Dangerous Liaisons: The Metabolic Syndrome and Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is an underrecognized manifestation of the metabolic syndrome. The term refers to a spectrum of fatty liver disease that occurs in the absence of significant alcohol consumption. At the benign end of the spectrum, most patients with NAFLD have fatty liver alone (simple steatosis). Only a small proportion (approximately 10%) also have features of liver cell injury or fibrosis, referred to as nonalcoholic steatohepatitis (NASH). This distinction between simple steatosis and NASH is important because the natural history of these categories differs substantially. Patients with simple steatosis usually have a benign prognosis from the point of view of liver disease (1-4). In contrast, up to 20% of patients with NASH may ultimately develop advanced liver disease (1, 3-5). The prognosis of NASH-related cirrhosis is poor: It results in liver failure or liver-related death in approximately one third of cases (6, 7). Hepatocellular cancer is also a recently recognized complication of NASH-related cirrhosis (6, 8). Although only a minority of patients with NAFLD develop advanced liver disease, this condition is causing increasing alarm because of its marked prevalence. A recent large population-based study from the United States found a prevalence of hepatic steatosis of 34% (9). However, NAFLD is not just a western disease. Increasing rates of NAFLD are being reported in the Asia-Pacific area and have been attributed to the epidemic of obesity and type 2 diabetes spreading throughout this region (10). Data from cross-sectional studies have shown that NAFLD is associated with insulin resistance, which is a key factor driving the development of steatosis (11). The pathogenesis of steatohepatitis and progressive liver injury is less clearly delineated but is likely to involve further insults that lead to increased proinflammatory cytokine production, oxidative stress, and mitochondrial dysfunction (12). In this issue, Hamaguchi and colleagues (13) examined the relationship between the metabolic syndrome and NAFLD in healthy Japanese men and women drinking 20 g or less of ethanol per day. Unlike previous cross-sectional work, their study was longitudinal. Because this is one of the first large longitudinal cohort studies published, in which participants in effect acted as their own controls and so reduced confounding variables, it provides more convincing evidence of a causal relationship between the metabolic syndrome and NAFLD. The authors were able to identify both prevalent and incident cases, providing important new data on the rate of development or regression of NAFLD and confirming the role of the metabolic syndrome and weight change. On abdominal ultrasonography, fatty liver was identified in 18% of the study sample, with a 2.5-fold higher prevalence in men than in women. The mean body mass index (BMI) of patients with NAFLD was in the obese range for people of Asian descent at 25.6 kg/m2 for men and 25.7 kg/m2 for women. These figures are similar to other published prevalence data from Japan (14) and confirm that Japanese persons have an elevated risk for comorbid conditions at a lower BMI than white populations (in the latter, persons with BMIs >30 kg/m2 are considered to be obese). This may be due to ethnic-specific differences in body composition profiles (15). Sex-related differences in fat distribution may also contribute to the striking distinction in the prevalence of NAFLD between Asian men and women because visceral adiposity, assessed using waist circumference, is more closely associated with the metabolic syndrome and its components than is BMI. Hamaguchi and colleagues' study clearly demonstrates the very strong relationship between NAFLD and the metabolic syndrome. Approximately one third of the patients in this study with NAFLD met the criteria for the metabolic syndrome, which is very similar to its reported prevalence in Italian patients with NAFLD (16). Among participants who were free of NAFLD at their original examination, 14% of men and 5% of women received new NAFLD diagnoses at the follow-up examinations. The most important observation from Hamaguchi and colleagues' study was that the metabolic syndrome carried a 4 to 11 times higher risk for future NAFLD. In addition, NAFLD developed with very small increases in body weight. A previous study from Japan demonstrated new onset of fatty liver in 14.3% of 35519 participants who had repeated liver ultrasonography over a 12-year period (14). The development of fatty liver was associated with an increase in BMI of 1 kg/m2 (around 2 to 3 kg), suggesting that relatively small changes in body weight may exert significant metabolic effects. Given the fundamental relationship between the metabolic syndrome and insulin resistance, Hamaguchi and colleagues' data provide further strong support for the central role of insulin resistance in the pathophysiology of NAFLD. The high prevalence of the metabolic syndrome in patients with NAFLD in Hamaguchi and colleagues' sample is of concern, since previous studies have shown that the presence of this syndrome increases the likelihood of more severe liver disease. In Marchesini and colleagues' Italian study of 304 patients with NAFLD but not overt diabetes (16), the presence of the metabolic syndrome conferred a higher risk for NASH (odds ratio, 3.2 [95% CI, 1.2 to 8.9]) and a high risk for advanced fibrosis (odds ratio, 3.5 [CI, 1.1 to 11.2]). As alluded to earlier, this subgroup of patients is at much higher risk for progressive liver disease and its attendant complications. Another important finding from the current study was that steatosis regressed in 16% of patients, although this was less likely in the presence of the metabolic syndrome. Of importance, regression was associated with a small weight loss (mean, 2.3 to 2.5 kg). This is encouraging because weight loss and lifestyle modification make up the principal management strategy for NAFLD and the metabolic syndrome. However, it is important to be aware that progression of fibrosis has been seen concurrently with a reduction in steatosis. In particular, once cirrhosis develops, fat and other histologic features of steatohepatitis may regress, leaving an inactive micronodular cirrhosis (17). Recent work suggests that many cases previously regarded as cryptogenic cirrhosis represent burnt out NASH. As Hamaguchi and colleagues point out in their Discussion, they were unable to investigate some important and clinically relevant issues. First, abdominal ultrasonography remains an imperfect tool to diagnose NAFLD, with an error rate of 10% to 30% (18). Newer methods, such as magnetic resonance spectroscopy, may perform better. Second, without biopsy it cannot be determined which patients with NAFLD have NASH, the progressive form of the disease. Liver function tests and other investigative serum measures have not been useful, and we rely mainly on the presence of clinical risk factors, such as marked obesity, hypertension, and diabetes, to estimate the likelihood of steatohepatitis and fibrosis (19, 20). Liver biopsy remains the gold standard for diagnosis but is not feasible for large, population-based studies. Finally, the role of physical activity and exercise in reducing NAFLD requires clarification. Small increments in weight change may be associated with changes in physical activity, and the two may be synergistic in improving or worsening metabolic variables. How does Hamaguchi and colleagues' study assist in the investigation and management of patients with NAFLD? It clearly shows that the metabolic syndrome and weight gain are risk factors for the disease and for new-onset cases. Nonalcoholic fatty liver disease is the hepatic expression of the metabolic syndrome. More important, Hamaguchi and colleagues' findings support the possibility that NAFLD might be reversible if BMI and aspects of the metabolic syndrome are managed effectively, even without normalization of weight. The high prevalence of NAFLD in Hamaguchi and colleagues' study sample reinforces just how important this disorder has become.