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Five horses were presented with signs of myopathy along with systemic malaise, hyperfibrinogenemia, hyperphosphatemia, and an elevated calcium phosphorus product (Ca*P). Postmortem findings were consistent with systemic calcinosis, a syndrome of calcium deposition in the tissue of organs including lungs, kidneys, muscle, and heart that has not been previously described in horses.
Calcinose et calciphylaxie systémiques suspectées chez 5 chevaux. Cinq chevaux ont été présentés avec des signes de myopathie et un malaise systémique, d’hyperfibrinogénémie, d’hyperphosphatémie et d’un produit de phosphore de calcium élevé (Ca*P). Les constatations à l’autopsie étaient conformes à une calcinose systémique; un syndrome de dépôt de calcium dans les tissus conjonctifs des organes incluant les poumons, les reins, les muscles et le cœur n’avait pas déjà été décrit chez les chevaux.
(Traduit par Isabelle Vallières)
An overweight 6-year-old Paint gelding with a history of reluctance to move and dragging of the right hindlimb was treated unsuccessfully during the spring season with a 3-day course of phenylbutazone (Equi-Phar phenylbutazone, 1-g tablets; Vedco, St. Joseph, Missouri, USA), 4 mg/kg, PO, for the first 2 d and flunixin meglumine (Bananmine; Schering-Plough, Whitehouse Station, New Jersey, USA), 1.1 mg/kg, IM, for 1 d. He was fed a diet of pasture, grass hay, and sweet feed with 10% protein content. Re-evaluation 4 d later revealed palpable soreness of the right epaxial and left gluteal muscles and rear limb stiffness. Dexamethasone (2.0 mg injection; Vedco), 0.04 mg/kg, IV, ketoprofen (Ketofen, Fort Dodge, Overland Park, Kansas, USA), 2.4 mg/kg, IV, and vitamin E-Se, 816 IU vitamin E and 65.8 mg selenium IV, slowly, were administered. Eleven days later the horse was inappetent, possibly polyuric, and over the last 5 d, losing weight. The horse was dull, febrile (41°C), tachycardic (60 beats/min), and tachypneic (60 breaths/min) with nostril flaring, and had decreased muscle mass. He was treated with procaine penicillin G (Sterile Pencillin G Procaine Aqueous suspension; Butler, Dublin, Ohio, USA), 22 000 IU/kg, IM, gentamicin (Gentocin; Schering-Plough), 8 mg/kg, IV, and ketoprofen, 2.7 mg/kg, IV. On the following day, due to persistence of the pyrexia (40.4°C), the horse was treated with ketoprofen, 2.4 mg/kg, IV, and omeprazole (Gastorgard, Merial, Duluth, Georgia, USA), 4 mg/kg, PO, and referred to a veterinary clinic.
On day 1 at the West Coast Regional Surgi-Care Center for Horses referral hospital in Florida, the horse was dull, inappetent, had decreased borborygmi, scant dry dark feces, and marked epaxial and gluteal atrophy. He was weak in the hindlimbs, lame in the right hindlimb, and had muscle fasciculations in the right lumbar region. Fever (40.4°C), tachycardia (72 beats/min), and tachypnea (40 breaths/min) were present. The lungs appeared normal on the basis of auscultation and ultrasonography. Major abnormalities in complete blood work obtained on day 2 were elevated creatine kinase (CK), aspartate transaminase (AST) 2615 U/L (normal range: 48 to 375 U/L), phosphorus (P), and calcium phosphorus product (Ca*P) as seen in Table 1. The white blood cell count and the other serum electrolytes were within normal ranges. Abnormal findings from the urinalysis included borderline isosthenuria (specific gravity of 1.015) and pigmenturia (3+). Renal fractional excretion of phosphorus was within normal limits (0.270%). A peritoneal fluid analysis and gastroscopy revealed no abnormal findings. Blood cultures were negative for bacterial growth. Testing for Equine Infectious Anemia was negative. Electrocardiogram revealed a heart rate of 60 beats/min with first degree AV block.
