BACKGROUND AND AIMS:Hepatic stellate cell (HSC) activation is central to liver fibrosis, but emerging evidence suggests HSC homeostatic activity. We compared HSC functions in parenchymal injury (CCl 4 -driven) versus metabolic dysfunction-associated steatohepatitis (MASH; choline-deficient, high-fat diet-CD-HFD) and identified therapeutic targets preserving HSC homeostatic functions. APPROACH AND RESULTS:Inducible HSC ablation was performed in Lrat-iDTR mice during active fibrogenesis. Multi-parametric analyses were conducted to assess roles of HSCs in 2 established fibrosis models, with a focus on elucidating the cellular origins of myofibroblasts and the alterations in regeneration and ductular reaction. RNA-seq from human biopsies validated mechanisms. HSC depletion in the CD-HFD model not only exacerbated MASH but also elevated a-SMA + myofibroblasts derived from PDGFRα + portal fibroblasts, impaired hepatocyte function (metabolic zonation and regeneration), and enhanced the ductular reaction. Conversely, HSC depletion in the CCl 4 model attenuated fibrosis without affecting hepatic regeneration or metabolic zonation. Strikingly, 85.5% of quiescent HSC-enriched genes remained upregulated in MASH-associated HSCs, unlike in CCl 4 fibrosis. RNA-seq followed by in vivo studies identified extracellular matrix protein 1 (ECM1) as a master regulator of HSC quiescence, and HSC-specific ECM1 overexpression suppressed CCl 4 -induced fibrosis. In human biopsies (MASH, HBV, PBC, PSC), ECM1 expression inversely correlated with fibrosis stage. CONCLUSIONS:HSCs exhibit dual roles contingent on disease context: in MASH with moderate inflammation, they maintain homeostasis, whereas in massive CCl 4 -driven injury, activated HSCs promote fibrogenesis. ECM1 enforces HSC quiescence and facilitates fibrosis resolution. Anti-fibrotic therapies based on general HSC ablation may be harmful.

INTRODUCTION:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, and liver biopsy remains the gold standard for diagnosis. However, a subset of patients diagnosed with MASLD by imaging paradoxically exhibit steatosis grade S0 on liver biopsy, posing a diagnostic challenge. This study investigated the outcomes and causes of steatosis 0. METHODS:Steatosis 0 was defined as imaging-detected MASLD with a biopsy-defined steatosis grade S0. We used global cohorts to evaluate outcomes, histologic progression by paired biopsies, and possible causes. The cause analysis included MRI-proton density fat fraction (MRI-PDFF) for fat distribution, pathologist consistency testing, and comparison of serial biopsy sections. RESULTS:In a follow-up cohort of 3,273 biopsy individuals from 16 centers, 123 (3.8%) exhibited steatosis 0. Of these, 29.3% of them had advanced fibrosis (burnt-out MASLD) and demonstrated a risk of liver-related events, whereas those without advanced fibrosis had no such events. In the paired-biopsy cohort of 1,865 patients, 74 (4.0%) individuals initially showed steatosis grade S0; among them, 93.2% retained no or mild steatosis on follow-up biopsy. MRI-PDFF assessments in 42 MASLD patients revealed heterogeneous hepatic fat distribution, with some segments showing steatosis grade S0 despite elevated average liver fat. Interpathologist variability and discrepancies across consecutive biopsy sections contributed to misclassification of steatosis grade. DISCUSSION:Steatosis 0 represents a potential diagnostic gray zone in MASLD. It may be caused by burnt-out MASLD, uneven liver fat distribution, or variability in pathological assessment. Understanding the causes and implications of steatosis 0 is critical for diagnosis and management.

