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Background: Alcohol use after liver transplant (LT) is associated with higher rates of graft loss and increased mortality; however, there are limited data evaluating predictors of return to alcohol use using biochemical markers like phosphatidylethanol (PEth)., Methods: This multicenter retrospective cohort study evaluated psychosocial predictors of return to alcohol use using PEth testing in patients transplanted for alcohol-associated liver disease (ALD). The study included 223 patients at three centers who had received a LT for ALD and had at least one PEth measurement post-LT., Results: The rate of return to alcohol use was 6.9 cases per 100 person-years (26 patients total) over a median 555 days of follow-up after transplant. Younger age (HR 0.96; 95% CI 0.92-0.99, p = 0.02), mental health comorbidities (HR 2.83; 95% CI 1.25-6.39, p = 0.01), and non-Hispanic White race (HR 3.79; 95% CI 1.42-10.15, p = 0.01) were associated with return to alcohol use post-LT. There was no difference between post-LT return to alcohol use rates or short-term survival among patients with less than 6 months of sobriety prior to listing compared with those with more than 6 months. Patients with sustained alcohol use post-LT had increased odds of history of illicit substance use (OR 5.20; 95% CI 1.01-26.83, p = 0.04) but no significant difference in time from the last drink to listing (OR 1.03; 95% CI 0.18-5.80, p = 0.97)., Conclusions: These findings emphasize the importance of mental health comorbidities rather than period of sobriety in predicting post-LT return to alcohol use. Furthermore, the higher risk of return to alcohol use in non-Hispanic White patients suggests a potential disparity with referral and selection of higher risk White patients., (© 2024 Research Society on Alcohol.)

Background and Aims: The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports., Methods: This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates., Results: In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss., Conclusions: The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes., Impact and Implications: The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Limited data exist regarding the estimate of the prevalence of advanced liver fibrosis and cirrhosis in the general population. Therefore, we conducted a systematic review and meta-analysis to evaluate the global prevalence and risk factors of advanced fibrosis and cirrhosis., Methods: We searched Embase, PubMed, Scopus, and Web of Science from inception to April 30 2024, with no language restriction. We included cross-sectional studies reporting the prevalence of advanced liver fibrosis and/or cirrhosis in a sample of at least 100 individuals aged ≥18 years from the general population. Subjects with cirrhosis were included in the advanced fibrosis group. The pooled prevalence proportions utilizing a random-effects model and 95% confidence intervals (CIs) were estimated using global data., Results: A total of 46 studies fulfilled the eligibility criteria, comprising approximately 8 million participants from 21 countries. The pooled prevalence rates of advanced liver fibrosis and cirrhosis in the general population were 3.3% (95% CI, 2.4%-4.2%) and 1.3% (95% CI, 0.9%-1.7%) worldwide, respectively. A trend was observed for an increase in the prevalence of advanced fibrosis (P = .004) and cirrhosis (P = .034) after 2016. There were significant geographic variations in the advanced fibrosis and cirrhosis prevalence at continental and national levels (P < .0001). Potential risk factors for cirrhosis were viral hepatitis, diabetes, excessive alcohol intake, obesity, and male sex., Conclusions: The prevalence of advanced fibrosis and cirrhosis is considerable and increasing worldwide with significant geographic variation. Further research is needed to better understand the risk factors and how to mitigate them worldwide to address the growing global burden of cirrhosis., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Genetic factors contribute to the risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised., Aims: To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines., Methods: We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration-controlled transient elastography to assess for advanced fibrosis and cirrhosis., Results: Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m 2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis-4 index (FIB-4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB-4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk., Conclusions: Utilising a well-phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at-risk populations may improve risk prediction., (© 2024 John Wiley & Sons Ltd.)

Background: There are limited data on the prevalence and treatment of at-risk metabolic dysfunction-associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States., Aim: To estimate the prevalence of at-risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies., Methods: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis., Results: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m 2 , respectively. Among patients with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co-existing T2DM and obesity, the prevalence of MASLD, at-risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively)., Conclusion: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis is high, posing a significant risk for liver-related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH-related fibrosis., (© 2024 John Wiley & Sons Ltd.)

