Metabolic Syndrome and Severity of Fibrosis in Nonalcoholic Fatty Liver Disease: An Age-Dependent Risk Profiling Study

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In this study of 863 patients with a histological diagnosis of NAFLD, and characterized for all components of the MS, we found that IFG/diabetes, low HDL and visceral obesity, but not high triglycerides and arterial hypertension, were independent risk factors for severe liver fibrosis. When discriminating patients according to classes of age, the risk for severe fibrosis was driven by low HDL and mostly by IFG/Diabetes and obesity in patients in the lower and middle age tertiles, with the higher risk observed in patients with all three metabolic risk factors. Conversely, IFG/diabetes and low HDL, not visceral obesity, were the main predictors of severe fibrosis in patients in the older age tertile. Notably these results were further confirmed after correction for genetic, biochemical and metabolic-HOMA- risk factors for fibrosis.

Metabolic alterations share similar pathogenic triggers like IR, and as expected in the same individual, different metabolic disturbances can coexist, together contributing to liver damage. MS has been associated with severe fibrosis [8], and the higher the number MS components, the greater   the severity of fibrosis [13]. Consistent with these data obesity, diabetes, dyslipidemia and hypertension have also been associated with NAFLD severity/progression [12-15]. However, these studies took into account the number of metabolic risk factors or the effect of a singular risk factor but not the age-dependent quantitative and qualitative impact of their combinations.

In our study, we confirmed that the prevalence of severe fibrosis increased according to the number of metabolic features. However, a more critical analysis allowed us to confirm the association of only visceral obesity, IFG/diabetes and low HDL cholesterol with the severity of hepatic fibrosis. Notably, this feature was obtained by considering together all the components of the metabolic syndrome and after adjusting for age, gender and biochemical markers of liver fibrosis, and was further confirmed by correcting for PNPLA3 genotype. In this manner we identified the independent weight of each metabolic alteration as a risk factor for severe fibrosis in NAFLD.

The most relevant finding of our study lies in the assessment of the impact of different metabolic profiles on the severity of fibrosis according to classes of age. Notably, we found that among patients in the lower and middle age tertiles, the risk for severe fibrosis was driven by low HDL and mostly by visceral obesity and IFG/diabetes, with the higher risk in patients with all three metabolic alterations. Conversely, among patients in the higher age tertile the risk was mainly driven by both HDL and IFG/Diabetes, with the higher risk in those with this association and without impact of obesity. Noteworthy, internal validation of these results make us confident on their robustness.

The lack of effect of obesity on the severity of fibrosis in older patients is difficult to explain even if some hypotheses can be entertained Obesity is a principal determinant of NAFLD and its progression [22]. However, it should be possible that in older patients the impact of obesity-related metabolic alterations like diabetes and atherogenic dyslipidemia overcomes obesity per se. In addition, recent evidence assessing the impact of obesity on mortality and cardiovascular outcomes suggests that aging can attenuate the association between high BMI and poor outcomes [23,24]. Besides, the higher weight of low HDL on severe fibrosis in older patients could be the expression of a more severe diabetes and age-related atherogenic dyslipidemia phenotype.

In our study we did not find an independent association between arterial hypertension and severity of fibrosis, while a recent meta-analysis identified hypertension as a risk factor for fast fibrosis progression in NAFLD [25]. Differences in assessed outcomes (fibrosis severity vs fibrosis progression), and the lack of individual patient data in the meta-analysis, could explain the discrepancies in the results.

The main limitation of this study is the cross-sectional design that makes us unable to definitively ascertain the temporal relationship between metabolic alterations and the severity of fibrosis in NAFLD. A further methodological question is the potentially limited external validity of the results for different populations and settings. Our study included a cohort of Caucasian patients enrolled at tertiary care centers, who may be different in terms of both metabolic features and severity of liver disease, from the majority of prevalent cases of NAFLD in the general population. In spite of these limits, strengths of this study are internal validation and the large sample size, that allowed us to stratify patients according to metabolic profiles and classes of age.

From a clinical point of view our study suggests that in patients with NAFLD, while all components of MS should be assessed for the evaluation of cardiovascular risk, considering the assessment of liver damage, the presence of IFG/diabetes, visceral obesity and low HDL, considered alone and in combinations allows oneto identify age-dependent metabolic profiles at different risk for severe liver fibrosis. Notably, the ability of prediction by our model did not change when considering also HOMA, an expression of IR, suggesting that the assessment of a not widely available parameter like insulin does not add a significant advantage in the prediction of the risk of fibrosis when added to classical MS components. However, the lack of OGIS ─an expression of peripheral IR and predicting severe fibrosis better than HOMA [26]─ could affect the interpretation of these results.

In conclusion, this study on a large cohort of patients with a histological diagnosis of NAFLD demonstrated that among all components of MS, IFG/diabetes, low HDL and visceral obesity are those mostly associated with the severity of fibrosis. Notably, metabolic profiles at risk for severe fibrosis changed according to age, with low HDL and mostly both obesity and IFG/Diabetes being dominant in patients in the lower and middle age tertiles, while low HDL cholesterol and IFG/Diabetes but not visceral obesity in those in the higher age tertile.