb laminitis (SLL) in a large equine practice and referral hospital setting in the UK and to discuss the implications for future epidemiological studies. The clinical notes were searched electronically for a combination of 'laminitis AND (contralateral OR supporting OR overload OR weight bearing)'. The prevalence of SLL within each identified denominator population and the corresponding 95% CI were calculated. SLL developed in nine horses, one donkey and one pony. Thoroughbreds were the most commonly affected breed (72.7 per cent, CI 46.4 to 99.1 per cent), aged 2-14 years (median six years), and only mares (n=9) and stallions (n=2) were represented. SLL was not restricted to horses that were non-weightbearing lame, it developed within 4-100 days after injury (median 14.5 days) and occurred most commonly in a forelimb (54.6 per cent, CI 25.1 to 84.0 per cent). During the same time frame, a total of 65,327 horses were registered with Rossdales Equine Practice, resulting in an overall practice prevalence of SLL of 0.02 per cent (CI 0.01 to 0.03 per cent). Future epidemiological studies to investigate risk factors for SLL prevention will, therefore, be a logistical challenge.
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Pituitary pars intermedia dysfunction is a common problem with which equine practitioners are becoming involved ever more frequently. This current review aims to outline recommendations for diagnosis, treatment and monitoring of the condition when encountered in practice.