Background & Aims: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis., Methods: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured., Results: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years., Conclusion: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: Recently, the American Gastroenterological Association and the American Association for the Study of Liver Diseases developed clinical pathways to evaluate populations at high risk for NAFLD. We assessed the diagnostic performance of the new guidance in a well-phenotyped cohort of patients with Type 2 diabetes mellitus (T2DM)., Approach and Results: This prospective study enrolled patients age ≥50 years with T2DM. Participants underwent a standardized clinical research visit with MRI and ultrasound-based assessment of liver fat and stiffness and Enhanced Liver Fibrosis (ELF) testing. Of 417 participants (36% men) with T2DM with FIB-4 and MRE data, the prevalence of NAFLD was 64% and 12% had advanced fibrosis (MRE≥3.63 kPa). Applying the American Gastroenterological Association pathway of FIB-4 and vibration-controlled transient elastography, the false negative rate was 3.3% and 18% would qualify for specialty referral. Applying the FIB-4 + ELF American Association for the Study of Liver Diseases pathway, the false negative rate was 4.5%, but 50% would qualify for specialty referral. Applying higher ELF cut points improved the pathway, yielding a similar false negative rate of 4.9% but decreased specialty referral to 27%., Conclusion: Validation of the American Gastroenterological Association clinical pathway in a prospectively recruited cohort with T2DM revealed a low false negative rate and avoided specialty referral in a large percentage of patients. The American Association for the Study of Liver Diseases pathway with FIB-4 + ELF resulted in a high rate of specialty referral, which improved with the utilization of higher ELF cut points and may serve as an alternative for primary care and endocrinology clinics without access to vibration-controlled transient elastography., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD., Aims: To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments., Methods: This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic., Results: AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies., Conclusions: This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD., (© 2024 John Wiley & Sons Ltd.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD., Aims: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF)., Methods: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk., Results: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk., Conclusions: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD., (© 2023 John Wiley & Sons Ltd.)

Background: Progression to cirrhosis in non-alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH-related significant fibrosis and cirrhosis is unclear., Aim: To investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH-related significant fibrosis and cirrhosis., Methods: In this meta-analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI-derived protein density fat fraction (MRI-PDFF) were enrolled, and 296 patients with longitudinal follow-up were analysed. MRE combined with fibrosis-4 (MEFIB-index), and MRI-PDFF were used to measure liver fibrosis and fat, respectively. MEFIB-negative, MEFIB-positive+ MRI-PDFF ≥5% and MEFIB-positive+ MRI-PDFF <5% were defined as no significant liver fibrosis, NASH with significant fibrosis and higher liver fat content, and NASH with significant fibrosis and low liver fat content groups, respectively. The primary outcome was hepatic decompensation, HCC and death., Results: The rates of decompensation, HCC and mortality were highest in the NASH with significant fibrosis and low liver fat group (33%, 17% and 17%, respectively), followed by the NASH with significant fibrosis and higher liver fat group (18%, 13% and 13% respectively), and lowest in the no significant fibrosis (MEFIB-negative) group (0%, 1% and 2% respectively). In multivariable-adjusted analysis, low liver fat content was strongly associated (HR = 42.2 [95% CI: 7.5-235.5, p < 0.0001]) with HCC, decompensation and death. Sensitivity analyses for patients with cirrhosis (MRE ≥5 kPa) determined consistent findings., Conclusions: Low liver fat content in patients with burnt-out NASH-related significant fibrosis and cirrhosis is associated with an increase in hepatic decompensation, HCC and mortality., (© 2023 John Wiley & Sons Ltd.)

