Cholangitis is inflammation of the portal region of the liver with infiltration into bile duct epithelium or within the duct lumen. Cholangiohepatitis is inflammation of that has extended into periportal areas and surrounding hepatocytes beyond the limiting plate.
Feline cholangitis/cholangiohepatitis syndrome (CCHS) is the most common acquired inflammatory liver disease in domestic cats.
Both cholangitis and cholangiohepatitis are more common in cats than dogs. The anatomic difference between the biliary and pancreatic ducts in cats compared with dogs has long been considered an underlying risk factor.
Feline CCHS coexists with inflammatory processes in the duodenum, pancreas, and kidneys (chronic interstitial nephritis).
Numerous concurrent conditions have been identified in cats with CCHS, whether the inflammatory infiltrate is predominantly neutrophilic (suppurative), lymphocytic or lymphoplasmacytic (nonsuppurative), or whether it actively involves bile duct destruction. Disorders associated with feline CCHS include the following:
bacterial infections (primary or chronic)
septicemia
cholecystitis
cholelithiasis
extrahepatic bile duct obstruction (EHBDO)
trematode infestation
toxoplasmosis
inflammatory bowel disease
primary cholangitis
pancreatitis
neoplasia (eg, pancreatic or gallbladder or bile duct adenocarcinoma)
biliary cystadenoma
various ductal malformations (eg, choledochal cyst, diffuse ductal plate malformation [congenital hepatic fibrosis associated with polycystic liver malformation], Caroli malformation)
Liver lobe involvement in feline CCHS is variable, and the extent and severity of histologic lesions may not be fully ascertained on a single liver biopsy or with small (eg, 18-gauge) core biopsy needle. Some biopsy sections may show modest or moderate periductal inflammation and hepatitis, whereas other liver lobes reveal complete elimination of bile ducts and lack active inflammation owing to loss of bile duct epitopes that may drive the inflammation. Cats with disease in multiple organ systems have much shorter survival times if untreated. However, because CCHS is slowly progressive, cats can survive several years beyond initial diagnosis without therapeutic interventions.
Suppurative CCHS causes the most overt clinical illness. Affected cats have been found to have a shorter duration of illness (< 5 days) prior to initial evaluation, with young or middle-aged adults predominating (range, 3 months to 16 years).
Clinical signs include pyrexia, lethargy, dehydration, inappetence, vomiting, and variable jaundice. Many cats manifest abdominal pain, and some have palpable hepatomegaly.
Clinicopathologic features are similar to those of other forms of CCHS, with moderate to marked increases in transaminases (ALT, AST) and more modest increases in alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) activities. Surprisingly, some cats lack cholestatic enzyme abnormalities. Most cats are hyperbilirubinemic, some have concurrent renal azotemia, and many demonstrate a left shift and toxic neutrophils on their leukogram.
Concurrent hepatic lipidosis (HL) may confuse initial assessments.
Abdominal ultrasonography may reveal EHBDO; abnormalities consistent with cholecystitis, choledochitis, pancreatitis, or inflammatory bowel disease; diffuse hepatic parenchymal hyperechogenicity consistent with HL; coarse parenchymal echogenicity; or no abnormalities. A coarse or heterogeneous hepatic parenchymal pattern sometimes recognized may reflect parenchymal inflammation or periductule or portal tract fibrosis and inflammation. Thoracic radiography often reveals a large sternal lymph node reflecting abdominal inflammation or sepsis.
Medical treatment is usually provided before surgical intervention (biliary decompression surgery for EHBDO, cholecystectomy for cholecystitis, cholecystotomy for cholelithiasis) and liver biopsy. Disorders causing stasis of bile flow must be rectified, because they increase risk of opportunistic infection involving the biliary system. Aspiration or biopsy imprint cytology of liver and bile usually reveals bacterial organisms and suppurative inflammation.
Gram-stain characterization of bacteria on cytologic specimens assists in selection of antimicrobial agents and may provide the only confirmation of bacterial infection. Cultures may be negative because of prior antibiotic administration or failure to culture for anaerobic bacteria. Commonly isolated bacteria include Escherichia coli, Streptococcus, Clostridium, Bacteroides, and Actinomyces.
Treatment involves broad-spectrum antimicrobials effective against anaerobic and gram-negative enteric opportunists, ursodeoxycholic acid, S-adenosylmethionine (SAMe), vitamin E, water-soluble vitamins, enteral alimentation with a maximum-calorie diet formulated for cats, and judicious administration of fluid therapy and electrolyte supplements to correct and maintain hydration and electrolyte status.
