Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank.

Nuclear magnetic resonance (NMR)-based plasma fatty acids are objective biomarkers of many diseases. Herein, we aim to explore the associations of NMR-based plasma fatty acids with the risk of hepatocellular carcinoma (HCC) and chronic liver disease (CLD) mortality in 252,398 UK Biobank participants. Here we show plasma levels of n-3 poly-unsaturated fatty acids (PUFA) and n-6 PUFA are negatively associated with the risk of incident HCC [HRQ4vsQ1: 0.48 (95% CI: 0.33-0.69) and 0.48 (95% CI: 0.28-0.81), respectively] and CLD mortality [HRQ4vsQ1: 0.21 (95% CI: 0.13-0.33) and 0.15 (95% CI: 0.08-0.30), respectively], whereas plasma levels of saturated fatty acids are positively associated with these outcomes [HRQ4vsQ1: 3.55 (95% CI: 2.25-5.61) for HCC and 6.34 (95% CI: 3.68-10.92) for CLD mortality]. Furthermore, fibrosis stage significantly modifies the associations between PUFA and CLD mortality. This study contributes to the limited prospective evidence on the associations between plasma-specific fatty acids and end-stage liver outcomes.

Relationship between skeletal muscle mass loss and metabolic dysfunction-associated fatty liver disease among Chinese patients with metabolic dysregulation.

OBJECTIVE: The aim of this study was to explore the correlation between skeletal muscle content and the presence and severity of metabolic dysfunction-associated fatty liver disease in patients with metabolic dysregulation in China. METHODS: A cross-sectional study was conducted among patients from the endocrinology outpatient department at Ningbo First Hospital, in Ningbo, China, in April 2021. Adult patients with metabolic dysregulation who accepted FibroScan ultrasound were included in the study. However, those without clinical data on skeletal muscle mass were excluded. FibroScan ultrasound was used to noninvasively evaluate metabolic dysfunction-associated fatty liver disease. The controlled attenuation parameter was used as an evaluation index for the severity of liver steatosis. Bioelectrical impedance analysis was used to measure the skeletal muscle index. RESULTS: A total of 153 eligible patients with complete data were included in the final analysis. As the grading of liver steatosis intensifies, skeletal muscle index decreases (men: Ptrend<0.001, women: Ptrend=0.001), while body mass index, blood pressure, blood lipid, uric acid, aminotransferase, and homeostatic model assessment of insulin resistance increase (Ptrend<0.01). After adjusting for confounding factors, a negative association between skeletal muscle index and the presence of metabolic dysfunction-associated fatty liver disease was observed in men (OR=0.691, p=0.027) and women (OR=0.614, p=0.022). According to the receiver operating characteristic curve, the best cutoff values of skeletal muscle index for predicting the metabolic dysfunction-associated fatty liver disease presence were 40.37% for men (sensitivity, 87.5%; specificity, 61.5%) and 33.95% for women (sensitivity, 78.6%; specificity, 63.8%). CONCLUSION: Skeletal muscle mass loss among patients with metabolic dysregulation was positively associated with metabolic dysfunction-associated fatty liver disease severity in both sexes. The skeletal muscle index cutoff value could be used to predict metabolic dysfunction-associated fatty liver disease.

ZJU Index as a Predictive Tool for Diabetes Incidence: Insights from a Population-Based Cohort Study.

