Feline Cholangiohepatitis Complex

LIVER DISEASE

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FELINE CHOLANGIOHEPATITIS COMPLEX Deborah G. Day, DVM, MS

The cholangitis/ cholangiohepatitis complex includes three characteristic histopathologic lesions, each reflecting progressive stages of one disease. Suppurative cholangitis/ cholangiohepatitis, long-term nonsuppurative cholangitis/ cholangiohepatitis, and biliary cirrhosis comprise this syndrome. Although the histologic appearance of the cholangiohepatitis complex is well characterized, the pathogenesis is incompletely understood, and the etiology is undetermined. Cholangitis refers to inflammation of the intrahepatic biliary system, cholangiohepatitis denotes inflammation of the biliary system that has spread to include the adjacent hepatocytes, and biliary cirrhosis is the sequella to long-term inflammation that results in portal fibrosis and bile duct hyperplasia. 17• 44 This syndrome is common in cats and included 24 of 80 (30%) cats in one study/ and 29 of 185 (16%) in another study. 25 In the latter report, cases of hepatitis with a known etiology were listed separately, which may have resulted in a slightly lower estimation of cholangiohepatitis than expected. A disease that is similar to sclerosing cholangitis in humans has been reported in the catY· 15• 30 Primary sclerosing cholangitis is a longterm fibrosing inflammatory disease of intrahepatic and extrahepatic bile ducts, characterized by interlobular bile duct hyperplasia, fibrosis, and mild inflammation. 30 Whether this is a separate disease or a form of suppurative or nonsuppurative feline cholangitis is unknown.

From the Animal Health Center, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 25 • NUMBER 2 • MARCH 1995

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SUPPURATIVE CHOLANGITIS/CHOLANGIOHEPATITIS

Neutrophilic infiltration of portal triads characterizes acute suppurative cholangitis, a disease rarely diagnosed in cats, possibly because this disease results in very early histologic change that occurs before the onset of clinical signs?, 46 Suppurative cholangiohepatitis is often seen and is characterized by periportal and hepatic parenchymal invasion of neutrophils, Bile ductules may be filled with white blood cell debris, and mild fibrosis and bile duct hyperplasia may be present 46 Enteric organisms often are isolated from the bile of these cats, suggesting that ascending intestinal bacterial infection is the underlying etiology. Additionally, suppurative cholangiohepatitis has been associated with long-term pancreatitis, cholelithiasis, hepatobiliary parasites, anatomic abnormalities of the biliary tract, nephrotic syndrome, and periductal biliary fibrosis. 20, 22, 23 , 26, 28 Additional infectious agents associated with suppurative cholangiohepatitis include a coccidia-like organism, likely from the protozoan family Eimeriidae,34 a protozoan parasite similar to Hepatozoon canis/ 4 and toxoplasmosis. 42 Sex and breed predispositions for suppurative cholangitis/ cholangiohepatitis have not been recognized. Although cats of any age may be affected, middle-aged to old cats are most commonly affected?, zo, zz, 41 Weight loss, icterus, depression, anorexia, vomiting, and fever are common signs associated with this disorder. Signs are vague and often intermittent, suggesting a long-term disease process in some cats. Hematologic abnormalities may include neutrophilia with a left shift and lymphopenia. Biochemical findings are variable, but ALT, AST, and ALP enzyme activities are often mildly to moderately increased. Hyperbilirubinemia is the most consistent biochemical abnormality?, 8, 20, 41 Fasting serum bile acid (FSBA) concentrations were normal in 6 of 12 (50%) 8 and three of eight (37.5%)7 cats with cholangiohepatitis, but postprandial serum bile acid (PPSBA) concentrations are usually abnormal. Hepatic biopsy is required for definitive diagnosis of this disease. Suppurative cholangitis/ cholangiohepatitis is a diffuse cholestatic disease, thus collection of a liver sample by noninvasive methods may be diagnostic. Fine-needle aspiration is the least invasive method of obtaining hepatic cells. for cytologic examination. This technique requires minimal to no sedation and is easy to perform,Z9 but does not allow examination of hepatic architecture, which is essential for diagnosing suppurative cholangiohepatitis. Percutaneous blind or ultrasoundguided needle biopsy is a fast, inexpensive, and relatively safe method for obtaining hepatic tissue for histologic evaluation. The tissue specimen is small compared with wedge biopsies, but this method usually provides an adequate specimen for diagnosis. The technique may be performed using light to moderate sedation, depending on the temperament and clinical status of the cat. Rarely is general anesthesia required. This technique and various needle types have been described. 18, 19 Possible complications include hemorrhage, hepatic laceration, biopsy of adjacent organs, and perforation of the gallbladder, biliary structures, or

