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CASE I – N96-4286 (AFIP 2597323)
Signalment: 5-year-old, spayed female domestic shorthair cat (Felis domesticus).
History: This cat presented with a sudden onset of severe dyspnea. After no response to treatment with dexamethasone, amoxicillin, and theophylline, the cat was euthanized. The referring veterinarian submitted sections of lung for histologic examination.
Gross Pathology: Prominent bronchi and bronchioles were observed on cut sections of lung specimens.
Laboratory Results: No laboratory results were available.
Contributor’s Diagnosis and Comment: Bronchitis and bronchiolitis, eosinophilic, chronic and acute, multifocal, moderate, with eosinophilic endarteritis, eosinophilic periarteritis, alveolar ductal and arterial smooth muscle hyperplasia, and peribronchial glandular hyperplasia, lung.
The epithelial linings of many bronchi are sloughed and there are increased numbers of bronchial glands. Small numbers of eosinophils, lymphocytes, and macrophages, with occasional plasma cells and mast cells, infiltrate bronchial and bronchiolar walls, peribronchial connective tissue, and adjacent periarterial tissue. Peribronchial and periarterial stromal tissue is expanded by small clear spaces (edema). Hyperplasia and hypertrophy of smooth muscle cells of the tunica muscularis thicken walls of medium-sized and large pulmonary arteries. Small numbers of eosinophils expand the tunica intima of some arteries, and multifocally infiltrate the tunica muscularis. There are small clear spaces between myocytes of the tunica muscularis, and some cells have a vacuolated cytoplasm. The arteries are constricted. The smooth muscle of bronchioles and alveolar ducts is prominent. Some bronchioles contain small numbers of eosinophils and macrophages. There is diffuse, mild congestion of alveolar septal capillaries and larger blood vessels. Many alveolar spaces contain increased numbers of macrophages, and there is mild, multifocal, intra-alveolar hemorrhage. Subpleural connective tissue is expanded by small clear spaces, with small numbers of scattered eosinophils, macrophages, and lymphocytes. There is multifocal hypertrophy of mesothelial cells.
By histomorphology, the lesions are most consistent with the diagnosis of feline asthma, also referred to as allergic bronchitis or allergic pneumonia. Affected cats usually have a history of chronic pulmonary disease, with bronchial gland hyperplasia and smooth muscle hypertrophy of airways and arteries, as in this case. Animals often die as a result of acute exacerbation of the pre-existing pulmonary disease. The inciting antigens that cause pulmonary lesions and acute attacks are not known. Numerous agents have been implicated, including cat litter dust, cigarette smoke, and aerosol sprays. There has been some debate as to the role of viral and bacterial respiratory infections in the pathogenesis of this disease.
Medial hypertrophy of pulmonary arteries is often observed in cases of feline asthma. Similar arterial and bronchial lesions have been observed in cats infected experimentally with Toxocara canis larvae, and in cats infected naturally with Aelurostrongylus abstrusus. Nematode eggs or larvae were not observed in this case, nor were eosinophilic granulomas seen, as with larval migration. Lesions of pulmonary eosinophilic endarteritis previously have been observed in cats with experimental Toxocara canis infection.
AFIP Diagnosis: Lung: Bronchitis and bronchiolitis, exudative, eosinophilic and lymphoplasmacytic, diffuse, moderate, with pulmonary arterial fibromuscular hypertrophy, and eosinophilic endarteritis, periarteritis, and pleuritis, domestic shorthair, feline.
