Published:
August 1, 2010


Approach to the Patient with
Liver Disease: A Guide to
Commonly Used Liver Tests

William D. Carey

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Laboratory assessment of the patient with suspected or clinically obvious liver disease is context dependent. For example, the acutely ill jaundiced patient with a history of prolonged alcohol ingestion requires a different laboratory assessment than the well patient in whom one or more standard liver test results are discovered to be abnormal during routine testing. Additionally, the sequence of liver tests depends heavily on the question asked. If it is to determine whether this well person whose brother was recently diagnosed with hemochromatosis also has this genetic disease, then a series of tests will be initiated to detect iron overload. If it is to determine whether this spouse has been infected with hepatitis B, then blood tests related to hepatitis B will be required. Thus, algorithms for the evaluation of liver disease need to be considered skeptically.

This chapter is designed to discuss a useful way of thinking about liver tests. It emphasizes limitations of and alternative explanations for isolated abnormalities of common liver test results. Information in this chapter should be combined with discussions of specific liver diseases elsewhere in this section. A final caveat relates to terminology. Tests done in clinical laboratories do not measure any functional capacity of the liver. Hence, the commonly used term liver function tests is inaccurate, and the term liver tests is used in this chapter. Guidelines on the interpretation and evaluation of abnormal liver test results have been published.1,2 Useful algorithms are presented that parallel the recommendations in this chapter.

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.

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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
Liver Disease Category

Test Hepatocellular Cholestatic Infiltrative
AST, ALT higher than alkaline phosphatase level Typical
Alkaline phosphatase higher than AST, ALT levels Typical
Elevation of alkaline phosphatase with near-normal AST, ALT levels Typical Typical

ALT, alanine aminotransaminase; AST, aspartate transaminase.
© 2002 The Cleveland Clinic Foundation.


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
Fraction In Serum As Measured As Present in Urine
Unconjugated Albumin-bound Indirect-reacting bilirubin Never
Conjugated Unbound Direct-reacting bilirubin Yes, when serum bilirubin level exceeds 3-4 mg/dL

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
Cause Direct-Reacting Bilirubin Indirect-Reacting Bilirubin Associated Features
Liver disease (many types) Elevated Elevated or normal Liver enzyme levels often elevated
Hemolysis Normal Elevation represents more than 90% of total bilirubin Anemia usual; increased reticulocyte count; normal liver enzyme levels (although LDH may be elevated)
Gilbert's syndrome Normal Elevation represents more than 90% of total bilirubin (common) No abnormal liver tests; no anemia; onset in late adolescence; fasting makes bilirubin rise

LDH, lactate dehydrogenase.
© 2002 The Cleveland Clinic Foundation.


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.

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Determination of specific liver disorders

Acute Alcoholic Hepatitis

Acute alcoholic hepatitis may be mild or life threatening. The pattern of liver test abnormality is hepatocellular. Additionally, the AST level is higher than the ALT level but rarely exceeds 400 IU/mL. The AST is typically in the 100 to 200 IU/mL range, even in severe disease, and the ALT level may be normal, even in severe cases. The degree of bilirubin level increase and prothrombin time elevation are better indicators of severity of disease than the level of enzyme elevation. The important corollary of this observation is that an AST or ALT elevation, or both, of, for example, 800 IU/mL is not likely to be explained by acute alcoholic hepatitis, even in an alcoholic.

Viral Hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (AST and ALT level elevations predominate). Persons with no symptoms and normal aminotransferase levels may be infected. In addition, a great deal of confusion is caused by abnormal viral markers, many of which do not indicate active infection but rather immunity. These concepts are more fully developed elsewhere in this section in the chapters on viral hepatitis. A clinical practice guideline on viral hepatitis is also available.4

Hepatitis A

Hepatitis A virus (HAV) infection is an acute self-limited disease in most cases, although it may rarely be fatal. Diagnosis is made through the use of antibody tests (anti-HAV). The standard screening tests contain reagents that will test positive for the presence of immunoglobulin M (IgM) anti-HAV or immunoglobulin G (IgG) anti-HAV. This test will therefore be positive with any exposure: acute, remote, or via immunization. Thus, it is not useful to determine whether a patient with acute hepatitis has hepatitis A.

Because IgM anti-HAV is present for only a few months after acute infection, the key to diagnosis of acute hepatitis A is to measure IgM anti-HAV. Selective testing of IgM anti-HAV is required to establish the serologic diagnosis of acute hepatitis A (Table 5).

