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Extensive Dystrophic Pulmonary Calcification in a Welsh Pony Mare
Journal of Equine Veterinary Science 34 (2014) 1234–1239
Contents lists available at ScienceDirect
Journal of Equine Veterinary Science journal homepage: www.j-evs.com
Case Report
Extensive Dystrophic Pulmonary Calcification in a Welsh Pony Mare Angelika Schoster DrMedVet, DVSc, DACVIM, DECEIM a, b, *, Alexandra Bratton BSc, DVM, DVSc b, M. Kimberly J. McGurrin BSc, DVM, DVSc, DACVIM b a b
Equine Department, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 December 2013 Received in revised form 23 June 2014 Accepted 9 July 2014 Available online 16 July 2014
A 12-year-old Welsh pony mare was presented to the Ontario Veterinary College Teaching Hospital for signs of intermittent lethargy and increased abdominal breathing effort of 6 months duration. After physical examination, blood work, bronchoscopy, bronchoalveolar lavage, and diagnostic imaging of the thorax and attempted lung biopsy, pulmonary mineralization of unknown origin was suspected. The pony was treated palliative for 7 months with nonsteroidal anti-inflammatories and inhaled corticosteroids to treat accompanying airway inflammation before being euthanized because of poor prognosis and deterioration of clinical signs. On postmortem examination, the pulmonary architecture of the right and left cranioventral lung lobes, accessory lobe, and cranial potions of the left caudal lung lobe was replaced by hard mineralized tissue. No other organs other than a mediastinal lymph node and the lung were affected by mineralization. After decalcification, thick sheets of fibrous connective tissue organized into layers and lamellae replaced the normal architecture of the pulmonary parenchyma in more than 90% of the lung lobe examined on histopathology. The findings were consistent with generalized severe pulmonary fibrosis and dystrophic calcification. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Lung calcification Mineralized lung
1. Introduction
2. Case Presentation
Dystrophic pulmonary calcification is a rare clinical syndrome associated with varying underlying disorders in humans, dogs, and horses. This case report describes a case of extensive generalized dystrophic pulmonary calcification involving both cranioventral lung lobes to an extent not reported before. No signs of neoplasia, previous respiratory disease, or metabolic disease were present.
A 12-year-old Welsh pony mare was presented for a history of lethargy and increased respiratory effort. The pony was used as a show hunter up until the time of presentation. For 6 months before presentation, the pony began tiring easily when being ridden and intermittent increased abdominal effort during breathing was observed. No coughing or other signs were observed. Appetite and fecal output were normal. The referring veterinarian reported no abnormalities on repeated physical examination. Serial blood hematology and biochemistry over the next 6 months showed persistent anemia (red blood cell count, 5.4 1012 to 6.4 1012 cells/L; reference range, 8.8 1012 to 12.5 1012 cells/L; hematocrit, 0.27–0.31 L/L; reference range, 0.32–0.52 L/L; hemoglobin, 102–105 g/L; reference
* Corresponding author at: Angelika Schoster, DrMedVet, DVSc, DACVIM, DECEIM, Clinic for Equine Internal Medicine, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057, Zurich, Switzerland. E-mail address: [email protected] (A. Schoster). 0737-0806/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jevs.2014.07.002
A. Schoster et al. / Journal of Equine Veterinary Science 34 (2014) 1234–1239
range, 110–190 g/L) and hyperglobulinemia (64–69 g/L; reference range, 22–40 g/L). Transient mild mature neutrophilia (8.3 109 cells/L; reference range, 2.7–6.7 109 cells/L) was also noted. A course of antibiotic treatment with trimethoprim sulfonamide (24 mg/kg PO, every 12 hours for 20 days) was administered, and mild improvement was noted; however, hematological abnormalities and exercise intolerance were unchanged. The pony was regularly dewormed and vaccinated against influenza and tetanus and had been in current ownership for 9 years. The current owners reported no prior medical problems; however, no history from the previous owner was available. On presentation to the Ontario Veterinary College, University of Guelph, the mare was bright and in good body condition (body condition score [BCS], 3/5; 313 kg). Mild tachypnea (respiratory rate, 36 breaths/min) with increased abdominal effort was present. Increased bronchial sounds were auscultated diffusely over the caudodorsal lung fields bilaterally. Reduced lung sounds, most evident on rebreathing, were noted cranioventral. No crackles or wheezes were heard. All other findings on physical examination were within normal limits. Hemogram and serum biochemical abnormalities included anemia, hyperfibrinogenemia, hypoalbuminemia, and hyperglobulinemia. No others significant abnormalities were present (Table 1). Results for a coagulation profile including plasma prothrombin time and partial thromboplastin time and arterial blood gas analysis, including pH, partial oxygen pressure, partial carbon dioxide pressure, base excess, and bicarbonate, were normal. On thoracic radiographs, a mineralized opacity in the caudoventral region of the lungs, immediately caudal to the heart was present (Fig. 1). A second mineralized opacity was present cranial to the heart. The caudodorsal aspect of the lungs had a mild interstitial pattern. Dorsoventral radiographs confirmed that the mineral opacities were present bilaterally (Fig. 2). There were normal contours of the cardiomediastinum. On thoracic ultrasound imaging, an irregular surface of the right ventral lung, multiple comet-tail or ring-down artifacts, and additionally several 3.5-cm round focal areas of consolidation were present. On the left side, the visceral pleura was thickened (up to 1 cm) creating a “rindlike” appearance. In addition, the pleural margin was irregular with multifocal ring-down artifacts and several lesions extending into the pulmonary parenchyma (Fig. 3). Abdominal ultrasound imaging result was normal. Attempt at ultrasound-guided lung biopsy failed because of the abnormal consistency of the lung tissue preventing penetration of the visceral pleura bilaterally. Bronchoscopy illustrated severe bronchoconstriction and a blunted carina. Cytologic evaluation of bronchoalveolar lavage fluid supported severe inflammatory airway disease: nucleated cell count, 2.1 109 cells/L (reference range, 0.2–0.4 109 cells/L); lymphocytes, 49% (reference range,15%–30%); macrophages, 35% (reference range, 35%–70%); mast cells, 3% (reference range, 0%–2%); and segmented neutrophils, 14% (reference range, 0%–4%); macrophages were activated and Curschmann spirals were present. No bacteria or crystalline material was seen.
