Liver Disease
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Go to: Microhepatia and GI ulceration
Go to: Liver enzymes and tests
Go to: Weight loss, anorexia, abdominal pain
Go to: Cushing's Disease Consensus Statement
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Liver Disease
Hepatic disease may be heralded by relatively specific signs (e.g., hepatomegaly, microhepatia, icterus, ascites, hepatic encephalopathy associated with meals) or may be associated with nonspecific signs (e.g., depression, weight loss, anorexia, vomiting). The latter are common presenting complaints of many diseases, which is why serum biochemistry profiling is indicated in patients with chronic signs or evidence of systemic disease. It is important to note that no consistent signs or laboratory abnormalities are found in all patients with hepatic disease. When screening for hepatic disease, one should request at least CBC, serum ALT, SAP, gamma-glutamyl transpeptidase (GGT), total bilirubin, albumin, cholesterol, BUN, glucose, urinalysis, and abdominal imaging. Hepatic function tests (bile acids, ammonia tolerance, clotting times, and others) ultrasonographic examination, hepatic biopsy, or contrast angiography and portography is usually necessary for definitive diagnosis. Abnormalities in hepatic-specific enzymes may result from primary hepatic disease but also occur because of secondary hepatic involvement from a primary nonhepatic disease (e.g., glucocorticoid hepatopathy, inflammatory bowel disease, pancreatitis). After identifying abnormalities in ALT, aspartate transferase (AST), SAP, or GGT, one should investigate first for a primary nonhepatic disease, because nonhepatic disease is the most common cause of increased values. In such cases the liver usually has reactive but reversible degenerative changes. Laboratory tests should be used for two main purposes: (1) to identify the presence of hepatic disease and (2) to determine if a biopsy or radiographic contrast procedure is indicated.
Microhepatia: Small Liver
A small liver suggests atrophy (due to portosystemic shunts, hepatic arteriovenous [AV] fistulas), fibrosis and cirrhosis, or diffuse massive hepatic necrosis (Figure 9-5 ). Radiographically, hepatic atrophy tends to be characterized by sharp borders as opposed to the rounded or blunted hepatic margins typically associated with fibrosis and cirrhosis. Some patients with primary hepatic fibrosis severe enough to cause portal hypertension also have sharp hepatic margins, however. Many patients with marked hepatic atrophy due to portosystemic shunting are relatively young (<1 to 2 years) and have had signs of hepatic disease since (or before) weaning, whereas most patients with cirrhosis are middle-aged or older and clearly have late onset of clinical signs. Hepatic AV fistula is an uncommon cause of microhepatia, but it is usually diagnosed in dogs less than 2 years of age. However, some dogs are first diagnosed as having a single congenital portosystemic shunt when they are more than 10 years old. Likewise, although acquired portosystemic shunts are classically thought of as occurring in older dogs, they can be diagnosed in dogs less than 6 months old.
Diagnostic approach to altered hepatic shape or size in dogs and cats.
Hepatic atrophy causes abnormalities in hepatic function tests (e.g., bile acids, ammonia, or ammonium chloride tolerance test) but may yield normal or abnormal ALT, SAP, BUN, and serum albumin. A single normal or abnormal hepatic function test result does not mean that other hepatic function tests will have similar results. Preprandial and postprandial serum bile acid concentrations are sensitive function tests. (NOTE: Cholestatic diseases also increase bile acids; therefore, bile acids are not a “pure” test of hepatic function.) However, if hepatic disease is strongly suspected and the serum bile acid concentrations are not as high as anticipated, one should not hesitate to perform other tests to characterize the liver. If hepatic atrophy is likely, abdominal ultrasonography, contrast portography, hepatic biopsy, or a combination of these might be considered.
Small livers with clearly rounded or blunt hepatic margins are usually cirrhotic. Significant increases in serum ALT and SAP are often present, but some dogs with marked hepatic cirrhosis have normal hepatic enzymes. Serum albumin and BUN are more variable. If cirrhosis appears likely, a biopsy is indicated. Most cirrhotic livers can be identified grossly by their nodular or “cobblestone” appearance. However, significant fibrosis can be present without major gross changes, and severe nodular hyperplasia may resemble a cirrhotic liver. Acquired multiple shunts visible at laparoscopy or laparotomy are usually due to cirrhosis but can be secondary to congenital hepatic AV fistula, venoocclusive disease, or portal vein obstruction. If the liver is not clearly cirrhotic or fibrotic, a mesenteric venoportogram may be indicated in patients with acquired shunting.
Hepatomegaly: Enlarged Liver
Focal or asymmetric hepatic enlargement generally necessitates further laboratory investigation, imaging, and possibly biopsy. Neoplasia is a prominent but not invariable cause of focal hepatomegaly. The magnitude of the enlargement is not prognostic.