Background: In previous studies, the ZJU index was reported to be a superior predictor of nonalcoholic fatty liver disease in the Chinese population compared to the Fatty Liver Index. However, whether the ZJU Index is significantly associated with diabetes among Asian populations has not been determined. Methods: The NAGALA study was carried out at Murakami Memorial Hospital (Gifu, Japan) beginning in 1994. This study included the data of the subjects who underwent health check-ups from 2004 to 2015. The ZJU Index comprises body mass index (BMI), fasting plasma glucose, triglyceride, and alanine aminotransferase-to-aspartate aminotransferase (ALT) levels and an adjustment point for females. We conducted Cox proportional hazard regression to evaluate the association between quartiles of the ZJU Index and the risk of incident diabetes. Participants: A total of 15,464 individuals who underwent health check-ups were included in this study. Results: A total of 373 cases of incident diabetes were documented during 93,350 person-years of follow-up. As the ZJU index increased, the incidence of diabetes gradually increased (P <0.001). According to the multivariable model adjusted for metabolic covariates, the fourth quartile of the ZJU Index was positively associated with the risk of diabetes compared to the first quartile (HR=2.519, 95% CI=1.297-4.891). Subgroup analysis revealed that the association between the ZJU index and diabetes risk was significant in subjects aged younger than 40 years (HR=3.327, 95% CI=1.544-7.171), in females (HR=4.480, 95% CI=1.302-15.419), in individuals with a BMI<25 kg/m2 (HR=3.812, 95% CI=1.992-7.293) and in individuals with a nonregular exercise (HR=2.479, 95% CI=1.193-5.152). Conclusion: We observed a positive association between the ZJU Index and incident diabetes in the general population.

Long-term Use of Proton Pump Inhibitors is Associated With An Increased Risk of Nonalcoholic Fatty Liver Disease.

BACKGROUNDS: The adverse effects of long-term use of proton pump inhibitors (PPIs) have led to growing concern. The association between PPIs use and the risks of nonalcoholic fatty liver disease (NAFLD) remains controversial. GOAL: The aim of this study was to investigate the association between PPIs use and the risks of NAFLD among the general adult population in the United States. STUDY: We performed a cross-sectional study by extracting data from the National Health and Nutrition Examination Survey of 2017 to 2018. The association between PPIs use and NAFLD risks was analyzed by weighted multivariate logistic regression. RESULTS: Among the 4238 participants included in this study, 2167 were diagnosed with NAFLD. In the multivariate logistic regression model, PPIs use was associated with increased risks of NAFLD [odds ratio (OR): 1.318, 95% CI: 1.044-1.663; P=0.020]. This association was nonsignificant in participants taking PPIs for ˂5 years (OR: 0.846, 95% CI: 0.579-1.238; P=0.390), whereas it remained significant in participants taking PPIs for more than 5 years (OR: 2.016, 95% CI: 1.366-2.975; P=0.031). Further analysis showed that the use of PPIs was positively associated with risks of severe hepatic steatosis (OR: 1.451, 95% CI: 1.034-2.036; P=0.031) but not with mild-to-moderate steatosis (OR: 1.242, 95% CI: 0.886-1.741; P=0.208). CONCLUSIONS: This study indicated that taking PPIs was associated with increased risks of NAFLD, especially severe hepatic steatosis. Awareness should be raised regarding the potential risks of NAFLD when prescribing PPIs.

Modifiable lifestyle factors, genetic and acquired risk, and the risk of severe liver disease in the UK Biobank cohort: (Lifestyle factors and SLD).

BACKGROUND: Lifestyle intervention is important for the treatment of liver diseases. AIMS: To clarify the association of healthy lifestyle with severe liver disease (SLD) and assessed whether genetic susceptibility and acquired fibrosis risk can modify the association. METHODS: We included 417,986 UK Biobank participants who were free of SLD at baseline. Information on seven modifiable lifestyle factors was collected through a baseline questionnaire. SLD was defined as a medical diagnosis of cirrhosis, hepatocellular carcinoma or liver failure. Cox proportional hazards models were used to evaluate the association between healthy lifestyle factors and risk of incident SLD. The polygenic risk score (PRS) and fibrosis-4 index (FIB-4) were calculated and set as an interaction term. RESULTS: During a median follow-up of 12.6 years, 4542 fatal and non-fatal SLD incidents were identified. A higher overall lifestyle score was associated with a significantly lower SLD risk (Ptrend <0.001). An increment of 1-point lifestyle score combined with a 1-SD increment in FIB-4 or PRS was associated with an additional reduction of 3% or 2% in SLD risk. CONCLUSIONS: In European individuals, a healthy lifestyle is associated with a lower risk of incident SLD, which is more pronounced among individuals with a higher genetic and fibrosis risk.