Conference Comment: The structure and function of the respiratory tract includes the ability to readily react to inhaled allergens. Mast cells and lymphoid tissue in the walls of the trachea and pulmonary airways are integral to type I IgE-mediated hypersensitivity reactions and respond quickly following re-exposure to antigen. In atopic asthma, allergens are initially presented to T-helper 2 cells by dendritic cells, causing production and release of cytokines such as IL-4 and IL-5. These cytokines induce B cells to produce IgE, stimulate the growth of mast cells (IL-4), and induce the growth and activation of eosinophils (IL-5). IgE antibodies attach themselves to the Fc receptors on mast cells and basophils. Upon re-exposure to the sensitizing antigen during the acute phase reaction, mucosal mast cells with attached IgE are induced to degranulate which results in histamine release and relaxation of mucosal intercellular tight junctions. More allergen is then able to reach the submucosal mast cells, leading to increased vascular permeability, edema, and influx of eosinophils and other inflammatory cells. Stimulation of parasympathetic vagal receptors induces bronchoconstriction and increased mucus production.
In the late-phase of the type I hypersensitivity reaction, infiltrating leukocytes are attracted by cytokines and move along chemotactic gradients derived from mast cells, other inflammatory cells, vascular endothelium, and airway epithelium. Airway epithelial cells produce eotaxin, a potent chemoattractant and activator of eosinophils. Release of major basic protein by eosinophils, in turn, causes airway epithelial damage and airway constriction. Both the acute and late-phase reactions in IgE-mediated hypersensitivity are responsible for the prolonged manifestations of feline asthma.
Contributor: Royal Veterinary College, Department of Pathology and Infectious Diseases, Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, United Kingdom
References: 1. Dungworth DL: The respiratory system. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., pp. 573, 684-685, Academic Press, San Diego, CA, 1993
2. Kobzik L: The lung: bronchial asthma. In: Robbins Pathologic Basis of Disease, ed. Cotran RS, Kumar V, Collins T, 6th ed., pp. 712-716, WB Saunders Co., Philadelphia, PA, 1999
3. Moses BL, Spaulding GL: Chronic bronchial disease of the cat. Vet Clin North Am Sm Anim Prac 15(5):929-948, 1985
4. Parsons JC, Bowman DD, Grieve RB: Pathological and haematological responses of cats experimentally infected with Toxocara canis larvae. Intl J Parasit 19(5):479-488, 1989
CASE II – E3202/99 (AFIP 2738552)
Signalment: 2-year-old filly trotter
History: The horse was referred for reduced performance, fever, anorexia, weight loss, bilaterally symmetrical alopecia, and scaling skin in periocular, axillary, inguinal, and pectoral regions. There were petechiae in the oral mucosa, and subcutaneous edema in the ventral neck. The horse was euthanized because of disease progression and resistance to corticosteroid therapy.
Gross Pathology: Skin lesions were characterized by alopecia and scaling with crusts, erosions and ulcerations localized on limbs. There was splenomegaly, mesenteric lymphadenopathy, mild enteritis, and mild, chronic, multifocal periportal hepatitis.
Laboratory Results: A blood smear showed erythrocyte anisocytosis and rouleaux formation. Serum biochemical analysis revealed increased total bilirubin and mild hypoalbuminemia. Urine analysis was characterized by mild proteinuria with negative sediment. Hemostatic profile showed decreased antithrombin III (87%) and increased fibrin D-dimers (0.37ng/mL). ANA test was positive (1:40 titer). On sternal bone marrow examination, marked erythroid hyperplasia (M:E ratio 1:4) and moderate numbers of mature plasma cells were detected.
Contributor’s Diagnosis and Comment: Multifocal, moderate to severe, lymphocytic, cell-poor, interface dermatitis; severe, multifocal, cell-rich lymphocytic mural folliculitis; apoptosis and hydropic degeneration of basal keratinocytes, multifocal thickening of basement membrane, multiple micropustules, and pigmentary incontinence.
Additional histopathological findings were severe follicular splenic and lymph node hyperplasia, and mild to moderate, diffuse membranoproliferative glomerulonephritis. Immunohistochemical analysis performed on skin sections revealed a positive linear deposition of IgG along basement membranes. 98% of lymphoid cells were CD3-positive. CD8 and CD4 analysis is under investigation.
