Jian-Gao Fan, M.D., Ph.D., Center for Fatty Liver Disease, Department of Gastroenterology, Shanghai First People’s Hospital, Jiaotong University, Shanghai 200080, China

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in clinical practice. Insulin resistance (IR) and oxidative stress play an important role in the development and progression of NAFLD [1-4]. Mortality in patients with NAFLD is significantly higher than in the age- and gender-matched general population, with malignancy, cardiovascular disease (CVD), and liver-related complications being the most common causes of death [1,3,5]. Liver-related morbidity and mortality in NAFLD only occur when the disease has progressed to advanced fibrosis and cirrhosis. Thus, significant fibrosis is rarely encountered in patients with simple steatosis, while nonalcoholic steatohepatitis (NASH) has a real potential for fibrosis progression [1,2,5]. Disease progression to NASH and cirrhosis appears to be very slow, and only a few patients will develop advanced, life-threatening liver disease. As an indolent form of liver disease, NAFLD may be secondary to primary biliary cirrhosis, and patients are expected to reach cirrhosis only late in life. Thus, in many cases of NAFLD, competing risks may take a heavier toll on chances of survival and quality of life than the hepatic disease [6].Thus, although excessive hepatic fat accumulation is the starting point and prerequisite condition for liver injury in IR states, it may also be a condition with far-reaching metabolic consequences, from diabetes control to increased cardiovascular morbidity [2,6].

Relationship of NAFLD with Metabolic Syndrome

The term MetS refers to a cluster of cardiovascular risk factors associated with IR. An association between NAFLD and MetS has been finally established for some retrospective and prospective studies [1,2,4]. MetS is a strong predictor of NAFLD, and NAFLD is less likely to regress in those participants with the MetS at baseline [7]. Abdominal obesity, hypertension, dyslipidemia, and T2DM are pathological conditions frequently associated with NAFLD, and their coexistence within the same individual increases the likelihood of having more advanced forms of liver disease [1,2,4,8]. Compared with abdominal obesity and overall obesity, fatty liver has the highest frequency of clustering, greater specificity, higher positive predictive value, and most attributable risk as a percentage for detecting risk factors clustering [9]. IR is almost a universal finding in patients with NAFLD, and NAFLD is considered the hepatic manifestation of the MetS [1,2,4].

The correlation of liver fat content with insulin sensitivity independent of body fat content is found in the absence of clinical steatosis individuals [10], and most patients with NAFLD are hyperinsulinemic and more insulin resistance (IR) compared with non-steatotic healthy subjects. While the nexus between NAFLD and IR is invariable, the potential relationship has been reviewed elsewhere [11]. However, what is becoming evident experimentally is that the more severe the steatosis, the more likely is the hepatic pathology to be steatohepatitis rather than simple steatosis [1-4,12]. On the other hand, patients with NASH are older, exhibit more advanced IR, and more marked metabolic complications than simple steatosis [2-4].

Although there is a near universal association between NAFLD and MetS irrespective of obesity, NAFLD is not rare in nonobese, nondiabetic adults at the initial diagnosis [13-18]. This group appears to contain relatively younger males with milder histology, abdominal adiposity, and hyperinsulinemia [13-18]. Thus, fatty liver itself is an IR state, not only in subjects with additional metabolic disorders, but also in lean subjects with normal glucose tolerance, since hepatic fat accumulation can lead to hepatic IR; the latter sometimes might occur prior to any alternation in peripheral insulin action, with the resultant hepatic IR inducing peripheral IR [2,4]. Thus, these results have stimulated an interest in the possible role of NAFLD in the development of metabolic complications.

In a prospective population study, fasting triglycerides predicted increased rates of atherosclerosis progression in models that included age, gender, race, hypertension, and smoking; however these results were no longer significant after adjustment for LDL particle concentration.5

A second aspect of the controversy relates to the timing of triglyceride measurements. Triglycerides are conventionally measured after an 8 to 12 hour fast6  in order to avoid the variability in triglycerides after a meal, and provide more reproducible calculations of LDL-cholesterol concentrations7 that serve as the primary emphasis of national guidelines to assess cardiovascular risk.6 However, except in the first hours of the morning individuals are in the postprandial state most of the time.

NAFLD and Increased Incidence of Metabolic Disorders

The presence of mildly raised serum liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT), are the most and often the only laboratory abnormality found in NAFLD patients [1,4,19]. In subjects without viral hepatitis or excessive alcohol consumption, persistent liver enzymes elevation is regarded as surrogate markers of NAFLD [1-4,20-22]. Recently, a number of prospective cohort studies showed that these markers independently predict the development of metabolic complications [23-30].

