Elsevier

Diabetes & Metabolism

Volume 43, Issue 3, June 2017, Pages 229-239
Diabetes & Metabolism

Original article
An extended fatty liver index to predict non-alcoholic fatty liver disease

https://doi.org/10.1016/j.diabet.2016.11.006Get rights and content

Abstract

Background

In clinical practice, there is a strong interest in non-invasive markers of non-alcoholic fatty liver disease (NAFLD). Our hypothesis was that the fold-change in plasma triglycerides (TG) during a 2-h oral glucose tolerance test (fold-change TGOGTT) in concert with blood glucose and lipid parameters, and the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3 might improve the power of the widely used fatty liver index (FLI) to predict NAFLD.

Methods

The liver fat content of 330 subjects was quantified by 1H-magnetic resonance spectroscopy. Blood parameters were measured during fasting and after a 2-h OGTT. A subgroup of 213 subjects underwent these measurements before and after 9 months of a lifestyle intervention.

Results

The fold-change TGOGTT was closely associated with liver fat content (r = 0.51, P < 0.0001), but had less power to predict NAFLD (AUROC = 0.75) than the FLI (AUROC = 0.79). Not only was the fold-change TGOGTT independently associated with liver fat content and NAFLD, but so also were the 2-h blood glucose level and rs738409 C>G SNP in PNPLA3. In fact, a novel index (extended FLI) generated from these and the usual FLI parameters considerably increased its power to predict NAFLD (AUROC = 0.79–0.86). The extended FLI also increased the power to predict changes in liver fat content with a lifestyle intervention (n = 213; standardized beta coefficient: 0.23–0.29).

Conclusion

This study has provided novel data confirming that the OGTT-derived fold-change TGOGTT and 2-h glucose level, together with the rs738409 C>G SNP in PNPLA3, allow calculation of an extended FLI that considerably improves its power to predict NAFLD.

Introduction

Non-alcoholic fatty liver disease (NAFLD) has gained much attention in recent years because of its high prevalence, amounting to > 30% in the general population and to > 70% in certain high-risk groups, such as morbidly obese individuals and patients with type 2 diabetes (T2D) [1]. NAFLD is strongly associated not only with progressive hepatic disease, but also with cardiometabolic disorders, as it is also thought to be involved in the pathogenesis of cardiometabolic diseases, although the causal relationships are still not fully understood [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12].

Diagnosis of NAFLD by the gold-standard method, liver biopsy, is invasive and, therefore, not feasible in routine clinical practice [13], [14]. Proton magnetic resonance spectroscopy (1H-MRS) is considered the most accurate non-invasive method for measuring liver fat content [15], [16]. However, in addition to the high costs that limit its use, the infrastructure and knowledge needed to implement the technique are only available in a limited number of institutions. Therefore, 1H-MRS is currently applied mostly for research purposes. Routine ultrasound is also being used to diagnose NAFLD, but the technique has only moderate sensitivity when liver fat content exceeds 20–30% [17].

Consequently, there has been intense interest in blood markers that, alone or in combination with clinical parameters, might be able to identify patients with NAFLD. Accordingly, NAFLD or liver fat indexes have been developed. However, some of them have only moderate predictive power and/or cannot be easily or widely used in routine clinical practice because they involve several parameters, such as insulin, that may either not be readily measurable or display wide variability in their measurement, depending on the method used [18], [19], [20], [21]. Furthermore, as there is such wide variability in the decrease of liver fat content with lifestyle interventions [22], [23], it is important to investigate whether such indexes can predict such decreases in those situations.

It is therefore of considerable interest to identify readily measurable blood parameters that can either autonomously predict NAFLD with relatively high sensitivity and specificity, or improve the predictive power of the established indexes. For this reason, only blood parameters that are commonly measured, such as serum liver enzymes, lipids and lipoproteins, or show no, or very little, variability between different laboratories were tested in the present study. In addition, the predictive power of the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3, the strongest genetic determinant of NAFLD, was also studied [24]. As it was recently shown that plasma triglycerides (TGs) measured during an oral glucose tolerance test (OGTT) are closely related to abdominal obesity and insulin resistance [25], which themselves strongly correlate with liver fat content, circulating TGs were tested not only in the fasting state, but also after a standard 2-h 75-g OGTT.

Section snippets

Subjects

Data from 330 Caucasians, 130 men and 200 women, from the southern part of Germany were analyzed. These individuals had participated in the Tübingen Lifestyle Intervention Program (TULIP) [23], [26]. Subjects were included in that study when they fulfilled at least one of the following criteria: family history of T2D; body mass index (BMI) > 27 kg/m2; and previous diagnosis of impaired glucose tolerance and/or gestational diabetes. All were considered healthy according to physical examination and

Subjects’ demographics, anthropometrics and metabolic characteristics

Clinical characteristics of the 330 subjects (130 men and 200 women) who had data at baseline are shown in Table 1. A total of 17 subjects had newly diagnosed T2D, based on elevated fasting and/or 2-h OGTT glucose values, or increased HbA1c values, and 71 had impaired glucose tolerance (IGT). Those with NAFLD had more visceral fat mass and higher concentrations of serum liver enzymes. They also had higher levels of glucose, 2-h FFAs, LDL cholesterol, and fasting and 2-h TGs, but lower HDL

Discussion

Considering the hepatic and metabolic consequences of fat accumulation in the liver [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], there is an important medical need for a simple, accurate and cost-effective biomarker of liver fat content. At least four such surrogate markers have been proposed: the SteatoTest [18]; the FLI [19]; the NAFLD-LFS [20]; and the HSI [21]. Among them, the FLI was shown to predict NAFLD in several populations [2], [19], [33], [34], [35], but mostly with

Disclosure of interest

The authors declare that they have no competing interest.

Contribution statement

Study concept and design: N. Stefan, L. Scheja and H.-U. Häring. Acquisition of data: K. Kantartzis, I. Rettig, J. Machann, F. Schick, A. Fritsche, N. Stefan, A. Gastaldelli, E. Bugianesi. Analysis and interpretation of data: K. Kantartzis, N. Stefan, A. Gastaldelli, E. Bugianesi, M.B. Schulze and H.-U. Häring. Drafting of the manuscript: K. Kantartzis and N. Stefan. Critical revision of the manuscript for important intellectual content: K. Kantartzis, I. Rettig, H. Staiger, A. Fritsche,

Funding support

This study was supported by grants from the Deutsche Forschungsgemeinschaft (KFO 114), and the Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD) and the initiative for individualized medicine (iMED). N. Stefan was supported by a Heisenberg Professorship of the Deutsche Forschungsgemeinschaft (STE-1096/1-3).

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