What we Know About Laminitis (Bluegrass Laminitis Symposium)

When it comes to laminitis, everyone's got a pet theory--their favorite explanation of why it occurs, how to prevent it, and/or how to treat it. The reason we have these theories is because research hasn't yet been able to give us solid, unassailable explanations for much of the disease's processes and treatment.

But there are some concepts that we do know, for sure, about laminitis. During the recent Bluegrass Laminitis Symposium, held Jan. 25-28 in Louisville, Ky., Rustin Moore, DVM, PhD, Dipl. ACVS, professor and chair of the Department of Veterinary Clinical Sciences at The Ohio State University, reviewed research on several aspects of laminitis for the audience of farriers and veterinarians.

"A complete knowledge and understanding of laminitis and its complex pathophysiologic cascade remains elusive despite substantial efforts by many scientists and clinicians over the last few decades, and, thus, preventive and therapeutic management strategies remain empirical and anecdotal with little emphasis on evidence-based medicine," he began. "Today I will review the pathophysiology of laminitis as well as principles and current thinking on preventive and treatment strategies, and discuss selected research studies and their practical implications."

Anatomy and Causes
Moore first quickly reviewed the anatomy of the laminae that attach the horse's hoof to the coffin bone within his foot. "There are dermal (inner) and epidermal (outer) laminae�interdigitating (interlocking) leaflike tissues that have primary and secondary projections to provide a large surface area for attachment and structural support," he said. "Several biomechanical forces affect the digit and stress the laminae, including weight bearing, ground reaction forces, and the pull of the deep digital flexor tendon on the coffin bone, which has a lever effect with shearing/tearing forces at the toe with breakover."

He noted that laminitis often occurs secondary to inflammatory-type conditions, including the following:

  • Colic (gastrointestinal disease);
  • Endotoxemia (presence of endotoxins in the bloodstream) and/or septicemia (presence of disease-causing pathogens in the bloodstream);
  • Pleuropneumonia (infection and inflammation of the membranes covering the lungs�the pleura�and the lungs themselves);
  • Enterocolitis (inflammation of the small intestine and colon);
  • Metritis (uterine infection and inflammation);
  • Grain overload;
  • Excessive weight-bearing on the contralateral limb (opposite a limb with severe, nonweightbearing injury, as with Barbaro)
  • Pasture-induced carbohydrate overload; and 
  • Metabolic/endocrine (hormonal) disturbances such as insulin resistance

Little is known about the progression of pathologic (disease) processes that occur in the foot with laminitis, he said, but he listed the following disease processes that are believed to occur at various times during the disease:

  • Decreased blood flow to the foot and perfusion of the laminae (ischemia)with possible hypoxia (decreased oxygen in the tissues) of the laminae;
  • Injury due to reperfusion (restoration of blood flow) after an ischemic episode;
  • Hyperemia (increased blood flow);
  • Inflammation;
  • Altered metabolism;
  • Apoptosis (programmed death of cells);
  • Enzymatic degradation (breaking down of tissues by enzyme overactivity);
  • Edema (fluid swelling);
  • Necrosis (death of tissues);
  • Laminar shearing/tearing;
  • Structural failure; and
  • Disruption and collapse

"Laminitis is most likely caused by a multifactorial, complex cascade including mediators such as vasoactive substances (those that alter blood flow), endotoxins, other toxins, inflammatory cells/mediators, and matrix metalloproteinase enzymes," Moore said.

Pathophysiologic Theories
Moore noted that there are at least five theories of how laminitis initially damages the hoof's laminae, ultimately resulting in changes to the foot's structure and microanatomy, weakening of the laminae, rotation/sinking of the coffin bone, and clinical signs of laminitis. These all have some research support, and they include the vascular or ischemic theory, enzymatic/toxic theory, inflammatory theory, metabolic/endocrine theory, and biomechanical theory.

Ischemic/vascular theory "This used to be one of the leading theories," Moore said. "It's accepted based on experimental investigation that there are blood flow abnormalities with laminitis; increased capillary pressure and venoconstriction (narrowing of the veins) have been proven. With increased capillary pressure, fluid leaks from the capillaries into the soft tissue. Because this area is encased between hard bone and the hard hoof wall, as it fills with more fluid, it becomes compressed in a compartmentlike syndrome, and more pressure causes more ischemia by compressing the small vessels and preventing the flow of blood. The question is whether this is the initiating factor or a byproduct of another process?"

