Abstract
Liver disease in cats is common. We recently reviewed 175 consecutive feline liver biopsies and several large categories were apparent. The largest groups included idiopathic or secondary hepatic lipidosis (26%), then cholangitis (25%), and neoplasia (20%). Bile duct adenoma (cyst adenomas) was the most common primary benign tumor and bile duct carcinoma the most common malignant neoplasia when the more common hematopoietic tumors were excluded. Hepatic cysts are also an occasional finding in some cats and rarely cause problems.
Inflammatory biliary tract disease in cats is distinctly different from dogs where the inflammatory disease is centered on hepatic parenchyma (i.e. hepatitis).1 In cats the inflammation is almost always centered on the bile ducts. The following will discuss these hepatobiliary disorders including their clinical manifestations.
Laboratory Evaluation
The best liver biochemistries for the diagnosis of feline biliary tract disease include ALP, GGT, total bilirubin and bile acids.2 The ALT and AST are quite variable and elevations don't always predict primary inflammatory biliary tract disease although these enzymes are frequently elevated to some degree. ALP is unique in cats in that the half-life is short (6 hours) compared to dogs (66 hours) and the feline liver is reported to contain smaller concentrations than found in dogs. Consequently, increases in serum ALP with cholestasis are not expected to rise with the same magnitude observed in dogs with similar diseases. ALP is also not induced by corticosteroids nor does a steroid hepatopathy occur in cats. Gamma-glutamyl transpeptidase (GGT) is a similar enzyme to ALP that increases with cholestasis and is more sensitive for feline inflammatory biliary tract disease than ALP. This may be in part because GGT arises from predominately bile duct epithelium. Cats affected with idiopathic hepatic lipidosis usually have marked increases in ALP while GGT concentrations show only mild increases, in contrast to cats with biliary tract disease where there are usually proportionally higher GGT concentrations than ALP concentrations. Hyperbilirubinemia is a common finding in the cat with liver disease. Mild hyperbilirubinemia is often noted in cats with primary liver disease but that alone is not always predictive of primary liver disease because other systemic or metabolic diseases may also cause an increase in bilirubin secondarily. Our observations however find that clinically icteric cats with bilirubin concentrations higher than 3.0 mg/dl are most likely to have primary hepatobiliary disease. Bile acid measurements are used to predict occult liver disease or to identify a suspected portal vascular anomaly.
The Cholangitis Complex
The complex of inflammatory biliary tract diseases in cats is controversial as far as nomenclature and pathologic interpretation of histological lesions.3 The lack of consistency in terminology has hindered our ability to clarify clinical syndromes, as to the etiology, therapy and prognosis of the various subtypes of this disorder. Recently the World Small Animal Veterinary Association (WSAVA) sponsored an international group of pathologists to standardize the histological classification of small animal liver disease. The WSAVA Liver Standardization Group has proposed a simplified classification scheme of biliary tract disease in cats.4 This manuscript will attempt to use that classification. WSAVA group proposes three distinct forms of cholangitis in cats: neutrophilic, lymphocytic and cholangitis associated with liver flukes. The neutrophilic form was subdivided into an acute (suppurative) and a chronic (non-suppurative or mixed forms). It is probable that the acute and chronic forms of cholangitis represent different stages or progression of a single disease. The term cholangitis is used in preference to cholangiohepatitis because the primary inflammatory process is centered on the bile ducts with minor secondary involvement of hepatocytes in most circumstances. Disruption of the limiting plate by extension of inflammation to involve hepatic parenchyma is not a common feature of the syndrome and when present it is an extension of primary cholangitis where the inflammation is centered on the intrahepatic bile ducts.
