Alcohol Drinking Impacts on Adiposity and Steatotic Liver Disease: Concurrent Effects on Metabolic Pathways and Cardiovascular Risks.

PURPOSE OF REVIEW: This integrative search aimed to provide a scoping overview of the relationships between the benefits and harms of alcohol drinking with cardiovascular events as associated to body fat mass and fatty liver diseases, as well as offering critical insights for precision nutrition research and personalized medicine implementation concerning cardiovascular risk management associated to ethanol consumption. RECENT FINDINGS: Frequent alcohol intake could contribute to a sustained rise in adiposity over time. Body fat distribution patterns (abdominal/gluteus-femoral) and intrahepatic accumulation of lipids have been linked to adverse cardiovascular clinical outcomes depending on ethanol intake. Therefore, there is a need to understand the complex interplay between alcohol consumption, adipose store distribution, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular events in adult individuals. The current narrative review deals with underconsidered and apparently conflicting benefits concerning the amount of alcohol intake, ranging from abstention to moderation, and highlights the requirements for additional robust methodological studies and trials to interpret undertrained and existing controversies. The conclusion of this review emphasizes the need of newer multifaceted clinical approaches for precision medicine implementation, considering epidemiological strategies and pathophysiological mechanistic. Newer investigations and trials should be derived and performed particularly focusing both on alcohol's objective consequences as putatively mediated by fat deposition, including associated roles in fatty liver disease as well as to differentiate the impact of different levels of alcohol consumption (absence or moderation) concerning cardiovascular risks and accompanying clinical manifestations. Indeed, the threshold for the safe consumption of alcoholic drinks remains to be fully elucidated.

The Histology-Driven Differential Diagnosis in Bowel Inflammatory Conditions Is Not All That Obvious: Evidence from a Survey Based on Digital Slides.

(1) Background: when the pathologist faces histologic slides from colonoscopies in daily practice, given the large number of entities and etiologies under inflammatory bowel conditions, in-depth definition of the histological spectrum and the recommendations of current guidelines are often not enough to conclusively define a diagnostic framework. Histological patterns should be organized hierarchically in flowcharts that consider the correlation with clinical data. We conducted an online survey asking a group of gastroenteropathologists to apply a pattern classification based on the most significant lesions in colitis differential diagnosis: crypt distortion and activity. (2) Methods: digital slides from 20 endoscopy samples were analyzed by twenty pathologists and classified according to the occurrence of crypt distortion (nondestructive-destructive colitis) and subsequently to the evidence of activity (ND1-2-3, D1-2). (3) Results: in 8 out of 20 (40%) cases, the participants reached a full agreement regarding the evaluation of crypt distortion (5 cases: nondestructive colitis; 3 cases: destructive colitis). The calculated agreement was k = 0.432. In the second-level quiz (ND1-2-3 and D1-2), full agreement between participants was achieved for 7 of the 28 (25%) possible classifications, with k = 0.229. (4) Conclusions: The findings from this survey are indicative of an unexpectedly low consensus, even among dedicated pathologists, about the recognition of histological changes that are commonly considered critical lesions in the histologic identification of bowel non-neoplastic diseases. In our opinion, these divergences imply a significant risk of misdiagnosis of bowel inflammatory conditions, hampering the usefulness of histological assessment.

A nutrigenetic precision approach for the management of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: The Patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP) is one of the major genetic determinant of non-alcoholic fatty liver disease (NAFLD) and is strongly regulated by changes in energy balance and dietary factors. We aimed to investigate the association between the PNPLA3 rs738409 SNP, nutrient intake and NAFLD severity. METHOD: PNPLA3-rs738409 SNP was genotyped in 181 patients with NAFLD who completed the EPIC Food Frequency Questionnaire. Liver steatosis was evaluated by Controlled Attenuation Parameter (CAP) (Fibroscan®530, Echosens). According to the established cut-off, a CAP value ≥ 300 dB/m was used to identify severe steatosis (S3). An independent group of 46 biopsy-proven NAFLD subjects was used as validation cohort. RESULTS: Overall, median age was 53 years (range 44; 62) and 60.2% of patients were male. Most subjects (56.3%) had S3 and showed increased liver stiffness (p < 0.001), AST (p = 0.003) and ALT levels (p < 0.001) compared to those with CAP<300 dB/m. At logistic regression analyses we found that the interaction between carbohydrates intake and the carriers of the PNPLA3 G risk allele was significantly associated with S3 (p = 0.001). The same result was confirmed in the validation cohort, were the interaction between high carbohydrate intake (48%) and PNPLA3 SNP was significantly associated with steatosis ≥33% (p = 0.038). CONCLUSION: The intake of greater than or equal to 48% carbohydrate in NAFLD patients carriers of the CG/GG allele of PNPLA3 rs738409 may increase the risk of significant steatosis.

