JPC SYSTEMIC PATHOLOGY
Signalment (JPC #1535964): Five-year-old quarter horse mare
HISTORY: This mare showed signs of "tying up" after being exercised. She became recumbent and began to pass coffee-colored urine. The mare was euthanatized 8 days after onset of signs. Clinical pathological findings include: BUN-25 (11-27); AST 1250 (160-412); ALT-1750 (no reference interval given); LDH-7200 (112-456).
HISTOPATHOLOGIC DESCRIPTION: Skeletal muscle: Multifocally and randomly affecting up to 75% of muscle fibers, individual myocytes are markedly swollen with pale vacuolated sarcoplasm (degeneration); hypereosinophilic, and hyalinzed with fragmented myofibrils, disruption of the endomysium, loss of cross-striations, occasional contraction bands, and nuclear pyknosis or karyolysis (necrosis); or lost with replacement by karyorrhectic debris, moderate numbers of macrophages and few fibroblasts. Multifocally few myocytes have nuclear internalization and increased basophilia with rowing of nuclei that are large with prominent nucleoli (regeneration), and there is moderate proliferation of satellite cells. Fibrin, edema, moderate numbers of histiocytes, lymphocytes and plasma cells multifocally infiltrate and expand the perimysium and endomysium.
MORPHOLOGIC DIAGNOSIS: Skeletal muscle: Degeneration and necrosis, monophasic, multifocal, random, moderate, with myofiber regeneration, and moderate histiocytic and lymphoplasmacytic myositis, quarter horse, equine.
CONDITION: Equine exertional rhabdomyolysis
SYNONYMS: Exertional rhabdomyolysis syndrome (ERS), exertional myopathy, ‘tying-up’, ‘Monday-morning disease’, ‘set fast’, azoturia, black water, paralytic myoglobinuria
- Sporadic disease of athletic horses worldwide; females appear to be predisposed
- Most often occurs secondary to underlying metabolic abnormalities of muscle rather than poor dietary management and exercise conditioning
- Most horses with ERS respond to a dietary change to high fat and fiber, low starch and sugar
- Predisposing conditions may include polysaccharide storage myopathy in many breeds (including quarter horse and Thoroughbred among others)
- Electrolyte imbalance, specifically hypokalemia, is considered a possible cause
- Affects type 2 (fast twitch, oxidative) muscle fibers [type 2B (2X) glycolytic and 2A oxidative-glycolytic fibers]; nutritional myopathies involve type 1 oxidative fibers
- Subclinical exertional myopathy apparently common in horses and sporadic cases may represent recurrent disease
- Strong evidence suggests autosomal dominant inheritance
- Previously suggested etiologies no longer implicated (excessive muscle lactate acidosis, equine hypothyroidism, vitamin E/selenium deficiency)
- Inciting cause > loss of integrity of the myocyte cell membrane (type 2, fast twitch, oxidative) > myocyte dysfunction > myocyte death > damaged fiber segments undergo hypercontraction > coagulative necrosis > myoglobin and enzymes released into surrounding tissues > myoglobin enters bloodstream > myoglobinuria > myoglobinuric nephropathy > renal failure in severe cases
- Myocyte death results in cellular inability to retain water > swelling within muscle sheath > compartment syndrome perpetuates muscle necrosis
- Tubular damage > preglomerular arterioles vasoconstriction via renin-angiotensin system, other mediators (adenosine, thromboxane, endothelin) > decreased GFR
- Myoglobinemia causes acute tubular necrosis via two pathways:
- Myoglobin heme group > lipid peroxidation > release iron > epithelial damage
- Renal ischemia > secondary to shock > chemical mediators of inflammation
- Tubular blockage (casts) > backpressure > oliguria/anuria >decreased GFR
- Tubular leakage > interstitial edema > increased interstitial pressure > further tubular collapse and damage
TYPICAL CLINICAL FINDINGS:
- Hindlimb weakness and/or pain occurs suddenly
- Variable: Often athletic, heavily muscled, and young (2-5 years old); horses with recurrent episodes of a stiff gait during or immediately after exercise or with sudden onset of weakness, lameness, pain, and reluctance to move; female horses are apparently predisposed
- More severely affected animals may be unable to continue to exercise; muscles are painful, rigid and swollen (gluteal, femoral, lumbar muscles), likely due to increased intramuscular pressure from oxidative membrane injury
- Muscle atrophy may occur in some cases
TYPICAL GROSS FINDINGS:
- Muscle: Moist, swollen, dark with dry streaks of pallor
- Kidney: Swollen with dark brown medullary streaks
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Damaged fiber segments generally undergo hypercontraction followed by coagulative necrosis
- Hyalinization, degeneration and necrosis of myofibers with minimal inflammation
- Contraction band necrosis, regeneration and fibrosis
- Lesions typically monophasic but may be polyphasic with repeat ERS episodes
- PAS staining should be performed on cases of exertional rhabdomyolysis for evidence of abnormal glycogen due, to the incidence of associated polysaccharide storage myopathy
