Discussion

Equine laminitis has several inciting causes/circumstances, including: 1) sepsis/systemic inflammatory conditions (e.g. gastrointestinal disease, septic metritis); 2) endocrinopathic (the laminitis that occurs in association with pituitary pars intermedia dysfunction or 'Equine metabolic syndrome'); 3) nutritionally- associated (grain overload or pasture-associated laminitis); and 4) mechanical overload (supporting limb laminitis). This divergent set of clinical associations lend support to the idea that laminitis is a syndrome rather than a single clinical entity, with the likelihood that several different inciting causes and pathogenic mechanisms can result in clinical laminitis. Knowledge of the pathophysiology of acute laminitis has been derived primarily from 4 experimental models, specifically: starch overload (~17 g starch/kg bwt per os); oligofructose (OF) overload (5.0 - 12.5 g/kg bwt per os); black walnut extract (BWE) administration; and more recently insulin- induced laminitis (Asplin et al. 2007; Belknap 2010; De Laat et al.
2010; Eades 2010; Pollitt and Visser 2010). Although data from studies using these models have provided insight into pathological processes during the prodromal phases of laminitis, a critical question relates to the applicability of this information to the laminitis seen in clinical practice. For example, these models are extreme in that they induce laminitis in the majority (~80%) of animals challenged. In contrast, only a very small proportion of any at-risk horse population (e.g. hospitalised animals with sepsis; a herd of horses maintained on the same pasture) develop clinical laminitis. With respect to pasture-associated laminitis, it also is apparent that some animals are prone to repeated episodes of laminitis (Menzies-Gow et al. 2010). These observations focus attention on animal genetic and phenotypic factors associated with resistance or susceptibility to disease, areas that cannot be readily addressed by the experimental models. The aim of this presentation is to review characteristics of each of the experimental models in the context of naturally-occurring laminitis.
The starch and OF overload as well as BWE models all invoke a systemic inflammatory response that precedes the development of clinical laminitis. As such, it has been proposed that these models mimic the laminitis that occurs in horses with sepsis/severe systemic illness (Belknap 2010; Eades 2010). In reality, however, the BWE model is relevant only to the rare instance in which horses are bedded on and ingest black walnut hardwood shavings. On the other hand, findings from the starch overload model are applicable to the laminitis that develops in animals subsequent to the ingestion of excessive grain or other starch-rich feedstuff. Anecdotally, the risk for development of laminitis is very high when horses consume more than 1.2 - 1.5 kg grain per 100 kg bwt (6 - 7.5 kg for a 500 kg horse) over a 1 - 2h period, especially grains with poor pre-caecal digestibility such as unprocessed wheat, barley or corn. However, susceptibility likely varies between individuals and smaller quantities of grain may induce laminitis in some animals. The OF model has been argued to mimic pasture- associated laminitis given the observed temporal relationship between forage fructan content and the incidence of laminitis in horses/ponies kept at pasture. It should be noted that the fructans in grasses are very different in structure to the simple oligofructoses used in the OF model, and even if similar triggering amounts of fructan can be ingested by horses and ponies at pasture this occurs over several hours rather than as a bolus. The nature and severity of systemic illness is another point of difference between the OF model and pasture laminitis the OF model is associated with fever, marked depression, diarrhoea and evidence of sepsis in multiple organ systems, all of which are rarely if ever detected in animals that develop pasture-associated laminitis.
Observational cohort studies have indicated that animals with a certain metabolic (insulin resistant) phenotype are predisposed to pasture laminitis (Bailey et al. 2008; Carter et al. 2009). In this context, the recent finding that laminitis can be induced in healthy horses and ponies by maintaining a very high (>1000 mu/l) insulin concentration (Asplin et al. 2007; De Laat et al. 2010) is potentially relevant to the pathogenesis of endocrinopathic and pasture laminitis, with episodes of laminitis linked to increases in circulating insulin associated with the consumption of feeds and forages with high nonstructural carbohydrate content. Although very high (>750 - 1000 mu/l) serum insulin concentrations have been detected in some horses and ponies with clinical laminitis, the author has observed similarly high insulin concentrations in animals without clinical laminitis and, conversely, some laminitis-prone animals do not exhibit abnormal insulin dynamics. It is possible that other factors contribute to lamellar pathology in the experimental insulin model, for example the effects of an increase in glucose flux during prolonged hyperinsulinaemia. In this context, de Laat et al. (2012) recently reported that 48 h of hyperglycaemia (~11 - 12 mmol/l) and associated endogenous hyperinsulinaemia (~200 mu/l) was associated with histological evidence of mild lamellar pathology in at least one foot of all treated horses (but not clinical laminitis). When these findings were interpreted in light of previous studies, the authors concluded that:laminitis may be induced by either insulin alone or a combination of insulin and glucose, but likely not by glucose alone. It also was suggested that a potential threshold for development of insulin-induced lamellar pathology may be at or below a serum concentration of ~200 mu/l (De Laat et al. 2012). However, as mentioned above, the clinical observation of profound hyperinsulinaemia in animals without evidence of clinical laminitis raises several questions regarding the cause-and-effect relationship between circulating insulin and laminitis. Perhaps some animals develop tolerance to the effects of high circulating insulin; if so, it will be impossible to determine a threshold of hyperinsulinaemia that portends development of laminitis in all animals. These apparent discrepancies highlight the difficulty in directly applying findings from the experimental models to field cases. Undoubtedly, the various experimental models provide some useful insight into the pathogenesis of the laminitis but they are unlikely to mirror all clinical manifestations.