Andrew H. Sparkes, BVetMed, PhD, DECVIM-CA, MRCVS
Cholangiohepatitis in the cat
For some time now, the term feline 'cholangiohepatitis' or 'cholangitis/cholangiohepatitis' syndrome has been used to describe a group of inflammatory liver diseases of the cat. A spectrum of clinical disease and histopathological liver changes has been described within this syndrome ranging from acute suppurative bacterial infection to chronic non-suppurative (lymphocytic) cholangitis. There is still considerable uncertainty and debate regarding the underlying aetiology of many cases of feline cholangiohepatitis, and the inter-relationship between the different forms of histopathological inflammatory changes that have been described.
The term suppurative cholangiohepatitis has been used to describe those cases where there is predominantly a neutrophilic infiltration centered around the portal triads. Characteristically, there is a substantial portal and periportal inflammatory infiltrate associated with some periportal necrosis, mild bile duct hyperplasia and inflammatory infiltration of the bile ducts and bile duct lumen. Mild fibrosis may also be present.
Recently, based on histological examination of tissues, two forms of cholangiohepatitis have been described-- acute and chronic. In the acute form the cellular infiltrate is predominantly neutrophilic, but there may also be some lymphocytes and plasma cells. Extension of the inflammation to the periportal hepatic tissue is common and associated with hepatocellular necrosis. The chronic form is characterised by a more mixed inflammatory infiltrate with approximately equal numbers of neutrophils and lymphocytes. Periportal necrosis may again be present and there is often more prominent bile duct proliferation and fibrosis. Again inflammatory infiltration into the wall and lumen of the bile duct is a common feature and may be associated with bile duct degeneration.
Non-suppurative cholangitis or cholangiohepatitis has been characterised by a periportal inflammatory infiltrate comprised of lymphocytes and plasma cells, with a variable degree of associated bile duct proliferation and fibrosis. In this condition, infiltration with neutrophils has been reported to be absent or only minimal. The terms 'progressive lymphocytic cholangitis', 'chronic lymphocytic cholangitis' and 'lymphocytic portal hepatitis' have all been used by different authors, but appear to be descriptions of the same underlying condition. In addition to the difference in the predominant type of inflammatory cell present, this form of disease lacks any evidence of inflammatory cell exudation within the lumen of the bile duct and in general there appears to be minimal or no spread of inflammation into the hepatic parenchyma surrounding the portal triad. Bridging fibrosis between portal areas (monolobular fibrosis) is a common and often prominent feature. Unlike suppurative cholangiohepatitis, in lymphocytic cholangitis there is no involvement of the extrahepatic biliary tree in the inflammatory response.
Cases of acute cholangiohepatitis are commonly assumed to originate from ascending bacterial infections from the duodenum. In some cases culture of bile or hepatic biopsy tissue has resulted in identification of the organism involved. Organisms recovered include E. coli, Clostridium spp., Bacteroides spp., Actinomyces spp.,and Streptococcus spp. However, possibly in part due to frequent use of antibiotics prior to extensive investigation of clinical cases, in general, isolation of bacteria is relatively uncommon. Furthermore, it has been suggested that although an ascending infection may be the underlying cause of many cases of cholangiohepatitis, the resulting inflammation may allow the generation of immune-mediated responses that perpetuate the condition even after the clearance of the original inciting cause. Cholangiohepatitis has been described in association with bile duct/gall bladder abnormalities which may predispose to infection, and has also been seen in association with cholelithiasis and bile sludging but whether these are a cause or effect of the cholangiohepatitis is uncertain. Concurrent (subclinical) pancreatitis is commonly seen with cholangiohepatitis, and almost certainly reflects the anatomical relationship between the bile duct and major pancreatic duct in this species. Inflammatory bowel disease has also been reported in association with cholangiohepatitis.
In contrast to cholangiohepatitis, cats with lymphocytic cholangitis do not have associated pancreatic or intestinal inflammation, and the nature of the inflammatory infiltrate has led to speculation that the disease may have an immunological basis. Parallels have been drawn with primary biliary cirrhosis in man, based principally on the histological characterisation of the lesions. Primary biliary cirrhosis (PBC) is generally thought to be an autoimmune condition with anti-mitochondrial antibodies being detected in around 90% and anti-nuclear antibodies in 50% of cases. Although these autoantibodies are not found exclusively in PBC, cDNA cloning of mitochondrial proteins has identified certain antigens where specific auto-antibodies are virtually diagnostic for PBC (e.g., the E2 sub-unit of the oxo-acid dehydrogenase complex), and the same has also been found to be true for some of the anti-nuclear antibodies (e.g., those directed against the gp210 nuclear pore membrane).
To date, investigations on the aetiopathogenesis of lymphocytic cholangitis in cats have been limited, but in a small study antimitochondrial antibodies were not detected in any of four cats examined. Recently though, anti-liver membrane antibodies have been reported in a high proportion of cats with both cholangiohepatitis and lymphocytic cholangitis.