He noted that support for this theory also includes measurement of digital Starling forces, or those forces affecting fluid movement in and out of blood vessels. "In the normal foot, the net pressure in capillaries is -1, meaning fluid moves into capillaries from the surrounding tissues," he explained. "But with experimental laminitis, pressure goes from -1 to +1, so fluid is pushed out of vessels into tissues. Tissue is compressed when fluid is added.

"I believe there is a fine balance to maintain regarding the vasculature in the foot," Moore opined. "Starling forces are based on pressures, which could increase with more fluid in the vessels, vessel contracture, etc. I think this could become important when hydrating a horse with IV fluids; a fair number of horses that are receiving large volumes of fluids because they have diarrhea and/or refluxing large amounts of fluid from their stomachs via a nasogastric tube often subsequently develop laminitis. It is possible that with vascular dysfunction and Starling force imbalance, it is feasible to �overhydrate" these horses, which could contribute to further imbalances in the microvasculature (small vessels) in the feet, contributing to the development of founder. This is anecdotal and not proven, but maybe there's enough disruption of fluid pressure that contributes."

Lastly, he reported that with carbohydrate-induced laminitis, decreased hoof temperature before the onset of lameness suggests decreased digital blood flow, while increased hoof temperature with the onset of lameness suggests subsequent increased blood flow.

Enzymatic/toxic theory Moore said this theory holds that digital blood flow and laminar perfusion with blood deliver currently undescribed laminitis trigger factors (LTFs) to the digit, where they evoke the production and activation of matrix metalloproteinase enzymes (MMPs). Overactivity of these enzymes has been demonstrated to cause degradation of the laminar basement membrane, which holds the dermal and epidermal laminae together. 

"With starch-induced laminitis, increased hoof temperature during the prodromal (early) stages is suggestive of increased digital blood flow and laminar perfusion; this is part of the basis for treating horses with cryotherapy to reduce blood flow and delivery of LTFs," he said (more on cryotherapy in a moment).

Inflammatory cascade "There are a number of cells involved in inflammation," Moore said. "Neutrophils (white blood cells) and platelets (cells involved in blood clotting) can have inflammatory roles and are thought to play a role in the development and progression of laminitis. Inflammatory mediators include cytokines, interleukin-1-beta, interleukins 6 an 8, and cyclooxygenase-2 (COX-2, an enzyme). With a black walnut extract-induced laminitis, Dr. Belknap (DVM, PhD, of The Ohio State University), et al. found a marked upregulation of COX-2 and decrease in COX-1 (often called the 'good' cyclooxygenase, compared to COX-2). You see the same thing with an oligofructose (starch) induction model. So this is evidence of inflammatory process occurring."

He also noted that increases in neutrophils in laminitic vs. normal horses have been demonstrated, and inflammation even has been demonstrated in the skin and other body areas. More leukocytes (white blood cells, which fight infection and are involved in inflammation) have been demonstrated in the skin of laminitic horses.

"So why do these (structural) laminitis changes manifest in the foot and not the skin or other organs?" he asked the audience. "We don't know yet; this might just be the result of biomechanical forces on the foot that don't exist in skin."

"This might help us better understand those horses that we say are so sore (with laminitis) that their manes and tails hurt," commented host Ric Redden, DVM, founder of the International Equine Podiatry Center in Versailles, Ky.

Metabolic theory "Insulin is a major regulatory hormone in glucose and fat metabolism, vascular function, inflammation, tissue remodeling, and the somatotropic axis of growth," Moore explained. "Insulin resistance alters insulin signaling by decreasing insulin action in certain resistant pathways while increasing insulin signaling in other unaffected pathways via compensatory hyperinsulinemia. In humans, altered insulin signaling is implicated in reduced glucose availability to insulin-sensitive cells, vasoconstriction and endothelial damage, and inflammatory response.