Ten-Day Vonoprazan-Amoxicillin Dual Therapy vs Standard 14-Day Bismuth-Based Quadruple Therapy for First-Line Helicobacter pylori Eradication: A Multicenter Randomized Clinical Trial.

INTRODUCTION: Whether 10-day short-course vonoprazan-amoxicillin dual therapy (VA-dual) is noninferior to the standard 14-day bismuth-based quadruple therapy (B-quadruple) against Helicobacter pylori eradication has not been determined. This trial aimed to compare the eradication rate, adverse events, and compliance of 10-day VA-dual regimen with standard 14-day B-quadruple regimen as first-line H. pylori treatment. METHODS: This prospective randomized clinical trial was performed at 3 institutions in eastern China. A total of 314 treatment-naive, H. pylori -infected patients were randomly assigned in a 1:1 ratio to either 10-day VA-dual group or 14-day B-quadruple group. Eradication success was determined by 13 C-urea breath test at least 4 weeks after treatment. Eradication rates, adverse events, and compliance were compared between groups. RESULTS: Eradication rates of VA-dual and B-quadruple groups were 86.0% and 89.2% ( P = 0.389), respectively, by intention-to-treat (ITT) analysis; 88.2% and 91.5% ( P = 0.338), respectively, by modified ITT analysis; and 90.8% and 91.3% ( P = 0.884), respectively, by per-protocol (PP) analysis. The efficacy of the VA-dual remained noninferior to B-quadruple therapy in all ITT, modified ITT, and PP analyses. The incidence of adverse events in the VA-dual group was significantly lower compared with that in the B-quadruple group ( P < 0.001). Poor compliance contributed to eradication failure in the VA-dual group ( P < 0.001), while not in the B-quadruple group ( P = 0.110). DISCUSSION: The 10-day VA-dual therapy provided satisfactory eradication rates of >90% (PP analysis) and lower rates of adverse events compared with standard 14-day B-quadruple therapy as first-line H. pylori therapy. TRAIL REGISTRATION NUMBER: ChiCTR2300070100.

Causal association of nonalcoholic fatty liver disease with 22 extrahepatic cancers: A Mendelian randomization study.

AIM: It is unclear whether nonalcoholic fatty liver disease (NAFLD) acts as a direct contributing factor to multiple extrahepatic cancers. We aimed to systematically investigate the causal relationships of NAFLD with extrahepatic cancers. METHODS: We conducted a two-sample Mendelian randomization analysis to assess the causal effects of NAFLD on 22 extrahepatic cancers. We examined the association of NAFLD with extrahepatic cancers using multiple methods in the largest genome-wide association study meta-analysis to date. We also replicated the analyses and performed two independent sensitivity analysis in the largest genome-wide association study of UK Biobank. RESULTS: Using the weighted median method, genetically predicted NAFLD was significantly associated with female breast cancer risk (odds ratio [OR] 15.99; 95% confidence interval [CI] 9.58-26.69). Genetically predicted NAFLD is associated with cervical and laryngeal cancers using the inverse variance weighting method, and the ORs were 2.44 (95% CI 1.43-4.14) and 1.94 (95% CI 1.35-2.78), respectively. We observed that patatin-like phospholipase domain-containing protein 3-driven and transmembrane 6 superfamily member 2-driven NAFLD were associated with increased risks of leukemia, lung cancer, and prostate cancers (all with p < 0.05). Furthermore, we confirmed the causal association between NAFLD and breast cancer using five known single-nucleotide polymorphisms of NAFLD and six genome-wide association study-identified variants. The ORs of the weighted median estimator was 10.76 (95% CI 8.27-13.98) and 10.76 (95% CI 8.25-14.04), respectively (p < 0.001). CONCLUSION: Genetically predicted NAFLD is associated with an increased risk of female breast cancer, as well as cervical, laryngeal, leukemia, lung, and prostate cancers.

