BACKGROUND:Treatment algorithms for hepatocellular carcinoma (HCC) account for tumor burden/stage and severity of liver disease. There are conflicting data on the differential benefit of curative versus non-curative treatments based on BCLC stage. Therefore, we sought to leverage a nationally representative sample of patients in the Veterans Health Administration (VHA) to address this question. METHODS:We performed a retrospective cohort study of patients with cirrhosis and HCC in the VHA. We conducted a landmark analysis and fit survival models, censored at 3 years, to evaluate the association of treatment type based on the highest level (non-curative vs. curative vs. combination), stratified by BCLC stage, for patients with early-stage to intermediate-stage HCC. RESULTS:We evaluated 1191 patients with confirmed HCC (535 received only non-curative treatment, 227 only curative, and 429 received a combination of curative and non-curative). Among BCLC-0 patients, patients who received curative-intent therapy had significantly better survival at all time points compared with patients receiving non-curative treatment only (HR ranging from 0.53 at 6 months to 0.77 at 3 years). In contrast, for patients with BCLC-A stage disease, receiving either curative treatment alone or combination therapy was associated with significantly better survival compared with non-curative treatment (HR ranged from 0.41 to 0.76 over the study period). However, for BCLC-B stage disease, only combination therapy had significantly better survival (HR 0.44 at 6 months to 0.65 at 3 years). CONCLUSIONS:Our real-world data demonstrate that among patients with early-stage to intermediate-stage HCC, curative-intent treatment is associated with the best survival for patients with BCLC-0 and BCLC-A stage disease, while combination therapy yields the best outcomes in patients with BCLC-B stage disease.

Introduction and Objectives: Steatotic liver disease (SLD) includes metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and their intersection (MetALD). SLD subtype classification may change over time; however, the impact of these transitions on major adverse liver outcomes (MALO) is unknown. Materials and Methods: We conducted a retrospective study of adults with imaging-confirmed steatosis (n=270,302) in the Veterans Health Administration (2010-2021). The primary exposure was change in SLD subtype classification between cohort entry (steatosis on imaging) and a 2-year landmark. The primary outcome was incident MALO (cirrhosis, decompensation, HCC, transplant, liver-related death). We calculated incidence rates per 100 person-years and multivariable cause-specific Cox regression models to examine the magnitud of the association between changes in SLD subtype and subsequent MALO. Results: At the 2-year landmark, 8.2% of those with baseline MASLD were reclassified to MetALD or ALD, 34.2% of those with baseline MetALD were reclassified to MASLD or ALD, and 64.0% of those with baseline ALD were reclassified to MASLD or MetALD. Among baseline MASLD, the risk of MALO was higher for those reclassified to MetALD (HR 1.55;95% CI 1.40-1.71) or ALD (HR 2.13;95% CI 1.66-2.74) compared with those who remained MASLD. Among baseline MetALD, the risk of MALO was lower for those reclassified to MASLD (HR 0.55;95% CI 0.48-0.64) and higher for those reclassified to ALD (HR 1.80;95% CI 1.58-2.06) compared with those who remained MetALD. Among baseline ALD, the risk of MALO was lower for those reclassified to MASLD (HR 0.31;95% CI 0.21-0.46) or MetALD (HR 0.82;95% CI 0.70-0.96) compared with those who remained ALD. Conclusions: Changes in SLD subtype classification are associated with distinct MALO risks.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has a global prevalence of 25

Background:Though the link between obesity and colorectal cancer (CRC) is convincing, the impact of weight loss after obesity on CRC risk is unknown. Methods:This pooled study from the Multiethnic Cohort, Nurses' Health Study and Health Professionals Follow-Up Study included adults aged 45-75, with 3+ available body mass index (BMI) measures. The primary analysis included persons of all weights, with exposure (BMI) subjected to group-based trajectory modeling. Time-to-incident CRC was evaluated using accelerated failure time models. A subanalysis evaluated the risk of CRC in persons with obesity who had weight loss, compared to persons with stable obesity. Results:A total of 193,046 persons were analyzed (median age 49 years, 66% female). Among persons with severe degrees of obesity who lost weight, there was a longer CRC-free duration in whites (acceleration factor [AF] 2.30, 95% confidence interval [CI] 1.23-4.29; P=0.01), persons of "Other" race (AF 2.54, 95%CI 2.45-2.63; P<0.001), Asian/Native Hawaiian/Other Pacific Islanders (AF 1.11, 95%CI 1.06-1.18; P<0.001), and Black/African Americans (AF 1.09, 95%CI 1.07-1.10; P<0.001). BMI was not associated with altered CRC risk in Hispanic/Latinos. Among 40,606 persons with obesity who had weight loss, higher degrees of weight loss were associated with a longer CRC-free duration. While weight loss of 5-10% had an AF of 1.14 (95%CI 1.04-1.24; P=0.01), the optimal degree of weight loss was 15-20%, AF 1.53 (95%CI 1.28-1.83; P<0.001). Conclusions:Weight loss after obesity is associated with a lower CRC risk in diverse populations. In persons with obesity, 15-20% weight loss appears to be optimal.