Table 5: Hepatitis A Antibody Testing In Different Clinical States
State Anti-HAV Total (IgG, IgM) IgM Anti-HAV
Acute hepatitis A Positive Positive
Resolved hepatitis A Positive Negative
Immunization Positive Negative

HAV, hepatitis A virus; IgG, immunoglobulin G; IgM, immunoglobulin M.

Hepatitis B

Like hepatitis A, hepatitis B produces hepatocellular enzyme level elevations (AST and ALT predominate). In adults who acquire hepatitis B, the infection almost always clears, but antibodies persist. In a few, the disease does not resolve, but becomes chronic. These patients retain serum markers of viral infection. Many blood tests are available for hepatitis B antigenic determinants and their antibodies. It is best to separate testing appropriate for the acute hepatitis situation from testing for chronic liver disease caused by hepatitis B. Only a few tests need to be considered by the generalist to determine the status of a patient with possible hepatitis B.

Acute Hepatitis B

Within 2 weeks of exposure, but often delayed for weeks or months, hepatitis B surface antigen (HBsAg) emerges. This antigen is present in the blood for a variable period, usually encompassing the time during which the patient is clinically ill and most likely to seek medical attention. For patients with mild symptoms whose testing may be delayed, the HBsAg level may have already declined. In this case, a second chance to make the diagnosis comes from detection of the IgM antibody directed against the hepatitis B core antigen, anti-HBc-IgM (Table 6).

Table 6: Hepatitis B Testing in Different Clinical States
Basic Tests Ancillary Tests

    
State HBsAg Anti-HBc Anti-HBs HBeAg Anti-HBe HBV DNA
Acute, early + + or − + +
Acute, late + or − + IgM + +
Resolved + IgG + +
Chronic carrier + + Variable Variable
Chronic with active features + + + +
Successful immunization +

HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBs, hepatitis B surface; HBV, hepatitis B virus.
© 2002 The Cleveland Clinic Foundation.

Chronic Hepatitis B

Chronic hepatitis B is characterized by a long-lasting persistence of HBsAg and anti-HBc (IgG). Anti-HBs is absent. An additional antigen-antibody system requires mention, the hepatitis B e antigen (HBeAg) and its antibody (anti-HBe). These tests are only relevant in the individual in whom the HBsAg is chronically positive. In chronic B infection in which HBeAg is also positive, there are usually active viral replication and significant liver injury. In time, HBeAg may be lost, replaced by its antibody, anti-HBe. This transformation is often associated with lower level infection (less viral replication) or HBV DNA, lower AST and ALT values, and less (or no) hepatic inflammation. These concepts and exceptions are discussed more fully elsewhere in this section in the chapters on viral hepatitis. A clinical practice guideline on viral hepatitis B has provided additional information on laboratory testing in various contexts of hepatitis B infection.5

Resolved Hepatitis B and Immunization Status

Confusion may arise in the interpretation of hepatitis B tests in a patient who has received hepatitis B immunization or has had previous hepatitis B. When such an individual develops a different type of liver disease, certain test results for hepatitis B will also be positive and interpretation may be difficult. In those immunized, only the antibody directed against the surface antigen (anti-HBs) will be present; in a patient with resolved hepatitis B, anti-HBs and the antibody directed against the hepatitis B core (anti-HBc) will usually be present. In this case, the anti-HBc will be of the IgG class, not IgM.

In acute hepatitis B in which delay in testing has occurred, the HBsAg may be absent. In such cases, the anti-HBc will be positive (but not anti-HBs). In remote (resolved) infection, only IgG anti-HBc is present. In acute infection, IgM anti-HBc will be detected.

Hepatitis C

Because infection with hepatitis C usually produces no symptoms or mild, nonspecific, flulike symptoms, it is not frequently diagnosed during the acute phase. The virus clears spontaneously in only about 15% of those infected. Although generally helpful for the diagnosis of chronic infection, antibody tests are not usually useful for acute hepatitis C virus (HCV) because emergence of the antibody is delayed for several months after infection.

To test for chronic HCV infection, the most commonly used anti-HCV antibody test is an enzyme immunoassay (EIA) or a variant. False-positive results may occur. The radioimmunoblot assay (RIBA) adds specificity to a positive anti-HCV EIA, but is probably of lesser use now that direct measurement of viral products in serum (HCV RNA) is widely available. HCV RNA is usually determined by the polymerase chain reaction (PCR) assay, although a simpler test, HCV RNA by bDNA is still done in some laboratories, but this latter test is not as sensitive as the PCR assay. HCV RNA in serum definitively establishes the presence of HCV infection. Some have wondered whether the initial screening test for HCV should therefore be the HCV RNA rather than an antibody test. Currently, however, because of cost considerations, the initial test for HCV should be an anti-HCV antibody test.