Impact of Chronotype and Mediterranean Diet on the Risk of Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

Late chronotype, the individual's aptitude to perform daily activities late in the day, has been associated with low adherence to the Mediterranean diet (MedDiet) and metabolic syndrome. The aim of this work was to investigate the potential association of chronotype and adherence to the MedDiet with the liver fibrosis risk in patients with non-alcoholic fatty liver disease (NAFLD). Liver stiffness was assessed in 126 patients by FibroScan®530. Significant (F ≥ 2) and advanced (F ≥ 3) hepatic fibrosis were defined according to liver stiffness values ≥7.1 kPa and ≥8.8 kPa, respectively. Chronotype (MSFsc) was defined by the Munich Chronotype Questionnaire, and adherence to the MedDiet was defined by the Mediterranean diet score (MDS). Overall, the median age was 55 (46-63) years, and 57.9% of participants were male. The principal comorbidities were type-2 diabetes mellitus (T2DM) (26.1%), arterial hypertension (53.1%), dyslipidaemia (63.4%), obstructive sleep apnoea (5.5%) and depression (5.5%). Most subjects (65.0%) had intermediate + late chronotype and showed higher mid-sleep on workdays (p < 0.001) and on work-free days (p < 0.001) compared to those with early chronotype. In the logistic regression model, intermediate + late chronotype (p = 0.024), MDS (p = 0.019) and T2DM (p = 0.004) were found to be significantly and independently associated with the risk of both F ≥ 2 And F ≥ 3. We observed that the intermediate + late chronotype and low adherence to the MedDiet were associated with both significant and advanced liver fibrosis in patients with NAFLD.

Impact of Health Related QoL and Mediterranean Diet on Liver Fibrosis in Patients with NAFLD.

Patients with non-alcoholic fatty liver disease (NAFLD) display impaired health-related quality of life (HRQoL) that is often linked to an unhealthy dietary pattern. The aim of this work was to investigate the impact of HRQoL and adherence to the Mediterranean diet on the risk of liver fibrosis (LF) in patients with NAFLD. LF was assessed in 244 patients through transient elastography (FibroScan®530. Echosens, Paris, France). Significant LF was defined according to liver stiffness measurements (LSM) values ≥ 7.1 kPa. The Mediterranean diet score and the Short Form-36 questionnaires were also completed. The median age was 54 (44-62) years and 57% of participants were male. A total of 42 (17.2%) participants had LSM ≥ 7.1 kPa and showed increased GGT (p = 0.001), glucose (p < 0.001), and triglycerides levels (p = 0.015) compared to those with LSM ≤7.0 kPa. Moreover, patients with significant LF had significantly lower scores related to Physical Functioning (p < 0.001) and Role Physical (p < 0.001). In the logistic regression analysis, lower role physical and lower adherence to the MedDiet (p = 0.001 and p = 0.009, respectively), after adjusting for age, diabetes, and obstructive sleep apnea, were associated with an increased risk of significant LF. Low adherence to MedDiet and low role physical may influence the risk of significant liver fibrosis in patients with NAFLD.

Fecal and Circulating Biomarkers for the Non-Invasive Assessment of Intestinal Permeability.

The study of intestinal permeability is gaining growing interest due to its relevance in the onset and progression of several gastrointestinal and non-gastrointestinal diseases. Though the involvement of impaired intestinal permeability in the pathophysiology of such diseases is recognized, there is currently a need to identify non-invasive biomarkers or tools that are able to accurately detect alterations in intestinal barrier integrity. On the one hand, promising results have been reported for novel in vivo methods based on paracellular probes, i.e., methods that can directly assess paracellular permeability and, on the other hand, on fecal and circulating biomarkers able to indirectly assess epithelial barrier integrity and functionality. In this review, we aimed to summarize the current knowledge on the intestinal barrier and epithelial transport pathways and to provide an overview of the methods already available or currently under investigation for the measurement of intestinal permeability.

