Hepatic Disease in Small Animals: Introduction

Clinical Findings and Pathophysiology

Laboratory Analyses

Treatment and Management

Hepatic Encephalopathy

Ascites

Coagulation Abnormalities

Bacterial Infections and Sepsis

Nutrition

Choleretic Agents

Anti-inflammatory Drugs

Limiting Fibrosis

The liver performs numerous functions that include but are not limited to lipid, carbohydrate, and protein metabolism; storage and metabolism of vitamins; storage of minerals, glycogen, and triglycerides; extramedullary hematopoiesis; and coagulation homeostasis. The liver also has immunologic activity, contributes to digestion by producing bile acids, and is essential for detoxification of many endogenous and exogenous compounds. The liver has a large storage capacity and functional reserve and is capable of regeneration. These properties are somewhat protective against permanent damage. However, the liver is also predisposed to secondary injury because of its ability to metabolize, detoxify, and store various compounds.

Clinical Findings and Pathophysiology:

Clinical signs can vary and include anorexia, vomiting, gastric ulceration, diarrhea, hepatic encephalopathy, fever, coagulation abnormalities, jaundice, ascites, polyuria and polydipsia, hepatomegaly or microhepatia, and weight loss. Understanding the pathophysiology of specific clinical signs facilitates appropriate treatment.

Hepatic encephalopathy is seen in a number of liver diseases. Clinical signs suggestive of hepatic encephalopathy include circling, head pressing, aimless wandering, weakness, ataxia, blindness, ptyalism, aggression, dementia, seizures, and coma. Although the pathophysiology is not completely understood, a synergistic effect between the failure of the liver to clear several neurotoxins (ammonia, mercaptins, and short-chain fatty acids) and an imbalance in plasma amino acids (γ-aminobutyric acid [GABA], aromatic amino acids) along with an increased sensitivity of the brain to these changes are considered to be the major contributing factors.

Currently ammonia is considered the primary neurotoxin contributing to the clinical signs of hepatic encephalopathy. Colonic bacteria metabolize proteins and urea into un-ionized ammonia, which is readily absorbed into the portal circulation. In animals with normal liver function, most of the ammonia is removed by hepatocytes and converted into amino acids or urea. However, with liver failure or in the case of portosystemic shunts, in which the portal blood bypasses the liver, blood ammonia levels remain high because of inadequate detoxification. Blood ammonia levels can also be increased during GI bleeding, azotemia, alkalosis, hypokalemia, and anorexia. Elevated ammonia levels have an inhibitory effect on the CNS.

GABA is an endogenously produced neuroinhibitor. Levels of GABA in the CNS are increased in hepatic disease by 2 means. Ammonia is a substrate for GABA; therefore, increased ammonia levels result in increased GABA levels in the CNS. Also, GABA-like compounds are produced by intestinal bacteria, and clearance is decreased in hepatic dysfunction, resulting in increased CNS uptake. GABA receptors are complexed with receptors for diazepam and barbiturates. An increase in the number or affinity of GABA receptors may explain why the use of these drugs can exacerbate signs of hepatic encephalopathy in animals with liver dysfunction.

Clinical signs have also been attributed to an imbalance of the ratio of branched-chain amino acids to aromatic amino acids. In liver dysfunction, the ratio of branched-chain amino acids to aromatic amino acids is decreased because of increased utilization of branched-chain amino acids by myocytes and decreased hepatic clearance of aromatic amino acids. Increased CNS uptake of aromatic amino acids is favored due to the imbalance.

Mercaptans are produced by intestinal bacteria as a result of metabolism of sulfur-containing amino acids (methionine). Mercaptan levels increase with decreased liver clearance. Elevated levels of ammonia and short-chain fatty acids compete with mercaptans for metabolism by the liver. The neurotoxic effects of mercaptans are thought to work synergistically with elevations of ammonia levels to contribute to hepatic encephalopathy.

Short-chain fatty acids have a barbiturate-like effect on the brain. Decreased liver catabolism results in increased blood levels, which have both a direct effect on the CNS and an indirect effect by interfering with hepatic metabolism of ammonia and mercaptans.