Once the presence of HCV is established, the genotype should be determined. There are six major HCV genotypes (1-6). Genotype has increasing importance for treatment determinations. This is discussed more fully elsewhere in this section (“Hepatitis C”) (Table 7).

Table 7: Hepatitis C Testing in Different Clinical States
State Anti-HCV (EIA) Anti-HCV (RIBA) HCV RNA (PCR or bDNA) Genotype
Acute + Types 1-6
Resolved (spontaneous or after treatment) + + Undetectable
Chronic + + + Types 1-6

EIA, enzyme immunoassay; HCV, hepatitis c virus; PCR, polymerase chain reaction; RIBA, radioimmunoblot assay.
© 2002 The Cleveland Clinic Foundation.

Iron and Copper Overload Diseases

Diseases characterized by iron overload and copper overload are discussed in detail elsewhere in this section (“Inherited Metabolic Liver Diseases: Hemochromatosis, Wilson's Disease”).

Iron Tests

Two paths may be considered to establish a diagnosis of hemochromatosis, genotypic and phenotypic. Diagnosis is most often made by phenotypic expression of disease—that is, by demonstration of excess circulating iron, ferritin, or iron accumulation within organs, especially the liver. Despite the excitement surrounding the genotypic diagnosis of hereditary hemochromatosis, it has been shown that phenotypic demonstration of iron overload is the most cost-efficient strategy.6 A practice guideline has been published that confirms this approach.7

The most useful tests for iron overload in serum are iron, iron-binding capacity, and percentage transferrin saturation. Serum ferritin levels are also useful and easily obtained. Hemochromatosis should be suspected in the following:8

  • Any adult with liver disease, especially men
  • Transferrin saturation higher than 55%
  • Ferritin level elevations higher than 200 µg/L in premenopausal women or higher than 300 µg/L in men and postmenopausal women

These thresholds are low; most patients who exceed them will not prove to have iron overload. Many inflammatory conditions, and especially other liver diseases, will result in elevations of ferritin or iron levels, or both, in the absence of total body iron excess.

Limitations of Serum-Based Tests of Iron Overload

Because both iron and ferritin are stored in liver cells, any condition that results in hepatocyte injury and release of intracellular contents into the blood will falsely raise iron, transferrin saturation, and ferritin levels. Therefore, in acute hepatic injury of any source, these tests will falsely suggest iron overload. Acute inflammation outside the liver may also falsely elevate serum-based iron tests. Tests of serum ferritin levels, iron, iron-binding capacity, and percentage saturation determined in the setting of markedly elevated aminotransferase levels (AST and ALT), such as those seen in acute viral hepatitis or massive hepatic necrosis, will be identical to those seen in hemochromatosis. Iron studies cannot be interpreted in the face of major elevations of transaminase levels.

Another limitation of iron studies relates to the time it takes for an individual with genetic hemochromatosis to accumulate excessive iron. In a young patient with this condition, who has not yet had enough time to accumulate iron (especially the premenopausal woman), screening tests for iron overload may be normal, even though the individual is at risk for the subsequent development of iron overload.

Confirmation of suspected iron overload from serum-based tests requires demonstration of an increased hepatic iron level, usually by liver biopsy. The value of the biopsy is twofold: It provides information about the degree of fibrosis or cirrhosis present, which is vital in predicting the risk of subsequent development of hepatoma, and it provides an assessment of iron stores. Because there is an age-dependent increase in hepatic iron in normal individuals, it is necessary to create an index that takes this into account. The hepatic iron index is calculated as follows:

Hepatic iron index = hepatic iron concentration (μmol/g dry weight) ÷ patient age (in years)

A hepatic iron index lower than 2.0 is normal; values higher than 2.0 are seen in hemochromatosis.9 Renewed interest in the assessment of hepatic iron by the evaluation of iron stains of liver biopsy material indicates that this is a satisfactory alternative to quantitative iron determination.10 Bone marrow iron stores are not adequate to assess total body iron stores; cases of hemochromatosis with absent stainable bone marrow iron have been reported.

