Development and validation of a machine learning-based model for varices screening in compensated cirrhosis (CHESS2001): an international multicenter study.

BACKGROUND AND AIMS: The prevalence of high-risk varices (HRV) is low among compensated cirrhotic patients undergoing EGD. Our study aimed to identify a novel machine learning (ML)-based model, named ML EGD, for ruling out HRV and avoiding unnecessary EGDs in patients with compensated cirrhosis. METHODS: An international cohort from 17 institutions from China, Singapore, and India were enrolled (CHESS2001). The variables with the top 3 importance scores (liver stiffness, platelet count, and total bilirubin) were selected by the Shapley additive explanation and input into a light gradient-boosting machine algorithm to develop ML EGD for identification of HRV. Furthermore, we built a web-based calculator for ML EGD, which is free with open access (http://www.pan-chess.cn/calculator/MLEGD_score). Unnecessary EGDs that were not performed and the rates of missed HRV were used to assess the efficacy and safety for varices screening. RESULTS: Of 2794 enrolled patients, 1283 patients formed a real-world cohort from 1 university hospital in China used to develop and internally validate the performance of ML EGD for varices screening. They were randomly assigned into the training (n = 1154) and validation (n = 129) cohorts with a ratio of 9:1. In the training cohort, ML EGD spared 607 (52.6%) unnecessary EGDs with a missed HRV rate of 3.6%. In the validation cohort, ML EGD spared 75 (58.1%) EGDs with a missed HRV rate of 1.4%. To externally test the performance of ML EGD, 966 patients from 14 university hospitals in China (test cohort 1) and 545 from 2 hospitals in Singapore and India (test cohort 2) comprised the 2 test cohorts. In test cohort 1, ML EGD spared 506 (52.4%) EGDs with a missed HRV rate of 2.8%. In test cohort 2, ML EGD spared 224 (41.1%) EGDs with a missed HRV rate of 3.1%. When compared with the Baveno VI criteria, ML EGD spared more screening EGDs in all cohorts (training cohort, 52.6% vs 29.4%; validation cohort, 58.1% vs 44.2%; test cohort 1, 52.4% vs 26.5%; test cohort 2, 41.1% vs 21.1%, respectively; P < .001). CONCLUSIONS: We identified a novel model based on liver stiffness, platelet count, and total bilirubin, named ML EGD, as a free web-based calculator. ML EGD could efficiently help rule out HRV and avoid unnecessary EGDs in patients with compensated cirrhosis. (Clinical trial registration number: NCT04307264.).

Renal and bone side effects of long-term use of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate in patients with Hepatitis B: a network meta-analysis.

BACKGROUND: Nucleoside analogues are currently applied as a first-line treatment for chronic hepatitis B (CHB) patients. However, the long-term effects of this type of treatment on kidney and bone tissue need to be further investigated. METHODS: We conducted a search of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) for treatment of CHB patients through October 29, 2023. Side effects of the three drugs were compared. Standardized mean difference (SMD), 95% confidence interval (95%CI), and surface under the cumulative ranking curve (SUCRA) were reported for each outcome. Further subgroup analysis was conducted according to duration of administration. RESULTS: ETV and TAF exhibited less effect on estimated glomerular filtration rate (eGFR) than TDF (SMD = -3.60 (95%CI: -1.94 ~ -5.26) and SMD = -4.27 (95%CI: -2.62 ~ -5.93)). ETV also exhibited less effect on creatinine rise than TAF and TDF (SMD = -0.55 (95%CI: -0.09 ~ -1.01) and SMD = -0.61 (95%CI: -0.15 ~ -1.06)). Moreover, the effect of TAF on bone mineral density (BMD) was less than that of TDF (SMD = -0.02 (95%CI: -0.01 ~ -0.02)). The probabilities of the three drugs changing relevant indicators exhibited similar patterns: eGFR (TDF (100.0%) > ETV (41.2%) > TAF (8.8%)), creatinine (TDF (94.7%) > TAF (54.7%) > ETV (0.6%)), BMD (TDF (79.7%) > ETV (50.6%) > TAF (19.6%)), and blood phosphorus (TDF (90.6%) > TAF (49.8%) > ETV (9.7%)). After 6 and 24 months of treatment, no statistically significant difference in renal function or bone tissue was observed between ETV and TDF. However, greater adverse effects on renal function were observed for TDF than ETV at 60 months compared to 12 months. TDF also exhibited greater adverse effects on bone tissue than ETV at 36 months than at 12 months. CONCLUSIONS: Long-term administration of TDF has resulted in stronger adverse effects than TAF and ETV in regard to both renal function and bone tissue in CHB patients. The effect of TAF on creatinine increase was greater than ETV. The difference in side effects between ETV and TDF was independent of treatment duration.

