L
Laboratories
Lactate
Lactation
Laminitis - definition
Laminitis - pathology
Leaky gut
Leeches
Leptin
Lethargy
Levothyroxine Sodium (Thyro-L)
Ligaments and tendons
Light
Lipids
Lipopolysaccharides
Liver
Lungs/Respiratory Diseases/RAO
Lyme disease
Lactate
Lactation
Laminitis - definition
Laminitis - pathology
Leaky gut
Leeches
Leptin
Lethargy
Levothyroxine Sodium (Thyro-L)
Ligaments and tendons
Light
Lipids
Lipopolysaccharides
Liver
Lungs/Respiratory Diseases/RAO
Lyme disease
Laboratories
EEFor ACTH and insulin testing:
UK
The Liphook Equine Hospital Laboratory
Endocrinopathic Laminitis - Liphook Equine Hospital 2017
Endocrinopathic Laminitis - Liphook Equine Hospital
Equine Metabolic Syndrome - Liphook Equine Hospital May 2015
Equine Cushing's Disease - Liphook Equine Hospital May 2015
The Potential Usefulness and Applications of Adiponectin Testing in Horses with Suspected EMS - Liphook Equine Hospital
France
Labeo Frank Duncombe Laboratory, Caen (uses Immulite CIA for ACTH testing - TBC)
Vetodiag, 14170 Berville, T: 02 31 41 00 00 (uses Immulite 2000 CIA for ACTH testing as at Sept 2018)
l’école vétérinaire de Lyon
Idexx à Alfortville
Cal à Troyes
UK
The Liphook Equine Hospital Laboratory
Endocrinopathic Laminitis - Liphook Equine Hospital 2017
Endocrinopathic Laminitis - Liphook Equine Hospital
Equine Metabolic Syndrome - Liphook Equine Hospital May 2015
Equine Cushing's Disease - Liphook Equine Hospital May 2015
The Potential Usefulness and Applications of Adiponectin Testing in Horses with Suspected EMS - Liphook Equine Hospital
France
Labeo Frank Duncombe Laboratory, Caen (uses Immulite CIA for ACTH testing - TBC)
Vetodiag, 14170 Berville, T: 02 31 41 00 00 (uses Immulite 2000 CIA for ACTH testing as at Sept 2018)
l’école vétérinaire de Lyon
Idexx à Alfortville
Cal à Troyes
USA
Cornell University Animal Health Diagnostic Center (uses Immulite CIA for ACTH testing)
Michigan State University Veterinary Diagnostic Laboratory (uses RIA for ACTH testing - TBC)
Canada
University of Guelph Animal Health Laboratory (uses CIA for ACTH testing, also sends ACTH to Michigan State University for RIA ACTH testing)
See ACTH seasonality and PPID
Cornell University Animal Health Diagnostic Center (uses Immulite CIA for ACTH testing)
Michigan State University Veterinary Diagnostic Laboratory (uses RIA for ACTH testing - TBC)
Canada
University of Guelph Animal Health Laboratory (uses CIA for ACTH testing, also sends ACTH to Michigan State University for RIA ACTH testing)
See ACTH seasonality and PPID
Lactate (l-lactate)
Dunkel B, Knowles EJ, Chang YM, Menzies-Gow NJ.
Influence of endocrine disease on l-lactate concentrations in blood of ponies.
J Vet Intern Med. 2021 May;35(3):1582-1588. doi: 10.1111/jvim.16079. Epub 2021 May 27. PMID: 34043845; PMCID: PMC8162605.
Keywords: adiposity, equine, insulin resistance, l‐lactate metabolism, pituitary pars intermedia dysfunction
"The study did not identify any correlation between blood l‐lactate concentrations and the investigated measures of endocrine health and blood l‐lactate concentrations were not different between ponies with and without increased autumnal ACTH concentrations and with and without ID."
Dunkel B, Knowles EJ, Chang YM, Menzies-Gow NJ.
Influence of endocrine disease on l-lactate concentrations in blood of ponies.
J Vet Intern Med. 2021 May;35(3):1582-1588. doi: 10.1111/jvim.16079. Epub 2021 May 27. PMID: 34043845; PMCID: PMC8162605.
Keywords: adiposity, equine, insulin resistance, l‐lactate metabolism, pituitary pars intermedia dysfunction
"The study did not identify any correlation between blood l‐lactate concentrations and the investigated measures of endocrine health and blood l‐lactate concentrations were not different between ponies with and without increased autumnal ACTH concentrations and with and without ID."
Lactation
Inappropriate lactation (galactorrhea) can be a symptom of PPID..
"Other clinical signs that have been reported in horses with PPID are persistent lactation and infertility, which are probably a consequence of altered release of prolactin and gonadotrophic hormones." HC Schott 2006
"Inappropriate mammary gland development and lactation: This problem is seen in mares with early or advanced PPID and is attributed to increased prolactin secretion from the pars intermedia." p12 Guide to Insulin Resistance and Laminitis for Equine Practitioners
Any mare producing milk outside of normal foaling lactation should be tested for PPID, and, if available, have prolactin levels tested.
"Other clinical signs that have been reported in horses with PPID are persistent lactation and infertility, which are probably a consequence of altered release of prolactin and gonadotrophic hormones." HC Schott 2006
"Inappropriate mammary gland development and lactation: This problem is seen in mares with early or advanced PPID and is attributed to increased prolactin secretion from the pars intermedia." p12 Guide to Insulin Resistance and Laminitis for Equine Practitioners
Any mare producing milk outside of normal foaling lactation should be tested for PPID, and, if available, have prolactin levels tested.
Laminitis - definition
What is laminitis?
Three forms of laminitis are currently recognised, with different pathologies, therefore the definition of laminitis may be slightly different depending on which form of the disease is being described. The three forms of laminitis are:
Endocrinopathic or insulin-associated or hyperinsulinaemia-associated laminitis
Sepsis associated laminitis
Supporting limb laminitis (mechanically induced)
"Laminitis is a common and debilitating disease of the equine hoof capsule and underlying dermal and bone tissues that results in damage to, and often functional failure of, the inner hoof capsule folds, called "lamellae", that mediate adhesion of the hoof capsule to the distal phalanx (Engiles et al. 2015, van Eps and Burns 2019)". Holl et al. 2022
What is laminitis?
Three forms of laminitis are currently recognised, with different pathologies, therefore the definition of laminitis may be slightly different depending on which form of the disease is being described. The three forms of laminitis are:
Endocrinopathic or insulin-associated or hyperinsulinaemia-associated laminitis
Sepsis associated laminitis
Supporting limb laminitis (mechanically induced)
"Laminitis is a common and debilitating disease of the equine hoof capsule and underlying dermal and bone tissues that results in damage to, and often functional failure of, the inner hoof capsule folds, called "lamellae", that mediate adhesion of the hoof capsule to the distal phalanx (Engiles et al. 2015, van Eps and Burns 2019)". Holl et al. 2022
Laminitis - pathology
de Laat MA, Pollitt CC
Ultrastructural examination of basement membrane pathology in horses with insulin-induced laminitis
Domestic Animal Endocrinology Volume 69, October 2019, Pages 30-34. doi.org/10.1016/j.domaniend.2019.04.004
Keywords: Epidermal basal cell, hemidesmosome, hyperinsulinemia, lamellae, transmission electron microscopy
Lamellar tissue from the left fore foot of 3 horses with artificially induced acute hyperinsulinaemic laminitis showed an extensively disorganized basement membrane zone, with "loss of uniformity of the lamina lucida and lamina densa, fragmentation and disorientation of the hemidesmosomes, and cytoskeletal disengagement of the hemidesmosomes", compared to controls. The mean lamellar basement membrane was twice as wide in laminitic horses as controls, and the number of hemidesmosomes half that of controls. Excessive cellular proliferation due to hyperinsulinaemia may disassemble hemidesmosomes and account for their loss, and the reduction in hemidesmosomes may contribute to the weakening of the dermal-epidermal junction and failure of the lamellae.
The research found that hyperinsulinaemia damages the basement membrane in horses, causing reduced hemidesmosome density and widening of the basement membrane, and this appears to be more extensive and severe in horses than ponies.
Journal of Veterinary Internal Medicine, 25: 540–548 (2011)
Role of Oxidative Tissue Injury in the Pathophysiology of Experimentally Induced Equine Laminitis: A Comparison of 2 Models
Burns T, Westerman T, Nuovo G, Watts M, Pettigrew A, Yin C, Belknap J
"These results do not support a prominent role for oxidative stress at examined time points in CHO-overload laminitis and support transient oxidative stress in the BWE model. Tissue oxidation does not appear to be a central early pathophysiologic event in CHO-associated laminitis."
Am J Vet Res. 2003 Jul;64(7):829-34 (PubMed)
Submural histopathologic changes attributable to peracute laminitis in horses
Morgan SJ, Hood DM, Wagner IP, Postl SP
"RESULTS: Analysis indicated that dermal and epidermal lesions were evident despite lack of visible separation of the epidermal basement membrane, can be found in horses without detectable lameness, and were nonspecific and progressive following onset of lameness. Furthermore, severity and location of lesions were associated with severity and duration of lameness.
CONCLUSION AND CLINICAL RELEVANCE:These observations are consistent with the concept that separation of the laminar epithelial basement membrane is a delayed step in the pathogenesis of acute laminitis, digital vascular hypoperfusion is an underlying cause for laminitis, and the potential for repeated episodes of subclinical laminitis may underlie the development of structural and mechanical changes consistent with chronic laminitis despite lack of clinical signs of acute laminitis."
Leaky gut
The intestinal tract selectively absorbs nutrients and prevents harmful substances crossing its barrier. Leaky gut describes the dysfunction of, and alterations in permeability of, the intestinal tract barrier.
Kopper JJ, Travers JL, Schott HC 2nd, Cook VL
Effect of body condition on intestinal permeability in horses
Am J Vet Res. Aug 2019;80(8):792‐798. doi:10.2460/ajvr.80.8.792
7 obese and 6 lean horses aged 8 to 15 years of age had an OST performed then euthanized 2 weeks later and tissue samples collected from the jejunum, ileum, cecum, pelvic flexure, right dorsal colon, and rectum. Mucosal permeability was assessed by measuring transepithelial resistance and lipopolysaccharide (LPS) flux across tissue samples mounted in Ussing chambers. 5 obese horses and 1 lean horse had evidence of insulin dysregulation, whereas 1 obese and 5 lean horses had no abnormalities in results of the OST. Mucosal transepithelial resistance did not differ in any intestinal segment between obese and lean horses. Obese horses had a significantly higher LPS flux across jejunal mucosa, compared with results for lean horses, but there were no significant differences between obese and lean horses for other intestinal segments. Obese horses may be at higher risk from chronic exposure to increased amounts of LPS, compared with the risk for lean horses.
"Leaky Gut" Linked to Obesity in Horses - KER August 2019
Stieler Stewart A, Pratt-Phillips S, Gonzalez LM
Alterations in Intestinal Permeability: The Role of the “Leaky Gut” in Health and Disease
Journal of Equine Veterinary Science 2017 Vol 52, p 10-22, https://doi.org/10.1016/j.jevs.2017.02.009 (DeepDyve) (Full paper)
The intestinal tract selectively absorbs nutrients and prevents harmful substances crossing its barrier. Leaky gut describes the dysfunction of, and alterations in permeability of, the intestinal tract barrier.
Kopper JJ, Travers JL, Schott HC 2nd, Cook VL
Effect of body condition on intestinal permeability in horses
Am J Vet Res. Aug 2019;80(8):792‐798. doi:10.2460/ajvr.80.8.792
7 obese and 6 lean horses aged 8 to 15 years of age had an OST performed then euthanized 2 weeks later and tissue samples collected from the jejunum, ileum, cecum, pelvic flexure, right dorsal colon, and rectum. Mucosal permeability was assessed by measuring transepithelial resistance and lipopolysaccharide (LPS) flux across tissue samples mounted in Ussing chambers. 5 obese horses and 1 lean horse had evidence of insulin dysregulation, whereas 1 obese and 5 lean horses had no abnormalities in results of the OST. Mucosal transepithelial resistance did not differ in any intestinal segment between obese and lean horses. Obese horses had a significantly higher LPS flux across jejunal mucosa, compared with results for lean horses, but there were no significant differences between obese and lean horses for other intestinal segments. Obese horses may be at higher risk from chronic exposure to increased amounts of LPS, compared with the risk for lean horses.
"Leaky Gut" Linked to Obesity in Horses - KER August 2019
Stieler Stewart A, Pratt-Phillips S, Gonzalez LM
Alterations in Intestinal Permeability: The Role of the “Leaky Gut” in Health and Disease
Journal of Equine Veterinary Science 2017 Vol 52, p 10-22, https://doi.org/10.1016/j.jevs.2017.02.009 (DeepDyve) (Full paper)
Leeches
Treating illness/disease with leeches is called hirudotherapy. Leeches have been applied to the coronary band of horses with laminitis, and some people believe improvements are seen. Theories put forward for improvements reported generally concern several chemicals that are contained in leech saliva:
Hirudin - an anti-coagulant - hirudin inhibits thrombin, prevents blood from clotting and inhibits platelet aggregation. Wounds can continue to bleed for up to 10 hours after the leeches have been removed.
However, it used to be thought that vasoconstriction was a causative factor in laminitis, but now it is known that endocrinopathic laminitis is caused by high levels of insulin acting on IGF-1 receptors, causing stretching and weakening of the laminae, and that vasodilation may be involved in the onset of endocrinopathic laminitis (see below).
It has been suggested that hirudin has anti-inflammatory properties.
However, endocrinopathic laminitis involves little or no inflammation.
A histamine-like vasodilator.
However, research by Melody de Laat published by the RIRDC in 2011* found increased hoof wall surface temperature in horses with insulin-induced laminitis, and suggested that vasodilation may be involved in the onset of endocrinopathic laminitis. To date, the only treatment shown effective to prevent sepsis-related laminitis is cyrotherapy (icing the feet), which causes vasoconstriction - the opposite of vasodilation. So causing vasodilation might appear to be contra-indicated for both endocrinopathic and sepsis-related laminitis.