Inhibiting Hepatocyte Uric Acid Synthesis and Reabsorption Ameliorates Acetaminophen-Induced Acute Liver Injury in Mice.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury worldwide. Uric acid (UA) is involved in sterile inflammation in many organs, but its role in APAP-induced liver injury remains elusive. METHODS: We quantified the concentration of UA in the serum and liver tissues of APAP-overdosed mice and explored the changes in proteins involved in UA synthesis, absorption, and degeneration on APAP stimulation. We also examined the effects of inhibiting hepatocyte UA synthesis or reabsorption on APAP-induced liver injury in mice. Furthermore, we explored the process of UA clearance by peripheral macrophages. RESULTS: APAP overdose significantly increased intrahepatic UA contents, which occurred earlier than apparent hepatocyte injury in APAP-overdosed mice. APAP overdose induced significant DNA leakage and may thereby increase the substrate of UA synthesis. APAP overdose also significantly increased the enzymatic activity of xanthine oxidase and urate oxidase and decreased the expression of the UA reabsorption transporter GLUT9 in hepatocytes. Inhibiting hepatocyte UA synthesis by febuxostat or reabsorption by hepatic-specific knockout of GLUT9 alleviated APAP-induced liver injury. Further experiments showed that monosodium urate but not soluble UA may be a major form of UA mediating hepatocyte injury. Additionally, monosodium urate further recruited circulating macrophages into the liver and then aggravated inflammation by increasing the levels of inflammatory factors and reactive oxygen species. Deletion of macrophages significantly ameliorated APAP-induced liver injury in mice. CONCLUSIONS: APAP overdose induces excessive UA production and leads to local high concentrations in the liver, which further injures cells and induces liver inflammation. Inhibiting the production of UA may be a potential therapeutic option for treating APAP-induced liver injury.

The sulfur microbial diet and risk of nonalcoholic fatty liver disease: a prospective gene-diet study from the UK Biobank.

BACKGROUND: The gut microbiota is closely related to liver diseases. The dietary pattern associated with sulfur-metabolizing bacteria in stool has been found to influence intestinal health. OBJECTIVE: We aimed to investigate whether consuming the sulfur microbial diet is associated with nonalcoholic fatty liver disease (NAFLD). METHODS: We included 143,918 participants of European descent from the UK Biobank. Information on serving sizes used per diet component was recorded by an online 24-h dietary assessment tool (Oxford WebQ). The total sulfur microbial diet score was constructed by summing the product of ß-coefficients and corresponding serving sizes. NAFLD was ascertained using hospital inpatient and death records. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI). Mediation analyses were used to investigate underlying mediators including body mass index, waist circumference, glucose, triglyceride, urate, and C-reactive protein. A polygenic risk score for NAFLD was constructed and stratified to assess whether the association is modified by genetic predisposition. RESULTS: After a median follow-up of 11.7 y (interquartile range: 11.3-12.5 y), we documented 1540 incident cases of NAFLD. After adjustment for covariates, we observed an overall J-shaped relationship between the sulfur microbial diet and risk of NAFLD. Those in the highest quartile of sulfur microbial diet score had a 46% increased risk of NAFLD [HRQ4vsQ1 (95% CI): 1.46 (1.26, 1.69)]. We also found that this association is partly mediated by metabolic disorders and systemic inflammation. In addition, the positive association was stronger among individuals at higher genetic risk for NAFLD (Pinteraction = 0.044). CONCLUSIONS: The sulfur microbial diet had adverse associations with incident NAFLD, particularly in those at a higher genetic risk. Our study may provide evidence on the role of sulfur-metabolizing bacteria in the diet-NAFLD association.

Estimated small dense low-density lipoprotein cholesterol and nonalcoholic fatty liver disease in nonobese populations.