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Table 1 Hematology and serum biochemistry of a horse affected with extensive generalized pulmonary calcification. Parameter
Reference Range
Hematocrit, L/L 0.28–0.44 RBC, 109 6.9–10.7 Hemoglobin, g/L 112–169 MCV, fL 36–45 MCH, pg 14–18 MCHC, g/L 369–426 Red cell distribution width, % 18–21 White blood cells, 109 5.1–11.0 Band neutrophils, 109 0–0.2 Seg. neutrophils, 109 2.8–7.7 Lymphocytes, 109 1.3–4.7 Monocytes, 109 0.1–0.8 9 Eosinophils, 10 0–0.7 Basophils, 109 0–0.2 Platelets, 109 83–270 Mean platelet volume, fL 6–11 BUN, mmol/L 4.2–8.9 Creatinine, mmol/L 80–130 Alk. Phos., IU/L 119–329 GGT, IU/L 7–54 GLDH, IU/L 1–7 SGOT (AST), IU/L 259–595 CK, IU/L 108–430 Total bilirubin, mmol/L 21–57 Direct bilirubin, mmol/L 2–3 Glucose, mmol/L 3.7–6.7 Sodium, mmol/L 136–144 Potassium, mmol/L 3.1–4.3 Chloride, mmol/L 95–104 Calcium, mmol/L 2.75–3.35 Phosphorus, mmol/L 0.73–1.71 Calcium phosphorus Not available 2 2 (mg /dL ) Magnesium, mmol/L 0.6–1.0 Anion gap, mmol/L 6–21 Total protein, g/L 58–75 Albumin, g/L 30–37 Globulin, g/L 26–41 Cholesterol, mmol/L 1.7–2.70 Haptoglobin, mmol/L 0.1–1.7 Fibrinogen, g/L 1.2–2.3
Initial
2 mo
7 mo
0.30 5.9 111 50 19 376 17.5 8.8 0 6.95 1.50 0.26 0.09 0 193 6.1 7.9 65 64 22 2 183 98 10 3 6.4 136 4.5 102 2.98 0.82 30.2
0.37 7.2 136 51 19 374 17.2 13.7 0 12.06 0.69 0.82 0 0.14 336 7.1 11.2 177 123 67 9 314 144 13 3 6.4 133 4.4 88 3.77 0.80 37.4
0.32 6.4 114 50 18 352 16.4 10.9 0 8.94 1.31 0.55 0 0.11 302 6.8 2.7 61 177 130 22 224 153 5 1 6.0 131 3.6 96 2.77 0.85 29.1
0.7 13 96 27 69 1.91 1.74 3.3
0.6 0.8 17 13 80 101 28 21 52 80 2.73 1.63 1.69 1.5 3.7
Alk. Phos., alkaline phosphatase; BUN, blood urea nitrogen; CK, creatinine kinase; GGT, gamma-glutamyl transferase; GLDH, glutamate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cells; Seg. neutrophils, segmented neutrophils; SGOT (AST), aspartate transaminase.
Aerobic culture of bronchoalveolar fluid was negative. An echocardiogram was performed and showed normal functional and anatomic indices of the heart. No signs of pulmonary hypertension were present (pulmonary artery diameter and tricuspid regurgitation flow velocity and/or pressure differential). Testing for rheumatoid factor was negative, and antinuclear antibody was positive. Protein electrophoresis showed a polyclonal gammopathy (total protein, 94 g/L; reference range, 58–75 g/L; albumin, 28 g/L; reference range, 25–36 g/L; globulin, 66 g/L; reference range, 26–41 g/L; alpha1-globulin, 2 g/L; reference range, 5–14 g/L; beta1-globulin, 8 g/L; reference range, 9– 18 g/L; gamma globulins, 42 g/L; reference range, 6–14 g/L). Immunoelectrophoresis showed increased levels of immunoglobulin G. No M-protein was detected.
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A. Schoster et al. / Journal of Equine Veterinary Science 34 (2014) 1234–1239
Fig. 1. Lateral radiograph of the lung of a horse affected with extensive generalized pulmonary calcification. A mineralized opacity in the caudoventral region of the lungs is present. A second mineralized opacity was present cranial to the heart. The caudodorsal aspect of the lungs had a mild interstitial pattern.
Final diagnoses included severe inflammatory airway disease and extensive pulmonary mineralization of unknown origin. The owners were advised to reduce exercise to light riding only, as the disease was suspected to be performance limiting and progressive in nature. Treatment with inhaled fluticazone (250 mg aerosol; four puffs (4.1 mg/ puff) every 12 hours for 3 weeks and then every 24 hours for 3 weeks) was prescribed to treat inflammatory airway disease. The pony presented again 2 months later because of deterioration. The owner reported that the pony had significant weight loss and decreased appetite. On presentation, the mare was quiet and in thin body condition (BCS, 2/ 5; 280 kg). Severe tachycardia (88 beats/min) and mild tachypnea (respiratory rate, 20 breaths/min) with increased abdominal effort were observed. Pulmonary auscultation was similar to the initial presentation. Electrocardiogram revealed sinus tachycardia. Arterial blood gas analysis, including pH, pO2, pCO2, base excess, and HCO3 , was normal. A single dose of flunixin meglumine was given IV (1.1 mg/kg). The heart was reauscultated 30 minutes later, and the heart rate had decreased to normal (36 beats/min). Consequently, the tachycardia was attributed to pain. Hemogram and serum biochemical analysis showed persistent hyperfibrinogenemia and hyperglobulinemia. Leukocytosis characterized by mature neutrophilia, and lymphopenia, was also noted (Table 1). Thoracic radiographs indicated no significant changes in comparison with those obtained on initial presentation. Recommendations to the owner included turn out on small pasture and cessation of exercise with a guarded prognosis
Fig. 2. Dorsoventral radiographs of the lung of a horse affected with extensive generalized pulmonary calcification.
if pain could not be controlled or clinical signs progressed. Flunixin meglumine (1.1 mg/kg PO, every 12 hours for 14 days) to alleviate pain was prescribed. Because of continued deterioration of clinical signs, further weight loss, and decrease in appetite, the owners elected humane euthanasia 7 months after initial presentation. On final presentation, the pony was quiet but alert and in poor body condition (BCS, 1.5/5; 300 kg). Mild tachycardia (48 beats/min) and moderate tachypnea (respiratory rate, 36 breaths/min) with increased abdominal
Fig. 3. Thoracic ultrasound image of a horse affected with pulmonary calcification. Picture shows image from the left 10th intercostal space 5 cm dorsal to the olecranon. The visceral pleura is thickened (up to 1 cm) creating a “rind-like” appearance of 1.1 cm thickness. In addition, the pleural margin is irregular with multifocal ring-down artifacts and several lesions extending into the pulmonary parenchyma.