Enzymes that stop proteinases activities, e.g MMPs, that have been implicated in the destruction of the basement membrane in sepsis-related laminitis.
However, endocrinopathic laminitis does not involve MMPs or basement membrane breakdown.
Medicinal Leeches: The Much-Maligned Traditional Healing Aid is Making a Comeback for Equine Lameness Therapy - Fran Jurga, May 2013, www.hoofcare.blogspot.com
Leeches for Laminitis: Can an Old Idea Work on Today’s Horses? Fran Jurga, June 2013, www.hoofcare.blogspot.com
Acute equine laminitis; solving the problem wiht 94% clinical success rate using medical leeches - Dr Sagiv Ben-Yakir
Rasch K
Veterinary hirudotherapy for horse laminitis results of a nationwide study in Germany
Zeitschrift Fur Ganzheitliche Tiermedizin: 1, 24-29, 2010
Veterinary Hirudotherapy and Equine Laminitis - Dr Sagiv Ben-Yakir, Autumn 2005, www.BTERFoundation.org
*de Laat M, Sillence M, McGowan C, Pollitt C
Insulin-Induced Laminitis - An investigation of the disease mechanism in horses
RIRDC Dec 2011
Treating illness/disease with leeches is called hirudotherapy. Leeches have been applied to the coronary band of horses with laminitis, and some people believe improvements are seen. Theories put forward for improvements reported generally concern several chemicals that are contained in leech saliva:
Hirudin - an anti-coagulant - hirudin inhibits thrombin, prevents blood from clotting and inhibits platelet aggregation. Wounds can continue to bleed for up to 10 hours after the leeches have been removed.
However, it used to be thought that vasoconstriction was a causative factor in laminitis, but now it is known that endocrinopathic laminitis is caused by high levels of insulin acting on IGF-1 receptors, causing stretching and weakening of the laminae, and that vasodilation may be involved in the onset of endocrinopathic laminitis (see below).
It has been suggested that hirudin has anti-inflammatory properties.
However, endocrinopathic laminitis involves little or no inflammation.
A histamine-like vasodilator.
However, research by Melody de Laat published by the RIRDC in 2011* found increased hoof wall surface temperature in horses with insulin-induced laminitis, and suggested that vasodilation may be involved in the onset of endocrinopathic laminitis. To date, the only treatment shown effective to prevent sepsis-related laminitis is cyrotherapy (icing the feet), which causes vasoconstriction - the opposite of vasodilation. So causing vasodilation might appear to be contra-indicated for both endocrinopathic and sepsis-related laminitis.
Enzymes that stop proteinases activities, e.g MMPs, that have been implicated in the destruction of the basement membrane in sepsis-related laminitis.
However, endocrinopathic laminitis does not involve MMPs or basement membrane breakdown.
Medicinal Leeches: The Much-Maligned Traditional Healing Aid is Making a Comeback for Equine Lameness Therapy - Fran Jurga, May 2013, www.hoofcare.blogspot.com
Leeches for Laminitis: Can an Old Idea Work on Today’s Horses? Fran Jurga, June 2013, www.hoofcare.blogspot.com
Acute equine laminitis; solving the problem wiht 94% clinical success rate using medical leeches - Dr Sagiv Ben-Yakir
Rasch K
Veterinary hirudotherapy for horse laminitis results of a nationwide study in Germany
Zeitschrift Fur Ganzheitliche Tiermedizin: 1, 24-29, 2010
Veterinary Hirudotherapy and Equine Laminitis - Dr Sagiv Ben-Yakir, Autumn 2005, www.BTERFoundation.org
*de Laat M, Sillence M, McGowan C, Pollitt C
Insulin-Induced Laminitis - An investigation of the disease mechanism in horses
RIRDC Dec 2011
Leptin
Leptin is an adipokine (a cytokine or chemical messenger) secreted by adipocytes (fat cells)/adipose tissue. Adiponectin is another adipokine.
Leptin sends messages to the brain about energy stores, body condition, reproduction and bone mass. In healthy mammals, leptin reduces appetite, inhibits insulin secretion, increases insulin sensitivity, stimulates heat production, increases fatty acid oxidation and reduces body fat.
Leptin deficiency causes obesity, but most obese mammals have elevated blood leptin levels, and it seems likely that obese mammals have an impaired response to leptin, referred to as leptin resistance, with some similarities to insulin resistance. In these obese mammals, leptin no longer suppresses food intake or reduces bodyweight, and may be associated with hyperinsulinaemia at the pancreatic level and reduced insulin sensitivity in peripheral tissues.
For a while it was thought that blood leptin concentrations might be associated with laminitis risk and diagnosis of EMS, but recent research has shown that leptin is not useful for the identification of laminitis prone horses and that leptin concentrations have the potential to be misleading in the investigation of EMS. Leptin is associated with body condition score, and it is now thought that increased leptin concentrations simply show that a horse has too much fat stored/is overweight.
In the USA leptin testing is being offered alongside insulin testing (at Cornell's Animal Health Diagnostic Center), but leptin testing is not generally offered in Europe. Leptin can be tested in serum or EDTA plasma.
From Cornell's Animal Health Diagnostic Center EMS testing:
"Leptin is a hormone produced by adipocytes. It is expected to be increased in EMS horses, but generally returns to normal before insulin does in treated horses. Leptin is useful for separating hyperinsulinemia caused by PPID from other causes, such as laminitis, stress, or non-fasted samples. It is also useful for tracking weight loss. This test can be performed on the same sample used for the Insulin baseline or ACTH/Insulin combination test."
From Cornell's Interpretation Information:
INTERPRETATION OF EQUINE LEPTIN TEST
LEPTIN: Additional Reference Ranges: Intermediate 4 - 7 ng/mL, High > 7 ng/mL. In Equine Metabolic Syndrome (EMS), the concentration of leptin is generally in the high or intermediate reference range above. However the leptin test is meant to be interpreted in the context of insulin testing for EMS. Unlike insulin, leptin is less likely to be affected by post-grain meal or stress, and thus may be useful in ruling out other causes of hyperinsulinemia. As with insulin, the higher the leptin concentration is, the more likely is the diagnosis of EMS. An intermediate to high leptin concentration without hyperinsulinemia may indicate that the horse is overweight or obese and at risk for developing EMS or is being treated for EMS.
Research involving lepin in horses:
Bamford NJ, Potter SJ, Baskerville CL, Harris PA, Bailey SR
Effect of increased adiposity on insulin sensitivity and adipokine concentrations in different equine breeds adapted to cereal-rich or fat-rich meals
Vet J. 2016 Aug;214:14-20. doi: 10.1016/j.tvjl.2016.02.002. Epub 2016 Feb 12
18 horses and ponies were studied for 20 weeks. Horses were fed ad lib hay plus either a high fat low glycaemic diet OR a high glucose diet OR a control diet. Fat and glucose fed horses put on weight to become obese and had increased leptin concentrations. However, increased adiposity did not reduce insulin sensitivity, and there were no differences between groups for adiponectin, TNF-alpha or SAA.
Pleasant RS, Suagee JK, Thatcher CD, Elvinger F, Geor RJ
Adiposity, plasma insulin, leptin, lipids, and oxidative stress in mature light breed horses
J Vet Intern Med. 2013 May-Jun;27(3):576-82
"Overconditioned and obese horses had higher plasma insulin (P < .001) and leptin (P < .01) levels than optimally conditioned horses."
Ungru J, Blüher M, Coenen M, Raila J, Boston R, Vervuert I
Effects of body weight reduction on blood adipokines and subcutaneous adipose tissue adipokine mRNA expression profiles in obese ponies
Vet Rec. 2012 Nov 24;171(21):528. doi: 10.1136/vr.100911. Epub 2012 Oct 7
15 obese ponies were classified either insulin resistant or insulin sensitive by FSIGT and placed on restricted energy diets. Significant weight loss occurred when ponies were fed 7 MJ DE per 100 kg bodyweight. Serum leptin was similar in obese insulin resistant and obese insulin sensitive ponies, and decreased significantly with weight loss. Obese insulin resistant ponies had significantly lower plasma adiponectin levels than obese insulin sensitive ponies.
"Plasma adiponectin was strongly related to IR, whereas serum leptin and RBP4 were closely linked to adiposity, independent of insulin sensitivity."
Díez E, López I, Pérez C, Pineda C, Aguilera-Tejero E.
Plasma leptin concentration in donkeys.
Vet Q. 2012;32(1):13-6. doi: 10.1080/01652176.2012.677867. Epub 2012 Apr 11. PMID: 22493943.
"Donkeys appear to have higher plasma leptin concentrations than horses and hyperleptinemia is correlated with BCS in donkeys."
Caltabilota TJ, Earl LR, Thompson DL Jr, Clavier SE, Mitcham PB
Hyperleptinemia in mares and geldings: assessment of insulin sensitivity from glucose responses to insulin injection
J Anim Sci. 2010 Sep;88(9):2940-9 (PubMed) (Full paper)
"It was concluded that hyperleptinemic horses, which are also hyperinsulinemic and have exaggerated insulin responses to glucose injection, are indeed less sensitive to insulin than normal horses with reduced leptin concentrations of the same body condition."
Carter RA, Treiber KH, Geor RJ, Douglass L, Harris PA
Prediction of incipient pasture-associated laminitis from hyperinsulinaemia, hyperleptinaemia and generalised and localised obesity in a cohort of ponies
Equine Vet J. 2009 Feb;41(2):171-8 (PubMed)
"RESULTS: Variables with diagnostic accuracy for the prediction of CL ponies included insulin, leptin, BCS, CNS, and NC:height ratio. Specific cut-off values of insulin (>32 mu/l), leptin (>73 ng/ml), BCS (> or = 7), CNS (> or = 4) and NC:height ratio (>0.71) had reproducible diagnostic accuracy for the prediction of laminitis. Combining tests did not result in higher diagnostic accuracy than individual tests of insulin or leptin during either evaluation.
CONCLUSIONS: Tests of insulin and leptin concentrations and measures of generalised (BCS) and localised (CNS or NC:height ratio) obesity were beneficial in the prediction of laminitic episodes."
Owens, Kellie Marie, MSc Thesis 2009
The Effect of Changes in Body Condition on Insulin Sensitivity, Leptin, and Adiponectin in Horses fed Forage-Only Diets
Carter RA, PhD dissertation 2008
Equine Obesity and its role in insulin resistance, inflammation and risk for laminitis
Buff PR, Messer NT, Cogswell AM, Johnson PJ, Keisler DH, Ganjam VK.
Seasonal and pulsatile dynamics of thyrotropin and leptin in mares maintained under a constant energy balance.
Domest Anim Endocrinol. 2007 Nov;33(4):430-6. doi: 10.1016/j.domaniend.2006.08.007. Epub 2006 Sep 25. PMID: 17055686.
Vet J. 2006 Nov;172(3):460-5. Epub 2005 Jun 29. (PubMed)
Adiponectin and leptin are related to fat mass in horses.
Kearns CF, McKeever KH, Roegner V, Brady SM, Malinowski K."These data suggest that leptin is proportional while adiponectin is inversely proportional to adiposity in horses."
J Am Vet Med Assoc. 2006 May 1;228(9):1383-90 (PubMed)
Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance.
Frank N, Elliott SB, Brandt LE, Keisler DH.
OBJECTIVE: To compare obese horses with insulin resistance (IR) with nonobese horses and determine whether blood resting glucose, insulin, leptin, and lipid concentrations differed between groups and were correlated with combined glucose-insulin test (CGIT) results.
ANIMALS: 7 obese adult horses with IR (OB-IR group) and 5 nonobese mares.
PROCEDURES: Physical measurements were taken, and blood samples were collected after horses had acclimated to the hospital for 3 days. Response to insulin was assessed by use of the CGIT, and maintenance of plasma glucose concentrations greater than the preinjection value for > or = 45 minutes was used to define IR. Area under the curve values for glucose (AUC(g)) and insulin (AUC(i)) concentrations were calculated.
RESULTS: Morgan, Paso Fino, Quarter Horse, and Tennessee Walking Horse breeds were represented in the OB-IR group. Mean neck circumference and BCS differed significantly between groups and were positively correlated with AUC values. Resting insulin and leptin concentrations were 6 and 14 times as high, respectively, in the OB-IR group, compared with the nonobese group, and were significantly correlated with AUC(g) and AUC(i). Plasma nonesterified fatty acid, very low-density lipoprotein, and high-density lipoprotein-cholesterol (HDL-C) concentrations were significantly higher (86%, 104%, and 29%, respectively) in OB-IR horses, and HDL-C concentrations were positively correlated with AUC values.
CONCLUSIONS AND CLINICAL RELEVANCE: Measurements of neck circumference and resting insulin and leptin concentrations can be used to screen obese horses for IR. Dyslipidemia is associated with IR in obese horses.
Cartmill JA, Thompson DL Jr, Storer WA, Crowley JC, Huff NK, Waller CA
Effect of dexamethasone, feeding time, and insulin infusion on leptin concentrations in stallions
J Anim Sci. 2005 Aug;83(8):1875-81
"feeding time, and more specifically the insulin increase associated with a meal, not cortisol rhythm, drives the postprandial increase in plasma leptin concentrations in horses."
Leptin in horses: Influences of body condition, gender, insulin insensitivity, feeding and dexamethasone
JA Cartmill, PhD dissertation 2004
"It was concluded that leptin in the horse is affected by adrenal and thyroid hormones as well as by glucose/insulin metabolism, and that a syndrome of obesity-related hyperleptinemia, hyperglycemia, and hyperinsulinemia exists in the horse that is similar to type II diabetes in humans."
Cubitt Tania A
Long Term and Short Term Changes in Leptin, Insulin and Glucose in Grazing Thoroughbred Mares
PhD dissertation November 2007
W. A. Storer, D. L. Thompson, Jr., C. A. Waller and J. A. Cartmill (Full Paper)
Hormonal patterns in normal and hyperleptinemic mares in response to three common feeding-housing regimens
J ANIM SCI 2007, 85:2873-2881.
