VCS 808 Metabolic Disorders of Horses 2023 Final Version.pptx

Metabolic Disorders of Horses VCS 80801 T E R E S A B U C H H E I T , DV M , M S , DAC V I M ( C R E D I T S T O D R. K I RA T Y S O N ) LECTURER, PURDUE UNIVERSITY Disorders of fat metabolism DYSLIPIDEMIAS AND HEPATIC LIPIDOSIS Normal Energy Metabolism Continuous intake of energy-poor diets (ro...

Metabolic Disorders of Horses VCS 80801 T E R E S A B U C H H E I T , DV M , M S , DAC V I M ( C R E D I T S T O D R. K I RA T Y S O N ) LECTURER, PURDUE UNIVERSITY Disorders of fat metabolism DYSLIPIDEMIAS AND HEPATIC LIPIDOSIS Normal Energy Metabolism Continuous intake of energy-poor diets (roughage) Hindgut fermenters Glucose-oriented metabolic pattern of nonruminants when fed diets high in soluble carbohydrates VFA-oriented metabolism similar to ruminants when fed roughage-based diet Normal Lipid Metabolism Lipolysis of triglycerides by hormone sensitive lipase (HSL)→ release of FFAs (NEFA’s) + glycerol into circulation NEFA’s are taken up by the hepatocytes and have 3 fates: • β-oxidation in the Krebs cycle for energy • Converted to triglycerides that are either stored or exported into circulation as very-low-density lipoproteins (VLDLs) Note: Incomplete oxidation of FFAs in the equine liver is minimal (ketonemia rare) ↓Glucos e ↑ Glucose Normal Lipid metabolism The VLDLs released into circulation are transported to peripheral tissues • Insulin and glucose-dependent insulinotropic polypeptide (GIP) stimulates LPL activity ↓Glucos e ↑ Glucose Cardiac muscle Lipoprotein lipase • Lipoprotein lipase (LPL) hydrolyzes the triglycerides from the VLDL and the triglycerides are taken up by cells of the peripheral tissues Skeleta l Muscle Adipose tissue Hypertriglyceridemia Negative energy balance → Increased lipolysis of fat stores Increased stress hormone release (cortisol, catecholamines) → increased lipolysis Azotemia – uremic inhibition of LPL activity → decreased clearance of triglycerides Neoplasia (rare) – possibly due to increased TNF-α (enhances lipolysis, decreases lipoprotein lipase activity) Abnormal lipid metabolism To maintain normoglycemia • Metabolic rate slows to decrease consumption of glucose • Glucagon secretion increases; insulin secretion decreases Negative energy balance → ↓ glucose → ↓ insulin/glucagon ratio → activate hormone sensitive lipase → excessive mobilization of peripheral fat stores → ↑ FFA release overwhelms the liver’s capacity for gluconeogenesis and ketogenesis → ↑ triglyceride formation → excessive VLDL’s in circulation → overwhelms the capacity of skeletal muscles and cardiac muscles to utilize the triglycerides → buildup of VLDL’s in circulation Abnormal Lipid Metabolism Increased FFAs and triglycerides interfere with action of insulin from suppressing HSL → increased rate of tissue lipolysis → worsening hypertriglyceridemia → overwhelms liver’s capacity to oxidize FA’s and to process triglycerides into VLDLs → accumulation of lipid metabolites in muscle and liver→ hepatic lipidosis (also renal lipidosis) Lipid accumulation in the liver • disrupts normal pathways responsible for insulin-induced glucose uptake in skeletal muscles • Interferes with gluconeogenesis Fulminant self-perpetuating hyperlipidemia Negative energy balance/marked lipolysis ◦Parasitism ◦Intestinal diseases ◦Laminitis ◦Respiratory diseases ◦PPID (equine Cushing syndrome) ◦ Esophageal choke ◦Obesity ◦ Dental disorders ◦Neonatal septicemia (miniature ◦ Transportation horse and donkey foals) or adult horses with systemic inflammation More common in adult ponies (esp. Shetland or fat ponies), Predisposing factors ◦Lactation ◦Pregnancy ◦Decrease in available feed or appetite donkeys and miniature horses of all ages, and horses with Cushing’s disease Dyslipidemias and Hepatic Lipidosis Definitive diagnosis requires documentation of increased circulating lipids: • Hypertriglyceridemia • Hyperlipidemia • Severe hypertriglyceridemia • Hyperlipemia • Hepatic Lipidosis