Liver function tests as indicators of metabolic syndrome

See Article on Page 27 Nonalcoholic fatty liver disease (NAFLD) is no longer considered to be a normal physiologic condition without any clinical significance. It is now widely accepted that nonalcoholic steatohepatitis (NASH), a type of fatty liver disease, can progress to end-stage liver disease and increase the risk of mortality. In addition, NAFLD patients are associated with a significantly higher overall mortality as well as liver-related mortality compared to the age- and gender-adjusted general population.1,2 Accordingly, several studies have been conducted to redefine the normal ranges of liver function tests, especially alanine aminotransferase (ALT) levels considering the influence of NAFLD on serum ALT level. However, there are two different ways to interpret ALT levels. Piton et al suggested that these levels should be interpreted with respect to the body mass index (BMI) considering the positive association between ALT level and BMI.3 However, this concept was questioned by Prati et al4 since NAFLD itself is not necessarily a benign liver disease without clinical significance. The normal range of ALT levels is significantly lower than the conventional cut-off levels (41 IU/L for men and 30 U/L for women) if patients with risk factors for NAFLD are excluded. This finding was also observed in a Korean population in which patients with NAFLD were excluded histologically.5 Another important study from Korea also showed a positive association between ALT level even within the normal range by conventional criteria and liver-related mortality.6 All these findings suggested that the normal range of ALT level (along with those of other liver function test factors) should be adjusted. However, several points should be considered before applying the revised upper limit of normal serum ALT levels. A study by Oh et al7 reported that the incidence of metabolic syndrome and NAFLD correlates with ALT and γ-glutamyltransferase (GGT) levels within the conventional reference ranges. About half of the subjects with ALT levels in the upper fourth quartile of the conventional normal range had fatty liver disease that appeared on ultrasonography. This finding strongly suggests that adjustment of the normal range for ALT level can increase the detection rates of patients with NAFLD. However, the study population consisted of individuals who underwent health check-ups voluntarily, and therefore could have introduced selection biases. Another unanswered question is what proportion of patients with NAFLD actually has histologically-diagnosed NASH. It is generally accepted that liver-related mortality does not increase in patients with simple steatosis. We do not and probably cannot conclusively determine if this is actually the case in near future since liver biopsy is still the only test that can differentiate NASH from simple steatosis. The incidence of NASH was reported to be 2.2% among Korean living liver donors among whom the overall incidence of NAFLD was 51.4%. 8 Therefore, the prevalence of NASH among individuals with NAFLD is estimated to be 4.3%. Since this study included patients with ALT level elevated up to 120 IU/L, the proportion of NASH cases may be different (probably lower) among fatty liver disease patients with normal ALT level as defined by conventional criteria. Therefore, further studies are needed to investigate whether the adjustment of the normal range of ALT levels is cost-effective or can reduce long-term liver-related mortality. Secondly, ALT or GGT (and other liver function tests) is primarily used for screening for liver disease and to determine the appropriate treatment for patients with liver diseases. Several follow-up studies have demonstrated that elevated ALT or GGT level is associated with increased overall mortality including death from cardiovascular disease or cancers and/or liver-related mortality.9,10 However, even though serum ALT and GGP levels may predict the development of metabolic syndrome or increased mortality, adoption of these tests to screen for metabolic syndrome or other diseases is quite a different story. For practical reasons, serum ALT or GGT levels are never used as an isolated test to screen for liver disease or other diseases in Korea. For example, the tests for routine health check-ups sponsored by the National Health Insurance Cooperation in Korea include height, weight, BMI, blood pressure, fasting blood glucose, total cholesterol, aspartate aminotransferase, and ALT and GGT levels. In addition, many other programs also include tests for serum HBsAg or anti-HCV antibodies. Although serum ALT or GGT level within the reference limits can predict the development of metabolic syndrome or future mortality rates, other parameters including BMI, blood pressure, fasting blood glucose levels, and total cholesterol levels, or combinations of these factors are probably more informative. Furthermore, in the study by Oh et al,7 serum ALT or GGT level was used to predict the presence of pre-existing metabolic syndrome, but their usefulness in predicting the development of metabolic syndrome or mortality is unknown. Therefore, it is still unclear whether the use of serum ALT or GGT levels within the upper fourth quartile of the conventional normal range is in fact helpful for detecting metabolic syndrome or predicting mortality in ordinary clinical practice. Thirdly, it is still unknown whether the increase in liver-related deaths in Korean people with slightly higher aminotransferase activity that still within the normal range can be attributed to NAFLD or other liver diseases including autoimmune hepatitis or Wilson's disease.6 In the study by Kim et al,6 serum HBsAg and/or anti-HCV antibody levels were not tested, and the presence of underlying liver cirrhosis was excluded only by a self-report questionnaire. History of alcohol abuse was also obtained only by the self-report questionnaire. Therefore, it is still unknown whether the increased number of liver-related deaths was caused by unreported chronic hepatitis B virus (HBV) infection and/or alcohol- related cirrhosis, or by other liver diseases including NAFLD, cryptogenic liver disease, autoimmune hepatitis, or Wilson's disease. Given that Korea is an area with endemic chronic HBV infection and high rates of alcohol abuse, the former scenario is more likely. Therefore, the clinical benefit from improved detection of NAFLD by a revised normal range of ALT or GGT is largely unknown, and should be addressed by future studies. In conclusion, many studies have demonstrated that the conventional normal range of ALT level or those of other liver function test factors should be adjusted to account for the influence of NAFLD. In addition, emerging data have suggested that serum ALT activity may serve not only as a marker of liver diseases but also as an indicator of metabolic syndrome or general health. However, despite its potential role as an indicator of NAFLD or metabolic syndrome even within the conventional reference ranges, it is still unknown whether the adjustment of the normal cut-off level of ALT can help reduce liver-related or overall mortality rates with acceptable cost-effectiveness. Future studies are needed to address this issue.