Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF).

BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

Machine learning models are superior to noninvasive tests in identifying clinically significant stages of NAFLD and NAFLD-related cirrhosis.

BACKGROUND AND AIMS: We assessed the performance of machine learning (ML) models in identifying clinically significant NAFLD-associated liver fibrosis and cirrhosis. APPROACH AND RESULTS: We implemented ML models including logistic regression (LR), random forest (RF), and artificial neural network to predict histological stages of fibrosis using 17 demographic/clinical features in 1370 patients with NAFLD who underwent liver biopsy, FibroScan, and labs within a 6-month period at multiple U.S. centers. Histological stages of fibrosis (≥F2, ≥F3, and F4) were predicted using ML, FibroScan liver stiffness measurements, and Fibrosis-4 index (FIB-4). NASH with significant fibrosis (NAS ≥ 4 + ≥F2) was assessed using ML, FibroScan-AST (FAST) score, FIB-4, and NAFLD fibrosis score (NFS). We used 80% of the cohort to train and 20% to test the ML models. For ≥F2, ≥F3, F4, and NASH + NAS ≥ 4 + ≥F2, all ML models, especially RF, had primarily higher accuracy and AUC compared with FibroScan, FIB-4, FAST, and NFS. AUC for RF versus FibroScan and FIB-4 for ≥F2, ≥F3, and F4 were (0.86 vs. 0.81, 0.78), (0.89 vs. 0.83, 0.82), and (0.89 vs. 0.86, 0.85), respectively. AUC for RF versus FAST, FIB-4, and NFS for NASH + NAS ≥ 4 + ≥F2 were (0.80 vs. 0.77, 0.66, 0.63). For NASH + NAS ≥ 4 + ≥F2, all ML models had lower/similar percentages within the indeterminate zone compared with FIB-4 and NFS. Overall, ML models performed better in sensitivity, specificity, positive predictive value, and negative predictive value compared with traditional noninvasive tests. CONCLUSIONS: ML models performed better overall than FibroScan, FIB-4, FAST, and NFS. ML could be an effective tool for identifying clinically significant liver fibrosis and cirrhosis in patients with NAFLD.

Magnetic resonance elastography-based prediction model for hepatic decompensation in NAFLD: A multicenter cohort study.

BACKGROUND AND AIMS: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. APPROACH AND RESULTS: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts ( p < 0.05). CONCLUSIONS: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

MRI-AST (MAST) Score Accurately Predicts Major Adverse Liver Outcome, Hepatocellular Carcinoma, Liver Transplant, and Liver-Related Death.

BACKGROUND & AIMS: The MRI-AST (MAST) score accurately identifies patients with at-risk nonalcoholic steatohepatitis, defined as nonalcoholic steatohepatitis with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2 at highest risk for disease progression. It is important to determine the robustness of the MAST score in predicting major adverse liver outcomes (MALO), hepatocellular carcinoma (HCC), liver transplant, and death. METHODS: This retrospective analysis included patients with nonalcoholic fatty liver disease from a tertiary care center who underwent magnetic resonance imaging proton density fat fraction, magnetic resonance elastography, and laboratory testing within 6 months from 2013 to 2022. Other causes of chronic liver disease were excluded. Hazard ratios between logit MAST and MALO (ascites, hepatic encephalopathy, or bleeding esophageal varices), liver transplant, HCC, or liver-related death were computed using a Cox proportional hazards regression model. We computed the hazard ratio of MALO or death associated with MAST scores 0.165-0.242 and 0.242-1.000, using MAST scores 0.000-0.165 as the reference group. RESULTS: Among 346 total patients, average age was 58.8 years with 52.9% females and 34.4% with type 2 diabetes. Average alanine aminotransferase was 50.7 IU/L (24.3-60.0 IU/L), aspartate aminotransferase was 38.05 IU/L (22.00-41.00 IU/L), platelets were 242.9 × 109/L (193.8-290.0 × 109/L), proton density fat fraction was 12.90% (5.90%-18.22%), and liver stiffness on magnetic resonance elastography was 2.75 kPa (2.07-2.90 kPa). Median follow-up was 29.5 months. Fourteen had adverse outcomes, including 10 MALO, 1 HCC, 1 liver transplant, and 2 liver-related deaths. The Cox regression of MAST versus adverse event rate had a hazard ratio of 2.01 (95% confidence interval, 1.59-2.54; P < .0001) for each 1 logit unit increases in MAST. The corresponding Harrell concordance statistic (C statistic) was 0.919 (95% confidence interval, 0.865-0.953). The MAST score ranges of 0.165-0.242 and 0.242-1.0, respectively, had adverse event rate hazard ratio of 7.75 (1.40-42.9; P = .0189) and 22.11 (6.59-74.2; P < .0000) relative to MAST 0-0.165. CONCLUSIONS: The MAST score noninvasively identifies at-risk nonalcoholic steatohepatitis and accurately predicts MALO, HCC, liver transplant, and liver-related death.

