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Alanine aminotransferase as an independent predictor of incident nonalcoholic fatty liver disease
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Giovanni Targher, University Hospital Division of Endocrinology, University Hospital of Verona, Italy, Massimo Franchini, Gian Cesare Guidi, Michele Muggeo, Giuseppe Lippi.
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giovanni.targher{at}univr.it Giovanni Targher, et al.
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Dear Editor, We read with interest the recent article by Chang et al demonstrating that higher serum alanine aminotransferase (ALT) concentrations, within the reference interval, independently predict the incidence of nonalcoholic fatty liver disease (NAFLD) in a large cohort of apparently healthy Korean men (1). Several prospective studies have previously shown that raised ALT levels, even within the reference interval, also predict the future development of type 2 diabetes (2, 3) and cardiovascular events independently of other known risk factors (4-6). In all of these studies, however, raised ALT levels have been used as a surrogate marker of NAFLD. We think the association of two conditions, that is raised ALT levels and incident NAFLD, does not necessarily prove causation. The greater incidence of NAFLD – as diagnosed by ultrasound – among those with sligthly increased ALT levels at baseline might most likely be explained by an underlying common mechanism, i.e., more severe degree of insulin resistance in those with higher ALT levels than in those with lower ALT levels. The fact that the association between increasing serum ALT levels and incident NAFLD remained significant even after adjustment for the HOMA-estimated insulin resistance may be simply due to the fact that the HOMA-IR score is not a good proxy measure of insulin resistance. This leaves us wondering how different the results would have been if the euglycemic clamp technique or other more accurate methods would have been used to measure insulin resistance. Another important caveat in the interpretation of the results of this study - that is also a major limitation of the study - is that the diagnosis or exclusion of NAFLD at baseline was based on serum liver enzymes and ultrasound imaging. We think some non-differential misclassification of NAFLD on the basis of liver enzymes and ultrasonography is likely (i.e., some of participants could have underlying NAFLD despite normal liver enzymes and a negative ultrasonography). This could also be partly confirmed by the unexpectedly high incidence of NAFLD during the short period of follow-up (<3 years) among the study participants having an average age of 36 years. Indeed, it is known that liver enzymes may be in the normal range in up to 70% of patients with diagnosed NAFLD and that the full histopathological spectrum of NAFLD may be present among patients with normal liver enzymes, which therefore cannot be reliably used to exclude the presence of NAFLD (7-9). Moreover, although liver ultrasonography is widely used for diagnosing NAFLD, this imaging method has a good sensitivity and a specificity only in detecting of moderate and severe hepatic steatosis, but it is not (totally) sensitive particularly when hepatic fat infiltration on liver biopsy is less than 33% (10). Only liver biopsy can be used to accurately determine the histological severity and prognosis of liver damage (7). REFERENCES 1. Chang Y, Ryu S, Sung E, Jang Y. Higher concentrations of alanine aminotransferase within the reference interval predict nonalcoholic fatty liver disease. Clin Chem 2007, doi 10.1373/clinchem.2006.081257 2. Sattar N, Scherbakova O, Ford I, O’Reilly DSJ, Stanley A, Forrest E, et al. Elevated alanine aminotrasferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study. Diabetes 2004; 53: 2855-2860 3. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D’Agostino RB, Haffner SM. Liver markers and development of the metabolic syndrome. The Insulin Resistance Atherosclerosis Study. Diabetes 2005; 54: 3140-3147 4. Ioannou GN, Weiss NS, Boyko EJ, Mozaffarian D, Lee SP. Elevated serum alanine aminotrasferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006; 43: 1145-1151 5. Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007, doi 10.1016/j.atherosclerosis. 2006.04.006 6. Targher G. Mini-review. Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens. Diabet Med 2007; 24: 1-6 7. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231 8. Day CP. Nonalcoholic fatty liver disease: current concepts and management strategies. Clin Med 2006; 6: 19-25 9. Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histological spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 37: 1286-1292 10. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002; 123: 745-750 |
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