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Background Magnetic resonance imaging-derived measures of liver fat and volume are emerging as accurate, non-invasive imaging biomarkers in non-alcoholic steatohepatitis ( NASH). Little is known about these measures in relation to histology longitudinally. Aim To examine any relationship between MRI-derived proton-density fat-fraction ( PDFF), total liver volume ( TLV), total liver fat index ( TLFI), vs. histology in a NASH trial. Methods This is a secondary analysis of a 24-week randomised, double-blind, placebo-controlled trial of 50 patients with biopsy-proven NASH randomised to oral ezetimibe 10 mg daily ( n = 25) vs. placebo ( n = 25). Baseline and post-treatment anthropometrics, biochemical profiling, MRI and biopsies were obtained. Results Baseline mean PDFF correlated strongly with TLFI (Spearman's ρ = 0.94, n = 45, P < 0.0001) and had good correlation with TLV ( ρ = 0.57, n = 45, P < 0.0001). Mean TLV correlated strongly with TLFI ( ρ = 0.78, n = 45, P < 0.0001). After 24 weeks, PDFF remained strongly correlated with TLFI ( ρ = 0.94, n = 45, P < 0.0001), maintaining good correlation with TLV ( ρ = 0.51, n = 45, P = 0.0004). TLV remained strongly correlated with TLFI ( ρ = 0.74, n = 45, P < 0.0001). Patients with Grade 1 vs. 3 steatosis had lower PDFF, TLV, and TLFI ( P < 0.0001, P = 0.0003, P < 0.0001 respectively). Regression analysis of changes in MRI- PDFF vs. TLV indicates that 10% reduction in MRI- PDFF predicts 257 mL reduction in TLV. Conclusions The MRI- PDFF and TLV strongly correlated with TLFI. Decreases in steatosis were associated with an improvement in hepatomegaly. Lower values of these measures reflect lower histologic steatosis grades. MRI-derived measures of liver fat and volume may be used as dynamic and more responsive imaging biomarkers in a NASH trial, than histology. [ABSTRACT FROM AUTHOR]

Background Limited data exist on the clinical presentation and non-invasive detection of liver fibrosis in adults with homozygous Z genotype alpha-1 antitrypsin ( AAT) deficiency. Aims To compare demographic, biochemical, histological and imaging data of AAT deficient patients to normal-control and biopsy-proven non-alcoholic fatty liver disease ( NAFLD) patients, and to assess the diagnostic accuracy of magnetic resonance elastography ( MRE) in detecting fibrosis in AAT deficiency. Methods Study includes 33 participants, 11 per group, who underwent clinical research evaluation, liver biopsy ( AAT and NAFLD groups), and MRE. Histological fibrosis was quantified using a modified Ishak 6-point scale and liver stiffness by MRE. Diagnostic performance of MRE in detecting fibrosis was assessed by receiver operating characteristic ( ROC) analysis. Results Mean (±s.d.) of age and BMI of normal-control, AAT and NAFLD groups was 57 (±19), 57 (±18), and 57 (±13) years, and 22.7 (±2.5), 24.8 (±4.0) and 31.0 (±5.1) kg/m2 respectively. Serum ALT [mean ± s.d.] was similar within normal-control [16.4 ± 4.0] and AAT groups [23.5 ± 10.8], but was significantly lower in AAT than NAFLD even after adjustment for stage of fibrosis ( P < 0.05, P = 0.0172). For fibrosis detection, MRE-estimated stiffness had an area under the ROC curve of 0.90 ( P < 0.0001); an MRE threshold of ≥3.0 kPa provided 88.9% accuracy, with 80% sensitivity and 100% specificity to detect presence of any fibrosis (stage ≥1). Conclusions This pilot prospective study suggests magnetic resonance elastography may be accurate for identifying fibrosis in patients with alpha-1 antitrypsin deficiency. Larger validation studies are warranted. [ABSTRACT FROM AUTHOR]

Background Current guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis. Aim To assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness. Methods We performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE. Results Mean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m2, respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger ( P = 0.028) and had higher mean BMI ( P = 0.0008), waist circumference ( P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase. Conclusions This proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort. [ABSTRACT FROM AUTHOR]

Background Pentraxin-2 ( PTX-2), a serum protein, inhibits inflammation and fibrosis, and recombinant PTX-2 is being tested as an anti-fibrotic agent. Aim To evaluate the association between serum PTX-2 levels and fibrosis stage in patients with non-alcoholic fatty liver disease ( NAFLD). Methods Serum pentraxin-2 levels were compared between four groups of well-characterised patients including NAFLD with no fibrosis, NAFLD with mild-moderate fibrosis (stage 1-2), NAFLD with advanced fibrosis (stage 3-4), and age-sex matched non- NAFLD controls. Results Sixty subjects were included in the study. The mean age was 58.9 years, 68% were male and 58% were Caucasian. In univariate analysis, serum PTX-2 levels significantly decreased from non- NAFLD controls to mild NAFLD with no fibrosis, to NAFLD with mild-moderate fibrosis and were lowest in patients with NAFLD and advanced fibrosis, in a dose-dependent manner ( P < 0.0001). In multivariable-adjusted analyses controlling for age, sex, albumin, and CRP, the results remained consistent and statistically significant. Serum PTX-2 level had an AUROC of 0.84 (95% CI: 0.71-0.97) for the diagnosis of NAFLD, and an AUROC of 0.77 (95% CI: 0.65-0.90) for the diagnosis of advanced fibrosis in NAFLD. Serum PTX-2 levels also decreased with increasing liver stiffness as estimated by magnetic resonance elastography ( r = −0.31, P = 0.02). Conclusions PTX-2 levels are significantly lower in patients with NAFLD compared to non- NAFLD controls, and decline further in patients with advanced fibrosis. PTX-2 may therefore be both a biomarker of disease and a potential target for anti-fibrotic therapy with the recombinant pentraxin-2. [ABSTRACT FROM AUTHOR]

