Feline Hepatobiliary Diseases

Feline Hepatobiliary Diseases

The incidence of feline liver disease is relatively common. The cholangitis/cholangiohepatitis complex and feline hepatic lipidosis are the major causes of hepatobiliary disease in cats, followed by neoplasia (lymphoma, bile duct). Other inflammatory liver diseases include infectious diseases such as feline infectious peritonitis (FIP) and toxoplasmosis. Hepatotoxicities are uncommon and most often associated with administration of drugs such as acetaminophen, diazepam and tetracyclines. Extrahepatic bile duct obstruction may be related to cholelithiasis or external compression (neoplasia and/or pancreatitis). Hepatic cysts are an infrequent finding and seldom cause problems. Metabolic diseases, like hepatic amyloidosis, are rare (Table 3).

Cholangiohepatitis/cholangitis Complex

The cholangiohepatitis/cholangitis complex is a common but ill-defined inflammatory disorder of the hepatobiliary system in cats. It is distinctly different from dogs, where inflammatory disease is usually centered on the hepatic parenchyma (hepatitis). In cats, the inflammation is almost always centered on the bile ducts. The classification has been complex, but it is now subdivided according to the type of cellular infiltrates into suppurative (neutrophilic) cholangitis/cholangiohepatitis, chronic (mixed inflammatory cell population) and lymphocytic cholangitis (Gagne et al., 1999; Weiss et al., 2001; WSAVA Liver Standardization Group, 2006). Lymphocytic portal hepatitis is furthermore a common finding in older cats, but is now thought to be of questionable clinical significance.

Suppurative cholangiohepatitis/cholangitis may begin as an ascending bacterial infection of the biliary tract, which results in neutrophilic inflammation of the bile ductules and portal triads. It is more common in males. Cats with acute suppurative cholangitis present acutely ill with fever, anorexia, vomiting and lethargy (Caney & Gruffydd-Jones, 2005). They are frequently icteric, and have neutrophilia and raised liver enzymes. Coliforms (E. coli) are the most common bacteria, but there is often a mixed infection including common components of the enteric flora. A positive bacterial culture of the bile or liver of affected cats may help in identifying causative organisms, although the incidence of positive cultures is inconsistent. Complications include sludged (inspissated) bile and cholelithiasis, which can cause partial or complete biliary obstruction and require treatment before the cholangiohepatitis can be controlled or resolved.

Feline suppurative cholangitis frequently coexists with other diseases, particularly pancreatitis and inflammatory bowel disease (Weiss et al., 1996). This association has been referred to as triaditis, and may be due to the fact that the pancreatic ducts and bile ducts join before entering the duodenum, allowing bacteria to enter in both. Ascending bacteria initiate the acute disease, and over time it can become chronic. The predominant signs of suppurative cholangiohepatitis are however usually attributable to hepatobiliary disease. It is nevertheless important to look for underlying disease, since these may affect the management and response to treatment (e.g., correction of cobalamin deficiency in cats with concurrent inflammatory bowel disease).

Treatment for cats with suppurative cholangiohepatitis includes fluid and electrolyte therapy as needed, nutritional support, antibiotic and choleretic therapy. In the longer term modified diets formulated for liver support are indicated, but in the early stages maintenance of caloric intake is the priority. Surgical intervention may be indicated for biliary decompression or to remove choleliths. The choice of antibiotics is ideally based upon bile and/or liver culture and sensitivity testing, but effective empirical choices are ampicillin (10 - 20 mg/kg IV, IM SC q6 - 8h), amoxicillin (11 - 22 mg/kg IM, SC or PO q8 - 12h), and cephalexin (20 - 20 mg/kg PO q8 - 12h). Metronidazole(7.5 - 10 mg/kg PO q12h) can be used in combination with a penicillin, and has a good anaerobic spectrum. Metronidazole is metabolized by the liver, and the dose should be reduced if there is severe hepatic insufficiency. Long-term antibiotic treatment for at least 2 months is recommended, since short duration of therapy may result in reoccurrence of clinical signs.

Choleretic therapy with ursodeoxycholic acid (10 - 15 mg/kg PO q24h) is of value in restoring bile flow, provided there is no biliary obstruction. Ursodeoxycholic acid also has anti-inflammatory, immunomodulatory and antifibrotic capacities, probably through changing the composition of the bile acid pool by reducing the proportion of hydrophobic bile acids that have toxic effects on hepatocellular membranes (Nicholson et al., 1996; Webster, 2006). Antioxidant therapy with vitamin E and S-adenosyl-methionine (SAMe) is furthermore useful to reduce oxidative stress associated with liver disease and cholestasis (Caney & Gruffydd-Jones, 2005).