Efficacy and safety of alfosbuvir plus daclatasvir in Chinese patients with hepatitis C virus genotypes 1, 2, 3, and 6 infection: An open-label, phase 2 study.

Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. Our previous studies indicated that alfosbuvir monotherapy was well-tolerated and druggable in healthy subjects and HCV-infected patients. Here, we evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV genotype 1, 2, 3 or 6. In this open-label study, patients with chronic HCV infection were randomly assigned with a 1:1:1 ratio to receive 12 weeks of daclatasvir 60 mg plus alfosbuvir at a dose of 400, 600 or 800 mg (Cohort A, B or C) daily. Randomization was stratified by HCV genotype and the presence or absence of cirrhosis at screening. The primary endpoint was a sustained virologic response 12 weeks after the end of treatment (SVR12). A total of 124 patients were enrolled in the study, all of whom were available for post-treatment week 12 assessments. SVR12 was achieved in 92.7% (38/41), 95.2% (40/42) and 100% (41/41) of patients in Cohort A, B and C respectively. The most common adverse events were hepatic steatosis, upper respiratory tract infection, hypercholesterolaemia, hypertriglyceridaemia, blood bilirubin increased, and total bile acids increased. There were no discontinuations due to adverse events, and no treatment-related serious adverse events were reported. Once-daily oral administration of alfosbuvir plus daclatasvir were highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3 or 6, suggesting this regimen could be a promising drug candidate for HCV treatment irrespective of genotype. (ClinicalTrials.gov number, NCT04070235).

Relationship of circulating total bilirubin, UDP-glucuronosyltransferases 1A1 and the development of non-alcoholic fatty liver disease: a cross-sectional study.

BACKGROUND: This study aimed to investigate the correlation of circulating total bilirubin (TB) and UGT1A1 with NAFLD in Chinese Han population. METHODS: 172 adults were enrolled from the Qingdao Municipal Hospital from May 2019 to October 2020. All individuals were examined with MRI-PDFF and divided into no steatosis, mild steatosis, moderate steatosis, and severe steatosis groups according to the MRI-PDFF values. The biochemical indexes and UGT1A1 were measured. RESULTS: There was no significant difference of circulating TB and UGT1A1 levels between NAFLD group and controls. In the moderate steatosis and severe steatosis groups, the circulating TB levels were higher than that in control group (all P < 0.05). In addition, circulating TB levels were weak positively associated with liver fat fraction in NAFLD patients (ρ = 0.205, P = 0.001). There was no significant correlation between circulating UGT1A1 levels with liver fat fraction in patients with NAFLD (ρ = 0.080, P = 0.179), but positively correlation was found in patients with severe steatosis (ρ = 0.305, P = 0.026). CONCLUSIONS: The circulating TB levels were significant high in patients with moderate and severe steatosis. Circulating TB levels were weakly associated with liver fat fraction in patients with NAFLD, and the circulating UGT1A1 levels were positively correlated with liver fat fraction in NAFLD patients with severe steatosis. TRIAL REGISTRATION: ChiCTR, ChiCTR1900022744. Registered 24 April 2019 - Retrospectively registered, http://www.chictr.org.cn/edit.aspx?pid=38304&htm=4 .

Association between the LRP5 rs556442 gene polymorphism and the risks of NAFLD and CHD in a Chinese Han population.