INTRODUCTION: Although metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with increased alcohol intake (MetALD) are identified as clinical entities; tools to identify patients from electronic health records (EHRs) to perform large outcome studies are lacking. METHODS: In this retrospective study of participants from the Veterans Analysis of Liver Disease cohort assembled from 1/1/2013 to 12/31/2022, a rule-based natural language processing (NLP) algorithm searched EHRs for imaging evidence of hepatic steatosis. This was combined with identification of cardiometabolic risk factors and harmful alcohol use. Algorithm-derived diagnoses of MASLD, MetALD, alcohol-associated steatotic liver disease (ALD), and no steatotic liver disease (SLD) were validated using a blinded review of randomly selected charts. RESULTS: Among 817,657 eligible veterans, SLD was present in over half (n = 438,209, 53.5%), including MASLD in 299,259 (36.5%), 99,163 with MetALD (12.1%), and 38,552 (4.7%) with ALD. The NLP algorithm had a high correlation with steatosis on chart review, with a κ of 0.86 (95% CI 0.82–0.90), sensitivity of 0.96, and specificity of 0.90. Classification of MASLD, MetALD, ALD, and no SLD by the algorithm also showed high correlation with chart review, with a κ of 0.87 (95% CI 0.82–0.91). This algorithm identified 299,259 (36.5%) of the study cohort with MASLD, compared with 23,218 patients (2.8%) identified using I nternational Classification of D iseases-9/10 codes. DISCUSSION: An algorithm combining rule-based NLP with cardiometabolic risk factors and alcohol use from EHRs accurately identifies and classifies SLD and can be applied in large epidemiologic studies of SLD in the Veterans Health Administration.

