David C. Twedt, DVM, DACVIM
Liver disease in both dog and cat is extremely common. Often the liver patient is identified based on abnormal liver enzymes discovered on the routine biochemical profile. However, most patients do not have primary hepatic disease but rather secondary hepatic involvement resulting from an extrahepatic event. This is because the liver is involved in most metabolic events and becomes damaged due to hypoxia, inflammatory cytokines, drugs, and chemicals. It should also be noted that the liver has a great reserve capacity and clinical signs of liver disease often do not appear until the disease is quite advanced.
A patient with liver disease could be normal, sick, or even neurological. It is therefore important to take a complete history and carefully examine each body system. The history should include any possible exposure to chemicals, toxins or drugs. Corticosteroids (oral or topical) will cause liver enzymes to increase in the dog and must be questioned in the history. Any ingestion of a drug or toxin that is metabolized by the liver has the potential to be injurious. Investigation into possible infectious exposure should also be carried out. For example, leptospirosis is a potential agent damaging the liver and/or kidneys.
Most of the clinical signs of liver disease in the dog are nonspecific and result in part due to the type of liver disease involved, the location and extent of damage. Because the liver has a great reserve capacity, there generally must be considerable damage to the hepatic parenchyma before clinical signs will occur from decreased hepatic function. Consequently, many liver disorders are "silent" or not detected until the damage is severe. The clinical signs tended to parallel the extent of hepatic damage. Early signs are usually vague. Gastrointestinal abnormalities including anorexia, nausea, vomiting, or diarrhea are among the most common signs in the patient with hepatobiliary disease. Excessive drinking (polydipsia [PD]) or urination (polyuria [PU]) can occur. Approximately 30% of dogs with portosystemic shunts have PD/PU. Often the urine is also reported to be very dark from bilirubinuria. Bilirubinuria is abnormal in the cat but can be normal in the dog. With chronicity there is weight loss that is aggravated with altered and unsatisfied nutritional and caloric requirements. Owners may report abdominal distention from hepatomegaly or ascites. Neurological signs from hepatic encephalopathy (HE) are often vague and can include ptyalism (increased salivation that is common in cats with HE), aggression, ataxia, lethargy, stupor, head pressing, circling, amaurosis (blindness), seizures and coma. Gastrointestinal ulceration and hemorrhage may occur in the patient with HE, especially when coagulation abnormalities have developed. Significant gastrointestinal bleeding will result in anemia and black, tarry feces.
The physical findings are quite variable. Jaundice (or icterus) is the yellowing of the skin and membranes from elevations in bilirubin levels in the blood. It is a reliable sign of hepatobiliary disease if hemolytic disorders are ruled out. Jaundice can be clinically detected when bilirubin levels approach 2–3 mg/dl. The non-pigmented body surfaces such as the pinna, sclera, and the soft palate are the best sites for detection of icterus in the dog and cat. A palpable enlarged liver is also an indication of liver disease. In most cases one is unable to palpate the normal liver because it is held within the confines of the rib cage. Elevating the front legs of the patient often lets the liver fall caudally making it possible to palpate the caudal aspects of the organ. Hepatomegaly or an enlarged liver occurs with infiltrative liver disease such as hepatic lipidosis, neoplasia, or congestion. In chronic hepatitis the liver is of normal or small in size and usually can't be palpated. Liver size is best determined using radiographs or ultrasound evaluation. Ascites may be detected and occurs when hepatic function is reduced and portal hypertension exists. In some cases abdominal distention from ascites can be severe and may be the presenting complaint of the owner. Often a fluid wave is detected upon abdominal palpation of the abdomen. Sometimes if there is a question of abdominal fluid, a simple abdominocentesis using a 20-g needle placed through the ventral abdomen with the dog in lateral recumbency may reveal free fluid. I generally do up to a four-quadrant tap around the umbilicus to collect fluid. I often use only a needle first, but, if no fluid returns, then I attach a syringe and apply suction. That fluid is collected in an EDTA and clot tube for analysis.