Generalized hepatomegaly necessitates careful clinicopathologic evaluation. Hepatomegaly may be the result of primary or secondary hepatic disease. Diagnosis may be confirmed with a history of exposure to certain toxins (TABLE 9-6, TABLE 9-7 ) or diagnosis of a systemic disease (e.g., hyperadrenocorticism) known to affect the liver. Changes in ALT, SAP, hepatic function tests, and hepatic size, although suggestive of hepatic disease, are not diagnostic of specific entities. This is true even in breeds with specific predispositions (e.g., Doberman pinschers, Bedlington terriers). Changes in the SAP or serum ALT may also be the result of primary nonhepatic disease (e.g., hyperadrenocorticism, inflammatory bowel disease, diabetes mellitus, heart failure). A definitive diagnosis usually requires hepatic biopsy. The clinician should first seek to rule out nonhepatic causes of secondary hepatic dysfunction. Hepatic biopsy should be considered in patients with obviously significant hepatic disease, those that do not have hyperadrenocorticism, and those that have persistent (more than 1 month) changes in serum ALT or SAP consistent with chronic or progressive hepatic disease or abnormal hepatic function tests (see Figure 9-5). It is not always possible to make these distinctions accurately; therefore, whenever hepatic biopsy is performed via laparotomy or laparoscopy, the rest of the abdomen should be explored and other organs sampled if the clinician doubts their involvement. Fine-needle aspirates with cytology are sometimes useful in detecting diffuse hepatic infiltrative disease and hepatic lipidosis (see Color Plate 5E); however, fine-needle aspirates (even when guided by ultrasound) often miss infiltrative processes, and a negative cytologic finding never excludes an infiltrative disease in the liver. In general, laparoscopy allows for much superior hepatic biopsies compared with ultrasound-guided biopsies.
TABLE 9-6
Drugs That Have Been Documented or Suspected to Cause Increased Alanine Aminotransferase (ALT) Levels Due to Hepatic Disease
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NOTE: These drugs do not reliably cause hepatic disease. In a patient with an increased ALT that is receiving one of these drugs, the medication probably should be stopped, if possible, and the ALT rechecked 2 to 4 weeks later. Those drugs that most reliably increase ALT are marked (important). The other drugs are less consistent but may still cause severe hepatic disease. Almost any drug could cause an increased ALT in a particular patient.
TABLE 9-7
Drugs That Have Been Documented or Suspected to Cause Cholestasis or Hepatic Enzyme Induction Resulting in Increased Serum Alkaline Phosphatase (SAP) Levels
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NOTE: Those drugs that most reliably increase SAP are marked (important). The other drugs are less consistent.
Hepatic Encephalopathy
Abnormal behavior, sometimes associated with eating, may be caused by hepatic encephalopathy, although hypoglycemia, primary CNS disease, and epilepsy must also be considered. Whenever possible, glucose should be measured on blood obtained during an episode. Evaluation of hepatic function is indicated in patients with behavioral changes, transient blindness, seizures, coma, or vague CNS abnormalities. Congenital (e.g., portosystemic shunt) and severe acquired hepatic disease (e.g., cirrhosis) may cause encephalopathy. Routine biochemical profiling may be suggestive, but hepatic function testing is mandatory, because these diseases may not significantly change serum ALT, SAP, albumin, BUN, glucose, or bilirubin determinations. Resting plasma ammonia concentrations are meaningful only if they are increased. A patient in an episode of hepatic encephalopathy may have increased or normal resting plasma ammonia concentrations. Ammonia tolerance testing (ATT) and pre- and postprandial serum bile acid concentrations appear to be the most sensitive and specific tests for hepatic dysfunction that causes hepatic encephalopathy. A very rare congenital urea cycle enzyme deficiency may cause hepatic encephalopathy and hyperammonemia without affecting enzymes or bile acids. Analysis of urea cycle enzymes in biopsy samples is necessary for diagnosis.
Icterus
Icterus is detected at physical examination or when serum or plasma is inspected at the laboratory. Hyperbilirubinemia always denotes hepatobiliary or hematopoietic disease (Figure 9-6 ). Hepatic and hematopoietic diseases are not always associated with icterus, and disease in either system may be secondary to other disorders. The presence or absence of icterus is not diagnostic or prognostic. Sepsis, pancreatitis, and inflammatory bowel disease sometimes cause secondary hepatic dysfunction that may include icterus.
Diagnostic approach to hyperbilirubinemia in dogs and cats. CBC, Complete blood count; RBC, red blood cell; FDP, fibrin degradation products.
TOTAL SERUM BILIRUBIN
Occasional Indications
Icterus (on either physical examination or inspection of nonhemolyzed serum or plasma), bilirubinuria (any amount in a cat or significant amounts in a dog), or suspected hepatic disease that is not apparent on other tests. The sclera have detectable icterus when the serum bilirubin is greater than 3 to 4 mg/dl, and the plasma is icteric when the serum bilirubin is greater than 1.5 to 2 mg/dl.
NOTE:
Icterus is absent in many animals (especially dogs) with hepatic disease. Serum bilirubin is not a sensitive test for hepatic disease.
