P. Jane Armstrong, DVM, MS, MBA, Diplomate ACVIM

1 Companion Animal SEARCH Print BACK HOME Hepatology FELINE CHOLANGITIS Inflammatory liver disease is the second most common biopsy diagnosis o...
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FELINE CHOLANGITIS Inflammatory liver disease is the second most common biopsy diagnosis of feline liver disease after hepatic lipidosis (Gagne, 1999). Inflammatory liver disease is a histopathological diagnosis; it must be made by liver biopsy. Cholangitis, inflammation of the bile ducts and ductules, is a much more important entity than hepatitis in cats (in contrast to the dog). The term ‘cholangitis’ is used in preference to ‘cholangiohepatitis’ as inflammatory disruption of the limiting plate to involve hepatic parenchyma is not a consistent feature and, when present, is usually an extension of a primary cholangitis. The term “cholangiohepatiitis’ has been commonly used in the past and may be applied when inflammation extends beyond the biliary tree into the hepatic parenchyma. P. Jane Armstrong, DVM, MS, MBA, Diplomate ACVIM University of Minnesota [email protected]

The WSAVA International Liver Standardization Group Classification (van den Ingh, 2006) introduced the following classification scheme for feline cholangitis: a. Neutrophilic cholangitis (NC) – Includes both acute and chronic forms which are distinguished histopathologically but not clinically b. Lymphocytic cholangitis (LC) c. Cholangitis associated with liver flukes Lymphocytic/plasmacytic inflammation in the portal areas (lymphocytic portal hepatitis) is thought to be a histological lesion associated with non-specific reactivity or aging in cats, rather than being a primary inflammatory disease of the liver. In this respect, it is similar to non-specific reactive hepatopathy in dogs, which is generally associated with inflammation elsewhere in the abdomen. Compared to cholangitis (inflammation centered on bile ducts), lymphocytic portal hepatitis lacks bile duct involvement, infiltration of inflammatory cells into hepatic parenchyma, or periportal necrosis. Liver enzyme activities in cats with this histopathological change are quite variable or even normal, icterus is uncommon, and most cats have prolonged survival, bringing into question the rationale for corticosteroid or other therapy, which has been suggested in the past. A recently published necropsy study reported that the distribution of type of cholangitis at the University of Pennsylvania was neutrophilic cholangitis (37/44 cases

Abstracts | European Veterinary Conference Voorjaarsdagen 2014

in the series) lymphocytic cholangitis (3), and fluke-associated (Callahan Clarke, 2011). Severity of inflammation varies between liver sections in individual cats, underscoring the need to obtain biopsy samples from multiple sites. Inflammatory bowel disease (IBD), pancreatitis, or both (so-called “triaditis”), commonly accompany cholangitis (Callahan Clark, 2011; Weiss, 1996). While the pathogenesis relating these three diseases remains unclear, the predominant theory is that underlying IBD may predispose cats to cholangitis and pancreatitis as a result of reflux of enteric bacteria into the shared opening of the pancreatic and common bile ducts. Neutrophilic Cholangitis Good clinical characterization of the various forms of cholangitis has necessarily lagged behind the histopathological descriptions. Neutrophilic cholangitis has previously been referred to as suppurative or exudative cholangitis or cholangiohepatitis. Despite being distinct histologically, almost complete overlap is seen in clinical findings between ANC and CNC subtypes of neutrophilic cholangitis (Callahan Clarke, 2011; Marolf, 2012). For this reason, they will be discussed together in this review. Acute neutrophilic cholangitis is thought to be caused by ascending bacterial infection and CNC is speculated to be a later stage of disease progression. Whereas the inflammatory infiltrate in ANC is predominantly neutrophilic, in CNC it is characterized by a mixed inflammatory response (roughly equal numbers of lymphocytes or plasma cells and neutrophils) within portal areas and bile ducts. Other features of chronicity include marked bile duct proliferation, bridging fibrosis, and pseudolobule formation. Neutrophilic cholangitis has been described in a wide age range of cats, but the median age is about 9 years. Cats with either form of NC and LC show anorexia and weight loss, lethargy and vomiting. Physical examination findings in cats with NC are fever, dehydration, icterus, abdominal pain, and hepatomegaly. Cats with ANC are most likely (55%) to have peripheral neutrophilia. Band neutrophils, neutropenia and anemia may also be present. With the exception of frequency of neutrophila, other laboratory findings do not differ regardless of whether the biopsy diagnosis is ANC, CNC