Impact of PNPLA3 rs738409 Polymorphism on the Development of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a complex disease, resulting from the interplay between environmental determinants and genetic variations. Single nucleotide polymorphism rs738409 C>G in the PNPLA3 gene is associated with hepatic fibrosis and with higher risk of developing hepatocellular carcinoma. Here, we analyzed a longitudinal cohort of biopsy-proven NAFLD subjects with the aim to identify individuals in whom genetics may have a stronger impact on disease progression. METHODS: We retrospectively analyzed 756 consecutive, prospectively enrolled biopsy-proven NAFLD subjects from Italy, United Kingdom, and Spain who were followed for a median of 84 months (interquartile range, 65-109 months). We stratified the study cohort according to sex, body mass index (BMI)

Prognostic Value of Simple Non-Invasive Tests for the Risk Stratification of Incident Hepatocellular Carcinoma in Cirrhotic Individuals with Non-Alcoholic Fatty Liver Disease.

Hepatocellular carcinoma (HCC) represents a relevant disease burden in cirrhotic patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the prognostic value of simple non-invasive tests (NITs) (AAR, APRI, BARD, FIB-4) for the stratification of HCC risk development in a cohort of 122 consecutive cirrhotic individuals with NAFLD. Over a median follow up of 5.9 (3.2-9.3) years, 13 (10.7%) developed HCC. Only FIB-4 was associated with HCC risk (HR = 1.27, 95% CI 1.03-1.58, p = 0.027). After evaluating different established FIB-4 cut-offs, the lowest cut-off of 1.45 allowed the ruling out of a greater number of patients with a minimal risk of HCC than the 1.3 cut-off (23 vs. 18 patients). Conversely, the cumulative incidence of HCC using the highest cut-off of 3.25 (rule in) was distinctly higher than the 2.67 cut-off (19.4% vs. 13.3%). After multivariate Cox regression analysis, these cut-offs were independently associated with HCC after adjusting for sex, BMI and T2DM (HR = 6.40, 95% CI 1.71-24.00, p = 0.006). In conclusion, FIB-4 values of <1.3 and >3.25 could allow for the optimal stratification of long-term HCC risk in cirrhotic individuals with NAFLD.

Prebiotics targeting gut-liver axis to treat non-alcoholic fatty liver disease.

Non-alcoholic steatohepatitis (NASH) is a high-prevalence, rapidly growing form of non-alcoholic fatty liver disease (NAFLD), which is closely linked to obesity and metabolic disorders. Gut microbiota has been increasingly recognized as a key factor in the onset of NAFLD in recent years. The liver can be strongly influenced by changes in the gut microbiota through the portal vein, giving the gut-liver axis a very important role in understanding the pathophysiology of liver diseases. A healthy intestinal barrier is characterized by selective permeability to nutrients, metabolites, water and bacterial products and its impairment may be a predisposing or aggravating condition for the progression of NAFLD. In most cases, NAFLD patients follow a Western diet pattern, which is closely linked to obesity and associated metabolic diseases, promoting inflammation, structural and behavioral changes in the gut microbiota. In fact, factors such as age, gender, genetic or environmental factors may induce a dysbiotic microbiota that promotes epithelial barrier dysfunction and increased intestinal permeability, favoring the progression of NAFLD. In this context, new dietary approaches, such as prebiotics, are emerging to prevent disease and maintain health. In this review, we reported the role of the gut-liver axis in the pathogenesis of NAFLD and investigated the potential therapeutic effect of prebiotics on the enhancement of intestinal barrier dysfunction, hepatic steatosis and, consequently, the progression of NAFLD.

The Predictive Role of Extracellular NAPRT for the Detection of Advanced Fibrosis in Biopsy-Proven Non-Alcoholic Fatty Liver Disease.

