Feline liver disease (Proceedings)

Hepatic lipidosis is the most common liver disease in cats in North America. In a retrospective study performed at the University of Minnesota evaluating liver biopsy specimens obtained from cats over a 10-year period, hepatic lipidosis accounted for 50% of all cases. Approximately 15% of cases were diagnosed as lymphocytic hepatitis, 11% as cholangiohepatitis, 10% neoplasia, 4% vacuolar degeneration, 3% congenital PSS, 2% toxic hepatopathy, 5% other. Greater than 75% of icteric cats have either of the following: lipidosis, cholangitis, FIP, neoplasia (lymphoma).

Feline Cholangitis/Cholangiohepatitis

Unlike in dogs, inflammatory liver disease of cats primarily involves the biliary tree. This disease was previously categorized as acute or suppurative cholangitis/cholangiohepatitis, chronic or nonsuppurative lymphocytic, lymphoplasmacytic cholangitis/cholangiohepatitis with (sclerosing cholangitis) or without destructive duct lesions. Recently these diseases have been re-categorized based upon histopathologic features. As described by the World Small Animal Veterinary Association (WSAVA) Liver diseases and Standardization Research Group 2006, inflammation of the bile duct can be differentiated into neutrophilic cholangitis, lymphocytic cholangitis, destructive cholangitis (dogs), and chronic cholangitis associated with liver fluke infestation.14 Clinical differentiation of the subcategories of the cholangitis is unreliable without a liver biopsy because clinical features are widely divergent; some cats show no signs and others present with severe acute illness.

Neutrophilic Cholangitis

Neutrophilic cholangitis is the most common form of cholangitis seen in cats. The pathogenesis is thought to result from ascending biliary bacterial infection; however this cannot always be demonstrated. Histopathologically affected bile ducts have neutrophils in their lumen, between biliary epithelial cells or in close association with the bile ducts. When the inflammation extends beyond the limiting plate into the hepatic parenchyma it becomes cholangiohepatitis. Neutrophilic cholangitis can be either acute or chronic. The chronic neutrophilic form has lymphocytes, plasma cells and variable neutrophils that make up the cellular infiltrate, whereas in the acute neutrophilic form cellular infiltrate is neutrophilic. The acute neutrophilic form is usually associated with enteric bacteria: E. coli (most common), Enterobacter, Staphylococcus sp., hemolytic Streptococcus sp., Bateroides, Clostridium. Helicobacter has been studied as a cause of cholangitis; its role is unclear although not likely an active participant. Chronic neutrophilic cholangitis is thought to possibly be a chronic progression of the acute form or perhaps an immune-mediated process triggered by persistent infection or inflammation. In many cases there appears to be a relationship of neutrophilic cholangitis with pancreatitis and inflammatory bowel disease (IBD). This is supported by a study finding 83% of cats with chronic biliary tract disease to have IBD and 50% having concurrent pancreatitis. It is speculated that the common channel, the junction of the pancreatic duct and the common bile duct before they enter the duodenum, may explain the association of cholangitis and pancreatitis whereby ascending bacteria from the intestine entering the common channel can ascend into both organs. This anatomical relationship in conjunction with normally high concentrations of enteric bacteria in the proximal intestine of cats as compared to dogs and the frequent concurrent association with IBD may play a part in the role of the etiopathogenesis of feline inflammatory liver disease. Some refer to this multiple organ involvement as the feline triaditis syndrome.

