History
A 4-year-old 2.8-kg neutered male British Shorthair cat was evaluated because of lethargy and hyporexia of 1 week’s duration. On examination, the cat was febrile and icteric; clinicopathologic abnormalities included high alkaline phosphatase activity (232 U/L; reference range, 10 to 30 U/L), low BUN concentration (9 mg/dL; reference range, 10 to 30 mg/dL), hyperbilirubinemia (total bilirubin concentration, 10.5 mg/dL; reference range, 0.1 to 0.6 mg/dL), slightly low albumin-to-globulin concentration (A:G) ratio (0.37 [albumin concentration of 1.9 g/dL and globulin concentration of 5.1 g/dL]; reference range, 0.39 to 2.9), high amylase activity (2,221 U/L; reference range, 300 to 1,100 U/L), monocytosis (1.54 X 109 monocytes/L; reference range, 0.00 to 1.50 X 109 monocytes/L), mild thrombocytopenia (exact value not available), hypophosphatemia (2.6 mg/dL; reference range, 3.4 to 8.5 mg/dL), hyperglycemia (188 mg/dL; reference range, 70 to 150 mg/dL), hyponatremia (135 mmol/L; reference range, 142 to 164 mmol/L), and hypokalemia (3.4 mmol/L; reference range, 3.7 to 5.8 mmol/L).
The cat was treated with IV fluid therapy and SC cefovecin sodium and B vitamin injections (exact doses not available) and was tube-fed for 4 days. Despite treatment, the cat became agonal and was euthanized by intracardiac injection of euthanasia solution. The carcass was submitted for necropsy. There was another cat in the household that was reportedly healthy.
Gross Findings
On external examination of the carcass, the mucous membranes, paw pads, and adipose tissues were diffusely icteric. The abdomen contained 10 mL of yellow-tinged, translucent fluid. The right limb of the pancreas was enlarged (2.8 X 1.3 X 1.6 cm), markedly nodular, tan to yellow, and multifocally gritty on cut section. The duodenum and pyloric antrum contained numerous 1- to 4-mm-diameter, round, tan, multifocal to coalescing nodules on the serosal surfaces (Figure 1). The liver was diffusely yellow- to green-tinged with a prominent lobular pattern and contained similar small nodules on the capsular surface. The gallbladder was distended with dark-green, mucoid material, which could not be expressed into the duodenal lumen. The common bile duct was distended and tortuous. The small intestines contained scant, pale-green to tan, watery ingesta. The colon contained abundant, thick, dark-green to brown, pasty feces. The renal cortices had numerous 2- to 4-mm-diameter cysts containing clear fluid. The lungs were diffusely bright pink and mottled red with numerous, variably distinct, 1- to 2-mm-diameter, tan, flat foci along the pleural surfaces. No other notable changes were observed.
Photograph of a 4-year-old British Shorthair cat that was evaluated because of lethargy and hyporexia of 1-week’s duration. Despite initiation of treatment, the cat’s condition declined rapidly and it was euthanized 4 days after evaluation. The ribs are at the top of the image, and the liver has been reflected cranially to view the gallbladder, pancreas, and duodenum. Notice the yellow-tinged adipose and yellow- to green-tinged liver with capsular nodules and a prominent hepatic lobular pattern, distended gallbladder, tortuous common bile duct, and enlarged, nodular pancreas adhered to a nodular duodenum (asterisk). No bile could be expressed into the duodenum. The renal cortex contains several 1- to 4-mm-diameter fluid-filled cysts.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photograph of a 4-year-old British Shorthair cat that was evaluated because of lethargy and hyporexia of 1-week’s duration. Despite initiation of treatment, the cat’s condition declined rapidly and it was euthanized 4 days after evaluation. The ribs are at the top of the image, and the liver has been reflected cranially to view the gallbladder, pancreas, and duodenum. Notice the yellow-tinged adipose and yellow- to green-tinged liver with capsular nodules and a prominent hepatic lobular pattern, distended gallbladder, tortuous common bile duct, and enlarged, nodular pancreas adhered to a nodular duodenum (asterisk). No bile could be expressed into the duodenum. The renal cortex contains several 1- to 4-mm-diameter fluid-filled cysts.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photograph of a 4-year-old British Shorthair cat that was evaluated because of lethargy and hyporexia of 1-week’s duration. Despite initiation of treatment, the cat’s condition declined rapidly and it was euthanized 4 days after evaluation. The ribs are at the top of the image, and the liver has been reflected cranially to view the gallbladder, pancreas, and duodenum. Notice the yellow-tinged adipose and yellow- to green-tinged liver with capsular nodules and a prominent hepatic lobular pattern, distended gallbladder, tortuous common bile duct, and enlarged, nodular pancreas adhered to a nodular duodenum (asterisk). No bile could be expressed into the duodenum. The renal cortex contains several 1- to 4-mm-diameter fluid-filled cysts.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Formulate differential diagnoses, then continue reading.