Intrahepatic oxidative stress is a key driver of inflammation and fibrogenesis in non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of extracellular Nicotinamide phosphoribosyltransferase (eNAMPT) and extracellular nicotinic acid phosphoribosyltransferase (eNAPRT) for the detection of advanced fibrosis. eNAMPT and eNAPRT were tested in 180 consecutive biopsy-proven NAFLD patients and compared with liver stiffness (LS) and the FIB-4 score. eNAMPT was similarly distributed across fibrosis stages, whereas eNAPRT was increased in patients with advanced fibrosis (p = 0.036) and was associated with advanced fibrosis (OR 1.08, p = 0.016). A multiple stepwise logistic regression model containing significant variables for advanced fibrosis (eNAPRT, type 2 diabetes, age, male sex, ALT) had an area under the curve (AUC) of 0.82 (Se 89.6%, Sp 67.3%, PPV 46.7%, NPV 93.8%) when compared to that of LS (0.79; Se 63.5%, Sp 86.2%, PPV 66.0%, NPV 84.8%) and to that of the FIB-4 score (0.73; Se 80.0%, Sp 56.8%, PPV 44.9%, NPV 86.6%). The use of eNAPRT in clinical practice might allow for the better characterization of NAFLD patients at higher risk of disease progression.

Cross-Sectional and Longitudinal Performance of Non-Invasive Tests of Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

Background and aims: Non-invasive tests (NITs) are needed in clinical practice to replace histology for the identification of liver fibrosis and prognostication in Non-Alcoholic Fatty Liver Disease (NAFLD). Novel collagen-derived fibrogenesis markers including N-terminal type III collagen pro-peptide (PRO-C3) are among the most promising tools in this field. The aim of this study was to assess the diagnostic accuracy of PRO-C3, the derivative ADAPT score, and other NITs for the identification of advanced fibrosis (stages 3-4) and changes over 12 months of follow-up. Methods: In this longitudinal study, 96 patients with biopsy-proven NAFLD were evaluated at baseline, of which 50 underwent a follow-up visit after 12 months. Clinical-biochemical parameters, liver stiffness (LS) by transient elastography, PRO-C3, and other NITs (ADAPT, FIB-4, NFS, APRI) were collected at baseline and follow-up. Results: LS showed the best accuracy for the identification of advanced fibrosis, with Area under the Receiving Operator Curve (AUROC) 0.82 (0.73-0.89) for a cut-off value of 9.4 kPa. Among the other NITs, the ADAPT score showed the best accuracy, with AUROC 0.80 (0.71-0.88) for a cut-off of 5.02 (Se 62%, Sp 89%, PPV 74%, NPV 83%). The comparison between the AUROC of LS with that of ADAPT was not statistically different (DeLong test p value 0.348). At follow-up, LS was slightly reduced, whilst PRO-C3 displayed a significant increase from baseline median 11.2 ng/mL to 13.9 ng/mL at follow-up (p = 0.017). Accordingly, ADAPT score increased from median 5.3 to 6.1 (p = 0.019). The other NITs did not significantly change over 12 months. Conclusions: The ADAPT score shows the best performance among non-invasive scores for the identification of advanced fibrosis, not different from LS. Collagen-derived biomarker PRO-C3 and the derivative score ADAPT display significant changes over time, and may be useful tools for monitoring the progression of liver disease or assessing responses to treatments.

Role of Circadian Clock on the Pathogenesis and Lifestyle Management in Non-Alcoholic Fatty Liver Disease.

Several features of the modern lifestyle, such as weekly schedules or irregular daily eating patterns, have become major drivers of global health problems, including non-alcoholic fatty liver disease (NAFLD). Sleep is an essential component of human well-being, and it has been observed that when circadian rhythms are disrupted, or when sleep quality decreases, an individual's overall health may worsen. In addition, the discrepancy between the circadian and social clock, due to weekly work/study schedules, is called social jetlag and has also been associated with adverse metabolic profiles. Current management of NAFLD is based on dietary intake and physical activity, with circadian preferences and other environmental factors also needing to be taken into account. In this regard, dietary approaches based on chrononutrition, such as intermittent fasting or time-restricted feeding, have proven to be useful in realigning lifestyle behaviors with circadian biological rhythms. However, more studies are needed to apply these dietary strategies in the treatment of these patients. In this review, we focus on the impact of circadian rhythms and the role of sleep patterns on the pathogenesis and development of NAFLD, as well as the consideration of chrononutrition for the precision nutrition management of patients with NAFLD.