BACKGROUND: Multiple studies have demonstrated the involvement of low-density lipoprotein receptor-related protein 5 (LRP5) in metabolism-related diseases. This study explored the relationship between the LRP5 rs556442 gene polymorphism and the risks of non-alcoholic fatty liver disease (NAFLD) and coronary heart disease (CHD) in a Chinese Han population. METHODS: This retrospective case-control study included 247 patients with NAFLD, 200 patients with CHD, 118 patients with both NAFLD and CHD, and 339 healthy controls from June 2018 to June 2019 at Qingdao Municipal Hospital. Basic information and clinical characteristics were collected for all subjects. The genotype and allele frequency of LRP5 rs556442 were determined. RESULTS: The genotype distributions of LRP5 rs556442 differed significantly between the CHD and NAFLD + CHD groups (P < 0.05). The LRP5 rs556442 GG genotype markedly promoted the risk of NAFLD in CHD patients [odds ratio (OR) = 2.857, 95% confidence interval (CI): 1.196-6.824, P = 0.018). After adjustment for sex, age, and body mass index (BMI), this association remained significant (OR = 3.252, 95% CI: 1.306-8.102, P = 0.011). In addition, the LRP5 rs556442 AA + AG genotype was associated with an increased BMI in obese NAFLD patients (OR = 1.526, 95% CI: 1.004-2.319, P = 0.048). However, after adjustment for sex and age, this association was no longer significant (OR = 1.504, 95% CI: 0.991-2.282, P = 0.055). CONCLUSIONS: This study found that the LRP5 rs556442 GG genotype increased the risk of NAFLD in CHD patients and AA + AG genotype may be associated with an increased BMI in obese NAFLD patients among a Chinese Han population. Trial registration ChiCTR, ChiCTR1800015426. Registered 28 March 2018-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=26239 .

Chaetomorpha linum polysaccharides alleviate NAFLD in mice by enhancing the PPARα/CPT-1/MCAD signaling.

BACKGROUND: Green algae contain many polysaccharides. However, there is no information on whether Chaetomorpha linum polysaccharides (CLP) can modulate lipid and glucose metabolism. MATERIAL AND METHODS: CLP were extracted from chlorella and their components were characterized. Male C57BL/6 mice were randomized and provided with control chow as the control, or high fat diet (HFD) to induce nonalcoholic fatty liver disease (NAFLD). NAFLD mice were treated orally with water as the HFD group or with 50 or 150 mg/kg CLP daily for 10 weeks. The impact of CLP treatment on lipid and glucose metabolism and the PPARα signaling was examined by histology, Western blotting and biochemistry. RESULTS: CLP mainly contained arabinogalactan sulfate. Compared with the control, HFD feeding increased body weights, lipid droplet liver deposition and induced hyperlipidemia, liver functional impairment and glucose intolerance in mice. Treatment with CLP, particularly with a higher dose of CLP, limited the HFD-increased body weights and liver lipid droplet deposition, mitigated the HFD-induced hyperlipidemia and improved liver function and glucose tolerance in mice. Mechanistically, feeding with HFD dramatically decreased the expression of liver PPARα, CPT-1, and MCAD, but treatment with CLP enhanced their expression in a trend of dose-dependent in mice. CONCLUSIONS: These findings indicated that CLP treatment alleviated the gain in body weights, NAFLD, and glucose intolerance in mice after HFD feeding by enhancing the PPARα/CPT-1/MCAD signaling.

MiR-146a-5p, targeting ErbB4, promotes 3T3-L1 preadipocyte differentiation through the ERK1/2/PPAR-γ signaling pathway.

BACKGROUND: MicroRNAs (MiRNAs) are known to participate in preadipocyte differentiation, but the manner in which miR-146a-5p participates in this process remains unclear. This study was performed to examine the participation of miR-146a-5p in 3T3-L1 cell differentiation. MATERIAL AND METHODS: miR-146a-5p expression was upregulated and down-regulated to examine effects on 3T3-L1 cell differentiation. Bioinformatics analysis was performed to predict its target genes, and the signaling pathway it regulates was identified by qRT-PCR and Western blotting. The expression of miR-146a-5p in epididymal adipose tissue from obese mice and in an obese mouse adipose cell model was examined by qRT-PCR. RESULTS: 3T3-L1 cells differentiated into mature adipocytes successfully, as verified by increased areas of intracellular lipid droplets and elevated expression of mature adipocyte markers, and these cells had elevated miR-146a-5p expression. The intracellular lipid droplet and triglyceride contents and the expression of mature adipocyte markers were significantly increased in miR-146a-5p-overexpressing 3T3-L1 cells and markedly decreased in miR-146a-5p-inhibited 3T3-L1 cells. ErbB4 was a predicted target gene of miR-146a-5p. In miR-146a-5p-overexpressing 3T3-L1 cells, ErbB4 expression and ERK1/2 phosphorylation were decreased and the expression of PPAR-γ was increased; the opposite was observed in miR-146a-5p-inhibited 3T3-L1 cells. In addition, miR-146a-5p expression was significantly increased in the mouse epididymal adipose tissue and adipose cell model. CONCLUSIONS: Upregulated miR-146a-5p expression was related to 3T3-L1 cell differentiation. MiR-146a-5p promoted 3T3-L1 cell differentiation by targeting ErbB4 and via the ERK1/2/PPAR-γ signaling pathway.