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or LC. Other laboratory findings that may be present are increases in serum activities of ALT, AST, GGT, and ALP and hyperbilirubinemia. Surprisingly, serum liver enzyme activities are within reference range in many cats. Hepatic encephalopathy, abnormal coagulation parameters, hypoalbuminemia, low BUN, and hypocholesterolemia are all very uncommon. Routine abdominal radiographs rarely contribute to making a diagnosis of NC but may help exclude other diseases that can cause similar clinical signs. Sonographic changes in NC and LC have recently been reported in 26 cats (Marolf, 2012). Interestingly, hepatobiliary sonography in most cats with cholangitis of any form reveals abnormalities in only a small percentage of cats. Hepatomegaly, hyperechoic hepatic parenchyma, tortuous and dilated cystic and common bile ducts,, and echogenic gallbladder contents may be seen. Identifying gallbladder debris (“gallbladder sludge”) in cats is currently somewhat confounding, as it cannot be considered an incidental finding as it is in dogs. Increased gallbladder wall thickness was not statistically significant in the Marolf study, but bacterial cholecystitis can be associated with NC and such cases may have a thickened gallbladder wall (Brain, 2011). Inspissation of bile, which may cause partial or complete obstruction of the common bile duct, may accompany cholangitis and may require surgical treatment before the disease can be controlled or resolved. Marolf investigated the use of magnetic resonance imaging (MRI) and MR cholangiopancreatography (MRCP) in cats suspected to have cholangitis and/or pancreatitis. Combined MRI and MRCP was reported to provide useful diagnostic information in both groups of cats including gall bladder wall thickening, gall bladder wall moderate contrast enhancement and/or gall bladder debris in cats with cholangitis (Marolf, 2013). Marolf et al reported that cats with NC are more likely than cats with LC to have evidence of pancreatic disease detected on sonographic examination. These changes included diffuse pancreatic enlargement and hypoechoic pancreatic parenchyma. Callahan Clark also described sonographic changes in the pancreas in 81% of cats with any form of cholangitis.

Abstracts | European Veterinary Conference Voorjaarsdagen 2014

Neutrophilic cholangitis is most commonly caused by ascending bacterial infections of gastrointestinal origin. Protozoal infections have been identified occasionally (toxoplasmosis, coccidiosis and hepatozoonosis). Whenever possible, a 22-23 g ultrasound-guided gallbladder aspirate for bile cytology and culture should be performed, along with liver biopsies. Suppurative inflammation and bacteria may be observed on bile cytology. If surgery is performed, biopsy +/- culture of the gallbladder wall and cholelith (if found) and biopsy of the liver are possible. Bacterial isolates are typical enteric organisms, most frequently Escherichia coli, sometimes in combination with other organisms. Other reported isolates include Streptococcus spp, Clostridium spp, Salmonella enterica serovar Typhimurium. Enterococcus spp, Bacteroides spp, and Staphylococcus spp. Anaerobes are uncommonly isolated. In the author’s experience, the rate of positive bile cultures is low in NC, even in untreated cats, but cultureindependent studies on bile provide further support for the role of enteric bacteria in pathogenesis. Using a florescence in situ hybridization (FISH) assay, investigators have observed intrahepatic bacteria in 33% of cats with cholangitis, and intrahepatic bacteria were more prevalent in cats with NC than LC (Twedt, unpublished data). Primary treatment of NC centers around antibiotic therapy, ideally based on bile culture and sensitivity. Amoxicillin-clavulinic acid or a cephalosporin are good choices if cultures are negative or not obtained. Some cases will require a fluoroquinolone (marbofloxacin) before a response is seen. These antimicrobials may be combined with metronidazole (7.5 mg/kg PO BID) to extend the spectrum to anaerobes and more coliforms. Treatment with antibiotics for 4-6 weeks is recommended, even though most cats improve clinically within one week if antibiotic selection is appropriate. Other aspects of therapy include fluid, electrolyte and nutritional maintenance, pain management, and emesis control. Since maropitant undergoes hepatic metabolism, it may be prudent to use a lower dose initially for control of vomiting (0.5 mg/kg q 24h PO, SQ, IV). If coagulation abnormalities are present, administer vitamin K1 (0.5–1.5 mg SQ using a 25 g needle) 2-3 times at 12 hr intervals before performing biopsies or other surgery. Surgical intervention is recommended if discrete choleliths or complete biliary obstruction is identified. Cholecystectomy is occasionally necessary in cases of acute cholecystitis if gallbladder rupture has occurred or there is concern regarding