AIMS/INTRODUCTION: To explore the association between estimated small dense low-density lipoprotein cholesterol (sdLDL-C) and the risk of incident nonalcoholic fatty liver disease (NAFLD) in nonobese populations. MATERIALS AND METHODS: This study included participants who underwent health checkups in 2014 and were followed up until 2019. We carried out Cox proportional hazards regression analyses to evaluate the association of estimated sdLDL-C with NAFLD. Discordance analyses were carried out to estimate the relative NAFLD risk in estimated sdLDL-C versus low-density lipoprotein cholesterol (LDL-C) discordant/concordant groups. Estimated sdLDL-C was calculated by equations based on LDL-C and triglycerides. The diagnosis of NAFLD was based on the presence of abdominal ultrasonography after excluding other causes of chronic liver disease. RESULTS: Over a mean follow-up period of 26,694 person-years, 844 incident NAFLD cases were recorded. Compared with the first quartile of estimated sdLDL-C, the fourth quartile was associated with a 2.933-fold increased risk of NAFLD (95% confidence interval 2.095-4.107). With the increase in estimated sdLDL-C, the risk of NAFLD gradually increased both in participants within the normal range of LDL-C (hazard ratio 2.854, 95% confidence interval 1.650-5.617) and beyond the normal range of LDL-C (hazard ratio 2.636, 95% confidence interval 1.263-5.502). In addition, the inconsistent high estimated sdLDL-C/low LDL-C group was associated with an increased risk of NAFLD, but not the low estimated sdLDL-C/high LDL-C group. CONCLUSIONS: Estimated sdLDL-C was positively associated with the risk of incident NAFLD in a nonobese population, independent of LDL-C.

Relationship between skeletal muscle mass loss and metabolic dysfunction-associated fatty liver disease among Chinese patients with metabolic dysregulation

SUMMARY OBJECTIVE: The aim of this study was to explore the correlation between skeletal muscle content and the presence and severity of metabolic dysfunction-associated fatty liver disease in patients with metabolic dysregulation in China. METHODS: A cross-sectional study was conducted among patients from the endocrinology outpatient department at Ningbo First Hospital, in Ningbo, China, in April 2021. Adult patients with metabolic dysregulation who accepted FibroScan ultrasound were included in the study. However, those without clinical data on skeletal muscle mass were excluded. FibroScan ultrasound was used to noninvasively evaluate metabolic dysfunction-associated fatty liver disease. The controlled attenuation parameter was used as an evaluation index for the severity of liver steatosis. Bioelectrical impedance analysis was used to measure the skeletal muscle index. RESULTS: A total of 153 eligible patients with complete data were included in the final analysis. As the grading of liver steatosis intensifies, skeletal muscle index decreases (men: Ptrend<0.001, women: Ptrend=0.001), while body mass index, blood pressure, blood lipid, uric acid, aminotransferase, and homeostatic model assessment of insulin resistance increase (Ptrend<0.01). After adjusting for confounding factors, a negative association between skeletal muscle index and the presence of metabolic dysfunction-associated fatty liver disease was observed in men (OR=0.691, p=0.027) and women (OR=0.614, p=0.022). According to the receiver operating characteristic curve, the best cutoff values of skeletal muscle index for predicting the metabolic dysfunction-associated fatty liver disease presence were 40.37% for men (sensitivity, 87.5%; specificity, 61.5%) and 33.95% for women (sensitivity, 78.6%; specificity, 63.8%). CONCLUSION: Skeletal muscle mass loss among patients with metabolic dysregulation was positively associated with metabolic dysfunction-associated fatty liver disease severity in both sexes. The skeletal muscle index cutoff value could be used to predict metabolic dysfunction-associated fatty liver disease.

Different dietary carbohydrate component intakes and long-term outcomes in patients with NAFLD: results of longitudinal analysis from the UK Biobank.