Background Two-dimensional magnetic resonance elastography (2D- MRE) is an advanced magnetic resonance method with high diagnostic accuracy for predicting advanced fibrosis in non-alcoholic fatty liver disease ( NAFLD) patients. However, no prospective, head-to-head comparisons between 2D- MRE and clinical prediction rules ( CPRs) have been performed in patients with biopsy-proven NAFLD. Aim To compare the diagnostic utility of 2D- MRE against that of eight CPRs ( AST: ALT ratio, APRI, BARD, FIB-4, NAFLD Fibrosis Score, Bonacini cirrhosis discriminant score, Lok Index and NASH CRN model) for predicting advanced fibrosis in a prospective cohort with paired liver biopsy as the gold standard. Methods This is a cross-sectional analysis of a prospective study of 102 patients (58.8% women) with biopsy-proven NAFLD, 2D- MRE and clinical research assessment within 90 days of biopsy. Receiver operating characteristic ( ROC) analysis was performed to assess the performance of 2D- MRE and CPRs for predicting advanced fibrosis. Results The mean (± s.d.) age and BMI were 51.3 (±14.0) years and 31.7 (±5.5) kg/m2 respectively. 48, 26, 9, 13 and 6 patients had stage 0, 1, 2, 3 and 4 fibrosis respectively. The area under ROC curve ( AUROC) was 0.957 for 2D- MRE and between 0.796 and 0.861 for the CPRs. FIB-4 was the best-performing CPR at predicting advanced fibrosis with AUROC of 0.861. In head-to-head comparisons using the DeLong test, 2D- MRE had significantly better AUROC ( P < 0.05) than each CPR for predicting advanced fibrosis. Conclusion Compared to clinical prediction rules, 2D- MRE provides significantly higher accuracy for the diagnosis of advanced fibrosis in NAFLD patients. [ABSTRACT FROM AUTHOR]

Background There are limited data regarding the clinical, biochemical and liver histological characteristics of patients with HIV-associated nonalcoholic fatty liver disease ( NAFLD), and whether this entity differs in presentation and severity from primary NAFLD Aim To examine the clinical and histological differences between HIV-associated NAFLD and primary NAFLD. Methods This is a cross-sectional, case-control study comparing patients with HIV-associated NAFLD vs. patients with primary NAFLD. HIV-infected patients were identified from a database of consecutive liver biopsies performed at the University of California at San Diego, over a 13-year period. HIV-infected patients with biopsy-proven NAFLD were selected as cases, after exclusion of other causes of liver disease and hepatic steatosis. Age-sex-matched controls with biopsy-proven primary NAFLD were randomly identified from the same pathology database. All biopsies underwent a standardised, detailed, histological research evaluation by a liver pathologist who was blinded to clinical and case-control status. Results Compared to age-sex-matched patients with primary NAFLD ( n = 33), patients with HIV-associated NAFLD ( n = 33) had significantly higher mean aspartate aminotransferase ( P < 0.001), alanine aminotransferase ( P < 0.001), alkaline phosphatase ( P = 0.003) and serum triglycerides ( P = 0.024). Similarly, compared to age-sex-matched primary NAFLD, patients with HIV-associated NAFLD had significantly higher rates of definite steatohepatitis (37% vs. 63%, P = 0.04), and more features of liver injury, including lobular inflammation (<0.001) and acidophil bodies (<0.001). Conclusion Compared to age-sex-matched primary NAFLD, HIV-associated NAFLD has increased severity of liver disease and a higher prevalence of NASH. [ABSTRACT FROM AUTHOR]

Background Non-alcoholic steatohepatitis ( NASH) is a common cause of serum alanine aminotransferase ( ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. Aim To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. Methods The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis ( PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity ( NAS) and fibrosis. Results ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients ( P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS ( P < 0.001), but not fibrosis scores ( P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both ( P < 0.05). Weight loss (≥2 kg) was also associated with ALT response ( P < 0.001), improvements in NAS ( P < 0.001) and fibrosis ( P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (≥2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. Conclusions Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: . [ABSTRACT FROM AUTHOR]

Background Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy-proven non-alcoholic fatty liver disease ( NAFLD). Aim To quantify pancreatic fat using a novel magnetic resonance imaging ( MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD. Methods This is a cross-sectional study including 43 adult patients with biopsy-proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH- CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction. Results The average MRI-determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI-determined pancreatic fat content increased significantly with increasing histology-determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 ( P = 0.004) respectively. Pancreatic fat content was lower in patients with histology-determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1-2 fibrosis, and 6.9% in stage 3-4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status. Conclusions In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD. [ABSTRACT FROM AUTHOR]

Background Conventional magnetic resonance imaging ( MRI) techniques that measure hepatic steatosis are limited by T1 bias, T2* decay and multi-frequency signal-interference effects of protons in fat. Newer MR techniques such as the proton density-fat fraction ( PDFF) that correct for these factors have not been specifically compared to liver biopsy in adult patients with non-alcoholic fatty liver disease ( NAFLD). Aim To examine the association between MRI-determined PDFF and histology-determined steatosis grade, and their association with fibrosis. Methods A total of 51 adult patients with biopsy-confirmed NAFLD underwent metabolic-biochemical profiling, MRI-determined PDFF measurement of hepatic steatosis and liver biopsy assessment according to NASH- CRN histological scoring system. Results The average MRI-determined PDFF increased significantly with increasing histology-determined steatosis grade: 8.9% at grade-1, 16.3% at grade-2, and 25.0% at grade-3 with P ≤ 0.0001 (correlation: r2 = 0.56, P < 0.0001). Patients with stage-4 fibrosis, when compared with patients with stage 0-3 fibrosis, had significantly lower hepatic steatosis by both MRI-determined PDFF (7.6% vs. 17.8%, P < 0.005) and histology-determined steatosis grade (1.4 vs. 2.2, P < 0.05). NAFLD patients with grade 1 steatosis were more likely to have characteristics of advanced liver disease including higher average AST: ALT (0.87 vs. 0.60, P < 0.02), GGT (140 vs. 67, P < 0.01), and INR (1.06 vs. 0.99, P < 0.01), higher stage of fibrosis and hepatocellular ballooning. Conclusions MRI-determined proton density-fat fraction correlates with histology-determined steatosis grade in adults with NAFLD. Steatosis is non-linearly related to fibrosis progression. In patients with NAFLD, a low amount of hepatic steatosis on imaging does not necessarily indicate mild disease. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2012; 35: 66-75 Summary Background Thiazolidinediones (TZDs) have been used in the treatment of non-alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically. Aim To conduct a meta-analysis of randomised, placebo-controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH. Methods Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters. Results Four good quality RPCTs derived from three continents were included. The meta-analysis showed that TZDs ( n = 169) were significantly better than placebo ( n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33-3.36), 2.58 (95% CI, 1.68-3.97) and 3.39 (95% CI, 2.19-5.25) respectively. The improvement in combined necroinflammation with TZD ( n = 58) vs. placebo ( n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03-14.06]), but improvement in fibrosis was not. When pioglitazone ( n = 137) was analysed alone, the improvement in fibrosis with pioglitazone ( n = 137) vs. placebo ( n = 134) (combined OR 1.68 [95% CI, 1.02-2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment. Conclusions Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo-controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 1018–1027 Background Chronic infection with hepatitis C, genotype 2/3, responds better than other genotypes to peginterferon and ribavirin treatment. We hypothesized that a lower dose of peginterferon would be as effective, but less toxic than standard doses. Aim To test the hypothesis that a lower dose of peginterferon would be as effective as, but less toxic than, standard doses. Methods A total of 30 patients were treated with low-dose peginterferon alfa-2a (90 μg/week) and 27 patients with standard doses (180 μg/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard-dose treatment. Viral and serum inducible protein 10 (IP-10) levels were measured and early viral kinetic parameters were calculated. Results Sustained virological response was achieved in 68% of the low-dose and 87% of the standard-dose patients (per protocol, P = 0.79 for non-inferiority). Re-treatment was successful in all patients who tolerated full dose and duration. The standard-dose group had greater first-phase declines of viral levels and faster time to negativity. The second-phase slope was not dose-dependent. IP-10 induction was significantly greater with the standard dose. Although fatigue and general feeling during treatment were worse for standard dose, haematological toxicity and depression did not differ between groups. Conclusion A lower dose of peginterferon is associated with some symptomatic benefit, but the response is not equivalent to standard dosing. [ABSTRACT FROM AUTHOR]