Neck Circumference for NAFLD Assessment during a 2-Year Nutritional Intervention: The FLiO Study.

Neck circumference (NC) and its relationship to height (NHtR) and weight (NWtR) appear to be good candidates for the non-invasive management of non-alcoholic fatty liver disease (NAFLD). This study aimed to evaluate the ability of routine variables to assess and manage NAFLD in 98 obese subjects with NAFLD included in a 2-year nutritional intervention program. Different measurements were performed at baseline, 6, 12 and 24 months. The nutritional intervention significantly improved the anthropometric, metabolic and imaging variables. NC was significantly associated with the steatosis degree at baseline (r = 0.29), 6 m (r = 0.22), 12 m (r = 0.25), and 24 m (r = 0.39) (all p < 0.05). NC was also significantly associated with visceral adipose tissue at all the study time-points (basal r = 0.78; 6 m r = 0.65; 12 m r = 0.71; 24 m r = 0.77; all p < 0.05). NC and neck ratios combined with ALT levels and HOMA-IR showed a good prediction ability for hepatic fat content and hepatic steatosis (at all time-points) in a ROC analysis. The model improved when weight loss was included in the panel (NC-ROC: 0.982 for steatosis degree). NC and ratios combined with ALT and HOMA-IR showed a good prediction ability for hepatic fat during the intervention. Thus, their application in clinical practice could improve the prevention and management of NAFLD.

Interactive Role of Surrogate Liver Fibrosis Assessment and Insulin Resistance on the Incidence of Major Cardiovascular Events.

Introduction: The combination of easy-to-obtain validated biomarkers is interesting in the prognostic evaluation of patients at cardiovascular risk in a precision medicine scenario. The evaluation of the effect modification of insulin resistance and liver fibrosis with the Triglyceride-Glucose index (TyG) and Fibrosis-4 index (FIB4) might provide prognostic information in patients at cardiovascular risk. Patients and methods: A retrospective cohort study was performed with 2055 patients recruited in the Vascular Metabolic CUN cohort. The studied outcome was the incidence rate of major cardiovascular events (MACE). The Systematic Coronary Risk Evaluation (SCORE), FIB4 and TyG indexes were calculated according to validated formulas. Results: FIB4 and TyG showed a synergistic interaction using validated cut-offs for both indexes in the prediction of MACE (Hazard ratio (HR) 1.05 CI95% 1.01-1.08) which remained after adjustment by age, sex, SCORE subgroup, presence of diabetes, or previous MACE using standardized cut-off (HR 2.29 CI95% 1.33-3.94). Finally, a subgroup with significant TyG and FIB4 showed a higher cardiovascular risk in the study population (adjusted HR 3.34 CI 95% 1.94-5.77). Conclusion: The combined interpretation of TyG and FIB4 indexes might have a potential predictive value of major cardiovascular events.

Morbid liver manifestations are intrinsically bound to metabolic syndrome and nutrient intake based on a machine-learning cluster analysis.

Metabolic syndrome (MetS) is one of the most important medical problems around the world. Identification of patient´s singular characteristic could help to reduce the clinical impact and facilitate individualized management. This study aimed to categorize MetS patients using phenotypical and clinical variables habitually collected during health check-ups of individuals considered to have high cardiovascular risk. The selected markers to categorize MetS participants included anthropometric variables as well as clinical data, biochemical parameters and prescribed pharmacological treatment. An exploratory factor analysis was carried out with a subsequent hierarchical cluster analysis using the z-scores from factor analysis. The first step identified three different factors. The first was determined by hypercholesterolemia and associated treatments, the second factor exhibited glycemic disorders and accompanying treatments and the third factor was characterized by hepatic enzymes. Subsequently four clusters of patients were identified, where cluster 1 was characterized by glucose disorders and treatments, cluster 2 presented mild MetS, cluster 3 presented exacerbated levels of hepatic enzymes and cluster 4 highlighted cholesterol and its associated treatments Interestingly, the liver status related cluster was characterized by higher protein consumption and cluster 4 with low polyunsaturated fatty acid intake. This research emphasized the potential clinical relevance of hepatic impairments in addition to MetS traditional characterization for precision and personalized management of MetS patients.