BACKGROUND: This study aimed to investigate the association between the intake of different dietary carbohydrate components and the long-term outcomes of non-alcoholic fatty liver disease (NAFLD). METHODS: We used prospective data from 26,729 NAFLD participants from the UK Biobank cohort study. Dietary information was recorded by online 24-hour questionnaires (Oxford WebQ). Consumption of different carbohydrate components was calculated by the UK Nutrient Databank Food Composition Table. Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI). A substitution model was used to estimate the associations of hypothetical substitution for free sugars. RESULTS: During a median of 10.5 (IQR: 10.2-11.2) years and a total of 280,135 person-years of follow-up, 310 incident end-stage liver disease (ESLD) and 1750 deaths were recorded. Compared with the lowest quartile, the multi-adjusted HRs (95% CI) of incident ESLD in the highest quartile were 1.65 (1.14-2.39) for free sugars, 0.51 (0.35-0.74) for non-free sugars, and 0.55 (0.36-0.83) for fiber. For overall mortality, the multi-adjusted HRs (95% CI) in the highest quartile were 1.21 (1.04-1.39) for free sugars, 0.79 (0.68-0.92) for non-free sugars, and 0.79 (0.67-0.94) for fiber. Substituting free sugars with equal amounts of non-free sugars, starch or fiber was associated with a lower risk of incident ESLD and overall mortality. CONCLUSIONS: A lower intake of free sugars and a higher intake of fiber are associated with a lower incidence of ESLD and overall mortality in NAFLD patients. These findings support the important role of the quality of dietary carbohydrates in preventing ESLD and overall mortality in NAFLD patients.

Remnant cholesterol and severity of nonalcoholic fatty liver disease.

BACKGROUND: Serum remnant cholesterol levels are being increasingly acknowledged as a causal risk factor for atherosclerotic disease, regardless of conventional lipid parameters. The positive association between remnant cholesterol and nonalcoholic fatty liver disease (NAFLD) has been revealed in previous studies. However, whether remnant cholesterol is associated with the severity of NAFLD remains unknown. This study aimed to explore the association between serum remnant cholesterol and the risk of NAFLD severity. METHODS: This cross-sectional study included a total of 6,053 participants who attended health checkups. The severity of hepatic steatosis was evaluated by liver ultrasound transient elastography. Univariable and multivariable logistic regression analyses were performed to calculate the odds ratio (OR) and 95% confidence interval (95% CI) for the association between remnant cholesterol and the severity of hepatic steatosis. To explore whether the association between remnant cholesterol and NAFLD severity was independent of conventional lipid parameters, we further investigated this association in individuals with normal values of low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides. RESULTS: In total, 36.9% of individuals had mild steatosis, and 5.9% had moderate-to-severe steatosis. The serum level of remnant cholesterol in nonsteatosis, mild steatosis and moderate-to-severe steatosis gradually increased (0.71 ± 0.33, 0.97 ± 0.52 and 1.07 ± 0.63 mmol/L, respectively). In the multivariable mode, remnant cholesterol was positively associated with mild hepatic steatosis (OR: 1.730, 95% CI: 1.541 - 1.941, P < 0.001) and moderate-to-severe steatosis (OR: 2.342, 95% CI: 1.765 - 3.109, P < 0.001). These associations were not significantly altered in individuals with normal triglycerides, HDL-C and LDL-C (OR: 1.664, 95% CI: 1.448 - 1.911, P < 0.001; OR: 2.269, 95% CI: 1.619 - 3.180, P < 0.001, respectively). CONCLUSIONS: Higher levels of serum remnant cholesterol were associated with more severe hepatic steatosis, regardless of conventional lipid parameters. Individuals with higher remnant cholesterol may need more attention in regular surveillance of NAFLD.

Circulating fatty acids, genetic risk, and incident coronary artery disease: A prospective, longitudinal cohort study.

The role of fatty acids (FAs) in primary prevention of coronary artery disease (CAD) is highly debated, and the modification effect by genetic risk profiles remains unclear. Here, we report the prospective associations of circulating FAs and genetic predisposition with CAD development in 101,367 U.K. Biobank participants. A total of 3719 CAD cases occurred during a mean follow-up of 11.5 years. Plasma monounsaturated FAs (MUFAs) were positively associated with risk of CAD, whereas the risk was significantly lower with higher n-3 polyunsaturated FAs (PUFAs) and more reductions in risk were detected among TT carriers of rs174547. Furthermore, increased plasma saturated FAs (SFAs) and linoleic acid were related to a significant increase in CAD risk among participants with high genetic risk (genetic risk score > 90%). These findings suggest that individuals with high genetic risk need to reduce plasma SFAs levels for CAD prevention. Supplementation of n-3 PUFAs for CAD prevention may consider individuals' genetic makeup.