Alveolar capillary dysplasia (ACD) is a rare and lethal cause of hypoxic respiratory failure in the neonate. Here we describe a term neonate with ACD that was found with a previously unreported p.Arg86Pro mutation in the FOXF1 (Forkhead Box-F1) gene and coexisting congenital anomalies, including colobomas of the iris and hemihyperplasia. This unique clinical presentation may indicate a novel, yet unconfirmed disease association for mutations in the FOXF1 gene. Rapid mutation analysis in FOXF1 may provide noninvasive early confirmation of ACD in neonates with respiratory failure and can aid in clinical decision making. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, with an estimated prevalence of 25-40%. We generated NASH patient profiles and used their outcomes to develop an interactive, web-based tool, NAFLD Simulator. NAFLD Simulator can predict survival, mortality due to liver, non-liver, and background causes, risk of hepatocellular carcinoma and cirrhosis. [Extracted from the article]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in people with HIV (PWH). The morphological spectrum of MASLD compared to matched controls and of the correlation between the NAFLD activity score (NAS) and fibrosis stage in PWH remains unknown., Methods: Overall, 107 liver biopsies from PWH with MASLD (MASLD-PWH) were matched to 107 biopsies from individuals with MASLD and without HIV (MASLD controls) on age at biopsy, race/ethnicity, sex, type 2 diabetes, body mass index (BMI) and alanine aminotransferase (ALT) level. Biopsies were scored using NAS., Results: Compared to MASLD-controls, MASLD-PWH had lower steatosis grade (OR: 0.65, 95% CI: (0.47-0.90), p = 0.01), lower lobular inflammation grade (OR: 0.55, 95% CI: (0.34-0.89), p = 0.02), less portal inflammation (OR: 0.42, 95% CI: (0.25-0.72), p = 0.002) and less ballooned hepatocytes (OR: 0.60, 95% CI: (0.41-0.88), p = 0.01). Thus, NAS was lower in MASLD-PWH (OR: 0.69, 95% CI: (0.56-0.85), p < 0.001) than in MASLD controls. There was a trend towards lower prevalence of steatohepatitis in MASLD-PWH (OR: 0.84, 95% CI: (0.68-1.03), p = 0.09). A multivariate analysis demonstrated that MASLD-PWH cases had significantly less steatosis (OR: 0.66, p = 0.03), portal inflammation (OR: 0.34, p = 0.001) and ballooned hepatocytes (OR: 0.55, p = 0.01), yet higher stage fibrosis (OR: 1.42, p = 0.03) compared to MASLD controls., Conclusion: The NAS and histological drivers of fibrosis (e.g. inflammation and hepatocyte ballooning) are less pronounced in MASLD-PWH, and yet fibrosis stage was generally higher when compared to matched controls with MASLD without HIV. This suggests HIV-specific factors beyond hepatic necroinflammation may contribute to fibrosis progression in MASLD-PWH., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background and Aims: The patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship., Approach and Results: A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p =0.03, and p -value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p -value for interaction between PNPLA3 and each factor<0.01., Conclusions: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: The 2023 nomenclature defined criteria for steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD), alcohol-associated liver disease (ALD), and the overlapping MASLD/ALD (MetALD). We aimed to assess racial and ethnic disparities in the SLD prevalence among United States (US) adults based on this new nomenclature., Methods: We undertook a cross-sectional study employing the 2017-2018 National Health and Nutrition Examination Survey (NHANES) database. We identified SLD according to a controlled attenuation parameter ≥288 dB/m, liver stiffness ≥7.2 kPa, or elevated aminotransferase levels. Alcohol use thresholds were established according to the updated SLD definition. We estimated prevalences using the complex design of the NHANES survey. Multivariable logistic regressions with complex design weights were employed., Results: A total of 5532 individuals are included. The mean age is 45.4 years, and 50.9% are women. The adjusted estimated prevalence of MASLD is 42.4% (95% CI: 41.1-43.8%), MetALD 1.7% (95% CI: 1.3-2.0%), and ALD 0.6% (95% CI: 0.3-0.8%). Hispanics exhibit a higher prevalence of SLD, but there are no significant differences in advanced fibrosis prevalence due to SLD among racial/ethnic groups. In MASLD, men, individuals aged 40-64 and ≥65 years, Hispanics, those with health insurance, higher BMI, diabetes, hypertension, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol or use of lipid-lowering agents are independently associated with a higher risk, while Blacks have the lowest risk. In MetALD, men and higher BMI are independently associated with a higher risk of MetALD in adjusted multivariable analysis. In ALD, the adjusted multivariable analysis shows that only health insurance is independently associated with a lower ALD risk., Conclusions: MASLD prevalence is high in the US, especially in men, older individuals, and Hispanics. MetALD and ALD prevalence was substantial but could be underestimated., (© 2024. The Author(s).)

Background: Major society guidelines recommend the fibrosis-4 index (FIB-4) as the initial step to risk stratifying people with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the proportion of people with MASLD-related hepatocellular carcinoma (HCC) and a low FIB-4., Methods: This cohort study included 613 consecutive adults (33% female) diagnosed with MASLD-related HCC from January 2008 to August 2023 at seven international centres in Australia, India, Japan, South Korea, Singapore and the United States. The primary objective was to determine the proportion of participants with a low FIB-4, defined as FIB-4 < 1.3, or < 2 if age > 65 years, in people without cirrhosis., Results: The mean (±SD) age and body mass index were 71 (±11) years and 27 (±7) kg/m 2 , respectively. Overall, 235 participants (38%) did not have known cirrhosis. The median FIB-4 was 3.90 (IQR 2.42-6.42). A total of 78 participants (13%) had a low FIB-4. Among participants without known cirrhosis (n = 235), 62 participants (26%) had a low FIB-4. Participants with a low FIB-4 had larger median total tumour diameter (p < 0.001) and lower median serum alpha-fetoprotein (p = 0.005), compared to participants without a low FIB-4. Cirrhosis was associated with lower odds of low FIB-4, but not other factors such as male sex, type 2 diabetes, or obesity., Conclusion: More than a quarter of those with MASLD-related HCC without cirrhosis have a low FIB-4. The proposed clinical care pathways may not identify these people for further evaluation., (© 2024 John Wiley & Sons Ltd.)

