The prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) is raising worldwide (1). Indeed, lipid metabolism associated disorders are the most rapidly increasing cause of morbidity and mortality among hepatic patients in Western countries (2). NAFLD can be considered a manifestation of the metabolic syndrome (MetS) burden in the liver (3, 4). In terms of pathogenesis, fatty liver disease is the result of the clustering of genetic inheritance, lifestyle factors, ageing, hepatotoxic drugs, co-morbidities and gut microbiota (5–11).

In this context, non-invasive assessment of liver steatosis using indexes, such as Hepatic Steatosis Index (HSI) were developed to select patients at a higher risk of NAFLD in population studies (12). These scales could provide a non-invasive longitudinal monitoring of patients and an objective quantitation of the effect of therapeutic measures on NAFLD status.

Weight loss is a major target in patients with fatty liver disease (13). In this context, changes in lifestyle have an impact on NAFLD status (7). Among dietary patterns, the Mediterranean Diet (MedDiet) provides a balanced nutrient composition, which should be strongly deemed in treating this disease (14). Furthermore, moderate physical activity (PA) has shown a healthy potential in the reduction of NAFLD morbid severity through the improvement of insulin resistance, anti-inflammatory effects and antioxidant mechanisms.

Likewise, both MedDiet and PA are closely related to quality of life (QoL) in patients with MetS (15, 16). The SF-36 index is widely used, being sensitive to changes and has been validated for the Spanish population, separating information through mental and physical components of QoL and providing a precision medicine approach to Health-Related Quality of life (HRQoL). The physical aggregated component of SF-36 (PCS) mainly accounts for categories related to physical function, physical role, vitality, body pain and general health perceptions. Thus, the PCS is relevant in the clinical setting for the screening of physical factors that influence medical issues in QoL (17, 18).

The personalization of indications and the linkage between lifestyle intervention and a short-term benefit in terms of quality of life could improve the adherence to healthy habits, which may benefit NAFLD patients. In this context, the objective of the present study is the longitudinal evaluation of the impact of MedDiet and Physical activity on Health-related Quality of Life according to a baseline non-invasive evaluation of the NAFLD status based on the HSI score in patients with MetS from the PREDIMED-Plus trial.

The results from the current research evidence the capacity of a non-invasive evaluation of NAFLD to modify the effect of lifestyle over Health-related Quality of Life. The increase in the adherence to a er-MedDiet pattern and PA might lead to more than a 5-fold increase in the aggregated physical domain of HRQoL depending on the presence of NAFLD, using previously validated and easy to fulfill scores such as SF-36 and HSI (18, 20). In this context, different methods of detection of liver steatosis have been previously validated, such as ultrasound, controlled attenuation parameters of FibroScan^©. Among them, HSI has demonstrated adequacy in the epidemiological study of liver disease (21), while demonstrating a high similar discrimination power than other more expensive or less available detection methods (22). Besides, our results provide a clinically relevant objectives in terms of er-MeDiet adherence and PA to improve HRQoL in patients with MetS and lower probability of NAFLD. To our knowledge, this is the first investigation to proof the differential effect of lifestyle measures in patients with MetS depending on a non-invasive assessment of liver steatosis.

Interestingly, in our cohort, the HSI score was associated to a lower adherence to er-MeDiet and PA performance and to a higher prevalence and of the components of MetS at baseline. These findings are endorsed by indirect findings and provide further evidence on the association of HSI score and the MetS features (3). Furthermore, these results reinforce the impact of liver steatosis in QoL (20) and might support previous evidence on the use of non-invasive methods for the individualization of patients with MetS in the clinical setting (23–25). Thus, the apparent resistance of patients with NAFLD to lifestyle measures in terms of HRQoL in the longitudinal analysis could adequate the prescription of the therapeutic armamentarium in these patients, bringing forward more aggressive treatments in selected subjects, such as GLP-1 analogs and bariatric surgery (26, 27). Beyond, the 10 point er-MeDiet adherence and 50 MET-h/week thresholds for the improvement of HRQoL in patients with lower probability of NAFLD may provide a goal of lifestyle change in these patients as well as an objective evaluation and counselling in the clinical setting. Therefore, our study could contribute to the development of new lifestyle-based intervention guidelines for patients with MetS according to the liver status which in fact, may also provide further benefits in the cardiovascular disease scenario, due to the association of NAFLD and atherosclerotic disease development (28, 29).

With regard of the impact of Mediterranean diet and PA in HRQoL depending on the liver status, some aspects should be emphasized. The effect of Mediterranean diet has been previously related to the MetS prevention and control after 1 year follow up (30). Besides, MedDiet pattern has also been related to HRQoL in previous series and in the present cohort (31). Similar results were found on PA relationship to HRQoL, with a direct relationship to the control of MetS and HRQoL. However, the concept of a modulation of NAFLD status in the impact of er-MeDiet and PA on HRQoL is new. In fact, interventions tend to be maximized in patients at higher risk (32). Thus, the capacity of HSI to identify patients with a better response to lifestyle as measured with HRQoL parameters might be related to the NAFLD morbidity burden (33). Other factor that could contribute to our results is the severity of the MetS among progressive HSI values. This fact might be related to a poorer metabolic flexibility of patients with NAFLD in terms of body composition (34), insulin resistance (35), microbioma (9) and redox/equilibrium (36) and thus, a reduction on the sensitivity to lifestyle change of this population due to a reduction in homeostasis capability (37).