The horse was treated symptomatically on day 1 with IV potassium penicillin, 22 000 IU/kg, q6h, gentamicin, 6.6 mg/kg, q24h, flunixin meglumine, 1.1 mg/kg, once, and intravenous balanced polyionic fluids with added calcium, magnesium, and phosphorus. Pyrexia, depression, and inappetence persisted, and enlarged submandibular lymph nodes were noted. On day 2, because of persistent pyrexia, the horse’s therapeutic regimen was switched to enrofloxacin, 5 mg/kg IV, q24h, ceftiofur, 2 mg/kg, IV, q12h, flunixin meglumine, 1.1 mg/kg, IV, q24h, and phenylbutazone, 4 mg/kg, IV, q24h. The horse began to eat hay and his rectal temperature declined from day 3 to 5 to 38.6°C. Blood samples were submitted for cytology and Anaplasma phagocytophila serology which returned on day 8 as a positive result on serology (1:640) and no evidence of hemoparasites on cytology. On day 5, right jugular vein thrombosis, acute forelimb lameness and bounding digital pulses developed. Despite treatment with sole support, hoof trimming, DMSO, 1 g/kg, IV, q24h, for 3d, phenylbutazone, 3 mg/kg, PO, q12h, and nitroglycerin patch placement, the laminitis progressed over 7 d to distal displacement of the 3rd phalanx. Muscle enzymes had declined but were elevated on day 6 (CK 1023 U/L; AST 1630 U/L), total protein had declined to 54 g/L (normal range: 56 to 86 g/L), and Ca*P was normal at 48.2. Due to the severity of the laminitis, the gelding was euthanized.
An acutely recumbent 14-month-old Quarter horse colt was presented to Auburn University College of Veterinary Medicine in Alabama during the summer season with a 3-day history of depression, inappetence, and pyrexia. Treatment by the referring veterinarian included IV dexamethasone (0.1 mg/kg), flunixin meglumine (1.1 mg/kg), and phenylbutazone (4 mg/kg).
On initial evaluation, the horse was in lateral recumbency, had a rectal temperature of 38.6°C, was tachycardic (80 beats/min), and tachypneic (28 breaths/min) with increased expiratory effort and an expiratory grunt. Mucous membranes were dry and injected. Preliminary blood work revealed an elevated white blood cell (WBC) count (26 000/μL; normal range: 6000 to 12 000/μL) and moderate azotemia (BUN 15.0 mmol/L; normal range: 1.8 to 11.8 mmol/L; Cr 495 μmol/L; normal range: 0 to 185 μmol/L). Serum titers for eastern equine encephalomyelitis (EEE), West Nile virus (WNV), and equine herpesvirus (EHV-1) were negative. The horse was sedated and placed in a sling. Treatment for rhabdomyolysis of unknown origin included hypertonic saline (1 L), Normosol-R continuous rate intravenous fluids, with added KCl and calcium, IV dexamethasone, 0.5 mg/kg, q12h, for 3 d, DMSO diluted in fluids, 0.5 g/kg, IV, q24h, for 3 d, and triple antibiotic ophthalmic ointment in both eyes. By day 2 the horse was able to stand and walk without the assistance of the sling. On day 3 the major abnormalities in blood work included markedly elevated muscle enzymes (CK 950 000 U/L; AST 14 800 U/L) and serum phosphorus (P 2.3 mmol/L) with a low serum calcium concentration of 0.57 mmol/L and normal Ca*P of 65.1 (Table 1). The WBC remained elevated with a mature neutrophilia (23 350/μL; normal range: 6000 to 12 000/μL). Hyperfibrinogenemia, hypoproteinemia, azotemia, and elevated liver enzyme activity (AST 30 600 IU/L; normal range: 144 to 350 IU/L and SDH 12.9 IU/L; normal range: 0.5 to 9.8 IU/L) were noted (Table 1). Unilateral jugular vein thrombophlebitis and facial edema developed and were treated with IV furosemide (Salix injection 5%, Intervet, Millsboro, Deleware, USA), 0.5 mg/kg, q12h, for 3 d, oral aspirin (Aspirin bolus; Butler), 50 mg/kg, q12h, for 3 d, IV ampicillin (Amp-Equine; Pfizer, New York, New York, USA), 22 mg/kg, q6h, for 9 d, hotpacking, and DMSO-nitrofurazone topical application. Diarrhea and severe ventral, limb, pre-putial, and