Background Aims: Cut-points for non-invasive tests (NITs) for risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD) were derived from predominantly non-Hispanic populations. It is unknown if these cut-points perform adequately in Hispanic individuals. We assessed the performance characteristics of current NIT cut-points among Hispanic patients and determined whether they could be further optimized., Approach Results: We prospectively enrolled 244 adults with biopsy-proven MASLD. Participants underwent a research visit with magnetic resonance elastography (MRE) and vibration controlled transient elastography (VCTE). Histology and imaging assessments were conducted centrally. Diagnostic performance was evaluated by area under the receiver-operating curve (AUROC) and optimal cut-points were identified by Youden J analysis. The mean (±SD) age and body mass index were 52.6 (±13) and 31.6 (±4.6) kg/m2. Overall, 40% had diabetes, 31% (N=75) were Hispanic. 40% of Hispanic and 28.4% of non-Hispanic patients had significant fibrosis. To detect significant fibrosis, MRE and VCTE exhibited significantly lower accuracy in Hispanic versus non-Hispanic participants (AUROC: MRE, 0.87 vs. 0.98, p=0.01; VCTE, 0.78 vs. 0.92, p=0.02). Clinical care algorithms yielded high false-negative rates among Hispanic participants (14% with low-risk FIB-4 and 21% with low-risk VCTE had advanced fibrosis on biopsy). Cut-points of 2.73 kPa for MRE and 6.9 kPa for VCTE were optimal to detect significant fibrosis in Hispanic individuals. Findings were validated in a Latin American cohort., Conclusions: Lower NIT cut-points may be needed to optimize surveillance for significant fibrosis due to MASLD in Hispanic populations commensurate with their higher burden and severity of disease., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis., Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment., Findings: Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related., Interpretation: Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development., Funding: Sagimet Biosciences., Competing Interests: Declaration of interests RL serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse Bio, Inipharma, Intercept, Inventiva, Ionis, Janssen, Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89Bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. RL has stock options in Sagimet Biosciences. In addition, his institution received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus. RL receives funding support from the National Institute of Diabetes and Digestive and Kidney Diseases (P30DK120515) and the John C Martin Foundation (RP124). KG, EBM, GK, MO'F, WM, and W-WT are current or former employees of Sagimet Biosciences and own or have options to purchase stock in the company. EL is a researcher for 89Bio, Akero Therapeutics, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, DSM, Eli Lilly, Enanta Pharmaceuticals, Enyo Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead Sciences, GSK, Hanmi Pharmaceuticals, Hightide Biopharma, Intercept Pharmaceuticals, Inventiva, Janssen Pharmaceuticals, Madrigal Pharmaceuticals, Merck & Co, NGM Biopharmaceuticals, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet Biosciences, Takeda, Terns Pharmaceuticals, Viking Therapeutics, and Zydus Pharmaceuticals. SAH was a scientific advisor or consultant for Akero, Aligos, Altimmune, Arrowhead, Auransa, Echosens, Galecto, Gilead, GSK, Hepion, Hepta Bio, HistoIndex, Humana, Inventiva, Kriya, Madrigal, Medpace, Merck, NeuroBo, Northsea, Novo Nordisk, Perspectum, Pfizer, Seal Rock, Sonic Incytes, Sagimet, Terns, and Viking. They received grant or research support from Akero, Altimmune, Axcella, BMS, Corcept, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, GSK, Hepion, Hightide, Immuron, Intercept, Inventiva, Ionis, Madrigal, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Poxel, Sagimet, Terns, and Viking. All other authors declare no competing interests., (Copyright © 2024 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.)

We aimed to compare the associations of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with coronary artery calcification (CAC). Patients who simultaneously underwent ultrasonography to diagnose hepatic steatosis and cardiac computed tomography to detect CAC were included. The presence and severity of CAC were defined with CAC-score thresholds of > 0 and > 300, respectively, and patients were divided into the following groups: no MASLD or MAFLD (reference), MASLD-only, MAFLD-only, and overlapping groups. Overall, 1,060/2,773 (38.2%) patients had CAC, of which 196 (18.5%) had severe CAC. The MASLD and MAFLD prevalence rates were 32.6% and 45.2%, respectively, with an overlap of 30.7%. In an ASCVD risk score-adjusted model, both MASLD (adjusted odd ratios [aOR], 1.21; 95% confidence interval [CI], 1.02-1.44; p = 0.033) and MAFLD (aOR 1.20; 95% CI 1.01-1.42, p = 0.034) were associated with CAC, whereas only MASLD (aOR 1.38; 95% CI 1.01-1.89, p = 0.041) was associated with severe CAC. Compared to the reference group, the overlapping group showed an association with CAC (aOR 1.22; 95% CI 1.01-1.47; p = 0.038); however, the MASLD and MAFLD subgroups did not differ in their association with CAC. MASLD may predict a higher risk of ASCVD more effectively than MAFLD., (© 2024. The Author(s).)

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses., (© 2024. The Author(s).)