Histopathologic Findings
Samples of all major organs and tissues were fixed in neutral-buffered 10% formalin and prepared for histologic evaluation. The most important changes were in the liver, gallbladder, common bile duct, pancreas, pancreatic lymph nodes, and small intestines. More than 70% of the pancreatic tissue was expanded and replaced by multifocal to coalescing pyogranulomatous inflammation and multifocal zones of necrosis (Figure 2), as well as fibrous connective tissue that was infiltrated by variable numbers of lymphocytes, plasma cells, and Mott cells. The few remaining pancreatic lobules were widely separated by bands of fibrosis and granulation tissue. The remaining acinar cells were swollen and vacuolated with scant zymogen granules. The pyogranulomas present throughout the pancreas, liver, lymph nodes, and intestinal tissues were characterized by a central core of necrotic cell debris mixed with variable numbers of neutrophils, followed by a rim of macrophages mixed with variable numbers of neutrophils, and finally an outermost layer composed of macrophages, lymphocytes, and plasma cells. Immunohistochemical staining of tissue sections revealed that the macrophages within the foci of pyogranulomatous inflammation and necrosis contained feline coronavirus (FCoV) antigen (Figure 3).
Photomicrographs of sections of the cat’s pancreas. There is severe interstitial fibrosis with lymphoplasmacytic inflammation (asterisks) and a focus of pyogranulomatous inflammation with central necrosis (arrow). H&E stain; bar = 100 µm. Inset—At higher magnification, the pyogranuloma is composed of a core of necrotic cell debris (caret), followed by a layer of macrophages mixed with few neutrophils (double-headed arrow), and finally an outer rim of loose collagen with low numbers of lymphocytes, macrophages, and plasma cells. H&E stain; bar = 20 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrographs of sections of the cat’s pancreas. There is severe interstitial fibrosis with lymphoplasmacytic inflammation (asterisks) and a focus of pyogranulomatous inflammation with central necrosis (arrow). H&E stain; bar = 100 µm. Inset—At higher magnification, the pyogranuloma is composed of a core of necrotic cell debris (caret), followed by a layer of macrophages mixed with few neutrophils (double-headed arrow), and finally an outer rim of loose collagen with low numbers of lymphocytes, macrophages, and plasma cells. H&E stain; bar = 20 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrographs of sections of the cat’s pancreas. There is severe interstitial fibrosis with lymphoplasmacytic inflammation (asterisks) and a focus of pyogranulomatous inflammation with central necrosis (arrow). H&E stain; bar = 100 µm. Inset—At higher magnification, the pyogranuloma is composed of a core of necrotic cell debris (caret), followed by a layer of macrophages mixed with few neutrophils (double-headed arrow), and finally an outer rim of loose collagen with low numbers of lymphocytes, macrophages, and plasma cells. H&E stain; bar = 20 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrograph of a section of the cat’s pancreas following feline coronavirus (FCoV)-specific immunohistochemical staining. The cytoplasm of macrophages within the pancreatic interstitium is positive for FCoV antigen, which is stained dark brown. Immunohistochemical stain for FCoV with 3,3′-diaminobenzidine chromogen and hematoxylin counterstain; bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrograph of a section of the cat’s pancreas following feline coronavirus (FCoV)-specific immunohistochemical staining. The cytoplasm of macrophages within the pancreatic interstitium is positive for FCoV antigen, which is stained dark brown. Immunohistochemical stain for FCoV with 3,3′-diaminobenzidine chromogen and hematoxylin counterstain; bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrograph of a section of the cat’s pancreas following feline coronavirus (FCoV)-specific immunohistochemical staining. The cytoplasm of macrophages within the pancreatic interstitium is positive for FCoV antigen, which is stained dark brown. Immunohistochemical stain for FCoV with 3,3′-diaminobenzidine chromogen and hematoxylin counterstain; bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Within the duodenum, the serosal nodules grossly corresponded to foci of pyogranulomatous inflammation that extended into and effaced the underlying tunica muscularis and submucosa. In these areas, macrophages also contained abundant intracytoplasmic FCoV antigen (Figure 4). Sections of the liver, stomach, mesenteric lymph nodes, and lungs contained similar foci of pyogranulomatous inflammation. Within the liver, there was severe extracellular cholestasis characterized by hyperplastic and tortuous bile ducts and canalicular plugs. In portal regions, bile ducts were often surrounded by concentric bands of fibrosis. Inspissated bile and canalicular plugs were often present in centrilobular and midzonal regions. Centrilobular to midzonal hepatocytes had cytoplasmic changes ranging from indistinct microvesiculation (glycogen type) to discrete round vacuoles (lipid type), with frequent nuclear hypertrophy or binucleation. The gallbladder epithelium was hyperplastic, and the lumen was severely expanded by inspissated eosinophilic and streaming basophilic material (mucus). The kidneys contained scattered cystic tubules lined by attenuated epithelium.
