David C. Twedt, DVM, DACVIM
Cholangitis is an inflammatory disorder of the hepatobiliary system. It is a disease complex that may be concurrently associated with duodenitis, pancreatitis, cholecystitis and/or cholelithiasis.1 The terminology is somewhat confusing and pathologists describe the condition differently. Based on the histological classification of the WSAVA Liver Standardization Group this complex has been separated into three histological groups; neutrophilic cholangitis, lymphocytic cholangitis and cholangitis associated with liver flukes.2
Bilirubin and gamma-glutamyl transpeptidase (GGT) are the most consistent laboratory abnormalities in cats with inflammatory liver disease. We reviewed 180 cases with elevated total bilirubin (TB>0.3 mg/dl, 5.13 µmol/L) and found cats with inflammatory hepatobiliary disease had a mean TB of 3.5 mg/dl (59.8 µmol/L). It appears that cats with TB of 3mg/dl (51.3 µmol/L) or greater are likely to have primary hepatobiliary disease. Gamma-glutamyl transpeptidase (GGT) is more sensitive for feline inflammatory liver disease than is ALP. ALP elevations are more specific for hepatic lipidosis often associated with marked increases in ALP while GGT concentrations show only mild rises.
This classification has previously been referred to as suppurative or exudative cholangitis /cholangiohepatitis and is the most common type of biliary tract disease observed in cats in North America. Neutrophilic cholangitis is thought to be the result of biliary tract infection ascending from the gastrointestinal tract. In the acute neutrophilic form (ANF), the lesions are exclusively neutrophilic or suppurative but over time it is thought that cases may progress to a chronic neutrophilic form (CNF) having a mixed inflammatory pattern containing variable numbers of neutrophils, lymphocytes and plasma cells.
Evidence for Bacteria
It is not uncommon to culture bacteria from cats having cholangitis however cultures are more often positive in the ANF than CNF. In most cases the organisms identified are enteric pathogens. We sought to determine the presence and distribution of bacteria within the livers of cats with neutrophilic cholangitis (ANF and CNF) by use of culture-independent methods and to compare those findings to culture results. A total of 40 archived liver biopsy samples were obtained at Colorado State University of cats with inflammatory hepatic disease and 14 cases with histologically normal livers. Histopathology was classified according to WSAVA guidelines. We found 16/40 (40%) cases had neutrophilic cholangitis with 3 cases of ANF and 13 cases of CNF. The unstained hepatic tissue sections were subjected to fluorescence in situ hybridization (FISH) using a 16S rDNA probe that recognizes bacteria in the genera (EUB338) and a non-EUB probe as a control.3 In the 3 cases of ANF all had a positive culture (2 Enterococcus spp, 1 E. coli). Two of the ANF cases had acute pancreatitis and 1 had chronic pancreatitis and IBD. 10/13 CNF cases were cultured and 4/10 cases had positive cultures (3 E. coli and 1 anaerobe) but 7 were FISH positive for EUB338 giving a total of 8/13 (61%) cases having bacteria by culture, FISH analysis or both. From this data and the expanded data presented on all 40 liver samples we believe there is evidence to support the role of bacteria involving the majority of cases of neutrophilic cholangitis with far less bacteria observed in other forms of feline inflammatory liver disease and the rare presence of bacteria in normal feline liver tissue.
Acute Neutrophilic Cholangitis
The ANF is thought to be the result of an ascending bacterial infection.4 Usually coliforms (E. coli) are cultured from the liver or bile. Inflammation can also extend into the hepatic parenchyma causing a cholangiohepatitis. Cats with this syndrome are usually young (~3-5 years) and present with acute illness usually a week or less in duration. They may have evidence of a fever, anorexia, vomiting or lethargy. A leukocytosis is generally identified on the CBC. The ALT and ALP are increased but variable and these cats are frequently icteric. Ultrasound should be performed to rule out pancreatitis and biliary obstruction. In some cases we will perform an ultrasound-guided cholecystocentesis for cytology and culture. A elevated feline PLI would support concurrent pancreatitis. A liver biopsy is required for histology and will confirm the diagnosis. The liver should always be cultured because of the relationship of bacteria and cholangitis. If obstruction is identified surgery becomes indicated to decompress and flush the biliary system. However, I always try to avoid surgical diversion of the biliary system unless it becomes the last resort.