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gallbladder wall integrity. Occasionally the bile becomes the consistency of a thick sludge; this requires vigorous flushing of the extrahepatic biliary system. This is best accomplished by opening the gallbladder and flushing antegrade down the common bile duct. Sometimes it is also necessary to open the duodenum and flush retrograde from the duodenal papilla. It is advisable to preserve normal biliary anatomy and avoid biliary bypass surgical techniques (cholecystoenterostomy) whenever possible because they are often associated with chronic postoperative problems. Since cats with NC may concurrently have pancreatitis and/or IBD, other therapies may be considered, such as cobalamin supplementation and dietary manipulation for IBD. Ursodeoxycholic acid (Ursodiol, Actigal®, Novartis, 10 to 15 mg/kg q24h PO) may be beneficial in cats with cholangitis. Benefits include amelioration of damage to cell membranes caused by retained toxic bile acids, improved biliary secretion of bile acids, improved bile flow (choleresis), limiting mitochondrial damage, and antifibrotic and immunomodulatory properties. Clinical trials in human patients with primary sclerosing cholangitis and some other forms of hepatitis document improved quality of life. Adverse effects in cats are uncommon and are usually limited to mild diarrhea. Some clinicians avoid using ursodiol when bile duct obstruction is a possibility. Fear of gallbladder rupture from the choleretic action of the drug appears is not supported in experimental rodent studies. High concentrations of bile acids, accumulation of heavy metals, and inflammation all cause free radical generation in the liver. Vitamin E and SAMe are commonly used as antioxidants; vitamin C, selenium and phosphatidylcholine may also be considered. The milk thistle extract isomer, silybin, is used for its hepatoprotective effects. Silybin is available in combination with SAMe (90 mg SAMe and 9 mg Silybin A+B; DenamarinTM, Nutramax Laboratories, Inc.). Lymphocytic Cholangitis Lymphocytic cholangitis is a chronic disease that affects the biliary tree and is slowly progressive. The inflammatory process in the biliary tree can result in marked, bizarre, sometimes saccular dilatations of the biliary tree. Hepatic lesions include lymphocytic inflammation directed at bile ducts with some cases having ductopenia, peribiliary

