ANGPTL3 Downregulation Increases Intracellular Lipids by Reducing Energy Utilization.

BACKGROUND: ANGPTL3 (angiopoietin-like protein 3) is a circulating protein with a key role in maintaining lipoprotein homeostasis. A monoclonal antibody against ANGPTL3 is an approved and well-tolerated treatment to reduce lipoproteins in familial hypercholesterolemia homozygotes. However, the reduction of hepatic ANGPTL3 synthesis using an antisense oligonucleotide unexpectedly resulted in a dose-dependent increase in liver lipid content and circulating transaminases, resulting in the termination of the clinical trial. Meanwhile, the use of silencing RNAs remains an area of active investigation. Our study sought to investigate whether intracellular downregulation of ANGPTL3 may lead to a primary increase in neutral lipids within the hepatocyte. METHODS: We downregulated ANGPTL3 by silencing RNA in primary human hepatocytes 3-dimensional spheroids, HepG2/LX-2 3-dimensional spheroids, and in HepG2, Hep3B2, and Huh7 cultured in 2 dimensions. RESULTS: ANGPTL3 downregulation increased neutral lipids in all models investigated. Interestingly, ANGPTL3 induced lower intracellular deiodinase type 1 protein levels resulting in a reduction in beta-oxidation and causing an increase in triglycerides stored in lipid droplets. CONCLUSIONS: In conclusion, intracellular ANGPTL3 downregulation by silencing RNA led to an increase in triglycerides content due to a reduction in energy substrate utilization resembling a primary intracellular hepatocyte hypothyroidism.

Gut Microbiota Profile Changes in Patients with Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease: A Metagenomic Study.

Gut microbiota imbalances have a significant role in the pathogenesis of Inflammatory Bowel Disease (IBD) and Non-Alcoholic Fatty Liver Disease (NAFLD). Herein, we compared gut microbial composition in patients diagnosed with either IBD or NAFLD or a combination of both. Seventy-four participants were stratified into four groups: IBD-NAFLD, IBD-only, NAFLD-only patients, and healthy controls (CTRLs). The 16S rRNA was sequenced by Next-Generation Sequencing. Bioinformatics and statistical analysis were performed. Bacterial α-diversity showed a significant lower value when the IBD-only group was compared to the other groups and particularly against the IBD-NAFLD group. ß-diversity also showed a significant difference among groups. The higher Bacteroidetes/Firmicutes ratio was found only when comparing IBD groups and CTRLs. Comparing the IBD-only group with the IBD-NAFLD group, a decrease in differential abundance of Subdoligranulum, Parabacteroides, and Fusicatenibacter was found. Comparing the NAFLD-only with the IBD-NAFLD groups, there was a higher abundance of Alistipes, Odoribacter, Sutterella, and Lachnospira. An inverse relationship in the comparison between the IBD-only group and the other groups was shown. For the first time, the singularity of the gut microbial composition in IBD and NAFLD patients has been shown, implying a potential microbial signature mainly influenced by gut inflammation.

MBOAT7 in liver and extrahepatic diseases.

MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non-alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss-of-function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID-19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.

Ultrasound Prevalence and Clinical Features of Nonalcoholic Fatty Liver Disease in Patients with Inflammatory Bowel Diseases: A Real-Life Cross-Sectional Study.

Background and Objectives: Inflammatory bowel disease (IBD) is a condition characterized by chronic intestinal inflammation. We can identify two major forms: Crohn's disease (CD) and ulcerative colitis (UC). One of the extraintestinal manifestations of IBD is nonalcoholic fatty liver disease (NAFLD). IBD and NAFLD share common pathogenetic mechanisms. Ultrasound (US) examination is the most commonly used imaging method for the diagnosis of NAFLD. This cross-sectional observational retrospective study aimed to evaluate the US prevalence of NAFLD in IBD patients and their clinical features. Materials and Methods: A total of 143 patients with IBD underwent hepatic US and were divided into two different groups according to the presence or absence of NAFLD. Subsequently, new exclusion criteria for dysmetabolic comorbidities (defined as plus) were applied. Results: The US prevalence of NAFLD was 23% (21% in CD and 24% in UC, respectively). Most IBD-NAFLD patients were male and older and showed significantly higher values for body mass index, waist circumference, disease duration, and age at onset than those without NAFLD. IBD-NAFLD patients showed a significantly higher percentage of stenosing phenotype and left-side colitis. Regarding metabolic features, IBD-NAFLD patients showed a significantly higher percentage of hypertension and IBD plus dysmetabolic criteria. Also, higher values of alanine aminotransferase and triglycerides and lower levels of high-density lipoproteins are reported in these patients. Conclusions: We suggest performing liver US screening in subjects affected by IBD to detect NAFLD earlier. Also, patients with NAFLD present several metabolic comorbidities that would fall within the new definition of metabolic-associated fatty liver disease. Finally, we encourage larger longitudinal studies, including healthy controls, to provide further confirmation of our preliminary data.