head edema, as well as hypoproteinemia (39 g/L; normal range: 60 to 86 g/L) were evident by day 7. Salmonella typhimurium, sensitive to chloramphenicol, was cultured from the feces. Despite treatment with 2.5 L of hetastarch and 4 L of plasma, hydrotherapy, metronidazole (Metronidazole tablets; Pliva, East Hanover, New Jersey, USA), 25 mg/kg, PO, q12h, chloramphenicol (Viceton; Bimeda, Oakbrook, Illinois, USA), 55 mg/kg, PO, q6h, probiotic gel (Probios Equine One Oral Gel; Bomac Vets Plus, Knapp, Wisconsin, USA), 15 g, PO, q24h, cimetidine (Tagamet, Glaxosmithkline, Phildelphia, Pennsylvania, USA), 3 mg/kg, IV, q8h, for 1d, omeprazole (2 mg/kg, PO, q24h), and ketoprofen (2.2 mg/kg, IV as needed) the horse’s condition deteriorated. On day 10, urinalysis revealed hyposthenuria (1.009), acidic pH (6.0), proteinuria (3+), pigmenturia (3+), and rare renal tubular epithelial casts. On day 14, phosphorus levels increased and total protein declined (Table 1). The horse continued to deteriorate and was humanely euthanized on day 15. Muscle biopsies of the left gluteal and semitendinosus muscle were taken immediately following euthanasia and transported on icepacks to the University of Minnesota Neuromuscular Diagnostic Laboratory for analysis.
Horse 3 was an 8-month-old Paint horse colt that presented to Okotoks Animal Clinic after exhibiting epaxial atrophy, lethargy, and a mild cough following shipping from Northwest USA to Alberta, Canada 2.5 wk earlier. Horse 4 was a 9-year-old Quarter horse gelding located in Indiana that exhibited stiffness, inappetence, pyrexia, and pigmenturia following the injection of a mycobacterium cell wall immunostimulant into a sarcoid on his hind limb 2 wk earlier. He had previously experienced 2 mild episodes of rhabdomyolysis and 1 episode of muscle atrophy and elevated liver enzymes after vaccination 5 y ago. Horse 5 was a 1-year-old Quarter horse filly that was presented to Colorado State University College of Veterinary Medicine with a cough and nasal discharge of 1 mo duration and which had fallen to the ground while on pasture with other yearlings. Duration of clinical signs prior to presentation ranged from 1 wk (Horse 3) to 4 wk (Horse 5) and all horses were presented in the autumn.
Upon presentation, all 3 horses were mildly febrile (38.6°C to 39°C) and horses 3 and 4 were tachycardic (60 beats/min and 80 beats/min, respectively). Horses 3 and 4 had epaxial muscle atrophy and horse 5 developed acute, profound gluteal muscle atrophy. Respiratory signs in horses 3 and 4 included labored breathing with increased abdominal effort and coughing. Horse 3 was diagnosed with mild pleuropneumonia based on history, clinical signs, and ultrasound examination and ultimately also developed ventral edema. Horse 4 was diagnosed with mild chronic tracheobronchitis with previous pulmonary hemorrhage by bronchoalveolar lavage and horse 5 with Type II inflammatory airway disease with a mastocytosis by endoscopy, radiography, and bronchoalveolar lavage. Horse 5 also developed jugular vein thrombosis.
Initial blood work performed in all horses showed high serum CK activity and initial or subsequent serum samples also showed hyperphosphatemia with high normal to high Ca*P (Table 1). Other abnormal findings included mild leukocytosis (13 100/μL to 23 400/μL; normal range: 4200/μL to 12 500/μL) hyperfibrinogenemia (5 to 8 mmol/L; normal range: 1 to 4 mmol/L), and mild hypoproteinemia (43 to 52 g/L; normal range: 53 to 79 g/L). Both horses 4 and 5 had pigmenturia. Urinalysis performed on horse 3 revealed hyposthenuria and aciduria (urine specific gravity 1.003 and pH 6.5). The findings from abdominocentesis performed on horses 4 and 5 were within normal limits. Horse 5 was negative on M protein serology and ELISA for Streptococcus equi subsp. equi.