INTRODUCTION Spontaneous bacterial peritonitis (SBP) is a common complication of decompensated cirrhosis with high mortality, and patients may have evidence of concomitant infection in other sources, including the bloodstream and urinary tract.1 The most common isolates from ascitic fluid are gram-negative enteric organisms (primarily Escherichia coli and Klebsiella) due to gut bacterial translocation2,3; however, the microorganism profile of culture data in other sources has not been well studied. Delineating the epidemiology of SBP across infectious sources and patient characteristics is important in identifying high-risk patients, tailoring effective antibiotic regimens, and antibiotic stewardship. We aimed to (1) investigate the distribution of organisms among patients with positive cultures (peritoneal fluid, blood, and urine) in a national cohort of patients with cirrhosis hospitalized with SBP and (2) model the risk of 30-day mortality in patients with positive versus negative cultures. METHODS This was a retrospective cohort study of adult patients with cirrhosis in the Veterans Outcomes and Costs Associated With Liver Diseases cohort4–6 with index hospitalization for SBP between January 2008 and October 2023. SBP was defined by paracentesis-obtained ascites fluid polymorphonuclear leukocyte count >250/mm3 in the hospital or up to 7 days prior to hospitalization as per prior methods.7 Baseline demographic data, body mass index, etiology of cirrhosis, MELD-Na prior to hospitalization, and MELD-Na on hospital presentation were collected. We analyzed culture growth stratified by source (blood, peritoneal, and urine samples) and Child-Pugh-Turcotte (CTP) class. In preparation for modeling of 30-day mortality, culture sources and results were categorized as urine/blood/peritoneal culture−; isolated urine culture+; blood culture+/peritoneal culture−, blood culture−/peritoneal culture+; and blood culture+/peritoneal culture+. A logistic regression model was fit with this primary exposure adjusted for age, sex, body mass index, race, etiology, prehospital MELD-Na, and diabetes (Supplemental Methods, https://links.lww.com/HC9/B891). Data management and statistical analyses were performed using STATA/BE 18.0 (College Station, TX). RESULTS A total of 5176 patients were included from 125 Veterans Health Administration centers; SBP was diagnosed at median hospital day 1 (IQR 0, 3). Patients were predominantly male (98%) and White (62%) with alcohol-associated liver disease (43.7%). On average, there was an increase in median MELD-Na from 16 to 24 at the time of hospitalization (Supplemental Table S1, https://links.lww.com/HC9/B891). Culture data identified organisms in 1748 patients (33.8%), with the majority identified in peritoneal fluid followed by blood and urine. E. coli was the most common organism across all fluid sources (urine 21.2%, blood 22.3%, peritoneal fluid 24.3%; p<0.001). There were significant differences in organism distribution across CTP classes for blood, peritoneal, and urine cultures (each p<0.001; Figure 1A–C). E. coli prevalence increased with liver disease severity in these groups (CTP A 29.9% vs. C 38.8% in blood; 35.2% vs. 39.2% in peritoneal fluid; 28.5% vs. 37.5% in urine), as did Klebsiella (eg, CTP A 15.5% vs. C 28.6% in blood). By contrast, S. aureus prevalence declined with increasing severity of liver disease (CTP A 35.5% vs. C 10.2% in blood; 17.2% vs. 5.4% in peritoneal fluid; 6.9% vs. 0.0% in urine). Enterococcus species were highly prevalent in urine cultures across all CTP classes (range 34.0%–37.5%).FIGURE 1: Distribution of most common organisms by CTP class in (A) blood cultures (B) peritoneal fluid cultures, and (C) urine cultures. Abbreviation: CTP, Child-Pugh-Turcotte.In adjusted analysis, patients who were blood culture+/peritoneal culture+ had a 2.49-fold increased odds of 30-day mortality versus culture− patients (95% CI: 1.92–3.22; Supplemental Table S2, https://links.lww.com/HC9/B891). Patients who were blood culture−/peritoneal culture+ had 1.47-fold increased odds of 30-day mortality versus those who were culture− (95% CI: 1.23–1.77), and patients who were blood culture+/peritoneal culture− had a 1.38-fold increased odds of mortality versus culture− patients (95% CI: 1.12–1.66); all p<0.001. DISCUSSION In this large cohort, there were significant differences in the microbiology of organisms in the blood, peritoneal fluid, and urine of patients with SBP across CTP classes. Higher CTP class was associated with higher rates of E. coli and Klebsiella infections and less S. aureus across all culture sources. The observed differences may reflect microbiome changes and potential differences in susceptibility to infection by selected organisms. Additionally, medication effects may impact the risk of selected microorganism infections. Lactulose and rifaximin, which are used for the treatment of HE, are known to alter the microbiome and increase the colonization of organisms in the gut.8 Prior studies also report that antibiotic overuse, nosocomial infections, and an increase in invasive procedures may shift the infectious landscape of SBP.3,9,10 However, no prior studies have explored the changing epidemiology of microorganisms across liver disease severity and multiple culture data sources. Further studies are needed to build on our findings and investigate the microorganism profile of patients treated for SBP and other infections and to evaluate resistance patterns based on specific antimicrobial exposures. Our study also demonstrated higher odds of 30-day mortality in patients with positive cultures from both blood and peritoneal fluid, followed by positivity in one source or the other, relative to culture-negative patients. It is likely that multiple positive cultures indicate a more disseminated infection in an already vulnerable host with decompensated cirrhosis. This finding provides insight into patient prognosis and supports early identification and aggressive interventions with appropriate antimicrobial therapy for these higher-risk patients. Consistent with our findings, concurrent bacteremia has been associated with poor outcomes in SBP resulting in higher mortality.2 Finally, urine culture positivity did not impact the odds of mortality; asymptomatic bacteriuria is possible in many cases, though similar rates of E. coli and Klebsiella in urine cultures suggest a shared underlying source (ie, gut translocation). Several limitations exist in this study. First, there are external validity limitations given that the Veterans cohort is predominantly male, largely White, and skewed toward HCV and alcohol-associated liver disease. Second, given the retrospective nature of this study, residual confounding is possible. Third, we were not able to explore antibiotic resistance patterns in this cohort or the influence of prior antibiotic exposure on microorganism distributions. These mark important areas of future inquiry. In conclusion, we observed changing distributions of microorganisms from culture data across CTP classes in patients hospitalized with SBP. Patients with positive culture data in both blood and peritoneal cultures had the highest risk of 30-day mortality, underscoring the need for early detection and aggressive management in this high-risk population.