A. Schoster et al. / Journal of Equine Veterinary Science 34 (2014) 1234–1239
effort were observed. Lung sounds, hemogram, and serum biochemical abnormalities were essentially unchanged in comparison with the initial presentation (Table 1). Repeat thoracic radiographs and ultrasound images were declined. The pony was euthanized and submitted for necropsy. On necropsy, the right cranioventral, accessory lung lobe and 20% of left cranioventral and cranial portion of the caudal lobes were replaced by hard mineralized tissue. The remaining portion of the caudal lung lobes failed to collapse and had a rubbery consistency but showed no evidence of mineralization (Figs. 4 and 5). Multiple mediastinal lymph nodes were mineralized and hard. The epicardial surface of the right and left auricles contained multiple, dark brown, hemorrhagic spots of varying size. The liver capsule was thick and fibrotic; on cut surface, the hepatic parenchyma had a reticular–acinar pattern. Sections of the abnormal lung tissue were decalcified before histologic examination. Thick sheets of fibrous connective tissue organized into layers and lamellae replaced the normal architecture of the pulmonary parenchyma in more than 90% of the lung lobe examined. There was increase in peribronchial and peribronchiolar fibrous connective tissue, and the adjacent bronchi and bronchioles were collapsed. The bronchiolar epithelium was atrophic, and submucosa was expanded by edema and neutrophilic plasma–lymphocytic infiltrate. An area adjacent to the sheets of connective tissue contained focal areas of hemorrhage and remnants of alveoli that were filled with large numbers of free floating foamy macrophages, neutrophils, and fibrin. Within the fibrous connective tissue were large foci containing hypereosinophilic acellular material. This material was organized in the form of concentric circles consistent with mineralization (Fig. 5). Histologic evaluation of the liver was consistent with hepatic fibrosis, hepatitis, and necrosis. The clinical, postmortem, and histopathologic findings were consistent with generalized severe pulmonary fibrosis and calcification.
Fig. 4. Gross pathology of the lungs of a horse affected with pulmonary dystrophic calcification. The right cranioventral, accessory lung lobe and 20% of left cranioventral and cranial portion of the caudal lobes are replaced by hard mineralized tissue. The remaining portion of the caudal lung lobes fails to collapse and has a rubbery consistency but shows no evidence of mineralization.
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Fig. 5. Gross pathology of cut sections of the lungs of a horse affected with pulmonary dystrophic calcification.
3. Discussion Ectopic calcification, which is defined as inappropriate formation of mineral crystals in soft tissue, which normally do not mineralize, occurs as squeal to varying underlying disorders and is divided broadly into metastatic and dystrophic calcification. Deposition of calcium in dead or dying tissue is termed dystrophic calcification, whereas metastatic calcification is defined as mineralization as a sequel to an underlying abnormality in regulatory mechanisms that prevent and activate mineralization in tissues [1,2]. A number of pathologic conditions predispose pulmonary tissue to calcification. In humans, dystrophic pulmonary calcification has been reported in association with, or secondary to, a variety of diseases such as alveolar microlithiasis, pulmonary amyloidosis, granulomatous lung disease, viral disease, parasitic disease, pulmonary vascular calcifications, or as an idiopathic disease [1,3–5]. Metastatic calcifications are caused by high levels of serum calcium and phosphate, which deposit in normal lung tissue. The most common causes in humans are hyperthyroidism, chronic renal failure, and neoplastic destructive bony lesions [6–8]. Internal organs most commonly affected by ectopic calcification include stomach, kidney, lungs heart, and blood vessels in humans [1]. In dogs, pulmonary calcification has been reported in association with Cushing disease, renal failure, or previous fungal infection generalized pulmonary neoplasia and as an idiopathic syndrome [9,10]. In cattle, metastatic pulmonary calcification has been reported, secondary to hypervitaminosis D, dietary imbalances, and plant toxicities [11,12]. In horses, calcification of the tunica media of the pulmonary artery has been identified in postmortem in 82% of studied racehorses without associated clinical signs [13]. In a case series, systemic calcinosis was described in five horses. All horses had multiple organs affected by calcium deposition, including muscle, kidney, lung, epicardium, pleura, and liver. Systemic calcinosis was hypothesized to be precipitated by an inflammatory condition, trauma, steroid, or plasma administration and because of an underlying disturbance of the calcium–phosphorus balance [14]. However, calcification exclusively of the lungs, particularly to this extent, has so far not been reported to the knowledge of the authors.
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In our case, no signs of underlying abnormalities in the calcium–phosphorus balance were present. Calcium blood concentration was elevated 2 months after the initial presentation; however, this was mild and transient. Phosphate concentrations were within normal limits, and the calcium phosphorus product ranged between 29.1 and 37.4 mg2/ dL2. Although there is no reference range for horses, in humans, values above 70 are considered as a measure for metastatic calcification. In a case series of five horses with suspected calcinosis, all five horses had a calcium–phosphorus product above 70, accompanied by hyperphosphatemia [14]. Vitamin D levels and parathyroid hormone levels were not assessed. Therefore, dystrophic calcification was considered more likely [3]. In our case, idiopathic pulmonary calcification cannot be ruled out; however, it is speculated in humans that cases of idiopathic pulmonary ossification might be a sequel to previously unidentified lung injury [1]. Chronic inflammation, evidenced by hyperglobulinemia, hypoalbuminemia, and hyperfibrinogenemia in our case, could have contributed to calcification through the effect of proinflammatory cytokines on bone resorption. However, as no abnormalities in calcium–phosphorous balance were present, it is more likely that the chronic signs of inflammation were secondary to the lung injury and calcification of the lungs. The positive antinuclear antibody could indicate an autoimmune disorder in this case; however, no further signs of autoimmune disease were found during the examination, and the lesions in this case were solely restricted to the lungs, making this a less likely contributive factor for the calcification. Nephrosis is a cause of pulmonary calcification in humans and was also seen in some of the