Abstracts | European Veterinary Conference Voorjaarsdagen 2014

fibrosis, portal B-cell aggregates, and portal lipogranulomas. Preliminary immunologic studies suggest that LC could have an immune-mediated etiology, perhaps to selfantigens exposed as a result of the chronic inflammatory process. One study (Warren, 2010) investigating 51 cats with LC found the majority of cases (69%) had a dense, predominant T-cell population with fewer cases having B-cells randomly distributed. These findings tend to support an immunological disorder. Other studies have focused on possible infectious etiologies using either FISH or bacterial DNA analysis; all have failed to support a primary infectious cause. Bacteria identified in the biliary tree are thought to be opportunistic secondary to dilatation and other changes (Otte, Vet Microbiol 2012). One research group, however, experimentally induced LC with infection with a Bartonella species. In some cases it is difficult to differentiate LC from lymphoma ; the PARR assay on histopathology slides may be useful to help make this distinction. PARR is a PCR assay in which DNA is amplified. Results can indicate that the majority of cells in the sample are derived from the same original clone (most consistent with neoplasia), or from multiple clones (most consistent with a reactive process). In cats, the PARR assay at Colorado State University has a specificity greater than 90% and a sensitivity estimated to be about 65% (i.e. it is estimated that the PARR assay detects 65% of confirmed feline lymphoma cases). The relationship of LC with hepatic lymphoma has not been well elucidated. The reported median age of LC cats is 11.5 yr (range 4-16), which is slightly older than for cats with NC. Males are over-represented and there appears to be a breed predisposition for Norwegian Forest cats (Otte, Vet J 2012) and perhaps Persian cats based on one British study (Lucke, 1984). There is considerable overlap of the clinical syndromes of NC and LC. Clinical signs are the same as for cats with NC: anorexia and weight loss, lethargy and vomiting, Jaundice is often present. Results of a recent retrospective study suggest LC in cats may not always cause clinical illness (Callahan Clark 2011). Except for neutrophilia being less common, laboratory findings are identical to those of NC although hyperglobulinemia may be present. Chronic inflammation in the bile ducts is associated with dilatations, which can be very tortuous and appear quite bizarre on sonographic evaluation. Lucke reported ascites some of the cats in his study; this has

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not been a feature of more recently reported cases. Unlike in dogs, ascites is a very rare clinical finding in cats with liver disease, as cirrhosis leading to portal hypertension is exceedingly uncommon. In the absence of better information about etiology, prednisolone (not prednisone) is usually used to treat cats diagnosed with LC based on the presumption of an immunemediated etiology. A dose of 1 mg/kg/day of prednisolone is used initially. Outcomes were not improved when prednisolone was dosed at 2 mg/kg/day compared to 1 mg/ kg/day (Otte, Vet J 2012). Long-term corticosteroid treatment is well tolerated by most cats, although cats should be carefully observed for signs consistent with diabetes mellitus or congestive heart failure. There are no reported studies using other types of immunosuppressive therapy. There are anecdotal reports of using chlorambucil in conjunction with prednisolone in severe cases. It should be noted that corticosteroid therapy is not contraindicated in cats with concurrent chronic pancreatitis or IBD and may actually be beneficial. Ursodiol may be used long-term in combination with prednisolone. If successful, the corticosteroid dosage is slowly tapered to an alternate day dose for long-term maintenance. A schedule commonly used is to start therapy at 1 mg/kg SID x 2 weeks, then progressively reduce the dose as follows: 0.5 mg/kg SID x 2 weeks; 0.5 mg/kg q 48 hours x 4 weeks. Biochemical values should be monitored prior to each reduction in dosage. If the clinical and biochemical response is satisfactory, doses as low as 0.5 mg/kg q 48 hours may be sufficient for long term maintenance. Because of the presence of opportunistic bacteria in the biliary tree of some affected cats, some clinicians will use antimicrobial therapy concurrently with steroids for the first 10-14 days of treatment. One study retrospectively comparing prednisolone or ursodeoxcholic acid (ursodiol) therapy showed an overall median survival time of 755 days in 26 LC cats. Prednisolone therapy was associated with better survival (Otte, Vet J 2012).