Background & Aims: The clinical significance of change in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in patients with non-alcoholic fatty liver disease (NAFLD) is not well-understood. We prospectively defined rates of progression to and regression from LSM-defined compensated advanced chronic liver disease (cACLD) and their associations with liver-related events (LREs)., Methods: Participants in the NASH Clinical Research Network-led NAFLD Database 2 and 3 studies were included. Progression to cACLD was defined as reaching LSM ≥10 kPa in participants with LSM <10 kPa on initial VCTE; regression from cACLD was defined as reaching LSM <10 kPa in participants with baseline LSM ≥10 kPa. LREs were defined as liver-related death, liver transplant, hepatocellular carcinoma, MELD >15, development of varices, or hepatic decompensation. Univariate and multivariable interval-censored Cox regression analyses were used to compare the cumulative LRE probability by LSM progression and regression status., Results: In 1,403 participants, 89 LREs developed over a mean follow-up of 4.4 years, with an annual incidence rate for LREs of 1.5 (95% CI 1.2-1.8). In participants at risk, progression to LSM ≥10 or ≥15 kPa occurred in 29% and 17%, respectively, whereas regression to LSM <10 or <15 kPa occurred in 44% and 49%, respectively. Progressors to cACLD (≥10 kPa) experienced a higher cumulative LRE rate vs. non-progressors (16% vs. 4%, adjusted hazard ratio 4.0; 95% (1.8-8.9); p <0.01). Regressors from cACLD (to LSM <10 kPa) experienced a lower LRE rate than non-regressors (7% vs. 32%, adjusted hazard ratio 0.25; 95% CI 0.10-0.61; p <0.01)., Conclusions: Change in LSM over time is independently and bi-directionally associated with risk of LRE and is a non-invasive surrogate for clinical outcomes in patients with NAFLD., Impact and Implications: The prognostic value of change in LSM in patients with NAFLD is not well understood. In this large prospective study of patients with NAFLD and serial vibration-controlled transient elastography exams, baseline and dynamic changes in LSM were associated with the risk of developing liver-related events. LSM is a useful non-invasive surrogate of clinical outcomes in patients with NAFLD., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) requires at least one of five cardiometabolic criteria. It is unclear whether these criteria can be used as predictors and treatment targets for complications including liver-related events and major adverse cardiovascular events (MACE)., Aims: To investigate the relationship between cardiometabolic criteria and complications., Methods: We conducted a nationwide, population-based study of 979,352 patients with MASLD. We investigated relationships between a number of criteria at baseline and liver-related events or MACE risks. In a separate longitudinal analysis, we included patients with five criteria at baseline and investigated the relationship between improving the criteria and the incidence of complications after 1 year., Results: The cumulative incidence of MACE, but not liver-related events, increased with increasing baseline cardiometabolic criteria. In the longitudinal study, multivariable analysis using patients with five criteria (no improvement) as the reference, adjusted hazard ratios (95% confidence interval) of MACE in patients with 4, 3, 2, and 0-1 criteria (1 to 4-5 criteria improvement) were 0.55 (0.52-0.58, p < 0.001), 0.20 (0.17-0.22, p < 0.001), 0.13 (0.11-0.16, p < 0.001), and 0.06 (0.02-0.3, p < 0.001), respectively. The risk of MACE decreased as the cardiometabolic criteria improved. There was no significant association between improvement of the criteria and liver-related events., Conclusions: Cardiometabolic criteria can be used as predictors and treatment targets for cardiovascular event risk in MASLD. Developing predictors and therapeutic targets for liver-related events is a future challenge., (© 2024 John Wiley & Sons Ltd.)

Background: Dysregulation of bile acids (BAs), as important signalling molecules in regulating lipid and glucose metabolism, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, static BA profiles during fasting may obscure certain pathogenetic aspects. In this study, we investigate the dynamic alterations of BAs in response to an oral glucose tolerance test (OGTT) among children with NAFLD., Methods: We recruited 230 subjects, including children with overweight/obesity, or complicated with NAFLD, and healthy controls. Serum BAs, 7-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) were quantified during OGTT. Clinical markers related to liver function, lipid metabolism and glucose metabolism were assessed at baseline or during OGTT., Findings: Conjugated BAs increased while unconjugated ones decreased after glucose uptake. Most BAs were blunted in response to glucose in NAFLD (p > .05); only glycine and taurine-conjugated chenodeoxycholic acid (CDCA) and cholic acid (CA) were responsive (p < .05). Primary BAs were significantly increased while secondary BAs were decreased in NAFLD. C4 and FGF19 were significantly increased while their ratio FGF19/C4 ratio was decreased in NAFLD. The dynamic pattern of CDCA and taurine-conjugated hyocholic acid (THCA) species was closely correlated with glucose (correlation coefficient r = .175 and -.233, p < .05), insulin (r = .327 and -.236, p < .05) and c-peptide (r = .318 and -.238, p < .05). Among which, CDCA was positively associated with liver fat content in NAFLD (r = .438, p < .05). Additionally, glycochenodeoxycholic acid (GCDCA), CDCA and THCA were potential biomarkers to discriminate paediatric NAFLD from healthy controls and children with obesity., Interpretation: This study provides novel insights into the dynamics of BAs during OGTT in paediatric NAFLD. The observed variations in CDCA and HCA species were associated with liver dysfunction, dyslipidaemia and dysglycaemia, highlighting their potential roles as promising diagnostic and therapeutic targets in NAFLD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis., Methods: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4., Results: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable., Conclusions: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 20%-30% of the general population and is linked to high-caloric western style diet. However, there are little data that specific nutrients might help to prevent steatosis., Methods: We analysed the UK Biobank (ID 71300) 24 h-nutritional assessments and investigated the association between nutrient intake calculated from food questionnaires and hepatic steatosis indicated by imaging or ICD10-coding. The effect of manganese (Mn) on subgroups with risk single nucleotide polymorphism carriage as well as the effect on metabolomics was investigated. All analyses are corrected for age, sex, body mass index, Townsend index for socioeconomic status, kcal, alcohol, protein intake, fat intake, carbohydrate intake, energy from beverages, diabetes, physical activity and for multiple testing., Results: We used a random forest classifier to analyse the feature importance of 63 nutrients and imaging-proven steatosis in a cohort of over 25 000 UK Biobank participants. Increased dietary Mn intake was associated with a lower likelihood of MRI-diagnosed steatosis. Subsequently, we conducted a cohort study in over 200 000 UK Biobank participants to explore the relationship between Mn intake and hepatic or cardiometabolic outcomes and found that higher Mn intake was associated with a lower risk of ICD-10 coded steatosis (OR = .889 [.838-.943], p < .001), independent of other potential confounders., Conclusion: Our study provides evidence that higher Mn intake may be associated with lower odds of steatosis in a large population-based sample. These findings underline the potential role of Mn in the prevention of steatosis, but further research is needed to confirm these findings and to elucidate the underlying mechanisms., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background & Aims: MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis., Methods: A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed., Results: Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53)., Conclusions: These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention., Impact and Implications: There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health., Clinical Trial Number(s): NCT02443116, NCT03976401, NCT03551522., (Copyright © 2024. Published by Elsevier B.V.)