horses in the case series [3]. The azotemia and slightly decreased sodium and chloride levels in this case could be early markers for nephrosis; however, no signs were found on gross pathology or histopathology indicating renal disease. The gross pathologic feature of extensive generalized calcification of a defined large region of the lung makes dystrophic pulmonary calcification the most likely diagnosis. The histologic lesions of the lung suggest previous episodes of chronic pulmonary injury, and the lesions were repaired and replaced by marked amounts of fibrous tissue and mineralization that grossly appeared as calcified. The mechanism of pulmonary calcification is not precisely known. Calcium is an important ion for cellular integrity, and an increase in intracellular calcium may contribute to injury. This increase results from a net influx of extracellular calcium and the release of intracellular calcium from mitochondria and the endoplasmic reticulum. The elevated intracellular calcium activates a number of enzymes, which promote necrotic cell death. In addition, there is leakage of cellular phospholipases into the extracellular space with entry of extracellular phospholipids into the dying cells. Degradation of phospholipids into fatty acids, followed by binding of calcium to the fatty acids, is the hypothesized mechanism for dystrophic calcification at injury sites. This “initiation phase” of dystrophic calcification is followed by a “propagation phase,” with further calcium and phosphate crystallization at the initial nidi of calcification. During cell injury, there is an early fall in pH,
followed by a shift to a neutral or alkaline pH as injury continues, the latter state further predisposing to ectopic calcification. The calcium-binding phosphoprotein, osteopontin, appears to play a role in dystrophic calcification [1]. Pulmonary calcification in humans usually involves a limited area of the lung and is often functionally unimportant. Even when present, the extent of physiological impairment does not necessarily correlate with the degree of macroscopic calcification. Some patients with extensive calcification may be asymptomatic, whereas others with more subtle calcification in the face of normal chest radiographs may have significant physiological impairment [15]. If clinical signs occur, they are characterized by dyspnea and coughing, as well as other symptoms of restrictive lung disease [1]. In dogs, there has been one case report where disease was generalized and was associated with pulmonary functional compromise [10]. Given the extent of the calcified lung area in this case, it is not surprising that clinical signs were present. The diagnosis in humans is usually incidental at autopsy and the disease itself considered rare [16]. Antemortem diagnosis of pulmonary calcification in humans has not been well described, and methods used most recently include plain or contrast radiography, computed tomography, and nuclear scintigraphy [17]. High-resolution computed tomography scan and 99m technetium–methylene diphosphate nuclear scintigraphy are more sensitive and specific than the chest X-ray for the detection of pulmonary calcification [18,19]. Because of the size limitation of the gantry, chest computed tomography could not be performed in our patient and nuclear scintigraphy was deemed unnecessary based on the obvious lesions on plain radiographs. Based on the few case reports where the disease was diagnosed antemortem, the clinical course of the disease is indolent in humans or slowly progressive, prognosis depends on age and the underlying conditions [20]. Treatment options for dystrophic pulmonary calcification are limited in humans as few cases are diagnosed antemortem. The literature contains no cases of spontaneous regression. Corticosteroids are often prescribed along with lowcalcium diets, however, have not shown any clear benefits. Any treatment in humans is considered experimental [16]. There are currently no reported cases of pulmonary calcification in horses to the degree that is present in this case. The discrete bilateral cranioventral distribution suggests that the calcification of the lung tissue followed necrosis of these regions. The liver lesions were likely because of previous injury and repair as no signs of right-sided congestive heart failure were present. This is also supported by mildly elevated liver enzymes 2 and 7 months after the initial presentation and could indicate hepatic injury around that time (Table 1). Because of the absence of evidence of calcification of the liver on gross pathology and histopathology, this appears unrelated to the calcification of the lungs. The dark hemorrhagic spots on the epicardium were most likely due to trauma from constant rubbing or impact against the mineralized lung. This is the first report of extensive dystrophic pulmonary calcification in a horse. The histologic lesions of the lungs of this horse suggest that the animal had previous
A. Schoster et al. / Journal of Equine Veterinary Science 34 (2014) 1234–1239
episodes of chronic pulmonary injury, and the lesions were repaired and replaced by marked amounts of fibrous tissue and mineralization that grossly appeared as calcified sequestrate. Given the extent of the calcification, it is likely that the insult occurred several years ago and the calcification has been progressing since but had been asymptomatic until presentation. Unfortunately, there was no further history available beyond the years of the current ownership in our case; therefore, we cannot rule in or rule out a previous pulmonary insult as the cause of pulmonary calcification. Acknowledgments The authors have no conflict of interest to declare. All authors declare that they contributed substantially to the acquisition of data of this case, drafting, and revising of the manuscript. All authors have read and approved the submission of the manuscript. Submission declaration: The presented paper is original, has not been published previously (except in the form of an abstract or academic thesis), is not under consideration for publication elsewhere, and its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out. If accepted, it will not be published elsewhere including electronically in the same form, in English, or in any other language, without the written consent of the copyright hold is original. References [1] Chan ED, Morales DV, Welsh CH, McDermott MT, Schwarz MI. Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med 2002;165:1654–69. [2] Kirsch T. Determinants of pathological mineralization. Curr Opin Rheumatol 2006;18:174–80. [3] Bendayan D, Barziv Y, Kramer MR. Pulmonary calcifications: a review. Respir Med 2000;94:190–3. [4] Murray J, Kielkowski D, Leiman G. The prevalence and age distribution of peripheral pulmonary hamartomas in adult males. An autopsy-based study. S Afr Med J 1991;79:247–9.
