American Gastroenterological AssociationAGA technical review on the evaluation of liver chemistry tests☆,☆☆
Section snippets
Criteria used to include and/or exclude data for consideration
In the data analysis used for this technical review, it should be stated that there are no type 1 data (well-designed randomized controlled trials) and few type 2 data (well-designed cohort [prospective or retrospective] studies with concurrent or historical controls) directly addressing the evaluation of liver chemistry tests. An initial MEDLINE literature search under the subject headings Liver, Chemistry, Function, and Test revealed over 14,000 references, with over 6000 references published
Interpretation of abnormal liver chemistry values
Normal laboratory values are defined as the mean of the distribution ± 2 standard deviations of the “normal” population.3 Therefore, by definition, 5% of normal patients will have abnormalities of any given test (2.5% are above and 2.5% are below the 2 standard deviation level). Although low liver chemistry values are not typically associated with disease states, 2.5% of “normal” individuals will have mild elevations of a given serum liver chemistry test. In addition, the “normal” population
Biological basis of liver chemistries
The term “liver chemistry tests” is a frequently used but poorly defined phrase that encompasses the numerous serum chemistries that can be assayed to assess hepatic function and/or injury (Table 1).Liver chemistry test Clinical implication of abnormality Alanine aminotransferase Hepatocellular damage Aspartate aminotransferase Hepatocellular damage Bilirubin Cholestasis, impaired conjugation, or biliary obstruction Alkaline phosphatase Cholestasis, infiltrative
Initial approach to the evaluation of abnormal liver chemistries tests
When a patient is identified as having an asymptomatic elevation of one or more liver chemistry test, the physician must decide what initial additional evaluation, if any, is clinically indicated. This will be based, at least in part, on the findings of the history and physical examination. Unfortunately, significant data are lacking on the cost-effectiveness of evaluating patients with asymptomatic abnormalities of liver chemistry tests; nor are there long-term prospective studies to define
Evaluation of abnormalities of the serum ALT and AST levels
There are numerous causes of increased serum ALT and AST levels in both symptomatic and asymptomatic patients. As previously mentioned, ALT and AST are enzymes released from damaged hepatocytes into the blood following hepatocellular injury or death, although they can originate from other tissues. Historical information and the physical examination are essential for the initial evaluation to determine whether the liver injury is acute or chronic, the underlying etiology, and associated systemic
Etiology of mild ALT and AST elevations (less than 5 times the upper limit of normal): ALT-Predominant elevation
Chronic viral hepatitis remains one of the most common causes of abnormal liver chemistries. HCV infection is a highly prevalent disease and a common cause of elevated liver enzymes, affecting nearly 2% of the American population.42 All patients with abnormal serum aminotransferases should be questioned for risk factors for HCV acquisition, including a history of intravenous or intranasal drug use, blood transfusion, exposure to unsterile needles (nosocomial, body piercing, tattoo placement),
Etiology of mild ALT and AST elevations (ALT and AST elevations less than 5 times the upper limit of normal): AST-predominant elevation
Alcohol use is a common cause of an elevated serum AST and is a cofactor for hepatic injury due to viral hepatitis and metabolic liver diseases.85, 86 Accurate and detailed assessment of alcohol intake must be elicited by interviewing patients and often other family members because accurate historical information is essential for making the diagnosis of alcohol-related liver injury. The quantity of alcohol and the length of time that alcohol has been consumed are important factors for the
Etiology of severe ALT and AST elevations (greater than 15 times the upper limit of normal)
The differential diagnosis for severe elevations of liver transaminases often differs from etiologies causing lesser elevations of the aminotransferases and is relatively limited (Table 6).95, 96Acute viral hepatitis (A–E, herpes) Medications/toxins Ischemic hepatitis Autoimmune hepatitis Wilson's disease Acute bile duct obstruction Acute Budd-Chiari syndrome Hepatic artery ligation
Evaluation of abnormalities of the serum bilirubin and alkaline phosphatase levels
Hyperbilirubinemia and serum elevations of hepatic alkaline phosphatase may be associated with cholestatic conditions. Cholestatic diseases can be categorized as either anatomic obstructions to bile flow (extrahepatic cholestasis) or as functional impairments of bile formation by the hepatocyte (intrahepatic cholestasis). Disorders causing hyperbilirubinemia, however, may not always be associated with abnormalities of the serum alkaline phosphatase or other serum liver chemistries. In fact,
Isolated unconjugated hyperbilirubinemia
The screening of asymptomatic patients for serum liver biochemistries will identify a large number of individuals with elevated serum unconjugated bilirubin levels. In fact, up to 5% of the population has Gilbert's syndrome, a benign condition of unconjugated hyperbilirubinemia with otherwise normal liver chemistries.24 Given the high prevalence and benign nature of this syndrome, it may be considered a normal variant of the population rather than a disease state. Gilbert's syndrome is caused,
Conjugated hyperbilirubinemia and elevated hepatic alkaline phosphatase
Cholestatic conditions may cause a conjugated hyperbilirubinemia, and elevated serum bilirubin levels may occur before the development of frank jaundice. Although the Dubin-Johnson and Rotor syndrome are rare genetic diseases caused by an impaired hepatocellular secretion of bilirubin glucuronides into the bile,112, 113 conjugated hyperbilirubinemias are more typically caused by hepatocellular diseases, biliary obstruction, toxins, or drugs (Table 8).Bile
Serum albumin and prothrombin time
The serum albumin and prothrombin time are commonly obtained serum tests that may be essential in the evaluation of hepatic function, although neither test is specific for evaluating liver function. Albumin levels may be diminished due to poor nutritional status, severe illness with protein catabolism, nephrosis, malabsorption, and other abnormalities of the gastrointestinal tract, whereas serum prothrombin time elevations may occur with malabsorption and with several acquired or genetic
Evaluation of the clinical indication for performing a liver biopsy
When evaluating a patient with abnormal serum liver chemistries, a common diagnostic decision facing the gastroenterologist is whether to perform a percutaneous liver biopsy. Liver biopsy can provide important prognostic and diagnostic information regarding the cause of the liver disease but should be performed only if the expected benefit exceeds the small risks of the procedure. Outpatient percutaneous liver biopsy can be performed safely in most patients, although complications requiring
Conclusion
This review of the medical literature on the evaluation of liver chemistry tests indicates, at least to the authors, that a reliable literature to make unequivocal recommendations for the diagnostic evaluation of patients with abnormal liver chemistry tests is lacking. There are no large, double-blinded, prospective studies and few uncontrolled studies addressing this issue. Several review articles have been published on the evaluation of liver chemistry tests, although the recommendations
Acknowledgements
The Clinical Practice Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the authors: William D. Carey, M.D., Richard H. Moseley, M.D., Karen Eun-Young Kim, M.D., and Giles Richard Locke III, M.D.
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Address requests for reprints to: Gary R. Lichtenstein, M.D., Chair, Clinical Practice Committee, AGA National Office, c/o Membership Department, 7910 Woodmont Avenue, 7th Floor, Bethesda, Maryland 20814. Fax: (301) 654-5920.
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This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice Committee. The paper was approved by the Committee on March 3, 2002 and the AGA Governing Board on May 19, 2002.