Ascites in patients with liver disease is secondary to a combination of portal hypertension and an imbalance in sodium and water homeostasis. Portal hypertension can be hepatic, due to intrahepatic obstruction; posthepatic, due to obstruction of the portal veins or increased portal blood volume; or prehepatic, due to obstruction or kinking of the caudal vena cava or secondary to right heart failure. Causes of hepatic portal hypertension include inflammation, fibrosis, necrosis, regenerative nodules, arteriovenous fistulas, or neoplastic masses. Imbalance in sodium and water homeostasis can either precede or result from portal hypertension. Ascites can be exacerbated by hypoalbuminemia. Cytologic evaluation of the ascitic fluid seen with hepatic failure is usually consistent with a modified transudate.

GI bleeding can be seen in animals with liver disease due to ulceration or coagulation abnormalities. The cause of ulceration is multifactorial. Hypoalbuminemia can lead to decreased turnover of gastric mucosal cells. The integrity of the gastric mucosal layer can also be affected negatively by portal hypertension and increased levels of histamine, both of which can cause mucosal edema. Increased bile acids within the GI lumen can both decrease the effectiveness of the mucosal barrier and increase lumen pH.

Laboratory Analyses:

Either regenerative or nonregenerative anemia can be seen in liver disease, depending on the underlying cause. Conversely, severe or acute anemia can inhibit liver function because of hypoxia. Leukocytosis can be seen with inflammatory diseases; leukopenia with sepsis. In general, changes in WBC counts are nonspecific. Platelet number and function can be decreased, and coagulation times prolonged. Coagulation abnormalities can be seen due to decreased production or activation of coagulation factors that are produced by the liver (Factors V, VII, IX, X, XI, XII, fibrinogen, prothrombin, antithrombin III, plasminogen, α₂-macroglobulin, and α₁-antitrypsin). Decreased GI absorption of vitamin K because of decreased bile production can also lead to coagulopathies.

Liver enzyme activity is often an indicator of liver dysfunction, although levels may be normal in certain situations, eg, end-stage liver disease. ALT and AST are cytosolic enzymes. Changes in cell permeability, hepatocellular degeneration or necrosis, and inflammation can cause release of ALT and AST from hepatocytes and subsequent increase of serum values. AST is a less reliable indicator of liver disease because it is not liver specific (AST is also present in heart, skeletal muscle, kidney, and brain); AST levels within hepatocytes are much lower than ALT levels and may return to normal before ALT as disease resolves. However, in dogs with hepatic metastases, AST may be a more sensitive indicator of disease than ALT or alkaline phosphatase (AP). ALT levels rise rapidly after hepatobiliary necrosis or inflammation. Extrahepatic biliary obstruction results in a more gradual increase in ALT. Drugs that induce microsomal enzymes, including anticonvulsants and prednisone, may cause an increase in ALT in dogs, although levels usually are lower than those associated with disease. Decrease in ALT levels with acute disease is usually a good prognostic indicator. However, in chronic disease, a decrease in ALT may be due to recovery or to a severe decrease in hepatocyte population, as seen with end-stage disease.

AP is a membrane-bound enzyme found in a number of different tissues. In dogs, significant increases in AP activity can be attributed to bone isoenzyme (young animals, panosteitis, bone tumors, and secondary renal hyperparathyroidism), corticosteroid isoenzyme (excessive corticosteroids, either exogenous or endogenous), or liver isoenzymes. With acute hepatocellular necrosis, AP values lag behind an increase in ALT values; they are usually mildly to moderately increased and can return to normal in 2-3 wk. Highest values are noted with cholestatic disease, extrahepatic bile duct obstruction, hepatic neoplasia, and enzyme induction. Increased AP levels can also be caused by hepatic inflammation and systemic infection or inflammation and have been reported as a possible paraneoplastic syndrome seen with mammary adenocarcinoma. Minor increases in AP activity can be seen in numerous diseases, including hypothyroidism, hyperthyroidism, diabetes mellitus, pancreatitis, anoxia, hyperthermia, thromboembolism, hypotension, septicemia, and endotoxemia. Anticonvulsants, glucocorticoids, thiacetarsamides, and ketoconazole can also cause an increase in AP.