The acute neutrophilic (ANC) form of cholangitis causes the most obvious clinical illness. These cats are sick and are usually presented for veterinary care with a history of less than 5 days of illness. The ages of cats can range from young to old, but are more commonly young or middle-aged cats. Clinical signs include pyrexia, lethargy, dehydration, inappetence, vomiting, and icterus. Some cats will exhibit pain on abdominal palpation and some may have hepatomegaly. Abnormalities seen on serum biochemical profile include moderate increases in ALT, AST and GGT with ALP increased to a lesser extent from ALT. Sometimes the cholestatic enzymes are normal. Most cats are hyperbilirubinemic. A left shift may be evident on the complete blood count and toxic changes can be seen. Sternal lymph node enlargement may be noted on thoracic radiographs. Abdominal ultrasound may reveal features consistent with concurrent disease: cholecystitis, pancreatitis, hyperechogenicity of the liver consistent with hepatic lipidosis, heterogeneous liver parenchyma indicating inflammation. Cholangitis cannot be diagnosed with ultrasound and sometimes no abnormalities are seen. Ultrasound can assist with fine needle aspirate for cytologic evaluation of liver parenchyma. Cytology can help to diagnose concurrent hepatic lipidosis. Cytologies can be gram stained to evaluate for bacteria. Biopsy and histopathology are needed to definitively diagnose cholangitis, whatever the category or form and cultures of liver tissue and/or bile will assist with antibiotic choice. Many times however, because these are usually fairly sick cats, medical therapy is often provided before liver biopsy can be obtained. If concurrent biliary obstruction is present, surgical intervention is needed once the patient is stable. Therapy consists of supportive care including fluid therapy, pain management, and antibiotics. Antibiotic therapy ideally is based upon culture and sensitivity results. If culture is obtained, antibiotic therapy should not be postponed until results are available. Broad-spectrum antibiotic coverage is recommended and good choices include Clavamox, a flouroquinolone (enrofloxacin) plus Clavamox. This author will empirically choose injectable ampicillin sodium/sublactam sodium and enrofloxacin while the cat is hospitalized and when released will send oral enrofloxacin and metronidazole home, if culture was not obtained. Antibiotic therapy is usually continued for a minimum of 4 weeks and sometimes continued for 12 weeks or for 1-2 weeks after liver values are normal. Ursodiol is also recommended. Nutritional support should be provided to cats that are persistently anorexic (>2-3 days including duration prior to presentation). A nasoesophageal tube (patient unable to undergo anesthesia) or an esophagostomy tube may be placed. Prognosis for acute form of neutrophilic cholangitis is usually good. Many cats will have a complete recovery. Some will progress to chronic neutrophilic cholangitis.

The chronic form (CNC) of neutrophilic cholangitis usually affects cats that are middle-aged to older. Duration of illness before presentation is usually weeks to years with most cats being sick for several months before presentation. Clinical illness may not be very obvious or signs are intermittent. Clinical signs include anorexia, lethargy, dehydration, weight loss, vomiting, diarrhea, icterus. Hepatomegaly is common. In the end-stage of disease cats may develop ascites, coagulopathy, and hepatic encephalopathy. Cats can have variable white blood cell counts. Hyperglobulinemia can be found in addition to elevations in ALT and AST. ALP and GGT can be variable. Hyperbilirubinemia is not consistent and can cycle in severity. Some cats can develop coagulopathies due to poor Vitamin-K absorption from biliary obstruction. Abdominal ultrasound may be normal or be similar to what is described for the acute form of neutrophilic cholangitis. Diagnosis is made with liver biopsy and histopathology. Supportive therapy if needed with fluid therapy, pain management, interventional nutrition should be provided. If a coagulopathy is present, Vit-K should be administered subcutaneously or intramuscularly as absorption from the gastrointestinal tract may be hindered. Antibiotic administration is recommended as for acute neutrophilic cholangitis/cholangiohepatitis and again ideally tailored to culture and sensitivity results. Antibiotics are usually given for at least 3-4 weeks. Immunomodulatory therapy is usually required. Prednisolone therapy (1-2 mg/kg PO BID) may be started with concurrently with antibiotics or 2 weeks after therapy. Prednisolone is usually tapered over about 8 weeks to 0.5 mg/kg every other day dosing. Additional immunomodulation may be supplied with chlorambucil. Additional therapies may include ursodiol, SAMe, Vitamin E, Milk Thistle.

As stated previously this disease process is definitively diagnosed through biopsy with histopathology and culture. Tissue samples of the liver and bile should be cultured as bile typically yields a higher positive culture rate. Liver biopsies can be obtained surgically or ultrasound-guided. Surgical biopsies are preferred. Surgery is especially indicated if biliary obstruction is present. In ANC or CNC obstruction can occur due to inspissated bile sludge or cholelith formation. The bowel and pancreas should be evaluated at surgery and biopsies considered to evaluate for feline triaditis (concurrent IBD, cholangitis, pancreatitis).

