NAFLD is being increasingly recognized as one of the major causes of chronic liver disease in Western countries and also in the developing countries (Clark, 2006
; Chitturi et al., 2007
; Ong and Younossi, 2007
). Recently, NAFLD is considered to be the hepatic component of MS (Tarantino et al., 2007
). In addition, some studies have demonstrated that ALT is associated with risks of type 2 diabetes mellitus and MS (Schindhelm et al., 2007
; Doi et al., 2007
). However, very little progress has been made in a large adult population in China. The purpose of our study was to investigate the association between ALT levels and MS in NAFLD.
In China, previous studies reported that the prevalence of the MS is 6.6% to 13.8% in the general population (Gu et al., 2005
; Yao et al., 2007
). In the present study, we found that, according to the ATP III definition, MS was more common among subjects with NAFLD (33.83%), based on liver ultrasonography, compared with subjects without NAFLD (10.62%). Similar findings have also been reported in previous studies (Clark, 2006
; Oh et al., 2006
). Our result supports that NAFLD is associated with the MS.
ALT is an indicator of liver injury and often used as a surrogate marker for NAFLD (Schindhelm et al., 2006
). However, the exact pathogenesis of raised ALT in NAFLD remains unclear. Current understanding of the progression of NAFLD involves a “2-hit” hypothesis. The first hit involves accumulation of excess fat in the hepatic parenchyma. This step has been linked to insulin resistance associated with MS, modulated mainly by adipocytokines and dysfunction of cellular TG synthesis and transport. On the basis of the first hit event, oxidation stress as a second hit event caused by reactive oxygen species (ROS) induces necroinflammation in the fatty liver (Adams et al., 2005
; Bugianesi et al., 2005
; Utzschneider and Kahn, 2006
). Vozarova et al.(2002
) reported that serum ALT concentrations were related to hepatic insulin resistance and suggested that a raised ALT reflects fatty changes in the liver. Oh et al.(2006
) investigated the association between increased ALT activity and the metabolic factors in NAFLD, in which MS was defined by the new International Diabetes Federation (IDF) definition. They found that central obesity, raised TG, reduced HDL-c and raised FPG are MS components that contributed to increased ALT activity. Schindhelm et al.(2007
) also reported that ALT was associated with risk of the MS in a general population of middle-aged Caucasian men and women after 6.4 years follow-up. In this study, among NAFLD subjects, we found that there were statistically significant correlations (P
<0.001) between the ALT levels and most metabolic risk factors. By multiple stepwise regression analysis we also observed that TG, FPG, BMI, WC, DBP and deceased HDL-c, which were components of MS, were associated with ALT levels in NAFLD subjects. Furthermore, mean ALT levels increased according to the number of MS components and ALT values in subjects with MS were significantly higher compared to those without MS. These might be explained that in NAFLD, the elevation of ALT levels might be the expression of excess deposition of fat in the liver as the result of various metabolic conditions and reflect ongoing inflammation which impairs insulin signaling both in the liver and in the entire body (Schindhelm et al., 2005
; Machado and Cortez-Pinto, 2006
; Tarantino et al., 2007
). Therefore, our results demonstrate a strong relationship between ALT levels and MS in NAFLD. NAFLD may be regarded as the hepatic manifestation of the MS. It is also implicated that the cluster of MS components might be the predictor of ALT elevations in subjects with NAFLD.
Although NAFLD is found to be closely related to metabolic disorders, it is interesting to be noted that a significant number of subjects with NAFLD (11.22%) have no features of MS defined by ATP III in our study. One contributing factor may be that the definition of central obesity using WC in ATP III criteria for the MS may not be appropriate for Asians, which may underestimate the subjects at risk in this study. It has been recognized that obesity-related metabolic disorders commence at much lower levels of BMI in Asians. Studies on body fat have shown that Asians have higher percentage adiposity at a lower BMI than Caucasians (Fan and Peng, 2007
). In previous studies, at lower BMI and WC, increased risk of having obesity-related cardiovascular risk factors was found in Asians (Lin et al., 2002
; Thomas et al., 2004
; Wildman et al., 2004
). Given the importance of MS in the diagnosis of NAFLD and the discrepancies in various criteria for MS, further work is needed to explore different criteria in all the subjects to determine which criterion best defines the MS in Asians. Another possible factor is that the possibility of residual confounding effects still exists in subjects with NAFLD because we obtained medical history and lifestyle characteristics with a simple questionnaire so that we were not able to exclude the possible presence of other rare causes of liver disease.
Our results show that the incidence of NAFLD in men (30.94%) was much higher than that in women (15.65%), and that in NAFLD men had higher ALT levels compared with women, except for the population of 50 years old or older. These results are consistent with those of previous studies and indicate that NAFLD is more prevalent in males (Schwimmer et al., 2005
; Arun et al., 2006
; Zelber-Sagi et al., 2006
). The pathogenic mechanism may be that men generally have greater abdominal visceral fat mass, which seems to be an important risk factor for NAFLD, even in patients with a normal BMI (Garcia-Monzón et al., 2000
). Compared with adipose tissue in other sites, visceral adipose tissue is more resistant to insulin, exhibits greater lipolysis, and produces more free fatty acids (Kabir et al., 2005
). Moreover, we observed the peak levels of ALT in women older than 50 years, which might be due to the menopausal status and lack of physical exercise in this period of time. It may, therefore, suggest that the prevention of NAFLD is more important for men and postmenopausal women.
In conclusion, we found a strong relationship between ALT levels and MS in patients with NAFLD and revealed that mean ALT levels increased with the number of MS components. These findings suggest that the cluster of MS components might be the predictor for ALT elevations in NAFLD. One of the limitations in the present study is that the diagnosis of fatty liver was based on ultrasound imaging, which was not confirmed by liver biopsy, the gold standard for the assessment of liver histology and a key test to diagnose NAFLD (Brunt, 2005