ISOLATED ABNORMALITIES IN LIVER TEST RESULTS

A common clinical scenario is the unanticipated discovery of an abnormal liver test result, obtained when a bundle of tests has been done for other reasons. Most clinical laboratories offer bundled blood tests, which often contain all or most of the following:

• Bilirubin

• Aspartate transaminase (AST, formerly referred to as serum glutamic-oxaloacetic transaminase, SGOT)

• Alanine transaminase (ALT, formerly called serum glutamic-pyruvic transaminase, SGPT)

• γ-Glutamyl-transpeptidase (GGTP)

• Alkaline phosphatase

• Lactate dehydrogenase (LDH)

An isolated elevation of just one test result should raise suspicion that a source other than the liver is the cause. Table 1 indicates nonhepatic sources of elevated values for certain tests commonly considered as liver tests. When several liver test results are simultaneously out of the normal range, consideration of nonhepatic sources becomes irrelevant.

Table 1 Nonhepatic Sources of Abnormalities for Select Laboratory Tests

Test	Nonhepatic Source
Bilirubin	Red blood cells (e.g., hemolysis, intra-abdominal bleed, hematoma)
AST	Skeletal muscle, cardiac muscle
LDH	Heart, red blood cells
Alkaline phosphatase	Bone, first-trimester placenta, kidneys, intestines

AST, aspartate transaminase; LDH, lactate dehydrogenase.

Special note should be made of the GGTP and LDH as liver tests. The GGTP level is too sensitive, frequently elevated when no liver disease is apparent. The only usefulness of the GGTP test is that it confers liver specificity to an elevated alkaline phosphatase level. An isolated elevation of the GGTP level does not need to be further evaluated unless there are additional clinical risk factors for liver disease.³ The LDH assay is insensitive and nonspecific because LDH is present in tissues throughout the body.

EVALUATION OF LIVER DISEASE BASED ON ENZYME LEVELS

It is customary and useful to categorize liver diseases into three broad categories—hepatocellular, in which primary injury is to the hepatocytes; cholestatic, in which primary injury is to the bile ducts; and infiltrative, in which the liver is invaded or replaced by nonhepatic substances, such as neoplasm or amyloid. Although there is a great deal of overlap in liver test result abnormalities seen in these three categories, particularly in cholestatic and infiltrative disorders, an attempt to characterize an otherwise undifferentiated clinical case as hepatocellular, cholestatic, or infiltrative often makes subsequent evaluation faster and more efficient. The AST, ALT, and alkaline phosphatase tests are most useful to make the distinction between hepatocellular and cholestatic disease.

The normal range for aminotransferase levels in most clinical laboratories is much lower than that for the alkaline phosphatase level. Accordingly, when considering levels of elevations, it is necessary to consider them relative to the respective upper limit of normal for each test compared. Consider a patient with an AST level of 120 IU/mL (normal, ≤40 IU/mL) and an alkaline phosphatase of 130 IU/mL (normal, ≤120 IU/mL). This represents a hepatocellular pattern of liver injury because the AST level is three times the upper limit of normal, whereas the alkaline phosphatase level is only marginally higher than its upper limit of normal.

Serum aminotransferase levels—ALT and AST—are two of the most useful measures of liver cell injury, although the AST is less liver specific than the ALT level. Elevations of the AST level may also be seen in acute muscle injury, cardiac or skeletal muscle. Lesser degrees of ALT level elevation may occasionally be seen in skeletal muscle injury or even after vigorous exercise. Diseases that primarily affect hepatocytes, such as viral hepatitis, will cause disproportionate elevations of the AST and ALT levels compared with the alkaline phosphatase level. The ratio of AST/ALT is of little benefit in sorting out the cause of liver injury except in acute alcoholic hepatitis, in which the ratio is usually greater than 2 and the AST level is 400 IU/mL or lower.

Mild elevations of the AST level, less than two times the upper limit of normal, are common. In part, this is explained by how normal values are calculated; normal is defined as the mean of the distribution ± 2 standard deviations (SDs). By this definition, 2.5% of normal persons have values above the normal range.² Common causes of mild increases in AST and ALT levels include reduction effect (e.g., status) and fatty liver disease seen most often in those with obesity, diabetes, or elevated blood lipid levels. Fatty liver is also seen in those who drink alcohol.