Prognosis for the acute form of neutrophilic cholangitis is usually quite good. It is very common to have complete recovery. Some cases, however, may progress to the chronic form. The chronic form of neutrophilic cholangitis has a variable prognosis. Patients may require long-term medications and may progress to end-stage cirrhosis. A mean survival time of 29 months for cats with acute and chronic cholangitis has been reported.

Lymphocytic cholangitis

Lymphocytic cholangitis (also sclerosing cholangitis, progressive lymphocytic cholangitis, chronic lymphocytic cholangitis) is a chronic inflammatory biliary tract disorder that seems to be progressive over months to years. It may be more common in Europe than in the US and is characterized histopathologically by moderated to marked lymphocytic infiltrates in the portal areas, lymphoid aggregates, variable fibrosis, and biliary hyperplasia. Cats can eventually develop widespread small duct destruction that leads to permanent hyperbilirubinemia. There are similarities between this disease process in cats and primary biliary cirrhosis in man. The disease processes seems to start in cats that are less than 4 years and one study showed an increase risk for Persian cats. Cats often have a history of weight loss and anorexia and may develop hyperglobulinemia, ascites, jaundice, coagulopathies, and hepatic encephalopathy. Hematologic and serum biochemical abnormalities seen are similar to that found in neutrophilic cholangitis. Liver biopsy and histopathology are needed for diagnosis. An immune-mediated etiology has been suggested; however there is variable to poor response seen with corticosteroid administration. SAMe therapy should be considered. Small cell lymphoma should be ruled out if lymphocytic infiltrates are severe.

Disorders that have been associated with the above forms of cholangitis include especially inflammatory bowel disease and pancreatitis (acute or chronic), cholecystitis, cholelithiasis, systemic bacterial infection, extra-hepatic bile duct obstruction, and biliary malformations.

Chronic Cholangitis Associated with Liver Flukes

Platynosomum sp are the most common liver fluke seen in North America, found mostly in tropical and subtropical regions (Florida, Hawaii, Bahamas, Puerto Rico). Cats are often asymptomatic however can develop clinical signs with heavy infestations including anorexia, weight loss, vomiting, diarrhea, and jaundice. The adult flukes measure about 5.8x2 mm and live in the gall bladder and bile ducts. The life cycle requires 2 intermediate hosts: a fresh water snail, then a fish, reptile, or amphibian. After ingestion of the secondary host, young flukes emerge in the intestines and migrate to the common bile duct, gall bladder, or hepatic ducts where they mature in approximately 8-12 weeks. Embryonated eggs are passed through the bile ducts to the intestines and excreted with the feces. Hematologic changes can include an eosinophilia; and, heavily infected cats can develop increased ALT and AST; ALP may remain normal or only mildly elevated. Hyperbilirubinemia may be seen. Histologic changes can be seen after three weeks of infection and increase in severity over time. Mixed neutrophilic and eosinophilic inflammation and distension of the bile ducts is seen early which can progress to biliary hyperplasia and progressive fibrosis surrounding the bile ducts. Abdominal ultrasound may show biliary obstruction involving the common bile duct, gall bladder, or intrahepatic ducts, gall bladder debris with flukes (hypoechoic oval structures with hyperechoic center), thickened GB wall, or hypoechoic hepatic parenchyma with prominent portal markings. Fecal examination may fail to detect eggs because of sporadic passage and empiric treatment with praziquantel (20mg/kg SQ q24h 3-5 days) is recommended if fluke infestation is suspected. Broad-spectrum antibiotics for possible bacteria introduced from migrating flukes and prednisolone for inflammation due to dying flukes should be considered as adjunctive therapy.

Lymphocytic Portal Hepatitis

This is characterized by lymphocytes and plasma cells limited to the portal areas and not biliary. It is a very common histopathologic finding in cats greater than 10 years of age and may be a non-specific reactive change secondary to systemic disease. Cats may or may not have elevations in liver enzymes and are not icteric. Treatment is likely not warranted.