Clinical Signs Hyperlipidemias Positive correlation between body condition and serum TG concentration Treatment Recognize at risk animals as early as possible • Serum triglycerides in clinical ill horses Gross observation of lipemia not sensitive Principles: ◦Treat underlying disease ◦Correct negative energy balance ◦Inhibit fat mobilization ◦Increase VLDL uptake by peripheral tissues Provide energy Enteral nutritional support ◦Palatable high energy feeds ◦High-fructose corn syrup at 5 kcal/kg/day (60-mL dose for 500 kg horse) divided q2h ◦Slurry feeds via intermittent NG tube or indwelling NG feeding tube 5% Dextrose IV (cannot deliver full caloric needs) Parenteral nutrition (monitor glucose) • Avoid lipids when serum TG > 1000 mg/dL Wean nursing foals Other Treatments Insulin therapy (suppresses hormone sensitive lipase and activates lipoprotein lipase) ◦Intermittent SC insulin ◦Insulin CRI ◦Monitor for hypoglycemia! Heparin (promotes peripheral triglyceride uptake and stimulates LPL activity) ◦Efficacy? Activity of LPL does not appear to be deficient in hyperlipemic ponies (increased 2-fold) [Watson et al. 1992] ◦Has been shown to rapidly reduce plasma triglyceride concentrations in both equine and human patients [Durham 2006] ◦Risk of heparin-induced thrombocytopenia and bleeding disorders (use short term) Calcium Disorders in the Horse HYPOCALCEMIA, HYPERCALCEMIA Calcium in horses Free or ionized form (50%–58%) Bound to proteins (40%–45%) Complexed to anions, such as citrate, bicarbonate, phosphate, and lactate (5%–10%) Free or ionized calcium (Ca2+) is the biologically active form of calcium Calcium physiologic functions Muscle contraction Hormone secretion Enzyme activation Cell division Cell membrane stability Neuromuscular excitability Blood coagulation Vasoconstrictio n Free radical production Cytokine release Protease activation Apoptosis Calcium Homeostasis 3 body systems • Kidney • Intestine • Bone 3 major hormones ◦Parathyroid hormone (PTH) ◦Calcitonin ◦1,25-dihydroxyvitamin D3 (Vitamin D or calcitriol) Parathyroid Hormone ↓ [Ca2+] ECF→ ↑PTH by parathyroid glands Stimulates osteoclastic bone resorption Increases Ca2+ reabsorption and urinary excretion of phosphate in renal tubules Stimulates Vit D3 (calcitriol) synthesis in the kidney ◦increases Ca2+ and phosphate absorption in the intestines ◦Increases renal reabsorption of Ca2+ ◦Inhibits PTH secretion in the parathyroid gland Calcitonin ↑[Ca2+]ECF → ↓ PTH, ↑ calcitonin Calcitonin Secreted by the C-cells of the thyroid gland ◦ Major: ↓Ca2+ and P by inhibiting osteoclastic bone resorption ◦ Minor: Inhibits renal tubular reabsorption of Ca2+ and P (excreted in the urine) Magnesium Also involved in calcium homeostasis Magnesium dependent: ◦ PTH release and action ◦ Vitamin D3 synthesis ↓ Mg will interfere with or impair Ca2+ concentrations Hypocalcemic Disorders Hypocalcemia Causes Acute kidney injury Heat stroke Cantharidin toxicosis (blister beetle) Hypomagnesemia Chronic kidney disease Late pregnancy Colic Liver disease Colitis Lactation tetany Endotoxemia Endurance exercise Excessive bicarbonate or furosemide administration Pleuropneumonia Primary hypoparathyroidism Retained placenta Rhabdomyolysis Sepsis Acute Hypocalcemia Neuromuscular excitability, muscle fasciculations, tremors, tetany ◦ Ca2+ binds Na+ channels → decreased Na+ permeability and increases voltage required for channel opening (increases depolarization threshold) ◦ Low Ca2+  hyperactivation of Na+ channels and highly excitable nerve fibers (spontaneous and continuous discharges) Clinical Signs Anxiety Hypersalivation Ataxia Muscle fasciculations Depression Stiff gait tremors Bruxism Sweating Colic/ileus Convulsions Synchronous diaphragmatic flutter Tachypnea with flared nostrils Death Tachycardia and arrhythmias (bradycardia if severe) Dysphagia Tetany Dyspnea Tremors Hyperexcitability Trismus (lock jaw) Synchronous Diaphragmatic Flutter “Thumps” Depolarization of right atrium