A number of laboratory tests run on a routine biochemical profile may be abnormal with liver disease. Common tests include the ALT, AST, GGT, ALP, total bilirubin (TB), albumin, glucose, cholesterol, and blood urea nitrogen (BUN). The ALT and AST are associated with hepatocellular injury. They are enzymes soluble in the liver cell that can leak out if a liver cell membrane is damaged or the cell dies. The magnitude of increase crudely reflects the number of affected hepatocytes. Aspartate transaminase (AST) is also found in abundance in skeletal muscle. Alkaline phosphatase (ALP) has 3 clinically significant serum isoenzymes identifiable in dogs that include liver, bone, and corticosteroid-induced fraction. The liver fraction is increased with cholestasis (conditions causing decreased flow of bile) that can originate from within the hepatocyte (or intracellular cholestasis) or from the bile ducts (extrahepatic cholestasis). In general, the greater the cholestasis, the higher ALP increases. Bone ALP increases with osteoblastic activity and is found in young growing dogs. The steroid ALP isoenzyme increases by induction from endogenous or exogenous glucocorticoids. The elevation can be dramatic 10- to 100-fold increases. A corticosteroid history must always be investigated. Gamma-glutamyl transferase (GGT) is primarily of hepatic origin and GGT increases generally parallel ALP increases in association with cholestasis. The presence of hyperbilirubinemia without hemolysis suggests moderate to severe hepatobiliary disease or extrahepatic obstruction. There are a number of other additional laboratory tests found on most routine biochemical profiles that evaluate hepatic function and should not be overlooked. These include albumin, glucose, and BUN. Changes in these tests usually occur with significant hepatic dysfunction. Other more specific function tests include blood ammonia, bile acids, and clotting times. My preferred specific function test is the measurement of serum bile acids. Serum bile acids are usually measured after a fast of 6–8 hours (pre-sample) and then the patient is fed a small amount of canned food and a 2-hour sample (postprandial sample) is obtained. Feeding makes the gallbladder contract elevating bile acid concentrations that the liver must metabolize. Bile acids become abnormal with hepatic dysfunction or portal systemic shunting.
Routine radiographs will tell liver size, shape and position. Ultrasound examinations of the liver are quite valuable and can give information of hepatic size, shape and density changes. Ultrasound is additionally helpful in evaluation of the extrahepatic biliary system for obstructions and for ultrasound direction of needle biopsies. Frequently, fine needle aspiration (FNA) for cytological evaluation is performed in conjunction with ultrasound. Although FNA is generally safe and easy to perform, interpretation of the cytological diagnosis of disease can be variable. One must be cautious in the interpretation of the results and use those FNA findings in conjunction with other diagnostics to support a diagnosis.
There are a number of indications for performing a liver biopsy, but one must carefully evaluate each case on its own merits and realize that there are no set hard and fast rules that must be abided to. A liver biopsy helps establish a diagnosis, prognosis, and formulate therapy. A liver biopsy can be obtained by needle biopsy with ultrasound direction, laparoscopy or surgery. We generally will perform histopathology, culture, and copper concentration determination on most biopsies.
I have four major general goals in liver therapy: 1) remove the etiology, 2) provide an adequate diet, 3) give specific therapy, and 4) provide general liver support. First step involves removing the primary etiology if it can be identified. In most cases the etiology is never determined. Short of treating the primary etiology most of the other therapies suggested are unproven in the management of liver disease in dogs and cats. A large part of the therapy is directed at providing adequate liver support.
Adjusting diet therapy should be considered in all cases; however, only general guidelines should be given. First, palatability is important to ensure adequate energy requirements are met. Next, there is a misconception about diet and liver disease that liver patients should be placed on a protein-restricted diet. Protein restriction should only be instituted in the patient that has clinical evidence of protein intolerance (i.e., hepatic encephalopathy). The goal of dietary therapy is to adjust the quantities and types of nutrients to provide needed nutrient requirements. Prescription liver diets are available but often not necessary unless the patient has advanced disease. Feline hepatic lipidosis results from severe anorexia and nutritional support is critical in these cases. We often place an esophageal feeding tube to provide needed nutrition. Esophageal feeding tubes are easy to place using light anesthesia and are generally well tolerated by most patients. Blenderized diets are easily placed through a 20-F feeding tube. Diets low in copper are recommended for dogs that have copper-associated liver disease that is only determined based on a liver biopsy. The formulated prescription liver diets have low copper concentrations, all other diets contain too much copper.
Specific therapy generally involves antibiotics for infection, anti-inflammatory therapy for some types of hepatitis, and therapy to remove hepatic copper in dogs having copper storage disorders.
Decreasing inflammation is a specific therapy for chronic hepatitis in the dog or in the cat with cholangitis. Anti-inflammatory therapy generally involves prednisolone. However, there has now been a trend to use immune suppressive therapy for greater anti-inflammatory effects that also alleviates the steroid side effects. Azathioprine or cyclosporine are both immunosuppressive agents that have commonly been used. Preliminary evidence suggests many patients with chronic hepatitis do well with these therapies.