Feline Hepatic Lipidosis (HL)

Feline hepatic lipidosis results from diffuse hepatocyte triglyceride accumulation from prolonged anorexia and weight loss. It leads to intrahepatic cholestasis and liver failure and is fatal without treatment but curable with food. Feline hepatic lipidosis can be divided into primary and secondary hepatic lipidosis. The syndrome of primary hepatic lipidosis is seen during periods of inadequate intake (often > 2 weeks) for forced very rapid weight loss (often >25% BW), unintentional food deprivation, change of a food that is unacceptable to the cat, sudden change in lifestyle or stress such as boarding, or new people or pets in the home. Secondary hepatic lipidosis occurs during periods of anorexia related to an underlying disease process such as other hepatic disorders (cholangitis), intestinal disorders, pancreatitis, neoplasia, and less likely kidney disease, DM, or cardiovascular disease.

Pathophysiology

Hepatic lipidosis is an acquired disorder of metabolism resulting in accumulation of triglycerides (TG) within hepatocytes in quantities sufficient to be visible with light microscopy. The accumulation of fat in the liver is potentially reversible and does not result in necrosis, inflammation, fibrosis, or cirrhosis. Fatty liver may be physiologic and by itself does not have deleterious effects on liver function. Fatty liver does not necessarily indicate the presence of liver disease but does signify an abnormality of cellular metabolism that may have other consequences on cellular function.

The amount of fat in the liver is determined by the balance between delivery of fatty acids to the liver and their removal. Fats are delivered to the liver via lipolysis, the release of fatty acids (FA) from adipose tissue, and synthesis of fatty acids within the hepatocytes from excess glucose and amino acids. Removal is via oxidation of fatty acids for energy and requires L-carnitine for transport of long-chain fatty acids into the mitochondria, and re-esterification to triglycerides and secretion as lipoproteins. If the rate of removal is less than the rate of delivery, fatty acids are stored in hepatocytes as triglycerides. There is a constant cycling of FA between the liver and adipose tissue. In the fed state there is a net flow of FA from the liver where they are synthesized to peripheral adipose tissue where they are stored as TG. During the fasted state the net flow is reversed. Liver uptake of FA from blood is a function of concentration so as FA concentration increases in the blood the liver takes up more FA. The capacity of the liver to dispose of FA is limited whereas the capacity for storage is unlimited. Thus the normal liver can remove fatty acids from blood to re-esterify them to TG at a rate that exceeds the capacity for removal. Mechanisms of fatty liver include increased lipolysis (increased FA delivery) such as seen with obesity (humans), brief starvation in well nourished animals, diabetes mellitus, hyperadrenocorticism, response to steroids or catecholamines from stress of underlying disease; a high rate of intrahepatic fatty acid synthesis (increased delivery) including that which is stimulated by excessive amounts of glucose substrate (dextrose containing IV fluids detrimental to cats with HL); defective oxidation (decreased removal) defective oxidation from mitochondrial impairment; defective excretion (decreased removal) from protein-calorie malnutrition/imbalance (chronic starvation or marked protein restricted diets), decreased synthesis/secretion of VLDL. Reversal of fatty liver occurs in response to correction of the primary abnormality.

In feline hepatic lipidosis, during a period of partial or complete anorexia of 1 week or longer (often > 2 weeks), increased peripheral lipolysis occurs through the stimulation of hormone sensitive lipase. Hormone sensitive lipase activity is increased by many of the same hormones that are increased during stress including glucagon, epi/norepinephrine, glucocorticoids, thyroid hormone, and growth hormone; it is inhibited by insulin. This results in an increase in FA delivery to the liver. Even though cats with hepatic lipidosis appear to have increased VLDL serum concentrations, this may not be sufficient to prevent lipid overload in hepatocytes. Obesity likely predisposes cats to HL during times of decreased food intake because of the quantity of free fatty acids that can be rapidly released from peripheral fat stores and possibly because of insulin resistance related to obesity. Baseline hepatic content may also be increased in obese cats.