AP increases in cats are liver-specific and tend to be less severe than in dogs. In cats, AP is primarily derived from the liver and has a significantly shorter half-life than in dogs, and there is no corticosteroid isoenzyme. Therefore, mild increases of AP in cats are significant indicators of liver disease. (Placental enzymes may cause slight increases late in pregnancy.) AP in cats is rarely affected by anticonvulsants or glucocorticoids but can be increased in diabetes mellitus, hyperthyroidism, and pancreatitis. Highest levels are seen in hepatic lipidosis. Increase of AP precedes increase of bilirubin in both dogs and cats with cholestasis.

The liver is the primary contributor to serum γ-glutamyl transferase (GGT), which increases with intrahepatic and extrahepatic cholestasis and pancreatitis. The kidney and pancreas also have high tissue levels of GGT but do not contribute to serum values. In dogs, GGT activity can be stimulated by glucocorticoids and anticonvulsants. In cats, GGT is increased to a greater degree than AP in cirrhosis, bile duct obstruction, and intrahepatic cholestasis. Little to no increase in GGT levels is seen with acute hepatic necrosis. GGT levels are lower than AP levels in cats with hepatic lipidosis.

Albumin levels during hepatic disease can be decreased due to decreased synthesis or increased volume of distribution (ascites). Decreased albumin level is usually an indicator of severe or chronic liver disease. Glomerular disease or protein-losing enteropathy must be excluded as a cause for hypoalbuminemia. Serum globulins that are synthesized in the liver (α- and β-globulins) can be decreased in chronic liver disease. However, immunoglobulin (γ-globulin) levels are usually increased in liver disease due to inflammation or immune stimulation.

Serum bilirubin levels >2.5-3.0 mg/dL result in clinical icterus. Bilirubin levels can be increased due to prehepatic causes (such as hemolysis) or to intrahepatic or extrahepatic cholestasis. Extrahepatic cholestasis usually results in higher levels of hyperbilirubinemia than intrahepatic causes. AP values increase before serum bilirubin values with intrahepatic cholestasis. In dogs, bilirubinuria can be detected before bilirubinemia because the renal threshold for bilirubin is very low. Cats have a much higher renal threshold, and bilirubinemia is detected before bilirubinuria. Common causes of hyperbilirubinemia in cats include idiopathic hepatic lipidosis, feline infectious peritonitis, toxoplasmosis, cholangiohepatitis, pancreatitis, lymphosarcoma, and myeloproliferative disease. Icteric cats with anemia should always be tested for hemobartonellosis.

Biliprotein, a form of bilirubin that is tightly bound to albumin, is not excreted in the urine and remains in the circulation for a prolonged time. When a significant amount of biliprotein is present, animals can be icteric without bilirubinuria and can remain icteric for several weeks to months after the cholestatic disease has resolved.

BUN can be decreased in animals with liver disease because of decreased conversion of ammonia to urea. Anorexia or a low-protein diet can also cause lower BUN values. Increased BUN may be seen in hepatic disease if the animal is dehydrated (prerenal azotemia).

Hypoglycemia can be seen with hepatic disease because the liver is essential for glucose metabolism. Hypoglycemia is also reported with portosystemic shunts, as a paraneoplastic syndrome in animals with hepatic neoplasia, and in animals with liver disease associated with sepsis.

Cholesterol values may be normal; increased due to decreased excretion and increased production with cholestasis; or decreased due to decreased synthesis, malabsorption, or increased bile acid synthesis. Hypercholesterolemia is seen in cats with cholestasis. Hypocholesterolemia can be seen in portosystemic shunts or end-stage liver disease.

Bile acid levels are used to evaluate liver function. Measurement of serum bile acids after fasting and postprandially reflect the degree of hepatocyte uptake, biliary secretion, and portal circulation—the 3 components of the enterohepatic pathway. Fasting levels >20 µmol/L in dogs and >15 µmol/L in cats, and postprandial levels of >25 µmol/L in dogs and >20 µmol/L in cats, indicate liver dysfunction. Postprandial bile acids may be more sensitive in determining liver dysfunction than fasting samples. Because icterus is an indicator of defective bile metabolism, measurement of serum bile acids is not necessary in icteric animals. When serum bile acid values are increased, a liver biopsy is recommended to determine the specific cause of dysfunction. Bile acids may be increased in certain nonhepatic diseases, including inflammatory bowel disease, hyperadrenocorticism, and pancreatitis.

