5

Evaluation of Liver Function: Introduction

Several biochemical tests are useful in the evaluation and management of patients with hepatic dysfunction. These tests can be used to (1) detect the presence of liver disease, (2) distinguish among different types of liver disorders, (3) gauge the extent of known liver damage, and (4) follow the response to treatment. Liver tests have shortcomings. They can be normal in patients with serious liver disease and abnormal in patients with diseases that do not affect the liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest a general category of liver disease, such as hepatocellular or cholestatic, which then further directs the evaluation. The liver carries out thousands of biochemical functions, most of which cannot be easily measured by blood tests. Laboratory tests measure only a limited number of these functions. In fact, many tests, such as the aminotransferases or alkaline phosphatase, do not measure liver function at all. Rather, they detect liver cell damage or interference with bile flow. Thus, no one test enables the clinician to accurately assess the liver's total functional capacity. To increase both the sensitivity and the specificity of laboratory tests in the detection of liver disease, it is best to use them as a battery. Those tests usually employed in clinical practice include the bilirubin, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests. When more than one of these tests provide abnormal findings, or the findings are persistently abnormal on serial determinations, the probability of liver disease is high. When all test results are normal, the probability of missing occult liver disease is low. When evaluating patients with liver disorders, it is helpful to group these tests into general categories. The classification we have found most useful is given in the following sections.

