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Globally, hepatocellular carcinoma (HCC) is a major cause of cancer-related death and a leading cause of morbidity and mortality in patients with chronic liver disease and cirrhosis. The predominant cause of HCC is shifting from viral to nonviral causes, in parallel with the high global prevalence of nonalcoholic fatty liver disease and increasing alcohol consumption in many countries. There have been promising recent advances in the treatment of all stages of HCC; however, improvements in early detection, increased utilization of HCC surveillance, and equitable access to HCC therapies are needed to curb increases in HCC mortality., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions. Early detection can identify at-risk patients who can be linked to hepatology care. The vibration-controlled transient elastography (VCTE) controlled attenuation parameter (CAP) is biopsy validated to diagnose hepatic steatosis (HS). We aimed to develop a novel clinical predictive algorithm for HS using the CAP score at a Veterans' Affairs hospital., Methods: We identified 403 patients in the Greater Los Angeles VA Healthcare System with valid VCTEs during 1/2018-6/2020. Patients with alcohol-associated liver disease, genotype 3 hepatitis C, any malignancies, or liver transplantation were excluded. Linear regression was used to identify predictors of NAFLD. To identify a CAP threshold for HS detection, receiver operating characteristic analysis was applied using liver biopsy, MRI, and ultrasound as the gold standards., Results: The cohort was racially/ethnically diverse (26% Black/African American; 20% Hispanic). Significant positive predictors of elevated CAP score included diabetes, cholesterol, triglycerides, BMI, and self-identifying as Hispanic. Our predictions of CAP scores using this model strongly correlated (r = 0.61, p < 0.001) with actual CAP scores. The NAFLD model was validated in an independent Veteran cohort and yielded a sensitivity of 82% and specificity 83% (p < 0.001, 95% CI 0.46-0.81%). The estimated optimal CAP for our population cut-off was 273.5 dB/m, resulting in AUC = 75.5% (95% CI 70.7-80.3%)., Conclusion: Our HS predictive algorithm can identify at-risk Veterans for NAFLD to further risk stratify them by non-invasive tests and link them to sub-specialty care. Given the biased referral pattern for VCTEs, future work will need to address its applicability in non-specialty clinics. Proposed clinical algorithm to identify patients at-risk for NAFLD prior to fibrosis staging in Veteran., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background & Aims: Texas has the highest age-adjusted incidence rate of hepatocellular carcinoma (HCC) in the United States. The Cancer Prevention and Research Institute of Texas has funded the Texas Collaborative Center for Hepatocellular Cancer (TeCH) to facilitate HCC research, education, and advocacy activities with the overall goal of reducing HCC mortality in Texas through coordination, collaboration, and advocacy., Methods: On September 17, 2022, TeCH co-sponsored a multi-stakeholder conference on HCC with the Baker Institute Center for Health and Biosciences. This conference was attended by HCC researchers, policy makers, payers, members from pharmaceutical industry and patient advocacy groups in and outside of Texas. This report summarizes the results of the conference., Results: The goal of this meeting was to identify different strategies for preventing HCC and evaluate their readiness for implementation., Conclusions: We call for a statewide (1) viral hepatitis elimination program; (2) program to increase nonalcoholic steatohepatitis and obesity awareness; (3) research program to develop health care models that integrate alcohol associated liver disease treatment and treatment for alcohol use disorder; and (4) demonstration projects to evaluate the effectiveness of identifying and linking patient with advanced fibrosis and cirrhosis to clinical care., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: Cirrhosis is the most important risk factor of hepatocellular carcinoma (HCC), and patients with cirrhosis are recommended to receive semiannual surveillance for early HCC detection. However, early cirrhosis is often asymptomatic and can go undiagnosed for years, leading to underuse of HCC surveillance in clinical practice. We characterized the frequency and associated factors of unrecognized cirrhosis in a national sample of patients with HCC from the United States., Methods: HCC patients aged 68 years and older, diagnosed during 2011 to 2015 were included from the SEERMedicare Linked Database. If cirrhosis was diagnosed within 6 months immediately preceding HCC diagnosis or after HCC diagnosis, cases were categorized as unrecognized cirrhosis. Factors associated with unrecognized cirrhosis were identified using logistic regression analyses. Factors associated with overall survival were evaluated using Cox regression analyses., Results: Among 5,098 HCC patients, 74.8% patients had cirrhosis. Among those with cirrhosis, 57.4% had unrecognized cirrhosis, with the highest proportion (76.3%) among those with NAFLD-related HCC. Male sex (aOR: 2.12, 95% CI: 1.83-2.46), non-Hispanic Black race (aOR: 1.93, 95% CI: 1.45-2.57), and NAFLD etiology (aOR: 4.46, 95% CI: 3.68-5.41) were associated with having unrecognized cirrhosis. Among NAFLD-related HCC patients, male sex (aOR: 2.32, 95% CI: 1.71-3.14) was associated with unrecognized cirrhosis. Unrecognized cirrhosis was independently associated with worse overall survival (aHR: 1.17, 95% CI: 1.08-1.27) compared to recognized cirrhosis., Conclusion: Unrecognized cirrhosis is common in NAFLD-related HCC, particularly among male and Black patients, highlighting these groups as important intervention targets to improve HCC surveillance uptake and outcomes.