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., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: There are limited data regarding the longitudinal association between MEFIB-Index (MRE combined with FIB-4) versus MAST-Score (MRI-aspartate aminotransferase) and hepatic decompensation., Aim: To examine the longitudinal association between MEFIB-Index versus MAST-Score in predicting hepatic decompensation in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: This was a longitudinal, retrospective analysis of subjects from United States, Japan, and Turkey who underwent a baseline MRE and MRI-PDFF and were followed for hepatic decompensation. Cox-proportional hazard analyses were used to assess the association between MEFIB-Index versus MAST-Score with a composite primary outcome (hepatic decompensation) defined as ascites, hepatic encephalopathy, and varices needing treatment., Results: This meta-analysis of individual participants (IPDMA) included 454 patients (58% women) with a mean (±SD) age of 56.0 (±13.5) years. The MEFIB-Index (MRE ≥3.3 kPa + FIB 4 ≥1.6) and MAST-Score (>0.242) were positive for 34% and 9% of the sample, respectively. At baseline, 23 patients met criteria for hepatic decompensation. Among 297 patients with available longitudinal data with a median (IQR) of 4.2 (5.0) years of follow-up, 25 incident cases met criteria for hepatic decompensation. A positive MEFIB-Index [HR = 49.22 (95% CI: 6.23-388.64, p < 0.001)] and a positive MAST-Score [HR = 3.86 (95% CI: 1.46-10.17, p < 0.001)] were statistically significant predictors of the incident hepatic decompensation. MEFIB-Index (c-statistic: 0.89, standard error (SE) = 0.02) was statistically superior to the MAST-Score (c-statistic: 0.81, SE = 0.03) (p < 0.0001) in predicting hepatic decompensation., Conclusion: A combination of MRI-based biomarker and blood tests, MEFIB-Index and MAST-Score can predict the risk of hepatic decompensation in patients with MASLD., (© 2023 John Wiley & Sons Ltd.)

Introduction: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19., Methods: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14., Results: Between 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m 2 . Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19., Conclusion: De novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19., Trial Registration: Clinicaltrials.gov NCT04366050., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

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/m 2 (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., Competing Interests: Declaration of interests RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics; and received research grants (via his institution) from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes, and Terns Pharmaceuticals; is a cofounder of LipoNexus; and has stock options in 89bio and Sagimet Biosciences. DQH has served as a consultant for Gilead Sciences and Eisai. AMA received grants from Novo Nordisk, Pfizer, and Target Pharma; payments were made to her institution. MN received grants from Allergan, Akero, Bristol-Myer Squibb, Gilead, Galectin, Genfit, GlaxoSmithKline, Conatus, Corcept, Enanta, Madrigal, Novartis, Novo Nordisk, Shire, Takeda, Terns, Viking, and Zydus. MN serves as a consultant to Altimmune, Boehringer-Ingelheim, Cytodyn, 89bio, EchoSens, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Prespecturm, Roche diagnostic and Siemens, Terns, and Takeda; received speaker fees from Novo Nordisk, EchoSens; served as an advisory board or data safety monitoring board for Altimmune, Boehringer-Ingelheim, Cytodyn, 89bio, EchoSens, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Prespecturm, Roche diagnostic and Siemens Altimmune, Boehringer-Ingelheim, Cytodyn, 89bio, EchoSens, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Prespecturm, Roche diagnostic and Siemens, Terns and Takeda; and owns stock/stock options in Rivus Pharma, CIMA, and ChronWell. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Adiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD)., Aim: We evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m 2 ), and genetic risk on liver fat and fibrosis., Methods: This is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score., Results: Our sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m 2 , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p < 0.001), clinically significant fibrosis (aOR 1.60 [95% CI: 1.40-1.84], p < 0.001) and cirrhosis (aOR 1.81 [95% CI: 1.38-2.37], p < 0.001). High-polygenic risk was significantly associated with liver fat and clinically significant fibrosis (p < 0.05)., Conclusion: Overweight-years is strongly associated with NAFLD and clinically significant fibrosis and combined with polygenic risk may assist in defining the trajectory of NAFLD., (© 2023 John Wiley & Sons Ltd.)