Metabolic-Dysfunction-Associated Fatty Liver Disease and Gut Microbiota: From Fatty Liver to Dysmetabolic Syndrome.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is the recent nomenclature designation that associates the condition of non-alcoholic fatty liver disease (NAFLD) with metabolic dysfunction. Its diagnosis has been debated in the recent period and is generally associated with a diagnosis of steatosis and at least one pathologic condition among overweight/obesity, type 2 diabetes mellitus, and metabolic dysregulation. Its pathogenesis is defined by a "multiple-hit" model and is associated with alteration or dysbiosis of the gut microbiota. The pathogenic role of dysbiosis of the gut microbiota has been investigated in many diseases, including obesity, type 2 diabetes mellitus, and NAFLD. However, only a few works correlate it with MAFLD, although common pathogenetic links to these diseases are suspected. This review underlines the most recurrent changes in the gut microbiota of patients with MAFLD, while also evidencing possible pathogenetic links.

Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease.

BACKGROUND & AIMS: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. METHODS: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. RESULTS: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. CONCLUSIONS: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression.

Metabolic and genetic determinants for progression to severe liver disease in subjects with obesity from the UK Biobank.

BACKGROUND: Obesity is among the main determinants of nonalcoholic fatty liver disease progression towards severe liver disease (SLD). However, risk factors for SLD in individuals with obesity have not been examined. OBJECTIVES: To identify the independent risk factors for SLD among participants with obesity from the UK Biobank. METHODS: A total of 80,224 UK Biobank participants with obesity (body mass index[BMI] > 30 kg/m2) and 242,822 without obesity, of European descent without clinical history of liver disease and liver cancer were prospectively followed for the onset of SLD, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation. Risk factors for incident SLD were assessed by Cox proportional hazards models. Different clinical phenotypes were derived by latent class analysis (LCA). RESULTS: Obesity conferred a 2.6-fold increased risk for SLD that was abolished after the inclusion of waist circumference (WC) in the model. Among individuals with obesity, age (adjusted hazard ratio [aHR] 1.05, 95%CI 1.03-1.07, p = 3.9 * 10-7), type 2 diabetes (aHR 2.18, 95%CI 1.55-3.05, p = 6.2 * 10-6), PNPLA3 rs738409 (aHR 1.59, 95%CI 1.33-1.9, p = 3.1 * 10-7) and WC (aHR 1.04, 95%CI 1.02-1.06, p = 8.5 * 10-6) were independent predictors of SLD. BMI category-specific WC thresholds allowed a better risk stratification compared to traditional ones. By LCA, the clinical phenotype at highest risk for SLD was that with BMI < 35 kg/m2 and WC above BMI-category specific thresholds. CONCLUSIONS: Age, WC, type 2 diabetes, and the PNPLA3 variant are the main risk factors for SLD in individuals with obesity. WC is the principal mediator of SLD risk conveyed by increased BMI. BMI category-specific WC-thresholds may refine the SLD risk more accurately than traditional thresholds.

Phytomedicines to Target Hepatitis B Virus DNA Replication: Current Limitations and Future Approaches.

Hepatitis B virus infection (HBV) is one of the most common causes of hepatitis, and may lead to cirrhosis or hepatocellular carcinoma. According to the World Health Organization (WHO), approximately 296 million people worldwide are carriers of the hepatitis B virus. Various nucleos(t)ide analogs, which specifically suppress viral replication, are the main treatment agents for HBV infection. However, the development of drug-resistant HBV strains due to viral genomic mutations in genes encoding the polymerase protein is a major obstacle to HBV treatment. In addition, adverse effects can occur in patients treated with nucleos(t)ide analogs. Thus, alternative anti-HBV drugs of plant origin are being investigated as they exhibit excellent safety profiles and have few or no side effects. In this study, phytomedicines/phytochemicals exerting significant inhibitory effects on HBV by interfering with its replication were reviewed based on different compound groups. In addition, the chemical structures of these compounds were developed. This will facilitate their commercial synthesis and further investigation of the molecular mechanisms underlying their effects. The limitations of compounds previously screened for their anti-HBV effect, as well as future approaches to anti-HBV research, have also been discussed.

Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05). CONCLUSIONS: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.

PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD.