R. Buff, B. R. Spader, C. D. Morrison and D. H. Keisler (Full Paper)
Endocrine responses in mares undergoing abrupt changes in nutritional management
J ANIM SCI 2006, 84:2700-2707.
J Anim Sci. 2002 Nov;80(11):2942-8 (PubMed) (Full paper)
Leptin in horses: tissue localization and relationship between peripheral concentrations of leptin and body condition.
Buff PR, Dodds AC, Morrison CD, Whitley NC, McFadin EL, Daniel JA, Djiane J, Keisler DH.
"Serum concentrations of leptin increased in horses with body condition score (1 = thin to 9 = fat; r = 0.64; P = 0.0001). Furthermore, serum concentrations of leptin were greater in geldings and stallions than in mares (P = 0.0002), and tended to increase with age of the animal (P = 0.08)."
Gentry LR, Thompson DL Jr, Gentry GT Jr, Davis KA, Godke RA, Cartmill JA.
The relationship between body condition, leptin, and reproductive and hormonal characteristics of mares during the seasonal anovulatory period.
J Anim Sci. 2002 Oct;80(10):2695-703. doi: 10.2527/2002.80102695x. PMID: 12413093.
Gentry, Laura Roland
Body Condition, Leptin, and Reproductive Characteristics in Horses
PhD dissertation December 2001. LSU Historical Dissertations and Theses
Research involving lepin in humans and other mammals:
Neuroreport. 2012 Dec 12. [Epub ahead of print] (PubMed)
Fat-mass-related hormone, plasma leptin, predicts brain volumes in the elderly.
Rajagopalan P, Toga AW, Jack CR, Weiner MW, Thompson PM
"Greater brain atrophy may occur in people with central leptin insufficiency, a marker of obesity."
Karsenty G, Oury F.
Biology without walls: the novel endocrinology of bone.
Annu Rev Physiol. 2012;74:87-105. doi: 10.1146/annurev-physiol-020911-153233. Epub 2011 Nov 7. PMID: 22077214 (Full: DeepDyve).
Morton GJ, Schwartz MW.
Leptin and the central nervous system control of glucose metabolism.
Physiol Rev. 2011 Apr;91(2):389-411. doi: 10.1152/physrev.00007.2010. PMID: 21527729; PMCID: PMC3379883.
Obes Rev. 2007 Jan;8(1):21-34 (PubMed)
The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review
Klok MD, Jakobsdottir S, Drent ML
"Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss." " In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant."
Leptin sends messages to the brain about energy stores, body condition, reproduction and bone mass. In healthy mammals, leptin reduces appetite, inhibits insulin secretion, increases insulin sensitivity, stimulates heat production, increases fatty acid oxidation and reduces body fat.
Leptin deficiency causes obesity, but most obese mammals have elevated blood leptin levels, and it seems likely that obese mammals have an impaired response to leptin, referred to as leptin resistance, with some similarities to insulin resistance. In these obese mammals, leptin no longer suppresses food intake or reduces bodyweight, and may be associated with hyperinsulinaemia at the pancreatic level and reduced insulin sensitivity in peripheral tissues.
For a while it was thought that blood leptin concentrations might be associated with laminitis risk and diagnosis of EMS, but recent research has shown that leptin is not useful for the identification of laminitis prone horses and that leptin concentrations have the potential to be misleading in the investigation of EMS. Leptin is associated with body condition score, and it is now thought that increased leptin concentrations simply show that a horse has too much fat stored/is overweight.
In the USA leptin testing is being offered alongside insulin testing (at Cornell's Animal Health Diagnostic Center), but leptin testing is not generally offered in Europe. Leptin can be tested in serum or EDTA plasma.
From Cornell's Animal Health Diagnostic Center EMS testing:
"Leptin is a hormone produced by adipocytes. It is expected to be increased in EMS horses, but generally returns to normal before insulin does in treated horses. Leptin is useful for separating hyperinsulinemia caused by PPID from other causes, such as laminitis, stress, or non-fasted samples. It is also useful for tracking weight loss. This test can be performed on the same sample used for the Insulin baseline or ACTH/Insulin combination test."
From Cornell's Interpretation Information:
INTERPRETATION OF EQUINE LEPTIN TEST
LEPTIN: Additional Reference Ranges: Intermediate 4 - 7 ng/mL, High > 7 ng/mL. In Equine Metabolic Syndrome (EMS), the concentration of leptin is generally in the high or intermediate reference range above. However the leptin test is meant to be interpreted in the context of insulin testing for EMS. Unlike insulin, leptin is less likely to be affected by post-grain meal or stress, and thus may be useful in ruling out other causes of hyperinsulinemia. As with insulin, the higher the leptin concentration is, the more likely is the diagnosis of EMS. An intermediate to high leptin concentration without hyperinsulinemia may indicate that the horse is overweight or obese and at risk for developing EMS or is being treated for EMS.
Research involving lepin in horses:
Bamford NJ, Potter SJ, Baskerville CL, Harris PA, Bailey SR
Effect of increased adiposity on insulin sensitivity and adipokine concentrations in different equine breeds adapted to cereal-rich or fat-rich meals
Vet J. 2016 Aug;214:14-20. doi: 10.1016/j.tvjl.2016.02.002. Epub 2016 Feb 12
18 horses and ponies were studied for 20 weeks. Horses were fed ad lib hay plus either a high fat low glycaemic diet OR a high glucose diet OR a control diet. Fat and glucose fed horses put on weight to become obese and had increased leptin concentrations. However, increased adiposity did not reduce insulin sensitivity, and there were no differences between groups for adiponectin, TNF-alpha or SAA.
Pleasant RS, Suagee JK, Thatcher CD, Elvinger F, Geor RJ
Adiposity, plasma insulin, leptin, lipids, and oxidative stress in mature light breed horses
J Vet Intern Med. 2013 May-Jun;27(3):576-82
"Overconditioned and obese horses had higher plasma insulin (P < .001) and leptin (P < .01) levels than optimally conditioned horses."
Ungru J, Blüher M, Coenen M, Raila J, Boston R, Vervuert I
Effects of body weight reduction on blood adipokines and subcutaneous adipose tissue adipokine mRNA expression profiles in obese ponies
Vet Rec. 2012 Nov 24;171(21):528. doi: 10.1136/vr.100911. Epub 2012 Oct 7
15 obese ponies were classified either insulin resistant or insulin sensitive by FSIGT and placed on restricted energy diets. Significant weight loss occurred when ponies were fed 7 MJ DE per 100 kg bodyweight. Serum leptin was similar in obese insulin resistant and obese insulin sensitive ponies, and decreased significantly with weight loss. Obese insulin resistant ponies had significantly lower plasma adiponectin levels than obese insulin sensitive ponies.
"Plasma adiponectin was strongly related to IR, whereas serum leptin and RBP4 were closely linked to adiposity, independent of insulin sensitivity."
Díez E, López I, Pérez C, Pineda C, Aguilera-Tejero E.
Plasma leptin concentration in donkeys.
Vet Q. 2012;32(1):13-6. doi: 10.1080/01652176.2012.677867. Epub 2012 Apr 11. PMID: 22493943.
"Donkeys appear to have higher plasma leptin concentrations than horses and hyperleptinemia is correlated with BCS in donkeys."
Caltabilota TJ, Earl LR, Thompson DL Jr, Clavier SE, Mitcham PB
Hyperleptinemia in mares and geldings: assessment of insulin sensitivity from glucose responses to insulin injection
J Anim Sci. 2010 Sep;88(9):2940-9 (PubMed) (Full paper)
"It was concluded that hyperleptinemic horses, which are also hyperinsulinemic and have exaggerated insulin responses to glucose injection, are indeed less sensitive to insulin than normal horses with reduced leptin concentrations of the same body condition."
Carter RA, Treiber KH, Geor RJ, Douglass L, Harris PA
Prediction of incipient pasture-associated laminitis from hyperinsulinaemia, hyperleptinaemia and generalised and localised obesity in a cohort of ponies
Equine Vet J. 2009 Feb;41(2):171-8 (PubMed)
"RESULTS: Variables with diagnostic accuracy for the prediction of CL ponies included insulin, leptin, BCS, CNS, and NC:height ratio. Specific cut-off values of insulin (>32 mu/l), leptin (>73 ng/ml), BCS (> or = 7), CNS (> or = 4) and NC:height ratio (>0.71) had reproducible diagnostic accuracy for the prediction of laminitis. Combining tests did not result in higher diagnostic accuracy than individual tests of insulin or leptin during either evaluation.
CONCLUSIONS: Tests of insulin and leptin concentrations and measures of generalised (BCS) and localised (CNS or NC:height ratio) obesity were beneficial in the prediction of laminitic episodes."
Owens, Kellie Marie, MSc Thesis 2009
The Effect of Changes in Body Condition on Insulin Sensitivity, Leptin, and Adiponectin in Horses fed Forage-Only Diets
Carter RA, PhD dissertation 2008
Equine Obesity and its role in insulin resistance, inflammation and risk for laminitis
Buff PR, Messer NT, Cogswell AM, Johnson PJ, Keisler DH, Ganjam VK.
Seasonal and pulsatile dynamics of thyrotropin and leptin in mares maintained under a constant energy balance.
Domest Anim Endocrinol. 2007 Nov;33(4):430-6. doi: 10.1016/j.domaniend.2006.08.007. Epub 2006 Sep 25. PMID: 17055686.
Vet J. 2006 Nov;172(3):460-5. Epub 2005 Jun 29. (PubMed)
Adiponectin and leptin are related to fat mass in horses.
Kearns CF, McKeever KH, Roegner V, Brady SM, Malinowski K."These data suggest that leptin is proportional while adiponectin is inversely proportional to adiposity in horses."
J Am Vet Med Assoc. 2006 May 1;228(9):1383-90 (PubMed)
Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance.
Frank N, Elliott SB, Brandt LE, Keisler DH.
OBJECTIVE: To compare obese horses with insulin resistance (IR) with nonobese horses and determine whether blood resting glucose, insulin, leptin, and lipid concentrations differed between groups and were correlated with combined glucose-insulin test (CGIT) results.
ANIMALS: 7 obese adult horses with IR (OB-IR group) and 5 nonobese mares.
PROCEDURES: Physical measurements were taken, and blood samples were collected after horses had acclimated to the hospital for 3 days. Response to insulin was assessed by use of the CGIT, and maintenance of plasma glucose concentrations greater than the preinjection value for > or = 45 minutes was used to define IR. Area under the curve values for glucose (AUC(g)) and insulin (AUC(i)) concentrations were calculated.
RESULTS: Morgan, Paso Fino, Quarter Horse, and Tennessee Walking Horse breeds were represented in the OB-IR group. Mean neck circumference and BCS differed significantly between groups and were positively correlated with AUC values. Resting insulin and leptin concentrations were 6 and 14 times as high, respectively, in the OB-IR group, compared with the nonobese group, and were significantly correlated with AUC(g) and AUC(i). Plasma nonesterified fatty acid, very low-density lipoprotein, and high-density lipoprotein-cholesterol (HDL-C) concentrations were significantly higher (86%, 104%, and 29%, respectively) in OB-IR horses, and HDL-C concentrations were positively correlated with AUC values.
CONCLUSIONS AND CLINICAL RELEVANCE: Measurements of neck circumference and resting insulin and leptin concentrations can be used to screen obese horses for IR. Dyslipidemia is associated with IR in obese horses.
Cartmill JA, Thompson DL Jr, Storer WA, Crowley JC, Huff NK, Waller CA
Effect of dexamethasone, feeding time, and insulin infusion on leptin concentrations in stallions
J Anim Sci. 2005 Aug;83(8):1875-81
"feeding time, and more specifically the insulin increase associated with a meal, not cortisol rhythm, drives the postprandial increase in plasma leptin concentrations in horses."
Leptin in horses: Influences of body condition, gender, insulin insensitivity, feeding and dexamethasone
JA Cartmill, PhD dissertation 2004
"It was concluded that leptin in the horse is affected by adrenal and thyroid hormones as well as by glucose/insulin metabolism, and that a syndrome of obesity-related hyperleptinemia, hyperglycemia, and hyperinsulinemia exists in the horse that is similar to type II diabetes in humans."
Cubitt Tania A
Long Term and Short Term Changes in Leptin, Insulin and Glucose in Grazing Thoroughbred Mares
PhD dissertation November 2007
W. A. Storer, D. L. Thompson, Jr., C. A. Waller and J. A. Cartmill (Full Paper)
Hormonal patterns in normal and hyperleptinemic mares in response to three common feeding-housing regimens
J ANIM SCI 2007, 85:2873-2881.
R. Buff, B. R. Spader, C. D. Morrison and D. H. Keisler (Full Paper)
Endocrine responses in mares undergoing abrupt changes in nutritional management
J ANIM SCI 2006, 84:2700-2707.
J Anim Sci. 2002 Nov;80(11):2942-8 (PubMed) (Full paper)
Leptin in horses: tissue localization and relationship between peripheral concentrations of leptin and body condition.
Buff PR, Dodds AC, Morrison CD, Whitley NC, McFadin EL, Daniel JA, Djiane J, Keisler DH.
"Serum concentrations of leptin increased in horses with body condition score (1 = thin to 9 = fat; r = 0.64; P = 0.0001). Furthermore, serum concentrations of leptin were greater in geldings and stallions than in mares (P = 0.0002), and tended to increase with age of the animal (P = 0.08)."
Gentry LR, Thompson DL Jr, Gentry GT Jr, Davis KA, Godke RA, Cartmill JA.
The relationship between body condition, leptin, and reproductive and hormonal characteristics of mares during the seasonal anovulatory period.
J Anim Sci. 2002 Oct;80(10):2695-703. doi: 10.2527/2002.80102695x. PMID: 12413093.