The clinical characteristics of pediatric inpatients with SARS-CoV-2 infection: A meta-analysis and systematic review.

Millions of people were infected with the coronavirus disease 2019 (COVID-19) all over the world. Data on clinical symptoms of pediatric inpatients with COVID-19 infection were unclear. The aim of study was to investigate the clinical features of pediatric inpatients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. PubMed, EMBASE, and the Cochrane Library were searched to seek for studies providing details on pediatric inpatients with SARS-CoV-2 infection which were published from 1st January to 21st April 2020. Studies with more than five pediatric inpatients were included in our meta-analysis.This study was registered in the PROSPERO database (CRD42020183550). As the results shown, fever (46%) and cough (42%) were the main clinical characters of pediatric inpatients with SARS-CoV-2 infection and the other clinical characters, such as diarrhea, vomiting, nasal congestion, and fatigue account for 10% in pediatric inpatients. The proportion of asymptomatic cases was 0.42 (95% confidence interval [CI]: 0.27-0.59) and severe cases was 0.03 (95% CI: 0.01-0.06). For the laboratory result, leukopenia (21%) and lymphocytosis (22%) were the mainly indicators for pediatric inpatients, followed by high aspartate aminotransferase (19%), lymphopenia (16%), high alanine aminotransferase (15%), high C-reactive protein (17%), leukocytosis (13%), high D-dimer (12%) and high creatine kinase-MB (5%). Regard to chest imaging features, unilateral and bilateral accounts for 22% in pediatric inpatients, respectively. In conclusion, compared with adult inpatients with SARS-CoV-2 infection, the pediatric inpatients had mild clinical characters, lab test indicators, and chest imaging features. More clinical studies focus on the pediatric patients with SARS-CoV-2 infection in other countries should be conducted.

Diagnostic accuracy assessment of molecular prediction model for the risk of NAFLD based on MRI-PDFF diagnosed Chinese Han population.

BACKGROUND: Several molecular prediction models based on the clinical parameters had been constructed to predict and diagnosis the risk of NAFLD, but the accuracy of these molecular prediction models remains need to be verified based on the most accurate NAFLD diagnostic method. The aim of this study was to verify the accuracy of three molecular prediction models Fatty liver index (FLI), NAFLD liver fat score system (NAFLD LFS), and Liver fat (%) in the prediction and diagnosis of NAFLD in MRI-PDFF diagnosed Chinese Han population. PATIENTS AND METHODS: MRI-PDFF was used to diagnose the hepatic steatosis of all the subjects. Information such as name, age, lifestyle, and major medical histories were collected and the clinical parameters were measured by the standard clinical laboratory techniques. The cut-off values of each model for the risk of NAFLD were calculated based on the MRI-PDFF results. All data were analyzed using the statistical analysis software SPSS 23.0. RESULTS: A total of 169 subjects were recruited with the matched sex and age. The ROC curves of FLI, NAFLD LFS, and Liver fat (%) models were plotted based on the results of MRI-PDFF. We founded that the accuracy of FLI, NAFLD LFS, and Liver fat (%) models for the prediction and diagnosis of NAFLD were comparative available in Chinese Han population as well as the validity of them in other ethnics and regions. CONCLUSIONS: The molecular prediction models FLI, NAFLD LFS, and Liver fat (%) were comparative available for the prediction and diagnosis of NAFLD in Chinese Han population. MRI-PDFF could be used as the golden standard to develop the new molecular prediction models for the prediction and diagnosis of NAFLD.

Seraprevir and sofosbuvir for treatment of chronic hepatitis C virus infection: A single-arm, open-label, phase 3 trial.

BACKGROUND AND AIM: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis. METHODS: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12). RESULTS: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention. CONCLUSIONS: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.

Proportion of NAFLD patients with normal ALT value in overall NAFLD patients: a systematic review and meta-analysis.