Two other methods of evaluating liver function are a fasting blood ammonia level and an ammonia tolerance test. If fasting blood ammonia levels are within normal limits, but liver disease is suspected, then an ammonia tolerance test can be conducted. Ammonium chloride is given at 100 mg/kg in a 5% solution orally or at 2 mL/kg of a 5% solution rectally (30 min after a cleansing enema). Rectal administration may be preferable because oral administration often induces vomiting. Blood ammonia is measured 20 and 40 min after administration. An ammonia tolerance test should be done with caution when hepatic encephalopathy is suspected because it can exacerbate clinical signs in these animals. Because ammonia is not affected by cholestasis, it can help differentiate between biliary and hepatic disease. Difficult sample handling limits use of this test in private practice.

Radiography is useful in determining liver size, irregular liver borders, choleliths, and diseases of the gallbladder that involve gas-producing bacteria. Ultrasonography can help to determine common bile duct obstruction and other biliary disease, differentiate between diffuse and focal lesions, and identify portosystemic shunts. Ultrasonographic-guided fine-needle aspirates or biopsy are relatively noninvasive procedures to obtain diagnostic liver specimens. In some situations, a wedge biopsy may be preferred to assure that the sample provides an accurate diagnosis. A complete coagulation profile should be done before attempting to collect any biopsy samples. Biopsy samples should be submitted for aerobic and anaerobic bacterial culture, cytology and histopathology, and, when appropriate, copper or toxicologic analysis. Nuclear scintigraphy is a valuable tool for identifying portosystemic shunts and other vascular anomalies.

Treatment and Management:

Early and appropriate therapy is critical for animals with acute and fulminate hepatic failure. Specific treatment should be administered if an underlying cause is identified. Attention to electrolyte and acid-base balance and proper nutrition provides the best environment for regeneration. In cases of chronic or end-stage liver disease, and in cases of acute liver disease when no underlying cause has been identified, supportive treatment is directed at slowing progression of disease and minimizing complications.

Hepatic Encephalopathy:

Treatment of acute hepatic encephalopathy is aimed at providing supportive therapy and rapidly reducing the neurotoxins being produced by the colon. Affected animals are usually comatose or semicomatose. Benzodiazepines and other sedatives should not be administered. Food should be withheld until the animal’s neurologic status improves. Fluids (2.5% dextrose and 0.45% saline with potassium chloride and vitamin B complex added) should be administered to correct dehydration and electrolyte and acid-base imbalances. Lactated Ringer’s solution should be avoided. Cleansing enemas of warm soapy water, followed by retention enemas of either lactulose (3 parts lactulose to 7 parts water at 20 mL/kg), 10% povidone-iodine solution (20 mL/kg), or neomycin (22 mg/kg) should be given every 6 hr until the animal is stable. Retention enemas should be maintained for 15-20 min; retention can be facilitated by use of a Foley catheter. Lactulose is a nonabsorbable disaccharide that interacts with bacterial flora and decreases encephalopathic toxin production. The sugars are not absorbed but are fermented in the colon to organic acids; this lowers colonic pH and traps ammonia in the ionized form, which prevents absorption. Disaccharides also provide an alternate substrate for bacterial metabolism and, therefore, decrease the amount of ammonia produced. In addition, disaccharides are osmotic cathartics and decrease noxious substances and ammonia-producing bacteria by purging. Neomycin and povidone-iodine directly alter the colonic bacterial population, decreasing the population of ammonia-producing bacteria.

Once the animal has been stabilized, treatment is aimed at preventing recurrence. Protein-restricted diets should be fed. If needed, oral lactulose (0.1-0.5 mL/kg, PO, bid-tid) along with antibiotic therapy, either neomycin (22 mg/kg, PO, bid) or metronidazole (7.5 mg/kg, PO, bid) are recommended. Antibiotic therapy works synergistically with lactulose.

