Chapter 71 Diseases of the Liver and Biliary Tract
DIAGNOSTIC STRATEGY FOR LIVER DISEASE
The liver has many diverse functions related to hepatic blood flow; protein, carbohydrate, and fat metabolism; detoxification and excretion of drugs and toxins; and formation and elimination of bile. Consequently, the clinical and laboratory abnormalities associated with liver failure are diverse.
Overview of the Diagnostic Strategy
Acute versus Chronic Disease
The clinical approach and management of patients with hepatic disease is dictated largely by the acute versus chronic nature of the hepatic disorder. Historical, physical, laboratory, and radiographic findings may suggest whether the hepatic disease is acute or chronic, but hepatic biopsy often is required for definitive evaluation. Classifying a disorder as acute or chronic has diagnostic, therapeutic, and prognostic implications.
Clinical signs of liver disease include those typically associated with hepatic dysfunction, such as jaundice, hepatic encephalopathy (HE), ascites, and excessive bleeding, and nonspecific signs such as vomiting, diarrhea, anorexia, lethargy, and weight loss, which overlap with signs of other body system disorders.
Polyuria and Polydipsia
Signs of Abnormal Bilirubin Excretion
Signalment and History
Chronic hepatic disease can be associated with recent onset of clinical signs and can initially seem to be an acute disease. However, persisting signs of weight loss and ascites and diagnostic findings of hypoalbuminemia and microhepatica are indicative of chronic hepatic disease.
Skin and Mucous Membranes
Palpate the abdomen carefully. The normal liver can be difficult to palpate in dogs and cats, and the edges are normally sharp, not rounded.
Perform a neurologic examination in animals with a history of neurologic signs. With HE, the neurologic examination may be normal or suggestive of diffuse cerebral disease (e.g., depression and dementia, disorientation, pacing, circling, head pressing, hypersalivation, seizures, or coma).
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:
Findings consistent with liver disease on routine laboratory tests are described below.
Complete Blood Count
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).
Figure 71-1 With hepatocyte injury, leakage of alanine aminotransferase (ALT) from the cytoplasm results in increased serum activity. Aspartate aminotransferase (AST) is primarily associated with mitochondria but is also present in the cytoplasm. Release of AST from the mitochondria requires a severe insult. Thus, with hepatocyte injury, ALT is more readily released and its activity level will usually be higher than that of serum AST.
Figure 71-2 Impaired bile flow (cholestasis) causes increased synthesis of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). ALP is a sensitive indicator of cholestasis in dogs but is less sensitive in cats (see text). With cholestatic disorders, increased ALP activity precedes hyperbilirubinemia. ALP and GGT lack specificity in differentiating between intrahepatic and extrahepatic cholestasis.
Many systemic diseases can secondarily affect the liver (reactive hepatopathy), causing increased liver enzyme activity, but these are not necessarily associated with clinical liver disease. For example, feline hyperthyroidism is commonly associated with increased liver enzyme activity without significant hepatic dysfunction.
Liver enzymes do not evaluate liver function. Thus, severe hepatic dysfunction may coexist with normal liver enzyme activity; conversely, increased liver enzyme activity may be detected in animals without significant hepatic dysfunction.
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.
Hepatocyte injury is associated with increased AST activity secondary to leakage from mitochondria and cytoplasm of hepatocytes (see Fig. 71-1).
Increased AST activity associated with hepatic injury generally parallels but is less than the increase in ALT activity, and CK is normal. Increased AST activity due to skeletal muscle injury is associated with increased CK activity and normal or mildly increased ALT activity.
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.
Hypercortisolism caused by glucocorticoid therapy or hyperadrenocorticism (Cushing’s disease) is the most common pathologic cause of increased serum ALP activity in dogs; it is usually attributed to an increase in CIALP.
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).
Other Biochemical Tests
Numerous biochemical tests can be altered by liver disease, including serum bilirubin, albumin, globulin, urea nitrogen, glucose, and cholesterol. Many of these parameters reflect some aspect of liver function; however, they lack sensitivity or specificity for liver disease.
Increased serum bilirubin concentration occurs secondary to hemolysis or cholestasis. Evaluate for underlying hemolytic disorders by performing a complete blood count (CBC) to detect anemia.
Albumin is synthesized exclusively by the liver. Because of a large reserve capacity for albumin production, hypoalbuminemia does not occur until the functional hepatic mass is reduced 70% to 80%.
Hypoalbuminemia associated with hepatic disease implies chronicity because of the long half-life of albumin.
Blood Urea Nitrogen
Blood urea nitrogen (BUN) concentration may be decreased secondary to liver disease because the liver is responsible for converting ammonia to urea. However, many non-hepatic factors (e.g., PU/PD, fluid diuresis, and low-protein diet) can also decrease BUN levels.
Hypoglycemia may occur secondary to hepatic dysfunction because of impaired hepatic gluconeogenesis, decreased hepatic glycogen stores, and decreased hepatic insulin degradation. However, because <30% of liver function is sufficient to maintain euglycemia, hypoglycemia is an insensitive indicator of hepatic function.
Serum electrolyte changes secondary to liver disease are variable.
Liver Function Tests
Liver function tests can document clinically significant hepatic dysfunction when liver disease is suspected, based on historical, clinical, laboratory, and radiographic findings. SBA determinations have largely replaced the use of organic anion dyes such as sulfobromophthalein (Bromsulphalein) and indocyanine green (ICG). Blood ammonia concentration and ammonia tolerance tests can specifically evaluate the portal circulation (for portosystemic shunts) and detect HE.
