Chapter 71 Diseases of the Liver and Biliary Tract
DIAGNOSTIC STRATEGY FOR LIVER DISEASE
Overview of the Diagnostic Strategy
Clinical Signs
Nonspecific Signs
• Vomiting is a common sign of liver disease. Hematemesis suggests gastroduodenal ulceration, a recognized complication of hepatobiliary disease.
Signs of Abnormal Bilirubin Excretion
• Pigmented urine (bilirubinuria) and jaundice (icterus) of the sclera, oral mucous membranes, and skin are classic signs of cholestatic liver disease. However, these findings are not specific for hepatobiliary disease and can also be caused by hemolytic disorders.
Coagulopathy
• Excessive bleeding (i.e., hemorrhages of the skin and mucous membranes, melena, and hematuria) occasionally is associated with liver disease, especially if hepatic damage is severe or is associated with common bile duct obstruction.
• Subclinical clotting abnormalities may become clinically apparent after liver biopsy, surgery, and development of gastroduodenal ulcers.
Hepatic Encephalopathy
• HE is a metabolic encephalopathy that occurs secondary to severe liver disease or portosystemic shunting of blood.
• Clinical signs include depression, hypersalivation, behavioral changes, altered consciousness, motor disturbances, seizures, and coma. As with other metabolic encephalopathies, signs typically wax and wane and are interspersed with normal periods.
• Ammonia, mercaptans, short-chain fatty acids, gamma-aminobutyric acid (GABA), and endogenous benzodiazepines are potential encephalopathic toxins that are produced in the colon by bacterial action on various substrates. Because the liver normally detoxifies these substances, systemic concentrations are low. With severe liver disease or portosystemic shunting, these potential toxins reach high concentrations in the systemic circulation and the central nervous system (CNS), resulting in clinical signs.
• Exacerbation of encephalopathy occurs after eating a meal high in protein because protein is a substrate for toxins such as ammonia and mercaptans.
Signalment and History
• The signalment often provides important clinical information, because breed predilections for specific liver diseases have been recognized, and young animals are more likely to be presented for congenital hepatic disorders such as portosystemic shunt.
• The history is helpful to characterize the clinical course of liver disease as acute or chronic. Recent onset of signs in an animal that was previously healthy suggests acute hepatic failure. However, because of the large functional reserve capacity of the liver, in occult chronic liver disease the clinical signs may be vague and may not be recognized by the owner until the final phase of hepatic decompensation.
• The history may provide important information regarding the potential for exposure to known causes of hepatic injury such as drug therapy, surgical and anesthetic procedures, and toxins or infectious agents.
• Determine if the animal has a history of intolerance to drugs normally metabolized by the liver, such as sedatives, tranquilizers, anticonvulsants, and anesthetics.
Physical Examination
Skin and Mucous Membranes
• Evaluate the sclera, oral mucous membranes, and skin for jaundice. Jaundice is not clinically detectable until serum bilirubin concentrations are >2.5 to 3.0 g/dl. In cats, subtle jaundice often is best detected on the palatine mucosa.
Abdominal Palpation
• Hepatomegaly is caused by passive venous congestion, diffuse inflammation, nodular hyperplasia, cysts, bile engorgement, marked biliary hyperplasia (cats), and infiltration by fat, glycogen, and neoplastic cells.
• Pain on palpation of the liver (hepatodynia) usually indicates acute liver disease. The pain is caused by stretching of the liver capsule and must be differentiated from pain arising in the pancreas, stomach, or spleen.
Routine Laboratory Evaluations
Because clinical findings in hepatobiliary disease often are vague, hepatic disease may not be suspected until biochemical tests identify elevated liver enzyme activity or other evidence of hepatic dysfunction (e.g., hyperbilirubinemia or hypoalbuminemia). Liver function studies such as serum bile acid (SBA) concentrations are used to achieve the following:
• Assess liver function when there is increased liver enzyme activity but normal serum bilirubin concentrations
Findings consistent with liver disease on routine laboratory tests are described below.
Complete Blood Count
• Mild to moderate anemia may occur secondary to liver disease because of blood loss (e.g., gastroduodenal ulceration or coagulopathy) or may be associated with normocytic-normochromic anemia of chronic disease.
• Erythrocytic microcytosis is a common finding in dogs and cats with portosystemic shunts. Decreased serum iron concentration, normal to increased serum ferritin concentration, and accumulation of stainable iron in the liver suggests that microcytosis is associated with abnormal iron metabolism (impaired iron transport or sequestration of iron) rather than absolute iron deficiency. Decreased availability of iron for hemoglobin synthesis appears to occur despite adequate tissue iron stores.