The WSAVA Liver Standardization Group believes the histological diagnosis of a
Neutrophilic Cholangitis
This disorder is usually observed in young to middle-aged cats (-3-5 years). Cats present with acute illness usually a week or several weeks in duration. Fever, anorexia, vomiting and lethargy are common signs. Vomiting is frequent with all biliary tract disease and is thought to be due to the rich autonomic innervation located in the bile ducts that through inflammation mediate input to the emetic center. Physical findings often reveal a fever, icterus and possibly abdominal pain upon palpation. Laboratory findings can be quite variable. A mild to moderate leukocytosis is common in most cats. Early in the course of disease when inflammation is limited to the larger bile ducts and gallbladder, total bilirubin and even liver enzymes may not be increased. In these cases there are minimal if any histological changes in the liver. Rarely, the author has seen very acute cases in which only the total bilirubin is elevated. More typically there are mild to moderate increases in ALP, GGT and bilirubin. When inflammatory cells extend into the hepatic parenchyma there will also be increases in ALT and AST concentrations. Serum bile acids are often increased as well. The diagnosis of acute neutrophilic cholangitis is supported by ultrasonographic characterization of the liver and extrahepatic biliary system. Sometimes there may be no hepatic abnormalities identified or there is evidence of prominent portal areas within the liver. In some cases the gallbladder is thickened and bile ducts can be quite dilated with or without obstruction. Evidence of obstruction using ultrasonography would be supported by diffuse intrahepatic ductular dilation.7 In some cases an ultrasound guided fine needle aspirate helps support the diagnosis when suppurative inflammation is observed on cytology. Acute neutrophilic cholangitis is confirmed with a liver biopsy showing invasion of neutrophils into the biliary system. Cultures should always be taken of the liver tissue in suspected cases. An ultrasound directed gallbladder puncture for culture and cytology of the bile is also very helpful in the diagnosis. The cytology of the bile will contain neutrophils and sometimes bacteria are observed. Safe gallbladder aspirates are obtained when the needle is directed through the right medial liver lobe and into the gallbladder where it is attached to the liver. If leakage should occur using this technique bile spills only into hepatic parenchyma and not into the peritoneal cavity. Once the diagnosis is made therapy is instituted. Fluid and electrolyte support is given as needed. Appropriate antibiotics are based on culture and sensitivity. When a culture is not available or is negative, antibiotics are selected that are effective against aerobic gram-negative enteric bacteria and are excreted into the bile. Suggestions include amoxicillin, amoxicillin-davulanic acid or cephalosporins. In rare cases an anaerobic infection is present and metronidazole would be indicated (7.5-10 mg/kg bid). Treatment duration should be long and for at least one month to assure pathogenic organisms are cleared. Ursodeoxycholic acid therapy should also be instituted (10-15 mg/kg/day). Bile sludge formation often occurs and is thought to be the result of deconjugation of bilirubin by bacterial enzymes. Cholelithiasis or bile sludge (thick inspissated bile) can lead to obstruction and require surgery to decompress the biliary tree. It is the author's opinion that if obstruction of the biliary system due to bile sludge of choleliths one should be preserve the normal anatomy if at all possible by either flushing the gallbladder or common duct or using temporary biliary stents. By-pass surgery should be performed as only a last resort. The prognosis for most acute neutrophilic cholangitis cases is good with appropriate therapy.
One study found 83% of affected cats with chronic biliary tract disease also had inflammatory bowel disease and 50% had concurrent chronic pancreatitis.5 The association of the three organs together has been referred by some to as the feline triaditis syndrome. The common channel theory, where the pancreatic ducts and bile ducts join as a common duct before entering the duodenum may be responsible. Speculation on the theory of cholangitis suggests that high bacterial numbers in the proximal duodenum in cats coupled with concurrent IBD, vomiting and the feline pancreaticobiliary anatomy predispose to reflux of bacteria and intestinal contents into the pancreatic and biliary system.
