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Neutrophils play a crucial role in host defense against infection. Aberrant neutrophil activation may induce tissue damage via sterile inflammation. Neutrophil accumulation has been identified as a feature of the inflammatory response observed in metabolic dysfunction-associated steatohepatitis (MASH) and has been associated with liver fibrosis and cirrhosis. Here, we performed the transcriptomic analysis of circulating neutrophils from mild and advanced MASH patients to identify the potential mechanism behind neutrophil contribution to MASH progression. Our findings demonstrated that circulating neutrophils from mild and advanced MASH display an increased activated transcriptional program, with the expression of pro-inflammatory factors and an amplified lifespan compared to cells from non-diseased controls. Our results also suggest that MASH progression is associated with a dynamic shift in the profile of circulating neutrophils. In the early stages of MASH, mature neutrophils predominate in the bloodstream. As hepatic inflammation and fibrosis progress, the premature release of immature neutrophils into the circulation occurs. These immature neutrophils exhibit a pro-inflammatory profile that may exacerbate inflammation and promote fibrosis in MASH.

Background: We previously showed that the pattern of liver biopsy iron staining is associated with metabolic dysfunction–associated steatohepatitis (MASH) severity and fibrosis. The goal of the current study was to further examine the relationships between hepatic iron deposition and disease severity in a large biopsy-proven cohort of nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Methods: Adult patients enrolled in the NASH CRN Non-alcoholic Fatty Liver Disease (NAFLD) Database, PIVENS, or FLINT studies from November 2004 to May 2022 were included. Patient demographics, clinical, and laboratory data were compared between patients with different iron deposition patterns. Multivariate logistic regression analysis was performed to identify the relationship between the iron deposition pattern and advanced fibrosis. Results: A total of 2833 patients were included; 1166 patients (41%) had positive hepatic iron staining. Two hundred seventy-two (9.6%) patients had hepatocellular (HC) iron, 284 (10%) had iron in the reticuloendothelial system (RES), and the remaining (21.4%) had mixed iron deposition. A higher proportion of patients with RES iron had grade 3 steatosis (29%), severe hepatocyte ballooning (47%), severe lobular inflammation (15%), cirrhosis (16%), and definite MASH (71%). On multivariate regression analysis, patients with RES iron had higher odds of advanced fibrosis (adjusted OR: 1.34, 95% CI: 1.11–1.62, p =0.003), while patients with HC iron had lower odds of advanced fibrosis (aOR: 0.68, 95% CI: 0.55–0.83, p <0.001). Conclusions: Hepatic iron is common in patients with MASH. Patients with a RES iron pattern have a severe disease, while those with HC iron have milder disease. These data provide insights into the potential role of hepatic iron in the pathogenesis of MASH.

Background: Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications. Methods: Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): 37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p). Results: Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66–1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96–1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87–1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72–1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67–1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80–1.34]) suggesting a differential impact of ATxV on LT probability. Conclusions: The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.