The clinical signs can be exacerbated by GI bleeding, infection, glucocorticoid use (resulting in increased catabolism of tissue protein), neoplasia, fever, azotemia or dehydration (due to increased blood urea concentration), constipation (causing increased generation of colonic neurotoxins), metabolic alkalosis (favoring both production of ammonia by the kidneys and uptake of urea by the blood-brain barrier), and use of diazepam and barbiturates (synergetic neuroinhibitors). Use of H₂-receptor antagonists and sucralfate, control of fever and infection, proper hydration, and minimal (if any) use of antiseizure medication can help alleviate these complications.

Ascites:

The first step in control of ascites is dietary sodium restriction. However, sodium-restricted diets alone are often not sufficient, and diuretics are recommended. Diuretic therapy should be directed at slowly reducing ascites without causing dehydration, metabolic alkalosis, and hypokalemia. Spironolactone (1-3 mg/kg, PO, bid) is recommended initially; if spironolactone is not effective, furosemide (1-2 mg/kg, PO, bid) can be added. If ascites is causing respiratory compromise, then abdominocentesis is recommended to temporarily reduce fluid buildup. Periodic abdominocentesis is also recommended if ascites is refractory to treatment. Possible complications when removing large volumes of fluid by abdominocentesis include hypotension and hypoalbuminemia. Therefore, as little fluid as possible should be removed to keep the animal comfortable.

Coagulation Abnormalities:

In cases of acute hepatic failure, bleeding disorders are usually associated with disseminated intravascular coagulation (DIC). Treatment for DIC with anemia requires fresh whole blood transfusion, which is preferred over packed RBC for presence of clotting factors. (Fresh whole blood is also preferred over stored blood in animals with hepatobiliary disease because ammonia tends to build up during storage.) Alternatively, if anemia is not present, fresh frozen plasma transfusion can be used. Regardless of whether fresh whole blood or plasma is used, the unit should be incubated with heparin (100 U/kg) for 30 min. Additional heparin therapy is recommended at 50 U/kg, SC, tid for 24 hr, then 25 U/kg, SC, tid for 24 hr, then 10 U/kg, tid until the coagulation profile is within normal limits.

In chronic liver disease, coagulopathies are generally due to decreased production and/or absorption of coagulation factors. Vitamin K deficiency can be prevented by administration of vitamin K₁ at 0.5 mg/kg, SC or IM, bid for 3 days. In cholestasis or severe hepatic disease, chronic therapy with parenteral vitamin K₁ (0.5 mg, every 7-20 days, SC or IM) is indicated.

Bacterial Infections and Sepsis:

Animals with acute hepatic failure and chronic hepatobiliary disease are predisposed to bacterial infections. In acute hepatic failure, septicemia may be masked as fever; hypoglycemia and leukocytosis might be mistaken for manifestation of the hepatic disease and not associated with sepsis. Ampicillin and cephalosporins are active against both gram-positive and anaerobic organisms, enrofloxacin and gentamicin against gram-negative bacteria. In chronic disease, the infection is more likely to be intrahepatic, and both aerobic and anaerobic cultures should be performed. Empiric use of antibiotics should include drugs specifically active against GI flora and avoid drugs that are extensively metabolized by the liver. Appropriate choices pending culture and sensitivity include ampicillin (22 mg/kg, PO or IV, tid-qid), metronidazole (7.5 mg/kg, PO, bid), cephalexin (22 mg/kg, PO or IV, tid), enrofloxacin (2.5-5 mg/kg, PO, IM, or IV, bid) and amikacin (5 mg/kg, SC, IM, or IV, bid-tid). Combination antibiotic therapy may be necessary to adequately cover the spectrum of bacteria associated with infection.

Nutrition:

Adequate calorie intake, with the bulk of energy supplied by carbohydrates (20-40% of the diet) in the form of complex carbohydrates such as rice and pasta, is recommended for most animals with liver disease. (Exceptions include cats with hepatic lipidosis and animals with hepatocutaneous syndrome.) A higher soluble fiber diet may be beneficial because fermentation of fiber in the colon, through various mechanisms, decreases ammonia production and absorption and reduces incidence of hepatic encephalopathy. Because it is difficult to maintain adequate caloric requirements with high-fiber diets, they should not be used in debilitated animals.