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other organs. 18• 21 Because of the possible association of this disease with cholelithiasis and extrahepatic bile duct obstruction, open-wedge biopsy has often been performed because the biliary system and pancreas may be examined at the time of biopsy. This technique allows visualization and exploration of the abdomen, palpation of the liver, expression of the gallbladder, and immediate correction of certain problems. Surgical biopsy does not require special equipment; however, this method is the most invasive, most expensive, and requires general anesthesia, which may be contraindicated in some cats with liver disease. Open-wedge biopsy techniques have been described. 6 • 37• 40 Recently, a technique using biliary cholescintigraphy was described as a noninvasive way to distinguish obstructive from nonobstructive hepatobiliary disease. 5 Radiography or ultrasonography may be helpful in identifying choleliths, cholecystitis, biliary neoplasia, and pancreatitis. White bile syndrome may be seen in cats with cholangiohepatitis and severe intrahepatic cholestasis, resulting in the absence of the normal green coloration of bile due to the absence of biliary pigment. 13• 46 Severe cholestasis or biliary obstruction blocks bile flow and secretion of biliary pigment into bile. Instead of the normal biliary secretions, bile is composed of fluid and mucus secreted by the gallbladder epithelium. 46 This condition is usually diagnosed during exploratory laparotomy or necropsy and warrants a poor prognosis. Aerobic and anaerobic culture of bile or hepatic tissue may be helpful in confirming the diagnosis, and sensitivity results aid in antibiotic selection. Enteric organisms, usually Escherichia coli, are most frequently cultured from the bile of cats with cholangitis/ cholangiohepatitis/0· 41 although an enterococcus, Bacteroides, Fusobacterium, and alpha hemolytic streptococcus have also been isolated. 26 Antibiotics are the mainstay of therapy for suppurative cholangitis/ cholangiohepatitis and are preferably chosen based on culture and sensitivity results of bile or hepatic tissue. In the absence of culture results, choose a broad-spectrum antibiotic that reaches therapeutic concentrations in bile, is not hepatotoxic, and does not require hepatic excretion. Ampicillin, amoxicillin, and cephalexin fit these criteria in humans and are frequently used in cats with hepatobiliary disease?· 11 Metronidazole is a good choice for anaerobes resistent to the penicillins previously listed, but the dosage may require reduction in cats with severe hepatic failure?· 11 • 12 Table 1 lists the dosages of antibiotics commonly used in treating feline liver disease. Controversy surrounds the use of corticosteroids for treatment of suppurative cholangiohepatitis. The addition of prednisolone or prednisone to the treatment regimen may be helpful for those cats that respond poorly to antibiotics or for those cats suspected to have had a more long-term course of disease. In such cases, an anti-inflammatory dosage of prednisolone (Table 1) may be tried cautiously in addition to antibiotic therapy. Cats with cholangiohepatitis often have thickened inspissated bile

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Table 1. DRUGS COMMONLY USED IN CATS FOR THE TREATMENT OF LIVER DISEASE Drug Amoxicillin Ampicillin Cephalexin Cephalothin Cefazolin Dehydrocholic acid Enalapril* Furosemide Metronidazole Prednisolone (anti-inflammatory) (immunosuppressive) Ursodeoxycholic acid Vitamin K,

