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Background and aims: The prevalence of non‐alcoholic fatty liver disease (NAFLD) is increasing globally. This study aimed to determine the prevalence of NAFLD and the probability of liver fibrosis in Italian primary care services. Methods: We carried out a population‐based and nested case–control study including all individuals aged 18 years and above registered at Italian primary care services. Data were collected from the general practitioners' network from 2010 to 2017. NAFLD cases were identified via the ICD‐9‐CM and Hepatic Steatosis Index score > 36 and were matched each up to 10 controls. Other causes of liver diseases were excluded. The risk of fibrosis was assessed using the FIB‐4 and NAFLD fibrosis scores (NFS). Results: NAFLD was present in 9% of the primary care population with high regional variability. Among NAFLD subjects: 25% had diabetes, 10% had chronic kidney disease, 11% had cardiovascular disease and 28% were obese. Furthermore, 30% had at least two comorbidities and 13% had cirrhosis. Once cirrhosis was excluded, the risk of any degree of fibrosis was 13.8% with NFS and 20.5% with FIB‐4 in subjects <65 years. Conclusions: Even if there is an identification gap in primary care, recorded cases with NAFLD have a high frequency of associated comorbidities. Despite regional variability, a close relation between cirrhosis and NAFLD exists (OR: 3.48, 95% CI: 3.23–3.76). Therefore, the use of non‐invasive tests should be promoted in primary care as a useful tool for the early identification of fibrosis risk, independently of evidence of steatosis. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross‐sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42‐0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14‐0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07‐0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10–8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down‐regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666‐675) [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7) , which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p < 0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p < 0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation. [Display omitted] • NAFLD is the leading cause of liver disorders and has a strong heritable component. • Rare loss-of-function ATG7 gene mutations increase the risk of severe liver disease in patients with NAFLD. • ATG7 mutations cause altered protein function and impairment of autophagy, leading to hepatocellular ballooning and inflammation. • The most frequent variant is responsible for a meaningful fraction of predisposition to ballooning and hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients. The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02–1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03–1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07–2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24–3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05). NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression. Unlabelled Image • Neurotensin (NTS) is involved in lipid metabolism and promotes HCC onset. • Increased plasma levels of pro-NTS have been associated MAFLD. • The rs1800832 NTS variant is associated with fibrosis and HCC in MAFLD patients. • Circulating Pro-NTS was correlated with fibrosis, cirrhosis, HCC in MAFLD patients. • NTS could be a biomarker for advanced liver disease and HCC in MAFLD patients. [ABSTRACT FROM AUTHOR]