BACKGROUND: ALT value is often used to reflect the hepatic inflammation and injury in NAFLD patients, but many studies proved that ALT values were normal in many NAFLD patients. The aim of this study was to identify the summarized proportion of NAFLD patients with normal ALT value in the overall NAFLD patients. METHODS: Electronic databases PubMed, EMBASE, Ovid, and the Cochrane Library were searched for potential studies published from January 1, 2000 to September 30, 2019. Studies that have reported the number of NAFLD or NASH patients with normal and abnormal ALT value were included and analyzed. Abstracts, reviews, case reports, and letters were excluded. RESULTS: A total of 11 studies with 4084 patients were included for assessing the summarized proportion of NAFLD patients with normal ALT in overall NAFLD patients. As the results shown, the summarized proportion of NAFLD patients with normal ALT value in overall NAFLD patients was 25% (95%CI: 20-31%) which was calculated by the random-effects model. The summarized proportion of NASH patients with normal ALT value in overall NASH patients was 19% (95%CI: 13-27%). Subgroup analysis includes region, study type, diagnostic method, and group size were conducted to investigate the resource of heterogeneity in the summarized proportion of NAFLD and NASH patients with normal ALT value. CONCLUSIONS: 25% NAFLD patients and 19% NASH patients possess the normal ALT value in the clinical manifestation. The value of ALT in the clinical diagnosis of NAFLD and NASH remains need be further testified.

MiR-30b-5p regulates the lipid metabolism by targeting PPARGC1A in Huh-7 cell line.

BACKGROUND: MiRNAs are a group of multifunctional non-coding RNAs which play an important role in the various physiological processes including the development of NAFLD. Recent studies have shown that miR-30b-5p tightly associated with the abnormal lipid metabolism in patients with NAFLD, but the detailed mechanism of miR-30b-5p in the lipid metabolism was remain unclear. The aim of this study was to investigate the effect of miR-30b-5p on the lipid metabolism in hepatocellular carcinoma Huh-7 cells. MATERIAL AND METHODS: The correlation of intracellular fat content with the expression of miR-30b-5p in Huh-7 cells and HepG2 cells was investigated by treated cells with different concentrations of FFAs. The effect of miR-30b-5p on the lipid deposition in Huh-7 cells was tested by oil red O staining and TG concentrations measurement. qRT-PCR and western blot were used to investigate the lipid metabolism-related genes PPAR-α, SREBP-1, and GULT1 in miR-30b-5p overexpressed or inhibited Huh-7 cells. Target genes of miR-30b-5p were predicted using starBase, miRDB, and TargetScan databases and verified by qRT-PCR and western blot. RESULTS: The expression of miR-30b-5p was significant decreased in the FFAs treated Huh-7 cells and HepG2 cells. Overexpressing miR-30b-5p in Huh-7 cells decreased the number and size of lipid droplets and intracellular TG concentrations in Huh-7 cells. Expression of fatty acid oxidation related gene PPAR-α was increased and expression of lipid synthesis related gene SREBP-1 was decreased in the miR-30b-5p overexpressed Huh-7 cells. In addition, miR-30b-5p regulates the intracellular lipid metabolism by targeting PPARGC1A. CONCLUSIONS: Overexpression of miR-30b-5p could reduce the intracellular fat deposition in Huh-7 cells, and miR-30b-5p might regulate the intracellular lipid metabolism by targeting the PPARGC1A in Huh-7 cells.

Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis.

BACKGROUND: NAFLD is tightly associated with various diseases such as diabetes, cardiovascular disease, kidney disease, and cancer. Previous studies had investigated the association between NAFLD and various extrahepatic cancers, but the available data to date is not conclusive. The aim of this study was to investigate the association between NAFLD and various extrahepatic cancers comprehensively. METHODS: Searches were conducted of various electronic databases (PubMed, EMBASE, Medline, and the Cochrane Library) to identify observational studies published between 1996 and January 2020 which investigated the association between NAFLD and extrahepatic cancers. The pooled OR/HR/IRR of the association between NAFLD and various extrahepatic cancers were analyzed. RESULTS: A total of 26 studies were included to investigate the association between NAFLD and various extrahepatic cancers. As the results shown, the pooled OR values of the risk of colorectal cancer and adenomas in patients with NAFLD were 1.72 (95%CI: 1.40-2.11) and 1.37 (95%CI: 1.29-1.46), respectively. The pooled OR values of the risk of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma in patients with NAFLD were 2.46 (95%CI: 1.77-3.44) and 2.24 (95%CI: 1.58-3.17), respectively. The pooled OR value of the risk of breast cancer in patients with NAFLD was 1.69 (95%CI: 1.44-1.99). In addition, NAFLD was also tightly associatied with the risk of gastric cancer, pancreatic cancer, prostate cancer, and esophageal cancer. CONCLUSIONS: NAFLD could significantly increase the development risk of colorectal adenomas and cancer, intrahepatic and extrahepatic cholangiocarcinoma, breast, gastric, pancreatic, prostate, and esophageal cancer. NAFLD could be considered as one of the influencing factors during the clinical diagnosis and treatment for the extrahepatic cancers.