Purpose of Review: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the United States and has a strong heritable component. Advances in understanding the genetic underpinnings of NAFLD have revealed important insights into NAFLD pathogenesis, prognosis, and potential therapeutic targets. The purpose of this review is to summarize data on common and rare variants associated with NAFLD, combining risk variants into polygenic scores to predict NAFLD and cirrhosis as well as emerging evidence on using gene silencing as a novel therapeutic target in NAFLD., Recent Findings: Protective variants in HSD17B13, MARC1 and CIDEB have been identified and a confer 10-50% lower risk of cirrhosis. Together, these as well as other NAFLD risk variants, including those in PNPLA3 and TM6SF2, can be combined to create polygenic risk scores associated with liver fat, cirrhosis, and hepatocellular carcinoma. Genomic analysis of extreme phenotypes including patients with lean NAFLD without visceral adiposity may uncover rare monogenic disorders with pathogenic and therapeutic implications and gene silencing strategies targeting HSD17B13 and PNPLA3 are being evaluated in early phase human studies as treatments for NAFLD., Summary: Advances in our understanding of the genetics of NAFLD will enable clinical risk stratification and yield potential therapeutic targets., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Psoriatic disease (PD) and non-alcoholic fatty liver disease (NAFLD) potentially share disease pathways given the numerous inflammatory pathways involved in both diseases and a higher prevalence of NAFLD in PD patients.  Metabolic syndrome and obesity are a key link between the two diseases, but even when controlling for this, associations between both diseases are still seen. Therapeutics that impact metabolic or inflammatory pathways may be impactful in both PD and NAFLD. In this review, we describe common inflammatory pathways contributing to both PD and NAFLD and critically review the potential impact of treatments for and on both diseases., Competing Interests: Disclosures/Conflicts of Interest Dr. Loomba serves as a consultant or advisory board member for Anylam/Regeneron, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Promethera, Sagimet, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, pH Pharma, and Siemens. He is also co-founder of Liponexus, Inc. Dr Guma serves as a consultant of SonomaBio, and has received grant support from Novartis, Pfizer, Gilead and Genetech. Dr Kavanaugh serves as a consultant of SonomaBio, and has received grant support from Novartis, and Pfizer. They had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background & Aims: There are limited prospective data on patients with type 2 diabetes mellitus (T2DM) specifically enrolled and systematically assessed for advanced fibrosis or cirrhosis due to non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to evaluate the prevalence of advanced fibrosis and cirrhosis in a prospectively recruited cohort of adults with T2DM., Methods: This prospective study enrolled adults aged ≥50 years with T2DM, recruited from primary care or endocrinology clinics. Participants underwent a standardized clinical research visit with MRI-proton density fat fraction (MRI-PDFF), magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE) and controlled-attenuation parameter. NAFLD was defined as MRI-PDFF ≥5% after exclusion of other liver diseases. Advanced fibrosis and cirrhosis were defined by established liver stiffness cut-off points on MRE or VCTE if MRE was not available., Results: Of 524 patients screened, 501 adults (63% female) with T2DM met eligibility. The mean age and BMI were 64.6 (±8.1) years and 31.4 (±5.9) kg/m 2 , respectively. The prevalence of NAFLD, advanced fibrosis and cirrhosis was 65%, 14% and 6%, respectively. In multivariable adjusted models, adjusted for age and sex, obesity and insulin use were associated with increased odds of advanced fibrosis (odds ratio 2.50; 95% CI 1.38-4.54; p = 0.003 and odds ratio 2.71; 95% CI 1.33-5.50; p = 0.006, respectively). Among 29 patients with cirrhosis, two were found to have hepatocellular carcinoma and one patient had gallbladder adenocarcinoma., Conclusion: Utilizing a uniquely well-phenotyped prospective cohort of patients aged ≥50 years with T2DM, we found that the prevalence of advanced fibrosis was 14% and that of cirrhosis was 6%. These data underscore the high risk of advanced fibrosis/cirrhosis in adults aged ≥50 years with T2DM., Impact and Implications: Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes (T2DM), however, there are limited prospective data characterizing the prevalence of advanced fibrosis and cirrhosis using the most accurate non-invasive biomarkers of liver fat and fibrosis. We show that 14% of older adults with T2DM have advanced fibrosis and 6% have cirrhosis, which places them at risk for liver failure and liver cancer. Accurate prevalence rates and comparative analysis regarding the diagnostic accuracy of non-invasive tests in this population will guide the optimal screening strategy and future cost-effectiveness analyses. These results will inform future Hepatology and Endocrinology practice guidelines regarding NAFLD screening programs in older adults with T2DM., (Copyright © 2022. Published by Elsevier B.V.)