There is a clinical need for a simple test implementable at the primary point of care to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) in the population. Blood plasma samples from adult patients with varying phenotypes of MASLD were used to identify a minimal set of lipid analytes reflective of underlying histologically confirmed MASLD. Samples were obtained from the NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database prospective cohort study (MASLD group; N = 301). Samples of control subjects were obtained from cohort studies at the University of California San Diego (control group; N = 48). Plasma samples were utilized for targeted quantitation of circulating eicosanoids, related bioactive metabolites, and polyunsaturated fatty acids by ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) lipidomics analysis. Bioinformatic approaches were used to discover a panel of bioactive lipids that can be used as a diagnostic tool to identify MASLD. The final panel of fifteen lipid metabolites consists of 12 eicosanoid metabolites and 3 free fatty acids that were identified to be predictive for MASLD by multivariate area under the receiver operating characteristics curve (AUROC) analysis. The panel was highly predictive for MASLD with an AUROC of 0.999 (95% CI = 0.986-1.0) with only one control misclassified. A validation study confirmed the resulting MASLD LIPIDOMICS SCORE, which may require a larger-scale prospective study to optimize. This predictive model should guide the development of a non-invasive "point-of-care" test to identify MASLD patients requiring further evaluation for the presence of metabolic dysfunction-associated steatohepatitis., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: EAD and RL are co-founders and hold equity in LipoNexus, Inc which has licensed technology from the University of California, San Diego. AS is a consultant and holds stock options in LipoNexus, Inc. Additionally, RL serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. He holds stock options in Sagimet Biosciences. His institution received research grants from Arrowhead Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Additionally, AS holds stock options in Genfit, Tiziana, Hemoshear, Rivus, Northsea, and Inversago. He has served as wa consultant to Gilead, Intercept, Boehringer Ingelhiem, Merck, Novo Nordisk, Eli Lilly, Madrigal, Alnylam, Hanmi, LG Chem, Takeda, Regeneron, Genentech, Siemens, Surrozen, Poxel, Path AI, Histoindex, Zydus, 89 Bio, Akero, and Salix. His institution has received grants from Gilead, Bristol Myers Squibb, Intercept, Novo Nordisk, Akero, Takeda, Merckw, Salix, Eli Lilly, Hanmi, Madrigal, Boehringer Ingelheim, and Pfizer. He received royalties from Elsevier and Uptodate.9., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The course of adults with ZZ alpha-1-antitrypsin deficiency (AATD) liver disease is unpredictable. The utility of markers, including liver biopsy, is undefined., Methods: A prospective cohort, including protocol liver biopsies, was enrolled to address these questions., Results: We enrolled 96 homozygous ZZ AATD adults prospectively at three US sites with standardized clinical evaluations, and protocol liver biopsies. Fibrosis was scored using Ishak (stages 0-6). Also, 51% of the 96 subjects had Ishak score >1 fibrosis (49% Ishak 0-1, 36% Ishak 2-3 and 15% ≥4). Elevated aspartate aminotransferase (AST) more than alanine aminotransferase (ALT), high body mass index (BMI), obesity, AST platelet ratio index and elevated serum Z alpha 1 antitrypsin (AAT) polymer levels were associated with increased fibrosis. Steatosis did not correlate to fibrosis. Increased fibrosis was associated with increased mutant Z polymer globular inclusions (p = .002) and increased diffuse cytoplasmic Z polymer on biopsy (p = .0029) in a direct relationship. Increased globule Z polymer was associated with increased serum AST (p = .007) and increased periportal inflammation on histopathology (p = .004), but there was no relationship of Z polymer hepatocellular accumulation with ALT, gamma glutamine transferase, inflammation in other parts of the lobule, necrosis or steatosis. Serum Z polymer levels were directly correlated to hepatic Z protein polymer content. Lung function, smoking and alcohol consumption patterns were not associated with fibrosis., Conclusion: In AATD high BMI, obesity and elevated AST are associated with increased fibrosis. Liver biopsy features are correlated to some serum tests. Serum Z AAT polymer levels could be a future biomarker to detect fibrosis early and is directly correlated to liver Z content., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α-dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage-specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α-specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype-specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.

Background US shear-wave elastography (SWE) and vibration-controlled transient elastography (VCTE) enable assessment of liver stiffness, an indicator of fibrosis severity. However, limited reproducibility data restrict their use in clinical trials. Purpose To estimate SWE and VCTE measurement variability in nonalcoholic fatty liver disease (NAFLD) within and across systems to support clinical trial diagnostic enrichment and clinical interpretation of longitudinal liver stiffness. Materials and Methods This prospective, observational, cross-sectional study (March 2021 to November 2021) enrolled adults with NAFLD, stratified according to the Fibrosis-4 (FIB-4) index (≤1.3, >1.3 and <2.67, ≥2.67), at two sites to assess SWE with five US systems and VCTE with one system. Each participant underwent 12 elastography examinations over two separate days within 1 week, with each day's examinations conducted by a different operator. VCTE and SWE measurements were reported in units of meters per second. The primary end point was the different-day, different-operator reproducibility coefficient (RDC DDDO ) pooled across systems for SWE and individually for VCTE. Secondary end points included system-specific RDC DDDO , same-day, same-operator repeatability coefficient (RC SDSO ), and between-system same-day, same-operator reproducibility coefficient. The planned sample provided 80% power to detect a pooled RDC DDDO of less than 35%, the prespecified performance threshold. Results A total of 40 participants (mean age, 60 years ± 10 [SD]; 24 women) with low ( n = 17), intermediate ( n = 15), and high ( n = 8) FIB-4 scores were enrolled. RDC DDDO was 30.7% (95% upper bound, 34.4%) for SWE and 35.6% (95% upper bound, 43.9%) for VCTE. SWE system-specific RDC DDDO varied from 24.2% to 34.3%. The RC SDSO was 21.0% for SWE (range, 13.9%-35.0%) and 19.6% for VCTE. The SWE between-system same-day, same-operator reproducibility coefficient was 52.7%. Conclusion SWE met the prespecified threshold, RDC DDDO less than 35%, with VCTE having a higher RDC DDDO . SWE variability was higher between different systems. These estimates advance liver US-based noninvasive test qualification by (a) defining expected variability, (b) establishing that serial examination variability is lower when performed with the same system, and (c) informing clinical trial design. ClinicalTrials.gov Identifier NCT04828551 © RSNA, 2024 Supplemental material is available for this article.