On the basis of clinical (autoimmune anemia, positive ANA test, glomerular involvement), histopathological (interface dermatitis) and immunohistochemical analysis, a diagnosis of systemic lupus erythematosus (SLE) was made.
SLE is an autoimmune multisystemic disease characterized by the development of autoantibodies against several self-antigens. The cause of the disease is unknown although a generalized failure of immune regulation of self-tolerance is suggested. Several factors, including genetic predisposition, immunologic factors, drugs, viruses, and sex hormones, are thought to play a role in the pathogenesis of SLE. The two mechanisms of direct injury by autoantibodies, and type III hypersensitivity reaction are involved in tissue damage.
SLE has been well documented in dogs, cats and mice. Dermatopathologic signs occur in 33% of canine and feline SLE cases. Only a few cases have been reported in the horse, with clinical signs and histopathologic skin lesions similar to those observed in our case. SLE is a rare disease of young horses, associated with cutaneous and systemic involvement.
AFIP Diagnosis: Haired skin: Dermatitis, lichenoid, lymphocytic, diffuse, moderate, with basal cell hydropic degeneration and necrosis (Civatte bodies), and intracorneal pustules, trotter, equine.
Conference Comment: The gross and histopathologic cutaneous lesions of systemic lupus erythematosus are diverse. The most characteristic and critical histologic finding is hydropic degeneration of the epidermal basal cell layer with a lichenoid band of lymphoplasmacytic inflammation within the superficial dermis, or an interface dermatitis that can obscure the dermoepidermal junction. Civatte bodies, a feature of all lichenoid dermatoses, represent apoptotic basal epidermal cells, and appear as round, hypereosinophilic bodies in the stratum basale. Subepidermal clefting may be seen occasionally in severe cases of SLE. Pigmentary incontinence within the superficial dermis occurs as a result of melanin released from degenerating basal cells. Similar changes often affect follicular epithelium. With chronic lesions, antigen-antibody deposition can result in a thickening of the basement membrane, producing a positive “lupus band.”
Other changes that are often seen include orthokeratotic and parakeratotic hyperkeratosis, epidermal hyperplasia, and adnexal atrophy. Few multinucleate, foreign body-type macrophages were present in many sections, but are not classically considered a feature of this entity.
Contributor: University of Padua, School of Veterinary Medicine, Institute of Veterinary Pathology and Hygiene, Agripolis, Strada Romea, 16, 35020 Legnaro (PD) Italy
References: 1. Geor RJ, Clark EG, Haines DM, Napier PG: Systemic lupus erythematosus in a filly. J Am Vet Med Assoc 197(11):1489-1492, 1990
2. Scott DW, Wolfe MJ, Smith CA, Lewis RM: The comparative pathology of non-viral bullous skin diseases in domestic animals. Vet Pathol 17(3):257-281, 1980
3. Yaeger J, Scott DW: The skin and appendages. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., pp. 531-738. Academic Press, London, England, 1993
CASE III – 95-9128 (AFIP 2505218)
Signalment: Three-year-old castrated male rabbit.
History: The rabbit was one of three pets housed together and maintained for six months on an improved diet of timothy hay, fresh vegetables and papaya tablets. There had been a mild weight loss associated with the diet change, and the rabbit had been anorexic for two days prior to presentation. In addition, it was passing scant feces and urine. The rabbit became lethargic and on presentation was in lateral recumbency. It had a heart rate of 220 bpm and respiratory rate of 50 per minute. The rabbit died before institution of medical therapy or diagnostic testing. The owner had been treating the rabbit for Cheyletiella spp. mites, and some hair loss was noted at the dorsal cervical region.
Gross Pathology: The major vessels had irregularly thickened, brittle, white walls. The endocardium of both atria was white and gritty; changes in the wall extended to the left atrioventricular valve. Two bands of minute, white flecks were present in the kidney. There was a prominent band at the superficial renal cortex and a less obvious line at the corticomedullary junction. A 3x2-cm, H-shaped ulcer was noted in the fundic mucosa of the stomach. The liver was pale and had an increased lobular pattern.