Independent and joint correlation of PNPLA3 I148M and TM6SF2 E167K variants with the risk of coronary heart disease in patients with non-alcoholic fatty liver disease.

BACKGROUND: CHD is reported to be the primary cause of death in patients with NAFLD. Genetic susceptibility genes contribute to the developmental risk of NAFLD or CHD. Whether the genetic factors could affect the risk of CHD in NAFLD patients is not clear. The aim of this study was to investigate the association of PNPLA3 I148M and TM6SF2 E167K variants with the risk of CHD in NAFLD patients in Chinese Han population. PATIENTS AND METHODS: PNPLA3 I148M and TM6SF2 E167K variants were genotyped in a cohort of 189 patients with NAFLD and CHD, as well as 242 patients with NAFLD and 242 healthy controls by gene sequencing. Additionally, serum lipids profiles were determined by standard clinical laboratory methods. RESULTS: The minor allele frequency of PNPLA3 I148M and TM6SF2 E167K were 0.39 and 0.06 in this cohort, respectively. The distributions of PNPLA3 I148M genotypes and alleles were significant different in NAFLD group vs controls and in NAFLD+CHD group vs NAFLD group (all P <  0.05). NAFLD patients who carry the CG + GG genotype suffered the relative lower risk of CHD than CC genotype carriers (OR = 0.6, 95%CI: 0.40-0.90, P = 0.01). In addition, PNPLA3 I148M and TM6SF2 E167K possess the joint correlation with the decreased risk of CHD in NAFLD patients with the increased number of risk alleles. Besides, PNPLA3 I148M and TM6SF2 E167K variants associated with the decreased serum lipid levels in overall series. CONCLUSIONS: There was a joint protective correlation of PNPLA3 I148M and TM6SF2 E167K variants with the developmental risk of CHD in NAFLD patients. PNPLA3 I148M and TM6SF2 E167K variants might correlated with the decreased risk of CHD in NAFLD patients by associated with the reduced serum lipid levels.

Association of TM6SF2 rs58542926 gene polymorphism with the risk of non-alcoholic fatty liver disease and colorectal adenoma in Chinese Han population.

BACKGROUND: Genetic factors affect the risk of non-alcoholic fatty liver disease (NAFLD) and colorectal adenoma (CRA) importantly. Transmembrane protein 6 superfamily member 2 (TM6SF2) rs58542926 is a significant genetic susceptibility site for NAFLD. The relationships of TM6SF2 rs58542926 with the risk of NAFLD and CRA in Chinese Han population were unclear. The aim of this study was to investigate the association of TM6SF2 rs58542926 with the risk of NAFLD and CRA, and the effect of CRA on TM6SF2 rs58542926 carried NAFLD patients. RESULTS: A total of 839 Chinese Han population were included in this retrospective study. TM6SF2 rs58542926 polymorphism was genotyped in B-type ultrasonography proven NAFLD patients with or without CRA, CRA patients and healthy controls, using polymerase chain reaction. Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS statistical software, version 16.0 for mac. There was a significant difference in the distribution of genotype and allele of TM6SF2 rs58542926 in NAFLD and NAFLD&CRA patients compared to controls. The CT + TT genotypes were tightly associated with the risk of NAFLD and NAFLD&CRA. TM6SF2 rs58542926 T allele promotes the abnormal regulation of lipids metabolism and liver injury in NAFLD patients and NAFLD&CRA patients. CRA aggravates the clinical performance of NAFLD in T allele carriers. CONCLUSIONS: We demonstrated the significant association between TM6SF2 rs58542926 polymorphism and the risk of NAFLD and NAFLD&CRA in a Chinese Han population. The TM6SF2 rs58542926 T allele promotes the abnormal regulation of lipid profiles and liver injury in NAFLD patients, NAFLD&CRA patients, and overall subjects.

Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis.