Urinalysis
• Urine specific gravity may be isosthenuric or hyposthenuric if liver disease is associated with PU/PD.
• Bilirubinuria is a sensitive indicator of abnormal bilirubin metabolism, and this finding precedes hyperbilirubinemia and jaundice. Bilirubinuria imparts a yellow-orange color to the urine. Bilirubin crystals may form in the presence of bilirubinuria.
• Urine urobilinogen is a colorless product of enteric bacterial degradation of bilirubin that is absorbed from the gut. A small portion of urobilinogen escapes the enterohepatic circulation and is excreted in the urine. The finding of urobilinogenuria indicates an intact enterohepatic circulation of bilirubin pigments. The absence of urobilinogenuria in a jaundiced animal suggests common bile duct obstruction. However, this test is not reliable in a clinical setting because many non-hepatic factors affect urine urobilinogen concentration, including altered intestinal flora, GI bleeding, intestinal absorption, renal excretion, urine pH, urine volume, and urine storage.
Liver Enzymes
Evaluation of serum liver enzyme activity is used as a screening test to detect liver disease. Increases in liver enzyme activity are not specific for the underlying hepatic disorder. However, liver enzymes can be used to categorize the underlying pathophysiologic mechanism. Increases in liver enzyme activity may occur secondary to hepatocellular injury and leakage (Fig. 71-1), or due to increased production stimulated by bile retention (cholestasis) or drug induction (Fig. 71-2).
Alanine Aminotransferase
Increased alanine aminotransferase (ALT) activity indicates hepatocyte injury with leakage of enzyme from the cytoplasm of the hepatocyte (see Fig. 71-1). The magnitude of ALT increase generally correlates with the number of injured hepatocytes.
• The largest increases in ALT activity occur with hepatocellular necrosis and inflammation (up to 100 times normal). Increases also occur with increased hepatocyte membrane permeability, such as that caused by hypoxia. Severe cholestasis can also cause secondary hepatocyte injury, with increases in ALT up to 20 to 40 times normal. Increased production of ALT by regenerating hepatocytes may account for persisting increases in enzyme activity after resolution of the initial injury.
• Anticonvulsant drug therapy (primidone, phenytoin, and phenobarbital) in dogs can be associated with mild increases in ALT activity (2 times normal) in the absence of obvious hepatocellular injury.
• Corticosteroid therapy or hyperadrenocorticism is associated with mild to moderate (2-10 times normal) increases in ALT activity.
• Small amounts of ALT are present in canine skeletal muscle; it has been shown that severe skeletal muscle degeneration or necrosis (canine muscular dystrophy, necrotizing myopathy, polymyositis) may be associated with increases in ALT activity of 5 to 25 times normal. When increased ALT activity is caused by muscle injury, creatine kinase (CK) and AST activity are also markedly increased. Whether ALT is liver specific in cats remains to be determined.
Aspartate Aminotransferase
Hepatocyte injury is associated with increased AST activity secondary to leakage from mitochondria and cytoplasm of hepatocytes (see Fig. 71-1).
• AST is not liver specific in dogs and cats; it is present in significant quantities in hepatocytes and skeletal muscle tissue.
• Comparison of activities of ALT, AST, and CK, a muscle enzyme, can indicate whether AST activity is increased due to hepatic or muscle injury.
Alkaline Phosphatase
Increases in serum alkaline phosphatase (ALP) activity are due to accelerated production of this enzyme, stimulated by cholestasis or drug induction (see Fig. 71-2). ALP is a membrane-associated enzyme present in many tissues; however, only liver, bone, and corticosteroid-induced isoenzymes contribute to serum ALP activity. Serum ALP activity in normal dogs and cats is usually due to the liver isoenzyme. An increase in this type of ALP activity indicates intrahepatic or extrahepatic cholestasis.
• Young growing animals or animals with severe bone disease may have mild increases in ALP activity due to the bone isoenzyme.
• Cats generally have smaller increases in serum ALP activity with hepatobiliary disease than do dogs owing to a limited capacity for ALP production and a shorter serum half-life (6 hours in cats versus 72 hours in dogs). Therefore, even small increases in serum ALP activity (2-3 times normal) in cats suggest significant cholestasis.