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[5] Lee MM, Schinella RA. Pulmonary calcification caused by Pneumocystis carinii pneumonia. A clinicopathological study of 13 cases in acquired immune deficiency syndrome patients. Am J Surg Pathol 1991;15:376–80. [6] Kempter H, Hagner G, Savaser AN, Huben H, Minguillon C. Metastatic pulmonary calcification in a patient with nonsecretory multiple myeloma. Respiration 1986;49:77–80. [7] Murris-Espin M, Lacassagne L, Didier A, Voigt JJ, Cisterne JM, Giron J, et al. Metastatic pulmonary calcification after renal transplantation. Eur Respir J 1997;10:1925–7. [8] Bestetti-Bosisio M, Cotelli F, Schiaffino E, Sorgato G, Schmid C. Lung calcification in long-term dialysed patients: a light and electronmicroscopic study. Histopathology 1984;8:69–79. [9] Berry CR, Hawkins EC, Hurley KJ, Monce K. Frequency of pulmonary mineralization and hypoxemia in 21 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2000;14:151–6. [10] Thrall DE, Goldschmidt MH, Clement RJ, Goldsmith B. Generalized extensive idiopathic pulmonary ossification in a dog: a case report. Vet Radiol 1980;21:104–7. [11] Petrie L, Breeze RG. Hypervitaminosis D and metastatic pulmonary calcification in a cow. Vet Rec 1977;101:480–2. [12] Bundza A, Stevenson DA. Arteriosclerosis in seven cattle. The Can Veterinary Journal La Revue Veterinaire Canadienne 1987;28: 49–51. [13] Arroyo LG, Hayes MA, Delay J, Rao C, Duncan B, Viel L. Arterial calcification in race horses. Vet Pathology 2008;45:617–25. [14] Tan JY, Valberg SJ, Sebastian MM, Davis GD, Kelly JR, Goehring LS, et al. Suspected systemic calcinosis and calciphylaxis in 5 horses. The Can Veterinary Journal La Revue Veterinaire Canadienne 2010; 51:993–9. [15] Tsuji T, Nakamura S, Komuro I, Mikami M, Baba M, Tanaka M. A living case of pulmonary ossification associated with osteoclast formation from alveolar macrophage in the presence of T-cell cytokines. Intern Med 2003;42:834–8. [16] Fernandez Crisosto CA, Quercia Arias O, Bustamante N, Moreno H, Uribe Echevarria A. Diffuse pulmonary ossification associated with idiopathic pulmonary fibrosis. Arch Bronconeumol 2004;40: 595–8. [17] Lara JF, Catroppo JF, Kim DU, da Costa D. Dendriform pulmonary ossification, a form of diffuse pulmonary ossification: report of a 26year autopsy experience. Arch Pathol Lab Med 2005;129:348–53. [18] Faubert PF, Shapiro WB, Porush JG, Chou SY, Gross JM, Bondi E, et al. Pulmonary calcification in hemodialyzed patients detected by technetium-99m diphosphonate scanning. Kidney Int 1980;18: 95–102. [19] Brodeur Jr FJ, Kazerooni EA. Metastatic pulmonary calcification mimicking air-space disease. Technetium-99m-MDP SPECT imaging. Chest 1994;106:620–2. [20] Peros-Golubicic T, Tekavec-Trkanjec J. Diffuse pulmonary ossification: an unusual interstitial lung disease. Curr Opin Pulm Med 2008; 14:488–92.
Contents lists available at ScienceDirect
Journal of Equine Veterinary Science journal homepage: www.j-evs.com
Case Report
Extensive Dystrophic Pulmonary Calcification in a Welsh Pony Mare Angelika Schoster DrMedVet, DVSc, DACVIM, DECEIM a, b, *, Alexandra Bratton BSc, DVM, DVSc b, M. Kimberly J. McGurrin BSc, DVM, DVSc, DACVIM b a b
Equine Department, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 December 2013 Received in revised form 23 June 2014 Accepted 9 July 2014 Available online 16 July 2014
A 12-year-old Welsh pony mare was presented to the Ontario Veterinary College Teaching Hospital for signs of intermittent lethargy and increased abdominal breathing effort of 6 months duration. After physical examination, blood work, bronchoscopy, bronchoalveolar lavage, and diagnostic imaging of the thorax and attempted lung biopsy, pulmonary mineralization of unknown origin was suspected. The pony was treated palliative for 7 months with nonsteroidal anti-inflammatories and inhaled corticosteroids to treat accompanying airway inflammation before being euthanized because of poor prognosis and deterioration of clinical signs. On postmortem examination, the pulmonary architecture of the right and left cranioventral lung lobes, accessory lobe, and cranial potions of the left caudal lung lobe was replaced by hard mineralized tissue. No other organs other than a mediastinal lymph node and the lung were affected by mineralization. After decalcification, thick sheets of fibrous connective tissue organized into layers and lamellae replaced the normal architecture of the pulmonary parenchyma in more than 90% of the lung lobe examined on histopathology. The findings were consistent with generalized severe pulmonary fibrosis and dystrophic calcification. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Lung calcification Mineralized lung
1. Introduction
2. Case Presentation
Dystrophic pulmonary calcification is a rare clinical syndrome associated with varying underlying disorders in humans, dogs, and horses. This case report describes a case of extensive generalized dystrophic pulmonary calcification involving both cranioventral lung lobes to an extent not reported before. No signs of neoplasia, previous respiratory disease, or metabolic disease were present.
A 12-year-old Welsh pony mare was presented for a history of lethargy and increased respiratory effort. The pony was used as a show hunter up until the time of presentation. For 6 months before presentation, the pony began tiring easily when being ridden and intermittent increased abdominal effort during breathing was observed. No coughing or other signs were observed. Appetite and fecal output were normal. The referring veterinarian reported no abnormalities on repeated physical examination. Serial blood hematology and biochemistry over the next 6 months showed persistent anemia (red blood cell count, 5.4 1012 to 6.4 1012 cells/L; reference range, 8.8 1012 to 12.5 1012 cells/L; hematocrit, 0.27–0.31 L/L; reference range, 0.32–0.52 L/L; hemoglobin, 102–105 g/L; reference
* Corresponding author at: Angelika Schoster, DrMedVet, DVSc, DACVIM, DECEIM, Clinic for Equine Internal Medicine, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, 8057, Zurich, Switzerland. E-mail address: [email protected] (A. Schoster). 0737-0806/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jevs.2014.07.002
A. Schoster et al. / Journal of Equine Veterinary Science 34 (2014) 1234–1239
range, 110–190 g/L) and hyperglobulinemia (64–69 g/L; reference range, 22–40 g/L). Transient mild mature neutrophilia (8.3 109 cells/L; reference range, 2.7–6.7 109 cells/L) was also noted. A course of antibiotic treatment with trimethoprim sulfonamide (24 mg/kg PO, every 12 hours for 20 days) was administered, and mild improvement was noted; however, hematological abnormalities and exercise intolerance were unchanged. The pony was regularly dewormed and vaccinated against influenza and tetanus and had been in current ownership for 9 years. The current owners reported no prior medical problems; however, no history from the previous owner was available. On presentation to the Ontario Veterinary College, University of Guelph, the mare was bright and in good body condition (body condition score [BCS], 3/5; 313 kg). Mild tachypnea (respiratory rate, 36 breaths/min) with increased abdominal effort was present. Increased bronchial sounds were auscultated diffusely over the caudodorsal lung fields bilaterally. Reduced lung sounds, most evident on rebreathing, were noted cranioventral. No crackles or wheezes were heard. All other findings on physical examination were within normal limits. Hemogram and serum biochemical abnormalities included anemia, hyperfibrinogenemia, hypoalbuminemia, and hyperglobulinemia. No others significant abnormalities were present (Table 1). Results for a coagulation profile including plasma prothrombin time and partial thromboplastin time and arterial blood gas analysis, including pH, partial oxygen pressure, partial carbon dioxide pressure, base excess, and bicarbonate, were normal. On thoracic radiographs, a mineralized opacity in the caudoventral region of the lungs, immediately caudal to the heart was present (Fig. 1). A second mineralized opacity was present cranial to the heart. The caudodorsal aspect of the lungs had a mild interstitial pattern. Dorsoventral radiographs confirmed that the mineral opacities were present bilaterally (Fig. 2). There were normal contours of the cardiomediastinum. On thoracic ultrasound imaging, an irregular surface of the right ventral lung, multiple comet-tail or ring-down artifacts, and additionally several 3.5-cm round focal areas of consolidation were present. On the left side, the visceral pleura was thickened (up to 1 cm) creating a “rindlike” appearance. In addition, the pleural margin was irregular with multifocal ring-down artifacts and several lesions extending into the pulmonary parenchyma (Fig. 3). Abdominal ultrasound imaging result was normal. Attempt at ultrasound-guided lung biopsy failed because of the abnormal consistency of the lung tissue preventing penetration of the visceral pleura bilaterally. Bronchoscopy illustrated severe bronchoconstriction and a blunted carina. Cytologic evaluation of bronchoalveolar lavage fluid supported severe inflammatory airway disease: nucleated cell count, 2.1 109 cells/L (reference range, 0.2–0.4 109 cells/L); lymphocytes, 49% (reference range,15%–30%); macrophages, 35% (reference range, 35%–70%); mast cells, 3% (reference range, 0%–2%); and segmented neutrophils, 14% (reference range, 0%–4%); macrophages were activated and Curschmann spirals were present. No bacteria or crystalline material was seen.