Therapy for these cats first includes fluid and electrolyte therapy if needed. Antibiotics are a critical part of the therapy as well. Ampicillin, ampicillin-clavulanic acid, cephalosporins and metronidazole have been suggested as effective antibiotics. Unless a culture and sensitivity says otherwise ampicillin or ampicillin-clavulanic acid are my choice because of the likelihood of E. coli and the fact that both are concentrated in the bile. It is recommended that cats be treated for at least 1 month or even longer with antibiotics. Short duration of therapy may result in reoccurrence of clinical signs. Ursodeoxycholic acid (Actigall 10-15 mg/kg/day) should be used as well. Abdominal discomfort and vomiting may be associated with hepatobiliary pain and buprenorphine (BuprenexTM) should be administered.
Chronic Neutrophilic Cholangitis
The CNF (neutrophilic, mixed or lymphocytic-plasmacytic) cholangitis may be the result of progression of the acute neutrophilic cholangitis. In the chronic stage the liver lesions are associated with the presence of a mixed inflammatory infiltrates in the portal areas consisting of neutrophils, lymphocytes and plasma cells.2,5 Possibly fibrosis, ductular proliferation or extension of inflammation into the hepatic parenchyma can occur as well.
There is also a direct relationship between chronic cholangitis and inflammatory bowel disease and chronic pancreatitis. One study found 83% of affected cats had inflammatory bowel disease and 50% had concurrent chronic pancreatitis.6 The association of the three together has been referred to as "feline triaditis". Possibly the common channel theory where the pancreatic ducts and bile ducts join before entering the duodenum explain this triad of clinical signs. Ascending bacteria initiate the acute disease and then over time it becomes chronic. In a yet unpublished study we have identified over 50% of affected cats to have evidence of bacteria in and around bile ducts of these cats suggesting that resident bacteria may be responsible for the chronic inflammation.
Affected cats are usually middle aged or older and have a long duration of signs being weeks to months. Presenting complaints are often vomiting, lethargy and anorexia. Signs may wax and wane and weight loss may be present. Physical findings identify jaundice in most, possibly hepatomegaly and rarely abdominal effusion.
The laboratory findings are variable. Most cats are icteric and there are variable increases in ALP/GGT or ALT/AST. Hyperglobulinemia is observed in over 50% if the cases. Ultrasound may reveal pancreatic, bile duct or gallbladder changes. The liver generally has a mixed echogenicity pattern with prominent portal areas. Cats with concurrent pancreatitis may have increases feline pancreatic lipase immunoreactivity (fPLI). A liver biopsy confirms the diagnosis.
The primary treatment involves immunosuppressive therapy using prednisolone at 2-4 mg/kg daily and then slowly tapering over 6 to 8 weeks to 0.5-1 mg/kg given once or every other day. This therapy does not appear to resolve this chronic disease but generally slows the progression and may minimizes the clinical signs. A course of antibiotic therapy for several weeks is administered for the possibility of a bacterial component and in light of our yet unpublished study more aggressive antibiotic therapy may be indicated. Ursodeoxycholic acid is a nontoxic hydrophilic bile acid that when administered changes the bile acid milieu. Ursodeoxycholic acid (10-15 mg/kg/day) is nontoxic and suggested for these cats and in fact may be even more beneficial than corticosteroids. This drug is reported to increase bile flow (choleresis), change bile acid concentrations to less toxic concentrations, reduce inflammation and fibrosis and improve liver enzymes. Liver support therapy such as SAMe, silibinin or other antioxidants may be of benefit in the long term management.