• Exogenous or endogenous glucocorticoids are associated with hepatic production of a novel isoenzyme of ALP, corticosteroid-induced ALP (CIALP), in dogs but not in cats. The CIALP isoenzyme can be distinguished from the liver isoenzyme (LALP) by levamisole inhibition using an automated analyzer. Increased CIALP activity is a consistent finding in dogs with spontaneous hyperadrenocorticism and absence of this isoenzyme is uncommon in this disorder.
• Increase in ALP activity associated with corticosteroid therapy varies considerably with the individual dog and the drug, dose, and duration of therapy. In the first 7 to 10 days of oral or parenteral glucocorticoid therapy, increases in ALP are primarily due to LALP activity. By 7 days, CIALP activity begins to increase, and it predominates in the serum after a month of therapy. Chronic treatment with otic, ophthalmic, and topical preparations is also capable of inducing ALP activity. Increases in CIALP activity do not necessarily imply the presence of iatrogenic hyperadrenocorticism, a suppressed pituitary-adrenal axis, or corticosteroid-induced hepatopathy, nor does it indicate that corticosteroid therapy must be discontinued.
• Increased CIALP activity is a sensitive but not a specific test for exposure to excess glucocorticoids (iatrogenic or endogenous). Increases in CIALP activity may be detected with diabetes mellitus, anticonvulsant drug therapy, primary hepatic disorders including neoplasia, hypothyroidism, and chronic illnesses (associated with disease-related stress and increased endogenous cortisol secretion). In this setting, a mixed pattern of increased CIALP and LALP activity is seen.
• Increased CIALP activity associated with exogenous or endogenous glucocorticoids may be accompanied by mild to moderate (2-10 times normal) increases in ALT activity that typically are of lesser magnitude than increases in ALP activity.
• Anticonvulsant drug therapy is associated with enzyme induction of the liver isoenzyme of ALP in dogs (but not in cats) in the absence of obvious hepatocellular injury. CIALP activity also may be increased in some dogs. Reported maximal increases for induced serum ALP activity include those caused by phenobarbital (30 times normal), primidone (5 times normal), and diphenylhydantoin (3 times normal).
Gamma-Glutamyltransferase
This membrane-associated enzyme is present in many tissues. Increased serum gamma-glutamyltransferase (GGT) activity usually reflects cholestasis and increased production by hepatocytes (see Fig. 71-2).
• Increased GGT activity parallels increased ALP activity in dogs, including increases associated with excess corticosteroids.
• In cats, serum GGT is more sensitive for detecting hepatobiliary disease than ALP. Serum GGT activity exceeds serum ALP activity in most hepatobiliary diseases; an exception is hepatic lipidosis, in which GGT activity may be normal or mildly increased despite a moderate to severe elevation of serum ALP.
Other Biochemical Tests
Bilirubin
• Fractionation of the total serum bilirubin into conjugated and unconjugated components (van den Bergh test) to distinguish the mechanism of hyperbilirubinemia is of little diagnostic value because there is considerable overlap in hemolytic, hepatocellular, and extrahepatic biliary disorders.
Albumin
• With chronic liver disease, fluid retention and dilution of existing serum albumin may also contribute to hypoalbuminemia.
• When the serum albumin is >1.5 g/dl, hypoalbuminemia contributes to the development of ascites and edema.
• Hypoalbuminemia is not specific for liver disease, and other causes of hypoalbuminemia such as urinary and gastrointestinal (GI) loss must be excluded.
Globulin
• Hyperglobulinemia due to increased gamma globulins occurs in some dogs and cats with chronic liver disease. The most likely mechanism is a systemic response to antigens that escape from the GI tract because of impaired hepatic mononuclear phagocyte system function or portosystemic shunting.
Glucose
• Because it indicates severe liver dysfunction, liver-associated hypoglycemia is a poor prognostic factor, except in dogs and cats with congenital portosystemic shunts.
• Some hepatic neoplasms such as hepatocellular carcinoma and adenoma, leiomyosarcoma, and hemangiosarcoma have been associated with profound hypoglycemia.
Cholesterol
• Hypercholesterolemia occurs with acute cholestatic disorders because of increased synthesis of cholesterol and decreased incorporation of cholesterol into bile acids; however, there are many non-hepatic causes of hypercholesterolemia.
Liver Function Tests
Serum and Urine Bile Acids
The normal physiology of bile acid metabolism is shown in Figure 71-3A In health, bile acids are confined to the enterohepatic circulation, and systemic concentrations are low. SBA concentrations increase in the systemic circulation with all types of liver disease (Fig. 71-3B). Because the liver has a large reserve capacity for synthesis of bile acids, even severe hepatic dysfunction does not cause decreased SBA concentrations.