Chronic cholangiohepatitis with a mixed inflammatory cell population is thought to be the result of progression of the acute suppurative form. This is generally due to an ascending biliary infection from the gut; liver flukes (Platynosomum concinnum) may be a rare contributing factor in endemic tropical areas (Haney et al., 2006). Presenting signs are intermittent vomiting, lethargy and anorexia, weight loss, and jaundice. A liver biopsy confirms the diagnosis, but concurrent pancreatitis and inflammatory bowel disease have to be taken into consideration. Treatment is empirical with immunosuppressive therapy (prednisolone, tapering over 2 - 4 weeks to 0.5 - 1 mg/kg once daily or every other day), antibiotics if indicated, choleretic therapy with ursodeoxycholic acid, and antioxidants. Liver fluke infestation is diagnosed upon hepatic biopsy or fecal examination, and treated with praziquantel (20 mg/kg/day for 3 days). This disease is slowly progressive, and may eventually result in cirrhosis, which has been compared to human biliary cirrhosis.

One beneficial effect of S-adenosylmethionine (SAMe) is believed to be the restoration of hepatic glutathione levels that are reduced in liver disease, leading to increased oxidative damage and exacerbation of liver disease. SAMe is critical in the defence against free oxygen radicals. Other beneficial effects may be due to increasing taurine levels (Figure 7), since taurine is required for bile acid conjugation and has a cytoprotective effect.

Figure 7. Production of cysteine and taurine from s-adenosyl-methionine (SAMe).  

Lymphocytic cholangitis is thought to be immune-mediated, and is characterized by lymphocytic infiltration around the bile ducts (Day, 1996). Persian cats are predisposed, but there is no sex bias (Lucke & Davies, 1984). The condition appears to be very chronic and slowly progressive, and affected cats present with a prolonged history of weight loss, anorexia and variable icterus; in addition, they often have hepatomegaly and a protein rich abdominal effusion. Hypergammaglobulinemia is common and may reflect the chronic nature of the disease, but needs to be differentiated from feline infectious peritonitis (FIP). Treatment is by immunosuppressive therapy with corticosteroids, which have both anti-inflammatory and anti-fibrotic properties. Prednisolone is commonly used at an initial immunosuppressive oral dose (2 - 4 mg/kg q12h), which is gradually reduced over 6 to 12 weeks according to the patient’s response. It should then be tapered to the lowest effective dose. The use of azathioprine should be avoided, since it may have severe adverse effects in cats. Alternative immunosuppressive agents include cyclosporine, chlorambucil, methotrexate and cyclophosphamide, but experience of their use and value is limited. Ursodeoxycholic acid, antioxidant therapy with SAMe and vitamin E, and nutritional support are furthermore important components of the management.

If ascites is severe, particularly if this is causing dyspnea due to pressure on the diaphragm, drainage by abdominal paracentesis may be indicated. Loop diuretics such as furosemide (1 - 2 mg/kg q12h) combined with restriction of dietary salt may be helpful in mild ascites. Potassium-sparing diuretics (e.g., spironolactone) are alternative agents for treating ascites.

Feline Hepatic Lipidosis

Feline hepatic lipidosis (FHL) is a unique syndrome characterized by severe hepatocellular accumulation of triglycerides (Figure 8) with resulting intrahepatic cholestasis and liver dysfunction. Cats that were previously overweight and are undergoing rapid weight loss are at increased risk (Biourge et al., 1994c); affected animals often have an underlying disorder that causes anorexia and catabolism (Scherk & Center, 2005). It occurs primarily in middle-aged to older cats, and there is no breed or sex predisposition.

Figure 8. Liver biopsy of a cat with hepatic lipidosis. Notice the progressive diffuse lipid vaculolization. The brown areas indicate cholestasis (H&E). (© V. Biourge).  

The etiology is incompletely understood but likely related to metabolic characteristics peculiar to cats, which are obligate carnivores with high requirements for protein, essential amino and fatty acids. Cats also have a high tendency to accumulate triglycerides in their hepatocytes, which is augmented during fasting after weight gain, resulting in progressive hepatocellular vacuolation. In hepatic lipidosis, the rate of peripheral fat mobilization exceeds that of hepatic triglyceride mobilisation and fat oxidation. Hepatic fat accumulation and vacuolation become so severe that it promotes oxidant injury, intrahepatic cholestasis and ultimately liver failure (Scherk & Center, 2005).