Fatty liver is associated with significant liver inflammation and increases the burden of advanced fibrosis in chronic HBV infection.

BACKGROUND: Concurrent non-alcoholic fatty liver disease (NAFLD) is common in patients with chronic HBV infection. But the impact of fatty liver on the histologic progression of HBV infection remains controversial. METHODS: Consecutive HBV-infected patients who underwent liver biopsy between 2016 and 2021 were included. Alcohol consumption and other types of viral hepatitis were excluded. All biopsies were scored for grading and staging by Scheuer's score, and the steatosis was scored as an estimate of the percentage of liver parenchyma replaced by fat. Logistic regression analyses were applied to assess the associated factors for significant liver inflammation (G ≥ 2), significant fibrosis (S ≥ 2) and advanced fibrosis (S ≥ 3). RESULTS: Among the 871 HBV-infected patients, hepatic steatosis was prevalent in 255 patients (29.28%). Significant liver inflammation was present in 461 patients (52.93%). Significant fibrosis was observed in 527 patients (60.51%), while advanced liver fibrosis was observed in 171 patients (19.63%). Patients with concomitant NAFLD were more likely to have significant liver inflammation and advanced fibrosis. Fatty liver was an independent risk factor for significant liver inflammation (OR: 2.117, 95% CI: 1.500-2.988), but it could not predict the development of fibrosis. Especially, in HBV-infected patients with persistent normal ALT (immune tolerant and inactive carrier phase), the presence of significant liver inflammation was higher in NAFLD than those without NAFLD. The prevalence of advanced liver fibrosis was higher in NAFLD than non-NAFLD only in the immune tolerant phase, while NAFLD did not increase fibrosis burden in other stages of HBV infection. We developed a predictive model for significant liver inflammation with the area under receiver operating characteristic curve (AUROC) of 0.825, and a model for significant fibrosis with the AUROC of 0.760. CONCLUSIONS: NAFLD is independently associated with significant liver inflammation, and increases the burden of advanced liver fibrosis in HBV-infected patients. The influence of NAFLD on the degree of liver inflammation and fibrosis is different in distinct clinical phases of chronic HBV infection.

Olfactomedin 4 deletion exacerbates nonalcoholic fatty liver disease through P62-dependent mitophagy in mice.

BACKGROUND & AIMS: Olfactomedin 4 (OLFM4) is a glycoprotein that is related to obesity and insulin resistance. This study aims to investigate the role and mechanisms of OLFM4 in nonalcoholic fatty liver disease (NAFLD). APPROACH & RESULTS: OLFM4 expression levels were significantly increased in liver samples from NAFLD patients and in cellular and mouse models of NAFLD. Cell lines deficient in or overexpressing OLFM4 and Olfm4-/- mice were established to study its role in NAFLD. OLFM4 deficiency significantly aggravated diet-induced hepatic steatosis and inflammation, while re-expression of OLFM4 ameliorated diet-induced hepatic steatosis and inflammation in mice. Mechanistically, OLFM4 deficiency disrupted mitochondrial structure and decreased mitophagy in hepatocytes, thereby aggravating hepatic lipogenesis, inflammation, and insulin resistance. Moreover, OLFM4 directly interacted with P62, and OLFM4 deficiency decreased mitophagy in both cellular and mouse models of NAFLD through a P62-dependent mechanism. We also show that blocking the P62-ZZ-domain using XRK3F2 prevented diet-induced NAFLD in Olfm4-/- mice. CONCLUSION: OLFM4 is significantly upregulated in NAFLD, and OLFM4 deletion exacerbates NAFLD through P62-dependent mitophagy.

Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma Presenting as a Colonic Polyp: Report of a Case with a Literature Review.