Changes in Liver Stiffness and Markers of Liver Synthesis and Portal Hypertension following Hepatitis C Virus Eradication in Cirrhotic Individuals.

The advent of direct antiviral agents (DAAs) has radically changed the natural history of hepatitis C virus (HCV) chronic liver disease. Even patients with cirrhosis may display improvements in liver function or features of portal hypertension following viral eradication. The aim of this study was to assess whether a HCV cure would lead to improvements in cirrhotic patients using simple, readily available tools in clinical practice, together with liver stiffness (LS) measurement. This is a retrospective study of cirrhotic patients with cured HCV infection, with or without previous decompensation. Clinical and biochemical parameters as well as LS measurements were collected before antiviral treatment with DAAs and after 6 months following sustained virological response. Hepatic synthesis was assessed by serum albumin levels. Portal hypertension was indirectly assessed by platelet count. Liver function was determined by the CHILD score. A total of 373 cirrhotic patients with successful HCV eradication were retrospectively included. After 6 months of follow-up, a significantly higher proportion of patients showed improved liver function, shifting from the CHILD B/C to CHILD A group, (71.4%, p < 0.001). Similarly, LS improved from a median of 19.3 kPa (14.7−27) at the baseline vs. a median of 11.6 (7.7−16.8 kPa) at follow-up (p < 0.001). The proportion of patients who showed improved hepatic synthesis was 66.0%, which was statistically different when compared to that of patients who had a worsened condition (0.3%) (p < 0.001). Moreover, when classifying the cohort according to the RESIST-HCV score, we found that a significant proportion of patients shifted into the "low risk" group following DAA treatment (52% baseline vs. 45.6% at follow-up, p = 0.004). Even in the decompensated patients, LS improved from 1.6 to 2-fold from the baseline. Antiviral treatment is effective in improving indirect signs of hepatic synthesis and portal hypertension. Similarly, the LS values displayed significant improvements, even in decompensated patients.

Diagnostic scores and scales for appraising Nonalcoholic fatty liver disease and omics perspectives for precision medicine.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is a rising epidemic burden affecting around 25% of the global population. Liver biopsy remains the reference for NAFLD. However, the application of several scales and clinical algorithms have been proposed to diagnose NAFLD using prediction questions and blood biomarkers. This review presents a summarized of the currently available and emerging diagnostic biomarkers and scores used to assess NAFLD. RECENT FINDINGS: The limitations of liver biopsy have fostered the development of alternative noninvasive strategies, which have been an area of intensive investigation over the past years. Diagnostic scores for NAFLD have shown to be a good alternative for disease diagnosis and prognosis due to a suitable applicability, good inter-laboratory reproducibility and widespread potential availability with reasonable costs. SUMMARY: The growing NAFLD pandemic urges clinicians to seek alternatives for screening, early diagnosis, and follow-up, especially for those with contraindications for liver biopsy. New promising noninvasive biomarkers and techniques have been developed, evaluated and assessed, including diagnostic biomarkers scores. Moreover, multiomics markers panels involving phenotype, genotype, microbiome and clinical characteristics from patients will facilitate the diagnosis, stratification and prognosis of NAFLD patients with precision medicine approaches.

A nutrigenetic tool for precision dietary management of non-alcoholic fatty liver disease deeming insulin resistance markers.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) development is linked to insulin resistance and influenced by environmental factors, but it also underlined a genetic predisposition. The aim of this research was to build a predictive model based on genetic and hepatic health information, deeming insulin resistance markers in order to personalize dietary treatment in overweight/obese subjects with NAFLD. METHODS: A 6-month nutritional intervention was conducted in 86 overweight/obese volunteers with NAFLD randomly assigned to 2 energy-restricted diets: the American Heart Association (AHA) diet and the Fatty Liver in Obesity (FLiO) diet. Individuals were genotyped using a predesigned panel of 95 genetic variants. A Genetic Risk Score (GRS) for each diet was computed using statistically relevant SNPs for the change on Fatty Liver Index (FLI) after 6-months of nutritional intervention. Body composition, liver injury and insulin resistance markers, as well as physical activity and dietary intake were also assessed. RESULTS: Under energy restriction, both the AHA and FLiO diets induced similar significant improvements on body composition, insulin resistance markers, hepatic health and dietary and lifestyle outcomes. The calculated score included in the linear mixed regression model was able to predict the change of FLI adjusted by diet, age and sex. This model allowed to personalize the most suitable diet for 72% of the volunteers. Similar models were also able to predict the changes on Triglycerides and Glucose (TyG) Index and retinol-binding protein 4 (RBP4) levels depending on diet. CONCLUSIONS: Models integrating genetic screening and insulin resistance markers can be useful for the personalization of NAFLD weight loss treatments.