Gentry, Laura Roland
Body Condition, Leptin, and Reproductive Characteristics in Horses
PhD dissertation December 2001. LSU Historical Dissertations and Theses
Research involving lepin in humans and other mammals:
Neuroreport. 2012 Dec 12. [Epub ahead of print] (PubMed)
Fat-mass-related hormone, plasma leptin, predicts brain volumes in the elderly.
Rajagopalan P, Toga AW, Jack CR, Weiner MW, Thompson PM
"Greater brain atrophy may occur in people with central leptin insufficiency, a marker of obesity."
Karsenty G, Oury F.
Biology without walls: the novel endocrinology of bone.
Annu Rev Physiol. 2012;74:87-105. doi: 10.1146/annurev-physiol-020911-153233. Epub 2011 Nov 7. PMID: 22077214 (Full: DeepDyve).
Morton GJ, Schwartz MW.
Leptin and the central nervous system control of glucose metabolism.
Physiol Rev. 2011 Apr;91(2):389-411. doi: 10.1152/physrev.00007.2010. PMID: 21527729; PMCID: PMC3379883.
Obes Rev. 2007 Jan;8(1):21-34 (PubMed)
The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review
Klok MD, Jakobsdottir S, Drent ML
"Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss." " In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant."
Lethargy
Lethargy can be a symptom of both PPID and EMS.
Horses with PPID are often described as becoming more quiet/subdued or lethargic.
Possible reasons for lethargy include:
insulin resistance,
increase in beta-endorphin,
or what appears to be lethargy (reluctance to move) could be due to an undetected concurrent disease or sub-clinical laminitis.
Horses with PPID are often described as becoming more quiet/subdued or lethargic.
Possible reasons for lethargy include:
insulin resistance,
increase in beta-endorphin,
or what appears to be lethargy (reluctance to move) could be due to an undetected concurrent disease or sub-clinical laminitis.
Levothyroxine Sodium (Thyro-L)
See also Thyroid hormones.
Levothyroxine sodium is a synthetic thyroid hormone that increases the metabolic rate. Although currently not licensed for horses in the UK, it can be prescribed under the Cascade for horses with laminitis (that cannot exercise) that are overweight, to help weight loss, particularly in horses that are not losing weight despite a calorie controlled diet. It is generally used short-term, e.g. 3-6 months. A calorie controlled and low sugar/starch diet is still required for horses taking Levothyroxine. For horses with EMS/insulin resistance, drugs should not be used as a substitute for diet, exercise and management changes.
Levothyroxine may cause increased activity, agitation, sweating and an increased heart rate. If you notice any side effects, contact your vet immediately and stop giving Levothyroxine until you have veterinary advice.
Levothyroxine - BEVA 2019
In humans,sub-clinical hyperthyroidism may be associated with bone loss, and to minimize the risk of osteoporosis, the dosage of levothyroxine sodium should be titrated to the lowest possible effective dose.
In humans, sucralfate, calcium carbonate, ferrous sulphate and soya reduce absorption of levothyroxine from the GI tract - leave several hours between feeding these substances and giving levothyroxine.
In humans taking phenylbutazone or acetylsalicylic acid (aspirin) concurrently with levothyroxine, false low total plasma concentrations have been observed.
See Levothyrox Pillintrip.com and Levothyroxine 25 mcg Tablets medicines.org.uk
Kritchevsky J, Olave C, Tinkler S, Tropf M, Ivester K, Forsythe L, Couetil L.
A randomised, controlled trial to determine the effect of levothyroxine on Standardbred racehorses.
Equine Vet J. 2022 May;54(3):584-591. doi: 10.1111/evj.13480. Epub 2021 Jul 28. PMID: 34101895.
Giving 0.25 mg/kg thyroxine for 2 weeks caused higher heart rates during exercise and recovery compared to horses not given thyroxine, and 3/6 horses given 0.25 mg/kg thyroxine developed cardiac arrhythmias including atrial fibrillation.
"Conclusions: Supra-physiologic thyroxine supplementation caused a decreased V200 during a standard exercise test and may result in cardiac arrhythmias."
Bertin FR, Eichstadt Forsythe L, Kritchevsky JE
Effects of high doses of levothyroxine sodium on serum concentrations of triiodothyronine and thyroxine in horses
Am J Vet Res. 2019 Jun;80(6):565-571. doi: 10.2460/ajvr.80.6.565. PMID: 31140852
Giving 480 mg of levothyroxine sodium to horses with normal thyroid hormones for 14 days resulted in markedly increased thyroid hormone concentrations. Hormone concentrations returned to pre-treatment levels within 3 weeks of discontinuing treatment.
According to Study reveals the dangers of thyroid supplements in fit horses by Jackie Bellamy Zions March 2019, fit Standardbreds treated with 0.25 mg/kg levothyroxine became more alert and difficult to handle, fatigued quicker, 4/6 horses developed cardiac arrhythmia (an irregular heart beat) and 1/6 developed atrial fibrillation.
Dr Kritchevsky warned that giving levothyroxine to a horse with a respiratory infection could compromise the horse's natural response to the infection, and said that “In the case of over conditioned horses, thyroxine supplementation is to be used only until the horse reaches a normal body weight”.
Thyro-L - LLoyd 2016
Chameroy KA, PhD dissertation 2010
Diagnosis and Management of Horses with Equine Metabolic Syndrome (EMS)
See p 473 ACVIM Consensus Statement Equine Metabolic Syndrome (2010)
Levothyroxine sodium can induce weight loss and improve insulin sensitivity.
Dose: horses and larger ponies (>350 kg) 48 mg/day, smaller ponies and miniatures 24 mg/day. Given in the feed for 3 - 6 months at the same time as diet and exercise changes are implemented.
It is very important to wean horses slowly off of Levothyroxine sodium by reducing the dose to half for 2 weeks and then half again for a further 2 weeks (so if full dose was 48 mg/day, reduce the dose to 24 mg/day for 2 weeks, then to 12 mg/day for 2 weeks, then stop).
Tóth F, Frank N, Geor RJ, Boston RC
Effects of pretreatment with dexamethasone or levothyroxine sodium on endotoxin-induced alterations in glucose and insulin dynamics in horses
Am J Vet Res. 2010 Jan;71(1):60-8
24 horses received 200 g of oats plus either 48 mg of levothyroxine, 20 mg of dexamethasone, or nothing (control) for 15 days and housed in individual stalls. Insulin sensitivity decreased in all groups, with the largest decrease in insulin sensitivity in the dexamethasone group. All horses were then given lipopolysaccharide (endotoxemia) (20 ng/kg) - this further decreased mean insulin sensitivity by 71% in the dexamethasone group, 63% in the control group, but did not decrease mean insulin sensitivity further in the levothyroxine group.
"Conclusions and clinical relevance: Insulin sensitivity decreased during the pretreatment period in all 3 groups, indicating that hospitalization " (box rest) "affected glucose and insulin dynamics. Dexamethasone significantly lowered SI, and endotoxemia further exacerbated insulin resistance. In contrast, there was no additional effect of endotoxemia on SI in horses pretreated with levothyroxine, suggesting that this treatment prevented endotoxemia-induced insulin resistance."
Diagnosis and Management of Insulin Resistance and Equine Metabolic Syndrome (EMS) in Horses - Nicholas Frank
Frank N, Elliott SB, Boston RC.
Effects of long-term oral administration of levothyroxine sodium on glucose dynamics in healthy adult horses.
Am J Vet Res. 2008 Jan;69(1):76-81. doi: 10.2460/ajvr.69.1.76. PMID: 18167090.
6 healthy mares with normal thyroid hormone function given levothyroxine at 48 mg/day for 48 weeks lost weight and had improved insulin sensitivity.
Frank N
Endocrinopathic Laminitis, Obesity-Associated Laminitis, and Pasture-Associated Laminitis
AAEP 2008
"In certain situations when obesity and IR persist despite dietary interventions, weight loss can be accelerated by administering levothyroxine sodiumc at a dosage of 4 teaspoons (48 mg) orally once daily for 3–6 mo. Levothyroxine reduces body fat mass and improves insulin sensitivity in horses that are kept off pasture and maintained on a controlled diet. Treated horses should be weaned off the drug once the ideal body weight has been attained by reducing the dosage to 2 teaspoons (24 mg) orally per day for 2 wk and then 1 teaspoon (12 mg) orally per day for 2 wk."
Guide to Insulin Resistance & Laminitis (2008) – Nicholas Frank, Raymond Geor, Steve Adair page 37 onwards.
Sommardahl CS, Frank N, Elliott SB, Webb LL, Refsal KR, Denhart JW, Thompson DL Jr.
Effects of oral administration of levothyroxine sodium on serum concentrations of thyroid gland hormones and responses to injections of thyrotropin-releasing hormone in healthy adult mares.
Am J Vet Res. 2005 Jun;66(6):1025-31. doi: 10.2460/ajvr.2005.66.1025. PMID: 16008227.
8 mixed-breed and Quarter Horse type mares were given increasing amounts of Levothyroxine - 24, 48, 72 then 96 mg - for 2 weeks at each dose, 4 similar horses acted as controls. They were fed around 9 kg of mixed grass hay and 500 g of grain, which met or exceeded calculated DE requirements for maintenance. In the treated group bodyweight changed from 32 kg loss to 5 kg gain, median loss of 19 kg, and from 4 kg loss to 20 kg gain, median loss 0 kg in the untreated group. Horses treated with 96 mg were easily agitated - more difficult to catch and more excitable in their pens and stalls. Total thyroxine (tT4) and free thyroxine (fT4) increased with levothyroxine dose.
Frank N, Sommardahl CS, Eiler H, Webb LL, Denhart JW, Boston RC.
Effects of oral administration of levothyroxine sodium on concentrations of plasma lipids, concentration and composition of very-low-density lipoproteins, and glucose dynamics in healthy adult mares.
Am J Vet Res. 2005 Jun;66(6):1032-8. doi: 10.2460/ajvr.2005.66.1032. PMID: 16008228.
In the same research (as Sommardahl et al. 2005) plasma triglyceride, total cholesterol and very low density lipoprotein (VLDL) decreased with levothyroxine treatment. Insulin sensitivity increased with levothyroxine treatment (based on IVGITT at the start and end of 8 weeks treatment) but glucose effectiveness and net insulin response were not affected by treatment.
"Conclusions and clinical relevance: Administration of L-T4 decreases blood lipid concentrations, improves insulin sensitivity, and increases insulin disposal in horses. Levothyroxine sodium may have potential as a treatment for horses with reduced insulin sensitivity."
Ligaments and tendons
Tendon or ligament laxity, suspensory ligament breakdown, and desmitis/tendonitis are listed as possible comorbidities or clinical signs in horses with both early and advanced PPID in the 2021 Equine Endocrinology Group Recommendations for the Diagnosis and Treatment of PPID.
In her October 2022 review of PPID (section 5.9), Naomi Kirkwood cites Hofberger's 2018 and 2015 papers (below), saying that suspensory ligament degeneration is recognised in both aged and PPID horses. These studies have shown reduced longitudinal arrangement of collagen fibres, inclusions of cartilage, haemorrhage and proteoglycan accumulation between fibres of the suspensory ligament in horses with PPID, with more cells staining for glucocorticoid receptors in suspensory ligaments of PPID horses compared to non-PPID horses. It is theorised that tissue disruption of cortisol metabolism may contribute to this suspensory ligament degeneration in horses with PPID.
Kirkwood, Naomi C; Hughes, Kristopher J; Stewart, Allison J.
Review Article: Pituitary Pars Intermedia Dysfunction (PPID) in Horses.
Veterinary Sciences October 2022, 9, 556. https://doi.org/10.3390/vetsci9100556 (Open Access).
Hofberger SC, Gauff F, Thaller D, Morgan R, Keen JA, Licka TF
Assessment of tissue-specific cortisol activity with regard to degeneration of the suspensory ligaments in horses with pituitary pars intermedia dysfunction
Am J Vet Res. 2018 Feb;79(2):199-210. doi: 10.2460/ajvr.79.2.199
"Horses with PPID had evidence of SL (suspensory ligament) degeneration with significantly increased proteoglycan accumulation. Neck skin tissue was found to be significantly thinner in PPID-affected horses than in young control horses.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that tissue-specific dysregulation of cortisol metabolism may contribute to the SL degeneration associated with PPID in horses."
Grubbs ST, Kirschner KA, Baus MR, Kremburg JR, Neal DL, Keefe TR
Clinical Signs Associated with PPID in the Equine Athlete
International Equine Endocrine Summit Jan 2017 p20
49 sports horses aged >10 were included in the study if they were documented to be showing at least one clinical sign of PPID. 19 of these 49 horses tested positive for PPID at 10 minutes post TRH administration, but only 2 of those 19 had positive baseline ACTH.
"The most common clinical signs observed in the PPID+ horses were delayed regional shedding, loss of epaxial muscle mass, regional adiposity, skeletal muscle atrophy and suspensory desmitis. PPID+ was significantly (P= 0.023) associated with lameness (suspensory desmitis, tendon laxity, superficial digital flexor tendonitis). Of the horses that were lame, 70% were PPID+. Based on the results of this study, the TRH stimulation procedure was required in 89% of enrolled horses for laboratory confirmation of PPID. In the sport horse, suspensory desmitis was significantly associated with PPID+ status. Veterinarians should include PPID in the list of differential diagnoses when examining sport horses with suspensory desmitis along with early and advanced clinical signs of PPID."
Hofberger S, Gauff F, Licka T
Suspensory ligament degeneration associated with pituitary pars intermedia dysfunction in horses
Vet J. 2015 Mar;203(3):348-50. doi: 10.1016/j.tvjl.2014.12.037. Epub 2015 Jan 6
DeepDyve
Tendon or ligament laxity, suspensory ligament breakdown, and desmitis/tendonitis are listed as possible comorbidities or clinical signs in horses with both early and advanced PPID in the 2021 Equine Endocrinology Group Recommendations for the Diagnosis and Treatment of PPID.