Antioxidants are provided during critical illness by administration of N-acetylcysteine (140 mg/kg initial dose [10% solution in NaC1], 70 mg/kg thereafter, every 8–12 hours, infused IV over 20 minutes via a 0.25-mcm filter). When oral administration is possible, SAMe is given by mouth. A combination of enrofloxacin, metronidazole, and ampicillin-sulbactam is often initially administered and adjusted based on culture and susceptibility test results from hepatobiliary or bile aspirates or tissue samples.
Antimicrobial treatment should begin before surgical intervention (because sepsis compromises postoperative survival) and continue for 8–12 weeks or until liver enzymes normalize. If liver enzymes remain increased, repeat ultrasonographic assessment is warranted to check for abnormalities involving biliary structures, pancreas, or gut, or development of lymphadenopathy. Repeated aspiration cytology or liver biopsy may be necessary.
Feline lymphocytic portal hepatitis is a diagnosis demonstrating inflammatory infiltrates without tropism for bile ducts but showing single-cell hepatocyte necrosis. It is presumed that many of these cases are responses to antigens or debris from the alimentary canal or reflect inflammatory cells delivered in the portal circulation.
Otherwise, this diagnosis may represent mild lesions in cats with CCHS when only a few portal triads are sampled from a relatively uninvolved liver lobe. Low-yield needle biopsies from cats with nonsuppurative CCHS may generate this diagnosis. In some cats, however, an inflammatory portal tract infiltrate is associated with single-cell hepatocyte necrosis, qualifying as a true portal hepatitis.
Nonsuppurative CCHS without destructive cholangitis is usually a T-cell–mediated or mixed T-cell with B-cell–mediated inflammatory syndrome affecting middle-aged or older cats. Concurrent infection with feline leukemia virus or feline immunodeficiency virus is uncommon, and there is no sex or breed predisposition. Duration of illness ranges from 2 weeks to several years, with most cats demonstrating clinical signs of illness for several months before initial presentation.
Clinical signs include intermittent vomiting and diarrhea and episodic illness characterized by anorexia or hyporexia, reclusiveness, or self-resolving jaundice. Hepatomegaly is common. It is uncommon for nonsuppurative CCHS to cause portal hypertension, acquired portosystemic shunts (APSSs), and abdominal effusion, because cats usually die from the effects of this syndrome before diffuse fibrosis evolves. Rather, cats with these features more likely have fibropolycystic biliary malformations.
The hemogram is variable, commonly demonstrating poikilocytosis and Heinz bodies. The leukogram is variable but typically does not display a left shift or toxic neutrophils. Hyperglobulinemia develops with chronicity; most cats have moderate to marked increases in ALT and AST activities with widely variable ALP and GGT activities depending on cyclic activity of the disease process. Hyperbilirubinemia is inconsistent and also appears cyclic.
Some cats are persistently jaundiced secondary to inflammatory obstruction or destruction of small and medium-sized bile ducts (nonsuppurative CCHS with destructive cholangitis); these often develop clinical coagulopathies responsive to vitamin K administration. Abdominal ultrasonographic findings overlap with those of suppurative CCHS; a nonuniform or coarse parenchymal pattern may be identified. However, cats with marked nonsuppurative CCHS may lack ultrasonographic hepatic or biliary abnormalities. Severity of histologic lesions is highly variable within and between liver lobes and between cats.
Initial treatment consists of appropriate antimicrobials, SAMe, vitamin E, supplementation of B vitamins, enteral alimentation with a maximum-calorie diet formulated for cats, and fluids and electrolyte supplements to correct and maintain hydration and correct electrolyte abnormalities. Broad-spectrum antimicrobial coverage (against anaerobic and gram-negative enteric opportunists) is recommended pending liver biopsy and culture results. Longterm treatment requires immunomodulation.
Ursodeoxycholic acid is used in cats lacking evidence of destructive cholangitis. However, ursodeoxycholic acid is no longer recommended for cats with destructive cholangitis based on evidence (experimental animal models, humans with sclerosing cholangitis) that it may provoke small duct injury in destructive cholangiopathies.
First-line immunosuppressive therapy is prednisolone, initially administered at 2–4 mg/kg, PO, every 24 hours, titrated to 5–10 mg/cat, PO, every 24 to 48 hours. Glucocorticoid dosing is titrated based on clinical assessments. Metronidazole (7.5 mg/kg, PO, every 12 hours) is also recommended to assist with immunomodulation and control of associated inflammatory bowel disease; adding this drug may allow decrease of the glucocorticoid dose. Continued administration of SAMe (40–50 mg/kg, PO, every 24 hours) and vitamin E (10 U/kg, PO, every 24 hours) is recommended.