and the second a lizard, gecko or toad. Affected cats acquire the parasite by ingesting the second intermediate host, so affected clinical cases are generally adult outdoor cats. Immature liver flukes migrate to the liver from the intestine via the bile ducts, causing marked thickening and cystic dilatation of the bile ducts. Bile duct enlargement and tortuosity can be observed ultrasonographically but it is important to note that other causes of cholangitis can result in these same changes. Adult flukes or operculated eggs may be observed within the bile ducts on histopathological examination or in feces. Episodes of vomiting, anorexia and fever are common and substantial increases in liver enzymes are observed. Icterus from severe cholestatic liver disease or bile duct obstruction can occur. Clinical signs range from asymptomatic cases to death from hepatic failure. The recommended treatment is praziquantel (20-30 mg/kg PO q24h for 3 days). Summary This review reports on what is currently known about the 3 main types of cholangitis (i.e., neutrophilic cholangitis, lymphocytic cholangitis and cholangitis caused by liver flukes). Neutrophilic cholangitis appears to be the most common form. Primary treatment is with antimicrobials based on the presumption of an ascending bacterial infection. The cause of lymphocytic cholangitis is not known, but is presumed to be immune-mediated. Therapy with corticosteroids is not uniformly successful but recent research suggests it improves survival. The inflammatory process in the biliary tree causes dilatations of the biliary tree, which likely facilitate migration of bacteria from the intestinal tract. More research is needed in order to generate evidence-based treatment guidelines. References 1 Brain PH, Barrs VR, Martin P, et al. Feline cholecystitis and acute neutrophilic cholangitis: clinical findings, bacterial isolates and response to treatment in six cases. J Fel Med Surg 2006;8:91-103. 2 Callahan Clark JE, Haddad JL, Brown DC, et al. Feline cholangitis: A necropsy study of 44 cats (1986-2008). J Fel

Cholangitis associated with liver flukes The trematode Platynosomum sp is the most common genus associated with chronic cholangitis in cats. It is found in subtropical and tropical climates of the world. The life cycle of Platynosomum sp includes two intermediate hosts, the first being a land snail

Abstracts | European Veterinary Conference Voorjaarsdagen 2014

Med Surg 2011; 13:570-6. 3 Gagne JM, Armstrong PJ, Weiss DJ, et al. Clinical features of inflammatory liver disease in cats: 41 cases (19831993). J Am Vet Med Assoc 1999; 214: 513-6. 4 Lucke VM, and Davies JD: Progressive lymphocytic cholangitis in the cat. J Small Anim Pract 1984; 25:249-60.

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5 Marolf AJ, Leach L, Gibbons DS, et al. Ultrasonographic findings of feline cholangitis. J Am Anim Hosp Assoc 2012;48:36-42. 6 Marolf AJ, Kraft SL, Dunphy TR, et al. Magnetic resonance (MR) imaging and MR cholangiopancreatography findings in cats with cholangitis and pancreatitis. J Fel Med Surg 2013; 15:285-94. 7 Otte CMA, Penning LC, Rothuizen J, et al. Retrospective comparison of prednisolone and ursodeoxycholic acid for the treatment of feline lymphocytic cholangitis. Vet J 2013; 195:205-9. 8 Otte CM, Gutiérrez OP, Favier RP, et al. Detection of bacterial DNA in bile of cats with lymphocytic cholangitis. Vet Microbiol. 2012 Apr 23;156:217-21. 9 Twedt DC and Armstrong PJ. Feline inflammatory liver disease. In Current Veterinary Therapy XIV, Bonagura JD and Twedt DC, eds. St Louis: Saunders Elsevier, 2009: 576-81. 10 van den Ingh TSGAM, Cullen JM, Twedt DC, et al. Morphological classification of biliary disorders of canine and feline liver. In: Rothuizen J, Bunch SE, Charles JA, et al. eds. WSAVA standards for clinical and histological diagnosis of canine and feline liver diseases. Edinburgh: Saunders Elsevier, 2006: 61-76. 11 Warren A, Center S, McDonough S, et al. Histopathologic features, immunophenotyping, clonality, and eubacterial fluorescence in situ hybridization in cats with lymphocytic cholangitis/cholangiohepatitis. Vet Path 2010;48:627-41. 12 Weiss DJ, Gagne JM, and Armstrong PJ: Relationship between inflammatory hepatic disease and inflammatory bowel disease, pancreatitis, and nephritis in cats. J Am Vet Med Assoc, 1996; 209:1114-6.

Abstracts | European Veterinary Conference Voorjaarsdagen 2014

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