Laboratory Results: None provided.
Contributor’s Diagnoses and Comment: 1. Kidney (blood vessels, tubular basement membranes, and Bowman’s capsules): Severe, chronic, multifocal to locally extensive mineralization (nephrocalcinosis, hypercalcemic nephropathy).
2. Bone: Mild, diffuse osteosclerotic osteodystrophy.
Etiology: Hypervitaminosis D
Within a band of the superficial cortex, there is frequent mineralization of Bowman’s capsules and tubular basement membranes. A similar, but narrower, band of mineralized tubules is present in the outer medulla. Fibrosis and mild interstitial infiltrate of lymphocytes, plasma cells, and occasional histiocytes and heterophils are present in the regions of marked mineral deposition. In common with vessels throughout the body, mineralized plaques and medial and intimal fibromuscular hypertrophy and hyperplasia thicken the walls of arteries. A mixture of “hypermineralized” lamellar and woven bone irregularly thickens the periosteum. Concentric deposits of a similar appearing substance narrow the lumina of scattered Haversian and Volkmann’s canals. The cortical endosteum is affected to a much lesser extent. The abnormal matrix is deeply basophilic and flocculent.
The margin of safety in the administration of excess dietary vitamins is greater with the water-soluble vitamins since they are more easily excreted. Vitamin D is fat-soluble and, consequently, is stored rather than excreted. Storage occurs primarily in adipose tissue, muscle, and liver, with vitamin release when the fat is metabolized. Vitamin D metabolites function to maintain serum calcium and phosphorus for normal bone mineralization through the vitamin’s effects on gastrointestinal absorption of these elements. Clinically, with excess vitamin D the serum calcium and phosphorus are elevated.
The principal consequences of hypervitaminosis D are attributable to hypercalcemia, which results in metastatic calcification. Metastatic calcification is observed in patients with deranged calcium metabolism, in contrast to dystrophic calcification that has its origin in cell injury. The distribution of mineral deposits in soft tissues is variable, but there is a predilection for the fibroelastic tissues of any organ, particularly the arteries, pulmonary alveolar septa, the mucosa and muscularis of the stomach, and the kidneys.
Hypercalcemia causes decreased excitability of gastrointestinal smooth muscle and skeletal muscle, behavioral changes, and possible cardiac arrhythmias. Hypercalcemia interferes with antidiuretic hormone receptors in the renal tubular epithelial cells, and with transport of sodium and chloride into the renal medullary interstitium, thereby reducing the medullary concentration gradient. In severe cases, calcium injury to the kidneys results in azotemia. The injury to the kidneys may be a direct toxic effect of the elevated calcium in the serum and filtered tubular fluid. Furthermore, hypercalcemia may result in vasoconstriction of renal vessels and ischemia. The initial renal tubular epithelial cell injury is mitochondrial. Necrotic epithelial cells may slough and form casts, which may then mineralize. Nephrons near the medulla are affected first, and the lesion progresses toward the capsule. The convoluted tubules are the most susceptible, with basement membranes often containing mineral deposits. Generally, no regenerative tubular changes are observed.
Skeletal changes in hypervitaminosis D depend on the level of dietary calcium and pattern of exposure. A marked, short-term excess of vitamin D results in increased osteoclastic activity. With continued administration, the matrix of woven bone produced by osteoblasts has a more tangled and fibrillar arrangement, with a greater affinity for calcium hydroxyapatite. This affinity results in a characteristic deeply basophilic ground substance. Eventually, a more eosinophilic substance that resembles osteoid replaces the matrix. Usually, however, the administration of the vitamin is intermittent. Bursts of osteosynthetic activity are observed, with large deposits of abnormal matrix laid down during periods of vitamin withdrawal. Broad, basophilic resting lines separate the layers of bone produced during each cycle.