BACKGROUND AND AIMS: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. METHODS: We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2) the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9. RESULTS: Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against nonalcoholic fatty liver disease (NAFLD) (OR: 0.42; 95% CI: 0.22-0.81; P = .01), NASH (OR: 0.48; 95% CI: 0.26-0.87; P = .01) and more severe fibrosis (OR: 0.55; 95% CI: 0.32-0.94; P = .03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis (P = .03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge. CONCLUSIONS: In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting that PCSK9 inhibition may be a new therapeutic strategy to treat NASH.

Nursing-sensitive outcomes in adult inflammatory bowel disease: A systematic review.

AIMS: To evaluate nursing activity through outcomes that are affected, provided, and/or influenced by nurses and defined as nursing-sensitive outcomes in adult IBD patients. DESIGN: Systematic review without meta-analysis. DATA SOURCES: PubMed, Embase, CINAHL, PsycINFO, and the Cochrane Library databases on August 2019. REVIEW METHODS: Peer-reviewed articles published between 2000-2020 were reviewed. The outcome measures were contextualized and presented by OMERACT Filter 2.0. RESULTS: Twenty-four studies were included. Eighteen nursing-sensitive outcomes were identified. These outcomes defined eight domains for health intervention, fitting into three core areas (resource use/economic impact, life impact, pathophysiological manifestations). Fifty-three measurement instruments were identified. CONCLUSIONS: Through 53 measurement tools, with use of OMERACT framework, 18 nursing-sensitive outcomes in the main 3 core areas were identified, highlighting the multidimensional role of nursing. Further insights are to be carried out to define nursing outcomes included in IBD nursing intervention studies. IMPACT: These results could serve as a cornerstone for further investigations and validation by a panel of experts to standardizing nursing activity in a multidisciplinary context.

Knowledge of Diagnostic and Therapeutic Aspects of IBD Among Nurses Working in Digestive Endoscopy: A Nationwide Italian Survey.

The importance of inflammatory bowel disease (IBD) dedicated nurses in endoscopy services is poorly explored. Non-IBD healthcare professionals who work in endoscopy units may underestimate the discomfort and the secondary psychological distress that endoscopic procedures cause in IBD patients. We performed a nationwide survey to evaluate the level of knowledge of nurses working in endoscopy facilities throughout Italy related to IBD patients' needs undergoing endoscopic procedures. A non-validate 45 items questionnaire divided into six sections was assembled by a group of experts and supervised by nurses and IBD-physicians as part of the board of IGIBD, ANOTE-ANIGEA and AGGEI. The questionnaire was sent to 397 nurses of which 335 (84.4%) responded to the questionnaire. The median level of knowledge registered was 29 ± 12, corresponding to a medium level of knowledge based on the scores described in the method section. One hundred eighty-three nurses (54.6%) reported a high score, 113 (33.7%) a medium score, and 39 (11.6%) a low score. The majority of nurses worked in high volume endoscopy centers, where the 48% were educated in IBD management. A Low level of knowledge was recorded regarding disease severity definition, bowel preparation strategies in severe colitis and evaluation of perianal fistula. This nationwide survey clearly shows that there is a need for endoscopic nurses to acquire specific knowledge in the IBD field. Dedicated pathways for IBD management in endoscopy, continuous educational programs for nurses and further studies to improve nurse education are needed.

Real-Life Effectiveness and Safety of Golimumab and Its Predictors of Response in Patients with Ulcerative Colitis.

BACKGROUND: Golimumab is a new anti-TNF-alpha monoclonal antibody for patients with ulcerative colitis. AIMS: To assess the short- and long-term effectiveness and safety of golimumab in daily clinical practice and to identify predictors of response. METHODS: Consecutive patients treated with golimumab in 22 Italian centers were enrolled. Clinical, laboratory, and endoscopic data were prospectively collected before and during treatment. A subgroup of patients completed a questionnaire to assess personal satisfaction with a golimumab autoinjector system. RESULTS: A total of 196 patients were included. After 3 months, 130 patients were responders (66.3%) and showed significant reductions in mean partial, total, and endoscopic Mayo scores and in mean ESR, C-reactive protein, and fecal calprotectin levels (p < 0.001). Multivariate analysis revealed that a higher total Mayo score (p < 0.001, OR 1.5, 95% CI 1.2-1.8) and naïve status to anti-TNF-alpha (p = 0.015, OR 3.0, 95% CI 1.2-7.5) were predictive of a favorable response. Seventy-seven (39.3%) of the 130 responders maintained a response at month 12 of therapy. There were 17 adverse events, 28 patients needed hospitalization, and 15 patients underwent surgery. Self-administration of the drug was appreciated by most patients. CONCLUSIONS: The efficacy and safety of golimumab in daily clinical practice were confirmed for the short- and long-term treatment of patients with active ulcerative colitis. Patients naïve to the anti-TNF-alpha monoclonal antibody and those with a higher total Mayo score were more likely to respond to golimumab.