Objective: As metabolic dysfunction-associated steatotic liver disease (MASLD) becomes more prevalent worldwide, it is imperative to create more accurate technologies that make it easy to assess the liver in a point-of-care setting. The aim of this study is to test the performance of a new software tool implemented in Velacur (Sonic Incytes), a liver stiffness and ultrasound attenuation measurement device, on patients with MASLD. This tool employs a deep learning-based method to detect and segment shear waves in the liver tissue for subsequent analysis to improve tissue characterization for patient diagnosis., Methods: This new tool consists of a deep learning based algorithm, which was trained on 15,045 expert-segmented images from 103 patients, using a U-Net architecture. The algorithm was then tested on 4429 images from 36 volunteers and patients with MASLD. Test subjects were scanned at different clinics with different Velacur operators. Evaluation was performed on both individual images (image based) and averaged across all images collected from a patient (patient based). Ground truth was defined by expert segmentation of the shear waves within each image. For evaluation, sensitivity and specificity for correct wave detection in the image were calculated. For those images containing waves, the Dice coefficient was calculated. A prototype of the software tool was also implemented on Velacur and assessed by operators in real world settings., Results: The wave detection algorithm had a sensitivity of 81% and a specificity of 84%, with a Dice coefficient of 0.74 and 0.75 for image based and patient-based averages respectively. The implementation of this software tool as an overlay on the B-Mode ultrasound resulted in improved exam quality collected by operators., Conclusion: The shear wave algorithm performed well on a test set of volunteers and patients with metabolic dysfunction-associated steatotic liver disease. The addition of this software tool, implemented on the Velacur system, improved the quality of the liver assessments performed in a real world, point of care setting., Competing Interests: Conflict of interest M.H., J.L., and C.S. are employees of Sonic Incytes. N.W. is a consultant for Sonic Incytes. S.G.: Research grant support for Viking, Zydus, Sonic Incytes, DSM. R.L. Is the Co-founder of LipoNexus Inc. and was an investigator of clinical trials sponsored by Sonic Incytes. R.L. receives funding support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), John C Martin Foundation (RP124). A.R.: Advisor /consultant for Abbvie, Gilead, Intercept/ Advanz, Janssen, Novo-Nordisc. He was an investigator of clinical trials sponsored by Sonic Incytes. T.H.: Receives Grant/Research Support from AbbVie, Allergan, Amgen, Biolinq, Bristol-Myers Squibb, Cytodyn, Assembly, Astra Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CARA, DURECT Corporation, Enanta, Escient, Fractyl, Galectin, Gilead, Grifols, HepQuant, Intercept, Janssen, Merck, Mirum, Novartis, Novo Nordisk, Nucorion, Pfizer, Provepharm, Regeneron, Salix Pharmaceuticals, Sonic Incytes, Terns Pharmaceuticals, Valeant. He was an investigator of clinical trials sponsored by Sonic Incytes. E.Y.: Dr. Eric Yoshida is an investigator of clinical research and clinical trials sponsored by: Sonic Incytes Inc, Pfizer Inc, Gilead Inc, Intercept Inc, Madrigal Inc, Novodisc Inc, Genfit Inc. He has also received a research grant from Paladin Laboratories. EP: None. MC has received research support from CareDx, Intercept and Sonic Incytes and consults for International Healthcare and Pfizer. He was an investigator of clinical trials sponsored by Sonic Incytes. N.A. has received consulting fees from Gilead, Glaxo Smith Kline, Jannsen, Sonic Incytes, Precision Biosciences, Intercept Pharmaceuticals. He has stock in Allurion. He is director, Liver Institute for Education and Research. He was an investigator of clinical trials sponsored by Sonic Incytes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2 + macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2 + macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2 + macrophages are superior collagen degraders. Lack of TREM2 + macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation., Competing Interests: Competing interests statement:R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. C.K.G. is a founder and member of the SAB of Asteroid Pharmaceuticals. A.E.F. is an employee and stockholder of Novo Nordisk. C.K.G. is a stockholder of Asteroid Therapeutics. R.L. is a co-founder and equity holder of LipoNexus Inc. R.L. received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals.

Background: There are limited prospective data among overweight and obese individuals on the prevalence of advanced fibrosis, and cirrhosis using advanced MRI-based methods in the USA. The aim of this study was to fill that gap in knowledge by prospectively determining the MRI-based prevalence of steatotic liver disease (SLD) and its subcategories, advanced fibrosis and cirrhosis among overweight and obese individuals residing in the USA., Methods: This is a cross-sectional analysis of prospectively enrolled overweight or obese adults aged 40-75 years from primary care and community-based settings in Southern California. Participants were classified as having SLD if MRI proton density fat fraction ≥5%, and subclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-related liver disease (ALD) consistently with the new nomenclature guidance per AASLD-EASL-ALEH. Advanced fibrosis and cirrhosis were defined as magnetic resonance elastography (MRE) ≥3.63 kPa and MRE ≥4.67 kPa, respectively., Results: The cohort included 539 participants with mean (±SD) age of 51.5 (±13.1) years and body mass index of 32.6 (±6.2) kg/m 2 , respectively. The prevalence of SLD, advanced fibrosis and cirrhosis was 75%, 10.8% and 4.5%, respectively. The prevalence of MASLD, MetALD and ALD was 67.3%, 4.8% and 2.6%, respectively. There was no difference in prevalence of advanced fibrosis and cirrhosis among subcategories., Conclusions: Using advanced MRI methods among community-dwelling overweight and obese adults, the prevalence of cirrhosis was 4.5%. Most common SLD subcategory was MASLD with 67% of individuals, whereas MetALD and ALD were less common. Systematic screening for advanced fibrosis among overweight/obese adults may be considered., Competing Interests: Competing interests: RL serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc, Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Cofounder of LipoNexus Inc. CBS reports payment to institution for non-federal research grants from ACR, Bayer, Foundation of NIH, GE, Gilead, Pfizer, Philips, Siemens, V Foundation; payment to institution for lab service agreements from OrsoBio, Enanta, Gilead, ICON, Intercept, Nusirt, Shire, Synageva, Takeda; payment to institution for institutional consulting from BMS, Exact Sciences, IBM-Watson, Pfizer; payment to self for personal consulting from Altimmune, Ascelia Pharma, Blade, Boehringer, Epigenomics, Guerbet, and Livivos; payment to self for royalties and/or honoraria from Medscape and Wolters Kluwer; ownership of stock options in Livivos; unpaid advisory board position in Quantix Bio; executive position for Livivos (Chief Medical Officer, unsalaried position with stock options and stock) through 28 June 2023; Principal Scientific Advisor to Livivos (unsalaried position with stock options and stock) since 28 June 2023; support for attending meetings and/or travel from Fundacion Santa Fe, Congreso Argentino de Diagnóstico por Imágenes, Stanford, Jornada Paulista de Radiologia and Ascelia Pharma; member (no payment) of Data Safety Monitoring board for National Cancer Institute funded Early Detection Research Network; equipment loans to institution from GE and Siemens. BS has been consulting for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen and Takeda. B.S.’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. BS is the founder of Nterica Bio. UC San Diego has filed several patents with BS as inventor., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors. This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as nonalcoholic fatty liver disease. The heterogeneity within this spectrum is influenced by several factors which include but are not limited to demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Aims: Magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE) have the potential to assess disease progression; however, repeatability data in people with cirrhosis are lacking. We aimed to assess the effect of disease severity on measurement variability and contribute to the evidentiary basis for the qualification of repeating liver stiffness measurements (LSM) in practice and research., Methods: This prospective study included 49 adult participants (58.3% female) with cirrhosis who underwent same-day repeat LSM examinations. The primary outcome was the same-day, same-operator repeatability coefficient% (RC%) and the within-case coefficient of variation (wCV) for each modality. Secondary outcomes include the intra-class correlation coefficient (ICC). The relationship between measurement variability (interquartile for VCTE, standard deviation for MRE) and disease severity (mean liver stiffness) was evaluated by linear regression with the coefficient of determination R 2 reported., Results: Same-day repeat MRE and VCTE exams were prospectively conducted in 33 and 45 participants, respectively. The RC% appeared 82% higher for VCTE versus MRE (38% vs. 21%), with consistent findings in head-to-head analyses. The wCV for VCTE and MRE was 14% and 8% respectively, indicating VCTE has 75% higher within-subject measurement variation than MRE. ICC was excellent for LSM by VCTE (0.92) and MRE (0.96). Measurement variability increased with mean liver stiffness for VCTE (R 2  = 0.78) and MRE (R 2  = 0.93)., Conclusion: Both VCTE and MRE demonstrated increased measurement variability with disease severity. However, MRE outperformed VCTE in terms of technical repeatability in patients with cirrhosis. These repeatability estimates may improve the qualification of NITs in practice., (© 2024 John Wiley & Sons Ltd.)