Nonalcoholic Steatohepatitis Drug Development Pipeline: An Update.

Nonalcoholic steatohepatitis (NASH) is a burgeoning global health crisis that mirrors the obesity pandemic. This global health crisis has stimulated active research to develop novel NASH pharmacotherapies targeting dysregulated inflammatory, cellular stress, and fibrogenetic processes that include (1) metabolic pathways to improve insulin sensitivity, de novo lipogenesis, and mitochondrial utilization of fatty acids; (2) cellular injury or inflammatory targets that reduce inflammatory cell recruitment and signaling; (3) liver-gut axis targets that influence bile acid enterohepatic circulation and signaling; and (4) antifibrotic targets. In this review, we summarize several of the therapeutic agents that have been studied in phase 2 and 3 randomized trials. In addition to reviewing novel therapeutic drugs targeting nuclear receptor pathways, liver chemokine receptors, liver lipid metabolism, lipotoxicity or cell death, and glucagon-like peptide-1 receptors, we also discuss the rationale behind the use of combination therapy and the lessons learned from unsuccessful or negative clinical trials.

MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.

BACKGROUND & AIMS: Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with fibrotic non-alcoholic steatohepatitis (Fibro-NASH) is a clinical priority, as these patients are at the highest risk of disease progression and will benefit most from pharmacologic treatment. MRI-based proton density fat fraction (MRI-PDFF) and MR elastography (MRE) can risk-stratify patients with NAFLD by assessing steatosis and fibrosis, respectively. We developed a highly specific MRI-based score to identify patients with Fibro-NASH. METHODS: This analysis included derivation (n = 103) and validation (n = 244) cohorts of patients who underwent MRI, liver biopsy, transient elastography, and laboratory testing for NAFLD from 2016-2020 in 2 tertiary care centers. To identify Fibro-NASH, a formula was developed based on MRI-PDFF, MRE, and a third variable with highest balanced accuracy per logistic regression. The MRI-aspartate aminotransferase (MAST) score was created and compared to NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and FibroScan-aspartate aminotransferase (FAST) scores. RESULTS: The MAST score demonstrated high performance and discrimination in the validation cohort (AUC 0.93; 95% CI 0.88-0.97). In the validation cohorts, the 90% specificity cut-off of 0.242 corresponded to a sensitivity of 75.0%, positive predictive value (PPV) of 50.0% and negative predictive value (NPV) of 96.5%, whereas the 90% sensitivity cut-off of 0.165 corresponded to a specificity of 72.2%, PPV of 29.4%, and NPV of 98.1%. Compared to NFS and FIB-4, MAST resulted in fewer patients having indeterminate scores and an overall higher AUC. Compared to FAST, MAST exhibited a higher AUC and overall better discrimination. CONCLUSION: The MAST score is an accurate, MRI-serum-based score that outperforms previous scores in non-invasively identifying patients at higher risk of Fibro-NASH. LAY SUMMARY: Identifying patients with non-alcoholic steatohepatitis and significant fibrosis - who need treatment and are at risk of clinical liver-related outcomes - is a clinical priority. We developed a more accurate score using MRI-based technologies and a laboratory blood test (aspartate aminotransferase) that outperforms previous non-invasive scores for the identification of patients at higher risk of liver disease progression.