Effects of listening to music in digestive endoscopy: A prospective intervention study led by nursing.

AIMS: To explore whether music can reduce anxiety and pain in patients who underwent diagnostic endoscopic examinations in conscious and deep sedation and to assess degree of satisfaction and willingness to repeat the procedure. DESIGN: Prospective study led by nursing. METHODS: Between March 2019-June 2019, consecutive outpatients undergoing endoscopic examinations were simple matched into four groups: Group 1: conscious sedation with music; Group 2: conscious sedation without music; Group 3: deep sedation with music and Group 4: deep sedation without music. Ten minutes before the procedure, two trainee nurses applied music. State-Trait Anxiety Inventory was used to evaluate anxiety. RESULTS: Before and at the end of the procedure, patients who listened to music had a lower level anxiety than those who did not listen and, also, reported lower pain intensity during procedure. Only within Group 1 median anxiety, measured after the procedure, is lower than that measured before. In the bivariate logistic regression model, pain and listening to music were independent factors for satisfaction and willingness to repeat procedure. CONCLUSION: music in digestive endoscopy reduce pain and anxiety in conscious sedation, thus could be used to reduce anxiety in support to conscious sedation leading to lower usage of deep sedation and consequently reduction of costs and adverse events. IMPACT: Anxiety in digestive endoscopy limits patients' satisfaction. Music in digestive endoscopy as a specific nursing intervention could reduce anxiety of patients. This nursing intervention study confirms positive effect of music in digestive endoscopy. As part of nursing management, the addition of music to daily care practice in digestive endoscopy may reduce anxiety and increase the patient's degree of satisfaction. Use of music could limit deep sedation use in digestive endoscopy with consequent reduction of risks for patients, execution times, and costs of procedures.

Ulcerative Colitis as an Independent Risk Factor for Hepatic Steatosis.

Inflammatory bowel disease (IBD) is an inflammatory condition of the gastrointestinal tract encompassing Crohn disease and ulcerative colitis, often associated with extraintestinal manifestations. Nonalcoholic fatty liver disease represents one of the described inflammatory bowel disease-related liver diseases. To understand the IBD contribution to nonalcoholic fatty liver disease onset, we compared liver fat content and fibrosis between IBD patients and healthy controls integrating medical and nursing expertise (integrated nursing approach). A total of 95 patients and 53 healthy volunteers were recruited. Only nondiabetic and nonobese individuals were included in the study. Liver evaluation was performed by an experienced nurse using transient elastography. We found that IBD patients had higher liver fat content than the control group (p = .003). Bonferroni post hoc analyses revealed that patients with Crohn disease or ulcerative colitis had higher liver fat than the control group. We also found that ulcerative colitis was associated with more than a 4-fold increased risk for mild steatosis and 7-fold increased risk for moderate/severe steatosis independently from other risk factors such as glucose and body mass index. In conclusion, we showed for the first time that ulcerative colitis is an independent risk factor for hepatic steatosis measured by transient elastography.

Gastrointestinal Symptoms of and Psychosocial Changes in Inflammatory Bowel Disease: A Nursing-Led Cross-Sectional Study of Patients in Clinical Remission.

Background and Objectives: Nursing management in Inflammatory Bowel Disease (IBD) is focused on global patient care. Starting from basic knowledge of diagnostic and therapeutic management, nurses can assess the impact of IBD on patients' quality of life not only at the physical level, but also at the psychological, social, and emotional levels. The aim of this study was to evaluate the impact of gastrointestinal symptoms on psychosocial changes in IBD patients in remission through nursing-led Patient-Reported Outcomes. Materials and Methods: We performed a cross-sectional study of 109 IBD patients in clinical and endoscopic remission. Specialist nurses invited patients to complete questionnaires on gastrointestinal symptoms and quality of life through the Patient-Reported Outcomes Measurement Information System (PROMIS). Results: We found that the gastrointestinal symptoms that the patients reported had a significant impact on the analyzed aspects of health. More specifically, belly pain, diarrhea, and bloating were associated with depressive symptoms (p < 0.001), anxiety (p < 0.001), fatigue (p < 0.001), and sleep disturbances (p < 0.001). Moreover, these symptoms also significantly affected patients' social dimension in terms of satisfaction with participation in social roles (p < 0.001, p < 0.05, and p < 0.001 for belly pain, diarrhea, and bloating, respectively) and physical functions (p < 0.001). The results were virtually the same in a multivariable analysis adjusted by age, gender, body mass index (BMI), and disease duration. Conclusions: Even during remission, gastrointestinal symptoms are the main factors that influence quality of life in IBD patients. This exploratory study highlights the need to adopt validated questionnaires in clinical practice, and demonstrates that PROMIS is a valid, objective, and standardized instrument that can help nursing staff to better define the consequences of the disease in a patient's daily life.