Dosage (mglkg)

Frequency (hours)

Routet

8-12 8-12

11-22 10-25 11-22 22 1Q-20 1Q-15 0.125-0.25 2.5-5/cat 7.5-10

12-24 24-48 8-12

IM, SQ, PO IV, IM, SQ, PO PO IV, IM,SQ IV, IM,SQ PO PO PO PO

1.1 2.2-4.4 1Q-15 5 mg/cat

24-48 24-48 24 12-48

PO PO PO IM, PO

*See text for discussion. tiV = intravenous; IM = intramuscular; SO

8 6-8 8 8

=

subcutaneous; PO

=

oral.

secretions, possibly associated with long-term cholestasis or bacterial infection. Bile sludging may occur in the gallbladder, bile duct, or intrahepatic bile ductules. Cholecystotomy, removal of the sludged bile material, as well as irrigation of the common bile duct, may be required in some cats. Bile sludging severe enough to require surgical intervention is usually associated with a poor prognosis. 7' 46 Various choleretics have been advocated empirically for use in this disease, but efficacy is unproven. Because of its purported hydrocholeretic properties, dehydrocholic acid (Table 1) has been recommended to promote bile flow and prevent bile sludging. The long-term safety of dehydrocholic acid in cats has not been established. This drug should not be used in the presence of extrahepatic bile duct obstruction. Ursodeoxycholic acid (UDCA) is a dihydroxy bile acid used for gallstone dissolution and for treatment of long-term cholestatic liver disease in humans. The exact mechanism of action is unknown, but UDCA is thought to ameliorate the toxic effects of hydrophobic bile acids on hepatocellular membranes16 and to change the composition of the bile acid pool.38 Several studies have documented a decrease in serum hydrophobic bile acids/' 33 while others have not. 3 Also, UDCA may modulate the immune-mediated hepatobiliary destruction that occurs in humans with primary biliary cirrhosis. An in vitro study demonstrated suppression of immunoglobulin G (IgG), IgM, IgA, 'Y-interferon, interleukin-2 (IL-2), and IL-4 in cell cultures exposed to UDCA. 45 Additionally, serum IgG 2 and IgM2, 38 concentrations decreased in humans with primary biliary cirrhosis treated with UDCA. Clinical signs, biochemical parameters, and histologic changes improved significantly in humans with primary biliary cirrhosis and primary sclerosing cholangitis.3' 31, 38 Clinical improvement has been reported in a dog with long-

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term cholestatic liver disease using this drug. 43 No side effects were observed when UbCA was administered to healthy cats for 3 months (Table 1).1°Clinical studies evaluating the efficacy of this drug in cats with long-term cholestatic liver disease are needed. The prognosis for the suppurative form of cholangiohepatitis has been considered poor, but information about long-term follow-up is lacking. A single case report documents resolution of neutrophilic infiltrates 11 months after diagnosis. Length of antibiotic administration was not disclosed in that report, but the cat continued to be normal clinically and biochemically 4 years after initial diagnosisY This disease has been reported to undergo spontaneous remission in some cats or progress to long-term nonsuppurative cholangiohepatitis. 17