BACKGROUND & AIMS:Fibrosis-4 Index (FIB-4) is a noninvasive tool for assessing liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). However, its role of dynamic FIB-4 for assessing fibrosis progression and predicting clinical outcomes remains unclear. The aim of this study was to examine the association between changes in FIB-4 and changes in liver stiffness, fibrosis progression, and outcomes in MASLD. METHODS:Three cohorts were analyzed: VCTE-Prognosis cohort (n = 10,203) for stiffness progression, Paired Liver Biopsy cohort (n = 1,145) for fibrosis progression, and Wenzhou Real-World (WRW) cohort (n = 41,105) for clinical outcomes. Stiffness progression was defined as an increase in liver stiffness measurement, and fibrosis progression by a 1-stage increase. Outcomes included all-cause mortality, cardiovascular events, and liver-related events (LREs). FIB-4 was dichotomized into low (<1.3) and high (≥1.3). Increases were defined as ≥20% rise and to ≥1.3 in the low FIB-4 group, and ≥20% rise in the high FIB-4 group. RESULTS:In the VCTE-Prognosis cohort, stiffness progression was more likely with increasing vs stable FIB-4 (adjusted odds ratio [OR], 2.36; P < .001) in those with low baseline FIB-4. In the high FIB-4 group, stiffness progression rates increased from stable to increasing FIB-4 (adjusted OR, 3.42; P < .001). In the Paired Liver Biopsy cohort, fibrosis progression was more frequent with increasing FIB-4 (adjusted OR, 2.20; P = .004 in low FIB-4; adjusted OR, 3.68; P < .001 in high FIB-4). In the WRW cohort, an increase in dynamic FIB-4 was linked to higher risks for all-cause mortality, cardiovascular events, and LREs (all P < .001). CONCLUSIONS:Dynamic FIB-4 monitoring tracks fibrosis and stiffness progression and predicts clinical outcomes in MASLD.

Background & Aims:The relationship between biopsy-proven liver fibrosis progression and renal function decline in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) has not been fully elucidated. We used an automated quantitative liver fibrosis assessment (qFibrosis) technique to investigate the temporal changes in regional liver fibrosis. Methods:This retrospective longitudinal study included 68 MASLD patients and their paired formalin-fixed sections of liver biopsies. One hundred eighty-four fibrosis parameters were quantified in five different hepatic regions, including portal tract, peri-portal, zone 2, peri-central and central vein regions, and qFibrosis continuous values were calculated for all samples based on 10 fibrosis parameters using qFibrosis assessment. Liver fibrosis progression (QLF+, n = 18) and regression (QLF-, n = 23) was defined as at least a 20% relative change in qFibrosis over a 23-month follow-up. Renal function decline was assessed by estimated glomerular filtration rate (eGFR) changes. Results:The eGFR decline was greater in the QLF+ group (106.53 ± 13.71 ml/min/1.73 m2 vs. 105.28 ± 12.46 ml/min/1.73 m2) than in the QLF- group (110.87 ± 14.58 ml/min/1.73 m2 vs. 114.18 ± 14.81 ml/min/1.73 m2). In addition, liver fibrosis changes in the central vein and pericentral regions were more strongly associated with eGFR decline than in periportal, zone 2 and portal tract regions. We combined these parameters to construct a prediction model, which better differentiated eGFR decline (a cut-off value of qFibrosis combined index = 0.52, p <0.001). Conclusions:A decline in renal function is significantly related to liver fibrosis progression in MASLD. Regional qFibrosis assessment may efficiently predict eGFR decline, thus highlighting the importance of assessing renal function in patients with MASLD with worsening liver fibrosis. Impact and implications:The study shows that liver fibrosis progression assessed by qFibrosis may be associated with renal function decline, which provides a new perspective for understanding complex pathological processes. A combination of artificial intelligence and digital pathology may earlier and more precisely quantify the progression of regional liver fibrosis, thus better identifying changes in renal function. This opens the possibility of early interventions, which are essential to improve patients' outcomes.

BACKGROUND:Non-invasive assessment of improvement in fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is an important clinical problem. We aimed to develop and validate the fibrotic MASH resolutionVCTE index, a non-invasive tool for identifying fibrotic MASH resolution and predicting liver-related events (LREs). METHODS:We collected data from 2,017 individuals who had two liver biopsies, separated in time, across 40 centers in the first dataset. This dataset included two independent cohorts, which were used to develop and externally validate the tool (including the baseline and change in acFibroMASH index plus change in serum alanine aminotransferase levels). The second independent dataset, comprising 17,949 patients who underwent vibration-controlled transient elastography (VCTE) at 16 centers, was used to examine associations between the developed index and the risk of incident LREs. FINDINGS:After application of the inclusion and exclusion criteria, 252 and 8,752 patients were included in the first and second datasets, respectively. The fibrotic MASH resolutionVCTE index accurately identified fibrotic MASH resolution with an area under the receiver operating curve (AUROC) of 0.82 (95% CI 0.74-0.90) in the derivation cohort and 0.80 (95% CI 0.72-0.88) in the validation cohort. Patients with a fibrotic MASH resolutionVCTE index >0.61 had a substantially lower risk of incident LREs than those with an index <0.24 (adjusted-hazard ratio 0.043). The index achieved AUROCs of 0.86 and 0.87, respectively, for predicting the 5- and 10-year probability of not developing LREs. CONCLUSIONS:This global multicenter study suggests that the fibrotic MASH resolutionVCTE index may offer a non-invasive approach to estimate fibrotic MASH resolution and stratify long-term risk of LREs. FUNDING:National Natural Science Foundation.