Clinical Findings and Diagnosis

Hepatic lipidosis can affect cats of all ages, however most seem to be middle aged with a median of approximately 7 years. There seems to be no breed or gender predilection. Many cats are overconditioned historically or at presentation and have a history of persistent anorexia. Additionally owners may report vomiting, weight loss, diarrhea or constipation, poor hair coat, jaundice. Most cats are bright and alert at presentation unless severe hypokalemia is present or hepatic encephalopathy (HE). HE appears to be uncommon in cats with HL. Cats with HE are often depressed to stuporous, may appear disoriented, and be hypersalivating. Cervical ventroflexion can be seen with severe hypokalemia. On physical examination cats will have obvious jaundice (70%), hepatomegaly, dehydration, pallor, muscle wasting, and seborrhea. Complete blood count is often times normal; however, nonspecific abnormalities can be seen such as a non-regenerative anemia or a stress leukogram. Heinz bodies are a common finding. Biochemical abnormalities usually show the typical pattern of cholestatic liver disease with increased ALP and bilirubin. ALT and AST may be increased but usually not in the same proportion as the ALP. GGT increases are usually not seen. When cats with cholangitis are compared to cats with HL, lipidotic cats tend to have a higher bilirubin concentration, and ALT and ALP activities. Hypertriglyceridemia is common and hypercholesterolemia may be seen. Electrolyte abnormalities can be seen including hypokalemia and hypomagnesaemia. Hypophsophatemia can be seen but is more often encountered after treatment has been initiated (refeeding syndrome). Cats can have prolonged coagulation times mostly due to decreased vitamin K absorption from severe cholestasis. Coagulation tests were reportedly abnormal in approximately 45% of cases in one study but few cat showed bleeding tendencies.2 PIVKA may be more sensitive in detecting coagulation abnormalities in cats. Hepatomegaly may be seen on abdominal radiographs. Ultrasounographically the liver parenchyma is hyperechoic in cats with hepatic lipidosis. This is not a specific finding as obese cats can have a hyperechoic liver relative to the falciform fat. Diagnosis of hepatic lipidosis can be made based upon compatible history, clinical signs, biochemical and ultrasonographic findings, plus cytologic +/- histopathologic confirmation. Discordant results can be seen in cats with hepatic lipidosis when cytology and histopathology are compared and definitive diagnosis requires histopathology. Cytology is a very useful diagnostic tool, showing vacuolation of a majority of sampled hepatocytes. Mixed microvesicular (vacuoles uniform and do not displace nucleus) and macrovesicular (vacuoles larger than the nucleus that displace the nucleus) patterns are seen in feline hepatic lipidosis. Cytology will not identify a concurrent liver disease such as cholangitis. Since some cats with have secondary HL investigation of an underlying disease process is warranted which may necessitate liver biopsy. Biopsy can be performed with a biopsy needle via ultrasound guidance or surgically (laparotomy/laparoscopy). There can be discordant histopathologic results between needle biopsy samples and larger samples obtained surgically. This author does not commonly perform liver biopsies on cats that are suspected of having HL, unless improvement is not seen with initial therapy.