Measurement of direct (conjugated) and indirect (unconjugated) bilirubin fractions is not useful and should not be done. Hemolytic, hepatic, and biliary tract diseases have unpredictable variation in the amount of each fraction. Other tests are required to identify the cause of hyperbilirubinemia.
Analysis
Measured in serum or heparinized plasma by spectrophotometric and dry reagent methods. The latter require dilutions if the bilirubin is greater than 7.5mg/dl. Bilirubin is stable at 4°C for 7 days if not exposed to bright light. Measurement of urine bilirubin is discussed in Chapter 7.
Normal Values
Dogs, less than 1.0 mg/dl; cats, less than 1.0 mg/dl.
Danger Values
Dogs, uncertain, but values greater than 20 mg/dl cause concern (i.e., kernicterus); cats, unknown.
Artifacts
Exposure to bright sunlight or fluorescent lighting can decrease bilirubin by 50% per hour. See Introduction to Serum Chemistries.
Drug Therapy That May Alter Serum Bilirubin
Decreased bilirubin may be caused by drugs that cause hepatic enzyme induction (e.g., phenobarbital). Increased bilirubin may be the result of drugs causing hemolytic anemia (Table 9-8 ) or acute hepatic necrosis (see Table 9-6).
TABLE 9-8
Selected Substances That Have Been Documented or Suspected to Cause Hemolytic Anemia
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NOTE: These substances do not always cause anemia, but they have the potential and should be withdrawn, if possible, in patients with hemolytic anemia.
Causes of Hypobilirubinemia
Do not exist.
Causes of Hyperbilirubinemia
Hemolytic disease and hepatobiliary disease are the two main causes (see Figure 9-6). A CBC should be determined in every icteric patient to help rule out hemolytic disease. RBC numbers must decrease rapidly and significantly to cause clinical icterus. Very regenerative anemias may suggest that icterus is due to immune-mediated hemolytic anemia (IMHA). Reticulocytosis, hemoglobinemia, hemoglobinuria, erythrocytic autoagglutination, spherocytosis, positive Coombs' test results, splenomegaly, or hepatomegaly are often present. See Chapter 3 for further discussion of IHA and other regenerative anemias (e.g., Heinz body, zinc intoxication, Haemobartonella). Bilirubinuria theoretically should be absent in hemolytic disease but is often present in IHA because canine kidneys conjugate bilirubin. The clinician must not be misled by increases in ALT because severe, acute hemolytic anemia may cause increased ALT (ostensibly caused by acute hepatic hypoxia).
Severe hepatic disease (especially acute necrosis) is sometimes accompanied by DIC and subsequent hemolytic anemia. These cases may be difficult to distinguish from IHA. However, anemia caused by DIC is usually not as regenerative as in IHA; in addition, the presence of RBC fragments, thrombocytopenia, increased fibrin degradation products (FDP), decreased antithrombin III, prolonged clotting time, and abnormal hepatic function tests usually allows differentiation, as do vomiting, abdominal pain, and encephalopathy when present.
Dogs and cats often have relatively severe hepatic disease before icterus is observed; however, the magnitude of the total serum bilirubin is not prognostic or diagnostic. Secondary hepatic disease (reactive disease or so-called bystander phenomenon as the result of septicemia, toxemia, or inflammation) may have icterus similar to that occurring in primary hepatic disease. Certain bacterial endotoxins and acute-phase inflammatory mediators are thought to alter normal bilirubin metabolism and cause increases in total bilirubin concentrations.
Most feline hepatic diseases cause icterus; the most common conditions include hepatic lipidosis, cholangitis and cholangiohepatitis, hepatic lymphoma, and FIP. Icterus in cats is an indication for CBC and a serum biochemistry panel. Icterus in cats that is not caused by hemolysis usually indicates a hepatic biopsy, because most of these cats have primary hepatic disease. Biopsy is necessary to differentiate causes and institute specific treatment.
Common causes of nonhemolytic icterus in dogs include pancreatitis obstructing the bile duct, cholecystitis, chronic hepatitis, hepatic lymphoma, acute hepatic necrosis, hepatic cirrhosis, and intrahepatic cholestasis. Icterus in dogs is an indication for CBC and a serum biochemistry panel (to include at least ALT, SAP, BUN, cholesterol, and albumin). Imaging (radiographs, ultrasonography, or both) is indicated to help determine if primary hepatic disease or biliary tract obstruction exists. If primary hepatic disease is diagnosed, hepatic biopsy is usually indicated. If pancreatitis is present, surgery is not indicated unless a chronic bile duct obstruction necessitates bypassing the common bile duct with a cholecystoduodenostomy (rarely needed) or a pancreatic abscess is present. If coexisting extrahepatic disease is found, it should be investigated.
Go to: Regurgitation and vomiting
Go to: Liver enzymes and tests
Go to: Weight loss, anorexia, abdominal pain
Go to: Cushing's Disease Consensus Statement
Reference:
Published online 2009 May 15. doi: 10.1016/B0-72-168903-5/50014-8
Michael D. Willard and David C. Twedt