Professor of Internal Medicine, Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, University Utrecht
Cholangitis in cats is a complex of diseases, about which there has been much controversy. There are several names in use, which are in part overlapping. The WSAVA liver standardization group has judged that at present there is no ground to define more than three inflammatory biliary diseases in cats: 1) neutrophilic cholangitis, 2) lymphocytic cholangitis, and 3) liver fluke infection.
This is an inflammation of the biliary tree (intra- and extrahepatic bile ducts and the gall bladder) characterized by presence of neutrophils in the bile, but often also within the epithelial cells lining the bile ducts.
Neutrophilic cholangitis is essentially a septic inflammatory disease. In nearly all untreated cases it is possible isolate bacteria from the bile. By far the most common bacterium associated with this disease is E. coli, but occasionally Pseudomonas or other species can be identified. The most likely route of infection is believed to be ascending from the duodenum. The disease may be favoured by pre-existing gall stones, lymphocytic cholangitis, liver flukes, or pancreatitis. However, in the vast majority of the cases no predisposition can be identified. The disease is typically an acute septic disease, with leucocytosis. The disease may cause cholestasis, but jaundice is not present in all cases. Most cats with neutrophilic cholangitis have elevated plasma bile acid concentrations and alkaline phosphatase, but there are also cats without any obvious clinical or biochemical sign of hepatobiliary disease. The disease may become more chronic and the originally pure neutrophilic inflammation may then become a mixed inflammatory cell inflammation with neutrophils, plasma cells and lymphocytes. Chronic cases may also develop some fibrosis in the portal areas, and the chronic cholestasis may result in proliferation of bile ductules.
Clinical signs are general malaise, and usually increased body temperature. The bile ducts have a rich autonomic innervation, and these cats have therefore nausea with more or less pronounced anorexia and/or vomiting. Reduced appetite and vomiting are present in virtually all cats with neutrophilic cholangitis. Cholestasis may be variable and although most of these cats have yellow mucous membranes, some don't show icterus.
Clinicopathological features usually include leucocytosis, increased plasma bile acids, ALT and AP, and often hyperbilirubinaemia. These liver-specific parameters are not specific and are thus not diagnostic. Ultrasonography often shows no abnormalities of the biliary tract or the liver. In rare chronic cases the lumen of the common bile duct may be dilated. Ultrasound-guided puncture of the gall bladder with a thin needle (22G) is diagnostic. Bile should be examined cytologically and by culture. Cytology reveals the presence of neutrophils, whereas normal bile contains no cells whatsoever. Bacterial may also be found cytologically, but culture is needed to identify and specify the infection, and to allow sensitivity testing. In most cases the colour of the bile, which is normally dark brown, becomes dark green. The diagnosis may be completed with histopathology of the liver. Histopathological lesions may be variable of intensity and irregularly distributed in milder cases. Therefore histopathology does not always permit to make a definite diagnosis
Treatment and Prognosis
Neutrophilic cholangitis should be treated with antibiotics, preferably based on sensitivity testing after culture. In most cases routine choices like amoxicillin are effective. A three weeks' course is adequate. These cats have a good prognosis, provided the absence of complicating factors.
Lymphocytic cholangitis is characterized by infiltration of the portal tracts with small lymphocytes. These lymphocytes may also be present in the lumen and epithelial cells of the bile ductules. This is a chronic disease and there may be pronounced fibrosis in the portal areas. Fibrous connections between portal areas (bridging fibrosis) may be called biliary cirrhosis. This disease is common but the symptoms are so non-specific that it may be easily overlooked.
The disease progresses slowly and affects the entire biliary tree. Inflammation of the bile ducts causes irregular dilatations and fibrosis of the bile ducts. The liver lesions are confined to pure lymphocytic inflammation of the portal tracts, chronic cases develop portal fibrosis and proliferation of bile ductules. There is usually no severe portal hypertension or associated symptoms like ascites or hepatic encephalopathy. Nearly all cats have very high gamma globulin levels which would be better compatible with activation of plasma cells than with the presence of only lymphocytes. In most textbooks the advised therapy is with immunosuppressive drugs, such as prednisone or methotrexate. The underlying assumption is that lymphocytic cholangitis is an immune-mediated disease, and that immunomodulation may stop the progression. There are no documented reports that this treatment is indeed effective.