stimulates action potentials in the phrenic nerve as it crosses over the heart ◦ Seen as a rhythmic movement on the flank from diaphragmatic contractions that are synchronous with the heartbeat Hypocalcemic Tetany Excessive and sustained skeletal muscular contractions due to increased cell membrane excitability secondary to low ionized Ca2+ Mares 2 weeks before foaling to up to a few days after weaning ◦At risk mares: ◦Producing large amounts of milk ◦Eating a low calcium diet or grazing lush pastures ◦Performing physical work (Draft mares) Horses transported for long periods (transit tetany) Prolonged physical activity (eg, endurance horses) Any horse with hypocalcemia Lactation Tetany Exercise-Induced Hypocalcemia Intensively exercised horses (endurance horses) may develop electrolyte and acid-base abnormalities ◦ Hypocalcemia and hypomagnesemia are consistent findings ◦ Ca2+ loss in sweat ◦ Hypochloremic metabolic alkalosis → ↑ Ca2+ binding to albumin, lactate, phosphate and bicarbonate ◦ Parathyroid gland dysfunction Cantharidin Toxicity (Blister Beetle) Dead beetles crushed and baled into alfalfa hay Toxic principle: cantharidin ◦ Highly irritating to mucous membranes → cell damage and necrosis ◦ Inflammation and ulceration of GI tract ◦ Bladder irritation (excreted by kidney) ◦ ↓ Ca2+ and Mg Diagnosis: urine cantharidin test Ileus Smooth muscle cells vs skeletal muscle ◦more voltage-gated Ca2+ channels ◦fewer voltage-gated Na+ channels Extracellular Ca2+ is important for the action potential → slower and prolonged contractions Conditions that cause ionized hypocalcemia may lead to ileus Hypoparathyroidism Primary hypoparathyroidism ◦Decreased synthesis and secretion of PTH Secondary hypoparathyroidism ◦Secondary to magnesium depletion or inflammatory cytokines (sepsis) Pseudohypoparathyroidism ◦PTH resistance Primary Hypoparathyroidism Clinical signs consistent with hypocalcemia ◦ Ataxia ◦ Seizures ◦ Hyperexcitability ◦ Synchronous diaphragmatic flutter ◦ Tachycardia, tachypnea ◦ Muscle twitching, fasciculations ◦ Stiff gait ◦ Recumbency ◦ Ileus, colic Hypocalcemia results from ↓ PTH Characteristics/diagnosis: ◦ Hypocalcemia ◦ Hyperphosphatemia ◦ Normal or ow serum PTH ◦ Hypomagnesemia ◦ Hypercalciuria ◦ Hypophosphaturia Hypocalcemia: Treatment Acute – correct hypocalcemia ◦23% Calcium gluconate slowly ◦50 mL/5 L bag of IV fluids ◦Can ↑5-10x dose if needed Chronic ◦Oral calcium carbonate ◦Limestone: 100-300 g/horse/day ◦Oral dicalcium phosphate (100-200 g/horse/day) ◦Low dose Vit. D (if ↓Ca absorption) ◦Mg supplementation Hypercalcemic Disorders Hypercalcemic disorders Two categories: •Primary hyperparathyroidism 1. Parathyroid-dependent hypercalcemia •Secondary hyperparathyroidism 2. Hypercalcemia independent of parathyroid gland function •Chronic kidney disease Poor Prognosis •Neoplasia/humoral hypercalcemia of malignancy (pseudohyperparathyroidism) •Hypervitaminosis D •Calcinosis and Idiopathic systemic granulomatous disease (rarely) Primary Hyperparathyroidism Parathyroid-dependent hypercalcemia Excessive secretion of PTH Parathyroid gland does not respond to negative feedback of Ca2+ ◦ Parathyroid adenomas ◦ Parathyroid hyperplasia ◦ Parathyroid carcinoma Lab findings ◦ ↑Ca ,↓P, ↑ PTH, phosphaturia Secondary Hyperparathyroidism Renal secondary hyperparathyroidism ◦ CKD/↓ GFR → phosphorus retention and hypervitaminosis D → ↑ PTH (directly or secondary to ↓ Ca2+) ◦ Hypophosphatemia and hypercalcemia consistent findings ◦ Not well-recognized in horses Nutritional Secondary Hyperparathyroidism Diet low in Calcium, high in phosphorus, phosphorus/calcium ratio ≥ 3:1, or pastures high in oxalates  ↑↑P (reduced intestinal Ca2+ absorption) and ↑PTH secretion Other names: bran disease, miller’s (wheat) disease, bighead, osteodystrophia fibrosa, osteitis fibrosa, and equine osteoporosis Clinical signs: Enlargement of facial bones (osteodystrophia fibrosa or big head) Upper respiratory noise Lameness, stiffness, physitis (physeal enlargement) and limb deformities Poor body condition Hypervitaminosis D Ingestion of plants containing 1,25(OH)2D-like compounds (Jessamine shrub in US, Solanum sp.) Hypervitaminosis D increases GI and renal absorption Ca and P (hyperphosphatemia is the most consistent laboratory finding, serum calcium levels are variable, +/- azotemia and hyposthenuria) ↑Vit D  parathyroid cell atrophy and ↓PTH secretion Clinical signs Poor ◦ Weight loss ◦ Poor appetite ◦ Lameness, stiffness, reluctance to move (calcification of ligaments and tendons) ◦ Acute death (calcification of myocardial tissue) ◦ Kidney disease secondary to mineralization ◦ Mineralization of soft tissues and other organs Prognosis Treatment: glucocorticoids (dexamethasone) to decrease intestinal absorption of calcium, increase urinary excretion of calcium, and decrease bone resorption (questionable results, prognosis poor) Pseudohyperparathyroidism Paraneoplastic condition – humoral hypercalcemia of malignancy (parathyroid hormone-related protein) In horses, HHM reported to be associated with: ◦Gastric squamous carcinoma ◦Adrenocortical carcinoma ◦Other squamous cell carcinoma ◦Lymphosarcoma ◦Multiple myeloma ◦Ameloblastoma Lab abnormalities: ◦Hypercalcemia ◦Hypophosphatemia ◦Hypocalciuria, hyperphosphaturia ◦Normal or ↓ PTH concentrations ◦↑ PTHrP +/- soft tissue mineralization Suspected in any horse with hypercalcemia, no evidence of renal disease, and normal or low concentrations of PTH Hypercalcemia: Treatment Rarely an emergency Differential diagnosis important in treatment Mild to moderate hypercalcemia: treat underlying cause Low calcium diets (no alfalfa) Severe hypercalcemia: • 0.9% saline • Furosemide (inhibits Na+/K+/2Cl- cotransporter in distal tubules → ↑ urinary calcium excretion) Mineralization of organs poor prognosis (hypervitaminosis D) Phosphate Disorders Hyperphosphatemia Closely linked to disorders of calcium metabolism • Nutritional secondary hyperparathyroidism • Acute Kidney Injury • Massive tissue necrosis (tumor lysis syndrome, rhabdomyolysis, hemolysis, intestinal infarction) • Hypervitaminosis D • Hypoparathyroidism • Foals treated with phosphate-containing enemas At risk of developing soft-tissue mineralization and calcinosis Hypophosphatemia Renal failure Malignancies secreting parathyroid hormone-related peptide (PTHrP) - Humoral Hypercalcemia of Malignancy/HHM) Hyperparathyroidism Parenteral nutrition Hyperinsulinism Hypophosphatemia results from the intracellular shift of P i in patients with ◦ Severe sepsis ◦ Malnourishment (refeeding syndrome) ◦ Alkalosis ◦ Hyperglycemia/hyperinsulinemia ◦ Iatrogenic to parenteral nutrition Refeeding Syndrome Sequela to reintroduction of food in previously deprived horses (onset of clinical signs 1-19 days following reintroduction of feed Introduction of CHO’s (glucose) → insulin release → ↑ uptake and use of phosphate by cells → deficit of intracellular and extracellular phosphorus (also potassium and magnesium) → widespread dysfunction of cellular processes → neurologic dysfunction, cardiovascular, respiratory, and renal failure https:// Questions? [email protected] References Watson T.D., Burns L., Love S. et al. Plasma lipids, lipoproteins and post-heparin lipases in ponies with hyperlipaemia.Equine Vet J. 1992; 24: 341-346 Durham A.E. Clinical application of parenteral nutrition in the treatment of five ponies and one donkey with hyperlipaemia.Vet Rec. 2006; 158: 159-164 Hughes K.J., Hodgson D.R. Dart A.J. Equine hyperlipaemia: a review. Aust Vet J. 2004; 82: 136-142 Dunkel B., McKenzie 3rd, H.C. Severe hypertriglyceridaemia in clinically ill horses: diagnosis, treatment and outcome. Equine Vet J. 2003; 35: 590-595 McKenzie H.C. Equine Hyperlipidemias. Vet Clin North Am Equine Pract. 2011 Apr;27(1):5972. Toribio R.E. Disorders of Calcium and Phosphate Metabolism in Horses. Vet Clin North Am Equine Pract. 2011 Apr;27(1):129-147. Smith B.P. Large Animal Internal Medicine, 6th Ed.