The test of choice for clinical evaluation of liver function is the combined fasting and 2-hour postprandial SBA test.
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.
Figure 71-3 A, Bile acids are synthesized in the liver, secreted into the biliary system, and stored in the gallbladder during fasting. With ingestion of a meal, cholecystokinin release stimulates gallbladder contraction and entry of bile acids into the intestinal tract. Bile acids are efficiently reabsorbed in the distal ileum and carried in the portal blood back to the liver, thus completing the enterohepatic circulation. In the healthy animal, the liver removes 90% to 95% of bile acids from the portal circulation during the first pass of the enterohepatic circulation. This allows only small amounts of bile acids to escape to the systemic circulation. Normal serum concentrations are therefore low (fasting < 15μmol/L, postprandial < 25μmol/L). B, Hepatocellular dysfunction or cholestasis interferes with hepatic uptake, storage, and secretion of bile acids. Thus, impaired extraction of bile acids from the portal blood results in increased serum bile acid concentrations. With portosystemic shunting, bile acids in the portal blood are diverted directly into the systemic circulation.
Fasting Serum Bile Acid Concentration
A fasting serum bile acid (FSBA) concentration obtained after a 12-hour fast is a sensitive, specific measure of hepatobiliary function in dogs and cats. Normal FSBA values in dogs and cats are <20μmol/L. When concentrations exceed 30μmol/L, a liver biopsy may be warranted to evaluate the underlying liver disease.
Postprandial Serum Bile Acid Concentration
Postprandial serum bile acid (PPSBA) concentration is an endogenous challenge test of liver function. Whether PPSBA concentration is a more useful diagnostic test than FSBA concentration remains unclear. In dogs, similar information is provided by either test in most hepatobiliary disorders. Notable exceptions include dogs with portosystemic shunts or cirrhosis, because with these disorders, FSBA can be in the normal range. In cats, the diagnostic efficacy of PPSBA exceeds that of FSBA for all hepatic disorders, including portosystemic shunts. For best diagnostic utility, paired FSBA and 2-hour PPSBA is recommended. To perform the PPSBA concentration test, take the following steps:
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.
Blood Ammonia Concentration
Ammonia is metabolized by the liver, and normal plasma concentrations are low. Measurement of ammonia is technically difficult, and appropriate sample handling requires heparinized blood samples to be stored immediately on ice, cold-centrifuged, and assayed as soon as possible.
Ammonia Tolerance Test
This is a more sensitive test than blood ammonia concentration for documenting portosystemic shunting. However, the ammonia tolerance test (ATT) is contraindicated if resting ammonia levels are already increased, because no further diagnostic information will be obtained and performing an ATT can cause signs of HE. Note: The ATT is not recommended for use in cats.
Protein C, an anticoagulant protein synthesized in the liver, has been investigated as a clinical marker of liver disease. Preliminary results show decreased protein C concentrations in 100% of dogs with liver failure, 98% of dogs with portosystemic shunt, and 30% of dogs with hepatic microvascular dysplasia. The role of protein C in the detection of liver disease awaits further clinical studies.
Parameters of Hemostasis
The liver plays a central role in the coagulation and fibrinolytic systems. The liver is responsible for synthesis of all coagulation factors except factor 8, von Willebrand factor. Fibrinogen, antithrombin, and protein C are all synthesized in the liver and can be decreased with hepatic dysfunction. Activated coagulation factors and fibrinolytic enzymes are also cleared by the liver.
Thrombocytopenia and Platelet Dysfunction
Blood Gas Analysis
Various acid-base imbalances may occur secondary to liver disease, including respiratory alkalosis, metabolic alkalosis, metabolic acidosis, and mixed acid-base disturbances.
Abdominal Fluid Analysis
Abdominal radiographs are useful to evaluate for the following:
If hepatic neoplasia is suspected, take thoracic films to evaluate for pulmonary metastases.
Ultrasonography can be used to image the liver non-invasively, especially when abdominal effusion precludes survey radiographic evaluation. A normal ultrasonographic appearance of the liver does not eliminate the possibility of significant hepatic pathology; however, ultrasonography is diagnostically useful to achieve the following:
Fine-needle aspiration (FNA) of the liver for cytology is commonly performed because it is easy and safe, does not require sedation or anesthesia, and provides rapid preliminary information. However, the diagnostic accuracy of cytology versus histopathology of the liver is controversial. Studies suggest a lack of correlation exists as much as 50% of the time. Cytology of impression smears of liver biopsy tissue correlates better than samples obtained by fine-needle aspirate.
Liver biopsy often is required to definitively characterize the nature and severity of hepatic disease, to differentiate acute from chronic disorders, and to assess response to therapy. Selection of the best procedure for obtaining a liver biopsy depends on numerous factors, including liver size, presence of coagulopathy, diffuse versus focal hepatic lesions, presence of biliary tract obstruction, presence of other intra-abdominal abnormalities, likelihood of surgical resection of a mass, tolerance of general anesthesia, available equipment, and expertise of the clinician.
Perform a hemostasis screen prior to liver biopsy to detect coagulopathy. After the biopsy is performed, monitor for bleeding from the biopsy site.
Ultrasound-Guided Needle Biopsy
This technique is the most common percutaneous method used for liver biopsy. However, it is dependent on the availability of equipment and clinician expertise.
Laparoscopy provides direct visualization of the liver and adjacent structures such as the pancreas and extrahepatic biliary tract. Biopsies also are obtained under direct visualization.