Risk of disease progression and clinical outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with fibrosis stage and presence of "at-risk metabolic dysfunction-associated steatohepatitis (MASH)." Although liver biopsy is considered the gold standard to diagnose MASH and stage of fibrosis, biopsy is infrequently performed in clinical practice and has associated sampling error, lack of interrater reliability, and risk for procedural complications. Noninvasive tests (NITs) are routinely used in clinical practice for risk stratification of patients with MASLD. Several NITs are being developed for detecting "at-risk MASH" and cirrhosis. Clinical care guidelines apply NITs to identify patients needing subspecialty referral. With recently approved Food and Drug Administration treatment for MASH and additional emerging pharmacotherapy, NITs will identify patients who will most benefit from treatment, monitor treatment response, and assess risk for long-term clinical outcomes. In this review, we examine the performance of NITs to detect "at-risk MASH," fibrosis stage, response to treatment, and risk of clinical outcomes in MASLD and MASH., Competing Interests: R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals, and Viking Therapeutics. R.L. has stock options in Sagimet Biosciences. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus Inc., (Thieme. All rights reserved.)

Introduction: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM)., Methods: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS)., Results: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF., Discussion: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist., (Copyright © 2024 by The American College of Gastroenterology.)

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.)

Objectives: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally, with an estimated prevalence exceeding 25%. Variants in the PNPLA3 and HSD17B13 genes have been a focus of investigations surrounding the etiology and progression of NAFLD and are believed to contribute to a greater burden of disease experienced by Hispanic Americans. However, little is known about socioeconomic factors influencing NAFLD progression or its increased prevalence among Hispanics., Materials and Methods: We cross-sectionally analyzed 264 patients to assess the role of genetic and socioeconomic variables in the development of advanced liver fibrosis in individuals at risk for NAFLD., Results: Adjusting for age, sex, body mass index, and PNPLA3 genotype, lacking a college degree was associated with 3.3 times higher odds of advanced fibrosis (95% confidence interval [CI]: 1.21-8.76, p = 0.019), an effect comparable to that of possessing the major PNPLA3 risk variant. Notably, the effect of PNPLA3 genotype on advanced fibrosis was attenuated to nonsignificance following adjustment for education and other socioeconomic markers. The effect of the protective HSD17B13 variant, moreover, diminished after adjustment for education (odds ratio [OR]: 0.39 [95% CI: 0.13-1.16, p = 0.092]), while lower education continued to predict advanced fibrosis following multivariable adjustment with an OR of 8.0 (95% CI: 1.91-33.86, p = 0.005)., Discussion: Adjusting for education attenuated the effects of genotype and Hispanic ethnicity on liver fibrosis, suggesting that social factors-rather than genes or ethnicity-may be driving disease severity within some populations. Findings reveal the importance of including socioenvironmental controls when considering the role of genetics or ethnicity in complex disease., (© 2024 The Author(s). American Journal of Biological Anthropology published by Wiley Periodicals LLC.)

Objectives: Multicenter studies reporting outcomes following tracheostomy in children with congenital heart disease are limited, particularly in patients with single ventricle physiology. We aimed to describe clinical characteristics and outcomes in a multicenter cohort of patients with single ventricle physiology who underwent tracheostomy before Fontan operation., Design: Multicenter retrospective cohort study., Setting: Twenty-one tertiary care pediatric institutions participating in the Collaborative Research from the Pediatric Cardiac Intensive Care Society., Patients: We reviewed 99 children with single ventricle physiology who underwent tracheostomy before the Fontan operation at 21 institutions participating in Collaborative Research from the Pediatric Cardiac Intensive Care Society between January 2010 and December 2020, with follow-up through December 31, 2021., Interventions: None., Measurements and Main Results: Death occurred in 51 of 99 patients (52%). Cox proportional hazard analysis was performed to determine factors associated with death after tracheostomy. Results are presented as hazard ratio (HR) with 95% CIs. Nonrespiratory indication(s) for tracheostomy (HR, 2.21; 95% CI, 1.14-4.32) and number of weeks receiving mechanical ventilation before tracheostomy (HR, 1.06; 95% CI, 1.02-1.11) were independently associated with greater hazard of death. In contrast, diagnosis of tricuspid atresia or Ebstein's anomaly was associated with less hazard of death (HR, 0.16; 95% CI, 0.04-0.69). Favorable outcome, defined as survival to Fontan operation or decannulation while awaiting Fontan operation with viable cardiopulmonary physiology, occurred in 29 of 99 patients (29%). Median duration of mechanical ventilation before tracheostomy was shorter in patients who survived to favorable outcome (6.1 vs. 12.1 wk; p < 0.001), and only one of 16 patients with neurologic indications for tracheostomy and 0 of ten patients with cardiac indications for tracheostomy survived to favorable outcome., Conclusions: For children with single ventricle physiology who undergo tracheostomy, mortality risk is high and should be carefully considered when discussing tracheostomy as an option for these children. Favorable outcomes are possible, although thoughtful attention to patient selection and tracheostomy timing are likely necessary to achieve this goal., Competing Interests: Dr. Mastropietro received funding from Telan, Meltz, Wallace, and Eide Law Firm, and Bioporto. Dr. Werho received funding from University of California San Diego; his institution received funding from the American Heart Association; and he disclosed that he is a board member of the Pediatric Cardiac Intensive Care Society and the Pediatric Cardiac Critical Care Consortium. Dr. Yates received funding from Alexion Pharmaceuticals. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Introduction: This study investigates the applicability of the new metabolic dysfunction-associated steatotic liver disease (MASLD) nomenclature to the real-world TARGET-NASH US adult cohort., Methods: The new MASLD/metabolic steatohepatitis nomenclature was applied to patients enrolled with pragmatic diagnoses of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), and NASH cirrhosis and concordance were determined between the definitions., Results: Approximately 99% of TARGET-NASH participants met the new MASLD diagnostic criteria. Approximately 1,484/1,541 (96.3%, kappa 0.974) nonalcoholic fatty liver patients (metabolic dysfunction-associated steatotic liver), 2,195/2,201 (99.7%, kappa 0.998) NASH patients (metabolic steatohepatitis), and 1,999/2,003 (99.8%, kappa 0.999) NASH cirrhosis patients met the new criteria., Discussion: The new MASLD nomenclature is highly concordant with the previous TARGET-NASH pragmatic definitions., (Copyright © 2024 by The American College of Gastroenterology.)