In her October 2022 review of PPID (section 5.9), Naomi Kirkwood cites Hofberger's 2018 and 2015 papers (below), saying that suspensory ligament degeneration is recognised in both aged and PPID horses. These studies have shown reduced longitudinal arrangement of collagen fibres, inclusions of cartilage, haemorrhage and proteoglycan accumulation between fibres of the suspensory ligament in horses with PPID, with more cells staining for glucocorticoid receptors in suspensory ligaments of PPID horses compared to non-PPID horses. It is theorised that tissue disruption of cortisol metabolism may contribute to this suspensory ligament degeneration in horses with PPID.
Kirkwood, Naomi C; Hughes, Kristopher J; Stewart, Allison J.
Review Article: Pituitary Pars Intermedia Dysfunction (PPID) in Horses.
Veterinary Sciences October 2022, 9, 556. https://doi.org/10.3390/vetsci9100556 (Open Access).
Hofberger SC, Gauff F, Thaller D, Morgan R, Keen JA, Licka TF
Assessment of tissue-specific cortisol activity with regard to degeneration of the suspensory ligaments in horses with pituitary pars intermedia dysfunction
Am J Vet Res. 2018 Feb;79(2):199-210. doi: 10.2460/ajvr.79.2.199
"Horses with PPID had evidence of SL (suspensory ligament) degeneration with significantly increased proteoglycan accumulation. Neck skin tissue was found to be significantly thinner in PPID-affected horses than in young control horses.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that tissue-specific dysregulation of cortisol metabolism may contribute to the SL degeneration associated with PPID in horses."
Grubbs ST, Kirschner KA, Baus MR, Kremburg JR, Neal DL, Keefe TR
Clinical Signs Associated with PPID in the Equine Athlete
International Equine Endocrine Summit Jan 2017 p20
49 sports horses aged >10 were included in the study if they were documented to be showing at least one clinical sign of PPID. 19 of these 49 horses tested positive for PPID at 10 minutes post TRH administration, but only 2 of those 19 had positive baseline ACTH.
"The most common clinical signs observed in the PPID+ horses were delayed regional shedding, loss of epaxial muscle mass, regional adiposity, skeletal muscle atrophy and suspensory desmitis. PPID+ was significantly (P= 0.023) associated with lameness (suspensory desmitis, tendon laxity, superficial digital flexor tendonitis). Of the horses that were lame, 70% were PPID+. Based on the results of this study, the TRH stimulation procedure was required in 89% of enrolled horses for laboratory confirmation of PPID. In the sport horse, suspensory desmitis was significantly associated with PPID+ status. Veterinarians should include PPID in the list of differential diagnoses when examining sport horses with suspensory desmitis along with early and advanced clinical signs of PPID."
Hofberger S, Gauff F, Licka T
Suspensory ligament degeneration associated with pituitary pars intermedia dysfunction in horses
Vet J. 2015 Mar;203(3):348-50. doi: 10.1016/j.tvjl.2014.12.037. Epub 2015 Jan 6
DeepDyve
Light - daylight, blue light
In 2021 Researchers at University College Dublin in collaboration with Gluck Equine Research Centre in Kentucky were recruiting horses with PPID and hypertrichosis in the northern hemisphere to take part in a large scale study to investigate whether blue light treatment has an effect on PPID horses over 12 months. An earlier study (Miller et al 2022 below) found that PPID horses fitted with Equilume blue light masks which stimulate daylight had lighter winter coats and slower hair growth than untreated horses. Applications to take part in the research closed on 22 October 2021.
Blue light may hold the key for improving coat condition in horses with PPID
Miller AB, Murphy BA, Adams AA
Impact of blue light therapy on plasma adrenocorticotropic hormone (ACTH) and hypertrichosis in horses with pituitary pars intermedia dysfunction
Domestic Animal Endocrinology Jan 2022 Vol 78 106651. Published online 27 July 2021. https://doi.org/10.1016/j.domaniend.2021.106651
Key points:
Artificial lengthening of the photoperiod did not affect ACTH in this study.
PPID horses receiving blue light therapy had lighter hair weights than controls.
Blue light treatment appears to reduce hypertrichosis severity in horses with PPID.
O'Brien C, Darcy-Dunne MR, Murphy BA
The effects of extended photoperiod and warmth on hair growth in ponies and horses at different times of year
PLoS ONE 14 Jan 2020 15(1) e0227115. https://doi.org/10.1371/journal. pone.0227115
In 2021 Researchers at University College Dublin in collaboration with Gluck Equine Research Centre in Kentucky were recruiting horses with PPID and hypertrichosis in the northern hemisphere to take part in a large scale study to investigate whether blue light treatment has an effect on PPID horses over 12 months. An earlier study (Miller et al 2022 below) found that PPID horses fitted with Equilume blue light masks which stimulate daylight had lighter winter coats and slower hair growth than untreated horses. Applications to take part in the research closed on 22 October 2021.
Blue light may hold the key for improving coat condition in horses with PPID
Miller AB, Murphy BA, Adams AA
Impact of blue light therapy on plasma adrenocorticotropic hormone (ACTH) and hypertrichosis in horses with pituitary pars intermedia dysfunction
Domestic Animal Endocrinology Jan 2022 Vol 78 106651. Published online 27 July 2021. https://doi.org/10.1016/j.domaniend.2021.106651
Key points:
Artificial lengthening of the photoperiod did not affect ACTH in this study.
PPID horses receiving blue light therapy had lighter hair weights than controls.
Blue light treatment appears to reduce hypertrichosis severity in horses with PPID.
O'Brien C, Darcy-Dunne MR, Murphy BA
The effects of extended photoperiod and warmth on hair growth in ponies and horses at different times of year
PLoS ONE 14 Jan 2020 15(1) e0227115. https://doi.org/10.1371/journal. pone.0227115
Lipids
M Coleman, N Cohen, R Walzem, J Sucholdolski, T Minamoto, A Kieffer, J Mawyer, J Belknap, L
Bramlage, S Eades, B Fraley, H Galantino-Homer, R Geor, R Hunt, M McCue, W McIlwraith, R
Moore, J Peroni, H Townsend, N White
Lipid Profiling in Laminitic, Obese, and Healthy Horses
3rd Equine Endocrine Summit 2014 p 34
Lipoproteins are water-miscible macromolecules enabling the transport of lipids in blood.
Lipoprotein profiling was performed on blood from 9 laminitic horses (laminitis episode within previous 4 weeks) and 11 non-laminitic horses.
8/9 laminitic horses were obese, 2/11 non-laminitic horses were obese.
High density lipoproteins (HDL) and total lipoprotein were significantly greater for obese horses than for non-obese horses.
M Coleman, N Cohen, R Walzem, J Sucholdolski, T Minamoto, A Kieffer, J Mawyer, J Belknap, L
Bramlage, S Eades, B Fraley, H Galantino-Homer, R Geor, R Hunt, M McCue, W McIlwraith, R
Moore, J Peroni, H Townsend, N White
Lipid Profiling in Laminitic, Obese, and Healthy Horses
3rd Equine Endocrine Summit 2014 p 34
Lipoproteins are water-miscible macromolecules enabling the transport of lipids in blood.
Lipoprotein profiling was performed on blood from 9 laminitic horses (laminitis episode within previous 4 weeks) and 11 non-laminitic horses.
8/9 laminitic horses were obese, 2/11 non-laminitic horses were obese.
High density lipoproteins (HDL) and total lipoprotein were significantly greater for obese horses than for non-obese horses.
Lipopolysaccharides (LPS)/Endotoxins
Lipopolysaccharides (LPS), often referred to as endotoxins, are found in the outer membrane of Gram-negative bacteria such as Salmonella and Escherichia, and are released during death or excessive growth of bacteria. LPS can stimulate a low grade inflammatory response by the immune system. LPS is an exogenous pyrogen, i.e. it induces fever.
Tadros EM, Frank N, De Witte FG, Boston RC
Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome
Am J Vet Res. 2013 Jul;74(7):1020-9
6 healthy horses and 6 EMS horses were given treatments of an IV infusion of lipopolysaccharide (LPS) (20 ng/kg) in saline and saline alone. Baseline insulin-modified frequently sampled IV glucose tolerance tests were carried out 27 hours before and 0.5 and 21 hours after treatment. LPS treatment decreased insulin sensitivity and increased area under the serum insulin concentration curve in both healthy and EMS horses, compared to saline only treatment. Horses with EMS had a greater increase in the area under the plasma glucose curve following LPS treatment than healthy horses. "Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time".
"CONCLUSIONS AND CLINICAL RELEVANCE:Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations".
Tadros EM, Frank N, Donnell RL
Effects of equine metabolic syndrome on inflammatory responses of horses to intravenous lipopolysaccharide infusion
Am J Vet Res. 2013 Jul;74(7):1010-9
"Results supported the hypothesis that EMS affects horses' inflammatory responses to endotoxin by prolonging cytokine expression in circulating leukocytes. These findings are relevant to the association between obesity and laminitis in horses with EMS."
Tóth F, Frank N, Elliott SB, Geor RJ, Boston RC
Effects of an intravenous endotoxin challenge on glucose and insulin dynamics in horses
Am J Vet Res. 2008 Jan;69(1):82-8
16 horses had IV LPS or saline one week, then IV saline or LPS the following week in a crossover study.
13/16 horses showed mild colic and leukopenia following LPS treatment.
Baseline FSIGT tests showed "mean +/- SD insulin sensitivity was 2.9 +/- 1.9 x 10(4) L x min(1) x mU(1); this significantly decreased to 0.9 +/- 0.9 x 10(4) L x min(1) x mU(1) 24 hours after treatment (69% reduction) and was 1.5 +/- 0.9 x 10(4) L x min(1) x mU(1) 48 hours after treatment. At baseline, mean +/- SD acute insulin response to glucose was 520 +/- 196 mU x min x L(1); this significantly increased to 938 +/- 620 mU x min x L(1) (80% increase) and 755 +/- 400 mU x min x L(1) (45% increase) at 24 and 48 hours after LPS treatment, respectively.
Conclusions: "insulin sensitivity was decreased for 24 hours after IV injection of LPS, and affected horses had a compensatory pancreatic response. These disturbances in glucose and insulin dynamics may contribute to development of laminitis in horses."
Brooks AC, Menzies-Gow NJ, Wheeler-Jones C, Bailey SR, Cunningham FM, Elliott J
Endotoxin-induced activation of equine platelets: evidence for direct activation of p38 MAPK pathways and vasoactive mediator production
Inflamm Res. 2007 Apr;56(4):154-61
Sprouse RF, Garner HE, Green EM
Plasma endotoxin levels in horses subjected to carbohydrate induced laminitis
Equine Vet J. 1987 Jan;19(1):25-8
13/20 horses developed Obel grade 3 laminitis after carbohydrate overload, and of these, 11 had increases in plasma endotoxin from control levels of less than 0.1 ng/litre to values ranging from 2.4 to 81.53 ng/litre.
Mani, Venkatesh
Understanding intestinal lipopolysaccharide permeability and associated inflammation
2012 PhD thesis Iowa State University
Research carried out on pigs.
Do lipopolysaccharides cause or contribute to laminitis?
Lipopolysaccharide (LPS), an endotoxin, is a major component of gram negative bacteria. Researchers have not been able to induce laminitis by administering LPS.
Tadros EM, Frank N
Effects of continuous or intermittent lipopolysaccharide administration for 48 hours on the systemic inflammatory response in horses
Am J Vet Res. 2012 Sep;73(9):1394-402
LPS-C - 4 healthy horses received a total dose of 80 μg LPS via constant rate infusion (80 ml/h) for 48 hours;
LPS-B - 4 healthy horses received a total dose of 80 μg LPS as 8 bolus IV injections of 10 μg every 6 hours;
CON - healthy horses received saline via constant rate infusion )80 ml/h) for 48 hours (controls).
All LPS treated horses had signs of depression and mild colic which abated, and increased expression of interleukin-1β, interleukin-6, and interleukin-8 (results were not significantly different between constant rate or bolus groups) Cytokine expression was significantly higher on day 1 than day 2 of LPS treatment. Interleukin-1β expression was positively correlated with rectal temperature and expression of other cytokines. No signs of laminitis were seen.
Glucose and insulin dynamics did not differ significantly between groups.
"Conclusions: Horses developed LPS tolerance within approximately 24 hours after administration was started, and the method of LPS administration did not affect the magnitude or duration of systemic inflammation. Laminitis was not induced in horses."
Tadros EM, Frank N, Newkirk KM, Donnell RL, Horohov DW
Effects of a "two-hit" model of organ damage on the systemic inflammatory response and development of laminitis in horses
Vet Immunol Immunopathol. 2012 Nov 15;150(1-2):90-100 Epub 2012 Sep 7
24 horses due for euthanasia received either IV LPS (5 ng/kg/h for 8 hours) or saline. 24 hours later they were all given 5 g/kg BW oligofructose by nasogastric tube (2,500 g OF/500 kg horse). Horses were euthanised when they developed Obel grade 2 laminitis or 48 hours after being given OF if they hadn't developed laminitis.
Both LPS and OF independently increased temperature, heart rate, respiratory rate and blood interleukin (IL)-1β gene expression, but this was not worse in LPS treated horses.
63% of horses developed laminitis, and the Incidence of laminitis was no different between treatment groups.
Horses that developed laminitis had greater area under the blood IL-1β expression curves and liver and lung gene expression of IL-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-α than horses that didn't develop laminitis following OF administration.
Conclusion: Endotoxin pretreatment did not enhance responses to OF. Systemic inflammation was more pronounced in horses that developed laminitis, and tissue-generated inflammatory mediators could pose a greater risk than those produced by circulating leukocytes.
Tadros EM, Frank N
Endotoxemia as a predisposing factor for laminitis in horses
ACVIM 2012
Katz LM, Bailey SR
A review of recent advances and current hypotheses on the pathogenesis of acute laminitis
Equine Veterinary Journal Volume 44, Issue 6, pages 752–761, November 2012
Hunt RJ, Allen D, Moore JN
Effect of endotoxin administration on equine digital hemodynamics and starling forces
Am J Vet Res. 1990 Nov;51(11):1703-7
"Although marked alterations in vascular function are seen after administration of endotoxin, these changes do not parallel those documented in association with experimentally induced laminitis."