Treatment and Prognosis

The cornerstone of therapy for hepatic lipidosis is enteral nutrition. Enteral nutrition may be best achieved initially by placement of a nasoesophageal feeding tube on the day of admission. NE tube placement does not require anesthesia and many times may be placed with only topical anesthetic required. This allows time for careful rehydration with IV fluids, correction of electrolyte imbalances (especially potassium), and administering parenteral Vit K, while enabling early enteral nutrition. Once the cat is hemodynamically stable, anesthesia for placement of an esophagostomy or gastrostomy tube (PEG) may be considered. Diets that are recommended for feeding of cats with hepatic lipidosis are those that are rich in protein (30-40% energy), moderate in lipids (50% energy), and relatively low in carbohydrates (20% energy). Diets that may fit these criteria include Clinicare (Abbot), EnteralCare HPL (PetAg), IAMS Maximum Calorie, Hill's Prescription Diet a/d or m/d, or Purina DM. If hepatic encephalopathy is a concern, a lower protein diet may be desirable such as Purina NF, Hill's prescription diet k/d or l/d. Five or sometimes 8 French NE tubes can be placed in most cats; only liquid diets can be given through NE tubes. Fourteen French esophagostomy tubes and 18 French gastrostomy tubes may be placed in cats. Canned diets that are blenderized with water can be used through these tubes. Considerations to be taken into account include caloric requirements per day of the cat, volume and frequency of feeding. Cats that have prolonged anorexic can be volume sensitive and are at risk of developing refeeding syndrome if daily caloric requirements are met too quickly. Resting energy requirements (RER) are usually calculated based upon an optimal weight if BCS exceeds 3/5 to prevent overfeeding. RER may be calculated at approximately 50 to 60 kcal/kg BW/day or (30 x kg BW) + 70. Approximately 20-30 % of the RER should be fed on the first day, dividing the feedings into every 4-6 hours. Every 24 hours this amount may be increased by 10% (prolonged complete anorexia > 7 days) - 30% until the daily RER is reached. When fed food should be at room temperature and fed over approximately 10-20 minutes. Feeding should be stopped if retching, salivation, or gulping is seen during the feeding and re-initiated at a later time more slowly and possibly with less volume. The tube must be flushed after each feeding to prevent clogging. Additional water may be supplied through the feeding tube as well to meet the patients' fluid needs by subtracting the total water needs by how much is being supplied with the feedings. Vomiting is a common problem in HL cats and antiemetic therapy should be instituted. Options include metoclopramide, maropitant, dolasetron, ondansetron, or chlorpromazine. Care must be taken with the later to assure that hypotension is not induced. Antacid medications are often used as well such as famotidine or lansoprazole to alleviate gastritis/esophagitis due to acid damage. Cobalamin therapy may be considered especially for cats with concurrent inflammatory bowel disease. Vitamin K is often administered as many cats with HL suffer from coagulopathies secondary to poor vitamin K absorption; this is particularly important if a biopsy is obtained. L-carnitine, N-acetyl cysteine, SAMe, milk thistle, vitamin E, thiamine, and short-term taurine supplementation are recommended by some. Appetite stimulants should be avoided as they are unreliable for ensuring adequate caloric intake and encourage a false sense of nutritional success. Many have been reported to cause liver failure in cats. If hepatic encephalopathy is suspected or confirmed by measuring ammonia levels treatment with lactulose and an antibiotic (neomycin or amoxicillin) are recommended. A lower protein diet may also be considered. Monitoring of electrolytes especially potassium and phosphorous and glucose is very important in the first few days to week of therapy for HL as refeeding syndrome can occur. Hypophosphatemia (<1.5 mg/dL) can lead to hemolytic anemia. Hypokalemia can worsen HL and cause severe muscle weakness, among other problems.

Prognosis seems to be impacted by concurrent disease and how early nutritional support is implemented. Recovery rates in cats that do not have serious/fatal underlying conditions are reported to be approximately 80%-88%. Cats making a successful recovery demonstrate a decline by 50% in bilirubin within 7-10 days. Cats that succumb to disease usually do so within 7-10 days. Cats may need to be tube fed for weeks to months requiring owners to be active participants in their recovery. Cats are unlikely to have a recurrence of disease.

References

1. Gagne JM, et.al. JAVMA 1999;214:513-516.

2. Center SA, et.al. JVIM 1993;7:349-359.

3. Brown B, et.al. JVIM 2000;14:20-26.

4. Center SA. Vet Clin Small Anim 2005;35:225-269.

5. Armstrong JP, et.al. Vet Clin Small Anim 2009;39:599-616.

6. Center SA. Vet Clin Small Anim 2009;39:543-598.

7. Lucke VM, et.al. JSAP 1984;25:249-260.

8. Newell SM, et.al. JAVMA 1998;213:94-98.

9. Biourge VSemin Vet Med Surg 1997;12:34-44.

10. Prasse KW, et.al. Vet Path 1982;19:99-108.

11. Wagner KA, et.al. JVIM 2007;21:417-424.

12. Brain PH, et.al. JFMS 2006;8:91-103.

13. Weiss DJ, et.al. JAVMA 1996;209:1114-1116.

14. Cullen JM. Vet Clin Small Anim 2009;39:395-418.

15. Gagne JM, et.al. Vet Path,, 1996, 521-526.