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Letters to the Editor |
1 Health Screening Center
2 Department of Occupational, Medicine and
3 Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Korea
4 Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Ulsan, Korea
aAddress correspondence to this author at: Kangbuk Samsung Hospital, 108 Pyung dong, Jongro-Gu, Seoul, Korea 110-746. Fax 82-2-2001-2626; e-mail sh703.yoo{at}samsung.com.
To the Editor:
First, the relationship between alanine aminotransferase (ALT) and nonalcoholic fatty liver disease (NAFLD) has not yet been clearly established, although increased liver enzymes are usually used as a surrogate marker of NAFLD. Tagher et al. have also noted that liver enzymes may be within the reference interval in up to 70% of patients diagnosed with NAFLD and that the full histological spectrum of NAFLD may be present in patients with normal liver enzymes. Our observations were therefore novel and have potential importance in understanding the relationship between ALT and NAFLD. Furthermore, several issues need to be clarified about ALT, including the isoforms of ALT and the role of different ALT isoforms in humans (1).
Second, regarding the adjustment of confounders, such as insulin resistance, we did not perform this study using the euglycemic clamp and cannot comment on Tagher’s concerns about the interrelation between ALT, NAFLD, and insulin resistance as assessed by the euglycemic clamp technique. Indeed, performance of studies with large samples are not feasible with the glucose clamp methods. Fortunately, other investigators have reported that the homeostasis model assessment of insulin resistance (HOMA-IR) is strongly related to clamp-measured insulin resistance (2). Furthermore, a recent study using sophisticated techniques such as MRI and the oral glucose tolerance test has shown that only half of the patients with MRI-assessed fatty liver disease had increased ALT, whereas even modest ALT increases within the reference interval were associated with deterioration in glucose and lipid metabolism as well as insulin resistance (3). As we noted in our article, even in participants without any features of the metabolic syndrome, any increase of serum ALT, even that within the reference interval, continued to predict the incidence of NAFLD (4). To date, although the relationship between ALT and NAFLD remains to be elucidated, our observation supports the idea that ALT is not only a consequence but also a predictor of NAFLD. We agree with Tagher and colleagues that insulin resistance as assessed by sophisticated techniques such as the euglycemic clamp method could be helpful in understanding the relationship between ALT and NAFLD through a pathway that is distinct from systemic insulin resistance.
Third, regarding the determination of NAFLD, Tagher et al. raised a concern regarding the ultrasound (US) measurements used in our study, the sensitivity of early fatty infiltration (<33%), and the limited ability, as we also discussed in our article, to differentiate simple steatosis from inflammation or fibrosis (4). Whether the degree of misclassification of fatty liver diagnoses based on US varies according to the ALT concentration is presently unknown. As Tagher et al. note, nondifferential misclassification, if present, would tend to reduce the strength of the associations between ALT and NAFLD.
Finally, Tagher and colleagues found differences in the incidence of NAFLD in our study and a previously reported study by Suzuki et al. (5). These differences may have been in part attributable to differences in both the study populations and the outcome measures. In the study by Suzuki et al. (5), the study participants were 20–59 years old, were 26.8% female, and the incidence of increased transaminasemia was highest among males 20–39 years old (5). Our study population, however, was composed of only males, and the majority (70.8%) were 30–39 years old. Outcome measurements in the Suzuki et al. (5) study were based on increased ALT whereas ours were based on US. For exploratory purposes, we performed ancillary analyses to estimate the incidence of increased ALT as an outcome measure. Whereas 984 incident cases of US-based NAFLD developed during 13 882.4 person-years of follow-up [incidence density (ID), 74.1 per 1000 person-years; 95%, CI 69.5–78.7], 700 incident cases of increased ALT, defined as serum ALT 
35 U/L, developed during 13 822.4 person-years of follow-up (ID, 50.6 per 1000 person-years; 95% CI, 46.9–54.4). To minimize the effect of existing fatty infiltration on the baseline ALT, additional analyses were performed by excluding participants with incident NAFLD that occurred during the first 1 or 2 years of follow-up (Table 1
). Although the magnitude of the association between ALT and NAFLD was slightly reduced, this analysis did not qualitatively change any of the observed associations (Table 1
). Future research will shed light on the question of what underlies the relationship between ALT and an increased risk of NAFLD.
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We appreciate the opportunity to clarify our findings. The letter by Tagher and colleagues raises several important issues in the interpretation of our findings.
Acknowledgments
Grant funding/support: None declared.
Financial disclosures: None declared.
References
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