Although administration of LPS did not cause laminitis, pretreatment with LPS did increase the incidence of laminitis when horses were given oligofructose, compared to oligofructose only:
Tóth F, Frank N, Chameroy KA, Bostont RC
Effects of endotoxaemia and carbohydrate overload on glucose and insulin dynamics and the development of laminitis in horses
Equine Vet J. 2009 Dec;41(9):852-8
3 groups of 8 horses:
LPS - 8 hours of 7.5 ng/kg BW/hour IV continuous rate infusion;
OF - 5 g/kg BW oligofructose by nasogastric tube (so 2,500 grams oligofructose for a 500 kg horse);
LPS/OF - LPS followed 16 hours later by OF (presumably administered as above?).
FSIGT was carried out 24 hours before and 48 hours after treatment.
LPS - developed leucopenia and induced clinical signs consistent with systemic inflammation.Mean acute insulin response to glucose increased. 0/8 horses developed clinical laminitis.
OF - induced clinical signs consistent with systemic inflammation. 2/8 horses developed clinical laminitis.
LPS/OF - developed leucopenia and induced clinical signs consistent with systemic inflammation.Mean acute insulin response to glucose increased. 5/8 horses developed clinical laminitis.
Insulin sensitivity signficantly decreased over time but was not significantly different between groups.
"Conclusions: Endotoxaemia and carbohydrate overload reduce insulin sensitivity in horses. Endotoxin pretreatment does not affect the alterations in glucose metabolism induced by carbohydrate overload."
Bailey SR, Adair HS, Reinemeyer CR, Morgan SJ, Brooks AC, Longhofer SL, Elliott J
Plasma concentrations of endotoxin and platelet activation in the developmental stage of oligofructose-induced laminitis
Vet Immunol Immunopathol. 2009 Jun 15;129(3-4):167-73. Epub 2008 Nov 7
"Absorption of endotoxin (lipopolysaccharide; LPS) into the plasma has been observed in one experimental model of laminitis, but does not cause laminitis when administered alone. Thus, the potential role of endotoxin is unclear. Platelet activation has previously been demonstrated in the developmental stage of laminitis.""These data indicate that small quantities of endotoxin may move into the circulation from the large intestine after the sharp decrease in pH that occurs as a result of carbohydrate fermentation. Correlating these findings with in vitro studies suggests that LPS may primarily activate platelets, leading indirectly to the activation of leukocytes. Therefore, endotoxin may contribute in the initiation of the early inflammatory changes observed in experimental models of acute laminitis."
Administration of LPS has affected behaviour, haematologic and coagulation values, increased heart rate and body temperature and caused decreased digital blood flow and laminar perfusion (and appeared to cause clinical signs of laminitis!):
Duncan SG, Meyers KM, Reed SM, Grant B
Alterations in coagulation and hemograms of horses given endotoxins for 24 hours via hepatic portal infusions
Am J Vet Res. 1985 Jun;46(6):1287-93
Horses given infusions of 1 µg/kg BW LPS into the hepatic portal vein per hour for 24 hours (12 mg LPS/500 kg horse) collapsed in the first hour (without an accompanying hypotension), had decreased neutrophils and increased circulating fibrinogen, and a shortening of the recalcification tests, 1-stage prothrombin time, and activated partial thromboplastin time. All horses showed signs of hoof discomfort and "either stood with the 4 feet together beneath the body or continually shifted their weight from one front foot to the other. Hoof temperature decreased approximately 3 degrees (C) during this time and remained decreased for the duration of the experiment".
Ingle-Fehr JE, Baxter GM
Evaluation of digital and laminar blood flow in horses given a low dose of endotoxin
Am J Vet Res. 1998 Feb;59(2):192-6
6 healthy horses were given IV 0.1 µg/kg BW endotoxin (50 µg/500 kg horse). Compared to controls, endotoxin treatment caused a significant decrease in digital blood flow, increases in heart rate and body temperature, and decreased laminar perfusion.
It is hypothesised that LPS is not able to induce laminitis on its own, but plays an important role in the development of laminitis.
Patan-Zugaj B, Gauff FC, Licka TF
Effects of the addition of endotoxin during perfusion of isolated forelimbs of equine cadavers
Am J Vet Res. 2012 Sep;73(9):1462-8
Forelimbs from slaughtered horses were perfused with 80 ng LPS/l for 10 hours, and increased width and other changes were seen in the laminae.
Reisinger N, Schaumberger S, Nagl V, Hessenberger S, Schatzmayr G
Milk Thistle Extract and Silymarin Inhibit Lipopolysaccharide Induced Lamellar Separation of Hoof Explants in Vitro
Toxins (Basel). 2014 Oct; 6(10): 2962–2974. Published online 2014 Oct 6
Treating endotoxaemia
Polymyxin B (PMB) is known to bind and neutralize endotoxins, and has been used on horses:
Morresey PR, Mackay RJ
Endotoxin-neutralizing activity of polymyxin B in blood after IV administration in horses
Am J Vet Res. 2006 Apr;67(4):642-7
5 healthy horses were given:
1. 1 mg of polymyxin B (PMB)/kg BW was given IV.
2. 1 mg of PMB/kg BW was given IV every 8 hours for 5 treatments.
Conclusions: PMB given as multiple infusions to healthy horses did not accumulate in the vascular compartment and appeared safe. Results support repeated IV use of 1 mg of polymyxin B/kg at 8-hour intervals as treatment for endotoxemia.
Barton MH, Parviainen A, Norton N
Polymyxin B protects horses against induced endotoxaemia in vivo
Equine Vet J. 2004 Jul;36(5):397-401
4 groups of 6 healthy horses received 20 ng endotoxin/kg BW IV plus one of:
5000 u PMB/kg BW IV 30 mins before endotoxin infusion;
5000 u PMB/kg BW IV 30 mins after endotoxin infusion;
1000 u PMB/kg BW IV 30 mins prior to endotoxin infusion;
saline (controls).
Neutrophil count, serum tumour necrosis factor (TNF) activity, plasma thromboxane B2 concentration and urine GGT:creatinine ratio were measured.
PMB treatment before or after endotoxin infusion significantly reduced fever, tachycardia and serum TNS, compared to controls. Horses that received 5000 u PMB/kg BW IV 30 mins before endotoxin infusion had the best response.
Conclusion: "PMB may be a safe and effective treatment of endotoxaemia, even when administered after onset. Although nephrotoxicity was not demonstrated with this model, caution should be exercised when using PMB in azotaemic patients".
Schwarz B, Anen C, van den Hoven R
Preliminary Data of a Retrospective Study on Neurological Side Effects after Administration of Polymyxin B to Endotoxaemic Horses
Equine Veterinary Journal Special Issue: Clinical Research Abstracts of the British Equine Veterinary Association Congress 2013
Volume 45, Issue Supplement S44, pages 18–19, September 2013
6/18 horses being treated with 5000 iu polymyxin/kg BW IV every 8 hours for endotoxaemia showed a self-limiting weak ataxic gait between 24 and 36 hours after starting treatment. Concurrent use of neostigmine may have potentiated PBD side effects.
MacKay RJ, Clark CK, Logdberg L, Lake P
Effect of a conjugate of polymyxin B-dextran 70 in horses with experimentally induced endotoxemia
Am J Vet Res. 1999 Jan;60(1):68-75
"When used in combination with a cyclooxygenase-inhibiting drug, PBD (polymyxin B-dextran 70) has potential for treatment of horses with endotoxemia".
Reisinger N, Schaumberger S, Nagl V, Hessenberger S, Schatzmayr G
Milk Thistle Extract and Silymarin Inhibit Lipopolysaccharide Induced Lamellar Separation of Hoof Explants in Vitro
Toxins (Basel). 2014 Oct; 6(10): 2962–2974. Published online 2014 Oct 6
Lipopolysaccharides (LPS), often referred to as endotoxins, are found in the outer membrane of Gram-negative bacteria such as Salmonella and Escherichia, and are released during death or excessive growth of bacteria. LPS can stimulate a low grade inflammatory response by the immune system. LPS is an exogenous pyrogen, i.e. it induces fever.
Tadros EM, Frank N, De Witte FG, Boston RC
Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome
Am J Vet Res. 2013 Jul;74(7):1020-9
6 healthy horses and 6 EMS horses were given treatments of an IV infusion of lipopolysaccharide (LPS) (20 ng/kg) in saline and saline alone. Baseline insulin-modified frequently sampled IV glucose tolerance tests were carried out 27 hours before and 0.5 and 21 hours after treatment. LPS treatment decreased insulin sensitivity and increased area under the serum insulin concentration curve in both healthy and EMS horses, compared to saline only treatment. Horses with EMS had a greater increase in the area under the plasma glucose curve following LPS treatment than healthy horses. "Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time".
"CONCLUSIONS AND CLINICAL RELEVANCE:Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations".
Tadros EM, Frank N, Donnell RL
Effects of equine metabolic syndrome on inflammatory responses of horses to intravenous lipopolysaccharide infusion
Am J Vet Res. 2013 Jul;74(7):1010-9
"Results supported the hypothesis that EMS affects horses' inflammatory responses to endotoxin by prolonging cytokine expression in circulating leukocytes. These findings are relevant to the association between obesity and laminitis in horses with EMS."
Tóth F, Frank N, Elliott SB, Geor RJ, Boston RC
Effects of an intravenous endotoxin challenge on glucose and insulin dynamics in horses
Am J Vet Res. 2008 Jan;69(1):82-8
16 horses had IV LPS or saline one week, then IV saline or LPS the following week in a crossover study.
13/16 horses showed mild colic and leukopenia following LPS treatment.
Baseline FSIGT tests showed "mean +/- SD insulin sensitivity was 2.9 +/- 1.9 x 10(4) L x min(1) x mU(1); this significantly decreased to 0.9 +/- 0.9 x 10(4) L x min(1) x mU(1) 24 hours after treatment (69% reduction) and was 1.5 +/- 0.9 x 10(4) L x min(1) x mU(1) 48 hours after treatment. At baseline, mean +/- SD acute insulin response to glucose was 520 +/- 196 mU x min x L(1); this significantly increased to 938 +/- 620 mU x min x L(1) (80% increase) and 755 +/- 400 mU x min x L(1) (45% increase) at 24 and 48 hours after LPS treatment, respectively.
Conclusions: "insulin sensitivity was decreased for 24 hours after IV injection of LPS, and affected horses had a compensatory pancreatic response. These disturbances in glucose and insulin dynamics may contribute to development of laminitis in horses."
Brooks AC, Menzies-Gow NJ, Wheeler-Jones C, Bailey SR, Cunningham FM, Elliott J
Endotoxin-induced activation of equine platelets: evidence for direct activation of p38 MAPK pathways and vasoactive mediator production
Inflamm Res. 2007 Apr;56(4):154-61
Sprouse RF, Garner HE, Green EM
Plasma endotoxin levels in horses subjected to carbohydrate induced laminitis
Equine Vet J. 1987 Jan;19(1):25-8
13/20 horses developed Obel grade 3 laminitis after carbohydrate overload, and of these, 11 had increases in plasma endotoxin from control levels of less than 0.1 ng/litre to values ranging from 2.4 to 81.53 ng/litre.
Mani, Venkatesh
Understanding intestinal lipopolysaccharide permeability and associated inflammation
2012 PhD thesis Iowa State University
Research carried out on pigs.
Do lipopolysaccharides cause or contribute to laminitis?
Lipopolysaccharide (LPS), an endotoxin, is a major component of gram negative bacteria. Researchers have not been able to induce laminitis by administering LPS.
Tadros EM, Frank N
Effects of continuous or intermittent lipopolysaccharide administration for 48 hours on the systemic inflammatory response in horses
Am J Vet Res. 2012 Sep;73(9):1394-402
LPS-C - 4 healthy horses received a total dose of 80 μg LPS via constant rate infusion (80 ml/h) for 48 hours;
LPS-B - 4 healthy horses received a total dose of 80 μg LPS as 8 bolus IV injections of 10 μg every 6 hours;
CON - healthy horses received saline via constant rate infusion )80 ml/h) for 48 hours (controls).
All LPS treated horses had signs of depression and mild colic which abated, and increased expression of interleukin-1β, interleukin-6, and interleukin-8 (results were not significantly different between constant rate or bolus groups) Cytokine expression was significantly higher on day 1 than day 2 of LPS treatment. Interleukin-1β expression was positively correlated with rectal temperature and expression of other cytokines. No signs of laminitis were seen.
Glucose and insulin dynamics did not differ significantly between groups.
"Conclusions: Horses developed LPS tolerance within approximately 24 hours after administration was started, and the method of LPS administration did not affect the magnitude or duration of systemic inflammation. Laminitis was not induced in horses."
Tadros EM, Frank N, Newkirk KM, Donnell RL, Horohov DW
Effects of a "two-hit" model of organ damage on the systemic inflammatory response and development of laminitis in horses
Vet Immunol Immunopathol. 2012 Nov 15;150(1-2):90-100 Epub 2012 Sep 7
24 horses due for euthanasia received either IV LPS (5 ng/kg/h for 8 hours) or saline. 24 hours later they were all given 5 g/kg BW oligofructose by nasogastric tube (2,500 g OF/500 kg horse). Horses were euthanised when they developed Obel grade 2 laminitis or 48 hours after being given OF if they hadn't developed laminitis.
Both LPS and OF independently increased temperature, heart rate, respiratory rate and blood interleukin (IL)-1β gene expression, but this was not worse in LPS treated horses.
63% of horses developed laminitis, and the Incidence of laminitis was no different between treatment groups.
Horses that developed laminitis had greater area under the blood IL-1β expression curves and liver and lung gene expression of IL-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-α than horses that didn't develop laminitis following OF administration.