Serum alkaline phosphatase is comprised of a heterogeneous group of enzymes. Hepatic alkaline phosphatase is most densely represented near the canalicular membrane of the hepatocyte. Accordingly, diseases that predominately affect hepatocyte secretion (e.g., obstructive diseases) will be accompanied by elevations of alkaline phosphatase levels. Bile duct obstruction, primary sclerosing cholangitis and primary biliary cirrhosis, are some examples of diseases in which elevated alkaline phosphatase levels are often predominant over transaminase level elevations (Table 2).

Table 2 Category of Liver Disease by Predominant Serum Enzyme Abnormality

It is apparent that infiltrative liver diseases most often result in a pattern of liver test result abnormalities similar to those of cholestatic liver disease. Differentiation often requires imaging studies of the liver. Liver imaging by ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) most often identifies infiltration of the liver by mass lesions such as tumors. Imaging by cholangiography—endoscopic retrograde cholangiography, transhepatic cholangiography, or magnetic resonance cholangiography—identifies many bile duct lesions that cause cholestatic liver disease. Liver biopsy is often needed to confirm certain infiltrative disorders (e.g., amyloidosis) and microscopic biliary disorders such as primary biliary cirrhosis.

Bilirubin Level Elevations

Bilirubin is produced by the normal breakdown of pigment-containing proteins, especially hemoglobin from senescent red blood cells and myoglobin from muscle breakdown. Bilirubin released from such sources, tightly albumin bound, is delivered to the liver, where it is efficiently extracted and conjugated by hepatic glucuronidation and sulfation. Conjugated bilirubin is rapidly excreted into bile and removed from the body through the gut. Therefore, the amount of conjugated bilirubin present in serum in healthy subjects is trivial (<10% of measured total bilirubin). An elevated level of conjugated serum bilirubin implies liver disease. Because only conjugated bilirubin appears in urine, the finding of bilirubinuria also implies liver disease.

Most laboratories report only total bilirubin levels, the sum of the conjugated and unconjugated portions. It is sometimes useful to determine the fraction of total serum bilirubin that is unconjugated versus conjugated, usually referred to as fractionation of bilirubin. The main clinical situation in which this is useful is when all the standard liver test results are normal, except the total bilirubin. Laboratories report the total bilirubin as well as the conjugated and unconjugated portions. To make matters more confusing, the conjugated bilirubin is sometimes referred to as the direct-reacting bilirubin and the unconjugated as the indirect-reacting bilirubin (Table 3).

Table 3 Bilirubin Fractions Present in Blood and Urine

Normally, 90% or more of measured serum bilirubin is unconjugated (indirect-reacting). When the total bilirubin level is elevated and fractionation shows that the major portion (≥90%) is unconjugated, liver disease is never the explanation. Instead, the clinical suspicion should turn to one of two explanations. If the patient is young and healthy, an inherited decrease in the inability to conjugate bilirubin is likely; it is referred to as Gilbert’s syndrome. It causes no symptoms and is associated with no liver disease. Interestingly, fasting and intercurrent illnesses such as influenza often make the level of unconjugated bilirubin even higher in those with Gilbert’s syndrome. This syndrome is easily diagnosed when all the standard liver test results are normal, and 90% or more of the total bilirubin is unconjugated. There is no need for an imaging study or liver biopsy in cases of suspected Gilbert’s syndrome.

Elevations of the unconjugated bilirubin level, when the conjugated bilirubin level remains normal, may also indicate an increased load of bilirubin caused by hemolysis. Anemia and an elevated reticulocyte count are usually present in such cases (Table 4).

Table 4 Common Causes of Isolated Bilirubin Elevation

Many mistakenly interpret elevations of direct-reacting bilirubin to indicate that cholestatic (obstructive) liver disease is present. It is apparent from Table 2 that the serum bilirubin level plays no useful role in categorizing a case as hepatocellular, cholestatic, or infiltrative. The bilirubin level may be normal or elevated in each type of disorder. Viral hepatitis A, a prototypic hepatocellular disease, may frequently be associated with bilirubin levels that are high, whereas primary biliary cirrhosis, a prototypic cholestatic disorder, is associated with a normal serum bilirubin level except in later stage disease. Serum bilirubin levels should be disregarded when trying to decide whether the liver test pattern is more suggestive of hepatocellular or cholestatic disease.