Feline Cholangitis

Liver disease is a common clinical finding in the cat. The disorders that occur most frequently are hepatic lipidosis, chronic inflammatory disease (cholangitis), neoplasia, and hepatocellular necrosis (such as toxic or drug-related conditions). Based on a 10-year retrospective study of feline liver biopsy data from the University of Minnesota, inflammatory liver disease is the second most common category of liver disease in cats in the United States after hepatic lipidosis (Gagne et al, 1996). This chapter covers only liver disorders associated with cholangitis.

The Cholangitis Complex

In 2006 the World Small Animal Veterinary Association (WSAVA) Liver Standardization Group published a simplified classification scheme for inflammatory liver disease in cats (van den Ingh et al, 2006). Inflammatory liver disease was grouped into three different types of cholangitis based on histopathologic findings: neutrophilic cholangitis ([NC], subdivided into acute and chronic forms), lymphocytic cholangitis (LC), and cholangitis associated with liver flukes (see Chapter 133 in the previous edition of Current Veterinary Therapy). The term cholangitis was adopted in preference to cholangiohepatitis because, unlike in dogs, the primary inflammatory changes in cats are centered on bile ducts and ductules. The categories are based on the type of cellular infiltrate, degree of periportal fibrosis, presence of destructive lesions in the bile ductules, and evidence of fluke infestation. In some cases of feline cholangitis, inflammatory changes may disrupt the limiting plate of the portal triad and extend into hepatic parenchyma. When this occurs, the term cholangiohepatitis is appropriate. Chronic inflammatory disease of the hepatic parenchyma, unrelated to specific infectious diseases such as feline infectious peritonitis or toxoplasmosis, is rare in cats and unlike that in dogs, in which chronic hepatitis represents the major class of inflammatory liver disease.

Although the histopathologic classification of cholangitis is now well described, good clinical characterization of the various forms of cholangitis has lagged necessarily behind the pathologic description. What has become clear is the clinical syndromes of NC and LC overlap considerably, and few clinical distinctions can be made between the acute and chronic forms of NC.

Pathologists also describe lymphocytic portal hepatitis in some feline hepatic biopsies. Lymphocytic portal hepatitis is no longer classified as a primary inflammatory hepatobiliary disease. This pathologic change seems to represent a nonspecific reaction to disease occurring in an extrahepatic location or as an aging change. As opposed to cholangitis (inflammation centered on bile ducts), lymphocytic portal hepatitis lacks bile duct involvement, infiltration of inflammatory cells into hepatic parenchyma, and periportal necrosis. Liver enzymes in cats with this histopathologic change are variable or normal, icterus is uncommon, and most cats with lymphocytic portal hepatitis have prolonged survival, bringing into question the rationale for corticosteroid or other therapy, which has been suggested in the past.

Neutrophilic Cholangitis

NC previously has been referred to as suppurative or exudative cholangitis or cholangiohepatitis. It is the most common type of biliary tract disease observed in cats in North America in one study (Callahan Clark et al, 2011) but was identified with approximately equal frequency to LC in another (Marolf et al, 2012). NC can be subdivided pathologically into an acute neutrophilic form (predominantly neutrophilic infiltration) and a chronic neutrophilic form (having a mixed cellular infiltrate of neutrophils, lymphocytes, and plasma cells). The classical histologic description of the acute form of NC is neutrophils within the walls and lumen of biliary ducts and surrounding the portal areas. Sometimes bacteria can be seen in the bile duct lumen or walls. Biliary hyperplasia, a sign of chronicity, is common in the chronic form, and occasionally periductal (sclerosing) fibrosis and bridging fibrosis may develop. The cause of the acute form is thought to be bacterial from gastrointestinal origin, whereas the chronic form may represent a later stage of the same disease process, possibly triggered by persistent infection or inflammation. Bacterial entry either by the biliary system or hematogenous uptake is possible. Protozoal infections have been identified rarely, including toxoplasmosis, coccidiosis, and hepatozoonosis. Despite being somewhat distinct histologically, almost complete overlap is seen in clinical findings between the two NC subtypes (Callahan Clark et al, 2011; Marolf et al, 2012). For this reason, they are discussed together in this chapter. NC has been described in a wide age range of cats, but the median age is about 9 years. Affected cats with either form of NC show anorexia, weight loss, lethargy, and vomiting. Cats with LC also have these same presenting signs. Physical examination findings are identical in cats with the acute and chronic forms of NC and may include fever, dehydration, icterus, abdominal pain, and hepatomegaly. A majority of cats (55%) demonstrate peripheral neutrophilia. One report indicated that cats with the acute form were more likely to exhibit neutrophilia (50%) than cats with the chronic form (30%) (Callahan Clark et al, 2011). Band neutrophils, neutropenia, and anemia also may be present. Other laboratory findings include increases in serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltranspeptidase (GGT), alkaline phosphatase (ALP), and hyperbilirubinemia. Surprisingly, serum liver enzyme activities are within reference range in many cats. Signs of hepatic dysfunction, such as hepatic encephalopathy, abnormal coagulation parameters, hypoalbuminemia, low blood urea nitrogen (BUN), and hypocholesterolemia, are uncommon. With the exception of frequency of neutrophilia, these laboratory findings do not differ regardless if the histopathologic diagnosis is either the NC or LC form.

