Mortality in nonalcoholic fatty liver disease: Clues from the cremona study
Authors: Leon A. Adams
Journal: Hepatology (2011)

BMI, body mass index; FLI, fatty liver index; GGT, gamma glutamyltransferase; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. As the "father of modern medicine", Hippocrates is credited as being an astute and critical observer of the natural history of disease. He categorized disease as either acute or chronic, and his observations helped him conclude that illness was due to natural rather than spiritual or mystical forces.1 Today, an understanding of the natural history of a disease is necessary for any physician dealing with illness. At an individual patient level, quantifying and predicting future disease morbidity and mortality assists in counseling and prognostication, and determines the need for treatment as well as its timing and intensity. At a population level, quantification of the disease-related health burden in the community is important for health resource allocation and prioritization and institution of public health preventative and treatment measures. Nonalcoholic fatty liver disease (NAFLD) is a liver condition whose natural history is still in the process of being defined. Over the past 2 decades, the prevalence of NAFLD has increased in parallel with the prevalence of its underlying pathogenic factors, namely obesity, insulin resistance, and the metabolic syndrome.2, 3 Consequently, family physicians and specialists are frequently encountering patients with NAFLD. It is clear some of these patients may progress to end-stage liver disease; notably, the number of liver transplants performed for NAFLD-related cirrhosis has been increasing over the past decade in the United States.4 However, clinical experience tells us that only a small minority of patients with NAFLD develop significant liver-related morbidity. NAFLD has also been associated with increased risk of developing cardiovascular disease and diabetes; however, whether this association increases mortality rates in patients with NAFLD is less clear.5, 6 Unfortunately, the natural history of NAFLD is difficult to elucidate, and it remains challenging to quantify the magnitude of hazard for patients with NAFLD and to identify which are at most risk of disease morbidity. NAFLD is largely asymptomatic and thus often undiagnosed or only found incidentally during investigation of other conditions. Furthermore, the diagnosis requires liver imaging or biopsy, which are logistically difficult to apply to large numbers of individuals from the general population. Finally, similar to most chronic liver conditions, it requires years to evaluate the endpoints of end-stage liver disease and death. Thus, to date, there has been a paucity of population-based studies examining the natural history of NAFLD. In this issue of HEPATOLOGY, Calori and colleagues have overcome some of these obstacles, to detail the impact of fatty liver on mortality in a large (n = 2011) population-based cohort from Cremona in Northern Italy over a 15-year period.7 Fatty liver was diagnosed using a noninvasive predictive algorithm (the fatty liver index [FLI]), which is based on the combination of body mass index (BMI), waist circumference, and serum triglyceride and gamma glutamyltransferase (GGT) levels. The FLI is a continuous measure, ranging from 0 to 100, that was previously validated to predict ultrasound-diagnosed fatty liver in a similar population-based cohort from the Dionysos Nutrition and Liver Study.8 Over the 15-year observation period, 25% of the general population died, with cardiovascular disease accounting for 45% of deaths, malignancy for 36% of deaths, and liver disease for 7% of deaths. Significantly, FLI was predictive of all-cause and liver-, cardiac-, and cancer-related death; it, however, remained significant only for liver-related death after adjustment for baseline insulin resistance. Therefore, can we conclude NAFLD independently increases mortality risk in the general population, and furthermore, can we use the FLI to prognosticate risk for our patients with NAFLD? Before we can do so, a few caveats need to be applied; the FLI was originally developed to predict a binary outcome (the presence or absence of alcoholic and nonalcoholic fatty liver). The diagnostic accuracy of the FLI has not been validated in separate cohorts, and the sensitivity and specificity for hepatic steatosis at the recommended cutoff of 60 in the original study was only 61% and 86%, respectively.8 In the current study, however, the score is used as a continuous variable. Thus, it is not certain whether the score is identifying subjects with fatty liver, who then have a poorer prognosis or whether it reflects