The cause for the rapid mobilization of peripheral fat is as yet unknown. When anorexic, cats lack essential amino acids that are necessary for mobilization of fat stores as very low-density lipoproteins (Biourge et al., 1994a). In addition, several nutritional deficiencies develop including protein malnutrition, which aggravate the liver disease (Center, 2005). Cats with liver disease, including hepatic lipidosis, often have reduced hepatocellular levels of the endogenous antioxidants vitamin E and glutathione. This increases oxidative stress and aggravates hepatocellular damage (Center et al., 2002). Hepatocellular carnitine deficiency has furthermore been documented and may promote lipid accumulation in the liver; carnitine supplementation has been shown to be helpful to prevent hepatic lipidosis in obese cats during complete fasting (Blanchard et al., 2002), but it’s role in the management of this disease is still controversial (Ibrahim et al., 2003).

Cats with FHL usually present with a history of prolonged anorexia, rapid weight loss and vomiting. There is typically a significant loss of muscle mass while abdominal and inguinal fat stores are spared. On initial presentation, these cats are jaundiced, lethargic and have hepatomegaly. Some cats develop remarkable hypersalivation (Figure 9) as a result of hepatic encephalopathy. Hyperbilirubinemia, marked elevations in serum ALP but moderate elevations in serum gGT, and increased serum bile acids are consistent findings. Monitoring of ALP is a useful way to assess liver lipid accumulation: in anorexic cats, SAP is consistently above physiological range three weeks before hyperbilirubinemia and clinical signs appear (Biourge et al., 1994b).

Figure 9. Ptyalism associated with feline hepatic lipidosis. Some cats develop remarkable ptyalism, thought to reflect hepatic encephalopathy. (© Sharon Center (reprinted from Waltham Focus 14.2, 2004).  

Cats with FHL should be investigated for the presence of underlying disease, particularly pancreatitis and inflammatory bowel disease. Nonregenerative anemia, hypokalemia and coagulation abnormalities may be present. Serum vitamin B12 level determination is useful to rule out coexistent hypocobalaminemia, which adversely affects liver function.

A definitive diagnosis requires a liver biopsy and hepatic cytology. It is advisable to do this only after administration of at least three doses of vitamin K1 (0.5 - 1.5 mg/kg q12h), since fat-soluble vitamins are often deficient in view of the severe cholestasis.

Treatment for idiopathic hepatic lipidosis needs to be aggressive, since otherwise mortality rates are high. Initial therapy requires rehydration with balanced electrolyte solutions; replacement of potassium depletion is important as normokalemia improves survival. Adequate nutrition is however the cornerstone of treatment and prevention of feline hepatic lipidosis (Center, 2005). Since these cats are typically profoundly anorexic, tube feeding is usually initially necessary to provide the essential nutrients. Oral force-feeding is generally contra-indicated, since this can lead to further food aversion. Initially, a nasoesophageal tube may be used (Figure 10), and once the patient is more stable an esophageal or gastrostomy (PEG) tube can be inserted for longer-term use. Feeding a high quality diet for 2 - 6 weeks, or until the cat begins to eat on its own again, is the most important aspect of treatment. Dietary protein content is important since it helps hepatic regeneration. For most cats with hepatic lipidosis, proteins can represent 35 - 50% of dietary calories. If a cat exhibits signs of hepatic encephalopathy, the dietary protein content can then be progressively lowered to the minimum level of 25%.

Figure 10. Nasoesophageal tube as a supportive measure for anorexic cats. (© V. Biourge).  

Other supportive measures aim at controlling vomiting and providing nutritional supplements:

- L-carnitine supplementation (250 mg/cat/day) to improve lipid metabolism

- Antioxidant therapy with SAMe (200 mg/day; 20 mg/kg q12h when given with food) and vitamin E (20 - 100 IU daily PO)

- B vitamins are advised since these cats will have depleted hepatic stores, and it will improve appetite and cellular metabolism. Parenteral vitamin B12 supplementation (1 mg IM) is suggested because of the multifactorial causes of FHL, many of which lead to vitamin B12 deficiency.

Toxic Hepatopathies

The liver is uniquely susceptible to toxicities, since it detoxifies all agents coming from the portal blood. Acute toxic hepatopathies are however rare in cats and usually due to administration of certain therapeutic agents, such as diazepam, tetracyclines, acetaminophen, stanozolol, and methimazole (Harkin et al., 2000, Hooser, 2000). Signs appear within a few days or weeks following administration and are characterized by anorexia, increased liver enzymes, hyperbilirubinemia, and may progress to acute hepatic failure unless the drug is discontinued at the first sign of increases in serum ALT levels. Histopathology mainly reveals hepatic lobular necrosis. Discontinuing the drug is essential for recovery, coupled with fluid, electrolyte and nutritional support, and antioxidant therapy. The cat’s susceptibility to adverse drug reactions may be partially due to its inability to glucuronidate some metabolites in combination with its tendency for accelerated depletion of glutathione stores; however, some drug reactions are idiosyncratic.

