Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
One important difference between dogs and cats is the relatively very low capacity of the liver enzymes responsible for conjugation of cholephilic substances to make them more polar as a prerequisite for biliary or urinary excretion. The low glucuronosyl transferase capacity is important for the metabolism of endogenous products such as bilirubin and exogenous compounds, either drugs or toxins. The elimination of drugs like chloramphenicol, non-steroidal anti-inflammatory drugs and anticonvulsants depends on this function of the liver. Hence, toxic side effects develop much easier in cats in case of overdosage or reduced liver function.
Cats also are often unable to synthesise arginine, taurine and carnitine. Arginine is an important intermediate metabolite in the hepatic urea cycle, so that fasting cats often develop hyperammonaemia. Cats, unlike dogs, may have hepatic encephalopathy in case of parenchymal liver disease without portosystemic collateral circulation. Arginine and taurine are involved in the hepatic production of apoproteins which are used to form the very low density lipoproteins. These lipoproteins are the form in which the liver can secrete triglycerides into the circulation for further metabolization. Insufficient availability of arginine and taurine may lead to accumulation of triglycerides in the liver, for example in case of fasting. Taurine also plays a role in detoxification, since it is being used by the liver as a conjugating group to make substances such as bile acids more hydrophilic. Taurine is also involved in glutathione metabolism which is one of the major routes in the detoxification of many toxins.
Cats may have different forms of cholangitis, which have been named under various titles in the literature. There are in fact three different forms: neutrophilic cholangitis, lymphocytic cholangitis, and cholangitis due to liver flukes. Neutrophilic cholangitis is due to an ascending infection from the intestinal tract. Histologically there are neutrophils in lumens of the bile ducts and in the epithelium of the walls. There may be some neutrophilic inflammatory reaction around the bile ducts in the portal areas. This is usually an acute disease, but when it becomes more chronic, there may be a mixture of neutrophils, lymphocytes and plasma cells. The diffuse inflammation of the entire biliary tree causes cholestasis. Most of these cats, but not all, are distinctly icteric. There is no obstruction at the entrance of the common bile duct in the duodenum; hence there is no distension of the bile ducts.
The signs are those of acute or subacute (1–3 weeks) inflammation with general illness, often fever, and icterus. The degree of icterus is variable.
The bile acids and in many cases also the activity of ALT in plasma are elevated, but this is not specific. Ultrasonography usually reveals no changes; there may be thickening of the gall bladder wall. The diagnosis can only be made by examining bile. Gall bladder puncture with a thin needle should be performed under ultrasonographic guidance. Bile should be evaluated cytologically and by culture, which permits also to make an antibiogram. Histology of a liver biopsy is helpful, but examination of the bile is essential. Without this examination, a case may be missed.
Antibiotics which are well excreted into bile are indicated. We prefer a 3–4 weeks medication with amoxycillin and clavulanic acid. It is advisable to evaluate the therapy by re-examination of the bile after completion. The prognosis is usually very good if the diagnosis is made in time.
This form of cholangitis behaves much different from the neutrophilic form. It is a very chronic disease, progressing slowly over many months or even years. The type of inflammatory cell is exclusively lymphocytic. The inflammation is detectable in the lumen of bile ducts, in the bile duct epithelium, and it progresses around the bile ducts in the portal areas. The inflammation causes portal fibrosis, and in very chronic cases there may be bridging fibrosis between portal areas of different lobules causing severe fibrotic changes. The very chronic inflammation of the bile ducts causes irregular distension of the bile ducts in and outside the liver. The wall of the bile ducts is usually thickened. The sometimes very wide bile ducts are readily detectable with ultrasonography. The differential diagnosis for this picture is extrahepatic bile duct obstruction. The latter condition is rare whereas lymphocytic cholangitis is quite frequent in cats. Histologically the two diseases are distinctly different. The lymphocytic inflammation suggests an autoimmune type of continuing destruction of biliary and liver cell epithelium. The most prominent finding with blood examination is a high gamma globulin level, similar to what is usual in cats with FIP. The liver tends to be enlarged and is therefore palpable in many cases. The diffuse inflammation of the entire biliary tree causes cholestasis; these cats are often icteric, but not in all cases.