NONSUPPUFlATIVE CHOLANGITIS/ CHOLANGIOHEPATITIS

The etiology of nonsuppurative cholangitis/ cholangiohepatitis is unclear, but long-term inflammation associated with progression of suppurative cholangitis/ cholangiohepatitis, other inflammatory disease, and immune-mediated disease have been proposed as pathogenic mechanisms in this disease. Nonsuppurative cholangitis has been associated with pancreatitis and liver flukes.u, 39 Histologically, this disease differs from suppurative cholangitis/ cholangiohepatitis with lymphocytic and plasmacytic periportal inflammation, bile ductule hyperplasia, and periportal fibrosis being the predominant histologic findings (Fig. 1).32· 39 Some of the cases reported have had significant hepatic lymphoid aggregates, which were compared with the lesions observed in humans with primary biliary cirrhosis. 27· 39 Unlike suppurative cholangitis/ cholangiohepatitis complex, neutrophilic infiltrates are minimal. Sex and breed predispositions have not been identified for nonsuppurative cholangiohepatis, although Persian cats were overrepresented in one study.7· 32· 39 As opposed to suppurative cholangitis/cholangiohepatitis, this disease primarily affects cats younger than 4 years of age (range, 6 months to 10 years). 32· 39 Ascites and icterus were the most common signs of illness associated with this disease in one report; however, six of seven cats with ascites had histologic evidence of cirrhosis.32 Weight loss, anorexia, depression, and fever are uncommonly observed with this disease. Most of these cats are bright and alert, with a normal or increased appetite, but show intermittent evidence of systemic illness. Hematologic abnormalities, such as mild anemia, reflect longterm disease. Biochemical abnormalities are similar to those seen with suppurative cholangiohepatitis, except hyperglobulinemia and hypoalbuminemia are common findings. Hepatomegaly or lymphadenopathy may be present. Hepatic biopsy is required for definitive diagnosis of this disease. Percutaneous needle biopsy is often diagnostic, but if patency of the biliary system is in doubt, an exploratory laparotomy may be more

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Figure 1. Low-power view of feline liver with mild portal fi brosis characteristic of long-term cholangiohepatitis. Portal tracts are increased in prominence as a result of portal fibrosis and proliferation of bile ducts. Bridging of portal tracts between lobules is observed at the right, with incipient bridging evident at the center of the photograph. Inflammatory infiltrates are minimal. The clear oval space at the lower left is a central vein. (Courtesy of Dr. William Maslin)

helpful by allowing inspection of the biliary system . Noninvasive techniques, such as ultrasonography or hepatobiliary scintigraphy, may be helpful in determining biliary patency without the added risk of anesthesia and surgery. Culture of bile or hepatic tissue should be performed to rule out a bacterial etiology and need for specific antibiotic therapy. Treatment of nonsuppurative cholangiohepatitis is largely empirical. Antibiotics were discussed with suppurative cholangiohepatitis and should be used initially in the treatment of nonsuppurative ch olangitis / cholangiohepatitis as previously discussed. Immunosuppressive dosages of corticosteroids (see Table 1) should be added to the treatment plan once nonsuppurative cholangitis / cholangiohepatitis is identified, tapering the dose during a 30 to 60 day period. Therapeutic uses of UDCA were discussed with treatment of suppurative cholangiohepatitis. This drug may prove useful in the treatment of long-term nonsuppurative cholangiohepatitis, esp ecially if immune modulation is one mechanism of action of this drug. Response of this disease to therapy is variable. Some cats respond well initially, but relapse w hen therapy is discontinued. Others respond poorly to therapy and die or are euthanatized as a result of progressive signs of disease. A few cats seem to do well for prolonged periods (months to years) after drug therap y is discontinued. 32• 39

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BILIARY CIRRHOSIS

Biliary cirrhosis seems to be the end-stage result of long-term cholangiohepatitis in some cats?· 32• 39 This disease is uncommon in cats, possibly because most cats with severe cholangiohepatitis die before reaching this stage of disease. Although biliary cirrhosis is presumed to result from progressive cholangiohepatitis, feline biliary cirrhosis may represent a distinct disease of unknown etiology. Common clinical findings in cats with cirrhosis include icterus, hepatomegaly, cachexia, and ascites. 46 Serum liver enzymes may be normal or increased. Additional serum biochemical abnormalities include hypoalbuminemia, hyperglobulinemia, and hyperbilirubinemia. Coagulopathy may be evident. Hypoalbuminemia, coupled with a coagulopathy that is unresponsive to vitamin K1 therapy, indicates a poor prognosis. Hepatomegaly is commonly present in cats with cirrhosis, and the liver has a firm, nodular appearance. Histologically, severe portal fibrosis, bile duct hyperplasia, nodular hyperplasia, and a variable degree of chronic inflammation characterizes feline biliary cirrhosis (Fig. 2).44 Hepatic biopsy is necessary for definitive diagnosis. Percutaneous biopsy techniques should be performed using extreme caution. Openwedge biopsy may be safer because of the greater visualization obtained from this procedure, which may be needed because of the possibility of