Background & Aims: The extent to which nonalcoholic fatty liver disease (NAFLD) contributes to hepatocellular carcinoma (HCC) prevalence in contemporary practices and whether there are any etiologic differences in surveillance receipt, tumor stage, and overall survival (OS) remain unclear. We aimed to estimate the burden of NAFLD-related HCC and magnitude of associations with surveillance receipt, clinical presentation, and outcomes in a contemporary HCC cohort., Methods: In a cohort of HCC patients from the Surveillance, Epidemiology and End Results-Medicare database between 2011 and 2015, we used multivariable logistic regression to identify factors associated with surveillance receipt, early-stage tumor detection, and curative treatment. Cox regression was used to identify factors associated with OS., Results: Among 5098 HCC patients, NAFLD was the leading etiology, accounting for 1813 cases (35.6%). Compared with those with hepatitis C-related HCC, NAFLD was associated with lower HCC surveillance receipt (adjusted odds ratio, 0.22; 95% confidence interval [CI], 0.17-0.28), lower early-stage HCC detection (adjusted odds ratio, 0.49; 95% CI, 0.40-0.60), and modestly worse OS (adjusted hazard ratio, 1.20; 95% CI, 1.09-1.32). NAFLD subgroup analysis showed that early-stage HCC, absence of ascites/hepatic encephalopathy, surveillance, and curative treatment receipt were associated with improved OS. NAFLD patients with coexisting liver disease were more likely to have surveillance, early-stage detection, curative treatment, and improved OS than NAFLD patients without coexisting liver diseases., Conclusions: NAFLD is the leading etiology of HCC among Medicare beneficiaries. Compared with other etiologies, NAFLD was associated with lower HCC surveillance receipt, early-stage detection, and modestly poorer survival. Multifaceted interventions for improving surveillance uptake are needed to improve prognosis of patients with NAFLD-related HCC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Identifying patients in whom ultrasound may be inadequate to exclude the presence of hepatocellular carcinoma (HCC) can inform interventions to improve screening effectiveness. We aimed to characterize correlates of suboptimal ultrasound quality and changes in ultrasound quality over time in patients with cirrhosis undergoing HCC screening., Methods: We performed a retrospective cohort study of patients with cirrhosis who underwent ultrasound examination at 2 large health systems between July 2016 and July 2019. Exam adequacy was graded by radiologists using the LI-RADS Visualization Score (A, B, C); we evaluated changes in visualization over time among patients with >1 ultrasound exams. We performed multivariable logistic regression to identify characteristics associated with limited ultrasound visualization (scores B or C)., Results: Of 2053 cirrhosis patients, 1685 (82.1%) had ultrasounds with score A, 262 (12.8%) had score B, and 106 (5.2%) had score C. Limited visualization was associated with alcohol-related or nonalcoholic fatty liver disease cirrhosis and presence of class II-III obesity. Among 1546 patients with >1 ultrasounds, 1129 (73.0%) had the same visualization score on follow-up (1046 score A, 60 score B, 23 score C). However, 255 (19.6%) of 1301 with score A at baseline had limited visualization when repeated (230 score B, 25 score C), and 130 (53.1%) of 245 patients with baseline limited visualization had good visualization when repeated., Conclusions: Nearly 1 in 5 patients with cirrhosis had moderately-severely limited ultrasound visualization for HCC nodules, particularly those with obesity or alcohol-related or nonalcoholic fatty liver disease cirrhosis. Ultrasound quality can change between exams, including improvement in many patients with limited visualization., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression., Methods: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122)., Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients., Conclusion: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Competing Interests: MN has been on the advisory board for 89BIO, Gilead, Intercept, Pfizer, Novartis, Novo Nordisk, Allergan, Blade, EchoSens, Fractyl, Terns, OWL, Siemens, Roche Diagnostic, and Abbott; has received research support from Allergan, Bristol Myers Squibb, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Pfizer, Madrigal, Novartis, Shire, Viking’ and Zydus; and is a minor shareholder or has stocks in Anaetos, Rivus Pharma, and Viking. FK reports grants from Merck and Gilead. AGS has been on advisory boards and served as a consultant for Wako Diagnostics, Roche, Exact Sciences, Glycotest, Bayer, Eisai, Exelixis, Bristol Myers Squibb, AstraZeneca, Genentech, and TARGET-RWE. NER declared no competing interests.

