THE MERCK VETERINARY MANUAL
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Feline Cholangitis/Cholangiohepatitis Syndrome

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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 versus 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 bacterial infections (primary or chronic), septicemia, cholecystitis, cholelithiasis, EHBDO, trematode infestation, toxoplasmosis, inflammatory bowel disease, primary cholangitis, pancreatitis, neoplasia (eg, gallbladder adenocarcinoma, bile duct cystadenoma), and various ductal malformations (eg, choledochal cyst, polycystic liver disease, biliary dysplasia).

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 tru-cut biopsies (eg, 18 gauge). Some biopsy sections may show modest or moderate duct inflammation and hepatitis, while other liver lobes reveal complete elimination of bile ducts and lack active inflammation. Cats with disease in multiple organ systems have significantly shorter survival times if untreated. However, because CCHS is slowly progressive, cats can survive several years beyond initial diagnosis without therapeutic intervention.

Suppurative CCHS causes the most overt clinical illness. These cats have a shorter duration of illness before presentation (<5 days), with young or middle-aged adults predominating (range 3 mo to 16 yr). 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 other forms of CCHS, with moderate to marked increases in transaminases (ALT, AST) and more modest increases in AP and GGT activity. Some cats have no cholestatic enzyme abnormalities. Most cats are hyperbilirubinemic, some have concurrent renal azotemia, and many have a left shift and toxic neutrophils on the leukogram. Concurrent HL may confuse initial assessments. Abdominal ultrasonography may reveal EHBDO; abnormalities consistent with cholecystitis, choledochitis, pancreatitis, or inflammatory bowel disease, and diffuse hepatic parenchymal hyperechogenicity consistent with HL may be seen. A heterogeneous hepatic parenchymal pattern may sometimes be recognized, reflecting parenchymal inflammation. However, in some cats, no ultrasonographic changes are identified. Thoracic radiography often reveals a large sternal lymph node reflecting abdominal inflammation/sepsis.

Medical treatment is often 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 reveal bacterial organisms and suppurative inflammation. Gram stain of cytologic specimens showing bacteria assist in selection of antimicrobial agents. Commonly isolated bacteria include Escherichia coli, Streptococcus, Clostridium, Bacteroides, and Actinomyces. Cultures may be negative because of prior antibiotic administration or failure to culture for anaerobic bacteria.

Treatment involves broad-spectrum antimicrobials effective against anaerobic and gram-negative enteric opportunists, urso-deoxycholic acid, SAMe, vitamin E, water-soluble vitamins, enteral alimentation with a feline formulated maximum calorie diet, and judicious administration of fluids 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, bid-tid, infused IV over 20 min through a 0.25 μm 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 sensitivity reports from hepatobiliary or bile aspirates or tissue samples. Treatment with antimicrobials should be initiated before surgical intervention because sepsis compromises postoperative survival. Antimicrobial treatment is continued for 8–12 wk or until liver enzymes normalize. If liver enzymes remain increased, repeat ultrasonographic assessment is warranted to check for abnormalities involving biliary structures, pancreas, gut, or lymphadenopathy. Repeat aspiration cytology or liver biopsy may be necessary.

Feline lymphocytic portal hepatitis is likely not a disease entity but may reflect nonspecific inflammatory infiltrates delivered by the portal vasculature. Otherwise, it may represent apparent lesions in feline CCHS when only minimal portal triads have been sampled from a relatively uninvolved liver lobe. Low-yield needle biopsies from cats with nonsuppurative CCHS may generate this diagnosis.

Nonsuppurative CCHS without destructive duct lesions is a T-cell mediated inflammatory syndrome that most often affects cats middle-aged or older. Concurrent infection with FeLV or FIV is uncommon, and there is no gender or breed predisposition. Duration of illness ranges from 2 wk to several years; most cats have been ill for several months before initial presentation. Clinical signs include intermittent vomiting and diarrhea and episodic illness that may be associated with self-resolving jaundice. Hepatomegaly is common. It is uncommon for nonsuppurative CCHS to cause portal hypertension and abdominal effusion because cats usually succumb before diffuse fibrosis becomes established.