All 3 horses were presumptively diagnosed with and treated for respiratory disease (pleuropneumonia, tracheobronchitis, inflammatory airway disease). Conventional treatment with nonsteroidal antiinflammatories, a variety of antibiotics, and intravenous fluids did not result in clinical improvement. Due to progression of respiratory distress, muscle wasting, and elevations in serum CK activity, additional treatments were added including dexamethasone in horses 3 and 4, furosemide, albuterol via aeromask in horse 4 for acute severe respiratory distress, and clenbuterol, vitamin E, and acepromazine in horse 5. Horse 3 was euthanized due to persistent recumbency that developed 7 d after presentation, horse 4 was euthanized at Rood and Riddle Equine Hospital due to nonresponsive respiratory distress on day 5, and horse 5 was euthanized on day 8 due to poor prognosis for future performance.
Complete postmortem examinations were performed on horses 2, 4, and 5 whereas tissues from horses 1 and 3 were submitted to pathologists for review. Primary gross findings were areas of pallor in the skeletal muscle (5/5 horses), heart (3/4), lungs (3/5), kidneys (5/5), liver (1/5), and abnormal appearance of the vessels of the small intestine (1/5). DNA was extracted from tissues and tested for the mutations associated with polysaccharide storage myopathy (GYS1) and malignant hyperthermia. No genetic mutations were identified.
Formalin-fixed muscle biopsies of the semimembranosus, semi-tendinosus, and/or gluteal muscles of 4 of the 5 horses were evaluated by the University of Minnesota Neuromuscular Diagnostic Laboratory; 2 samples were obtained antemortem and 3 samples were obtained postmortem. One sample was evaluated by IDEXX Central Laboratory for Veterinarians, Vancouver, British Columbia. The characteristic features of at least 1 sample per horse was diffuse anguloid atrophy, myofibers with centrally located nuclei, acute Zenker’s necrosis of scattered myofibers and marked dystrophic calcification of myofibers confirmed by staining with Von Kossa stains. Evaluation of multiple muscle samples from horses 1 and 2 showed that myofiber degeneration and calcification was more pronounced in gluteal muscles (affecting up to 80% of fibers in horse 2) than semimembranosus muscles. Muscle from horse 1 showed macrophage infiltration of myofibers and scattered large basophilic multinucleated giant cells. Horse 3 showed perimysial fibrosis in muscle samples and epaxial muscle from horse 4 had a mononuclear vasculitis.
In 3 out of 4 horses where the heart was examined (horses 2, 3, and 4), scattered myocytes appeared swollen, pale, lacked cross-striations, and many were fragmented with accumulation of basophilic calcified debris with little evidence of regeneration. Horse 4 also had dystrophic calcification of the endothelium of the aorta and aortic sinuses, and fibrous connective tissue surrounding arteries, which in some cases contained thrombi. No abnormal findings were noted upon examination of the heart of horse 1.
Calcification within pulmonary tissues was present in 4 of 5 horses. Calcification occurred mainly in the primary bronchioles (horses 1 and 2), alveoli (horse 3), and in the bronchiolar musculature, bronchial cartilages, and alveolar walls (horse 4). Horse 3 also exhibited pleural fibrosis, mild emphysema, and pulmonary edema with some multifocal areas of lymphocytic inflammation. In horse 4, some vessels contained thrombi, and there was diffuse hyaline degeneration of the alveoli as well as infiltration of alveoli and bronchi with neutrophils. Horse 5 had mild interstitial pneumonia with vasculitis and perivascular cuffing, but no mineralization.
Submucosal vessels of the small intestine of horse 4 exhibited calcification of the tunica intima. There was also focally extensive hemorrhage in the intestinal submucosa. The intestine was also examined in horse 2 and found to exhibit diffuse acute enteritis. The intestine was not examined in the remaining 3 horses. The liver of horse 3 contained zones of hepatocellular necrosis with calcification around the portal triads. No abnormalities were found in the liver of horse 2 and there was mild lymphoplasmacytic periportal inflammation of the liver of horse 5. The liver was not examined in the remaining 2 horses.