"Although no direct evidence exists for insulin's role in these mechanisms in the laminitic horses, changes in the glucose availability, vasculature, and inflammation have all been demonstrated in hoof separation," he went on. "Insulin resistance was first implicated in the pathogenesis of laminitis in the 1980s using tolerance tests. Work by Treiber, et al., provides evidence of insulin resistance as a predisposing condition for laminitis."

Biomechanical theory Laminitis has also been known to result from mechanical overload situations, such as excessive work on very hard surfaces or one leg bearing excessive weight when the contralateral limb (opposite forelimb or hind limb) has a severe, nonweightbearing injury (contralateral or supporting limb laminitis).

In the former case, the mechanism is thought to be damage to the laminae from mechanical trauma (such as from the hard surfaces), resulting in the inflammation and pain of laminitis. In the latter, the excessive, constant weight bearing is thought to either damage the laminae directly or alter blood supply long enough to deprive them of nutrients, leading to tissue damage, noted Moore.

He pointed out that all or many of the pathways described above are likely involved in the complex pathophysiologic cascade of laminitis.

Treatments, Proven and Otherwise
"Despite intensive treatment, many horses do not respond and return to their intended use due to chronic pain and debilitation," Moore said. "It is often career-ending and possibly life-threatening, especially if it is not caught very early. We will continue to be less than pleased with our success with this disease until we have a more complete understanding of the pathophysiology of laminitis. Additional focused, relevant, multidisciplinary, leading-edge research is greatly needed.

"Therapeutic principles can include treating the primary disease (if one is known), modulating digital blood flow and laminar perfusion, normalizing digital Starling forces, providing anti-endotoxic therapy, anti-inflammatory medication, antioxidants, analgesic (pain-killing) drugs, endocrine (hormone) therapy for horses with hormonal disturbances, nutritional/dietary support, therapeutic support, and shoeing," he went on.

Moore described several treatment options and research on their use.

Cryotherapy "This is not a new concept for preventing laminitis, just newly revisited and evaluated," he commented. "Potential benefits include vasoconstriction, resulting in decreased blood flow and decreased delivery of LTFs, decreased cell and tissue metabolism in laminae, decreased activation of MMPs, and anti-inflammatory activity.

He noted that continuous cryotherapy (keeping the foot below 5�C for 48 hours) is well-tolerated and has been proven an effective and safe method in horses at risk of laminitis--when applied before lameness develops. One study that cooled one foot on normal and laminitis-induced horses found slightly elevated activity of MMPs in treated vs. normal feet, but their activity in cooled feet was much lower than in untreated feet. The cooled feet also showed no lameness and better tissue architecture scores than untreated feet.

"The key thing is to do it quickly; it's not of much use once the horse is acutely laminitic," Moore noted. "It's a preventive, not a treatment."

Hot and cold therapy While this study did not evaluate laminitis treatment in affected horses, it aimed to measure blood flow in the healthy foot under hot and cold conditions via counting of radioisotope-labeled microspheres placed into the circulation. Knowledge of temperature's effects on blood flow can provide information on the effect of temperature on blood flow and perfusion, and perhaps offer insight regarding the use of cryotherapy. Temperatures evaluated were cold (10�C, or 50�F), normal (32�C, or 89.6�F), and warm (54�C, or 129.2�F).

"Cold decreased blood flow significantly and heat significantly increased it over normal," he reported. "This work probably needs to be repeated in laminitic horses."

Pressure and blood flow Another phase of the blood flow study evaluated the effects of loading on blood flow; this, again, was not a test of a specific therapy, but an attempt to understand the normal dynamics of the foot; this knowledge can be applied to preventive and therapeutic treatment.

Loading conditions included the horse standing normally, standing on one foreleg, and standing with no weight on the leg (with the limb held up). 
"Under normal loading, approximately 550 microspheres were found," he reported. "When the horse stood only on one front foot, there was a significant decrease in microspheres. When the extra weight came off, microspheres increased back to nearly normal. Zero weight bearing had no significant effect.

"If you measure blood flow as we usually do, up near the fetlock, those measures did not change," he commented. "But we did see significant changes in the laminar circulation with microspheres. So we probably need to reassess a lot of the work out there that did not use the right methodology to see these changes."