As a single agent, SAMe has decreased nonsuppurative CCHS-associated inflammation in a few studied cats. Chlorambucil (2 mg/cat, PO, every 24 hours, titrated to every other or every third day) is used in cats that do not respond to anti-inflammatory glucocorticoid and metronidazole treatment. Treatment usually returns bilirubin concentrations to normal; however, cyclic increases in enzyme activity remain, although at lower magnitudes.
Cats with nonsuppurative CCHS with destructive cholangitis (sclerosing cholangitis) can eventually develop widespread small duct destruction causing permanent hyperbilirubinemia and intermittent acholic feces due to a histologic progressive ductopenia. This subset of CCHS is confirmed by finding defining histologic features that include the following:
infiltration of bile ductules with lymphocytes
peripheralization of bile ductules to the margin of portal tracts
evidence of involuting bile ducts
lipogranulomas (when ducts have been eliminated)
scant lymphoid nodules (B cells) consistent with an inflammation
periductular sclerosing fibrosis without other features suggesting EHBDO
In some cases, confirmation of bile duct involution and peripheralization to the edge of portal tracts requires immunohistochemistry using a cytokeratin antibody. Marked differences between liver lobes in status of portal tract inflammation may be seen; in lobes with elimination of biliary ductules, inflammation can be mild or inapparent. Approximately 30% of cats with destructive cholangitis treated with glucocorticoids develop diabetes mellitus. Inflammatory involvement of pancreatic ducts with the T-cell–mediated destructive cholangiopathy may influence this outcome.
Clinically affected ductopenic cats require once- or twice-weekly vitamin K1 injections and water-soluble vitamin E (polyethylene glycol alpha-tocopherol succinate, 10 U/kg, PO, every 24 hours). Overdosing vitamin K1 can cause serious hemolytic anemia, and overdosing vitamin E can lead to insufficient vitamin K activity.
Affected cats should be investigated for severe inflammatory bowel disease and B12 adequacy. Hematology and serum biochemistry features are similar to those of cats with non-duct-destructive CCHS. Immunomodulation with prednisolone does little to moderate enzyme activity or hyperbilirubinemia in destructive CCHS when used as monotherapy immunosuppression. Instead, methotrexate or chlorambucil is used initially with glucocorticoids.
Pulsatile methotrexate is given at a total daily dose of 0.4 mg/cat divided into three treatments given on a single day (0.13 mg per dose, PO) once every 7–10 days. Alternatively, methotrexate may be given IV or IM with a 50% dose decrease.
Folic acid, 0.25 mg PO, every 24 hours is concurrently administered to prevent methotrexate-associated hepatotoxicity, GI toxicity, or hematopoietic effects. The dosage of methotrexate must be decreased in cats with renal azotemia. Methotrexate imposes profound immunosuppression at the recommended dosage, and careful monitoring for complicating infections is essential.
Alternatively, treatment with chlorambucil, as described above, can be used instead of methotrexate. Concurrent treatment with SAMe is recommended, along with low-dose prednisolone and metronidazole. Treatment for concurrent inflammatory bowel disease with a hypoallergenic diet also may be beneficial.
Cobalamin deficiency must be corrected, with cats chronically supplemented if deficiency is proved via laboratory testing. Low cobalamin concentrations should raise concern for severe small-bowel malabsorption (especially small-cell lymphoma) or severe pancreatic disease.
In lymphoproliferative disease masquerading as lymphocytic CCHS, lesions are characterized by dense portal lymphocyte infiltrates that penetrate hepatic sinusoids. However, involved lymphocytes lack convincing morphology for classification as a neoplastic population; this syndrome may represent a transition phase between conventional inflammatory disease and overt neoplasia. Treatment with chlorambucil has proved beneficial in some cats (2 mg/cat, PO, every 48 to 72 hours), combined with treatments described for CCHS.
Affected cats may survive for several years with minimal clinical signs. Immunohistochemical staining and other molecular tests (investigation of clonality) may help differentiate this syndrome from lymphoma.
In small-cell lymphoma masquerading as lymphocytic CCHS, dense lymphocytic portal infiltrates penetrate hepatic sinusoids. However, this population of cells has morphology consistent with a diagnosis of small-cell lymphoma. Treatment with chemotherapy protocols for feline lymphoma is recommended, along with judicious administration of nutritional, vitamin, and antioxidant support. Many of these cats respond to chlorambucil treatment for several years.
Affected cats may have concurrent intestinal involvement, although some cats with overt hepatic lymphosarcoma have inflammatory bowel disease, and some cats with overt enteric lymphosarcoma have non-neoplastic nonsuppurative CCHS. Evolution of chronic inflammation to a neoplastic process is suspected in each organ system.