All horses had evidence of mineralization of either the glomeruli (horses 1, 4) renal tubules (horses 2, 3, 4), or collecting ducts (horse 5). Horse 1 also had evidence of renal tubular necrosis, with locally extensive areas of coagulative necrosis in the cortex and medulla. In horse 2, the interstitium showed multifocal infiltration with fibrous connective tissue, macrophages, some lymphocytes, and plasma cells. Horse 3 demonstrated acute tubulonephrosis. In both horses 3 and 4, tubules in the medullary rays were dilated and contained eosinophilic material and neutrophils. Some vessels also contained thrombi.
The final diagnosis for horse 1 was chronic nephritis with mild mineralization and chronic necrotizing myopathy with mineralization. The final pathologic diagnosis for horse 2 was severe renal tubular necrosis with marked multifocal tubular and glomerular mineralization, degeneration, necrosis, and calcification of skeletal and cardiac muscle, and salmonellosis. Horse 3 was ultimately diagnosed with multifocal fibrosis and calcification of multiple organs including the skeletal muscle, kidney, lung, epicardium, pleura, and liver, with multifocal fibrosing myositis and equivocal glomerulonephritis. The diagnosis for horse 4 was pulmonary hyaline membrane disease, pulmonary, renal, and myocardial thrombosis, skeletal myodegeneration, and mineralization of the lung, kidney, heart, trachea, intestine, aorta, and skeletal muscles. Finally, horse 5 was ultimately diagnosed with severe skeletal muscle necrosis with calcification, renal tubule mineralization, mild interstitial pneumonia, and mild lymphoplasmacytic periportal inflammation of the liver.
This study describes a novel syndrome of systemic dystrophic calcification in 5 adult horses characterized by malaise, mild fever, stiffness, and loss of muscle mass particularly over the lumbar and gluteal area. Serum CK and AST activities were elevated and horses consistently had hyperphosphatemia along with hyperfibrinogenemia. A mild leukocytosis was evident in 4/5 horses. Cough (3/5), tachypnea (3/5), and respiratory distress (1/5) were present in some horses. This condition was associated with a fatal outcome and diagnosis was established after review of postmortem histopathology. Horses were euthanized due to progressive weakness, inability to remain standing, respiratory distress, laminitis, or salmonellosis. Whether these complications were a direct result of systemic dystrophic calcification was not always clear; however, dystrophic calcification was a significant finding in the skeletal muscle of all horses and in the lungs of 4/5 horses. Other common features at postmortem examination were dystrophic calcification of cardiac myofibers, renal tubules and, in 1 horse, the tunica intima of intestinal vessels.
This syndrome described in horses from across North America most closely resembles a rare condition in humans called metastatic calcification or systemic calcinosis, as well as calciphylaxis. Although these terms have been used interchangeably, systemic calcinosis more specifically is characterized by calcium deposition in the connective tissue of organs, including the lungs, kidneys, stomach, heart, and skin (1). All 5 horses in the present study had evidence of systemic calcinosis; however, they also had an uncommon feature of systemic calcinosis in humans, which was muscle fiber calcification (2–4). Calciphylaxis more specifically includes calcification of the tunica intima or tunica media of small to intermediate vessels, leading to ischemia and tissue necrosis (1,3,5,6). Only 1 of 5 horses in the present study showed specific signs of calciphylaxis. Calciphylaxis involving the aorta, coronary arteries, and pulmonary arteries was recently reported in 1 horse with chronic muscle atrophy and stiffness (7). Both systemic calcinosis and calciphylaxis are characterized by elevated Ca*P, are often found in dialysis patients with hyperphosphatemia and chronic renal failure, and are thought to share the same underlying mechanism (1).