In the methodological arena, the design quality of PREDIMED plus provides strength to the present results in terms of inclusion criteria fulfillment, anthropometric and laboratory tests and adherence to er-MeDiet and PA patterns assessment (19). Besides, the SF-36 Physical summary and the HSI index are well validated and universally used indexes in the evaluation of both HRQoL and liver steatosis (18, 20). Even though, some limitations should be addressed. First, the cohort recruitment was designed to evaluate the effect of the intervention on dietary patterns and PA in patients with MetS. Then, the present findings should be externally validated in a different cohort. In this context, the present analysis does not follow the original strategy of the cohort, resembling to a per-protocol evaluation by using patient information about erMeDiet and PA adherence according to patient declaration and not due to the distribution between the control and intervention branches. Although the characteristics of the full PREDIMED plus trial do not allow to uncover the intervention and control groups, no differences were found in the proportion of patients in the intervention and control groups among HSI < 36 and HSI > 36 (p > 0.05). Besides, although HSI is a remarkable non-invasive tool in the detection of NAFLD, this index is not designed for NAFLD staging. In fact, biopsy directed studies have demonstrated a different distribution of NASH in patients with MetS than in those with type 2 diabetes mellitus (38). Although the NAFLD staging may exceed the objective of the present study, this feature could be addressed in future studies. Yet, the present results are valuable from the clinical point of view, providing remarkably similar assessment of the influence of adherence to healthy lifestyle patterns in patients’ health as that of the consultation room. The longitudinal multivariate analysis and adjustments, using features related to HRQoL such as waist circumference obesity, MetS features (39), alcohol consumption (40) and total caloric intake (41, 42) provide plausibility to the present results.

In summary, the demonstration of the influence of NAFLD in the response to lifestyle modifications might represent an interesting tool for personalization and precision medicine in the cardiovascular risk epidemiological and clinical scenarios emphasizing the mediation of liver status in the therapeutical response. The present findings could encourage future research in the individualization of treatment of patients with MetS based on liver condition.

The detection of NAFLD by the HSI index in patients with MetS might identify subjects with lower sensitivity to lifestyle changes in terms of HRQoL. Patients with lower NAFLD probability begun to obtain improvement on HRQoL at 10 points of er-MeDiet adherence and 50 MET-h/week, providing precision medicine prescriptions depending on liver condition status.

There are restrictions on data availability for the PREDIMED-Plus trial due to the signed consent agreements around data sharing, which only allow access to external researchers for studies following the project purposes. Requestors wishing to access the PREDIMED-Plus trial data used in this study can make a request to the PREDIMED-Plus trial Steering Committee chair: jordi.salas@urv.cat. The request will then be passed to members of the PREDIMED-Plus Steering Committee for deliberation.

The studies involving human participants were reviewed and approved by Predimed Plus trial. The patients/participants provided their written informed consent to participate in this study.

MAM-G, NB, DC, JLV, AMA-G, JW, JesV, DR, JL-M, RE, FT, JL, JS-M, AB-C, JT, AM, XP, MD-R, PMM, JosV, MM, IA, AM-R, IC-G, JK, AG-R, OL, OP, AG, MZ, JV-L, MCSO, IM, EB, JAM, JO and LD designed and conducted the research. DM-U, RS-C, PV, JM and LD conceived the study idea and the analysis design. LD supervised the research and DM-U and RS-C carried out the analysis procedures, bibliographic research, data preparation, statistical analysis and wrote initial drafts. RS-C assisted with statistical analysis and R programming. PV and JO participated in the scientific discussion of experimental results. All the authors assisted in manuscript revision for intellectual content and approved it.

The present study received funding from coordinated FIS project official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigación para la Salud (FIS) which is co-funded by the European Regional Development Fund (including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332, PI20/01802, PI20/00138, PI20/01532, PI20/00456, PI20/00339, PI20/00557, PI20/00886, PI20/01158), the Special Action Project “Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus”, the Recercaixa (grant number 2013ACUP00194) funding and the grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013; PS0358/2016; PI0137/2018), the SEMERGEN grant; Department of Health of the Government of Navarra (61/2015), the Fundació La Marató de TV (Ref. 201630.10), the coordinated grant supported by the European Research Council (Advanced Research grant 2014–2019; agreement #340918), the grant of support to research groups 35/2011 (Balearic Islands Government; FEDER funds). This study has been carried out thanks to the funds provided by Ministerio de Ciencia e Investigación through grants from PROYECTOS DE I+D+I «RETOS INVESTIGACIÓN» (RTI2018-095569-B-I00) and «PROGRAMACIÓN CONJUNTA INTERNACIONAL» (PCI2018-093009).

Author JS-S reports grants from CIBEROBN, ISCIII (Spain), during the conduct of the study; non-financial support from Nut and Dried Fruit Foundation, personal fees from Instituto Danone Spain, grants from Nut and Dried Fruit Foundation to this institution, grants from Eroski Distributors and personal fees from Nut and Dried Fruit Foundation, outside the submitted work. Moreover, he gratefully acknowledges the financial support by ICREA under the ICREA Academia program. The author DR declares the funding of the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017. The author RS-C acknowledges financial support from the Juan de la Cierva Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-038168- I). The author ER reports grants, personal fees, non-financial support and other from California Walnut Commission, grants, personal fees, non-financial support and other from Alexion, personal fees, non-financial support and other from Ferrer International, personal fees from Amarin, personal fees, non-financial support and other from Danone, outside the submitted work. The author JL-M reports personal fees and non-financial support from AMGEN, personal fees and non-financial support from SANOFI, personal fees from MSD, personal fees from Laboratorios Dr. Esteve, and personal fees from NOVO-NORDISK, outside the submitted work.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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