Almost all bones are affected, but changes are especially noticed in the long bones. The osteosclerosis of long bones may involve inhibition of bone resorption due to secondary hypercalcitoninism and the primary anabolic effects of vitamin D and its metabolites.
For man and domestic animals, the normal level of 25-hydroxyvitamin D is 30-50 ng/ml, and toxicity occurs at levels of 200-400 ng/ml. Normal levels of 1,25-hydroxyvitamin D lie between 20 and 45 pg/ml. Chronic disorders of vitamin D metabolism may occur at levels 20 times the daily requirement, which in most species is at 200-1200 lU/kg diet. In rabbits, hypervitaminosis D will develop when rations contain only five times the normal level of vitamins D2 or D3; rabbits are unusual in that their serum calcium concentration is directly related to their dietary calcium intake.
Ingestion of certain calcinogenic plants (Solanum malacoxylon; the cause of Enteque seco, Manchester wasting disease, and Naalehu disease; Cestrum diurnum, and Trisetum flavescens) that contain 1,25-dihydroxycholecalciferol-glycoside results in changes of hypervitaminosis D. Solanum torvum, S. verbascifolium, and possibly S. ausuriale and Dactylus glomerata have a similar effect, but the precise mechanism is not understood. Accidental ingestion of rodenticides containing cholecalciferol (vitamin D3) is another frequent cause of toxicity.
AFIP Diagnoses: 1. Kidney, Bowman’s capsules, interstitium, tubular basement membranes, vessels: Mineralization, multifocal, moderate, rabbit, breed not specified, lagomorph.
2. Bone: Osteosclerosis, diffuse, mild.
Conference Comment: The contributor has provided an excellent, concise summary of this entity. Other potential causes of hypercalcemia and tissue mineralization include neoplasia (e.g., malignant lymphoma, plasma cell myeloma, and carcinoma of the apocrine glands of the canine anal sac), primary hyperparathyroidism, renal disease (especially in horses), canine hypoadrenocorticism, granulomatous diseases (e.g., blastomycosis in dogs), and osteolytic lesions.
Contributor: Angell Memorial Animal Hospital, Department of Pathology, 350 South Huntington Avenue, Boston, MA 02130
References: 1. Chew DJ, Capen CC: Hypercalcemic nephropathy and associated disorders. In: Current Veterinary Therapy VII, pp. 1067-1072. WB Saunders Co., Philadelphia, PA, 1980
2. Dougherty SA, Center SA, Dzanis DA: Salmon calcitonin as adjunct treatment for vitamin D toxicosis in a dog. J Am Vet Med Assoc 196(8):1269-1272, 1990
3. Hass GM, Trueheart RE, Taylor CB, Stumpe M: An experimental histologic study of hypervitaminosis D. Am J Pathol 34(3):395-431, 1958
4. Kane AB, Kumar V: Environmental and nutritional pathology. In: Robbins Pathologic Basis of Disease, ed. Cotran RS, Kumar V, Collins T, 6th ed., pp. 45, 441-446. WB Saunders Co., Philadelphia, PA, 1999
5. Lewis LD, Morris ML, Hand MS: Small Animal Nutrition: Clinical Nutrition III, pp. 1-22, 1-23, 4-11, 12-7, 12-11. Mark Morris Associates, Topeka, KS, 1987
6. Palmer N: Bones and joints. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 1, pp. 81-83. Academic Press, San Diego, CA, 1993
7. Shell LG, Saunders G: Arteriosclerosis in a rabbit. J Am Vet Med Assoc 194(5):679-680, 1989
8. Smith HA, Jones TC, Hunt RD: Veterinary Pathology, pp. 67-68. Lea & Febiger, Philadelphia, PA, 1983
9. Sumner-Smith G: Hormonal control of mineral metabolism and bone cell activity. In: Bone in Clinical Orthopaedics: A Study in Comparative Osteology, pp. 242-244. WB Saunders Co., Philadelphia, PA, 1982
CASE IV – 00-1142 (AFIP 2737283)
Signalment: 27-day-old, female grand eclectus parrot, Eclectus roratus roratus.