BACKGROUND AND AIMS:Spontaneous bacterial peritonitis (SBP) leads to high rates of acute kidney injury (AKI), hepatorenal syndrome, and mortality. Population-based studies on contemporary SBP epidemiology are needed to inform care. In a large, national cohort of patients diagnosed with SBP and confirmed by ascitic fluid criteria, we characterized ascitic fluid characteristics, in-hospital and 12-month mortality, AKI, and recurrent SBP. APPROACH AND RESULTS:We investigated how individual and bundled quality measures for SBP associated with outcomes after multi-level adjustment for health-system, patient clinical factors, and quality measures. Individual and bundled quality metrics were inpatient antibiotics within 48 hours, i.v. albumin, repeat paracentesis within 48 hours, recognition of SBP, and prophylactic antibiotics upon discharge. Among 4330 patients with newly diagnosed SBP, in-hospital mortality was 15.5%, and 12-month mortality was 56.6%. The incidence of stage 1 AKI was 26.6%, 15.7% for stage 2, and 22.8% for stage 3. The cumulative incidence of recurrent SBP was 10.3%. Guideline-recommended albumin was the only individual metric associated with reduced in-hospital mortality (HR: 0.73, 95% CI: 0.59-0.91). Receipt of a higher number of metrics from the SBP bundle was associated with progressively lower 12-month post-discharge mortality: patients who received 3, 4, and 5 SBP bundle components had 20%, 38%, and 56% lower hazard of mortality, respectively, relative to those receiving 2 or fewer (all p <0.001). The SBP bundle was associated with a lower incidence of stage 3 versus stage 0-2 AKI (OR: 0.66, 95% CI: 0.51-0.86). CONCLUSIONS:Prospective implementation of evidence-based SBP bundles may improve care outcomes and mortality in SBP.

Dissemination of organisms from the gut microbiota is a major contributor to sepsis and critical illness. Patients with cirrhosis are prone to systemic infections and are commonly prescribed the carbohydrate lactulose to manage hepatic encephalopathy (HE) 1 . Commensal metabolism of lactulose is believed to reduce pathobiont colonization through short-chain fatty acid production, but its direct effects on gut pathobionts remain unexplored 2 . Here, we show that lactulose consumption unexpectedly selects for mutations in Escherichia coli lactose (lac) operon regulation, enhancing its metabolic fitness and colonization capacity. This is mediated by selection for constitutive expression of the lac operon through mutations in its regulatory components. Using in vitro systems, murine models, and clinical samples, we demonstrate that these mutations enable E. coli to exploit lactulose as a carbon source, bypassing host carbohydrate metabolism and increasing its intestinal colonization. Despite its long-standing use in HE treatment, we find that lactulose has a paradoxical association with risk of infection hospitalization in patients with cirrhosis in a large epidemiologic study. The emergence of lactulose-adapted E. coli strains could be suppressed by a dietary oligosaccharide that competitively inhibits lactulose uptake. These findings reveal a mechanism by which dietary substrates exert selective pressure on the microbiome, with implications for diet-based strategies to modulate microbial evolution and infection risk.

BACKGROUND & AIMS:Causes of death across steatotic liver disease (SLD) subtypes remain incompletely characterized in routine clinical practice. We aimed to quantify and compare cause-specific mortality in patients with SLD. METHODS:We conducted a retrospective cohort study of adults with imaging-confirmed hepatic steatosis receiving outpatient care in the national Veterans Health Administration (2010-2021). The primary exposure was SLD subtype, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and their intersection (MetALD). The primary outcome was cause-specific mortality, stratified by baseline cirrhosis. RESULTS:Among 366,433 adults (mean age, 60.5 years; 7.7% female; 67.6% non-Hispanic White), 77.9% had MASLD, 17.5% had MetALD, and 4.6% had ALD. Over a median follow-up of 5.4 years, the 10-year cumulative incidences of cardiovascular disease (CVD)- and extrahepatic cancer-related deaths among patients without cirrhosis were 8.1% and 7.5% for MASLD, 7.5% and 7.4% for MetALD, and 8.1% and 7.4% for ALD. Among patients with cirrhosis, the 10-year cumulative incidences of liver- and CVD-related deaths were 9.2% and 17.3% for MASLD, 17.7% and 13.0% for MetALD, and 22.1% and 11.5% for ALD. Compared with non-cirrhotic MASLD (0.04 per 100 person-years), liver-related mortality was higher for MetALD (0.19 per 100 person-years; hazard ratio 3.38; 95% CI 3.02-3.78) and highest for ALD (0.40 per 100 person-years; hazard ratio 6.99; 95% CI 6.08-8.04). This progressive increase persisted in cirrhosis but was less pronounced. CONCLUSIONS:CVD and extrahepatic cancer were leading causes of death across SLD subtypes in the absence of cirrhosis, while liver- and CVD-related deaths predominated in patients with cirrhosis. MetALD and ALD were associated with progressively higher risks of liver-related mortality compared with MASLD. These findings underscore the need for integrated strategies addressing alcohol use, cardiovascular risk, and cancer screening to reduce preventable deaths. IMPACT AND IMPLICATIONS:Causes of death across the steatotic liver disease (SLD) spectrum remain incompletely characterized in routine clinical settings. In this large nationwide cohort study, we evaluated cause-specific mortality in patients with MASLD, MetALD, and ALD. We showed that cardiovascular disease and extrahepatic cancer were the primary causes of death in patients without cirrhosis across SLD subtypes, while liver disease and cardiovascular disease were predominant in those with cirrhosis. Importantly, MetALD and ALD were associated with progressively increasing risks of liver-related mortality compared to MASLD. Our findings highlight the need for integrated care models that simultaneously address cardiovascular risk factors, implement strategies to reduce alcohol consumption, and promote cancer screening to mitigate preventable deaths in SLD.