BACKGROUND AND AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to severe forms such as metabolic dysfunction-associated steatohepatitis (MASH). Effective treatments for MASH are urgently needed. This study aimed to evaluate the efficacy and safety of chiglitazar, a PPAR pan-agonist, in MASLD with hypertriglyceridemia and insulin resistance. APPROACH AND RESULTS:In this phase II multicenter, randomized, double-blind and placebo-controlled study, 104 patients with MASLD with hypertriglyceridemia and insulin resistance were randomized 2:2:1 to receive 48 mg, 64 mg of chiglitazar, or placebo once daily for 18 weeks. The primary endpoint was the percentage change in liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) at week 18. Chiglitazar significantly reduced liver fat content, with percentage change from baseline at week 18 of -28.1% (95% CI -37.5 to -18.7) in the 48 mg group and -39.5% (95% CI -49.0 to -30.0) in the 64 mg group, compared with -3.2% (95% CI -16.8 to 10.4) in placebo group. The differences compared with placebo were -24.9% ( p <0.05) for the 48 mg group and -36.3% ( p <0.001) for the 64 mg group. Chiglitazar also significantly improved liver injury-related biomarkers such as ALT, AST, and γ-GT. Liver fibrosis indicators, lipid parameters, insulin resistance, and metabolic syndrome showed an improved trend. Both doses of chiglitazar were well tolerated, with most adverse events being mild to moderate. CONCLUSIONS:Chiglitazar significantly reduced liver fat content in MASLD with hypertriglyceridemia and insulin resistance, with a dose-dependent effect and a favorable safety profile.

OBJECTIVES:Etiological therapy has been documented to improve portal hypertension. We aimed to analyze the effectiveness of etiological therapy on hepatic venous pressure gradient (HVPG) reduction by conducting a systematic review and meta-analysis. METHODS:Literature search of the PubMed, EMBASE, and Cochrane Library was performed to identify studies involving patients with PHT published up to January 2024. The absolute HVPG reduction and the HVPG response rate were assessed. Pooled analyses were performed using random-effects models, and the heterogeneity was evaluated using sensitivity and subgroup analyses. RESULTS:Altogether 21 studies were included for analysis. After etiological therapy, the absolute reduction in HVPG was 2.25 mmHg (95% confidence interval [CI] 1.80-2.71). Longer (> 1 year) duration of etiological therapy showed more significant HVPG reduction compared with those treated with 1 year or less (3.02 mmHg vs. 2.24 mmHg, p = 0.001). A more pronounced HVPG reduction was also observed in patients with viral hepatitis-induced cirrhosis than in those with non-viral hepatitis-induced cirrhosis (2.39 mmHg vs. 1.27 mmHg, p = 0.001). Furthermore, 64% and 41% of patients showed ≥ 10% HVPG reduction and a reduction of ≥ 20% or to ≤ 12 mmHg, respectively, after etiology control. CONCLUSION:Effective etiology control can significantly decrease HVPG and increase the HVPG response rate, which may contribute to the improvement of the prognosis of cirrhotic patients.