Three Different Genetic Risk Scores Based on Fatty Liver Index, Magnetic Resonance Imaging and Lipidomic for a Nutrigenetic Personalized Management of NAFLD: The Fatty Liver in Obesity Study.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population. The pathogenesis of NAFLD is complex; available data reveal that genetics and ascribed interactions with environmental factors may play an important role in the development of this morbid condition. The purpose of this investigation was to assess genetic and non-genetic determinants putatively involved in the onset and progression of NAFLD after a 6-month weight loss nutritional treatment. A group of 86 overweight/obese subjects with NAFLD from the Fatty Liver in Obesity (FLiO) study were enrolled and metabolically evaluated at baseline and after 6 months. A pre-designed panel of 95 genetic variants related to obesity and weight loss was applied and analyzed. Three genetic risk scores (GRS) concerning the improvement on hepatic health evaluated by minimally invasive methods such as the fatty liver index (FLI) (GRSFLI), lipidomic-OWLiver®-test (GRSOWL) and magnetic resonance imaging (MRI) (GRSMRI), were derived by adding the risk alleles genotypes. Body composition, liver injury-related markers and dietary intake were also monitored. Overall, 23 SNPs were independently associated with the change in FLI, 16 SNPs with OWLiver®-test and 8 SNPs with MRI, which were specific for every diagnosis tool. After adjusting for gender, age and other related predictors (insulin resistance, inflammatory biomarkers and dietary intake at baseline) the calculated GRSFLI, GRSOWL and GRSMRI were major contributors of the improvement in hepatic status. Thus, fitted linear regression models showed a variance of 53% (adj. R2 = 0.53) in hepatic functionality (FLI), 16% (adj. R2 = 0.16) in lipidomic metabolism (OWLiver®-test) and 34% (adj. R2 = 0.34) in liver fat content (MRI). These results demonstrate that three different genetic scores can be useful for the personalized management of NAFLD, whose treatment must rely on specific dietary recommendations guided by the measurement of specific genetic biomarkers.

Effects of two personalized dietary strategies during a 2-year intervention in subjects with nonalcoholic fatty liver disease: A randomized trial.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) management is focused on lifestyle modifications, but long-term maintenance is a challenge for many individuals. This study aimed to evaluate the long-term effects of two personalized energy-restricted dietary strategies on weight loss, metabolic and hepatic outcomes in overweight/obese subjects with NAFLD. METHODS: Ninety-eight subjects from the Fatty Liver in Obesity (FLiO) study (NCT03183193) were randomly assigned to the American Heart Association (AHA) or the FLiO dietary group in a 2-year controlled trial. Anthropometry, body composition (DXA), biochemical parameters and hepatic status (ultrasonography, Magnetic Resonance Imaging, and elastography) were assessed at baseline, 6, 12 and 24 months. RESULTS: Both the AHA and FLiO diets significantly reduced body weight at 6 (-9.7% vs -10.1%), 12 (-6.7% vs -9.6%), and 24 months (-4.8% vs -7.6%) with significant improvements in body composition, biochemical and liver determinations throughout the intervention. At the end of the follow-up, the FLiO group showed a greater decrease in ALT, liver stiffness and Fatty Liver Index, among others, compared to AHA group, although these differences were attenuated when the analyses were adjusted by weight loss percentage. The FLiO group also showed a greater increase in adiponectin compared to AHA group. CONCLUSIONS: The AHA and FLiO diets were able to improve body weight and body composition, as well as metabolic and hepatic status of participants with overweight/obesity and NAFLD within a 2-year follow-up. These findings show that both strategies are suitable alternatives for NAFLD management. However, the FLiO strategy may provide more persistent benefits in metabolic and hepatic parameters.