Hepatic copper accumulation is very rare in cats, in contrast to dogs. Liver disease associated with periacinar copper accumulation has been described in a small number of Siamese cats, and some cats with chronic lymphocytic cholangitis were reported to have copper positive granules within portal hepatocytes (Haynes & Wade 1995; Fuentealba & Aburto 2003). There are no reports of treatment.

Portosystemic Shunts

Feline portosystemic shunts (PSS) are less common in cats than in dogs. They are usually congenital, single and extrahepatic (Figure 11), and are in most cases found in cats less than 2 years of age. Cats very rarely develop acquired portosystemic shunts due to portal hypertension (Langdon et al., 2002).

Figure 11. Digital subtraction angiogram of cat with congenital extrahepatic PSS. Before ligation: the perfusion of the liver is altered. (© CR Lamb, Royal Veterinary College, Londres, GB).  

Most cats with PSS are domestic shorthairs, but in purebreds there may be a breed predisposition in Persians and Himalayans (Levy et al., 1995). The history most commonly includes failure to thrive or weight loss, and variable signs of hepatic encephalopathy (lethargy and depression, ataxia, seizures, behavioral changes, blindness; intermittent hypersalivation can furthermore be a symptom of HE in cats) and occasionally ammonium biurate urolithiasis. There may also be a history of tranquilizer or anesthetic intolerance. Affected cats sometimes have copper colored irises, but this is not specific for shunts.

Hematological and biochemical abnormalities may include anemia, red cell microcytosis, increased ALT, and decreases in serum glucose and cholesterol. Cats with PSS can have normal albumin concentrations. Urinalysis abnormalities include low urine specific gravity and ammonium biurate crystalluria. Because of increased urinary excretion of ammonia and uric acid, dogs and cats may also develop uroliths. Urate uroliths are often radiolucent and therefore may not be detectable on survey radiographs unless they are combined with struvite. Elevations of both pre- and postprandial serum ammonia concentrations, or marked elevation of the postprandial values in relationship to the preprandial ones are common. Radiography usually shows small liver size, and ultrasonography is useful to detect the presence and location of a shunt.

Medical management of HE with lactulose, oral antibiotics and a protein-restricted diet stabilizes cats in anticipation of surgery and is also used for those patients in which surgical correction is not possible. Surgical options for PSS occlusion are shunt ligation, or attenuation and slow vessel occlusion using ameroid constrictors or cellophane banding (Kyles et al., 2002; Hunt et al., 2004). Complete ligation of the shunt (Figure 12) in a single procedure is possible in less than half of the cases. Partial ligation however commonly results in recurrence of clinical signs (Schunk, 1997). Repeated staged surgeries to completely ligate the shunt vessel may be more effective in these cases (Tillson et al., 2002), with a good long-term prognosis if complete ligation eventually is achieved.

Figure 12. Digital subtraction angiogram of cat with congenital extrahepatic PSS after ligation. Satisfactory perfusion of the liver. (© CR Lamb, Royal Veterinary College, Londres, GB).  

Hepatic Amyloidosis

Systemic amyloidosis also involving the liver is generally secondary to chronic systemic inflammatory responses. However, predominant hepatic amyloidosis has been described as an uncommon familial disorder in young adult Siamese and Oriental shorthair cats, and as sporadic cases in other breeds (Van der Linde-Sipman et al., 1997). Hepatic involvement has also been described in familial amyloidosis of Abyssinian cats, but signs of renal disease predominate in this breed. Clinical signs may be vague and suggestive of liver disease, but accumulation of hepatic amyloid sometimes results in spontaneous hepatic rupture and acute hemorrhagic abdominal effusion (Beatty et al., 2002). Diagnosis is based on cytology of a liver aspirate or a biopsy, which have been stained with Congored. There is currently no treatment for this condition in cats.

Hepatobiliary Neoplasia

Hemolymphatic neoplasia, mainly including lymphoma, is the most common form of hepatobiliary neoplasia in the cats. Primary hepatobiliary neoplasms occur uncommonly. Clinical signs are often vague and nonspecific, and cats may also be asymptomatic. Finding a cranial abdominal mass or hepatomegaly is the most frequent physical abnormality. Diagnosis is by ultrasound and confirmatory biopsy. Lymphoma may be amenable to chemotherapy protocols, some smaller primary tumors could be explored surgically to see whether they can be excised.

Hepatic amyloidosis has been described as an uncommon familial disorder in young adult Oriental shorthair and Abyssinian cats.