Conclusion: Endotoxin pretreatment did not enhance responses to OF. Systemic inflammation was more pronounced in horses that developed laminitis, and tissue-generated inflammatory mediators could pose a greater risk than those produced by circulating leukocytes.
Tadros EM, Frank N
Endotoxemia as a predisposing factor for laminitis in horses
ACVIM 2012
Katz LM, Bailey SR
A review of recent advances and current hypotheses on the pathogenesis of acute laminitis
Equine Veterinary Journal Volume 44, Issue 6, pages 752–761, November 2012
Hunt RJ, Allen D, Moore JN
Effect of endotoxin administration on equine digital hemodynamics and starling forces
Am J Vet Res. 1990 Nov;51(11):1703-7
"Although marked alterations in vascular function are seen after administration of endotoxin, these changes do not parallel those documented in association with experimentally induced laminitis."
Although administration of LPS did not cause laminitis, pretreatment with LPS did increase the incidence of laminitis when horses were given oligofructose, compared to oligofructose only:
Tóth F, Frank N, Chameroy KA, Bostont RC
Effects of endotoxaemia and carbohydrate overload on glucose and insulin dynamics and the development of laminitis in horses
Equine Vet J. 2009 Dec;41(9):852-8
3 groups of 8 horses:
LPS - 8 hours of 7.5 ng/kg BW/hour IV continuous rate infusion;
OF - 5 g/kg BW oligofructose by nasogastric tube (so 2,500 grams oligofructose for a 500 kg horse);
LPS/OF - LPS followed 16 hours later by OF (presumably administered as above?).
FSIGT was carried out 24 hours before and 48 hours after treatment.
LPS - developed leucopenia and induced clinical signs consistent with systemic inflammation.Mean acute insulin response to glucose increased. 0/8 horses developed clinical laminitis.
OF - induced clinical signs consistent with systemic inflammation. 2/8 horses developed clinical laminitis.
LPS/OF - developed leucopenia and induced clinical signs consistent with systemic inflammation.Mean acute insulin response to glucose increased. 5/8 horses developed clinical laminitis.
Insulin sensitivity signficantly decreased over time but was not significantly different between groups.
"Conclusions: Endotoxaemia and carbohydrate overload reduce insulin sensitivity in horses. Endotoxin pretreatment does not affect the alterations in glucose metabolism induced by carbohydrate overload."
Bailey SR, Adair HS, Reinemeyer CR, Morgan SJ, Brooks AC, Longhofer SL, Elliott J
Plasma concentrations of endotoxin and platelet activation in the developmental stage of oligofructose-induced laminitis
Vet Immunol Immunopathol. 2009 Jun 15;129(3-4):167-73. Epub 2008 Nov 7
"Absorption of endotoxin (lipopolysaccharide; LPS) into the plasma has been observed in one experimental model of laminitis, but does not cause laminitis when administered alone. Thus, the potential role of endotoxin is unclear. Platelet activation has previously been demonstrated in the developmental stage of laminitis.""These data indicate that small quantities of endotoxin may move into the circulation from the large intestine after the sharp decrease in pH that occurs as a result of carbohydrate fermentation. Correlating these findings with in vitro studies suggests that LPS may primarily activate platelets, leading indirectly to the activation of leukocytes. Therefore, endotoxin may contribute in the initiation of the early inflammatory changes observed in experimental models of acute laminitis."
Administration of LPS has affected behaviour, haematologic and coagulation values, increased heart rate and body temperature and caused decreased digital blood flow and laminar perfusion (and appeared to cause clinical signs of laminitis!):
Duncan SG, Meyers KM, Reed SM, Grant B
Alterations in coagulation and hemograms of horses given endotoxins for 24 hours via hepatic portal infusions
Am J Vet Res. 1985 Jun;46(6):1287-93
Horses given infusions of 1 µg/kg BW LPS into the hepatic portal vein per hour for 24 hours (12 mg LPS/500 kg horse) collapsed in the first hour (without an accompanying hypotension), had decreased neutrophils and increased circulating fibrinogen, and a shortening of the recalcification tests, 1-stage prothrombin time, and activated partial thromboplastin time. All horses showed signs of hoof discomfort and "either stood with the 4 feet together beneath the body or continually shifted their weight from one front foot to the other. Hoof temperature decreased approximately 3 degrees (C) during this time and remained decreased for the duration of the experiment".
Ingle-Fehr JE, Baxter GM
Evaluation of digital and laminar blood flow in horses given a low dose of endotoxin
Am J Vet Res. 1998 Feb;59(2):192-6
6 healthy horses were given IV 0.1 µg/kg BW endotoxin (50 µg/500 kg horse). Compared to controls, endotoxin treatment caused a significant decrease in digital blood flow, increases in heart rate and body temperature, and decreased laminar perfusion.
It is hypothesised that LPS is not able to induce laminitis on its own, but plays an important role in the development of laminitis.
Patan-Zugaj B, Gauff FC, Licka TF
Effects of the addition of endotoxin during perfusion of isolated forelimbs of equine cadavers
Am J Vet Res. 2012 Sep;73(9):1462-8
Forelimbs from slaughtered horses were perfused with 80 ng LPS/l for 10 hours, and increased width and other changes were seen in the laminae.
Reisinger N, Schaumberger S, Nagl V, Hessenberger S, Schatzmayr G
Milk Thistle Extract and Silymarin Inhibit Lipopolysaccharide Induced Lamellar Separation of Hoof Explants in Vitro
Toxins (Basel). 2014 Oct; 6(10): 2962–2974. Published online 2014 Oct 6
Treating endotoxaemia
Polymyxin B (PMB) is known to bind and neutralize endotoxins, and has been used on horses:
Morresey PR, Mackay RJ
Endotoxin-neutralizing activity of polymyxin B in blood after IV administration in horses
Am J Vet Res. 2006 Apr;67(4):642-7
5 healthy horses were given:
1. 1 mg of polymyxin B (PMB)/kg BW was given IV.
2. 1 mg of PMB/kg BW was given IV every 8 hours for 5 treatments.
Conclusions: PMB given as multiple infusions to healthy horses did not accumulate in the vascular compartment and appeared safe. Results support repeated IV use of 1 mg of polymyxin B/kg at 8-hour intervals as treatment for endotoxemia.
Barton MH, Parviainen A, Norton N
Polymyxin B protects horses against induced endotoxaemia in vivo
Equine Vet J. 2004 Jul;36(5):397-401
4 groups of 6 healthy horses received 20 ng endotoxin/kg BW IV plus one of:
5000 u PMB/kg BW IV 30 mins before endotoxin infusion;
5000 u PMB/kg BW IV 30 mins after endotoxin infusion;
1000 u PMB/kg BW IV 30 mins prior to endotoxin infusion;
saline (controls).
Neutrophil count, serum tumour necrosis factor (TNF) activity, plasma thromboxane B2 concentration and urine GGT:creatinine ratio were measured.
PMB treatment before or after endotoxin infusion significantly reduced fever, tachycardia and serum TNS, compared to controls. Horses that received 5000 u PMB/kg BW IV 30 mins before endotoxin infusion had the best response.
Conclusion: "PMB may be a safe and effective treatment of endotoxaemia, even when administered after onset. Although nephrotoxicity was not demonstrated with this model, caution should be exercised when using PMB in azotaemic patients".
Schwarz B, Anen C, van den Hoven R
Preliminary Data of a Retrospective Study on Neurological Side Effects after Administration of Polymyxin B to Endotoxaemic Horses
Equine Veterinary Journal Special Issue: Clinical Research Abstracts of the British Equine Veterinary Association Congress 2013
Volume 45, Issue Supplement S44, pages 18–19, September 2013
6/18 horses being treated with 5000 iu polymyxin/kg BW IV every 8 hours for endotoxaemia showed a self-limiting weak ataxic gait between 24 and 36 hours after starting treatment. Concurrent use of neostigmine may have potentiated PBD side effects.
MacKay RJ, Clark CK, Logdberg L, Lake P
Effect of a conjugate of polymyxin B-dextran 70 in horses with experimentally induced endotoxemia
Am J Vet Res. 1999 Jan;60(1):68-75
"When used in combination with a cyclooxygenase-inhibiting drug, PBD (polymyxin B-dextran 70) has potential for treatment of horses with endotoxemia".
Reisinger N, Schaumberger S, Nagl V, Hessenberger S, Schatzmayr G
Milk Thistle Extract and Silymarin Inhibit Lipopolysaccharide Induced Lamellar Separation of Hoof Explants in Vitro
Toxins (Basel). 2014 Oct; 6(10): 2962–2974. Published online 2014 Oct 6
Liver
PPID and the liver
Horses with PPID may have raised liver enzymes:
McFarlane D
Equine pituitary pars intermedia dysfunction
Vet Clin North Am Equine Pract. 2011 Apr;27(1):93-113 (PubMed)
Clinical Pathology - "Other abnormalities in horses with PPID may include increased liver enzyme activities, which may be an indication of steroid-induced hepatopathy."
Glover CM, Miller LM, Dybdal NO, Lopez A, Duckett WM, McFarlane D
Extrapituitary and Pituitary Pathological Findings in Horses with Pituitary Pars Intermedia Dysfunction: A Retrospective Study
Journal of Equine Veterinary Science - March 2009 Vol. 29, Issue 3, Pages 146-153
At post mortem, swollen and vacuolated hepatocytes (consistent with steroid-induced hepatopathy) were found in 19/26 horses with PPID, compared to 3/18 controls. Of the 19 horses with liver abnormalities, 10 had adrenocortical hyperplasia.
Hepatic Insulin Clearance
The liver is the primary site of insulin clearance - approximately 70% of insulin secreted by the pancreas is cleared by the liver.
The amount of insulin in the circulation is the result of the amount of insulin secreted from the beta-cells of the pancreas AND the amount of insulin cleared from the circulation by the liver.
Total insulin in circulation = insulin secreted from pancreas - insulin cleared by liver.
Increased insulin secretion and/or decreased insulin clearance will lead to hyperinsulinaemia. Hyperinsulinaemia in horses is known to cause laminitis.
Equine Vet J. 2010 Mar;42(2):149-55.
Measurement of C-peptide concentrations and responses to somatostatin, glucose infusion, and insulin resistance in horses
Tóth F, Frank N, Martin-Jiménez T, Elliott SB, Geor RJ, Boston RC
"Hyperinsulinaemia in insulin resistant horses may be associated with both increased insulin secretion and decreased insulin clearance."
See also C-peptide.
Insulin resistance, obesity and Non Alcoholic Fatty Liver Disease (NAFLD) in the liver cause insulin clearance to be reduced.
Hepatic Insulin Resistance
Nicholas Frank
Equine Metabolic Syndrome
Vet Clin Equine 27 (2011) 73-92
Above normal GGT and AST are found in some horses with EMS, and fat accumulation in liver cells is commonly seen in EMS horses at post mortem, suggesting that hepatic lipidosis may develop in some EMS horses, similar to non-alcoholic fatty liver disease (NAFLD) being associated with insulin resistance in humans.
Obesity (in humans) increases inflammation and activation of immune pathways which can affects liver function.
Liver samples from laminitic horses and obese horses with clinical signs of metabolic disease were found to have increased key mediators of the Toll-like Receptor Signaling Pathway:
Stokes AM, McGeachy M, Carlisle K, Garza F, Keowen ML
Potential role of the toll-like receptor signaling pathway in equine laminitis
FASEB J.April 200923 (Meeting Abstract Supplement) 929.1
Non-Alcoholic Fatty Liver Disease in humans
In human with NAFLD, high levels of fat in the liver are associated with insulin resistance; weight loss and exercise have been shown to reduce liver fat accumulation and increase insulin sensitivity - see Genetics Links Nonalcoholic Fatty Liver Disease to Insulin Resistance.
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1709-15
Effect of liver fat on insulin clearance
Kotronen A, Vehkavaara S, Seppälä-Lindroos A, Bergholm R, Yki-Järvinen H
Liver enzymes AST and ALT are usually elevated, Alk P and GGT may also be elevated (ALT is not generally measured in horses) - see Am Fam Physician. 2006 Jun 1;73(11):1961-8. Nonalcoholic fatty liver disease. Bayard M, Holt J, Boroughs E.
Insulin clearance is decreased in NAFLD - the liver is the primary site of insulin clearance - see:
Diabetes Care. 2013 Apr;36(4):901-7
Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study
Lee CC, Haffner SM, Wagenknecht LE, Lorenzo C, Norris JM, Bergman RN, Stefanovski D, Anderson AM, Rotter JI, Goodarzi MO, Hanley AJ
Liver Disease
According to Andy Durham (Hepatic Insufficiency p 592 Equine Applied and Clinical Nutrition 2013), insulin resistance is a common feature of hepatic failure in horses
and in humans:
World J Hepatol. 2011 May 27; 3(5): 99–107
Insulin resistance and chronic liver disease
Takumi Kawaguchi, Eitaro Taniguchi, Minoru Itou, Masahiro Sakata, Shuji Sumie, and Michio Sata
Investigating Liver Disease - Liphook Equine Hospital
Liver disease in the horse: clinical signs and diagnostic aids - Michelle Henry Barton, May 2007, DVM360
Nutritional Guidance - Liver Disease - Spillers
Liver pathology/blood tests
DeNotta SL, Divers TJ.
Clinical Pathology in the Adult Sick Horse: The Gastrointestinal System and Liver.
Vet Clin North Am Equine Pract. 2020 Apr;36(1):105-120. doi: 10.1016/j.cveq.2019.11.004. Epub 2020 Jan 22. PMID: 31982231; PMCID: PMC7127838.
Iron overload and the liver
Iron Overload - Iron Disorders Institute
According to the Iron Disorders Institute, humans with iron overload are likely to have raised GGT possibly due to a fatty liver, and iron overload increases the risk of liver disease, metabolic syndrome and may accelerate neurodegenerative diseases. Symptoms of iron overload listed include: liver disease, chronic fatigue, joint pain, elevated blood sugar, elevated liver enzymes, diabetes mellitus.