WBC counts are variable but typically do not display a left shift or toxic neutrophils. Poikilocytes are common, and Heinz bodies may be evident. Hyperglobulinemia develops with chronicity; most cats have moderate to marked increases in ALT and AST. Increases in AP and GGT activity are widely variable and depend on the cyclic activity of the disease process. Hyperbilirubinemia is inconsistent and also appears cyclic. Some cats are persistently jaundiced secondary to inflammatory obstruction of small and medium-sized bile ducts (nonsuppurative CCHS with destructive duct lesions) and these develop symptomatic coagulopathies responsive to vitamin K administration (0.5–1.5 mg/kg, SC or IM, 3 doses at 12-hr intervals before biopsy). Abdominal ultrasonographic findings overlap with those of suppurative CCHS; a non-uniform or coarse parenchymal pattern may be identified. However, cats with marked nonsuppurative CCHS may lack ultrasonographically detectable hepatic parenchymal or biliary system abnormalities. Severity of lesions is highly variable within and between liver lobes and between cats.

Initial treatment consists of appropriate antimicrobials, ursodeoxycholic acid, SAMe, vitamin E, B vitamin supplementation, enteral alimentation with a feline formulated maximum calorie diet, and fluids to correct and maintain hydration and 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. First-line immunosuppressive therapy is prednisolone, initially administered at 2–4 mg/kg ideal body weight, PO, sid, with the dose titrated to 5–10 mg/day, sid to every other day based on treatment response. Adding metronidazole (7.5 mg/kg, PO) may assist with immunomodulation and control of associated inflammatory bowel disease and may allow reduction of the glucocorticoid dose. Continued administration of SAMe (40–50 mg/kg/day, PO) and vitamin E (10 U/kg/day) are recommended.

As a single agent, SAMe has resolved CCHS-associated inflammation in a few cats. Chlorambucil is used in cats that fail to respond to antiinflammatory glucocorticoid and metronidazole intervention (chlor-ambucil dosage: 2 mg/cat/day, sid, titrated to every other or every third day). Treatment usually returns bilirubin concentrations to normal but cyclic increases in enzyme activity remain, although at lower magnitudes.

Cats with nonsuppurative CCHS with destructive duct lesions (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 identified by application of a cytokeratin immunohistochemistry stain on liver samples. Affected cats show duct involution, peripheralization of bile ductules in the portal triads, T-cell immunotargeting, and lipogranulomas where ducts have been eliminated. Approximately 30% of these cats become diabetics; the pancreas may harbor T-cell ductal targeting.

Symptomatic ductopenic cats require weekly vitamin K1 injections (see Fat-soluble Vitamins) and water-soluble vitamin E (polyethylene glycol α-tocopherol succinate, 10 U/kg/day, PO). Overdosing vitamin K1 can cause serious hemolytic anemia. 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 duct-targeting CCHS. Instead, methotrexate or chlorambucil are used initially. Pulsatile methotrexate is given at a total daily dose of 0.4 mg/cat divided into 3 treatments on a single day (0.13 mg/kg, PO per dose) once every 7–10 days. Alternatively, methotrexate may be given IV or IM with a 50% dose reduction. Folic acid, 0.25 mg/day, PO, is concurrently administered to prevent methotrexate-associated hepatotoxicity. The dosage of methotrexate must be reduced 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 may be beneficial. Cobalamin deficiency must be corrected and cats chronically supplemented if deficiency proven on 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 infiltration that penetrate, hepatic sinusoids. However, involved lymphocytes lack convincing microscopic details for classification as a neoplastic population. Treatment with chlorambucil has proven beneficial in some cats (2 mg/cat given every other or every third day), combined with treatments previously described for CCHS. Affected cats may survive for several years with minimal clinical signs. Immunohistochemical staining and other molecular tests (investigation of clonality) may be necessary to differentiate this form of CCHS from lymphoma. Evolution of lymphoproliferative disease to lymphoma is suspected.

In small-cell lymphoma masquerading as lymphocytic CCHS, dense lymphocytic portal infiltrates penetrates into hepatic sinusoids. Treatment with chemotherapy protocols for feline lymphoma is recommended, along with judicious administration of nutritional, vitamin, and antioxidant support. Many cats with small cell lymphoma will respond to chlorambucil, as described above, for several years. Affected cats may have concurrent intestinal involvement, although some cats with overt liver lymphosarcoma have inflammatory bowel diseases and some cats with overt enteric lymphosarcoma have non-neoplastic nonsuppurative CCHS. Evolution of chronic inflammation to a neoplastic process is suspected.

Last full review/revision March 2012 by Sharon A. Center, DVM, DACVIM

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