Serum metabolites detect the presence of advanced fibrosis in derivation and validation cohorts of patients with non-alcoholic fatty liver disease.
Caussy Cyrielle,Ajmera Veeral H,Puri Puneet,Hsu Cynthia Li-Shin,Bassirian Shirin,Mgdsyan Mania,Singh Seema,Faulkner Claire,Valasek Mark A,Rizo Emily,Richards Lisa,Brenner David A,Sirlin Claude B,Sanyal Arun J,Loomba Rohit
OBJECTIVE:Non-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis. DESIGN:This is a cross-sectional analysis of a prospective cohort including 156 well-characterised patients with biopsy-proven NAFLD and two cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling. RESULTS:In the cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively. CONCLUSION:A combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an and two independent cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.
Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease.
Ma Jiantao,Hennein Rachel,Liu Chunyu,Long Michelle T,Hoffmann Udo,Jacques Paul F,Lichtenstein Alice H,Hu Frank B,Levy Daniel
BACKGROUND & AIMS:Dietary modification has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent its development. We performed a prospective study to examine the association between diet quality change and change in liver fat. We also examined the association between genetic risk score and liver fat change in individuals with different levels of diet quality change. METHODS:Our study included 1521 participants who attended the seventh and eighth examinations (1998-2001 and 2005-2008) of the second-generation cohort or attended the first and second examinations (2002-2005 and 2008-2011) of the third-generation cohort in the Framingham Heart Study. The self-administered semiquantitative 126-item Harvard food frequency questionnaire was used to determine dietary intake in the year leading up to an examination. We assessed levels of liver fat using liver-phantom ratio (LPR) on computed tomography images from 2002 through 2005 and again from 2008 through 2011. LPR values are inversely related to liver fat: increased LPR indicates decreased liver fat. We examined associations of changes in 2 diet scores, the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI), with changes in liver fat and new-onset fatty liver. We evaluated interactions between diet score change and a weighted genetic risk score for NAFLD, determined based on multiple single-nucleotide polymorphisms identified in genome-wide association studies of NAFLD. The primary outcome was change in LPR between baseline and follow-up measurement. RESULTS:For each 1 standard deviation increase in MDS, the LPR increased (meaning liver fat decreased) by 0.57 (95% confidence interval [CI] 0.27-0.86; P < .001) and the odds for incident fatty liver decreased by 26% (95% CI 10%-39%; P = .002). For each 1 standard deviation increase in AHEI, LPR increased by 0.56 (95% CI 0.29-0.84; P < .001) and the odds for incident fatty liver decreased by 21% (95% CI 5%-35%; P = .02). Increased diet scores were also associated with reduced odds of developing more-advanced fatty liver. Higher genetic risk scores were associated with increased liver fat accumulation in participants who had decreased MDS (P < .001) or AHEI scores (P = .001), but not in those with stable or improved diet scores (P for gene-diet interaction <.001). CONCLUSIONS:In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD.
Nonalcoholic Fatty Liver Disease 2020: The State of the Disease.
Cotter Thomas G,Rinella Mary
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. In the United States, NAFLD and its subtype, nonalcoholic steatohepatitis, affect 30% and 5% of the population, respectively. Considering the ongoing obesity epidemic beginning in childhood, the rise in diabetes, and other factors, the prevalence of NAFLD along with the proportion of those with advanced liver disease is projected to continue to increase. This will have an important impact on public health reflected in health care costs, including impact on the need for liver transplantation, for which nonalcoholic steatohepatitis is already close to becoming the most common indication. NAFLD patients with evidence of nonalcoholic steatohepatitis and advanced fibrosis are at markedly increased risk of adverse outcomes, including overall mortality, and liver-specific morbidity and mortality, respectively. Identification of this cohort of NAFLD patients is paramount, given the associated poorer outcomes, in order to target resources to those who need it most. Various noninvasive tools have been developed in this regard. This review provides an update on the epidemiology, clinical and prognostic features, and diagnostic approach to patients with NAFLD.
Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease.
Azzu Vian,Vacca Michele,Virtue Samuel,Allison Michael,Vidal-Puig Antonio
Adipose tissue and the liver play significant roles in the regulation of whole-body energy homeostasis, but they have not evolved to cope with the continuous, chronic, nutrient surplus seen in obesity. In this review, we detail how prolonged metabolic stress leads to adipose tissue dysfunction, inflammation, and adipokine release that results in increased lipid flux to the liver. Overall, the upshot of hepatic fat accumulation alongside an insulin-resistant state is that hepatic lipid enzymatic pathways are modulated and overwhelmed, resulting in the selective buildup of toxic lipid species, which worsens the pro-inflammatory and pro-fibrotic shift observed in nonalcoholic steatohepatitis.
Metabolic Inflammation-A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease?
Gehrke Nadine,Schattenberg Jörn M
Nonalcoholic fatty liver disease (NAFLD) is a global and growing health concern. Emerging evidence points toward metabolic inflammation as a key process in the fatty liver that contributes to multiorgan morbidity. Key extrahepatic comorbidities that are influenced by NAFLD are type 2 diabetes, cardiovascular disease, and impaired neurocognitive function. Importantly, the presence of nonalcoholic steatohepatitis and advanced hepatic fibrosis increase the risk for systemic comorbidity in NAFLD. Although the precise nature of the crosstalk between the liver and other organs has not yet been fully elucidated, there is emerging evidence that metabolic inflammation-in part, emanating from the fatty liver-is the engine that drives cellular dysfunction, cell death, and deleterious remodeling within various body tissues. This review describes several inflammatory pathways and mediators that have been implicated as links between NAFLD and type 2 diabetes, cardiovascular disease, and neurocognitive decline.