New Guidelines Provide a Clearer Path Forward for Abnormal Liver Tests

William F. Balistreri, MD


February 01, 2018

In This Article

Changing Perspectives on Liver Testing

To provide high-quality, cost-effective healthcare, a rational approach to the appropriate evaluation of serum liver chemistries is essential for all healthcare professionals. As is the case for all medical tests, liver chemistries must be interpreted in the context of the patient's risk factors for disease, symptoms, and history and physical examination findings.[1]

This overview provides an updated perspective on this issue in the context of recently announced guidance.[2]

What Current Panels Provide

Comprehensive metabolic profile testing (panels) is widely used to screen individuals who present for routine evaluation, as well as those referred for elevated liver enzyme values. The standard comprehensive, most commonly ordered panel includes measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin.

These liver chemistry tests are indirect markers of hepatobiliary disease or liver injury; they are not "liver function tests." True tests of liver function include prothrombin time and others that are not commonly performed, such as measurement of hepatic substrates that are cleared by hepatic uptake or metabolism.

The pattern of findings on liver chemistry tests may provide clues to the nature of the injury. Hepatocellular disease is typically defined as a disproportionate elevation of the AST and ALT levels compared with alkaline phosphatase levels, whereas cholestatic disease is signaled by a disproportionate elevation of the alkaline phosphatase level compared with AST and ALT levels. In addition, because ALT is present primarily in the liver, it is a more specific marker of hepatocellular injury than AST, which is present in the liver as well as other organs, including cardiac muscle, skeletal muscle, kidney, and brain. Thus, an increase in AST without an elevation in ALT is suggestive of cardiac or muscle disease.

In patients presenting with an isolated alkaline phosphatase elevation, cholestatic injury can be confirmed by measurement of the serum gamma-glutamyltransferase (GGT) level or fractionation of alkaline phosphatase isoenzymes to differentiate liver alkaline phosphatase from nonliver sources. Of note, given its lack of specificity for liver disease, GGT should not be used as a screening test for underlying liver disease in the absence of abnormal liver chemistries.[2]

Elevated total serum bilirubin levels should be fractionated to assess the relative contribution of conjugated and unconjugated bilirubin fractions; an elevated serum conjugated bilirubin level implies hepatocellular disease or biliary obstruction.

The "R ratio" has been proposed to assess whether the pattern of liver injury is hepatocellular, cholestatic, or mixed.[2,3] The ratio is calculated using this formula:

R = (ALT value ÷ ALT upper limit of normal [ULN]) ÷ (alkaline phosphatase value ÷ alkaline phosphatase ULN )

An R ratio greater than 5 suggests hepatocellular injury, less than 2 suggests cholestatic injury, and 2-5 indicates a mixed pattern.


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