Figure 2. High-power view of a feline liver with long-term cholangiohepatitis or early cirrhosis. There is marked thickening of the portal tract with fibrous connective tissue. A microabscess is seen and is associated with the markedly enlarged and hyperplastic bile duct located at the center. Several smaller bile ducts are noted at the upper and lower left of the photograph . Heavy aggregates of lymphocytes and plasma cells are seen at the periphery of the portal tract. The clear space at the left is a portion of a dilated portal vein. (Courtesy of Dr. William Maslin)

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severe hemostatic abnormalities. If a severe coagulopathy is presen1, biopsy should be postponed, or fresh whole blood transfusion should be administered prior to the biopsy procedure. Vitamin K1 therapy (see Table 1) may be helpful in correcting the coagulopathy, if severe cholestasis rather than loss of functional hepatic mass is the underlying cause of the hemostatic defect. With advanced cirrhosis, vitamin K1 therapy is unlikely to be helpful. Ascites is a rare clinical finding in cats with liver disease, but it may be present in cats with cirrhosis. 46 Hepatic fibrosis may cause increased intrahepatic vascular resistance with subsequent portal hypertension and increased intravascular hydrostatic pressure. Consequently, blood is sequestered in the portal vasculature, decreasing the effective plasma volume. The renin-angiotensin-aldosterone system is activated, and sodium and water retention is promoted. Portal blood volume is also expanded, and ascites formation is enhanced. Hypoalbuminemia may also predispose to ascites formation by decreasing plasma oncotic pressure. Usually, portal hypertension and hypoalbuminemia are present when ascites develops in clinical cases. 24 Ascites may be controlled in cats with biliary cirrhosis but rarely eliminated. Low salt diets may be beneficial in reducing ascites formation, but salt restriction must be severe to be effective in most casesP Protein should not be restricted in cats, especially if hypoalbuminemia is present, unless hepatic encephalopathy (HE) is present or develops. Because of the resistance of cats in accepting new diets, dietary changes should not be made when cats are ill, unless the cat likes the new diet and eats readily. Loop diuretics, such as furosemide (see Table 1), prevent renal sodium reabsorption, promote diuresis, and may be helpful in reducing ascites formation in mild cases. Cats are exquisitely sensitive to the effects of furosemide, and dehydration, hypokalemia, and anorexia frequently result. Azotemia, hypokalemia, and anorexia (through tissue catabolism) predispose to HE. Thus, serum electrolytes, hydration status, and appetite must be closely monitored. Loop diuretics may be less effective than expected when hyperaldosteronism develops. 36 Aldosterone promotes sodium reabsorption in the distal renal tubule, overriding the sodium excretion promoted by the loop diuretic. If hyperaldosteronism is suspected in cats with biliary cirrhosis, blockage of sodium reabsorption through use of an angiotensin converting enzyme inhibitor may be appropriate. The author has successfully used enalapril (Vasotec) for refractory ascites in dogs with liver disease. A suggested initial dosage of enalapril in cats is listed in Table 1. The low end of the dosage range should be used initially, especially if it is used in conjunction with furosemide. Possible side effects include hypotension, azotemia, anorexia, vomiting, and diarrhea. Enalapril requires hepatic conversion to the active form, enalaprilat, but whether this is of practical significance is unknown. A kinetics study in humans with cirrhosis has documented that the half-life of enaliprilat is prolonged compared to healthy controls, but there were no differences in blood pressure or heart rate between