Importance:Steatotic liver disease is a major cause of advanced liver disease and is associated with increased risks of long-term adverse outcomes. However, estimates in steatotic liver disease subtypes according to the revised nomenclature are limited in population-based cohorts. Objective:To compare the risks of adverse liver outcomes, major adverse cardiovascular events (MACE), and all-cause mortality across steatotic liver disease subtypes. Design, Setting, and Participants:A retrospective cohort study of adults with imaging-confirmed hepatic steatosis receiving outpatient care within the national Veterans Health Administration (2010-2021) was carried out. Data were analyzed from April 2024 to March 2025. Exposures:Steatotic liver disease subtypes, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), or their intersection (MetALD). Main Outcomes and Measures:The primary outcomes were the incidence of adverse liver outcomes (cirrhosis, decompensation, hepatocellular carcinoma, liver transplant, liver-related death), MACE (myocardial infarction, stroke, heart failure, cardiovascular death), and all-cause mortality. Results:Of 341 601 adults (mean [SD] age, 59.5 (13.2) years; 227 954 non-Hispanic White [66.7%]; 27 606 female [8.1%]), 264 192 had MASLD (77.3%), 61 070 had MetALD (17.9%), and 16 339 had ALD (4.8%). Over a median (IQR) follow-up of 5.5 (3.0-8.4) years, compared with MASLD, MetALD had a higher incidence of adverse liver outcomes (1.12 vs 0.61 per 100 person-years; hazard ratio [HR], 1.56; 95% CI, 1.50-1.62) and all-cause mortality (2.74 vs 2.60 per 100 person-years; HR, 1.08; 95% CI, 1.05-1.10), but similar incidence of MACE. ALD had a higher incidence of adverse liver outcomes (1.78 vs 0.61 per 100 person-years; HR, 2.33; 95% CI, 2.20-2.47) and all-cause mortality (3.42 vs 2.60 per 100 person-years; HR, 1.42; 95% CI, 1.36-1.48) than MASLD, but similar incidence of MACE. The incidence of adverse liver outcomes per 100 person-years increased 10-fold with a higher degree of fibrosis (Fibrosis-4 score <1.30 vs >2.67) across MASLD (0.28 vs 3.02), MetALD (0.39 vs 4.31), and ALD (0.61 vs 5.05). Severe alcohol use, alcohol use disorder, and diabetes were the factors most strongly associated with adverse liver outcomes. Conclusions and Relevance:This cohort study found that patients with MetALD and ALD had modestly higher risks of adverse liver outcomes and all-cause mortality than those with MASLD, with similar risks of MACE. Alcohol and fibrosis assessments may help identify patients at increased risk for long-term adverse outcomes.