Background: Follicular dendritic cell (FDC) sarcoma is an uncommon mesenchymal origin neoplasm derived from the abnormal proliferation and differentiation of FDCs. Epstein‒Barr virus-positive inflammatory follicular dendritic cell sarcoma (EBV+ iFDCS), which used to be known as the inflammatory pseudotumour (IPT)-like variant, occurs exclusively in the liver and spleen and has rarely been reported in the gastrointestinal tract. Case study: Here, we report a case of a 52-year-old woman with a special family history undergoing a routine physical examination. The colonoscope revealed an approximately 18 mm transverse colonic polyp, and the endoscopic polypectomy was performed. Microscopically, the excised polypoid mass was composed predominantly of inflammatory cells scattered with atypical ovoid to spindle tumor cells. Interestingly, there was a remarkable infiltration of IgG4+ cells. Immunohistochemistry showed that the tumor cells were positive for CD21, CD23 and CD35. EBV-encoded mRNA (EBER) in situ hybridization also gave positive signals. These histopathology features supported the diagnosis of EBV+ iFDCS. The patient was free of disease over 1-year follow-up. Conclusion: Identification of the potential pathogenesis sites of EBV+ iFDCS in extra-hepatosplenic regions is necessary for correct and timely diagnosis, and we consider it very meaningful to share our experience of diagnosing this tumor type. Furthermore, we summarize the clinicopathological features of EBV+ iFDCS presenting as a colon polyp after a thorough review of the literature.

Association between night shift work and NAFLD: a prospective analysis of 281,280 UK Biobank participants.

CONTEXT: This study aimed to investigate the association between night shift work and the risk of nonalcoholic fatty liver disease (NAFLD). METHODS: We conducted a prospective analysis of 281,280 UK Biobank participants. Cox proportional hazards models were used to estimate the association of night shift work with incident NAFLD. Polygenic risk score analyses were performed to assess whether a genetic predisposition to NAFLD modified the association. RESULTS: During a median follow-up of 12.1 years (3,373,964 person-years), 2,555 incident NAFLD cases were identified. Compared with workers who never/rarely worked night shifts, those who worked some night shifts or usual/permanent night shifts were 1.12 (95% CI: 0.96-1.31) and 1.27 (95% CI: 1.08-1.48) times more likely to develop NAFLD, respectively. Among the 75,059 participants who had reports on lifetime experience of night shift work, those with a longer duration, a higher frequency, more consecutive night shifts and a longer length per shift all showed higher risks of incident NAFLD. Further analyses showed that the association between night shift work and incident NAFLD was not modified by a genetic predisposition to NAFLD. CONCLUSIONS: Night shift work was associated with increased risks of incident NAFLD.

A simpler definition of MAFLD precisely predicts incident metabolic diseases: a 7-year cohort study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel definition proposed in 2020 with a relatively complex set of criteria. Thus, simplified criteria that are more applicable are required. This study aimed to develop a simplified set of criteria for identifying MAFLD and predicting MAFLD-related metabolic diseases. METHODS: We developed a simplified set of metabolic syndrome-based criteria for MAFLD, and compared the performance of the simplified criteria with that of the original criteria in predicting MAFLD-related metabolic diseases in a 7-year follow-up. RESULTS: In the 7-year cohort, a total of 13,786 participants, including 3372 (24.5%) with fatty liver, were enrolled at baseline. Of the 3372 participants with fatty liver, 3199 (94.7%) met the MAFLD-original criteria, 2733 (81.0%) met the simplified criteria, and 164 (4.9%) were metabolic healthy and met neither of the criteria. During 13,612 person-years of follow-up, 431 (16.0%) fatty liver individuals newly developed T2DM, with an incidence rate of 31.7 per 1000 person-years. Participants who met the simplified criteria had a higher risk of incident T2DM than those who met the original criteria. Similar results were observed for incident hypertension, and incident carotid atherosclerotic plaque. CONCLUSION: The MAFLD-simplified criteria are an optimized risk stratification tool for predicting metabolic diseases in fatty liver individuals.