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Table 1 Hematology and serum biochemistry of a horse affected with extensive generalized pulmonary calcification. Parameter
Reference Range
Hematocrit, L/L 0.28–0.44 RBC, 109 6.9–10.7 Hemoglobin, g/L 112–169 MCV, fL 36–45 MCH, pg 14–18 MCHC, g/L 369–426 Red cell distribution width, % 18–21 White blood cells, 109 5.1–11.0 Band neutrophils, 109 0–0.2 Seg. neutrophils, 109 2.8–7.7 Lymphocytes, 109 1.3–4.7 Monocytes, 109 0.1–0.8 9 Eosinophils, 10 0–0.7 Basophils, 109 0–0.2 Platelets, 109 83–270 Mean platelet volume, fL 6–11 BUN, mmol/L 4.2–8.9 Creatinine, mmol/L 80–130 Alk. Phos., IU/L 119–329 GGT, IU/L 7–54 GLDH, IU/L 1–7 SGOT (AST), IU/L 259–595 CK, IU/L 108–430 Total bilirubin, mmol/L 21–57 Direct bilirubin, mmol/L 2–3 Glucose, mmol/L 3.7–6.7 Sodium, mmol/L 136–144 Potassium, mmol/L 3.1–4.3 Chloride, mmol/L 95–104 Calcium, mmol/L 2.75–3.35 Phosphorus, mmol/L 0.73–1.71 Calcium phosphorus Not available 2 2 (mg /dL ) Magnesium, mmol/L 0.6–1.0 Anion gap, mmol/L 6–21 Total protein, g/L 58–75 Albumin, g/L 30–37 Globulin, g/L 26–41 Cholesterol, mmol/L 1.7–2.70 Haptoglobin, mmol/L 0.1–1.7 Fibrinogen, g/L 1.2–2.3
Initial
2 mo
7 mo
0.30 5.9 111 50 19 376 17.5 8.8 0 6.95 1.50 0.26 0.09 0 193 6.1 7.9 65 64 22 2 183 98 10 3 6.4 136 4.5 102 2.98 0.82 30.2
0.37 7.2 136 51 19 374 17.2 13.7 0 12.06 0.69 0.82 0 0.14 336 7.1 11.2 177 123 67 9 314 144 13 3 6.4 133 4.4 88 3.77 0.80 37.4
0.32 6.4 114 50 18 352 16.4 10.9 0 8.94 1.31 0.55 0 0.11 302 6.8 2.7 61 177 130 22 224 153 5 1 6.0 131 3.6 96 2.77 0.85 29.1
0.7 13 96 27 69 1.91 1.74 3.3
0.6 0.8 17 13 80 101 28 21 52 80 2.73 1.63 1.69 1.5 3.7
Alk. Phos., alkaline phosphatase; BUN, blood urea nitrogen; CK, creatinine kinase; GGT, gamma-glutamyl transferase; GLDH, glutamate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cells; Seg. neutrophils, segmented neutrophils; SGOT (AST), aspartate transaminase.
Aerobic culture of bronchoalveolar fluid was negative. An echocardiogram was performed and showed normal functional and anatomic indices of the heart. No signs of pulmonary hypertension were present (pulmonary artery diameter and tricuspid regurgitation flow velocity and/or pressure differential). Testing for rheumatoid factor was negative, and antinuclear antibody was positive. Protein electrophoresis showed a polyclonal gammopathy (total protein, 94 g/L; reference range, 58–75 g/L; albumin, 28 g/L; reference range, 25–36 g/L; globulin, 66 g/L; reference range, 26–41 g/L; alpha1-globulin, 2 g/L; reference range, 5–14 g/L; beta1-globulin, 8 g/L; reference range, 9– 18 g/L; gamma globulins, 42 g/L; reference range, 6–14 g/L). Immunoelectrophoresis showed increased levels of immunoglobulin G. No M-protein was detected.
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Fig. 1. Lateral radiograph of the lung of a horse affected with extensive generalized pulmonary calcification. A mineralized opacity in the caudoventral region of the lungs is present. A second mineralized opacity was present cranial to the heart. The caudodorsal aspect of the lungs had a mild interstitial pattern.