Fasting Serum Bile Acid Concentration
• Increased concentrations occur with hepatocellular and cholestatic disorders that interfere with hepatic uptake or secretion of bile acids and with portosystemic shunting, in which bile acids are diverted directly into the systemic circulation (see Fig. 71-3B).
• Serial evaluation of SBA concentration to monitor liver function may not have merit unless the SBA concentration returns to normal. This is because there are wide fluctuations in SBA concentration in a given patient with liver disease within a 24-hour period (although all values are abnormal).
• Dogs and cats receiving the oral synthetic bile acid, ursodiol, may have an increase in SBA concentration because of the absorption of the drug and reflection of its presence in the serum.
• In dogs with unexplained increases in SBA, consider the possibility of small intestinal bacterial overgrowth causing increases in unconjugated bile acids.
• Healthy Maltese dogs were reported to have significantly higher SBA (mean 70μmol/L α50; range 1–362μmol/L) as measured by the enzymatic spectrophotometric method than as measured by high-performance liquid chromatography, suggesting the presence of additional reacting substances or unusual bile acids in their serum. However, a methodological problem related to lipemia or hemolysis cannot be excluded. It is also possible that these dogs had underlying hepatic microvascular dysplasia.
Postprandial Serum Bile Acid Concentration
• Obtain a serum sample for FSBA concentration, and then feed at least 2 teaspoons of food to small dogs and cats (<5 kg) and at least 2 tablespoons to larger patients.
• To ensure gallbladder contraction, feed a diet high in fat (e.g., Hill’s Pet Prescription Diet p/d and Hill’s Pet Prescription Diet c/d for cats). For encephalopathic animals in which a high-protein diet is contraindicated, substitute a protein-restricted diet and add a few milliliters of corn oil per feeding.
• Results: In normal dogs and cats, PPSBA concentrations are <25μmol/L and peak 2 hours after a meal. A liver biopsy may be indicated when concentrations are >30μmol/L.
Urine Bile Acids
Recently, urine bile acids (UBAs) have been investigated as a diagnostic tool in dogs and cats. Normally only small amounts of bile acids are present in the urine. Liver disease and increased SBA result in increased excretion of bile acids in the urine. Potential advantages of UBA over a random FSBA are that UBA may reflect an average value over time, ease of sample collection, and lack of interference from oral ursodiol administration.
• UBAs are normalized with urine creatinine (Cr), and values are expressed as UBA/Cr (μmol/mg) × 100. Values greater than 7.3 are abnormal in dogs. Values greater than 4.4 are abnormal in cats.
• Timing of urine collection to the 4- to 8-hour post-prandial period may improve diagnostic performance, particularly in dogs with congenital portosystemic shunting where sensitivity of UBA (taken 4 to 8 hours after eating) was 100% compared with 84% for FSBA and 98% for PPSBA.
Blood Ammonia Concentration
• Measurement of blood ammonia concentration primarily is indicated to document HE. However, normal values do not exclude this diagnosis, because other toxins can contribute to the encephalopathy.
• Portosystemic shunting (congenital or acquired) is the most common mechanism of hyperammonemia, but severe, diffuse hepatic disease (especially acute hepatic necrosis) also increases blood ammonia concentrations.
• Blood ammonia values have poor sensitivity in detecting other types of hepatobiliary disease without portosystemic shunting.
• Blood ammonia concentration is not a suitable screening test for congenital portosystemic shunt in young Irish wolfhounds since a transient metabolic hyperammonemia unassociated with liver disease occurs in this breed.
Ammonia Tolerance Test
• The test is performed in a fasted dog by giving 100 mg/kg of ammonium chloride (do not exceed a total dose of 3 g), either as a dilute solution by stomach tube or as a powder in a gelatin capsule.
• Take a heparinized blood sample before and 30 minutes (stomach tube method) or 45 minutes (capsule method) after administering the ammonium chloride. Vomiting may occur but does not invalidate the test.
• In normal dogs, there is no increase in blood ammonia concentration or a mild increase (<2 times greater than baseline). In dogs with portosystemic shunting, results are consistently abnormal (up to 10 times baseline values).
• The ATT and paired FSBA and PPSBA tests have equal sensitivity in detecting portosystemic shunting. Consequently, the SBA testing has largely replaced blood ammonia and ATT. Paired FSBA and PPSBA provide a better screening test because it detects a broader range of hepatobiliary disorders, and bile acids are stable, permitting routine laboratory analysis.