This is often a very chronic disease. Cats may be sick for many months or even years. Nausea is the most prominent sign. Signs are relatively mild and cats with lymphocytic cholangitis just have decreased, variable appetite, and occasional vomiting. As a result gradual weight loss is what the owners report. Only some 60-70% is clinically icteric (Utrecht University hospital population).
Clinicopathological findings may include high plasma bile acids and liver enzyme activities (ALT, AP). However, increased gamma globulin is the most consistent finding (95% of the cats). Leucocytosis is absent in the majority of the cases. Ultrasonography is very abnormal in most cats with lymphocytic cholangitis. The chronic inflammation causes dilatations and strictures of the bile ducts inside and outside the liver. The irregular, fibrous bile ducts with dilatations and strictures have a striking resemblance the ducts of humans with primary sclerosing cholangitis. Cytological evaluation of bile is usually not informative. Culture of bile is typically negative. Lymphocytic cholangitis is much more common in cats than bile duct obstruction. However, with the typical ultrasound findings the only differential diagnosis is extrahepatic cholestasis. Therefore, it is important to complete the diagnosis by taking a large core liver biopsy sample (16G biopsy needle). It is very important to use careful ultrasound guidance, since the liver may be filled with wide irregular bile ducts which should be avoided.
Reviewing our case records of cats that were treated with 2 mg prednisone/kg/day for long periods (six weeks to six months) and evaluated with repeated ultrasonography and liver biopsies, we have found that this medication had no significant effect on the course of the disease. In some cases there was a slight temporary improvement, but we have never seen permanent recovery. It is therefore hard to believe that the pathogenesis is predominantly immune-mediated. In recent series of cases we have treated these cats with ursodeoxycholic acid tablets (Ursochol®, 15 mg/kg/day), and found a much better response than with corticosteroid medication.
Cholangitis Due to Liver Fluke Infection
Chronic cholangitis associated with liver fluke infestation is regularly observed in cats in endemic areas. Infections are caused by members of the family Opisthorchiidae. These liver flukes require snails and sweet water fish as intermediary hosts. Cats become infected by eating raw sweet water fish in which metacercariae are encysted. Young liver flukes migrate from the small intestines to the liver via the bile ducts and cause inflammation of the common bile duct and the large extra- and intrahepatic bile ducts. This chronic inflammation results in malformation and irregular dilatation of these ducts. An inflammation of the smaller bile ductules in the portal areas is visible in liver histology; there is mixed cell inflammation with neutrophils, lymphocytes and plasma cells. Eosinophils are indicative for this disease but they are usually only present in limited numbers. Occasionally the typical eggs are seen in liver biopsy samples within the bile ductuli.
The disease gives lesions which are very similar to those in lymphocytic cholangitis. The chronic course, the clinical signs, the biochemical and haematological abnormalities found in blood examination, and the ultrasonographic abnormalities of the biliary tree are more or less identical. Histologically, the more mixed type of inflammation and if present the eosinophilic component of inflammatory reaction are indications of liver fluke infection. Careful histologic evaluation may reveal liver fluke eggs, which are of course diagnostic. It is important to realise that eating raw sweet water fish is the mode of infection and if this can be excluded, this pleas strongly against this diagnosis. Careful anamnesis is thus important to permit exclusion or inclusion of this differential diagnosis.
Treatment is with praziquantel given at a single daily dose of 20 mg/kg orally, given three consecutive days. If culture of the bile reveals bacteria, treatment with antibiotics for 3-6 weeks is important (see neutrophilic cholangitis). Cats may improve well clinically, but the malformed bile ducts will remain and make the cat sensitive to recurrent bacterial infections.