Background & Aims: Lean patients with non-alcoholic fatty liver disease (NAFLD) represent 10-20% of the affected population and may have heterogeneous drivers of disease. We have recently proposed the evaluation of patients with lean NAFLD without visceral adiposity for rare monogenic drivers of disease. Here, we aimed to validate this framework in a well-characterised cohort of patients with biopsy-proven NAFLD by performing whole exome sequencing., Methods: This prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness., Results: Six patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in ALDOB (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B ( APOB ). The pathogenicity of this APOB variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta = -0.51 g/L, 95% CI -0.65 to -0.36 g/L, p  = 1.4 × 10 -11 ) and higher liver fat on MRI (beta = +10.4%, 95% CI 4.3-16.5%, p  = 8.8 × 10 -4 ). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia., Conclusions: In this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype., Impact and Implications: Although most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease., (© 2023 The Author(s).)

Homeopathic remedies made primarily from eggshells, and therefore calcium, can be marketed for treatment of back pain and vaginal discharge. We present a case of a 23-year-old otherwise healthy woman who presented with acute liver failure (ALF) ultimately requiring liver transplantation as a result of taking increased doses of a homeopathic product with the primary ingredient of eggshells. Although relatively uncommon compared with medications such as acetaminophen, herbal supplements have been reported to cause drug-induced liver injury (DILI), thought to be primarily due to contaminants. This is the first known report of DILI resulting from a homeopathic product with the primary ingredient of eggshells, and it demonstrates the importance of early ALF recognition and treatment, as well as the importance of practicing caution when using homeopathic supplements., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P &lt; 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Background & Aims: Magnetic resonance elastography (MRE) is an accurate biomarker of liver fibrosis; however, limited data characterize its association with clinical outcomes. We conducted an individual participant data pooled meta-analysis on patients with nonalcoholic fatty liver disease to evaluate the association between liver stiffness on MRE and liver-related outcomes., Methods: A systematic search identified 6 cohorts of adults with nonalcoholic fatty liver disease who underwent a baseline MRE and were followed for hepatic decompensation, hepatocellular carcinoma, and death. Cox and logistic regression were used to assess the association between liver stiffness on MRE and liver-related outcomes, including a composite primary outcome defined as varices needing treatment, ascites, and hepatic encephalopathy., Results: This individual participant data pooled meta-analysis included 2018 patients (53% women) with a mean (± standard deviation) age of 57.8 (±14) years and MRE at baseline of 4.15 (±2.19) kPa, respectively. Among 1707 patients with available longitudinal data with a median (interquartile range) of 3 (4.2) years of follow-up, the hazard ratio for the primary outcome for MRE of 5 to 8 kPa was 11.0 (95% confidence interval [CI]: 7.03-17.1, P < .001) and for ≥ 8 kPa was 15.9 (95% CI: 9.32-27.2, P < .001), compared with those with MRE <5 kPa. The MEFIB index (defined as positive when MRE ≥3.3 kPa and Fibrosis-4 ≥1.6) had a robust association with the primary outcome with a hazard ratio of 20.6 (95% CI: 10.4-40.8, P < .001) and a negative MEFIB had a high negative predictive value for the primary outcome, 99.1% at 5 years. The 3-year risk of incident hepatocellular carcinoma was 0.35% for MRE <5 kPa, 5.25% for 5 to 8 kPa, and 5.66% for MRE ≥8 kPa, respectively., Conclusion: Liver stiffness assessed by MRE is associated with liver-related events, and the combination of MRE and Fibrosis-4 has excellent negative predictive value for hepatic decompensation. These data have important implications for clinical practice., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11 months. Two patients with <3 months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38 months of follow up. None of the patients who underwent LT >3 months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90 days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: Emerging data suggest that a 30% relative decline in liver fat, as assessed by MRI-proton density fat fraction (MRI-PDFF), may be associated with Non-Alcoholic Fatty Liver Disease Activity Score improvement, but the association between decline in MRI-PDFF and fibrosis regression is not known. Therefore, we aimed to examine the association between ≥30% relative decline in MRI-PDFF and fibrosis regression in non-alcoholic fatty liver disease (NAFLD)., Design: This prospective study included 100 well-characterised patients with biopsy-proven NAFLD with paired contemporaneous MRI-PDFF assessment at two time points. MRI-PDFF response was defined as ≥30% relative decline in MRI-PDFF. The primary outcome was ≥1 stage histological fibrosis regression., Results: The median (IQR) age was 54 (43-62) years and body mass index was 31.9 (29-36) kg/m 2 . In multivariable-adjusted logistic regression analysis (adjusted for age, gender, diabetes status, race/ethnicity, interval between biopsies, gamma-glutamyl transferase, liver stiffness by magnetic resonance elastography and change in platelet counts), MRI-PDFF response was an independent predictor of fibrosis regression with an adjusted OR of 6.46 (95% CI 1.1 to 37.0, p=0.04). The proportion of patients with MRI-PDFF response with fibrosis regression, no change in fibrosis and fibrosis progression was 40.0%, 24.6% and 13.0%, respectively, and the proportion of patients with MRI-PDFF response increased with fibrosis regression (p=0.03)., Conclusion: ≥30% reduction in MRI-PDFF in early phase trials can provide a useful estimate of odds of ≥1 stage improvement in fibrosis. These data may be helpful in sample size estimation in non-alcoholic steatohepatitis trials., Competing Interests: Competing interests: RL serves as a consultant or advisory board member for Alnylam/Regeneron, Arrowhead Pharmaceuticals, AstraZeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed, Gemphire, Gilead, Glympse Bio, GNI, GRI Bio, Inipharm, Intercept, Ionis, Janssen, Merck, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus, Promethera, Sanofi, Siemens and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer Ingelheim, Bristol Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Grail, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt, Pfizer, pH Pharma, Prometheus and Siemens. He is also co-founder of Liponexus. CBS reports grants from GE, Siemens, Philips, Bayer and Gilead; personal consultation fees from Blade, Boehringer and Epigenomics; consultation under the auspices of the University to AMRA, BMS, Exact Sciences, GE Digital and IBM Watson; lab service agreements from Enanta, Gilead, ICON, Intercept, NuSirt, Shire, Synageva and Takeda; and royalties or honoraria from Wolters Kluwer and Medscape, respectively, for educational materials, outside the submitted work. The other authors disclose no conflicts., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Magnetic resonance elastography (MRE) is an accurate biomarker of liver fibrosis; however, limited data characterize its association with outcomes. We aimed to evaluate the association between liver stiffness (LS) on MRE and liver-related outcomes., Methods: This is a longitudinal, retrospective analysis of subjects at risk of NAFLD who had MRE assessment. LS was estimated using MRE, and liver fat was assessed using magnetic resonance imaging proton density fat fraction. Univariable and multivariable survival and regression analyses were used to assess the association between LS on MRE and liver-related outcomes including a cumulative primary outcome of hepatic decompensation, hepatocellular carcinoma (HCC), or death., Results: In all, 265 patients (68% women) with a mean age of 50 (±18) years and 44% Hispanic ethnicity and 45.3% with NAFLD were included. A total of 76 liver-related events or death occurred, and there was 453 person-years of follow-up time in 97 patients with available follow-up. Each 1-kPa increase in LS was associated with 2.20-fold (95% CI: 1.70-2.84, p  < 0.001) increased odds of prevalent hepatic decompensation or HCC. A positive MEFIB index, a combination of MRE ⩾ 3.3 kPa and FIB-4 ⩾ 1.6, had a strong association with the primary outcome compared with those without, HR = 21.8 (95% CI: 4.28-111.4, p  < 0.001). The MEFIB index had a sensitivity of 75% and specificity of 90%, and a negative score was associated with 98% negative predictive value for incident liver-related events or death., Conclusion: LS assessed by MRE is associated with hepatic decompensation and death, and the MEFIB combination of MRE with FIB-4 may have high negative predictive value for liver-related events., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Loomba serves as a consultant or advisory board member for Bird Rock Bio, Celgene, Enanta, GRI Bio, Madrigal, Metacrine, NGM, Sanofi, Arrowhead Research, Galmed, GNI, Novo Nordisk, Merck, Siemens, Pfizer, Gilead, and Glympse Bio. In addition, his institution has received grant support from Allergan, BMS, BI, Daiichi-Sankyo Inc., Eli-Lilly, Galectin, Galmed, GE, Genfit, Intercept, Janssen Inc, Madrigal, Merck, NGM, Pfizer, Prometheus, Siemens, and Sirius. He is also the co-founder of Liponexus Inc., (© The Author(s), 2022.)