Photomicrographs of sections of the cat’s duodenum. A nodular aggregate of pyogranulomatous inflammation has expanded the duodenal tunica muscularis. H&E stain; bar = 200 µm. Inset—Section of the duodenum following FCoV-specific immunohistochemical staining. The cytoplasm of macrophages in a focus of pyogranulomatous inflammation is positive for FCoV antigen. Immunohistochemical stain for FCoV with 3,3′-diaminobenzidine chromogen and hematoxylin counterstain. Bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrographs of sections of the cat’s duodenum. A nodular aggregate of pyogranulomatous inflammation has expanded the duodenal tunica muscularis. H&E stain; bar = 200 µm. Inset—Section of the duodenum following FCoV-specific immunohistochemical staining. The cytoplasm of macrophages in a focus of pyogranulomatous inflammation is positive for FCoV antigen. Immunohistochemical stain for FCoV with 3,3′-diaminobenzidine chromogen and hematoxylin counterstain. Bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Photomicrographs of sections of the cat’s duodenum. A nodular aggregate of pyogranulomatous inflammation has expanded the duodenal tunica muscularis. H&E stain; bar = 200 µm. Inset—Section of the duodenum following FCoV-specific immunohistochemical staining. The cytoplasm of macrophages in a focus of pyogranulomatous inflammation is positive for FCoV antigen. Immunohistochemical stain for FCoV with 3,3′-diaminobenzidine chromogen and hematoxylin counterstain. Bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 259, 11; 10.2460/javma.19.03.0142
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: severe, chronic, multifocal to coalescing, necrotizing, pyogranulomatous pancreatitis, lymphadenitis, hepatitis, choledochitis, and serositis with intrahistiocytic FCoV antigen; and severe, chronic, diffuse cholestasis with biliary hyperplasia and periductular fibrosis.
Case summary: feline infectious peritonitis (FIP) characterized by severe, granulomatous, and necrotizing pancreatitis with choledochitis and posthepatic biliary obstruction in a cat.
Comments
Feline infectious peritonitis is an inflammatory syndrome caused by a pathogenic biotype of FCoV, for which there is no definitive treatment. In affected cats, FIP is almost universally fatal within 12 months after the onset of clinical signs.1 The case described in the present report involved a unique presentation of FIP, which manifested as fibrosing and necrotizing pancreatitis and choledochitis that resulted in posthepatic biliary obstruction and severe icterus. On the basis of the gross features, pancreatic neoplasia was initially considered in the differential diagnosis; however, histopathologic and immunohistochemical findings confirmed FIP.
Feline enteric coronavirus is shed in feces of healthy cats for up to 10 months and is considered ubiquitous in multiple-cat populations such as shelters, catteries, and multicat households. Among cats in single-cat households, 10% to 50% are positive for FCoV antibody.2,3 Feline enteric coronavirus is not highly pathogenic, and the most infected cats have no clinical signs or develop mild colitis before clearing the virus.1,3,4 It is important to note that cats with FIP do not shed the FIP-causative biotype of FCoV; horizontal transmission is not documented, and vertical transmission is rare.5,6,7 This may indicate that once the virus has mutated, it loses the ability to replicate in enterocytes.5 In cats, cases of FIP are more commonly attributed to infection with mutated biotypes of FCoV subtype I than infection with FCoV subtype II (which is a recombinant of FCoV subtype I and canine coronavirus).6,7
A biphasic age distribution has been identified for FIP cases, with most affected cats being < 3 years old or > 10 years old, and as many as 70% of patients are < 1 year old.3,5,7,8 Diagnosis of FIP is challenging because it is a clinical syndrome with vague signs brought about by a spectrum of inflammatory processes involving the balance between the host’s cellular immunity and humoral immunity. These signs may become apparent months to years after a cat is infected with FCoV.3,8,9 Because of the lack of antemortem direct testing or specific clinical signs, patient signalment (< 3 or > 10 years old) and origin (multicat household or facility) are crucial factors for consideration along with interpretation of indirect test results to reach a presumptive diagnosis of FIP.1,3,7,8 The age (4 years old) of the cat of the present report was not within the typical biphasic age distribution for FIP, making the antemortem diagnosis challenging, especially given the unusual presentation.