Avoidant Restrictive Food Intake Disorder Prevalent Among Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) alter their dietary behaviors to reduce disease-related symptoms, avoid feared food triggers, and control inflammation. This study aimed to estimate the prevalence of avoidant/restrictive food intake disorder (ARFID), evaluate risk factors, and examine the association with risk of malnutrition in patients with IBD. METHODS: This cross-sectional study recruited adult patients with IBD from an ambulatory clinic. ARFID risk was measured using the Nine-Item ARFID Screen. Nutritional risk was measured with the Patient Generated-Subjective Global Assessment. Logistic regression models were used to evaluate the association between clinical characteristics and a positive ARFID risk screen. Patient demographics, disease characteristics, and medical history were abstracted from medical records. RESULTS: Of the 161 participants (Crohn's disease, 45.3%; ulcerative colitis, 51.6%; IBD-unclassified, 3.1%), 28 (17%) had a positive ARFID risk score (≥24). Most participants (92%) reported avoiding 1 or more foods while having active symptoms, and 74% continued to avoid 1 or more foods even in the absence of symptoms. Active symptoms (odds ratio, 5.35; 95% confidence interval, 1.91-15.01) and inflammation (odds ratio, 3.31; 95% confidence interval, 1.06-10.29) were significantly associated with positive ARFID risk. Patients with a positive ARFID risk screen were significantly more likely to be at risk for malnutrition (60.7% vs 15.8%; P < .01). CONCLUSIONS: Avoidant eating behaviors are common in IBD patients, even when in clinical remission. Patients who exhibit active symptoms and/or inflammation should be screened for ARFID risk, with referrals to registered dietitians to help monitor and address disordered eating behaviors and malnutrition risk.

Inadequate Hepatocellular Carcinoma Screening in Patients With Nonalcoholic Steatohepatitis Cirrhosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease which can progress to cirrhosis and hepatocellular carcinoma (HCC). American Association for the Study of Liver Diseases (AASLD) guidelines recommend abdominal ultrasound, with or without serum alpha-fetoprotein, every 6 months for HCC surveillance in cirrhotic patients. GOALS: Describe HCC surveillance rates in NASH cirrhosis compared with hepatitis C (HCV) cirrhosis and the impact of surveillance on tumor size, treatment, and mortality. STUDY: Adults with NASH and HCV cirrhosis diagnosed with HCC from 2009 to 2016 were retrospectively evaluated. Patients were categorized into 3 mutually exclusive disease screening groups based on abdominal imaging with or without serum alpha-fetoprotein testing before HCC diagnosis. RESULTS: In total, 99 patients with NASH cirrhosis and 162 patients with HCV cirrhosis were evaluated. In total, 51.5% of NASH cirrhosis patients and 25.9% of HCV cirrhosis patients had no screening before HCC diagnosis. Patients with HCV cirrhosis were significantly more likely to undergo surveillance compared with patients with NASH cirrhosis (P=0.002). NASH cirrhosis patients who underwent complete screening had smaller tumors compared with those with incomplete screening and no screening (P=0.006). There were no differences in number of tumors at diagnosis or mortality between screening groups in patients with NASH cirrhosis (P=0.281 and 0.468, respectively). CONCLUSIONS: There is suboptimal HCC surveillance in NASH and HCV cirrhotic patients, with a greater proportion of patients with NASH cirrhosis not undergoing surveillance. Patients with NASH cirrhosis who had complete surveillance had smaller tumors at diagnosis, but there were no differences in treatment outcomes or mortality.

Excess non-COVID-19-related mortality among inflammatory bowel disease decedents during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic disrupted healthcare in the United States. AIM: To investigate COVID-19-related and non-COVID-19-related death and characteristics associated with excess death among inflammatory bowel disease (IBD) decedents. METHODS: We performed a register-based study using data from the National Vital Statistics System, which reports death data from over 99% of the United States population, from January 1, 2006 through December 31, 2021. IBD-related deaths among adults 25 years and older were stratified by age, sex, race/ethnicity, place of death, and primary cause of death. Predicted and actual age-standardized mortality rates (ASMRs) per 100000 persons were compared. RESULTS: 49782 IBD-related deaths occurred during the study period. Non-COVID-19-related deaths increased by 13.14% in 2020 and 18.12% in 2021 [2020 ASMR: 1.55 actual vs 1.37 predicted, 95% confidence interval (CI): 1.26-1.49; 2021 ASMR: 1.63 actual vs 1.38 predicted, 95%CI: 1.26-1.49]. In 2020, non-COVID-19-related mortality increased by 17.65% in ulcerative colitis (UC) patients between the ages of 25 and 65 and 36.36% in non-Hispanic black (NHB) Crohn's disease (CD) patients. During the pandemic, deaths at home or on arrival and at medical facilities as well as deaths due to neoplasms also increased. CONCLUSION: IBD patients suffered excess non-COVID-19-related death during the pandemic. Excess death was associated with younger age among UC patients, and with NHB race among CD patients. Increased death at home or on arrival and due to neoplasms suggests that delayed presentation and difficulty accessing healthcare may have led to increased IBD mortality.