BACKGROUND & AIMS:Hypertension is common in metabolic dysfunction-associated steatotic liver disease (MASLD), but its impact on long-term clinical outcomes and disease progression remains unclear. This study investigated the association of hypertension with the risk of adverse clinical outcomes and progression of liver stiffness/fibrosis in MASLD. METHODS:Three multicenter large cohorts were analyzed: the UK Biobank (UKBB) cohort to assess the risk of adverse clinical outcomes, the VCTE-Prognosis cohort to assess liver stiffness/fibrosis progression, and the Paired Liver Biopsy cohort to assess histologic liver fibrosis progression. Adverse clinical outcomes were defined as all-cause mortality, cardiovascular events, and/or liver-related events. Liver stiffness progression was defined as an increase in liver stiffness measurement from <10 kPa to ≥10 kPa or an increase of ≥20% for baseline liver stiffness measurement ≥10 kPa. Liver fibrosis progression was defined as a 1-stage fibrosis stage increase. Cox regression and Kaplan-Meier analyses were used to evaluate the impact of baseline hypertension on outcomes. RESULTS:A total of 107,316 adults from the UKBB cohort, 8,169 from the VCTE-Prognosis cohort, and 1,670 from the Paired Liver Biopsy cohort were included. The prevalence of hypertension was 37.1%, 33.4%, and 48.9%, respectively. In the UKBB cohort, hypertension was associated with long-term adverse clinical outcomes (adjusted hazard ratio [HR] 1.30, 95% CI 1.26-1.33, p <0.001). In the VCTE-Prognosis cohort, hypertension was associated with a higher risk of liver stiffness progression (adjusted HR 1.57, 95% CI 1.30-1.90, p <0.001), while in the Paired Liver Biopsy cohort, hypertension was associated with a greater risk of histologic liver fibrosis progression (adjusted HR 1.41, 95% CI 1.12-1.78, p = 0.004). Subgroup and sensitivity analyses supported these findings. CONCLUSIONS:Hypertension is a modifiable risk factor that increases the risk of adverse clinical outcomes and progression of liver stiffness and fibrosis in MASLD. IMPACT AND IMPLICATIONS:This study provides robust evidence from three large multicenter cohorts demonstrating that hypertension is independently associated with increased risks of adverse clinical outcomes and liver fibrosis progression in individuals with MASLD. These findings reveal that hypertension, traditionally managed from a cardiovascular perspective, also plays a critical and underrecognized role in liver disease progression, making them highly relevant for hepatologists, cardiologists, and primary care providers. Incorporating non-invasive fibrosis assessments into routine care for patients with MASLD and hypertension may facilitate early risk stratification and support targeted interventions to reduce both hepatic and cardiovascular complications.

Partial correlation analysis was performed to account for the interference of steatosis changes and inflammatory factors, to determine the true correlation between fibrosis and IVIM parameters (Dfast, Dslow, and F), and to evaluate the diagnostic efficacy of IVIM for liver fibrosis. A total of 106 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) examined by IVIM from November 2016 to November 2023 at our hospital were retrospectively included. Preliminary analysis of each IVIM parameter and correlations with pathological findings were performed using Spearman correlation analysis, and partial correlation analysis was used to exclude the interference of other pathological factors, thus yielding the true correlations between IVIM parameters (Dfast, Dslow, and F) and pathology. The diagnostic efficacy of IVIM parameters for diagnosing MASLD was assessed via receiver operating characteristic (ROC) curve analysis. Spearman correlation analysis of all the IVIM parameters revealed correlations with steatosis, lobular inflammation, and ballooning. Partial correlation analysis indicated that Dfast was correlated with the pathological fibrosis stage (r = − 0.593, P < 0.001), Dslow was correlated with the pathological steatosis score (r = − 0.313, P < 0.05), and F was correlated with the pathological fibrosis stage and steatosis score (r = − 0.456 and 0.255, P < 0.001 and P < 0.05). In the diagnosis of hepatic fibrosis, significant hepatic fibrosis, advanced liver fibrosis and cirrhosis, Dfast achieved areas under the ROC curve of 0.763, 0.801, 0.853, and 0.897, respectively. The threshold values for diagnosing different fibrosis stages using Dfast (10–3 mm2/s) were 57.613, 54.587, 52.714, and 51.978, respectively. According to our partial correlation analysis, there was a moderate correlation between Dfast and F according to fibrosis stage, and Dfast was not influenced by inflammation or steatosis when diagnosing fibrosis in MASLD patients. A relatively close Dfast threshold is insufficient for accurately and noninvasively assessing various stages of MASLD fibrosis. In clinical practice, this approach can be considered an alternative method for the preliminary assessment of fibrosis in MASLD patients.