Accumulation of the metal copper in the liver is toxic to hepatocytes. If the liver biopsy of a dog with hepatitis indicates significant abnormal hepatic copper accumulation, then copper chelator therapy should be instituted. Chelation is considered when hepatic copper levels are greater than 1000 µg/g dry weight liver (normal < 400). Penicillamine is the most frequent copper chelator recommended for use in dogs. It binds with copper in the tissues and then promotes copper removal through the kidneys. Affected dogs are also always placed on a low-copper diet as well.
Antibiotics are indicated for primary or secondary hepatic or gallbladder (cholecystitis) infections. Cholangitis in cats is frequently associated with bacteria in their liver as well. Amoxicillin, cephalosporin, or metronidazole are commonly used antibiotics; however, selection of an appropriate antibiotic is best based on results of a culture and sensitivity.
Choleretic drugs have been shown to be of benefit in hepatic disease. Ursodeoxycholic acid (ursodiol) is a synthetic hydrophilic bile acid that essentially changes the bile acid pool from the more toxic hydrophobic bile acids to less toxic hydrophilic bile acids. Ursodeoxycholic acid has been shown to increase bile flow and to also have hepatoprotective effects.
There has been recent interest in the management of certain types of liver disease using antioxidants. Antioxidants provide liver support by promoting optimal hepatic function. Evidence shows that there is oxidative liver injury in dogs and cats with various types of liver disease. Glutathione is an important intracellular compound that prevents damage to the cell from drugs, toxins, or other injurious agents preventing oxidative damage. It is reported that close to half the dogs and cats with liver disease have reduced glutathione concentrations in the liver supporting that oxidative damage is taking place. There are many antioxidants used in support of liver disease, but the most common ones include vitamin E, S-Adenosylmethionine (SAMe), and milk thistle. SAMe is a naturally occurring compound found in all living organisms and is involved in a number of metabolic pathways that appear to be beneficial to the liver and plays a major role in production of the antioxidant glutathione in the hepatocyte. Milk thistle has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Silymarin, the extract of milk thistle, has many antioxidant and hepatoprotective properties.
Additional Specific Therapy
The remainder of the therapy for chronic hepatitis involves treatment of secondary complications. These occur as the disease becomes advanced. Hepatic encephalopathy, GI ulceration and ascites are common clinical occurrences in advanced hepatitis or cirrhosis.
The first step in the management of hepatic encephalopathy includes the use of enemas to clean the colon of both bacteria and protein substrates for ammonia production. Slightly acidic enemas will lower the pH of the colon, thus ionizing ammonia and reducing its absorption. Povidone iodine (betadine) can safely be given by enema as a 10% solution (weak tea color) that will both acidify the colon and have an antiseptic action reducing bacterial numbers. Lactulose (see below) can also be given by enema in treating the severe case of hepatic encephalopathy. Nonabsorbable intestinal antibiotics are also used to alter bowel flora and suppress urease-producing organisms important in formation of factors causing hepatic encephalopathy. A nondigestible disaccharide lactulose given orally acidifies the colon converting ammonia to ammonium that is poorly absorbable, thus trapping ammonia in the colon. The fermentation products of lactulose will also act as an osmotic laxative reducing colonic bacteria and protein substrates. If diarrhea develops the dose should be reduced.
Gastrointestinal ulceration not only causes gastrointestinal signs such as vomiting and anorexia, but blood loss into the intestinal tract promotes hepatic encephalopathy as blood is an excellent protein source for ammonia production. Gastric ulcers should be treated with the H2 blocker such as ranitidine and oral sucralfate.
Ascites occurs with advanced chronic liver disease. Diuretics are the major means of managing ascites in small animals. Too rapid removal of ascitic fluid can cause metabolic complications and can precipitate hepatic encephalopathy. The two diuretics most commonly used are furosemide and spironolactone. Spironolactone therapy is more effective with ascites associated with liver disease. If an animal has a very tense ascites, paracentesis should be performed to decrease the intra-abdominal pressure, relieve compression of the venous circulation, and to increase patient comfort.
Understanding the clinical aspects of liver disease, the laboratory changes, and common therapies is important when it comes to the nursing management of a case. Careful attention to details discussed should improve the recognition of disease but also the case management.