Liver disease and treatment in dogs and cats (Proceedings)

Canine and Feline liver disease diagnosis and treatment has improved dramatically over the last 20 years due to clinicians working to obtain a definitive diagnosis with improved diagnostic procedures. Knowledge gained over the years with more definitive diagnoses available has allowed clinical diseases to be separated into categories of infectious, inflammatory, immune-mediated, neoplastic, nutritional and toxic liver disease. Treatment aimed at the specific disease has improved outcome in our patients. Diagnostical procedures for more accurate diagnosis of liver disease includes physical exam findings, clinical pathology, radiology, scintigraphy, abdominal ultrasound (U/S), U/S guided fine needle aspirates and tissue biopsies and laparoscopy and exploratory celiotomy and tissue biopsies. Treatment is most successful if the primary cause can be eliminated however supportive care for complications of liver disease and hepatoencephalopathy can also be of great value as the liver heals.

Clinical Signs of Liver Disease

Patients often have non-specific signs of liver disease with a decreased appetite, anorexia, lethargy, weight loss, intermittent vomiting/diarrhea, and PU/PD. More specific signs of liver disease are icterus and ascites with a low protein content. Some patients have a chronic history while others have an acute history depending on the underlying condition and whether more than 80% of the liver has been affected and not functioning properly. Although clinical signs can be present before this occurs, most patients show signs of clinical disease at this stage.

Bacterial Liver Disease

Bacterial liver diseases are usually due to ascending infections from the GI tract via the portal vein or bile duct. The hepatic artery can also bring systemic bacteria to the liver such as leptospirosis. Gram positive, Gram negative and anaerobic bacteria are normal flora of the liver and can cause infectious diseases when the liver is overwhelmed by bacteria from the GI tract or the liver suffers a major insult in some way such as a toxin. Feline Suppurative Cholangitis/Cholangiohepatitis,in the first phase of the complex, canine cholangitis/cholangiohepatitis, hepatic abscesses, toxoplasmosis and leptospirosis are the most common presentations for bacterial liver disease.

Treatment

It is ideal to have a liver biopsy to culture the tissue for the specific bacteria and antibiotic sensitivity. Aerobic and anaerobic cultures should be submitted. Antibiotics can empirically be chosen based on the known bacterial flora of the liver. Ampillicin, cephalosporins, enrofloxacin, metronidazole (low dose 7mg/kg) and clindamycin and chloramphenicol are good choices in combination to cover the broad spectrum of bacteria.

Inflammatory Liver Diseases

Feline non-suppurative cholangiohepatitis in the second phase of the complex, canine chronic active hepatitis (CAH), canine copper hepatotoxicity, and possibly granulomatous hepatic disease are the most common diagnoses for inflammatory liver disease. Diagnosis by tissue biopsy is essential to identify the inflammatory cells present. Culture of liver tissues is also essential to eliminate bacterial disease as a component.

Treatment

Anti-inflammatories: prednisone, azathioprine (Imuran®), cyclosporine (Atopica®), and chlorambucil. Antioxidants have been shown to improve chronic hepatocyte damage that causes oxidative damage/ Vitamin E (alpha-tocopherol) has proven to be effective in humans with chronic hepatitis and it is suspected to be helpful in dogs and cats as well. Milk Thistle (Silymarin) and S-adenosylmethionine (Denosyl SD4) have also been shown to protect heptic damage due to toxins and corticosteroid induced hepatopathy. Denosyl provides the hepatocyte with glutamine which is necessary for metabolic reactions within the hepatocyte to maintain function of the liver. Anti-fibrotics may prevent collagen deposition during inflammation and stimulate collengenase activity to prevent cirrhosis which is the end-stage of liver inflammation and is irreversible. Colchicine is used often for this purpose however effectiveness in dogs has not been studied. Cholerectics such as Ursodeoxycholic Acid (Actigall®) replace "bad" bile acids (hydrophilic) with "good" bile acids (hydrophobic) in the intestine so that the "bad" bile acid does not cause hepatocyte damage during cholestasis. There are clinical reports in dogs that show improvement in liver enzymes and histopathology with its use.