The chronic form of neutrophilic cholangitis generally occurs in middle aged to older cats. The duration of illness is often chronic with waxing and waning signs for months to years. Typical signs include periods of anorexia, vomiting and weight loss. On physical examination approximately half the cats are jaundiced, and hepatomegaly is detected in some cats. Rarely abdominal effusion is found. Because of the triad relationship, cats may first present for either pancreatic or intestinal related signs. Laboratory findings are quite variable with approximately 50% of the cats having elevated bilirubin concentrations and the majority of cats having increased liver enzymes. GGT is more often elevated and proportionally higher than ALP. ALT increase is common in cats having the chronic form of neutrophilic cholangitis although the magnitude of increase is variable and usually not proportionally as high as GGT concentrations. Hyperglobulinemia is observed in over 50% if the cases. Ultrasound will reveal bile duct or gallbladder changes. The liver generally has a periportal hyperechogenicity and the intrahepatic and extrahepatic bile ducts may be torturous and dilated. The gallbladder may be thickened suggesting chronic cholecystitis. Occasionally cholelithiasis is observed. Cats with concurrent chronic pancreatitis will have a nodular irregular pancreas and often increases in feline pancreatic lipase immunoreactivi-ty (fPLI). Cats with advanced disease may develop cobalamin deficiency (Vitamin B12) and require supplementation. The primary treatment in chronic neutrophilic cholangitis involves antibiotics, ursodeoxycholic acid and immunosuppressive therapy. Clinical studies evaluating various therapies for this syndrome are lacking. Affected cats should be placed on a course of antibiotics as described above in addition to corticosteroid therapy. Prednisolone given at 2-4 mg/kg daily and then slowly tapered over 6 to 8 weeks to 1 mg/kg given once or every other day is a suggested protocol. Ursodeoxycholic acid (10-15 mg/kg/day) is nontoxic and is suggested for these cases. This drug will increase bile flow, change bile acid concentrations favoring the less toxic ursodeoxycholate, reduce inflammation and fibrosis and improve liver enzymes. A human correlate to chronic cholangitis in cats is primary biliary cirrhosis and ursodeoxycholic acid has been shown to have significant therapeutic effects on this condition. The disease in cats is slow and progressive, often scattered with flair ups. Approximately 50% of the cases will have a prolonged survival. The final stage of this disease complex is biliary cirrhosis with extensive fibrosis and bile duct proliferation that may end with liver failure associated with ascites and hepatic encephalopathy.
Lymphocytic Cholangitis
This is a less common chronic inflammatory biliary tract condition that slowly progresses over months and years in the cat. It is postulated this condition is the result of immune mediated mechanisms based on immunologic studies. Pathology is characterized by a consistent moderate to marked infiltration of small lymphocytes restricted to the portal areas, often associated with variable portal fibrosis and biliary proliferation.49 The lymphocyte infiltrates are centered on and may infiltrate into the walls of the bile ducts. There may be lymphoid aggregates, obliteration of bile ducts and biliary hyperplasia and fibrosis or bridging portal fibrosis. There may be a few portal plasma cells and eosinophils scattered in the portal areas. Well-differentiated lymphocytic lymphoma may be difficult to discriminate from lymphocytic cholangitis.4 The disease will rarely progress to cirrhosis.10
This condition appears to be very chronic, associated with weight loss, anorexia and variable icterus. Ascites and hepatic encephalopathy may occur. The liver enzymes are variable but hypergammaglobulinemia is common and is a reflection of the chronic nature of the disease. Because the disease develops slowly there may only be mild increases in liver enzymes. The high globulins in this condition would make FIP an important differential diagnosis. Ultrasonography finds the biliary tree distended and irregular. The usual long-term therapy has been prednisolone. It is reported in one series of cases that corticosteroids appeared to have no long-term effect on the disease progression and authors suggest ursodeoxycholic acid therapy may be a more logical long-term choice.” Antibiotic therapy should be used with a positive culture. The long-term prognosis is guarded and an important factor in survival is appropriate nutritional management for the patient.