Tests Based on Detoxification and Excretory Functions

Serum Bilirubin See also Chap. 38. Bilirubin, a breakdown product of the porphyrin ring of heme-containing proteins, is found in the blood in two fractions—conjugated and unconjugated. The unconjugated fraction, also termed the indirect fraction, is insoluble in water and is bound to albumin in the blood. The conjugated (direct) bilirubin fraction is water soluble and can therefore be excreted by the kidney. When measured by the original van den Bergh method, the normal total serum bilirubin concentration is <17 mol/L (1 mg/dL). Up to 30%, or 5.1 mol/L (0.3 mg/dL), of the total is direct-reacting (or conjugated) bilirubin. Elevation of the unconjugated fraction of bilirubin is rarely due to liver disease. An isolated elevation of unconjugated bilirubin is seen primarily in hemolytic disorders and in a number of genetic conditions such as Crigler-Najjar and Gilbert's syndromes (Chap. 38). Isolated unconjugated hyperbilirubinemia (bilirubin elevated, but less than 15% direct) should prompt a workup for hemolysis (Fig. 283-1). In the absence of hemolysis, an isolated unconjugated hyperbilirubinemia in an otherwise healthy patient can be attributed to Gilbert's syndrome and no further evaluation is required.   Figure 283-1 Algorithm for the evaluation of chronically abnormal liver tests. ERCP, endoscopic retrograde cholangiopancreatography; CT, computed tomography; AMA, antimitochondrial antibody; ANA, antinuclear antibody; SPEP, serum protein electrophoresis; TIBC, total iron-binding capacity; GGT, gamma glutamyl transpeptidase. In contrast, conjugated hyperbilirubinemia almost always implies liver or biliary tract disease. The rate-limiting step in bilirubin metabolism is not conjugation of bilirubin, but rather the transport of conjugated bilirubin into the bile canaliculi. Thus, elevation of the conjugated fraction may be seen in any type of liver disease. In most liver diseases, both conjugated and unconjugated fractions of the bilirubin tend to be elevated. Except in the presence of a purely unconjugated hyperbilirubinemia, fractionation of the bilirubin is rarely helpful in determining the cause of jaundice. Urine Bilirubin Unconjugated bilirubin always binds to albumin in the serum and is not filtered by the kidney. Therefore, any bilirubin found in the urine is conjugated bilirubin; the presence of bilirubinuria implies the presence of liver disease. A urine dipstick test can theoretically give the same information as fractionation of the serum bilirubin. This test is almost 100% accurate. Phenothiazines may give a false-positive reading with the Ictotest tablet. Blood Ammonia Ammonia is produced in the body during normal protein metabolism and by intestinal bacteria, primarily those in the colon. The liver plays a role in the detoxification of ammonia by converting it to urea, which is excreted by the kidneys. Striated muscle also plays a role in detoxification of ammonia, which is combined with glutamic acid to form glutamine. Patients with advanced liver disease typically have significant muscle wasting, which likely contributes to hyperammonemia in these patients. Some physicians use the blood ammonia for detecting encephalopathy or for monitoring hepatic synthetic function, although its use for either of these indications has problems. There is very poor correlation between either the presence or the degree of acute encephalopathy and elevation of blood ammonia; it can be occasionally useful for identifying the occult liver disease in patients with mental status changes. There is also a poor correlation of the blood serum ammonia and hepatic function. The ammonia can be elevated in patients with severe portal hypertension and portal blood shunting around the liver even in the presence of normal or near normal hepatic function. Serum Enzymes The liver contains thousands of enzymes, some of which are also present in the serum in very low concentrations. These enzymes have no known function in the serum and behave like other serum proteins. They are distributed in the plasma and in interstitial fluid and have characteristic half-lives, usually measured in days. Very little is known about the catabolism of serum enzymes, although they are probably cleared by cells in the reticuloendothelial system. The elevation of a given enzyme activity in the serum is thought to primarily reflect its increased rate of entrance into serum from damaged liver cells. Serum enzyme tests can be grouped into three categories: (1) enzymes whose elevation in serum reflects damage to hepatocytes, (2) enzymes whose elevation in serum reflects cholestasis, and (3) enzyme tests that do not fit precisely into either pattern. Enzymes That Reflect Damage to Hepatocytes The aminotransferases (transaminases) are sensitive indicators of liver cell injury and are most helpful in recognizing acute hepatocellular diseases such as hepatitis. They include the aspartate aminotransferase (AST) and the alanine aminotransferase (ALT). AST is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes in decreasing order of concentration. ALT is found primarily in the liver. The aminotransferases are normally present in the serumin low concentrations. These enzymes are released into the blood in greater amounts when there is damage to the liver cell membrane resulting in increased permeability. Liver cell necrosis is not required for the release of the aminotransferases, and there is a poor correlation between the degree of liver cell damage and the level of the aminotransferases. Thus, the absolute elevation of the aminotransferases is of no prognostic significance in acute hepatocellular disorders. Any type of liver cell injury can cause modest elevations in the serum aminotransferases. Levels of up to 300 U/L are nonspecific and may be found in any type of liver disorder. Striking elevations—i.e., aminotransferases >1000 U/L—occur almost exclusively in disorders associated with extensive hepatocellular injury such as (1) viral hepatitis, (2) ischemic liver injury (prolonged hypotension or acute heart failure), or (3) toxin or drug-induced liver injury. The pattern of the aminotransferase elevation can be helpful diagnostically. In most acute hepatocellular disorders, the ALT is higher than or equal to the AST. An AST:ALT ratio > 2:1 is suggestive while a ratio > 3:1 is highly suggestive of alcoholic liver disease. The AST in alcoholic liver disease is rarely >300 U/L and the ALT is often normal. A low level of ALT in the serum is due to an alcohol-induced deficiency of pyridoxal phosphate. The aminotransferases are usually not greatly elevated in obstructive jaundice. One notable exception occurs during the acute phase of biliary obstruction caused by the passage of a gallstone into the common bile duct. In this setting, the aminotransferases can briefly be in the 1000 to 2000 U/L range. However, aminotransferase levels decrease quickly, and the liver function tests rapidly evolve into one typical of cholestasis. Enzymes That Reflect Cholestasis The activities of three enzymes—alkaline phosphatase, 5'-nucleotidase, and gamma glutamyl transpeptidase (GGT)—are usually elevated in cholestasis. Alkaline phosphatase and 5'-nucleotidase are found in or near the bile canalicular membrane of hepatocytes, while GGT is located in the endoplasmic reticulum and in bile duct epithelial cells. Reflecting its more diffuse localization in the liver, GGT elevation in serum is less specific for cholestasis than are elevations of alkaline phosphatase or 5'-nucleotidase. Some have advocated the use of GGT to identify patients with occult alcohol use. Its lack of specificity makes its use in this setting questionable. The normal serum alkaline phosphatase consists of many distinct isoenzymes found in the liver, bone, placenta, and, less commonly, small intestine. Patients over age 60 can have a mildly elevated alkaline phosphatase (1 to 1½ times normal), while individuals with blood types O and B can have an elevation of the serum alkaline phosphatase after eating a fatty meal due to the influx of intestinal alkaline phosphatase into the blood. It is also nonpathologically elevated in children and adolescents undergoing rapid bone growth because of bone alkaline phosphatase, and late in normal pregnancies due to the influx of placental alkaline phosphatase. Elevation of liver-derived alkaline phosphatase is not totally specific for cholestasis, and a less than threefold elevation can be seen in almost any type of liver disease. Alkaline phosphatase elevations greater than four times normal occur primarily in patients with cholestatic liver disorders, infiltrative liver diseases such as cancer, and bone conditions characterized by rapid bone turnover (e.g., Paget's disease). In bone diseases, the elevation is due to increased amounts of the bone isoenzymes. In liver diseases, the elevation is almost always due to increased amounts of the liver isoenzyme. If an elevated serum alkaline phosphatase is the only abnormal finding in an apparently healthy person, or if the degree of elevation is higher than expected in the clinical setting, identification of the source of elevated isoenzymes is helpful (Fig. 283-1). This problem can be approached in several ways. First, and most precise, is the fractionation of the alkaline phosphatase by electrophoresis. The second approach is based on the observation that alkaline phosphatases from individual tissues differ in susceptibility to inactivation by heat. The finding of an elevated serum alkaline phosphatase level in a patient with a heat-stable fraction strongly suggests that the placenta or a tumor is the source of the elevated enzyme in serum. Susceptibility to inactivation by heat increases, respectively, for the intestinal, liver, and bone alkaline phosphatases, bone being by far the most sensitive. The third, best substantiated, and most available approach involves the measurement of serum 5'-nucleotidase or GGT. These enzymes are rarely elevated in conditions other than liver disease. In the absence of jaundice or elevated aminotransferases, an elevated alkaline phosphatase of liver origin often, but not always, suggests early cholestasis and, less often, hepatic infiltration by tumor or granulomata. Other conditions that cause isolated elevations of the alkaline phosphatase include Hodgkin's disease, diabetes, hyperthyroidism, congestive heart failure, and inflammatory bowel disease. The level of serum alkaline phosphatase elevation is not helpful in distinguishing between intrahepatic and extrahepatic cholestasis. There is essentially no difference among the values found in obstructive jaundice due to cancer, common duct stone, sclerosing cholangitis, or bile duct stricture. Values are similarly increased in patients with intrahepatic cholestasis due to drug-induced hepatitis, primary biliary cirrhosis, rejection of transplanted livers, and, rarely, alcohol-induced steatonecrosis. Values are also greatly elevated in hepatobiliary disorders seen in patients with AIDS (e.g., AIDS cholangiopathy due to cytomegalovirus or cryptosporidial infection and tuberculosis with hepatic involvement).