The chronic deformation of the bile ducts makes them prone to secondary infections, usually by intestinal E. coli. Such a superimposed infection may cause a more acute exacerbation of disease, and the typical lymphocytic inflammation may change to a more mixed type with also neutrophils and plasma cells.
Like in all biliary diseases, the main symptoms are caused by nausea: decreased appetite, irregular eating, occasional vomiting, and chronic weight loss. Cholestasis may give icterus, which is present in most but not all cases.
There may be palpable enlargement of the liver, and blood examination reveals high bile acid levels with variable increment of the ALT activity. The most consistent abnormal finding at blood examination is an increase in gamma globulin concentration. The chronic course with hypergammaglobulinaemia makes that the disease is often mistaken to be FIP. Ultrasonography indicates a diffusely enlarged liver, often with increased echodensity which is not specific either. In chronic cases the bile ducts are irregularly distended, both intra- and extrahepatic. These findings in association with the typical histological findings of the liver determine the diagnosis. The infection with liver flukes gives a very similar disease; only the history and the type of inflammatory cells distinguish the two bile duct diseases.
The disease responds well to medication with ursochol (ursodeoxycholic acid) which suppresses the inflammation. Long-term treatment is mandatory, at a dosage of 15 mg/kg/day, divided over two doses. It is important to evaluate the response by liver biopsies after 8 weeks treatment. Medication must be continued until there is no doubt about the cessation of the inflammation histologically. It is advisable to treat these cats during the first four weeks of medication also with amoxycillin and clavulanic acid to treat possible superimposed infections. Corticosteroids have often been advised, but evaluation of a series of these cats in Utrecht university companion animal clinic has revealed no beneficial effect at all of steroids. Recently, we have treated very ill cats, which were about to be euthanised, with intrabiliary administration of an antibiotic mixture, resulting in complete clinical improvement within 3–6 weeks. It seems that metronidazole was the most important component. This medication may be used in very severe cases. In the anaesthesized cat the gall bladder is punctured with a thin needle under ultrasound guidance, the bile is aspirated and replaced by the antibiotic. We have repeated this three times with weekly intervals, and saw improvement start one or two weeks after the last injection.
Chronic Cholangitis caused by Liver Flukes
Chronic cholangitis associated with liver fluke infestation is regularly observed in cats and rarely in dogs in endemic areas. Infections are caused by members of the family Opisthorchiidae, which require two intermediate hosts, the first being water snails and the second a wide variety of fish, in which the metacercariae are encysted. The final host acquires infection by ingestion of raw fish, and the young liver flukes migrate from the intestine to the liver by the bile ducts causing thickening and (cystic) dilatation of the common bile duct and hepatic ducts. The lesion is microscopically characterized by dilated larger bile ducts with papillary projections and marked periductal and portal fibrosis. A slight to moderate inflammation may be seen both within the ducts (neutrophils and macrophages) and in the portal areas (neutrophils, lymphocytes and plasma cells). Eosinophils may be present, but usually limited in numbers. The number of liver flukes and eggs within the dilated bile ducts varies markedly and regularly only limited evidence of liver flukes or eggs is seen. In cats and dogs, chronic cholangitis due to liver fluke infestation has been associated with the development of intrahepatic and extrahepatic cholangiocellular carcinomas.
The diagnosis is comparable with that for lymphocytic cholangitis. Eosinophilia (in blood or liver histology) indicates this specific etiology. Sometimes the typical eggs may be seen in the bile ducts histologically.
Anti parasitic treatment (praziquantel) is effective. Treatment usually needs to be repeated once or twice with two or three week intervals.