Although most commonly associated with chronic renal failure, nonuremic causes of calcinosis have recently been described (2). In the horses in our study, the disease most closely resembled nonuremic calcinosis (2). Renal lesions were present in some horses but these appeared to be more acute than chronic and serum creatinine was only mildly to moderately elevated. The review of 36 cases of human nonuremic calciphylaxis suggested an association with diseases such as primary hyperparathyroidism, connective tissue disease, alcoholic liver disease, and malignancies (2). Predisposing associations included corticosteroid use (22/36), warfarin use (9/36), albumin or blood transfusions (7/36), protein C or S deficiency (4/36), precipitating trauma (2/36), and diabetes (8/36) (2).
The pathophysiology of dystrophic calcification of tissues was suggested by Selye (8) to involve a “sensitizer” such as parathyroid hormone from primary hyperparathyroidism or renal failure, or an elevated Ca*P product of > 70. This is followed by a lag period and then calcification is precipitated by a “challenger” such as corticosteroids, immunosuppressants (1), blood products, and calcitriol (9). More recent research indicates that parathyroid hormone and corticosteroids may have a more direct effect on dystrophic calcification through upregulation of the receptor activator of nuclear factor kappa B ligand (RANK-L) (10,11). RANK-L is the primary activator of osteoclast formation with direct catabolic effects on bone, and acts to decrease osteoprotegerin expression, which inhibits osteoclast formation. The combined impact is to increase resorption of bone, leading to hyperphosphatemia. Severe rhabdomyolysis in some of the horses in the present study could also have contributed to hyperphosphatemia. Hyperphosphatemia in turn may lead to dystrophic calcification through 4 different processes: 1) passive calcium phosphate deposition from phosphate supersaturation in the blood, 2) an active process promoting the conversion of smooth muscle cells to osteogenic cell types, 3) high phosphorus levels directly increasing PTH secretion and transcription, and 4) high phosphorus interfering with renal production of 1,25-(OH)2D levels, which has been associated with increased coronary artery calcification in humans (12–14). The inflammatory response evident in the horses in the present study by hyperfibrinogenemia, could also have contributed to hyperphosphatemia and dystrophic calcification by the known synergistic effects of cytokines such as TNFα and IL6 with RANKL to enhance bone resorption (15). Given that 3 horses exhibited prominent respiratory disease (horses 3 to 5), 1 horse may have had anaplasmosis (horse 1), 1 horse had salmonellosis (horse 2), and 1 horse reacted to the administration of an immunostimulant prior to the onset of clinical signs (horse 4), the role of a predisposing inflammatory process in triggering systemic calcinosis cannot be ruled out. Each horse may have been “sensitized” by an elevated Ca*P product and calcification may have been precipitated by any combination of predisposing inflammatory disorders, administration of steroids (horses 1 and 4), trauma (horse 5), and plasma administration (horse 3). It is important to note that clinical signs were nonspecific and included multiple body systems, treatment was usually symptomatic, and definitive diagnosis was not achieved until postmortem examination. As the numbers in this study are small, no definitive statement can be made regarding predisposing associations with systemic calcinosis, as have been described in humans (2). Systemic calcification could also have contributed to respiratory distress in some of the horses in this study. A case of acute respiratory failure in a uremic human patient with systemic calcinosis, calciphylaxis, and calcified nodules in the lung has been reported (6).