Background: Despite an increasing burden of nonalcoholic steatohepatitis (NASH), limited data are available comparing outcomes of NASH-related hepatocellular carcinoma (HCC) versus other etiologies., Methods: Patient demographic and tumor characteristics were collected for 1,051 patients diagnosed with NASH-, alcohol-related liver disease (ALD)-, hepatitis C virus (HCV)-, and hepatitis B virus (HBV)-related HCC at 2 large health systems from January 2008 through December 2016. Patient demographics, clinical characteristics, and survival were compared. Risk-adjusted treatment receipt and overall survival (OS) were examined using multivariable analysis., Results: A total of 92 patients with NASH-related HCC were compared with 153 patients with ALD-, 719 with HCV-, and 87 with HBV-related HCC. Patients with NASH were older, more likely female, and more likely Hispanic white. Patients with NASH and HBV had more compensated liver disease than those with ALD or HCV, including significantly higher proportions having noncirrhotic HCC. Despite similar surveillance receipt and Barcelona Clinic Liver Cancer (BCLC) tumor stage at diagnosis, patients with NASH had higher rates of curative-intent therapy than those with other diseases. Unadjusted median OS was 16 months for NASH, 15 months for ALD, 14 months for HCV, and 8 months for HBV. In multivariable analysis, NASH was associated with worse OS compared with ALD (hazard ratio, 1.92; 95% CI, 1.3-2.5), but there was no difference between NASH- and HCV- or HBV-related HCC., Conclusions: Patients with NASH-related HCC present with more preserved liver function, including a higher proportion having noncirrhotic HCC, than other diseases. Despite patients having similar tumor stage at diagnosis, NASH is independently associated with worse survival compared with ALD, but similar survival compared with HCV and HBV.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting 75-100 million Americans. However, the disease burden may not be equally distributed among races or ethnicities. We conducted a systematic review and meta-analysis to characterize racial and ethnic disparities in NAFLD prevalence, severity, and prognosis., Methods: We searched MEDLINE, EMBASE, and Cochrane databases through August 2016 for studies that reported NAFLD prevalence in population-based or high-risk cohorts, NAFLD severity including presence of nonalcoholic steatohepatitis (NASH) and significant fibrosis, and NAFLD prognosis including development of cirrhosis complications and mortality. Pooled relative risks, according to race and ethnicity, were calculated for each outcome using the DerSimonian and Laird method for a random-effects model., Results: We identified 34 studies comprising 368,569 unique patients that characterized disparities in NAFLD prevalence, severity, or prognosis. NAFLD prevalence was highest in Hispanics, intermediate in Whites, and lowest in Blacks, although differences between groups were smaller in high-risk cohorts (range 47.6%-55.5%) than population-based cohorts (range, 13.0%-22.9%). Among patients with NAFLD, risk of NASH was higher in Hispanics (relative risk, 1.09; 95% CI, 0.98-1.21) and lower in Blacks (relative risk, 0.72; 95% CI, 0.60-0.87) than Whites. However, the proportion of patients with significant fibrosis did not significantly differ among racial or ethnic groups. Data were limited and discordant on racial or ethnic disparities in outcomes of patients with NAFLD., Conclusions: In a systematic review and meta-analysis, we found significant racial and ethnic disparities in NAFLD prevalence and severity in the United States, with the highest burden in Hispanics and lowest burden in Blacks. However, data are discordant on racial or ethnic differences in outcomes of patients with NAFLD., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)