Chronic Cholangitis Associated with Liver Flukes
Cholangitis associated with liver fluke infestation is often observed in cats from endemic areas of the country. Infections are caused by flukes of the family Opisthorchiidae found in southern tropical areas.12 The fluke requires two intermediate hosts, water snails and lizards, toads or fish. The final host acquires the infection by oral ingestion where the flukes then migrate up the common bile duct to cause biliary tract inflammation, thickening of bile ducts and marked bile duct dilation.4 There is periductal and periportal fibrosis as well. Sometimes the flukes or their eggs are observed on liver biopsy. Appropriate fecal examinations may detect fluke eggs and preferred therapy is with high doses of praziquantel.
Hepatic Cysts
Congenital hepatic cysts are relative common in the cat and are characterized by dilation of the intrahepatic bile duct system with variable degrees of fibrosis. It is believed to be caused by anomalous formation of intrahepatic bile ducts resulting from a developmental ductal plate abnormality.414 The ductal plate is the embryological origin of the developing bile ducts. This condition is often associated with concurrent renal cysts and is most commonly observed in the Persian cat.13 Cysts are single or multiple and of variable size. Very large cysts can impair hepatic function and may require surgical removal. Recently a hepatic cyst variation was described in which a ductal plate anomaly resulted in diffuse hepatic fibrosis, ascites and portal hypertension in a cat.15
Biliary Tract Neoplasia
Hematopoetic neoplasia is the most common liver neoplasia found in cats, however 70-80% of the non-hematopoetic neoplasias are of bile duct origin.6 Cholangiocellular adenoma (bile duct adenoma or biliary cystadenoma) is reported to cause up to 50% of non-hematopoetic tumors of the bile duct.16 They are often well circumscribed, often cystic and only cause clinical signs when they become large. Surgical removal has a good prognosis. The diagnosis of cholangiocellular adenoma is controversial and the WSAVA believe these tumors to be rare and that most cystic lesions are in fact derived from biliary development abnormalities (Von Meyenburg complexes) or congenital hepatic cysts.4 Bile duct adenocarcinomas arise either from hepatic or extrahepatic origin. Extrahepatic tumors may cause bile duct obstruction. They are highly malignant and often metastatic.
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The American Association of Feline Practitioners (AAFP) will present a research award in 2007 to a person doing meaningful research in feline medicine and/or surgery. The $15,000 award will be given to the researcher whose application shows the most clinical merit.
The 2006 research project and recipient of the award was:
“Prostaglandin E2 Signaling in the Feline Mammary Cancer: A Potential Target for Chemotherapy”
The research committee will give special consideration during the review and selection process to the following:
Completed Application.
IACUC Guidelines followed if Animals are used.
Clinical Significance.
Likelihood of Valid Findings based on Experimental Design and Statistical Analysis.
Review of Literature and References.
Strong preference will be given to Non-Euthanasia Studies.
Strong preference will be given to funding complete research projects, rather than partial funding of a project. This does not preclude matching funds.
Preference will be given to funding clinical studies utilizing patients, rather than research animals.
Preference will be given to grant proposals where less than or equal to 20% of the grant is required for technical support salaries.
Preference will be given to proposals utilizing clinical patients rather than proposals for methodology development.
The 2007 recipient of the research award is required to contact AAFP with a letter of acceptance to include an approximate timetable of your research so that we may have the check forwarded to you as soon as possible. Eighteen months after receipt of the grant, recipients must submit a 1,500-word progress report to the AAFP for reporting at the AAFP annual general meeting and inclusion in the AAFP newsletter. Within three years of receiving the grant, a final report of 5,000 words must be submitted to a journal approved by the AAFP Executive Board. In addition, the recipient must give a 60 minute presentation of their research findings and related clinical material at the AAFP Annual Meeting. The AAFP will pay airfare and one night hotel stay. The recipient must acknowledge the AAFP in any publication of data derived from the project.
Interested applicants should submit their names, addresses, and a synopsis of the work they are presently engaged in, as well as projected research. Enclosed is an instruction sheet and application form. Please note AAFP does NOT pay indirect costs.
All applications and 8 copies of the proposal must be received in the AAFP office by