OBJECTIVE: To systematically review studies about the diagnostic accuracy of magnetic resonance imaging proton density fat fraction (MRI-PDFF) in the classification of hepatic steatosis grade in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Areas under the summary receiver operating characteristic curves (AUROC), sensitivity, specificity, overall diagnostic odds ratio (DOR), diagnostic score, positive likelihood ratio (+LR), and negative likelihood ratio (-LR) for MRI-PDFF in classification of steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were compared and analyzed. RESULTS: A total of 6 studies were included in this meta-analysis (n = 635). The summary AUROC values of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 0.98, 0.91, and 0.90, respectively. Pooled sensitivity and specificity of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 0.93 and 0.94, 0.74 and 0.90, and 0.74 and 0.87, respectively. Summary +LR and -LR of MRI-PDFF for classifying steatosis grades 0 vs. 1-3, 0-1 vs. 2-3, and 0-2 vs. 3 were 16.21 (95%CI, 4.72-55.67) and 0.08 (95%CI, 0.04-0.15), 7.19 (95%CI, 5.04-10.26) and 0.29 (95%CI, 0.22-0.38), and 5.89 (95%CI, 4.27-8.13) and 0.29 (95%CI, 0.21-0.41), respectively. CONCLUSIONS: Our meta-analysis suggests that MRI-PDFF has excellent diagnostic value for assessment of hepatic fat content and classification of histologic steatosis in patients with NAFLD. KEY POINTS: • MRI-PDFF has significant diagnostic value for hepatic steatosis in patients with NAFLD. • MRI-PDFF may be used to classify grade of hepatic steatosis with high sensitivity and specificity.

TRIB1 rs17321515 gene polymorphism increases the risk of coronary heart disease in general population and non-alcoholic fatty liver disease patients in Chinese Han population.

BACKGROUND: Present evidences suggested that TRIB1 rs17321515 polymorphism was tightly associated with the increased risk of NAFLD and CHD. CHD is one of the main complications of NAFLD, whether TRIB1 rs17321515 polymorphism could affect the risk of CHD in general population and NAFLD patients in Chinese Han population was remain unknown. The present study was designed to investigate the association between TRIB1 rs17321515 polymorphism and the risk of CHD in general population and NAFLD patients in Chinese Han population, and investigate the effect of TRIB1 rs17321515 polymorphism on serum lipid levels. PATIENTS AND METHODS: TRIB1 rs17321515 gene polymorphism was genotyped using the polymerase chain reaction (PCR) in healthy controls (n = 175), CHD patients (n = 155), NAFLD patients (n = 146), and NAFLD+CHD patients (n = 156). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 24.0 statistical software. RESULTS: The TRIB1 rs17321515 AA+GA genotypes were the significant risk factors for the CHD in general population (OR = 1.788; 95% CI: 1.104-2.897; P = 0.018) and in the NAFLD patients (OR = 1.760; 95% CI: 1.071-2.891; P = 0.026). After adjusted for age, gender, and body mass index, the risk for CHD in general population (OR = 1.857; 95% CI: 1.116-3.089; P = 0.017) and NAFLD patients was still significant (OR = 1.723; 95% CI: 1.033-2.873; P = 0.037). In addition, TRIB1 rs17321515 A carriers possess the higher lipid profiles in the included subjects. CONCLUSIONS: TRIB1 rs17321515 AA+GA genotypes were significant associated with the risk of CHD in general population and in NAFLD patients in Chinese Han population. The rs17321515 A allele increases the serum lipid profiles in included subjects.

Combining I148M and E167K variants to improve risk prediction for nonalcoholic fatty liver disease in Qingdao Han population, China.

BACKGROUND: PNPLA3 I148M variant and TM6SF2 E167K variant are recognized as the major genetic modifiers of nonalcoholic fatty liver disease (NAFLD). The present study sought to evaluate the potential additive effect of the two variants on the risk of NAFLD in Qingdao Han Population, China. METHODS: We genotyped PNPLA3 I148M variant and TM6SF2 E167K variant in a cohort of 512 unrelated NAFLD patients and 451 healthy controls by sequencing and polymerase chain reaction analysis. In addition, serum lipid profiles and liver enzymes were determined by standard clinical laboratory methods. RESULTS: The minor allele frequencies were 45.48% for PNPLA3 148 locus G allele and 6.69% for TM6SF2 167 locus T allele. The PNPLA3 I148M variant was significantly associated with the risk of NAFLD in an additive model (CG, OR = 2.092, 95% CI: 1.551-2.820, P = 0.000; GG, OR = 4.566, 95% CI: 3.141-6.638, P = 0.000, respectively). And, our data suggested a strong link between the TM6SF2 E167K variant and the risk of NAFLD in a dominant model (CT + TT, OR = 2.327, 95% CI: 1.542-3.513, P = 0.000). In addition, the increasing of the number of risk alleles were associated with the risk of NAFLD (1 risk allele, OR = 1.687, P = 0.001; 2 risk alleles, OR = 4.326, P = 0.000; 3 risk alleles, OR = 6.018, P = 0.027, respectively). CONCLUSIONS: Combining the I148M and E167K variants in a manner of an additive effect could improve risk prediction for NAFLD in a Qingdao Han Population cohort. TRIAL REGISTRATION: Chinese Clinical Trial Register.gov : ChiCTR1800015426.