Clinical features and treatment
Cholangiohepatitis is commonly seen in middle to old-age cats and is associated with signs of jaundice, weight loss, lethargy, inappetence, vomiting and pyrexia. In some cases the signs are acute and dramatic, whereas in others they may be vague and chronic or intermittent. Neutrophilia with a left shift is seen in a proportion of cases, and hyperbilirubinaemia with elevations of ALT and SAP are common biochemical abnormalities. Therapy for cholangiohepatitis is usually based on antibiotic therapy which is either empirical (ampicillin, amoxicillin, cephalexin, metronidazole) or based on culture and sensitivity testing. The use of corticosteroids is more controversial but may have a role to play, particularly in the cases of chronic cholangiohepatitis. Additional therapeutic agents that have been used include colchicine (as an antifibrotic) and ursodeoxycholic acid (UCDA). Prognosis for these cases appears variable, and some may resolve completely. However, a recent report suggested that around 50% of cases survive less than a year.
The clinical presentation of lymphocytic cholangitis may overlap with cholangiohepatitis, but in many cases is strikingly different. Affected cats are often very bright and may have increased appetites in the face of weight loss. Clinical signs are often insidious in onset and chronic in nature, with jaundice and or ascites being common features. Elevations in liver enzymes and hyperglobulinaemia are common biochemical abnormalities in these cases. The ascitic fluid frequently has a high protein content unless severe fibrosis/cirrhosis has occurred. Treatment of lymphocytic cholangitis is aimed at suppressing the presumed immune-mediated damage, and thus immunosuppressive doses of corticosteroids have traditionally been used. These are now often combined with colchicine and UCDA therapy although clinical trials to demonstrate benefit from these treatments are lacking. As with cholangiohepatitis, the prognosis for lymphocytic cholangitis is variable. A few cats respond dramatically well to therapy, but many require continual therapy to control clinical signs and in some the response is poor. There is frequently progression over time leading to increased fibrosis and cirrhosis and ultimately death.
Ursodeoxycholic acid (3α, 7β-dehydroxy-5β-cholanic acid) has traditionally been used in Chinese medicine (derived from the bile of bears) to treat liver disease. It became commercially available as a synthetic product in 1957. Naturally occurring bile acids are steroids, synthesised from cholesterol and are typically lipophilic (playing an important role in fat emulsification and digestion). However, UDCA is hydrophilic bile acid that is not synthesised by many animals. UDCA accounts for 3-4% of the bile acid pool in humans, but this is probably derived from bacterial conversion of primary bile acids in the intestine, as humans cannot synthesis UDCA.
The mechanism of action of UDCA in liver disease is diverse. In any cholestatic liver disease there will be accumulation of bile acids in liver, other tissues and circulation. Within the liver this results in cell membrane damage, induction of apoptosis and necrosis. Administration of UDCA competitive replaces endogenous bile acids and as UDCA is hydrophilic rather than lipophilic this reduces the cell membrane damage that can occur. UDCA administration also has a choleretic effect which may in itself be beneficial in liver disease, improving flow of bile acids in hepatocytes. The accumulation of bile acids in liver disease may also affect immunological mechanisms as this retention leads to increase hepatocyte expression of MHC class I and II molecules. Again, this effect as abrogated by administration of UDCA. Finally, the reduced damage to cell membranes resulting from UDCA administration may also reduced levels of oxidative stress in liver disease (which may also contribute to further liver damage).
There is no data currently documenting evidence of the benefit of UDCA in canine and feline hepatopathies, but it is well-tolerated, and based on human studies may be of some value. It is typically used at a dose of 15 mg/kg/day
SAMe is another drug with potential value in treatment of liver disease. Although it may have wide-ranging biochemical effects, in liver disease it is thought to be of major benefit by being a glutathione precursor and thus protecting against oxidative stress. Studies have documented low liver glutathione concentrations in a high proportion of feline (and canine) hepatopathies.
SAMe is a naturally occurring compound synthesised from methionine and ATP. It has crucial roles in cell metabolism and is found in all living organisms. SAMe is involved in three main biochemical pathways--aminopropylation (synthesis of polyamines), transmethylation (SAMe is a major methyl donor for biochemical reactions and synthesis of methylated compounds) and transulfuration (whereby glutathione is synthesised. The liver plays central role in SAMe homeostasis, being the major site of synthesis and degradation. 50% of the daily methionine intake is used to synthesis SAMe and 85% of methylation reactions involve SAMe. Exogenous administration of SAMe has been shown to increase hepatic SAMe concentrations and hepatic glutathione levels, and experimentally has been shown to provided some amelioration of liver injury.
Again, the true benefit of SAMe in canine and feline hepatopathies remains to be determined, but this is an extremely well-tolerated agent, and commonly used as supplementary therapy in hepatopathies at a dose of 15-20 mg/kg/day.