Increased accuracy in identifying NAFLD with advanced fibrosis and cirrhosis: independent validation of the Agile 3+ and 4 scores.

BACKGROUND AND AIMS: We explored 2 novel scores, Agile 3+ and 4, to identify advanced fibrosis (≥F3) and cirrhosis (F4), respectively, in NAFLD and compared their diagnostic performances to liver stiffness measurement (LSM) by vibration-controlled transient elastography and fibrosis-4 index (FIB-4) (for Agile 3+). APPROACH AND RESULTS: This multicenter study included 548 NAFLD patients with laboratory testing, liver biopsy, and vibration-controlled transient elastography within 6 months. Agile 3+ and 4 were applied and compared with FIB-4 or LSM alone. Goodness of fit was evaluated using a calibration plot and discrimination using area under the receiver operating curve. Area under the receiver operating curves was compared using the Delong test. Dual cutoff approaches were applied to rule out and rule in ≥F3 and F4. Median (interquartile range) age was 58 (15) years. Median body mass index was 33.3 (8.5) kg/m2. Fifty-three percent had type 2 diabetes, 20% had F3, and 26% had F4. Agile 3+ demonstrated an area under the receiver operating curve of 0.85 (0.81; 0.88) similar to that of LSM [0.83 (0.79; 0.86), p=0.142] but significantly higher than that of FIB-4 [0.77 (0.73; 0.81), p<0.0001). Agile 4's area under the receiver operating curve [0.85 (0.81; 0.88)] was similar to that of LSM [0.85 (0.81; 0.88), p=0.065). However, the percentage of patients with indeterminate results was significantly lower with Agile scores compared with FIB-4 and LSM (Agile 3+: 14% vs. FIB-4: 31% vs. LSM: 13%, p<0.001; Agile 4: 23% vs. LSM: 38%, p<0.001). CONCLUSIONS: Agile 3+ and 4 are novel vibration-controlled transient elastography-based noninvasive scores that increase accuracy in the identification of advanced fibrosis and cirrhosis respectively and are ideal for clinical use due to a lower percentage of indeterminant outputs compared with FIB-4 or LSM alone.

Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis.

BACKGROUND: Data are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) with and without type 2 diabetes. We aimed to assess the risk of hepatic decompensation in people with NAFLD with and without type 2 diabetes. METHODS: We did a meta-analysis of individual participant-level data from six cohorts in the USA, Japan, and Turkey. Included participants had magnetic resonance elastography between Feb 27, 2007, and June 4, 2021. Eligible studies included those with liver fibrosis characterisation by magnetic resonance elastography, longitudinal assessment for hepatic decompensation and death, and included adult patients (aged ≥18 years) with NAFLD, for whom data were available regarding the presence of type 2 diabetes at baseline. The primary outcome was hepatic decompensation, defined as ascites, hepatic encephalopathy, or variceal bleeding. The secondary outcome was the development of hepatocellular carcinoma. We used competing risk regression using the Fine and Gray subdistribution hazard ratio (sHR) to compare the likelihood of hepatic decompensation in participants with and without type 2 diabetes. Death without hepatic decompensation was a competing event. FINDINGS: Data for 2016 participants (736 with type 2 diabetes; 1280 without type 2 diabetes) from six cohorts were included in this analysis. 1074 (53%) of 2016 participants were female with a mean age of 57·8 years (SD 14·2) years and BMI of 31·3 kg/m2 (SD 7·4). Among 1737 participants (602 with type 2 diabetes and 1135 without type 2 diabetes) with available longitudinal data, 105 participants developed hepatic decompensation over a median follow-up time of 2·8 years (IQR 1·4-5·5). Participants with type 2 diabetes had a significantly higher risk of hepatic decompensation at 1 year (3·37% [95% CI 2·10-5·11] vs 1·07% [0·57-1·86]), 3 years (7·49% [5·36-10·08] vs 2·92% [1·92-4·25]), and 5 years (13·85% [10·43-17·75] vs 3·95% [2·67-5·60]) than participants without type 2 diabetes (p<0·0001). After adjustment for multiple confounders (age, BMI, and race), type 2 diabetes (sHR 2·15 [95% CI 1·39-3·34]; p=0·0006) and glycated haemoglobin (1·31 [95% CI 1·10-1·55]; p=0·0019) were independent predictors of hepatic decompensation. The association between type 2 diabetes and hepatic decompensation remained consistent after adjustment for baseline liver stiffness determined by magnetic resonance elastography. Over a median follow-up of 2·9 years (IQR 1·4-5·7), 22 of 1802 participants analysed (18 of 639 with type 2 diabetes and four of 1163 without type 2 diabetes) developed incident hepatocellular carcinoma. The risk of incident hepatocellular carcinoma was higher in those with type 2 diabetes at 1 year (1·34% [95% CI 0·64-2·54] vs 0·09% [0·01-0·50], 3 years (2·44% [1·36-4·05] vs 0·21% [0·04-0·73]), and 5 years (3·68% [2·18-5·77] vs 0·44% [0·11-1·33]) than in those without type 2 diabetes (p<0·0001). Type 2 diabetes was an independent predictor of hepatocellular carcinoma development (sHR 5·34 [1·67-17·09]; p=0·0048). INTERPRETATION: Among people with NAFLD, the presence of type 2 diabetes is associated with a significantly higher risk of hepatic decompensation and hepatocellular carcinoma. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis.