Routine abdominal radiographs rarely contribute to making a diagnosis of NC but may help exclude other diseases that can cause similar clinical signs. Somewhat surprisingly, it has been reported recently that most cats with cholangitis of any form have normal sonographic findings, including liver size, echogenicity, and biliary systems (Marolf et al, 2012). When abnormalities are present, they include hepatomegaly, hyperechoic hepatic parenchyma, dilated common bile duct (reference range <4 mm), and echogenic gallbladder contents. Identifying gallbladder debris in cats currently is somewhat confounding because it cannot be considered necessarily an incidental finding as it often is in dogs. Increased gallbladder wall thickness (reference range <1 mm) was not statistically significant in Marolf’s study. However, bacterial cholecystitis can be associated with NC, and such cases may have a thickened gallbladder wall (Brain et al, 2006). Cystic and common bile ducts may be tortuous and dilated. Inspissated bile may cause partial or complete obstruction of the common bile duct. Biliary obstruction is suggested sonographically by a dilated gallbladder, tortuous bile ducts, and a dilated common bile duct.

Enteric bacteria, most often Escherichia coli alone or, less commonly, in combination with other organisms, may be cultured from the bile or liver of cats with cholangitis, especially acute NC. Other reported bacterial isolates include Enterococcus spp., Bacteroides spp., Clostridia spp., Staphylococcus, and α-hemolytic Streptococcus spp. One reported case with NC and cholecystitis had Salmonella enterica serovar Typhimurium isolated from bile and feces (Brain et al, 2006). Although most reported organisms are aerobes, anaerobic organisms also may be found, so aerobic and anaerobic cultures should be requested on biliary and hepatic cultures.

In the authors’ experience, the rate of positive bile cultures is low in NC, even in untreated cats, but culture-independent studies on bile provide further support for the role of enteric bacteria in pathogenesis. Using a florescence in situ hybridization (FISH) assay, the authors (Twedt et al, 2013) have observed intrahepatic bacteria in 33% of cats with inflammatory liver disease they examined. The highest bacterial numbers in cats with E. coli were associated with NC, and intrahepatic bacteria were much more prevalent in cats with NC than the nonsuppurative LC.

Cats affected with cholangitis commonly have comorbidities, most often pancreatitis and inflammatory bowel disease (IBD). In addition, anorexia induced by cholangitis may precipitate a secondary hepatic lipidosis (see Chapter 149). Concurrent inflammation in the liver, pancreas, and small intestine of cats has been referred to as the feline triaditis syndrome. In the first report of feline triaditis, 83% of cats with cholangitis also had histologic evidence of IBD and 50% had concurrent chronic pancreatitis (Gagne et al, 1999). When pancreatitis was present, it was generally chronic and described predominantly as ductal inflammation and fibrosis. The authors (DT and KS) found that culture-independent in situ methods (FISH) in the evaluation of cats having pancreatitis indicated 35% (11 of 31) with moderate to severe forms had bacteria present (Twedt et al, 2013). The common channel theory, according to which the pancreatic ducts and bile ducts join as a common duct before entering the duodenum, may explain partially the relationship of cholangitis and chronic pancreatitis, in which bacterial infections in the biliary system are likely to involve the pancreatic ducts as well. This is supported by the fact that bile cultures are more frequently positive than liver cultures. However, the authors using FISH for bacterial localization found few bacteria were in the pancreatic or hepatic bile ducts but rather in the parenchyma, suggesting also possible portal translocation. With concurrent IBD and gastrointestinal dysbiosis along with the inflamed and leaky gut, enterohepatic translocation of bacteria such as E. coli, enterococcus, and Clostridium spp. could result. Anatomic abnormalities of the gallbladder or common bile duct or the presence of inspissated bile or choleliths also may predispose to, or accompany, cholangitis. Marolf found that cats with NC are more likely than cats with LC to have evidence of pancreatic disease detected on sonographic examination. These changes included diffuse pancreatic enlargement and hypoechoic pancreatic parenchyma. Callahan Clark (2011) also described sonographic changes in the pancreas in 81% of cats with cholangitis, with no difference in frequency between types of cholangitis. Feline pancreatic lipase (Spec fPL) concentration may be abnormal in cholangitis cats and may help support the diagnosis of concurrent pancreatitis.

Definitive diagnosis of NC requires a liver biopsy or biliary cytology and positive culture, but a tentative diagnosis often is made based on the clinical and laboratory findings coupled with a response to appropriate antibiotic therapy. Cytologic examination of fine-needle liver aspirates showing suppurative inflammation may help support the diagnosis, but liver aspiration cytology has a poor correlation with histopathology, especially in inflammatory liver disease. When peripheral neutrophilia is present, the inevitable blood contamination of the liver aspirate may be difficult to distinguish from neutrophilic inflammation in the liver. Whenever possible, a percutaneous ultrasound-guided gallbladder aspirate for bile cytology and culture should be performed, along with liver biopsies. Bile aspirates are relatively safe if a 20- or 22-gauge needle is directed through the right medial liver lobe and into the gallbladder lumen. With this approach, any bile leakage drains back into the liver and not into the peritoneal cavity. Suppurative inflammation and bacteria may be observed in the bile cytology and is diagnostic for NC. Occasionally, cytologic examination reveals many bacteria but few inflammatory cells. Techniques for biopsy include ultrasound-guided needle biopsy, laparoscopy, or laparotomy. The latter two techniques also make it possible to examine the extrahepatic biliary system, pancreas, and other intraabdominal structures. Surgery allows culture of the liver and gallbladder contents, gallbladder wall, and material obstructing the bile duct (if found) as well as biopsy of the liver, gallbladder wall, and extrahepatic biliary system.