Objectives: To evaluate the efficacy and image processing time of the dynamic contrast-enhanced MRI (DCE-MRI) exchange model in liver fibrosis staging and compare it to the efficacy of magnetic resonance elastography (MRE). Methods: The subjects were 45 patients with nonalcoholic fatty liver disease (NAFLD) who underwent MRE and DCE-MRI in our hospital. Liver biopsy results were available for all patients. Spearman rank correlation coefficients were used to compare the correlations among MRE, DCE-MRI and liver fibrosis parameters. Quantitative DCE-MRI parameters, MRE-derived liver stiffness measurement (LSM), and the results of a combined DCE-MRI + MRE logistic regression model were compared in terms of the area under the receiver operating characteristic curve (AUC). We also compared the scanning and postprocessing times of the MRE and DCE-MRI techniques. Results: The correlation coefficients between the following parameters of interest and liver fibrosis were as follows: capillary permeability–surface area product (PS; DCE-MRI parameter), −0.761; portal blood flow (Fp; DCE-MRI parameter), −0.754; MRE-LSM, 0.835. Some DCE-MRI parameters (PS, Fp) had slightly greater AUC values than MRE-LSM for diagnosing the presence or absence of liver fibrosis, and the combined model had the highest AUC value for all stages except F4, but there was no significant difference in the diagnostic efficacy of the DCE-MRI, MRE, and combined models for any stage of fibrosis. The average scanning times for MRE and DCE-MRI were 17 s and 330 s, respectively, and the average postprocessing times were 45.5 s and 342.7 s, respectively. Conclusions: In the absence of MRE equipment, DCE-MRI represents an alternative technique. However, MRE is a quicker and simpler method for assessing fibrosis than DCE-MRI in the clinic.

Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis is reversible. However, the dynamic morphology change in fibrosis regression remains unclear. We aim to explore the morphological characteristics of fibrosis regression in advanced MASH patients. Clinical and histological data of 79 biopsy-proved MASH patients with advanced fibrosis (F3–F4) were reviewed. The second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) image technology was used to quantitatively identify the R (regressive) septa from P (progressive) septa and PS (perisinusoidal) fibrosis. Non-invasive tests were used to compare the fibrosis level with and without R septa groups. Transcriptomics was used to explore hub genes and the underlying mechanism of the formation of R septa. The R septa were different from the P septa and PS fibrosis in detail collagen quantitation identified by SHG/TPEF technology. The R septa were found in MASH fibrosis-regressed patients, which met the definition of the “Beijing classification”. Therefore, patients were divided into two groups according to septa morphology: with R septa (n = 10, 12.7

BACKGROUND AND AIMS:Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH. METHODS:We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions. RESULTS:About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region. CONCLUSION:Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging.

Aortic carboxypeptidase-like protein (ACLP) is an extracellular protein involved in adipogenesis, epithelial-mesenchymal transition, epithelial cell hyperplasia, and collagen fibrogenesis. This study mainly aimed to analyze the potential role of adipocyte enhancer binding protein 1 ( AEBP1 ), the ACLP-encoding gene, as a pathological target or prognostic marker for liver fibrosis regardless of etiology. Dysregulation pattern, clinical relevance, and biological significance of AEBP1 gene in liver fibrosis were analyzed using publicly available transcriptomic profiles, different liver fibrosis mouse models, biological databases, and AEBP1 gene silencing followed by RNA sequencing in human hepatic stellate cells (HSCs). AEBP1 gene expression was upregulated and positively correlated with liver fibrogenesis independent of etiology, the protein of which was further verified in liver fibrosis mouse models induced by different pathogenic factors. A higher expression of liver AEBP1 gene had the potential to predict poor prognosis in liver fibrosis. Systematic bioinformatic analyses revealed that AEBP1 expression was HSCs-specific and associated with extracellular matrix (ECM) remodeling and its downstream mechanical–chemical signaling transition. AEBP1 knockdown by specific small interfering RNAs (siRNAs) in HSCs inhibited ECM-receptor interaction and immune-related pathways as well as HSC proliferation or activation. A high expression of AEBP1 was specifically associated with liver fibrosis and was related to a poor prognosis and predicted the role of AEBP1 in HSCs, providing a new insight for understanding AEBP1 in liver fibrosis.