Parameters of Hemostasis
• Mechanisms of excessive bleeding associated with hepatobiliary disease include primary failure of hepatocytes to synthesize clotting factors, DIC, and vitamin K deficiency. Vitamin K deficiency in hepatobiliary disease is usually caused by malabsorption of vitamin K secondary to complete bile duct obstruction. However, a vitamin K–responsive coagulopathy may sometimes be detected in dogs and cats with severe hepatic insufficiency, possibly due to marked intrahepatic cholestasis causing vitamin K malabsorption or the inability of the liver to reactivate vitamin K from its inactive (epoxide) form.
• Clinical evidence of bleeding secondary to hepatobiliary disease is uncommon; however, the frequency of abnormal coagulation tests is much higher.
Coagulation Tests
• Measure prothrombin time (PT) to evaluate the extrinsic coagulation system and activated partial thromboplastin time (APTT) to evaluate the intrinsic coagulation system. These tests can be abnormal in the presence of liver disease. Activated coagulation time also can be used as a rapid screening test for abnormalities of the intrinsic coagulation system. For further discussion of these tests, see Chapter 23.
• The PIVKA (proteins induced by vitamin K absence) clotting time is a more sensitive test than PT or APTT to detect bleeding tendencies in dogs and cats with liver disease. Normalization of PIVKA clotting time may occur after treatment with vitamin K1.
Abdominal Fluid Analysis
• Ascitic fluid that accumulates secondary to liver disease and hypoalbuminemia is usually a transudate. With hepatic venous congestion from vena caval obstruction or cardiac causes, the fluid typically is a modified transudate with protein concentration > 2.5 g/dl.
• Rupture of the biliary tract is associated with bile peritonitis. Grossly, the abdominal fluid appears yellow or green. Chemical tests for bilirubin are positive, and concentrations of bilirubin are higher in abdominal fluid than in serum. Cytologic examination reveals a mixed inflammatory infiltrate and bile-laden macrophages. Bacteria may be seen if bile peritonitis is complicated by sepsis.
Diagnostic Imaging
Survey Radiography
Abdominal radiographs are useful to evaluate for the following:
• Altered tissue characteristics such as mineralized hepatic densities (choleliths) and radiolucencies (abscesses)
If hepatic neoplasia is suspected, take thoracic films to evaluate for pulmonary metastases.
Ultrasonography
• Detect focal parenchymal abnormalities such as masses, abscesses, cysts, and regenerative nodules. The ultrasonographic appearance of these focal lesions often is similar, and biopsy is required for differentiation.
• Investigate disorders of the biliary tract and gallbladder, such as biliary obstruction, cholelithiasis, or gallbladder mucocele.
• Detect vascular lesions such as portosystemic shunts, hepatic arteriovenous fistulas, and hepatic venous congestion.
• Identify abnormalities in other abdominal organs that may be a cause or effect of liver disease (e.g., pancreas, spleen, kidneys, bladder, GI tract, adrenal glands, and lymph nodes). For example, urate or uric acid urolithiasis may be detected in animals with portosystemic shunts, the primary tumor may be identified in animals with hepatic metastases, and identification of adrenal gland enlargement may aid the diagnosis of steroid hepatopathy.
Liver Cytology
• Cytology of the liver is most useful if the pathologic process is diffuse and architectural relationships (which can be obtained only by histopathology) are not essential to the diagnosis. Examples include vacuolar hepatopathies such as feline hepatic lipidosis, diffuse hepatic neoplasia, and liver disease associated with infectious agents such as histoplasmosis.
• In cats, primary liver diseases such as lymphoma and cholangitis may be accompanied by hepatic vacuolar changes. These cats may be misdiagnosed as idiopathic hepatic lipidosis if cytology only reflects the vacuolated hepatocytes.
Liver Biopsy
Biopsy Methods
Ultrasound-Guided Needle Biopsy
• With ultrasound-guided biopsy, it is possible to obtain tissue from focal lesions (whether superficial or deep within the hepatic parenchyma), avoid structures adjacent to the liver, and monitor post-biopsy bleeding.
• Ultrasound-guided biopsy may be difficult if the liver is small or the ultrasonographer lacks experience.
Laparoscopy
• It is preferable to ultrasound-guided biopsy when excess bleeding is anticipated and to laparotomy when delayed wound healing (hypoalbuminemia) is anticipated.
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