Vasodilatory drugs The goal of these drugs is to increase blood flow and laminar perfusion. Moore reported that in one study, acepromazine was used in 57% of acute laminitis cases. Another found that it is used routinely or occasionally by 93% of clinicians. The drug has vasodilatory as well as sedative effects.
Acepromazine has been shown to increase digital blood flow via peripheral vasodilation with larger intravenous doses for up to 90 minutes, he reported. The dilatory response is greater in the veins than the arteries, he noted. Intramuscular dosage decreases systemic blood pressure, increases digital blood flow, and decreases packed cell volume.

However, he noted that these studies were done in normal horses, acepromazine might affect horses with laminitis damage differently, and further research is warranted.

Another vasodilatory drug used for laminitis is nitroglycerine, Moore said.  "One report said ponies with pasture-induced laminitis improved following nitroglycerine treatment, so its use became commonplace despite little or no additional research evidence. Nitroglycerine acts much like acepromazine; it relaxes smooth muscle especially in the veins."

He reported that one study found an increase in blood flow and nitric oxide concentrations when nitroglycerine was given intra-arterially, but not when it was given topically (i.e., via the patches that are sometimes used).

"So maybe we shouldn't be using it; it may not hurt anything, but it's not helping and is likely a waste time and money," he commented.
He added that isoxsuprine and pentoxyfylline had no demonstrable effects on blood flow in studies; however, pentoxyfylline could have other therapeutic effects via other mechanisms. More research needs to be done, he noted.

Anti-inflammatory medication "Anti-inflammatory therapy has remained a central component of laminitis pharmacotherapy over the years," Moore said. He reported increases from fivefold to 400-fold in inflammatory mediators such as cytokines and COX-2 in the early (pre-lameness) stages of laminitis.

"This inflammatory process continues into the acute stage of the disease when horses begin to exhibit signs of digital pain," he said. "Therefore, aggressive, prudent use of non-steroidal anti-inflammatory drugs (NSAIDs) is probably indicated in the horse known to be at risk of laminitis (i.e., colitis, grain overload, etc.) until approximately 48-72 hours after the horse is not showing clinical signs of toxemia. Due to the gastrointestinal and renal (kidney) toxicity caused by NSAIDs, close attention needs to be paid to the animal's history, the hydration status, and clinicopathologic data. Always consult a veterinarian before using these drugs and follow their recommendations regarding dose, frequency, and duration of treatment."

Diet/weight management for horses with metabolic problems "Specific quantitative tests that distinguish insulin resistance are essential to identify ponies and horses in need of special management to avoid laminitis," Moore advised. "Potential management strategies to avoid laminitis by increasing insulin sensitivity include reducing obesity, increasing exercise, and moderating dietary carbohydrates (particularly starch)."

Take-Home Message
"A more complete understanding of the pathophysiology of laminitis is needed to develop more effective preventive and therapeutic strategies," Moore stated. "There is a critical need for basic and applied research and dissemination of evidence-based medicine in this area. Everyone needs to work together and share knowledge, ideas, and experience."

Toward that end, Moore mentioned that a Havemeyer Equine Laminitis Research Workshop being organized by Drs. Jim Moore and Jim Belknap from the University of Georgia and Ohio State University, respectively, will be held in May of this year. "Invited laminitis researchers will convene to discuss current knowledge and future research directions regarding the pathophysiology of laminitis associated with sepsis and metabolic syndrome," he reported. "This workshop should serve to advance our collective understanding of laminar failure in septic and metabolic patients, and, in turn, help focus research efforts toward eventually developing more effective preventive and therapeutic strategies."

He also noted that the 4th International Equine Conference on Laminitis and Diseases of the Foot, which will be held in Palm Beach, Fla., in November, will provide yet more valuable information on this devastating disease for veterinarians, farriers, owners, and caretakers (for more information, see www.laminitisconference.com).

Stay tuned to The Horse magazine and www.TheHorse.com for reports as the veterinary community unlocks more laminitis mysteries.

About the Author

Christy M. West

Christy West has a BS in Equine Science from the University of Kentucky, and an MS in Agricultural Journalism from the University of Wisconsin-Madison.

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