Abstract Background Non-alcoholic steatohepatitis (NASH) had not yet been approved therapy. Electro-acupuncture (EA) has been reported to have potential efficacy. However, high-quality clinical evidence was still lacking. Methods NASH patients were randomized and allocated to either sham acupuncture (SA) or EA group in a 1:1 ratio, with the patient blinded. Each patient received 36 sessions of SA or EA treatment over 12 weeks, followed by additional 4 weeks. The primary outcome was the changes in relative liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Results A total of 60 patients were enrolled. From baseline to week 12, the reduction of relative liver fat content measured by MRI-PDFF in the EA group (− 33.6%, quantile range: − 52.9%, − 22.7%) was significantly more significant than that in the SA group (− 15.8%, quantile range: − 36.1%, − 2.7%) (p = 0.022). Furthermore, the EA group had more patients who achieved MRI-PDFF to 30% reduction at week 12 (53.3% vs. 25.9%, p = 0.035). EA treatment also significantly reduced body weight (− 3.0 vs. + 0.1 kg, p = 0.034) and BMI (− 1.5 vs. − 0.2 kg/m2, p = 0.013) at week 16. Except for AST (− 27.4 vs. − 16.2 U/L, p = 0.015), other biochemical varieties, including ALT, fasting-glucose, cholesterol, and triglyceride, showed no statistically significant difference. Both groups measured no significant changes in liver stiffness by magnetic resonance elastography (MRE). There were no serious adverse events in either group. Conclusions Twelve weeks of EA effectively and safely reduces relative liver fat content in NASH patients. Further multicenter randomized controlled studies are needed. Trial registration Chinese Clinical Trial Registry, ChiCTR2100046617. Registered 23 May 2021, http://www.chictr.org.cn/edit.aspx?pid=127023&htm=4

In this study we aimed to assess the clinicopathological characteristics and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) having distinct steatosis distribution patterns. Clinicopathological data of 238 individuals with biopsy-confirmed NAFLD were collected. Nonalcoholic steatohepatitis-clinical research network (NASH-CRN) and steatosis, activity and fibrosis (SAF)/fatty liver inhibition of progression (FLIP) algorithm were used. Cumulative incidence of liver-related events (LREs) was compared by Kaplan–Meier analysis. Univariate and multivariate logistic regression analyses were used to identify independent predictors for steatosis distribution. Eligible patients were categorized into three groups based on their steatosis distribution, including azonal steatosis (AS) (62 [26.1%]), perivenular steatosis (PVS) (147 [61.8%]), and the pan-acinar steatosis (PAS) groups (29 [12.1%]). There were significantly higher ballooning grade and disease activity ( P  < 0.05), more severe fibrosis ( P  < 0.001), and a higher cumulative incidence of LREs (hazard ratio [HR] 8.0, 95% confidence interval [CI] 2.34–27.35, P  < 0.0001) in the AS group than in the PVS and PAS groups after a median of 3.6-year follow-up. Multivariate logistic regression analysis revealed age (odds ratio [OR] 1.11, 95% CI 1.06–1.16, P  < 0.001) might be independently associated with AS distribution, and PNPLA3 rs738409 CG/GG genotype (OR 3.36, 95% CI 0.98–11.47, P  = 0.053) might also play a role. AS is associated with more severe disease activity and fibrosis stage in NAFLD, and predisposes toward poor prognosis. Age might be an independent predictor for AS in NAFLD, while PNPLA3 rs738409 CG/GG genotype might also play a role.

Objectives In this study we aimed to assess the clinicopathological characteristics and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) having distinct steatosis distribution patterns.Methods Clinicopathological data of 238 individuals with biopsy-confirmed NAFLD were collected. Nonalcoholic steatohepatitis-clinical research network (NASH-CRN) and steatosis, activity and fibrosis (SAF)/fatty liver inhibition of progression (FLIP) algorithm were used. Cumulative incidence of liver-related events (LREs) was compared by Kaplan-Meier analysis. Univariate and multivariate logistic regression analyses were used to identify independent predictors for steatosis distribution.Results Eligible patients were categorized into three groups based on their steatosis distribution, including azonal steatosis (AS) (62 [26.1%]), perivenular steatosis (PVS) (147 [61.8%]), and the pan-acinar steatosis (PAS) groups (29 [12.1%]). There were significantly higher ballooning grade and disease activity (P < 0.05), more severe fibrosis (P < 0.001), and a higher cumulative incidence of LREs (hazard ratio [HR] 8.0, 95% confidence interval [CI] 2.34-27.35, P < 0.0001) in the AS group than in the PVS and PAS groups after a median of 3.6-year follow-up. Multivariate logistic regression analysis revealed age (odds ratio [OR] 1.11, 95% CI 1.06-1.16, P < 0.001) might be independently associated with AS distribution, and PNPLA3 rs738409 CG/GG genotype (OR 3.36, 95% CI 0.98-11.47, P = 0.053) might also play a role.Conclusions AS is associated with more severe disease activity and fibrosis stage in NAFLD, and predisposes toward poor prognosis. Age might be an independent predictor for AS in NAFLD, while PNPLA3 rs738409 CG/GG genotype might also play a role.