Final diagnoses included severe inflammatory airway disease and extensive pulmonary mineralization of unknown origin. The owners were advised to reduce exercise to light riding only, as the disease was suspected to be performance limiting and progressive in nature. Treatment with inhaled fluticazone (250 mg aerosol; four puffs (4.1 mg/ puff) every 12 hours for 3 weeks and then every 24 hours for 3 weeks) was prescribed to treat inflammatory airway disease. The pony presented again 2 months later because of deterioration. The owner reported that the pony had significant weight loss and decreased appetite. On presentation, the mare was quiet and in thin body condition (BCS, 2/ 5; 280 kg). Severe tachycardia (88 beats/min) and mild tachypnea (respiratory rate, 20 breaths/min) with increased abdominal effort were observed. Pulmonary auscultation was similar to the initial presentation. Electrocardiogram revealed sinus tachycardia. Arterial blood gas analysis, including pH, pO2, pCO2, base excess, and HCO3 , was normal. A single dose of flunixin meglumine was given IV (1.1 mg/kg). The heart was reauscultated 30 minutes later, and the heart rate had decreased to normal (36 beats/min). Consequently, the tachycardia was attributed to pain. Hemogram and serum biochemical analysis showed persistent hyperfibrinogenemia and hyperglobulinemia. Leukocytosis characterized by mature neutrophilia, and lymphopenia, was also noted (Table 1). Thoracic radiographs indicated no significant changes in comparison with those obtained on initial presentation. Recommendations to the owner included turn out on small pasture and cessation of exercise with a guarded prognosis
Fig. 2. Dorsoventral radiographs of the lung of a horse affected with extensive generalized pulmonary calcification.
if pain could not be controlled or clinical signs progressed. Flunixin meglumine (1.1 mg/kg PO, every 12 hours for 14 days) to alleviate pain was prescribed. Because of continued deterioration of clinical signs, further weight loss, and decrease in appetite, the owners elected humane euthanasia 7 months after initial presentation. On final presentation, the pony was quiet but alert and in poor body condition (BCS, 1.5/5; 300 kg). Mild tachycardia (48 beats/min) and moderate tachypnea (respiratory rate, 36 breaths/min) with increased abdominal
Fig. 3. Thoracic ultrasound image of a horse affected with pulmonary calcification. Picture shows image from the left 10th intercostal space 5 cm dorsal to the olecranon. The visceral pleura is thickened (up to 1 cm) creating a “rind-like” appearance of 1.1 cm thickness. In addition, the pleural margin is irregular with multifocal ring-down artifacts and several lesions extending into the pulmonary parenchyma.
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effort were observed. Lung sounds, hemogram, and serum biochemical abnormalities were essentially unchanged in comparison with the initial presentation (Table 1). Repeat thoracic radiographs and ultrasound images were declined. The pony was euthanized and submitted for necropsy. On necropsy, the right cranioventral, accessory lung lobe and 20% of left cranioventral and cranial portion of the caudal lobes were replaced by hard mineralized tissue. The remaining portion of the caudal lung lobes failed to collapse and had a rubbery consistency but showed no evidence of mineralization (Figs. 4 and 5). Multiple mediastinal lymph nodes were mineralized and hard. The epicardial surface of the right and left auricles contained multiple, dark brown, hemorrhagic spots of varying size. The liver capsule was thick and fibrotic; on cut surface, the hepatic parenchyma had a reticular–acinar pattern. Sections of the abnormal lung tissue were decalcified before histologic examination. Thick sheets of fibrous connective tissue organized into layers and lamellae replaced the normal architecture of the pulmonary parenchyma in more than 90% of the lung lobe examined. There was increase in peribronchial and peribronchiolar fibrous connective tissue, and the adjacent bronchi and bronchioles were collapsed. The bronchiolar epithelium was atrophic, and submucosa was expanded by edema and neutrophilic plasma–lymphocytic infiltrate. An area adjacent to the sheets of connective tissue contained focal areas of hemorrhage and remnants of alveoli that were filled with large numbers of free floating foamy macrophages, neutrophils, and fibrin. Within the fibrous connective tissue were large foci containing hypereosinophilic acellular material. This material was organized in the form of concentric circles consistent with mineralization (Fig. 5). Histologic evaluation of the liver was consistent with hepatic fibrosis, hepatitis, and necrosis. The clinical, postmortem, and histopathologic findings were consistent with generalized severe pulmonary fibrosis and calcification.
Fig. 4. Gross pathology of the lungs of a horse affected with pulmonary dystrophic calcification. The right cranioventral, accessory lung lobe and 20% of left cranioventral and cranial portion of the caudal lobes are replaced by hard mineralized tissue. The remaining portion of the caudal lung lobes fails to collapse and has a rubbery consistency but shows no evidence of mineralization.
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Fig. 5. Gross pathology of cut sections of the lungs of a horse affected with pulmonary dystrophic calcification.
3. Discussion Ectopic calcification, which is defined as inappropriate formation of mineral crystals in soft tissue, which normally do not mineralize, occurs as squeal to varying underlying disorders and is divided broadly into metastatic and dystrophic calcification. Deposition of calcium in dead or dying tissue is termed dystrophic calcification, whereas metastatic calcification is defined as mineralization as a sequel to an underlying abnormality in regulatory mechanisms that prevent and activate mineralization in tissues [1,2]. A number of pathologic conditions predispose pulmonary tissue to calcification. In humans, dystrophic pulmonary calcification has been reported in association with, or secondary to, a variety of diseases such as alveolar microlithiasis, pulmonary amyloidosis, granulomatous lung disease, viral disease, parasitic disease, pulmonary vascular calcifications, or as an idiopathic disease [1,3–5]. Metastatic calcifications are caused by high levels of serum calcium and phosphate, which deposit in normal lung tissue. The most common causes in humans are hyperthyroidism, chronic renal failure, and neoplastic destructive bony lesions [6–8]. Internal organs most commonly affected by ectopic calcification include stomach, kidney, lungs heart, and blood vessels in humans [1]. In dogs, pulmonary calcification has been reported in association with Cushing disease, renal failure, or previous fungal infection generalized pulmonary neoplasia and as an idiopathic syndrome [9,10]. In cattle, metastatic pulmonary calcification has been reported, secondary to hypervitaminosis D, dietary imbalances, and plant toxicities [11,12]. In horses, calcification of the tunica media of the pulmonary artery has been identified in postmortem in 82% of studied racehorses without associated clinical signs [13]. In a case series, systemic calcinosis was described in five horses. All horses had multiple organs affected by calcium deposition, including muscle, kidney, lung, epicardium, pleura, and liver. Systemic calcinosis was hypothesized to be precipitated by an inflammatory condition, trauma, steroid, or plasma administration and because of an underlying disturbance of the calcium–phosphorus balance [14]. However, calcification exclusively of the lungs, particularly to this extent, has so far not been reported to the knowledge of the authors.