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groups in that study. 35 Studies evaluating this drug in cats with liver disease have not been performed, and further studies are needed. Alternatively, spironolactone, an aldosterone antagonist, may be tried in conjunction with furosemide administration. This drug competitively inhibits aldosterone at the distal renal tubule, preventing sodium, and water reabsorption. Hyperkalemia is a potential adverse effect, especially when used concurrently with potassium supplementation. Although corticosteroids are indicated for the treatment of nonsuppurative cholangiohepatitis, continued use with cirrhosis may produce unwanted side effects. Corticosteroids enhance sodium reabsorption, which may worsen ascites. Additionally, corticosteroids are catabolic, and the breakdown of body tissues may promote HE. Early use of UDCA may slow progression of biliary cirrhosis, but this drug is untested in cats with cirrhosis. UDCA therapy was discussed with treatment of suppurative cholangiohepatitis. SUMMARY

Feline cholangiohepatitis complex causes a diffuse intrahepatic cholestasis of unknown etiology. Recognized histologic forms include acute suppurative cholangitis/ cholangiohepatitis, long-term nonsuppurative cholangitis/ cholangiohepatitis, and biliary cirrhosis. Treatment of cholangiohepatitis complex varies based on histologic type. Thus a liver biopsy is necessary for definitive diagnosis and treatment. Because cholangiohepatitis complex causes diffuse hepatic change, percutaneous needle biopsies are often sufficient for obtaining a diagnosis. Antibiotics are used to treat all forms of feline cholangiohepatitis complex, but steroids may be of equal or greater importance for use in the treatment of long-term nonsuppurative cholangiohepatitis. Prognosis is guarded for cats with any form of cholangiohepatitis complex due to the variable response to treatment seen in many cats. Spontaneous remission occasionally occurs. ACKNOWLEDGMENT The author thanks Dr. William Maslin for producing the photographs for this article.

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34. Neufeld JL, Brandt RW: Cholangiohepatitis in a cat associated with a coccidia-like organism. Can Vet J 15:156, 1974 35. Ohnishi A, Tsuboi Y, Ishizaki T, et a!: Kinetics and dynamics of enalapril in patients with liver cirrhosis. Clin Pharmacal Ther 45:657, 1989 36. Perez-Ayuso RM, Arroyo V, Planas R, eta!: Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites. Gastroenterology 84:961, 1983 37. Pope ER: Liver biopsy the surgical approach. Vet Med Report 2:197, 1990 38. Poupon RE, Balkau B, Eschwege E, et a!: A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Eng! J Med 324:1548, 1991 39. Prasse KW, Mahaffey EA, DeNovo R, et a!: Chronic lymphocytic cholangitis in three cats. Vet Pathol 19:99, 1982 40. Putnam CW, Starzl TE: Simplified biopsy of the liver in dogs. Surg Gynecol Obstet 144:759, 1977 41. Shaker EH, Zawie DA, Garvey MS, et a!: Suppurative cholangiohepatitis in a cat. J Am Anim Hosp Assoc 27:148, 1991 42. Smart ME, Downey RS, Stockdale PHG: Toxoplasmosis in a cat associated with cholangitis and progressive pancreatitis. Can Vet J14:313, 1973 43. Thompson MB, Meyer DJ, Senior DF: Effects of treatment with ursodeoxycholic acid on bile acid profiles in a dog with chronic hepatic disease (abstract). In Ninth Forum of the American College of Veterinary Internal Medicine, New Orleans, LA, 1991, p. 886 44. Twedt DC: Cirrhosis: A consequence of chronic liver disease. Vet Clin North Am (Sm Anim Pract) 15:151, 1985 45. Yoshikawa M, Tsujii T, Matsumura K, eta!: Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology 16:358, 1992 46. Zawie DA, Garvey MS: Feline hepatic disease. Vet Clin North Am (Sm Anim Pract) 14:1201, 1984

Address reprint requests to Deborah G. Day, DVM, MS Animal Health Center College of Veterinary Medicine Mississippi State University PO Box 9825 Mississippi State, MS 39762-9825