Genotypic Diagnosis of Genetic Hemochromatosis

It has been known for years that many cases of hemochromatosis are inherited as an autosomal recessive trait. In many cases, a defective gene, called the HFE gene, is implicated. The presence of this inherited gene results in the production of a protein in which a tyrosine amino acid rather than a cysteine amino acid is present at position 282 of the HFE protein. A second missense gene that results in an aspartic acid (instead of histidine) at position 63 of the same protein may increase iron absorption in some patients. The abnormalities are called C282Y and H63D mutations, respectively.

The patient with hereditary hemochromatosis usually must have two abnormal genes (homozygosity). Most often, two C282Y genes are present, but occasionally a compound heterozygote (C282Y-H63D) will also have excess iron. Homozygosity for H63D does not usually result in excess iron absorption.

The value of genotypic diagnosis is primarily limited to the identification of at-risk family members after an index case has been discovered. HFE determination can identify young individuals at risk for iron overload before iron becomes excessive. In Australia, where almost all patients with genetic hemochromatosis demonstrate such genetic abnormalities, gene diagnosis can replace iron testing. However, in most parts of the world, only 60% to 80% of those with hemochromatosis have an HFE abnormality. Therefore, HFE testing is generally not a suitable screening test for iron overload. Reliance on phenotypic expression (iron overload) is still required.

Copper Tests

Although copper may accumulate to moderate excess in the liver in any chronic cholestatic liver condition, it does not appear to be injurious in these conditions. Wilson's disease is the main disease in which pathologic copper deposition results in serious liver injury, cirrhosis, and death. In Wilson's disease, copper also accumulates in the basal ganglia of the brain, where it produces a wide gamut of neurologic abnormalities. Patients may present with liver disease, brain disease, or both. This disorder is discussed in more detail elsewhere in this section (“Inherited Metabolic Liver Diseases: Wilson's Disease”).

Wilson's disease is rare. Untreated, it usually produces death before age 40 years. Therefore, it is most appropriate to consider this potential cause in a child or young adult with otherwise unexplained liver disease. Laboratory diagnosis is most often based on the finding of a low ceruloplasmin level. Because most acute and chronic liver diseases cause the ceruloplasmin level to be elevated, the finding of a low-normal or depressed ceruloplasmin level in a young patient with liver disease is suggestive of Wilson's disease. There are a few exceptions to this. A patient with acute fulminant liver failure of any sort may no longer have a liver capable of ceruloplasmin synthesis, so that patient may have a low serum level. Similarly, the patient with terminal end-stage liver disease may have a falling ceruloplasmin level. Finally, a few individuals have congenital hypoceruloplasminemia without copper accumulation and are healthy.

Autoimmune Liver Diseases: Autoimmune Chronic Hepatitis and Primary Biliary Cirrhosis

The two most common forms of autoimmune liver disease are autoimmune chronic hepatitis and primary biliary cirrhosis. Ninety percent of those with each disorder are women. Autoimmune chronic hepatitis is characterized by very high serum aminotransferase (ALT and AST) levels, whereas primary biliary cirrhosis is associated with predominant elevations of the alkaline phosphatase level, a cholestatic disorder. Each is associated with autoantibodies in the serum. The treatment for each is different, so accurate diagnosis is essential. Table 8 contrasts the laboratory findings of these two autoimmune liver disorders.

Table 8: Contrasting Features of Two Autoimmune Liver Diseases
Feature Autoimmune Chronic Hepatitis Primary Biliary Cirrhosis
AST, ALT 7-10 times upper limit of normal (ULN) 1-3 times ULN
Alkaline phosphatase 1-3 times ULN 2-10 times ULN
Anti-smooth muscle antibody positive 90% (usually high titer) 10%-20% (usually low titer)
Antimitochondrial antibody positive 10%-20% (usually low titer) 90%-100% (usually high titer)
Liver-kidney microsomal antibody positive Positive in some cases in which smooth muscle antibody is negative (rare in North America) Negative

ALT, alanine aminotransaminase; AST, aspartate transaminase.
© 2002 The Cleveland Clinic Foundation.

Interpretation of autoimmune markers in a patient with liver disease is highly context-dependent. Autoantibodies are common in low titer in a number of acute and chronic liver conditions, such as viral hepatitis. Therefore, the finding of autoantibodies in low titer is not sufficient evidence with which to make a diagnosis of autoimmune chronic hepatitis or primary biliary cirrhosis.

Autoimmune hepatitis should be rapidly recognized by its propensity to occur in women (90%) and to be associated with high transaminase levels (200 IU/mL or higher). In this disease, elevations of the gamma globulins (especially IgG) are pronounced. A myriad of autoimmune markers may be positive in autoimmune chronic hepatitis, but only a few are measured regularly: smooth muscle antibody, antinuclear factor, and liver-kidney microsomal (LKM) antibody. A liver biopsy is often done to establish the diagnosis of autoimmune chronic hepatitis.