Canine Copper Hepatotoxicity

Canine Copper Hepatotoxicity can be a primary or secondary disorder. Copper accumulation occurs in the hepatocyte due to damage to the mechanism that releases copper from cell. Primary copper hepatotoxicity is seen more commonly in Bedlington terriers, White Highland White terriers, Skye terriers and Doberman Pinschers however any breed can have the primary disorder. Secondary copper hepatotoxicity occurs secondary to inflammation in the liver. Chronic active hepatitis specifically in the dog may cause increased copper accumulation in the liver secondary to the primary cause of inflammation. Unless recognized this disorder may further damage the hepatocyte. When diagnosing liver disease in the dog with tissue biopsy, liver tissue quantification of copper levels should be performed. A piece of the liver tissue is put into a sterile red top tube and sent overnight on cold pack to a specified laboratory that does these measurements. Normal copper tissue levels is less than 400 ug/g of dry weight. Patients with copper levels above 750 ug/g dry weight should be treated with copper reduction therapy. Therapy includes a low copper diet such as Hill's Science diet L/D. Most important is therapy to remove copper from the liver. Zinc is effective in decreasing absorption of copper in the intestinal tract by increasing synthesis of metallothionine which copper binds to and is shed with epithelial cells. With mild increases in copper levels this is a good treatment option however it is slow to reduce copper levels and can take up to 3-6 months to reduce tissue levels below 400 ug/g. Side effects of vomiting is sometimes seen and hemolytic anemia possible although rarely a problem. Copper chelator therapy is much more effective at reducing tissue copper levels by removing copper from the hepatocyte. In copper levels greater than 2,000 ug/g a copper chelator should be used for faster decrease in copper levels. D-Penicillamine (Cupramine) increased metallothionine synthesis in the liver reducing copper levels 900 ug/g per year. Side effects of vomiting and anorexia are common and sometimes limits its use. Trientine (Syprine) – 2,2,2, tetramine can bind copper in serum and liver tissue by the same mechanism of D-Penicillamine and at the same rate of 900 ug/g per year reduced copper in the liver. This drug may be difficult to find. 2,3,2 Tetramine is the superior copper chelator in the Bedlington Terrier which can be resistant to copper reduction drugs. For all patients it is 4-9 times more potent than other chelators with reduction of copper in the liver by 3,000 ug/g per year. There are no side effects reported for either drug.

Feline Hepatic Lipidosis

Feline hepatic lipidosis is a syndrome that has an unknown etiology however histories of cats having periods of starvation over 1-2 weeks during boarding or another stress often precedes the disorder. Other problems such as colagniohepatitis, diabetes mellitus or hyperthyroidism may be present with periods of anorexia that may induce secondary hepatic lipidosis. There is no specific age, breed or sex predilication for this disorder. It is rare for a cat to have this disorder twice in its life although cases have been reported. Cats under the age of 2 years have a better prognosis for recovery although many older cats have successfully overcome this syndrome with early and proper treatment. Known mechanisms that occur in the hepatocyte that causes fatty accumulation within the cell are deficiencies in important proteins that carry fatty acids out of the cell called apoproteins. What initiates this process is unknown. Diagnosis includes clinical suspicion from history, clinical signs of liver failure with icterus commonly seen. Physical exam finding of an enlarged liver. Obese cats may be predisposed to this syndrome. Clinical pathology supporting liver failure should be present with increased ALP, ALT, AST and hyperbilirubinemia most commonly found. Abdominal ultrasound of the liver may show a very hyperechoic liver and a fine needle aspirate may confirm a hepatocyte with fat vacuoles throughout the cytoplasm on cytology. Laparscopic or surgical biopsy is needed to rule out primary causes of diseases in the liver that may have secondary hepatic lipidosis. Treatment must be started early in the process with aggressive nutritional support given via an enteral feeding tube (esophagostomy, or gastrotomy (PEG) tube) so that feedings of adequate nutritional requirements including a high protein diet and adequate calories are given. Force feedings and appetite stimulants are not sufficient to treat this disease because these cats are anorexic and not enough food can be given to treat adequately. Diets with high caloric content and protein content above 46% dry matter are indicated. Good choices are Hill's Science diet P/D or A/D or other equivalent diets. L-carnitine supplement has been reported to improve clinical signs more rapidly. Vitamin E and Vitamin K are also indicated to reduce hepatopathy and coagulopathy respectively.

Feline Cholangiohepatitis Complex

Feline cholangiohepatitis complex consists of a process that occurs in the liver over time. Initially it is thought that a bacterial infection occurs (suppurative phase) and then later the bacteria infection clears but induces an immune-mediated response (lymphocytic-plasmocytic phase) that is a chronic disease. In more severe cases biliary cirrhosis may occur which is not responsive to treatment. Suppurative disease is treated with broad-spectrum antibiotics to cover Gram positive/Gram negative/Anaerobic bacteria. Amoxicillin and metronidazole (7 mg/kg reduced dose) are good choices for empirical treatment. Liver biopsy is indicated to diagnose lymphocytic-plasmacytic disease with anti-inflammatories/immune-suppressive treatment indicated such as prednisone, chlorambucil and cyclosporine. Properly diagnosed these patients can do well if monitored regularly and treatment altered as needed. Other disease of the liver in the cat must be ruled out such as FIP, toxoplasmosis and lymphosarcoma.

Treatment of Liver Diseases in the Dog and Cat

The treatment of liver disease in the dog and cat ranges from specific therapies aimed at reversing the effects of a known etiology of the liver disease to supportive care of the patient while the liver repairs itself over time, such as in the case of liver toxicity. Secondary effects of liver failure such as coagulopathy, hepatoencephalopathy, vomiting, electrolyte and acid-base deficiencies, seizures, portal hypertension and ascites may occur in addition.