Vol. 2, No. 1, Winter/Spring 1995

This issue of the Liver Letter deals with a common problem faced by both family physicians and hepatologists: the patient with one or more abnormal liver chemistry tests. The technically incorrect term "liver function tests", abbreviated "LFT", is so widespread that I have given up lobbying against this term, and instead have lapsed into using it myself on occasion. Dr. Bain's approach to this problem of "abnormal LFTs" is both practical and cost-effective.

Please also note that this is the last issue of the Liver Letter that will be automatically mailed to you. To reduce mailing costs, we have included a reply coupon for you to fill out and mail back to the CLF. In the future, the Liver Letter will be mailed only to those who have returned the reply coupon included in this issue.

Samuel S. Lee, MD, F.R.C.P. (C)
The University of Calgary, Department of Medicine

LIVER FUNCTION TESTS

Vincent Bain, MD, F.R.C.P. (C)
University of Alberta

Liver Function tests (LFTs) are among the most commonly used investigations in clinical medicine. A sound understanding of why they become abnormal and a rational, cost effective approach to their investigation is essential. The aims of this article are:

1. to review the usual LFTs and the circumstances in which they become deranged
2. to look at patterns of liver injury as a basis for directing further investigation
3. to discuss indications for more invasive investigations, specifically liver biopsy and ERCP.

The standard LFTs (serum aminotransferase, alkaline phosphatase and bilirubin), in fact do not reflect function and might better be termed liver injury tests. Transaminases, or aminotransferases, catalyze the transfer of an amino group from an amino acid to ketoacid thereby forming a new amino acid. They are present in highest concentrations in cells from the liver, heart, skeletal muscle and erythrocytes. In hepatocytes, alanine transaminase (ALT) is present in higher concentrations than aspartate transaminase (AST) and therefore with liver injury, ALT exceeds AST (alcoholic liver disease is a notable exception). These enzymes become elevated as hepatocytes become necrotic or partially damaged; however, the magnitude of elevation correlates poorly with disease severity. For example, patients with mild viral hepatitis may have transaminase levels measured in the thousands for several weeks, yet there may be insufficient cellular injury to cause jaundice or prolongation of the prothrombin time. Alternatively, patients with severe alcoholic hepatitis or autoimmune chronic active hepatitis rarely have transaminase values in excess of 500 despite the presence of life-threatening disease.

Patients whose LFTs show a predominant rise in the transaminases have liver diseases which are characterized by hepatocellular damage. Examples include viral hepatitis, drug or toxin induced injury, or hepatic ischemia. Transaminases are useful as a screening test for the presence of many liver diseases, however notable exceptions are methotrexate induced damage, and alcoholic liver disease which may progress with little change in the LFTs. The AST or ALT are also useful to follow the activity of certain diseases to help judge the need for therapy or the response to therapy (e.g. steroids for autoimmune chronic active hepatitis or interferon for chronic HCV). The transaminases are not useful indicators of prognosis since viable cells may leak transaminases and because it is the extent of hepatic regeneration that more accurately reflects outcome.

Alkaline phosphatase represents a group of membrane associated enzymes which become elevated in response to increased intracellular concentrations of bile acids. This is secondary to increased pressures within the biliary ductal system as a result of either cholestasis or obstruction. Since alkaline phosphatase is present in other cells outside the liver, a hepatic origin can be confirmed by demonstrating an associated increase in the 5' nucleotidase or gamma-glutamyl transpeptidase (GGT). An elevation of the alkaline phosphatase is a sensitive indicator of intrahepatic cholestasis/obstruction or extrahepatic obstruction, whereas bilirubin will become elevated only when the process is advanced. Conditions commonly associated with a predominant elevation of the alkaline phosphatase include: extrahepatic obstruction, infiltrative liver diseases such as amyloidosis or neoplasia, granulomatous hepatitis (especially TB and sarcoid), certain drug reactions, and other chronic cholestatic conditions such as primary biliary cirrhosis and primary sclerosing cholangitis.

Bilirubin is a breakdown product of heme which is released as senescent erythrocytes are hemolyzed by the reticuloendothelial system. After uptake by the liver, bilirubin is conjugated with UDPG which enhances its water solubility and enables biliary excretion. The capacity of the liver to take up, conjugate and excrete bilirubin is large and a considerable increase in bilirubin load is required before this hepatic reserve is exceeded. Similarly, extensive parenchymal injury, widespread canalicular dysfunction or almost complete obstruction must be present before the serum bilirubin rises.

From the above discussion, it is clear that bilirubin is a true liver function test, but is insensitive in that it becomes increased only with advanced hepatocellular disease or high grade obstruction. Other true liver function tests include the serum albumin and the prothrombin time. They serve as a measure of the liver's synthetic function and are particularly useful in determining the extent of damage in acute or chronic hepatocellular injury.

Using the LFT Pattern to Direct Further Investigation

Table 1 illustrates commonly encountered conditions which should be considered in relation to the different patterns of abnormal LFTs. For patients with a hepatocellular pattern of injury, viral serology, a careful search for injurious drugs or toxins, autoantibodies and serum ceruloplasmin are appropriate. Ultrasounds, CT scans or liver spleen scans are unlikely to be helpful. A liver biopsy will be necessary where there is an unexplained and persistent elevation of the LFTs to establish the diagnosis and provide prognostic information in certain conditions such as chronic viral hepatitis, autoimmune diseases, Wilson disease, hemochromatosis and infiltrative conditions. The decision to proceed to liver biopsy must be individualized because of the rare, but potentially serious complication of bleeding.

Patients with an obstructive/cholestatic pattern should have an ultrasound to look for evidence of extrahepatic obstruction. Those with extrahepatic obstruction will require an ERCP or transhepatic cholangiogram to determine the site and cause of obstruction. ERCP is generally preferred because therapeutic maneuvres such as stone extraction of stenting can be done at the same time. Those without evidence of obstruction will usually require liver biopsy. In cases where there is an isolated elevation of the serum bilirubin, fractionation is helpful. In those with unconjugated hyperbilirubinemia, a diagnosis of Gilbert's disease, hemolysis or ineffective hematopoiesis should be sought. Those with conjugated hyperbilirubinemia usually have rare and often familial disorders of biliary excretion such as the Dubin-Johnson syndrome.

TABLE 1 - PATTERNS OF LIVER INJURY

Common Exceptions:

1. Mixed patterns of injury are common: the differential diagnosis is broader including entities from both hepatocellular and obstructive/cholestatic categories.
   
   
2. Patients recovering from acute hepatocellular injuries (regenerative phase) often have prominent elevations of the alkaline phosphatase.
   
   
3. Patients with acute biliary obstruction due to a ductal stone often have a prominent elevation of the transaminase.

Summary

Recognition of the pattern of abnormal liver function tests permits an accurate differential diagnosis to be formulated. Directed investigation will then lead to a diagnosis more quickly and with less expenditure of precious health care dollars.

If you would like more information on any of the over 100 types of liver disease, please call (416) 964-1953 or 1-800-563-5483, or email us at clf@liver.ca