The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.

Improvement in nonalcoholic fatty liver disease through bariatric surgery.

Content available: Author Interview and Audio Recording.

The Interplay Between Nonalcoholic Fatty Liver Disease and Kidney Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, involving approximately 25% of the general population and increasing in prevalence in patient populations afflicted with metabolic syndrome and type 2 diabetes. This article discusses the complex interplay between NAFLD and chronic kidney disease (CKD), as well as the underlying pathogenesis and mechanisms through which NAFLD and CKD are linked. Exploration of these sophisticated relationships and causative factors is essential to accurately assessing kidney function in patients with NAFLD, recommending pharmacologic treatment of disease, and identifying favorable avenues for future investigation.

Uniting epidemiology and experimental models: pancreatic steatosis and pancreatic cancer.

Research from epidemiologic studies and experimental animal models provide insights into the role of pancreatic steatosis in the development of pancreatic cancer. Epidemiologic data demonstrate that pancreatic steatosis is widely prevalent and significantly associated with both development and progression of pancreatic cancer. By focusing on current experimental models, this review elucidates potential cellular mechanisms underlying not only the pathophysiology of pancreatic steatosis itself, but also the pathogenesis behind pancreatic steatosis's role in changing the tumour microenvironment and accelerating the development of pancreatic cancer. This review further explores the impact of bariatric surgery on pancreatic steatosis and pancreatic cancer. Synthesizing knowledge from both epidemiologic studies and experimental animal models, this review identifies gaps in current knowledge regarding pancreatic steatosis and its role in carcinogenesis and proposes future research directions to elucidate the possible mechanisms underlying other obesity-associated cancers.

Nonalcoholic fatty liver disease prevalence and severity in Asian Americans from the national health and nutrition examination surveys 2017-2018.

Studies have examined nonalcoholic fatty liver disease (NAFLD) prevalence and severity in Asians; however, this is not well understood in Asian Americans (both East and South Asian Americans) as few studies have analyzed this population. We aimed to describe characteristics, prevalence of NAFLD, and its severity in Asian Americans in the National Health and Nutrition Examination Surveys (NHANES) from 2017 to 2018. Respondents 18 years and older with interview, laboratory testing, and transient elastography data were included. Other causes of liver disease were excluded. Controlled attenuation parameter (CAP) cutoff ≥ 274 dB/m, as published in the literature, defined NAFLD. Sensitivity analysis for CAP cutoffs ≥ 248 and ≥302 dB/m were performed. We found that 450 out of 3639 respondents were Asian Americans, and prevalence using CAP ≥ 274 dB/m was 43.23%. Using sensitivity analysis cutoffs of CAP ≥ 248 dB/m and CAP ≥ 302 dB/m, the prevalence was 57.38% and 28.03%, respectively. Compared with non-Asian Americans with NAFLD, Asian Americans with NAFLD had significantly lower body mass index (BMI) and less prevalent smoking history. Comorbidities, such as prediabetes, diabetes, and hypertension, were not significantly different between Asian and non-Asian Americans with NAFLD. Compared to non-Asian Americans with NAFLD, Asian Americans with NAFLD exhibited higher aminotransferases and triglycerides. Fibrosis assessed by transient elastography was not significantly different between Asian and non-Asian Americans with NAFLD. Despite decreased prevalence of BMI ≥ 30 kg/m2 , Asian Americans experienced similar NAFLD prevalence with increased hepatocellular injury and triglyceridemia compared to non-Asian Americans. Fibrosis stages were similar to non-Asian Americans.