Hepatic steatosis is a key histological feature of nonalcoholic fatty liver disease (NAFLD). The non-invasive quantification of liver fat is now possible due to advances in imaging modalities. Emerging data suggest that high levels of liver fat and its temporal change, as measured by quantitative non-invasive methods, might be associated with NAFLD progression. Ultrasound-based modalities have moderate diagnostic accuracy for liver fat content and are suitable for screening. However, of the non-invasive imaging modalities, MRI-derived proton density fat fraction (MRI-PDFF) has the highest diagnostic accuracy and is used for trial enrolment and to evaluate therapeutic effects in early-phase clinical trials in nonalcoholic steatohepatitis (NASH). In patients with NAFLD without advanced fibrosis, high levels of liver fat are associated with rapid disease progression. Furthermore, changes on MRI-PDFF (≥30% decline relative to baseline) are associated with NAFLD activity score improvement and fibrosis regression. However, an inverse association exists between liver fat and complications of cirrhosis. Liver fat decreases as liver fibrosis progresses towards cirrhosis, and the clinical importance of quantitative measurements of liver fat differs by NAFLD status. As such, patients with NAFLD should be stratified by fibrosis severity to investigate the utility of quantitative measurements of liver fat for assessing NAFLD progression and prognosis., (© 2021. Springer Nature Limited.)

The Nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) has been applied as a method for evaluating treatment response, and a ≥2-point improvement in NAS has been commonly used as an accepted end point in phase 2b clinical trials in nonalcoholic steatohepatitis. 1 , 2 Although liver fibrosis is the strongest histologic predictor of liver-related outcome and all-cause mortality in NAFLD, 3 , 4 the association between change in NAS and change in fibrosis stage has not been fully verified. Therefore, we aimed to examine the association between change in NAS and change in fibrosis stage in well-characterized patients with NAFLD who had a paired liver biopsy assessment., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States., Methods: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment., Results: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups., Conclusions: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic entity that requires a liver biopsy assessment to diagnose the progressive form of NAFLD called non-alcoholic steatohepatitis (NASH). Liver biopsy is invasive, subject to sampling and interobserver variability, and impractical to scale to the affected population of up to 1 billion affected individuals worldwide. Non-invasive imaging biomarkers have emerged as a key modality to address the major unmet need to diagnose, stage, and longitudinally monitor NAFLD., Scope of Review: In this review, we critically examine the use of non-invasive imaging biomarkers to diagnose NAFLD, NASH, and fibrosis stage., Major Conclusions: Ultrasound and magnetic resonance imaging (MRI) biomarkers of liver fat can diagnose NAFLD. MRI proton density fat fraction (MRI-PDFF) is better than liver biopsy, particularly for following longitudinal changes in liver fat in clinical trials. Imaging biomarkers to reliably diagnose NASH are under investigation, but when used alone, continue to have only modest diagnostic accuracy. However, the fibrosis stage has the strongest association with liver decompensation and mortality, and elastography has emerged as a reliable biomarker for liver fibrosis. We review the combination of biomarkers to risk stratify patients and identify individuals needing treatment and the implications of longitudinal changes in liver stiffness measurement., Competing Interests: Conflict of interest Potential conflicts of interest for Rohit Loomba: Dr. Loomba serves as a consultant or advisory board member for Bird Rock Bio, Celgene, Enanta, GRI Bio, Madrigal, Metacrine, NGM, Sanofi, Arrowhead Research, Galmed, NGM, GNI, Novo Nordisk, Merck, Siemens, Pfizer, Gilead, and Glympse Bio. His institution has received grant support from Allergan, BMS, BI, Daiichi-Sankyo Inc., Eli Lilly, Galectin, Galmed, GE, Genfit, Intercept, Janssen Inc., Madrigal, Merck, NGM, Pfizer, Prometheus, Siemens, and Sirius. He is also co-founder of Liponexus Inc., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Variants in multiple genetic loci modify the risk of non-alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis., Aim: To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis., Methods: This is a cross-sectional analysis derived from a well-characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE., Results: Two hundred sixty-four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1-8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2-18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19-0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype-age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a -0.41 kPa (95% CI: -0.76 to -0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis., Conclusion: Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non-invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk., (© 2021 John Wiley & Sons Ltd.)

Background & Aims: In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition., Methods: We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank., Results: Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10 -8 ) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P interaction < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P interaction < .001)., Conclusions: Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)