the continuum of metabolic parameters across the whole population that predict a poorer outcome. In addition, the current study also did not specifically exclude individuals with other liver diseases such as those deriving from hepatitis C and alcohol, which may act as potential confounders between the FLI and liver-related mortality. Despite these caveats, the study by Calori et al. remains one of the largest population-based cohorts with significant follow-up documenting mortality outcomes in subjects using a diagnostic measure of fatty liver. Their observations that FLI is associated with increased all-cause and liver- and cardiac-related death after age and sex adjustment is similar to findings from other hospital- and community-based cohorts (Table 1). In these studies, the increase in all-cause mortality rate in subjects with NAFLD was 30%-50% after one decade and increased with time to 70% after more than two decades.11, 12, 14 Among patients with type 2 diabetes, the increase in mortality rate associated with NAFLD may be even higher at more than two-fold after 10 years of follow-up.15 Conversely, among patients with NAFLD, hyperglycemia or diabetes is the only clinical factor that consistently prognosticates a higher all-cause mortality rate in patients with NAFLD.11, 16 The only other prognostic factor currently identified to predict mortality in subjects with NAFLD is the histological severity of disease. All-cause mortality is not increased in subjects with simple steatosis, whereas all-cause and cardiac- and liver-related death are all significantly higher in subjects with nonalcoholic steatohepatitis (NASH) compared to the general population.10, 12, 14 It is not clear however, whether it is the more severe liver disease or the associated underlying severe metabolic disease that is responsible for the increase in all-cause and cardiac-related mortality. In contrast to the majority of previous natural history studies, the Cremona study was able to account for potential confounding factors, including insulin resistance. After adjustment for insulin resistance, FLI was no longer predictive of all-cause, cardiovascular-, or cardiac-related mortality. This suggests that the metabolic milieu associated with NAFLD is intricately associated with outcomes. However, concerning liver-related death, FLI remained predictive even with adjustment for insulin resistance. Of the components of the FLI, measures of adiposity (BMI and waist circumference) and GGT levels were significantly associated with liver-related death rates. GGT was also the only component of the FLI that was predictive of all-cause mortality. Other large population studies have also found GGT levels to be independently predictive of all-cause, liver-related, diabetes-related, and cancer-related death.17 The associated risk of an elevated GGT may be modified by the presence of hepatic steatosis. A German cohort study found hepatic steatosis to be a significant predictor of all-cause and cardiac-related mortality in men when it was associated with high GGT levels, whereas high GGT levels were not predictive of death in the absence of hepatic steatosis.13 Elevated GGT levels are associated with a more severe histological spectrum of NAFLD, namely the presence of NASH and fibrosis, whereas reductions in GGT predict histological improvement in NAFLD following bariatric surgery.18 GGT levels are also strongly correlated with volume of visceral adipose tissue and severity of insulin resistance, two pathogenic risk factors for severe NAFLD.19 Furthermore, it has recently been described that serum GGT levels and metabolic traits, including insulin resistance and serum triglyceride levels, have shared genetic determinants which may include the β-2 adrenergic receptor gene.20 Thus, the GGT component of the FLI may reflect genetic and metabolic determinants of histologically severe NAFLD, which are associated with poorer outcomes. In conclusion, NAFLD and its intricately linked metabolic disturbances are associated with increased mortality rates. Severe NAFLD (i.e., NASH) is often related with severe metabolic disease (i.e., diabetes), both of which predict a poorer prognosis. Teasing apart the relative contributions of NAFLD versus metabolic abnormalities will require well-characterized cohorts with appropriate exclusions and accurately diagnosed NAFLD. Hippocrates urges us to "declare the past, diagnose the present, foretell the future". To foretell the future, we need further population cohort studies examining indicators such as the FLI and GGT in well-defined subjects with NAFLD. These studies will hopefully provide us with accurate mortality outcome data and useful markers to predict individual patient outcomes.