- Calcification / mineralization is NOT a feature
- Cardiac lesions not expected
- Kidney: Swollen proximal convoluted tubular epithelial cells; proteinaceous casts with orange pigmented (myoglobin) granules
- Serum chemistry, moderate to extreme elevations:
- Creatine kinase (CK, muscle specific)
- Alanine aminotransferase (ALT, muscle specific in large animals)
- Lactate dehydrogenase (LDH, not muscle specific)
- Aspartate aminotransferase (AST, not muscle specific)
- Myoglobinuria: Red- brown urine; does not clear on centrifugation; absence of erythrocytes in sediment; retention of color following addition of saturated ammonium sulfate to the urine; clear normal-colored plasma; no anemia
- Hematuria: Red, cloudy urine; clears on centrifugation; erythrocytes in sediment; possibly anemia
- Hemoglobinuria: Red- brown urine; does not clear on centrifugation; absence of erythrocytes in sediment; color clears following addition of saturated ammonium sulfate to the urine; reddish discoloration of plasma; evidence of anemia (hemoglobinemia)
- Broadening of the subsarcolemmic space and intermyofibrillar spaces (degeneration) with edema; myofibrillar waving
- Dilated sarcoplasmic reticulum (degeneration)
- Disassociation and disruption of myofilaments (myofibrillolysis)
- Disorganization and streaming of Z bands
- Small disintegrated mitochondria; large electron-dense deposits within mitochondria
- Malignant edema (gas gangrene): Ruminants, horses, and swine very susceptible; rarely carnivores; etiologies include Clostridium septicum, Clostridium perfringens, Clostridium novyi, Clostridium sordelli and Clostridium chauvoei; cellulitis > serohemorrhagic myositis, large gaseous and/or edematous areas adjacent to wounds
- Hyperkalemic periodic paralysis (HYPP): Myotonic disorder of quarter horse; often well-muscled; laryngeal muscle dysfunction > laryngospasms; no gross findings or histopathological lesions
- Polysaccharide storage myopathy (PSSM; M-M20): Myopathy of quarter horse and draft-related breeds; abnormal accumulation of intracytoplasmic PAS-positive, amylase-resistant material within type 2A oxidative-glycolytic and type 2B glycolytic fibers;
- 2 forms of PSSM:
- Glycogen synthase 1 gene (GYS1) positive-amylase resistant type
- GYS1 negative animals-amylase sensitive; accumulation of glycogen, glucose-6-phosphate and polysaccharide inclusions; autosomal recessive inheritance suggested
- Ischemic myopathy: Degenerative myopathy secondary to muscle hypoxia after prolonged anesthesia; from systemic hypotension, improper padding, prolonged recumbency; degenerative and/or regenerative within affected muscles
- Nutritional myopathy: Foals; associated with vitamin E or selenium deficiencies; affects temporal and masseter muscles; bilaterally symmetric atrophy; pale muscles with yellow to white streaks; myocardial lesions with nutritional myopathy, distinguishes from exertional or ischemic myopathy
- Ionophore toxicity (monensin): Cardiac, skeletal muscle necrosis; pale streaks
- Plant toxicity (Cassia occidentalis, coffee weed, box elder weed): Pale areas within the skeletal, cardiac muscle; multifocal areas of necrosis with zero to minimal mineralization
- Protozoal myopathy (Sarcocystis): Common incidental findings in skeletal muscle, cardiac myofibers; lacks inflammatory response, unless cysts rupture
- Exertional rhabdomyolysis: Dogs, nonhuman primates, cattle
- Canine exertional rhabdomyolysis: Racing greyhounds and racing sled dogs
- Racing greyhounds: Proposed predisposing factors include an excitable nature, lack of physical fitness, hot and humid conditions, and overexertion of physically fit dogs; gross lesions typically absent; histopathologic findings include acute degenerative changes found in susceptible muscles (longissimus, quadriceps, and biceps femoris muscles)
- Racing sled dogs: Sudden death may occur during racing; gross lesions not often seen
- Capture myopathy (CM): Massive muscle injury caused by overexertion or associated with restraint and/or transportation; reported in wild animals, marine mammals; resembles exertional rhabdomyolysis; circulating catecholamines may play a role; clinical signs include dyspnea, weakness, muscle tremors or muscle rigidity, hyperthermia, collapse, and often death
- Multifocal, monophasic skeletal muscle lesions; prominent muscle edema, indistinct pale streaks hemorrhagic streaking of skeletal muscle
- Malignant hyperthermia (pigs, dogs, humans, horses): Genetic defect of the calcium-release channel (ryanodine receptor – ryr1) of skeletal muscle sarcoplasmic reticulum in lean, heavily muscled pig breeds; halothane anesthesia may precipitate condition; also termed porcine stress syndrome or hertztod; autosomal dominant condition EXCEPT in pig (autosomal recessive)
- Canine exertional rhabdomyolysis: Racing greyhounds and racing sled dogs
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- Yazwinski M, Milizio JG, Wakshlag JJ. Assessment of serum myokines and markers of inflammation associated with exercise in endurance racing sled dogs. J Vet Intern Med. 2013; 27(2): 371-376.