Primary biliary cirrhosis is discussed in detail elsewhere in this section (“Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, and Other Cholestatic Liver Diseases”). In this condition, serum-based liver tests reveal a predominant elevation of the alkaline phosphatase level. An autoantibody most likely to be present in high titer in primary biliary cirrhosis is the antimitochondrial antibody, but determination of its presence may not be needed in clear-cut cases.11 An occasional patient may have features of autoimmune chronic hepatitis and primary biliary cirrhosis.

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Summary

  • Laboratory assessment of the patient with suspected or clinically obvious liver disease is context dependent. It is useful to categorize liver diseases into three broad categories: hepatocellular, cholestatic, and infiltrative.
  • Acute alcoholic hepatitis may be mild or life threatening. The pattern of liver test abnormality is hepatocellular. The AST level is higher than the ALT level but rarely exceeds 400 IU/mL, and the ALT level may be normal. The level of bilirubin elevation and prothrombin time elevation are better indicators of severity of disease than the level of enzyme elevation.
  • Viral hepatitis most often produces a hepatocellular pattern of injury (AST and ALT elevations predominate). Specific antigens and antibodies establish the diagnosis of viral hepatitis.
  • Two paths may be considered to establish a diagnosis of iron-loading disease (hemochromatosis), genotypic and phenotypic. Diagnosis is most often made by the phenotypic expression of disease. Wilson's disease is rare; untreated, it usually produces death before age 40 years. Laboratory diagnosis is usually based on the finding of a low ceruloplasmin level and increased copper levels.
  • Autoimmune chronic hepatitis is characterized by very high serum aminotransferase levels and high smooth muscle antibody titer. Primary biliary cirrhosis is mainly associated with alkaline phosphatase level elevations and a high antimitochondrial antibody titer.

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References

  1. American Gastroenterological Association. Medical position statement: Evaluation of liver chemistry tests. Gastroenterology. 2002, 123: 1364-1366.
  2. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002, 123: 1367-1384.
  3. Carey WD. How should a patient with an isolated GGT be evaluated? Cleve Clin J Med. 2000, 67: 315-316.
  4. Younossi ZM. Viral hepatitis guide for practicing physicians. Cleve Clin J Med. 2000, 67: (Suppl 1): S16-S45.
  5. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001, 34: 1225-1241.
  6. Adams PC, Valberg LS. Screening blood donors for hemochromatosis: Decision analysis model comparing genotyping to phenotyping. Am J Gastroenterol. 1999, 94: 1593-1600.
  7. Tavill AS. American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association: Diagnosis and management of hemochromatosis. Hepatology. 2001, 33: 1321-1328.
  8. Powell LW, George DK, McDonnell SM, Kowdley KV. Diagnosis of hemochromatosis. Ann Intern Med. 1998, 129: 925-931.
  9. Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986, 6: 24-29.
  10. Deugnier YM, Turlin B, Powell LW, et al: Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: A study of 192 cases. Hepatology. 1993, 17: 30-34.
  11. Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000, 31: 1005-1013.

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Suggested Readings

  • Adams PC, Valberg LS. Screening blood donors for hemochromatosis: Decision analysis model comparing genotyping to phenotyping. Am J Gastroenterol. 1999, 94: 1593-1600.
  • American Gastroenterological Association. Medical position statement: Evaluation of liver chemistry tests. Gastroenterology. 2002, 123: 1364-1366.
  • Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology. 1986, 6: 24-29.
  • Carey WD. How should a patient with an isolated GGT be evaluated? Cleve Clin J Med. 2000, 67: 315-316.
  • Deugnier YM, Turlin B, Powell LW, et al: Differentiation between heterozygotes and homozygotes in genetic hemochromatosis by means of a histological hepatic iron index: A study of 192 cases. Hepatology. 1993, 17: 30-34.
  • Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002, 123: 1367-1384.
  • Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000, 31: 1005-1013.
  • Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001, 34: 1225-1241.
  • Powell LW, George DK, McDonnell SM, Kowdley KV. Diagnosis of hemochromatosis. Ann Intern Med. 1998, 129: 925-931.
  • Tavill AS. American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association: Diagnosis and management of hemochromatosis. Hepatology. 2001, 33: 1321-1328.
  • Younossi ZM. Viral hepatitis guide for practicing physicians. Cleve Clin J Med. 2000, 67: (Suppl 1): S16-S45.