PPID and the liver
Horses with PPID may have raised liver enzymes:
McFarlane D
Equine pituitary pars intermedia dysfunction
Vet Clin North Am Equine Pract. 2011 Apr;27(1):93-113 (PubMed)
Clinical Pathology - "Other abnormalities in horses with PPID may include increased liver enzyme activities, which may be an indication of steroid-induced hepatopathy."
Glover CM, Miller LM, Dybdal NO, Lopez A, Duckett WM, McFarlane D
Extrapituitary and Pituitary Pathological Findings in Horses with Pituitary Pars Intermedia Dysfunction: A Retrospective Study
Journal of Equine Veterinary Science - March 2009 Vol. 29, Issue 3, Pages 146-153
At post mortem, swollen and vacuolated hepatocytes (consistent with steroid-induced hepatopathy) were found in 19/26 horses with PPID, compared to 3/18 controls. Of the 19 horses with liver abnormalities, 10 had adrenocortical hyperplasia.
Hepatic Insulin Clearance
The liver is the primary site of insulin clearance - approximately 70% of insulin secreted by the pancreas is cleared by the liver.
The amount of insulin in the circulation is the result of the amount of insulin secreted from the beta-cells of the pancreas AND the amount of insulin cleared from the circulation by the liver.
Total insulin in circulation = insulin secreted from pancreas - insulin cleared by liver.
Increased insulin secretion and/or decreased insulin clearance will lead to hyperinsulinaemia. Hyperinsulinaemia in horses is known to cause laminitis.
Equine Vet J. 2010 Mar;42(2):149-55.
Measurement of C-peptide concentrations and responses to somatostatin, glucose infusion, and insulin resistance in horses
Tóth F, Frank N, Martin-Jiménez T, Elliott SB, Geor RJ, Boston RC
"Hyperinsulinaemia in insulin resistant horses may be associated with both increased insulin secretion and decreased insulin clearance."
See also C-peptide.
Insulin resistance, obesity and Non Alcoholic Fatty Liver Disease (NAFLD) in the liver cause insulin clearance to be reduced.
Hepatic Insulin Resistance
Nicholas Frank
Equine Metabolic Syndrome
Vet Clin Equine 27 (2011) 73-92
Above normal GGT and AST are found in some horses with EMS, and fat accumulation in liver cells is commonly seen in EMS horses at post mortem, suggesting that hepatic lipidosis may develop in some EMS horses, similar to non-alcoholic fatty liver disease (NAFLD) being associated with insulin resistance in humans.
Obesity (in humans) increases inflammation and activation of immune pathways which can affects liver function.
Liver samples from laminitic horses and obese horses with clinical signs of metabolic disease were found to have increased key mediators of the Toll-like Receptor Signaling Pathway:
Stokes AM, McGeachy M, Carlisle K, Garza F, Keowen ML
Potential role of the toll-like receptor signaling pathway in equine laminitis
FASEB J.April 200923 (Meeting Abstract Supplement) 929.1
Non-Alcoholic Fatty Liver Disease in humans
In human with NAFLD, high levels of fat in the liver are associated with insulin resistance; weight loss and exercise have been shown to reduce liver fat accumulation and increase insulin sensitivity - see Genetics Links Nonalcoholic Fatty Liver Disease to Insulin Resistance.
Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1709-15
Effect of liver fat on insulin clearance
Kotronen A, Vehkavaara S, Seppälä-Lindroos A, Bergholm R, Yki-Järvinen H
Liver enzymes AST and ALT are usually elevated, Alk P and GGT may also be elevated (ALT is not generally measured in horses) - see Am Fam Physician. 2006 Jun 1;73(11):1961-8. Nonalcoholic fatty liver disease. Bayard M, Holt J, Boroughs E.
Insulin clearance is decreased in NAFLD - the liver is the primary site of insulin clearance - see:
Diabetes Care. 2013 Apr;36(4):901-7
Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study
Lee CC, Haffner SM, Wagenknecht LE, Lorenzo C, Norris JM, Bergman RN, Stefanovski D, Anderson AM, Rotter JI, Goodarzi MO, Hanley AJ
Liver Disease
According to Andy Durham (Hepatic Insufficiency p 592 Equine Applied and Clinical Nutrition 2013), insulin resistance is a common feature of hepatic failure in horses
and in humans:
World J Hepatol. 2011 May 27; 3(5): 99–107
Insulin resistance and chronic liver disease
Takumi Kawaguchi, Eitaro Taniguchi, Minoru Itou, Masahiro Sakata, Shuji Sumie, and Michio Sata
Investigating Liver Disease - Liphook Equine Hospital
Liver disease in the horse: clinical signs and diagnostic aids - Michelle Henry Barton, May 2007, DVM360
Nutritional Guidance - Liver Disease - Spillers
Liver pathology/blood tests
DeNotta SL, Divers TJ.
Clinical Pathology in the Adult Sick Horse: The Gastrointestinal System and Liver.
Vet Clin North Am Equine Pract. 2020 Apr;36(1):105-120. doi: 10.1016/j.cveq.2019.11.004. Epub 2020 Jan 22. PMID: 31982231; PMCID: PMC7127838.
Iron overload and the liver
Iron Overload - Iron Disorders Institute
According to the Iron Disorders Institute, humans with iron overload are likely to have raised GGT possibly due to a fatty liver, and iron overload increases the risk of liver disease, metabolic syndrome and may accelerate neurodegenerative diseases. Symptoms of iron overload listed include: liver disease, chronic fatigue, joint pain, elevated blood sugar, elevated liver enzymes, diabetes mellitus.
Lungs/Respiratory Diseases/RAO
Research has shown that horses with PPID are more likely to suffer from opportunistic or secondary infections than healthy horses - infections such as skin infections, sinusitis, pneumonia/RAO and abscesses. Horses with PPID have been found to have evidence of RAO and chronic pneumonia at necropsy, without having shown clinical signs of pneumonia - see:
Glover CM, Miller LM, Dybdal NO, Lopez A, Duckett WM, McFarlane D
Extrapituitary and Pituitary Pathological Findings in Horses with Pituitary Pars Intermedia Dysfunction: A Retrospective Study
Journal of Equine Veterinary Science - March 2009 Vol. 29, Issue 3, Pages 146-153
At necropsy, healthy controls were compared to age-matched horses with PPID (horses were considered to have PPID if they showed clinical signs and had pars intermedia adenomas/hyperplasia).
The main histopathologic findings in the lungs of horses with PPID were bronchiolitis (indicative of RAO/COPD), and bronchointerstitial inflammation (indicative of pneumonia).
15/24 (62.5%) horses with PPID showed two or more histological changes consistent with bronchiolitis (RAO), including "bronchiolar mucus with or without cellular debris, bronchiolar epithelial hyperplasia, peribronchiolar inflammation, and peribronchiolar fibrosis", compared to 2/9 (22.2%) age-matched controls.
10/24 (41.6%) horses with PPID showed moderate to severe bronchointerstitial inflammation, consistent with pneumonia, compared to 0/9 age-matched controls.
Horses with PPID had a greater overall lung severity score than age-matched controls.
The research suggests that increased levels of immune-suppressing hormones such as alpha-MSH, beta-endorphin and cortisol may make horses with PPID more prone to secondary infections.
Note that Ventipulmin (clenbuterol hydrochloride, a beta-2 adrenergic agonist) often prescribed for RAO, may cause ACTH, cortisol and insulin levels to increase - see TLS Forum.
TLS comment: TLS has seen a few horses with RAO that haven't appeared to respond well to conventional treatment for RAO, and that are perhaps worse in the autumn (August - October), that start to respond once PPID is diagnosed and treatment for PPID started. Given Glover's findings, perhaps horses that develop RAO without an obvious cause should be assessed for PPID.
Research has shown that horses with PPID are more likely to suffer from opportunistic or secondary infections than healthy horses - infections such as skin infections, sinusitis, pneumonia/RAO and abscesses. Horses with PPID have been found to have evidence of RAO and chronic pneumonia at necropsy, without having shown clinical signs of pneumonia - see:
Glover CM, Miller LM, Dybdal NO, Lopez A, Duckett WM, McFarlane D
Extrapituitary and Pituitary Pathological Findings in Horses with Pituitary Pars Intermedia Dysfunction: A Retrospective Study
Journal of Equine Veterinary Science - March 2009 Vol. 29, Issue 3, Pages 146-153
At necropsy, healthy controls were compared to age-matched horses with PPID (horses were considered to have PPID if they showed clinical signs and had pars intermedia adenomas/hyperplasia).
The main histopathologic findings in the lungs of horses with PPID were bronchiolitis (indicative of RAO/COPD), and bronchointerstitial inflammation (indicative of pneumonia).
15/24 (62.5%) horses with PPID showed two or more histological changes consistent with bronchiolitis (RAO), including "bronchiolar mucus with or without cellular debris, bronchiolar epithelial hyperplasia, peribronchiolar inflammation, and peribronchiolar fibrosis", compared to 2/9 (22.2%) age-matched controls.
10/24 (41.6%) horses with PPID showed moderate to severe bronchointerstitial inflammation, consistent with pneumonia, compared to 0/9 age-matched controls.
Horses with PPID had a greater overall lung severity score than age-matched controls.
The research suggests that increased levels of immune-suppressing hormones such as alpha-MSH, beta-endorphin and cortisol may make horses with PPID more prone to secondary infections.
Note that Ventipulmin (clenbuterol hydrochloride, a beta-2 adrenergic agonist) often prescribed for RAO, may cause ACTH, cortisol and insulin levels to increase - see TLS Forum.
TLS comment: TLS has seen a few horses with RAO that haven't appeared to respond well to conventional treatment for RAO, and that are perhaps worse in the autumn (August - October), that start to respond once PPID is diagnosed and treatment for PPID started. Given Glover's findings, perhaps horses that develop RAO without an obvious cause should be assessed for PPID.
Lyme disease (borreliosis)
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Lyme disease is a tick-borne zoonotic infectious disease caused by a Gram negative bacteria, Borrelia burgdorferi. It is present in many regions of the UK, Europe and North America, and commonly carried by deer ticks (Ixodes sp.).
Clinical signs in horses include neuroborreliosis, uveitis, and cutaneous pseudolymphoma. Other clinical signs including lameness (often unexplained lameness that may move from leg to leg), stiffness, joint swelling, reluctance to work/poor performance, mild fever, muscle soreness, lethargy/depression, weight loss, behavioural changes, neurological problems e.g. ataxia, hypersensitivity, and laminitis (potentially severe) have been reported anecdotally but are not well documented, and in the 2018 consensus statement Thomas Divers et al. suggest that there is no evidence of Lyme disease causing laminitis (see below). However, other vets e.g. Dr Eleanor Kellon suggest that horses with Lyme disease often show symptoms in the autumn, and that Lyme disease should be considered for horses that are "just not right", with unexplained laminitis or lameness, attitude changes, considered to have an unexplained virus, with or without a temperature. Diagnosis of Lyme disease is based on exposure to B. burgdorferi, cytology or histopathology of infected fluid or tissue and antigen detection. Treatment of Lyme disease in horses is similar to treatment of humans or small animals but treatment success might not be the same because of species differences in antimicrobial bioavailability and duration of infection before initiation of treatment. There are no approved equine label Lyme vaccines but there is strong evidence that proper vaccination could prevent infection in horses. |
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Dr Thomas Divers talks about Lyme disease in horses: What do we really know?
14 October 2020 Cornell Vet Equine Seminar Series
AAEP Infectious Disease Guidelines: Borrelia burgdorferi infection and Lyme disease 2020
Equine Lyme Disease (borreliosis) - EDCC AAEP 2020
An update on Borrelia burgdorferi - Jamie Prutton, Veterinary Practice May 2018
Divers TJ, Gardner RB, Madigan JE, Witonsky SG, Bertone JJ, Swinebroad EL, Schutzer SE, Johnson AL
Borrelia burgdorferi Infection and Lyme Disease in North American Horses: A Consensus Statement
J Vet Intern Med. 2018 Mar-Apr; 32(2): 617–632. Published online 2018 Feb 22. doi: 10.1111/jvim.15042
"Although anecdotal, web‐based, reports of equine Lyme disease causing laminitis, headshaking, hepatitis, nephritis, or fistulous withers can be found, there is little research and no overt clinical data to support the claims. The range of specific clinical signs associated with Lyme disease is certainly in need of further experimental and epidemiological evaluation, but future progress might well be on a case by case report basis. The best—documented, naturally occurring syndromes attributed to B. burgdorferi infection include neuroborreliosis, uveitis, and cutaneous pseudolymphoma. The association of B. burgdorferi infection with stiffness and lameness in horses is not well documented and there is no evidence of the infection causing laminitis."
Lyme Disease and Anaplasmosis - Liphook Equine Hospital (2016)
LYME DISEASE IN HORSES
Infectious Diseases of the Horse - TJ Divers, TS Mair and YF Chang
Divers TJ
Equine Lyme Disease
Journal of Equine Veterinary Science July 2013 Volume 33, Issue 7, Pages 488–492
Reduce the risk of Lyme disease - Equus 2017
Lyme disease in horses - Dr Eleanor Kellon 2016
Understanding Lyme disease - Peter Clegg MRCVS - Horse & Hound 2000
The Lowdown on Lyme Disease in Horses - Elaine Pascoe - Sept 2010 Practical Horseman
Lyme Disease Action (comprehensive list of symptoms including neurological symptoms seen in humans)
How could Lyme disease cause laminitis in horses?
By causing or worsening insulin resistance? Infections are known to induce insulin resistance in other species:
Diabetes Care. 2006 May;29(5):1058-64.
Burden of infection and insulin resistance in healthy middle-aged men.
Fernández-Real JM, López-Bermejo A, Vendrell J, Ferri MJ, Recasens M, Ricart W.
"CONCLUSIONS: Pathogen burden showed the strongest association with insulin resistance, especially with enteroviruses and C. pneumoniae seropositivity. We hypothesize that exposure to multiple pathogens could cause a chronic low-grade inflammation, resulting in insulin resistance."