Other differential diagnoses for the dystrophic calcification in the horses in the present study include hypervitaminosis D, immune-mediated myopathy, calciphylaxis, and nonuremic systemic calcinosis. Horses affected by hypervitaminosis D as seen in South American cattle and horses consuming Solanum glaucophyllum can exhibit similar dystrophic calcification of multiple tissues (16,17). The cases in the present report, however, came from a wide geographic distribution within North America and had no historical evidence of ingestion of toxic plants or supplementation with vitamin D. Furthermore, none of the horses exhibited classical signs of hypervitaminosis D such as hypercalcemia and gastrointestinal hemorrhage. Since calcitriol levels were not measured in these cases, the possibility of hypervitaminosis D cannot be definitively ruled out. In humans, dermatomyositis, an immune-mediated myopathy, may initially present with high serum CK activity, muscle pain, atrophy, and progress to calcinosis universalis, where calcium deposits occur in the skin, subcutaneous tissue, and tendinous/muscle tissues (18). Muscle wasting was a common feature of horses in the present study, and is a feature of immune-mediated myositis. However, only one muscle biopsy (horse 4) showed similar muscle histopathology to an immune-mediated myositis with a mononuclear vasculitis. The tissue distribution of calcification in skeletal muscle, heart, lung, and kidney of horses in our study also differs from that of dermatoymyositis where deposition predominates in the subcutaneous and tendinous tissues. Furthermore, elevated phosphorus and high Ca*P products are not reported with dermatomyositis (18). Dystrophic calcification has been reported in horses with neoplasia; however, postmortem examination did not reveal any evidence of neoplasia in the horses described in this study (19). A single case report has described soft tissue mineralization in a suckling foal related to nutritional secondary hyperparathyroidism due to low calcium and high phosphorus intake (20). Although no specific diet analyses were performed in the cases described, each horse was an adult with access to hay and/or commercial feed products and pasture. No other horses fed the same diet were affected.
An underlying etiology for the muscle wasting and rhabdomyolysis in horses in the present study was not identified. All horses were negative for polysaccharide storage myopathy and malignant hyperthermia. Nutritional myodegeneration can cause calcification of skeletal and cardiac muscle in foals but rarely in adult horses. Vitamin E and selenium concentrations were not measured at postmortem in any of the horses to definitively rule out a deficiency. An inflammatory myopathy resembling immune-mediated myopathy was found in the epaxial muscle of 1 horse but lymphocytic infiltrates and vasculitis were not evident in the other horses, making this diagnosis less likely. Systemic inflammation can lead to muscle wasting (5) through increased inflammatory cytokines such as TNFα, IL6 which upregulate the ubiquitin-proteasome system (21–23). This could possibly have contributed to muscle atrophy.
The similarity of clinical signs of immune-mediated myopathy (acute muscle atrophy over the topline in Quarter horse related breeds) and the signs in horses in the present study led to institution of corticosteroid treatment in horses 1, 3, and 4. In retrospect, because corticosteroids are believed to act as a “challenger” agent and worsen calciphylaxis in humans these drugs may not have been indicated in horses with hyperphosphatemia or elevated Ca*P (1,2). Products of Ca*P are often used as a measure of the potential for dystrophic calcification with a threshold for calciphylaxis in humans of 70 (1,5), although the cutoff varies among investigators to include values as low as 50 (2). In the present study, all horses exhibited a Ca*P > 70 at some point during hospitalization, with the exception of horse 4, which had a Ca*P of 66.1. To our knowledge a specific Ca*P normal range for horses has not been established.
A diagnosis of systemic calcinosis should be suspected if a horse presents with myopathy and systemic signs of malaise, hyperfibrinogenemia, hyperphosphatemia, an elevated Ca*P product, evidence of renal insufficiency, and calcification of muscle on biopsy. Other procedures used in humans that could be of diagnostic value in horses to detect diffuse calcification of organs include thoracic radiographs, nuclear scintigraphy, abdominal/thoracic ultrasonography, and lung or kidney biopsies if necessary. Measurement of parathyroid hormone concentrations would be of value to further characterize this syndrome in horses, as would postmortem examination of the parathyroid gland. The prognosis appears poor for horses and humans with signs of systemic calcinosis. In humans, mortality approaches 50%, with a life expectancy of 6 mo (6) and patients often succumb to sepsis (24). Measures that could be used to lower serum phosphorus include a low phosphate diet, achieved by feeding more forage and less grain — ideally grass hay or mature legume hay. Corn and beet pulp could be fed as they also contain low levels of phosphorus (25). Phosphate binders have not yet been investigated in horses but may be a potential therapy in the future. They are currently available to humans in the form of oral aluminum hydroxide gel, calcium salts, intravenous thiosulfate (26), a calcium- and aluminum-free phosphate binding drug called sevelaner, and lanthanum (11).
In conclusion, this study describes a novel syndrome of idiopathic systemic calcinosis in horses that is characterized by malaise, fever, muscle wasting, high serum muscle enzymes, and elevated phosphorus and Ca*P products. CVJ
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