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In our case, no signs of underlying abnormalities in the calcium–phosphorus balance were present. Calcium blood concentration was elevated 2 months after the initial presentation; however, this was mild and transient. Phosphate concentrations were within normal limits, and the calcium phosphorus product ranged between 29.1 and 37.4 mg2/ dL2. Although there is no reference range for horses, in humans, values above 70 are considered as a measure for metastatic calcification. In a case series of five horses with suspected calcinosis, all five horses had a calcium–phosphorus product above 70, accompanied by hyperphosphatemia [14]. Vitamin D levels and parathyroid hormone levels were not assessed. Therefore, dystrophic calcification was considered more likely [3]. In our case, idiopathic pulmonary calcification cannot be ruled out; however, it is speculated in humans that cases of idiopathic pulmonary ossification might be a sequel to previously unidentified lung injury [1]. Chronic inflammation, evidenced by hyperglobulinemia, hypoalbuminemia, and hyperfibrinogenemia in our case, could have contributed to calcification through the effect of proinflammatory cytokines on bone resorption. However, as no abnormalities in calcium–phosphorous balance were present, it is more likely that the chronic signs of inflammation were secondary to the lung injury and calcification of the lungs. The positive antinuclear antibody could indicate an autoimmune disorder in this case; however, no further signs of autoimmune disease were found during the examination, and the lesions in this case were solely restricted to the lungs, making this a less likely contributive factor for the calcification. Nephrosis is a cause of pulmonary calcification in humans and was also seen in some of the horses in the case series [3]. The azotemia and slightly decreased sodium and chloride levels in this case could be early markers for nephrosis; however, no signs were found on gross pathology or histopathology indicating renal disease. The gross pathologic feature of extensive generalized calcification of a defined large region of the lung makes dystrophic pulmonary calcification the most likely diagnosis. The histologic lesions of the lung suggest previous episodes of chronic pulmonary injury, and the lesions were repaired and replaced by marked amounts of fibrous tissue and mineralization that grossly appeared as calcified. The mechanism of pulmonary calcification is not precisely known. Calcium is an important ion for cellular integrity, and an increase in intracellular calcium may contribute to injury. This increase results from a net influx of extracellular calcium and the release of intracellular calcium from mitochondria and the endoplasmic reticulum. The elevated intracellular calcium activates a number of enzymes, which promote necrotic cell death. In addition, there is leakage of cellular phospholipases into the extracellular space with entry of extracellular phospholipids into the dying cells. Degradation of phospholipids into fatty acids, followed by binding of calcium to the fatty acids, is the hypothesized mechanism for dystrophic calcification at injury sites. This “initiation phase” of dystrophic calcification is followed by a “propagation phase,” with further calcium and phosphate crystallization at the initial nidi of calcification. During cell injury, there is an early fall in pH,
followed by a shift to a neutral or alkaline pH as injury continues, the latter state further predisposing to ectopic calcification. The calcium-binding phosphoprotein, osteopontin, appears to play a role in dystrophic calcification [1]. Pulmonary calcification in humans usually involves a limited area of the lung and is often functionally unimportant. Even when present, the extent of physiological impairment does not necessarily correlate with the degree of macroscopic calcification. Some patients with extensive calcification may be asymptomatic, whereas others with more subtle calcification in the face of normal chest radiographs may have significant physiological impairment [15]. If clinical signs occur, they are characterized by dyspnea and coughing, as well as other symptoms of restrictive lung disease [1]. In dogs, there has been one case report where disease was generalized and was associated with pulmonary functional compromise [10]. Given the extent of the calcified lung area in this case, it is not surprising that clinical signs were present. The diagnosis in humans is usually incidental at autopsy and the disease itself considered rare [16]. Antemortem diagnosis of pulmonary calcification in humans has not been well described, and methods used most recently include plain or contrast radiography, computed tomography, and nuclear scintigraphy [17]. High-resolution computed tomography scan and 99m technetium–methylene diphosphate nuclear scintigraphy are more sensitive and specific than the chest X-ray for the detection of pulmonary calcification [18,19]. Because of the size limitation of the gantry, chest computed tomography could not be performed in our patient and nuclear scintigraphy was deemed unnecessary based on the obvious lesions on plain radiographs. Based on the few case reports where the disease was diagnosed antemortem, the clinical course of the disease is indolent in humans or slowly progressive, prognosis depends on age and the underlying conditions [20]. Treatment options for dystrophic pulmonary calcification are limited in humans as few cases are diagnosed antemortem. The literature contains no cases of spontaneous regression. Corticosteroids are often prescribed along with lowcalcium diets, however, have not shown any clear benefits. Any treatment in humans is considered experimental [16]. There are currently no reported cases of pulmonary calcification in horses to the degree that is present in this case. The discrete bilateral cranioventral distribution suggests that the calcification of the lung tissue followed necrosis of these regions. The liver lesions were likely because of previous injury and repair as no signs of right-sided congestive heart failure were present. This is also supported by mildly elevated liver enzymes 2 and 7 months after the initial presentation and could indicate hepatic injury around that time (Table 1). Because of the absence of evidence of calcification of the liver on gross pathology and histopathology, this appears unrelated to the calcification of the lungs. The dark hemorrhagic spots on the epicardium were most likely due to trauma from constant rubbing or impact against the mineralized lung. This is the first report of extensive dystrophic pulmonary calcification in a horse. The histologic lesions of the lungs of this horse suggest that the animal had previous
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episodes of chronic pulmonary injury, and the lesions were repaired and replaced by marked amounts of fibrous tissue and mineralization that grossly appeared as calcified sequestrate. Given the extent of the calcification, it is likely that the insult occurred several years ago and the calcification has been progressing since but had been asymptomatic until presentation. Unfortunately, there was no further history available beyond the years of the current ownership in our case; therefore, we cannot rule in or rule out a previous pulmonary insult as the cause of pulmonary calcification. Acknowledgments The authors have no conflict of interest to declare. All authors declare that they contributed substantially to the acquisition of data of this case, drafting, and revising of the manuscript. All authors have read and approved the submission of the manuscript. Submission declaration: The presented paper is original, has not been published previously (except in the form of an abstract or academic thesis), is not under consideration for publication elsewhere, and its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out. If accepted, it will not be published elsewhere including electronically in the same form, in English, or in any other language, without the written consent of the copyright hold is original. References [1] Chan ED, Morales DV, Welsh CH, McDermott MT, Schwarz MI. Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med 2002;165:1654–69. [2] Kirsch T. Determinants of pathological mineralization. Curr Opin Rheumatol 2006;18:174–80. [3] Bendayan D, Barziv Y, Kramer MR. Pulmonary calcifications: a review. Respir Med 2000;94:190–3. [4] Murray J, Kielkowski D, Leiman G. The prevalence and age distribution of peripheral pulmonary hamartomas in adult males. An autopsy-based study. S Afr Med J 1991;79:247–9.
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