History: Parrot died acutely within 12 hours.
Gross Pathology: The proventriculus was enlarged and had focally extensive hemorrhage.
Laboratory Results: Avian polyoma virus was identified from the spleen by polymerase chain reaction assay. Electron micrographs of the spleen showed macrophages with enlarged nuclei, marginated chromatin, and numerous electron-dense particles.
Contributor’s Diagnoses and Comment: 1. Splenitis, mononuclear, diffuse, severe, with intranuclear viral inclusions.
2. Hepatitis, necrotizing, diffuse, severe, with intranuclear viral inclusions.
Etiologic Agent: Avian polyoma virus, avian polyoma virus disease (APVD).
Avian polyoma virus disease is an acute, rapidly fatal disease of hand-raised nestlings and budgerigars. Inhalation of the virus is the likely means of entry. Clinical signs, when they do occur, last for less than 24 hours and include weakness, pallor, subcutaneous hemorrhage, dehydration, inappetence, and crop stasis. Necropsy findings include generalized pallor, with subcutaneous and subserosal hemorrhages. Hepatomegaly, with or without mottling, and splenomegaly are common. Karyomegalic changes, with and without pannuclear inclusions, are prominent in splenic macrophages. Kupffer cells and glomerular mesangial cells often demonstrate similar nuclear change. Electron microscopy, immunofluorescent staining, in situ hybridization techniques, PCR of organ swabs, and inoculation of infected tissues into cell culture or eggs can confirm the presence of virus in dead birds.
AFIP Diagnoses: 1. Spleen: Splenitis, histiocytic, diffuse, moderate, with lymphoid depletion, and numerous intranuclear inclusion bodies, grand eclectus parrot, Eclectus roratus roratus, psittacine.
2. Liver: Necrosis, submassive, and hemorrhage, diffuse, with rare intranuclear inclusion bodies.
Conference Comment: A characteristic feature of APVD is an acute infection of macrophages within the splenic periarteriolar (Schweiger-Seidel) sheaths. It is thought that macrophages within these sheaths are responsible for removing antibody-coated APV from the circulation. Rather than neutralizing the virus, however, the antibody acts as a receptor to allow entrance into the macrophage. The diversity of lesions present with APVD may be due to the systemic infection of phagocytes. The release of macrophage-derived cytokines is believed to mediate increased capillary permeability and, consequently, the diffuse hemorrhages seen in infected birds.
Contributor: Livestock Disease Diagnostic Center, 1429 Newtown Pike, Lexington, KY 40511
References: 1. Altman RB: Infectious diseases. In: Avian Medicine and Surgery, ed. Altman RB, Clubb SL, Dorrestein GM, Quesenberry K, pp. 288-294. WB Saunders Co., Philadelphia, PA, 1997
2. Garcia AP, Latimer KS, Niagro FD, Ritchie BW, Campagnoli RP: Diagnosis of polyomavirus-induced hepatic necrosis in psittacine birds using DNA probes. J Vet Diagn Invest 6:308-314, 1994
3. Graham DL, Calnek BW: Papovavirus infection in hand-fed parrots: virus isolation and pathology. Avian Dis 31:398-410, 1987
4. Jacobson ER, Hines SA, Quesenberry K, Mladinich C, Davis RB, Kollias GV, Olsen J: Epornitic of papova-like virus-associated disease in a psittacine nursery. J Am Vet Med Assoc 185(11):1337-1341, 1984
5. Niagro FD, Ritchie BW, Latimer KS, et al: Polymerase chain reaction detection of PBFD and BFD virus in suspect birds. Proc Assoc Avian Vet, pp. 25-37, Phoenix, AZ, 1990
6. Phalen DN, Wilson VG, Graham DL: Characterization of avian
polyomavirus-associated glomerulopathy of nestling parrots. Avian
Dis 40:140-149, 1996
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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