How Should I Approach Elevated Liver Enzymes?

William F. Balistreri, MD

Disclosures

December 29, 2011

Question:

How should I approach elevated liver enzymes in primary care – how much investigation is warranted?

Response from William F. Balistreri, MD
Professor of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Staff Physician, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Deciphering elevated liver enzymes is a common challenge in clinical practice. A rational approach for the appropriate evaluation of serum liver chemistries is essential for providing high-quality, cost-effective healthcare. The interpretation of presumably abnormal liver chemistries must be done in the clinical context of a given patient. Mild elevations in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate a significant underlying disease; conversely these elevations may be transient and/or insignificant. However, an audit of primary care practices found that these abnormalities are not always investigated appropriately and that opportunities to intervene in treatable cases sometimes are missed.[1,2,3,4,5]

My approach is to ask 4 questions about the elevated value:

  • Is it real?

  • Is it significant?

  • Is the cause obvious?

  • If not -- what can I do?

Is it real? The first consideration in proper interpretation of ALT and AST results is to define "abnormal." Despite the widespread use of these tests, the threshold value for detecting liver disease is variable -- with different cutoff values based on age and gender.[6] The range of normal laboratory values is traditionally defined as the mean of the distribution (± 2 standard deviations) of a presumably representative healthy population. Therefore, by definition, 2.5% of healthy individuals will have an "abnormal" elevation of a given test. In addition, ALT/AST upper limits of normal (ULN) values used by individual laboratories are widely divergent -- this is likely related to the characteristics of the local populations sampled to define their reference ranges. If patients with potentially silent liver disease, such as nonalcoholic fatty liver disease (NAFLD) are not excluded, the distribution of ALT levels would be falsely skewed upward and the ULN will be set at a high mark. Clinically relevant ULNs for ALT and AST are likely lower than those frequently used.[7]

Is it significant? A seemingly relevant abnormality in these tests must be interpreted in context. The decision about the need for further diagnostic evaluation and/or the most appropriate evaluation can best be made on the basis of the specific clinical scenario of the individual patient. Those with significant (> 5-fold) elevations of ALT or AST, with an abnormal albumin, bilirubin, or prothrombin time, or with clinical evidence of chronic liver disease and/or hepatic decompensation should clearly undergo an expeditious evaluation.

Is the cause obvious? A recent study indicates that the most common cause of chronic liver disease in the United States is now NAFLD.[8]In the setting of obesity with other elements of the metabolic syndrome, the cause of the elevated enzymes could reasonably be assumed to be fatty liver.

What Can I Do?

The strategies employed to decipher abnormal liver enzyme levels of unclear etiology is evolving, as a result both of the changing spectrum of diagnostic possibilities as well as refinement in diagnostic modalities. Although no controlled clinical trials have examined the optimal approach for evaluating serum liver chemistries, guidelines have been proposed by the American Gastroenterological Association (AGA) and the American Association for the Study of Liver Disease (AASLD) for the interpretation and further diagnostic evaluation of patients.[1,9]

Evaluation begins with a thorough history, with detailed inquiry into the use of alcohol, medications (over-the-counter and prescription), or herbal products; the relevant family history; and any history of blood-product transfusion. Potential comorbidities, such as obesity/diabetes, celiac disease, heart disease, thyroid disease, and muscle disease must also be sought. AST levels in particular may be elevated as a result of musculoskeletal injury, including vigorous weight lifting or trauma. Next, a careful and complete physical examination may uncover signs of chronic liver disease. The recommended initial panel of laboratory tests includes a serum bilirubin level, prothrombin time, albumin, complete blood count with platelet count, hepatitis serologies, tTG for celiac disease screening, and iron studies.

When findings from these initial studies indicate that one or more diagnostic considerations are likely, subsequent evaluation should be directed toward establishing these diagnoses, rather than following an algorithm. An algorithm is most useful when there are no clinical clues or when the suspected diagnosis cannot be verified.[8]

If all of these tests are unremarkable, a decision about additional testing vs. observation should be made on the basis of the clinical scenario. If observation alone is elected, an interim management strategy includes cessation of alcohol use, attention to medication use, control of diabetes, and modification of lifestyle factors such as obesity. Close clinical follow-up and serial ALT/AST testing is important. If markedly elevated and/or persistently elevated levels are detected, or if significant symptoms or evidence of chronic or decompensated liver disease are present additional serologic and radiologic evaluations and potentially a liver biopsy may be warranted.

What about imaging? Depending on the clinical scenario, computerized tomography or abdominal MRI may be preferable to ultrasonography. State of the art MRI techniques can be used to document normal liver structure or to identify a fatty liver.

Role of liver biopsy. Noninvasive techniques may ultimately, in part, replace the use of liver histology, as in assessment of the severity of liver fibrosis. However, liver biopsy has long been considered an important diagnostic adjunct in the evaluation of abnormal liver tests of unclear etiology -- the "bottom line" -- that is, after a thorough history, physical examination, biochemical, serological, and imaging investigation have failed to uncover a diagnosis.[1,9,10,11] In the setting of abnormal liver tests of unclear etiology, the risks and benefits of a liver biopsy should be carefully weighed, and the decision to perform a liver biopsy must be individualized.

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