The present findings indicate that combinations of unfavorable determinants in lifestyle markedly increase the risk for fatty liver, as assessed using a recently developed predictor algorithm, FLI. The rather linear association between abnormal FLI and combined lifestyle risk factor status supports the view that significant benefits on liver health could be gained from simultaneous adherence to multiple low-risk lifestyle-related factors and from systematic behavior change support systems for individuals presenting with high-risk lifestyles [1–4, 7, 8]. Based on recent population surveys successful lifestyle interventions could lead to a striking reduction in mortality from both hepatic and extrahepatic causes [1, 2, 4, 17, 19]. Current data indicates that FLI, a non-invasive biomarker of steatosis, could perhaps be used as a clinical tool for patient guidance and motivation during interventions aimed at maintaining long-term lifestyle changes that promote the loss of liver fat.
Fatty liver is currently a highly common condition in high income countries being estimated to affect at least 25–30% of adults in general population and over 70% of those with gross obesity or diabetes [23–25]. Therefore, greater awareness of this phenomenon is important to prevent a looming public health crisis. Building of excess fat in liver cells has been regarded as the hepatic manifestation of the metabolic syndrome, which associates with cerebro- and cardiovascular disease risks, tissue triglyceride deposition, hyperinsulinemia and insulin resistance [10, 19, 23, 26–28]. Therefore, new non-invasive tools for detecting hepatic steatosis in an early phase are needed to prevent progression of liver disease and associated metabolic comorbidities. Although the FLI algorithm has recently been shown to improve the identification of fatty liver when compared with other non-invasive methods [11, 20, 29–31], as yet, only few studies have been available on the clinical applications of FLI or the effects of lifestyle factors on FLI.
Alcohol drinking, cigarette smoking, and physical inactivity are currently the main modifiable high-risk determinants of lifestyle [1]. The present findings indicate that each of these components and especially their co-existence increase the risk of metabolic aberrations in the liver. In obese individuals or in smokers, regular alcohol drinking even in relatively modest amounts may increase the risk for abnormal liver enzyme activities [6, 15, 18, 32]. The combined triggers from multiple unfavorable lifestyle factors may also stimulate inflammation and lead to progression of fibrosis [6, 12, 15, 16, 33]. The present findings also lend support to the view that no safe limit of alcohol consumption in relation to the risk of progression of non-alcoholic fatty liver disease (NAFLD) can be defined. Thus, questioning such patients about alcohol intake and other factors of lifestyle warrants further attention. Previous findings have indicated that there may be common pathogenic features in lifestyle-related disease manifestations, including systemic inflammatory response, oxidative stress and altered fatty acid metabolism [9, 34–36]. Therefore, use of FLI together with biomarkers reflecting the above mentioned pathophysiological pathways could also help in elucidating the primary mechanisms of fatty deposition in various behavioral phenotypes. Recently, a link between hepatic and extrahepatic manifestations of fatty liver have been proposed based on findings indicating that LDL oxidation in coronary atherosclerotic plaques can be boosted by the action of GGT enzyme, which is also a key mediator of oxidative stress [37, 38]. There may also be an interplay between oxidative stress and inflammation [13, 39–41]. In line with this view, current data shows that abnormalities in serum CRP, a biomarker and important regulator of inflammation also coincide with the burden of high-risk lifestyle factors and abnormalities in FLI.
Lack of physical activity has recently been recognized as an increasingly important lifestyle-associated contributor to poor health [42, 43]. Spending more time in sedentary behaviors associates with a wide variety of adverse health outcomes, including cardiovascular diseases, diabetes and carcinogenesis [1, 44–47]. The present data shows that physical inactivity is also a major independent contributor of abnormal FLI. Those with moderate and vigorous physical activity show markedly lower odds for fatty liver than those with sedentary activity. Sufficient doses of physical exercise could also have a major impact in reducing the adverse metabolic effects of unfavorable lifestyle. Regular physical activity may also be expected to lead to significant long-term health benefits in reducing hepatic steatosis and insulin resistance [35, 45, 48–50]. In accordance with this view, moderate or vigorous physical activity were recently shown to reduce fat, inflammation and oxidative stress in the liver even in cases without any notable changes in BMI status [35].
Previous studies have shown that poor diet characterized by high fat, high carbohydrate and insufficient vitamin intake may also provide triggers for hepatotoxicity [14, 46, 51–56]. Unfortunately, in this work information on the exact compositions of the diet were not available. It should, however, be noted that increasing lifestyle risk factor scores were found to correlate with high intake of coffee, which is in accordance with previous findings indicating an association between high cigarette consumption and coffee consumption [57]. On the other hand, it is notable that a large body of previous evidence has shown that coffee consumption is associated with a reduced risk for liver cirrhosis and liver enzyme elevations in alcohol consumers [58, 59]. Recently, coffee intake has also been suggested to be inversely related with the risk of NAFLD possibly by modulating pathways of the gut-liver axis [60].
A major strength of this study is the large sample size of over 12,000 participants with a comprehensive assessment of the relationships between FLI, other laboratory markers and lifestyle-related risk factors. Based on previous evidence indicating significant gender-differences in susceptibilities for liver disease, we have also included separate analyses for men and women. Although the present material was collected from different geographical areas in Finland, the population represents a Caucasian population with a high degree of environmental and genetic homogeneity. The main limitation of the study is the cross-sectional setting and lack of follow-up data to address possible causal relationships. The data on lifestyle determinants were based on self-reports and therefore we cannot rule out the possibility of recall bias or underreporting especially concerning the data reflecting socially less desirable behaviors, such as alcohol intake. Lack of detailed information on the patterns of diet may also be kept as a limitation of the study. Therefore, future longitudinal studies are clearly needed to examine causal relationships between factors of life style and fatty change in the liver. The possible role of FLI as a clinical tool for supporting behavior change in NAFLD patients also warrant future studies in large materials.
Taken together, current data demonstrates distinct relationships of lifestyle-related risk factors and fatty liver, which should be implicated in recommendations aimed at promoting liver health. The data also emphasizes the possibility of using FLI algorithm as a non-invasive clinical tool for providing feedback in approaches to reduce the number of unfavorable lifestyle risk factors and to prevent morbidity and mortality resulting from fatty liver disease and associated metabolic comorbidities. Interestingly, recent studies have indicated that FLI could also serve as a risk predictor for extrahepatic complications, such as chronic kidney disease [61].