COVID-19 and Inflammatory Bowel Disease: Patient Knowledge and Perceptions in a Single Center Survey.

Background and objectives: Spreading of SARS-CoV-2 infection from China to countries with a higher prevalence of inflammatory bowel disease (IBD) has generated concern among gastroenterologists and patients. The aim of this survey is to evaluate knowledge about clinical importance of COVID-19, disease management, prevention measures, and anxiety level during pandemic among patients with IBD. Material and methods: From 15th March to 15th April 2020, a questionnaire survey was administered to 200 patients with IBD by email or phone application. The questionnaire consisted of five sections: (1) anthropometric, demographic and clinical characteristics, (2) knowledge about clinical importance of COVID-19, (3) IBD management, (4) prevention measures, (5) anxiety level during pandemic. Results: One hundred forty two questionnaires were completed. Ninety-seven patients (68.3%) were males with a mean age of 46 years (SD 13; range 17-76). Fifty-four individuals (38%) were affected by Crohn disease and 88 (62%) by Ulcerative Colitis. Most patients reported high knowledge about clinical importance of COVID-19 (80%), IBD management (72%), and prevention measures (97%). Sixty-two percent of them showed moderate-high level of anxiety. High education level was independently associated with high knowledge about clinical importance of COVID-19 (odds ratio [OR] 5, 95% confidence interval [CI] 1.49-16.6, p = 0.009) and older age (OR 1, 95%, CI 1.01-1.1, p = 0.01), while the receipt of e-format educational material with low knowledge about clinical importance of COVID-19 (OR 3, 95%, CI 1.08-9.3, p = 0.03). Displaying an active disease appeared to be independently associated with low knowledge of IBD management (OR 5.8, 95% CI 1.4-22.8, p = 0.01) and no variables other than an older age was independently associated with higher level of anxiety (OR 1.04, 95% CI 1.009-1.09, p = 0.01). Conclusions: High educational level and aging promote knowledge about clinical importance of COVID-19, while e-format educational material does not. Taken together with findings that an active disease status compromises knowledge of IBD management and the high level of anxiety related to increasing age, these data suggest the need of further supporting patient-oriented strategies in IBD during Covid-19 pandemic.

The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. METHODS: We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. RESULTS: The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. CONCLUSIONS: We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection.

UNLABELLED: Chronic hepatitis C virus (HCV) infection may progress to cirrhosis and hepatocellular carcinoma (HCC). Recently, two genetic variants, DEPDC5 rs1012068 and MICA rs2596542, were associated with the onset of HCC in Asian subjects with chronic HCV infection. The aim of the present study was to analyze whether DEPDC5 and MICA genetic variants were associated with liver disease progression in European subjects with chronic HCV infection. In a Northern Italian discovery cohort (n = 477), neither DEPDC5 rs1012068 nor MICA rs2596542 were associated with HCC (n = 150). However, DEPDC5 rs1012068 was independently associated with cirrhosis (n = 300; P = 0.049). The association of rs1012068 with moderate to severe fibrosis was confirmed in an independent cross-sectional German cohort (n = 415; P = 0.006). Furthermore, DEPDC5 rs1012068 predicted faster fibrosis progression in a prospective cohort (n = 247; P = 0.027). Next, we examined the distribution of nonsynonymous DEPDC5 variants in the overall cross-sectional cohort (n = 912). The presence of at least one variant increased the risk of moderate/severe fibrosis by 54% (P = 0.040). To understand the molecular mechanism underlying the genetic association of DEPDC5 variants with fibrosis progression, we performed in vitro studies on immortalized hepatic stellate cells (LX-2). In these cells, down-regulation of DEPDC5 resulted in increased expression of ß-catenin and production of its target matrix metallopeptidase 2 (MMP2), a secreted enzyme involved in fibrosis progression. CONCLUSION: DEPDC5 variants increase fibrosis progression in European subjects with chronic HCV infection. Our findings suggest that DEPDC5 down-regulation may contribute to HCV-related fibrosis by increasing MMP2 synthesis through the ß-catenin pathway.