The prevailing theory regarding how FCoV becomes more pathogenic is that viral mutations are accumulated in each infected cat and any viral advantage in replication or pathogenicity, such as altered cell tropism from enterocytotropism to monocytotropism that allows evasion of the host’s immune system, determines the course of disease.10,11 There are 2 commonly referenced disease extremes, namely a more effusive (wet) and a less effusive (dry) form of the FIP syndrome. It is theorized that the more effusive form develops when the predominant physiologic process is a type III hypersensitivity reaction associated with a robust humoral immune response in the absence of an effective cell-mediated response.7,12 Immune complex deposition and consequent complement fixation recruits neutrophils that join the macrophage-rich inflammatory cell population, resulting in pyogranulomatous perivasculitis and leakage of protein-rich fluid from the vessels.8 The less effusive (or dry) form is thought to develop when cell-mediated immunity is more robust but not complete; this less effusive form resembles a type IV hypersensitivity reaction, in which infected macrophages are activated to induce T-cell apoptosis and to release vascular endothelial growth factor along with other proinflammatory cytokines, resulting in granulomatous lesions in target organs, often accompanied by necrosis and lymphoid depletion.5,9,12 On postmortem examination, the cat of the present report had a combination of the classic wet and dry forms of FIP.
Regardless of clinical signs, the test with highest specificity and sensitivity for detection of FCoV infection is immunohistochemical staining for FCoV antigen in monocytes in effusions or macrophages in tissues.3 Immunohistochemical staining of effusion preparations is complicated by the fact that FIP-associated effusions often contain very low numbers of monocytes. Hence, failure to find FCoV-infected cells in effusion preparations does not rule out the disease.3,7,8 Immunohistochemical analysis of tissue specimens is a comparatively more sensitive procedure, and it is 100% specific. However, collection of specimens is invasive; consequently, often a postmortem diagnosis is achieved.3,7,8
Antemortem diagnosis of FIP is challenging. Common clinicopathologic abnormalities associated with FIP include mild to moderate regenerative anemia and hyperproteinemia, the former of which is classically attributed to hypergammaglobulinemia.13 It appears that the serum A:G ratio has high diagnostic value, and at values > 0.8, FIP is unlikely.13 A high A:G ratio may be more useful to rule out FIP when the prevalence of the disease is low.10 In the cat of the present report, the slightly low A:G ratio was most likely driven by low albumin concentration, given the normal (albeit high-normal) γ-globulin concentration. Potential causes for hypoalbuminemia in cats with FIP include exudative loss of albumin into the peritoneal fluid and decreased liver production because of either the inflammatory response (albumin is a negative acute-phase protein) or decreased functional hepatic mass, or possibly a combination thereof.14 In cases of FIP with hyperproteinemia in the absence of other common laboratory abnormalities, serum protein electrophoresis may be helpful to determine the exact cause of protein concentration elevation. By far, the most common electrophoretic pattern in cats with FIP is a polyclonal gammopathy, although monoclonal gammopathy has rarely been reported.10 Thrombocytopenia and an inflammatory leukogram (leukocytosis with neutrophilia and a left shift) may also be detected in cats with FIP.14
Serum biochemical analysis may reveal hyperbilirubinemia and hyperbilirubinuria in cats with FIP, especially those with the more effusive form of FIP. High serum bilirubin concentration in cats with FIP is not a result of liver disease but is believed to be largely attributable to increased destruction of erythrocytes in lesions and in circulation, along with difficulties in glucuronidation in cats.10 The case described in the present report was further complicated by posthepatic biliary obstruction, which also causes hyperbilirubinemia.
The Rivalta test may be attempted on samples of effusions collected before or after death of cats with FIP.10 The test involves a few drops of abdominal or thoracic fluid being placed into a tube containing a weakly acetic solution; the appearance of white, flocculent material is interpreted as a positive result. Although this test was once thought to be confirmatory for FIP, false-positive results may be obtained for cats with lymphoma or bacterial peritonitis, among other conditions.10 The Rivalta test was not attempted in the present case.
Several treatment approaches have been used in cats with FIP, although the efficacy of those drugs has not been proven. Treatments include the use of drugs that inhibit viral replication (ie, protease inhibitors), the use of anti-inflammatory or immunosuppressive agents to control the immune response (ie, prednisone or tumor necrosis factor inhibitors), and the use of preparations that stimulate the immune system in an attempt to overcome the infection (ie, acemannan and nonviable Propionibacterium acnes).10
References
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