Fat restriction is not a major consideration in animals with hepatobiliary disease unless decreased bile acid production prevents dietary fat absorption and results in steatorrhea. If malabsorption of dietary fat is a factor, medium-chain triglycerides may be used as a source of fats.

Protein restriction is recommended only for animals with hepatic disease that are at risk of having clinical signs of hepatic encephalopathy. Protein levels should be sufficient to prevent tissue catabolism and maintain albumin levels without leading to hepatic encephalopathy by ammonia production. The amount of protein may not be as important as the type of protein. Vegetable and dairy protein sources such as soy, peanuts, and cheese are better sources than meat proteins.

Zinc may have antifibrotic and hepatoprotective properties by preventing the absorption of copper from the gut. Supplementation of zinc may be beneficial in dogs, although some dogs may not tolerate zinc because it is a gastric irritant.

Hypokalemia and decreased levels of B vitamins are common complications with liver disease, especially in cats, and supplementation is recommended. Vitamin C deficiency has been reported in dogs with hepatobiliary disease, and supplementation may be beneficial. Parenteral use of vitamin K is recommended in animals with bleeding tendencies.

If animals are anorectic, tube feeding should be considered. Nasogastric tubes are inexpensive, easily placed, and can provide a short-term solution to feeding anorectic animals. Esophagostomy tubes are also inexpensive, but require more expertise to place and esophageal and respiratory problems may develop with longterm use. Percutaneous gastrostomy tubes can be placed with or without an endoscope and should be used in animals that need longterm nutritional support. Gastrostomy tubes should remain in place for a minimum of 7 days to prevent complications at the gastrostomy site.

Choleretic Agents:

In cases in which there is evidence of intrahepatic cholestasis but not biliary obstruction, choleretic agents may be helpful. Ursodeoxycholic acid (10-15 mg/kg, PO, sid) stimulates flow of bile and may also have hepatoprotective and immunomodulating effects.

Anti-inflammatory Drugs:

Use of these drugs in treatment of chronic hepatobiliary disease is controversial. However, corticosteroids or azathioprine may be indicated if there is no evidence of infection, if an immune-mediated disease is associated with chronic hepatobiliary disease, or to decrease inflammation, which can contribute to ongoing necrosis and fibrosis. Corticosteroid therapy (eg, prednisone, 1-2 mg/kg, PO, divided bid, and reduced to 0.5 mg/kg, every other day) has been effective in Doberman Pinschers with chronic hepatobiliary disease and in cats with chronic cholangiohepatitis. Other cases of chronic hepatobiliary disease may benefit from anti-inflammatory therapy only if there is evidence of an underlying immune-mediated disease or active inflammatory disease without evidence of sepsis.

Detrimental effects of glucocorticoids in chronic hepatobiliary disease include sodium and water retention (which can either exacerbate or promote ascites formation), catabolic effects (which can promote hepatic encephalopathy), GI ulceration, pancreatitis, predisposition to secondary infections, glucose intolerance, and iatrogenic hyperadrenocorticism.

Azathioprine (2 mg/kg, PO, sid decreased to every 48 hr) has been recommended for use in chronic hepatobiliary disease either with or without glucocorticoids. Adverse effects of azathioprine include bone marrow suppression, pancreatitis, and GI toxicity. Azathioprine is not recommended in cats.

Limiting Fibrosis:

Hepatic fibrosis can eventually lead to cirrhosis. However, fibrosis is potentially reversible. Colchicine is both antifibrotic and anti-inflammatory. The dosage is 0.03 mg/kg, PO, sid. Adverse effects of colchicine include nausea, vomiting, and hemorrhagic diarrhea. Colchicine is available in formulations with and without probenecid. Formulations without probenecid should be used because probenecid can cause nausea and vomiting.

Zinc may also be useful in decreasing fibrosis. The recommended dosage is 1-2.2 mg/kg, PO, bid, 1 hr before meals. Zinc levels should be monitored every 2 wk, and plasma levels should be maintained at 200-300 µg/dL. Zinc therapy should be discontinued if levels are >1,000 µg/dL because of potential toxicity.