The disease is slow and progressive often scattered with periodic flair ups. Approximately 50% of the cases will have a prolonged survival. The final stage of this disease complex is biliary cirrhosis having extensive fibrosis and bile duct proliferation that may end with liver failure associated with ascites and hepatic encephalopathy.
This is a condition (severe lymphocytic portal hepatitis, progressive lymphocytic cholangitis or nonsuppurative cholangitis) is described as a very chronic inflammatory biliary tract condition that is progressive over months and years.2,7 Some describe it as being acute or chronic in nature. This disorder appears to be more common in European cats than in cats in North America. The pathology of the liver is characterized by a consistent moderate to marked infiltration of small lymphocytes predominately restricted to the portal areas, often associated with variable portal fibrosis and biliary proliferation. The later stages result in considerable distortion of liver architecture. The bile ducts can also become irregular with dilation and fibrosis. In some cases lymphocytic infiltrates in the portal areas may be confused with well-differentiated lymphocytic lymphoma. It is postulated that lymphocytic cholangitis could be the result of immune mediated mechanisms based on preliminary immunologic studies while others have found DNA fragments of Helicobacter pylori in the bile of some cats suggesting bacterial involvement in the pathogenesis of the disease.8 We have found bacteria to be less commonly associated with this condition using special fluorescent stains for enteric bacteria.
This syndrome is a slowly progressive chronic disease continuing over months and years. It is often first identified in cats under 4 years of age and Persian cats appear to be over-represented, suggesting a possible genetic predisposition.9 The most common clinical features observed late in the disease include ascites, jaundice, and hypergammaglobulinemia (in almost all cases). In advanced cases, ultrasonographic examination often demonstrates dramatic changes. Intra and extra-hepatic bile ducts with marked segmental dilations and areas of stenosis that may lead the operator to believe there is an obstruction. Ascites and hepatic encephalopathy occur late in the disease as a result of acquired portal hypertension and hepatic dysfunction.
The treatment for the chronic lymphocytic cholangitis involves using anti-inflammatory or immunosuppressive therapy in addition to supportive therapy as described with neutrophilic cholangitis. Some report lymphocytic cholangitis had a better response when treated with ursodeoxycholic acid than with corticosteroids. This finding may not be completely unexpected because ursodeoxycholic acid has been shown to have a positive treatment effect in humans having chronic primary biliary cirrhosis having a very similar histologic pattern to these chronic cases.
Complications of Cholangitis Syndrome
The following are conditions often observed with the cholangitis cases. Bile sludge and or cholithiasis often occur with inflammatory biliary tract disease. Thick inspissated bile or choleliths are thought to be the result of deconjugation of the normally soluble conjugated bilirubin from the action of bacterial enzymes or inflammatory products present in the biliary tree. Bile sludging is best managed by treating the primary cholangitis, treating any biliary tract infection, and by the use of choleretic agents to increase the flow of bile. Ursodeoxycholic acid (Actigall®) should be prescribed. Corticosteroids have a similar effect on bile flow and may also be useful. Complete obstructions may require surgery and in rare conditions a cholecystoduodenostomy or cholecystojejunostomy is required.
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2. van den Ingh TSGAM, et al. WSAVA Standards for Histological and Clinical Diagnosis for Canine and Feline Liver Disease 2006, 61.
3. Simpson KW, et al. Infection and Immunity 2006, 74(8); 4778.
4. Twedt DC, et al. Kirk's Current Veterinary Therapy XIV 2008, 576.
5. Gagne JM, et al. J Am Vet Med Assoc 1999;214(4):513.
6. Weiss DJ, et al. Semin Vet Med Surg (Small Anim) 1997; 12:22.
7. Rothuizen J. Proceedings of the 31st World Small Animal Congress 2006, 47.
8. Boomkens SY, et al. Immunol Med Microbiol 2006;42(3):307.
9. Lucke VM, et al. J Small Anim Pract 1984; 25:249.