BACKGROUND:The absence of validated methods to identify cholangiocarcinoma in real-world data has prevented the conduct of pharmacoepidemiologic studies to evaluate determinants of this malignancy and examine the effectiveness of cholangiocarcinoma treatments. OBJECTIVE:To determine the accuracy of International Classification of Diseases for Oncology, Third Edition (ICD-O-3)-based algorithms to identify cholangiocarcinoma and its subtype (intrahepatic or extrahepatic) within US Veterans Health Administration (VA) data. METHODS:We identified patients with cholangiocarcinoma ICD-O-3 diagnosis codes from January 2000-December 2019 in VA data. We developed eight algorithms utilizing ICD-O-3 histology codes for cholangiocarcinoma and further used ICD-O-3 topography codes for location (liver, intrahepatic bile duct, extrahepatic bile duct) plus maximum total bilirubin (≥ 3 mg/dL vs. < 3 mg/dL) within ± 45 days of diagnosis to identify cholangiocarcinoma subtype. Up to 80 patients were randomly selected for each algorithm, and their records were reviewed by two hepatologists. The positive predictive values (PPV) and 95% confidence interval (CI) for each algorithm were estimated. RESULTS:Among 2934 unique patients who met inclusion criteria, 574 were randomly selected for validation. All eight algorithms had high PPV for definite or probable cholangiocarcinoma, ranging from 83.8% (95% CI, 73.8%-91.1%) to 100.0% (95% CI, 95.5%-100.0%). Among three algorithms to identify intrahepatic cholangiocarcinoma, two had PPV ≥ 80% (range: 88.8% [95% CI, 79.7%-94.7%]-91.3% [95% CI, 82.8%-96.4%]). Among five algorithms to identify extrahepatic cholangiocarcinoma, four had PPV ≥ 80% (range: 80.0% [95% CI, 69.6%-88.1%]-94.0% [83.5%-98.7%]). CONCLUSION:These algorithms can be used in future pharmacoepidemiologic studies to evaluate medications associated with intrahepatic or extrahepatic cholangiocarcinoma.

Gallstone disease is a highly prevalent and costly gastrointestinal disease. Yet, genetic variation in susceptibility to gallstone disease and its implication in metabolic regulatory pathways remain to be explored. We report a trans-ancestry genome-wide association meta-analysis of gallstone disease including 88,063 cases and 1,490,087 controls in the UK Biobank, FinnGen, Biobank Japan, and Million Veteran Program. We identified 91 (37 novel) risk loci across the meta-analysis and found replication in statistically compelling signals in the All of Us Research Program. A polygenic risk score constructed from trans-ancestry lead variants was positively associated with liver chemistry and alpha-1-antitrypsin deficiency and negatively associated with total cholesterol and low-density lipoprotein levels among trans-ancestry and European ancestry groups in the Penn Medicine BioBank. Cross-trait colocalization analysis between risk loci and 44 liver, metabolic, renal, and inflammatory traits yielded 350 significant colocalizations as well as 97 significant colocalizations and 65 prioritized genes from expression quantitative trait loci from eight tissues. These findings broaden our understanding of the genetic architecture of gallstone disease.

BACKGROUND:Metabolic-associated steatotic liver disease (MASLD), caused by insulin resistance and the metabolic syndrome, may result in progressive liver fibrosis. Animal studies suggest that dietary content modulates liver fibrosis progression. Our aim was to identify dietary components and food-related behaviors that may be associated with fibrosis progression and liver-related outcomes in a well-characterized human MASLD cohort. METHODS:Patients with MASLD who had completed a detailed Lifestyle Survey, including a semiquantitative Food Frequency Questionnaire in the Veterans Health Administration Million Veteran Program, were included. The primary outcome was liver fibrosis progression using the Fibrosis-4 slope; the secondary outcome was time to cirrhosis by ICD9/10 codes. Key baseline covariates included: race/ethnicity, body mass index, diabetes mellitus, AUDIT-C score, and baseline Fibrosis-4 score. Using bootstrapped Elastic Net regression in R, self-reported food intake and scaled nutrient variables of interest associated with the outcomes were identified and then validated using multivariable Generalized Linear Model and Cox models. RESULTS:A total of 84,024 individuals with MASLD with nutritional data were included in this study. Median age at MASLD diagnosis was 56 years (IQR 49-63). Frequency of consumption of coffee, tea, vegetables (broccoli, spinach/collard greens), legumes, nuts, modest alcohol, white meat, rice/pasta, dairy, and intakes of specific nutrients including nitrate/vitamin K, caffeine, betaine, amino acids, and beta carotene were associated with reduced fibrosis progression. Consumption of white bread, cookies, breakfast cereals, and specific nutrients such as iron (non-heme), B vitamins, and flavanones were all significantly associated with increased fibrosis progression in MASLD (p<0.05). CONCLUSIONS:Dietary choices such as intake of processed foods, high-fructose foods, and refined carbohydrates may be associated with MASLD progression, while intake of vegetables, nuts, whole grains, and caffeine may be protective.