In the West of Scotland Coronary Prevention Study, a total of 139 men (2.5%) developed new diabetes over 5 years follow-up. ALT, but not AST, levels increased progressively with the increasing number of MetS abnormalities, and only sustained increase in ALT predicted a higher risk for T2DM. In stepwise regression, incorporating ALT and C-reactive protein (CRP) together with MetS criteria, elevated ALT (≥ 29 U/L) and CRP (≥ 3 mg/L) predicted incident T2DM. Thus, even elevated ALT levels within the "normal" range might predict incident diabetes, suggesting hepatic fat accumulation as a contributing factor for conversion to diabetes in men at risk [23,24].

Serum GGT was found specifically associated with the visceral adipose tissue (VAT) and hepatic fat content, but not with the subcutaneous fat area in patients with T2DM [25]. In order to investigate the association between serum GGT and risk of MetS and T2DM, Nakanishi et al. followed-up 2,957 MetS -free men and 3,260 nondiabetic men aged 35-59 years [26]. With adjustment for age, family history of diabetes, BMI, alcohol intake, cigarette smoking, regular physical activity, and white blood cell count, the risk of MetS and T2DM increased in correlation with the levels of serum GGT, ALT, AST, and alkaline phosphatase over a 7-year period. Additional adjustment for all of the other liver enzymes attenuated these associations, but serum GGT remained a significant risk factor for the risk of both MetS and T2DM. Thus, although mild elevations in liver enzymes are associated with features of the MetS, only raised GGT is an independent predictor of deterioration of metabolic disorders [26]. This may reflect the role of GGT in the dynamics of free radical generation, a factor involved in the pathogenesis of metabolic risk [25-27].

However, these studies have not measured insulin sensitivity (Si), which is important given associations of obesity and Si with NAFLD. In the IR Atherosclerosis Study of subjects aged 40-69 years, a total of 127 (20%) and 148 individuals (16%) had developed MetS and T2DM, respectively, after 5 years follow-up. Hanley et al. found that ALT and the AST-to-ALT ratio at baseline predict MetS independently of potential confounding variables, including directly measured Si and acute insulin response. In addition, AST and ALT were positively associated with incident T2DM after excluding former and moderate heavy drinkers [28,29]. Thus, elevations in ALT and GGT are considered as part of the MetS. However, it should be remembered that the isolated liver enzyme levels has a poor sensitivity and negative predictive of NAFLD, and the entire histological spectrum of NAFLD can be seen in patients with normal liver function tests [1,4,19].

Recently, Fan et al. have followed-up 358 patients with NAFLD and 788 age, sex, and occupation-matched counterparts for 6 years [31]. Both at baseline and follow-up, MetS components were present at a greater frequency among those with NAFLD than among controls. The prevalence of MetS was not formally assessed by predefined criteria at entry, but the authors found 26% of the NAFLD group and 12% of controls had three or more metabolic abnormalities at baseline; the corresponding figures for the follow-up study were 68% and 22%, respectively. Subjects with NAFLD were also more likely to develop new metabolic disorders than controls; a new diagnosis of T2DM was made in 20%, hypertriglyceridemia in 39%, obesity in 48%, and hypertension in 70% of subjects. Further, in an attempt to establish any separate effect of fatty liver on the incidence of metabolic disorders other than those common associations with overall obesity, a separate analysis was performed according to the characteristics at study entry. The incidence of hypertension, hypertriglyceridemia, hypercholesterolemia, impaired fasting glucose, and T2DM were significantly higher in the NAFLD group than controls with neither fatty liver nor obesity [31]. These results are consistent with the study of Friis-Liby et al, in which a significant proportion of patients with both clinical and histological diagnosis of NAFLD develop T2DM, dyslipidemia, and hypertension soon after diagnosis, although mean body weight had no change during follow-up [32]. Therefore, NAFLD is more predictive of the development of metabolic disorders than is obesity itself, and it can be considered an early predictor of MetS and T2DM.

The adverse influences of NAFLD on accelerated metabolic complications may be the consequence of liver fat accumulation and underlying VAT, the resultant hepatic and peripheral IR, and chronic subclinical inflammation and increased oxidative stress. In addition, decreased adiponectin concentrations might also be part of the possible mechanism [2,6]. However, it is not known whether lifestyle intervention and pharmacotherapy on NAFLD/NASH will ultimately prevent the development of metabolic complications.
In summary, patients with NAFLD and/or unexplained liver enzymes elevation are associated with the high incidence of metabolic complications in the future, suggesting that NAFLD is inclined to be more than a hepatic disease confined to classic boundaries. Although the presence of multiple features of MetS is associated with more advanced and more progressive NAFLD, cardiovascular risk may compete with liver-related complications in dictating the final outcome. It becomes mandatory to evaluate the diabetic and cardiovascular risk in NAFLD patients, and to consider careful surveillance and aggressive treatment not only of their liver disease, but also of the possible underlying metabolic complications [4,20].

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Please address correspondence to:
Professor Jian-Gao Fan
Director of Center for Fatty Liver Disease
Vice Chief of Department of Gastroenterology
Shanghai First People’s Hospital
Jiaotong University
Shanghai 200080, China