TRIB1 rs17321515 and rs2954029 gene polymorphisms increase the risk of non-alcoholic fatty liver disease in Chinese Han population.

BACKGROUND: Dysregulation of the lipid homeostasis is an independent risk factor for non-alcoholic fatty liver disease (NAFLD). Some studies had demonstrated that TRIB1 gene polymorphisms affect the plasma lipids metabolism, but no related data was available for TRIB1 gene polymorphisms in the lipids metabolism in Chinses Han population. The present study was conducted to investigate the association between TRIB1 gene polymorphisms (rs17321515 and rs2954029) and the risk of NAFLD in Chinese Han population and their effects on serum lipid profiles. PATIENTS AND METHODS: TRIB1 rs17321515 and rs2954029 gene polymorphisms were genotyped using the polymerase chain reaction (PCR) in B-type ultrasonography-proven NAFLD patients (n = 146) and healthy controls (n = 175). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 22.0 statistical software. RESULTS: The allele distributions of TRIB1 rs17321515 A and rs2954029 A were significant different between the NAFLD patients and healthy controls (P = 0.026, P = 0.045, respectively). The genotype distribution of TRIB1 rs17321515 was significant different between NAFLD patients and healthy controls (P = 0.038). The TRIB1 rs17321515 GA + AA genotype and TRIB1 rs2954029 TA + AA genotype markedly increase the NAFLD risk (OR = 1.885; 95%CI: 1.157-3.070; OR = 1.627; 95%CI: 1.011-2.619, respectively), after adjusted for age, gender, and body mass index, the NAFLD risk still significant (OR = 2.240; 95%CI: 1.196-4.197; OR = 2.050; 95%CI: 1.110-3.786, respectively). In addition, TRIB1 rs17321515 A and rs2954029 A carriers possess the higher lipid profiles in the included subjects. CONCLUSIONS: TRIB1 rs17321515 and rs2954029 were significant associated with the risk of NAFLD in Chinese Han population. The rs17321515 A and rs2954029 A allele increases the serum lipid profiles in Chinese Han population.

Apolipoprotein A5 gene polymorphisms are associated with non-alcoholic fatty liver disease.

BACKGROUND: Several studies have reported that apolipoprotein A5 (APOA5) is involved in the development of non-alcoholic fatty liver disease (NAFLD). However, no research has been performed regarding the association between APOA5 polymorphisms and the risk of NAFLD. This study aimed to explore the association between APOA5 gene polymorphisms and NAFLD in a Chinese Han population. METHODS: Genotypes of the SNPs (rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 in 232 NAFLD patients and 188 healthy controls were determined using polymerase chain reaction (PCR) analysis. Clinical characteristics were measured using biochemical methods. RESULTS: The five single nucleotide polymorphisms (SNPs) (rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 showed no significant association with NAFLD (P > 0.05). The rs10750097 with G allele showed a higher serum level of alkaline phosphatase (ALP) compared with C allele in overall series and NAFLD patients (P < 0.05). The rs1263173(A/A) carriers showed a higher level of glucose compared to the non-carriers in overall series (P < 0.05). The rs17120035(T/T) carriers showed a lower plasma TG level in overall series and NAFLD patients (P < 0.05), and the rs662799(G/G) carriers showed higher levels of plasma triglyceride (TG), ALP, and lower level of high-density lipoprotein (HDL) compared to non-carriers in NAFLD patients (P < 0.05). No significant difference were observed on the clinic parameters of APOA5 rs3135507(T/T) carriers in both group of overall series and NAFLD patients (P > 0.05). CONCLUSIONS: The five SNPs (rs10750097, rs1263173, rs17120035, rs3135507 and rs662799) of APOA5 gene are not associated with the risk of NAFLD in the Chinese Han population. The genotypes of rs10750097(G/G), rs1263173(A/A), rs17120035(T/T), and rs662799(G/G) performed a significant effect on clinic characteristics in overall series and NAFLD patients, indicating that these polymorphisms may be associated with NAFLD.