Export Background: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC). Aims: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound. Methods: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively. Results: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5–0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3–6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2–47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85–8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95–12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27–5.08). Conclusions: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3–6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels.

Chronic liver disease (CLD) and cirrhosis are leading contributors to global morbidity and mortality, with hepatocellular carcinoma (HCC) frequently arising in patients with advanced liver damage. This review explores the interplay between immune dysfunction and the progression of cirrhosis to HCC, emphasizing the pivotal role of immune status in HCC pathogenesis. Chronic inflammation, cirrhosis-associated immune dysfunction syndrome (CAIDS), and immunosenescence create a permissive environment for tumorigenesis by impairing immune surveillance and promoting hepatocyte stress. Key mechanisms include T cell exhaustion, dysregulated cytokine signaling, and gut-liver axis dysfunction, which collectively drive malignant transformation. Emerging immune biomarkers, such as PD-1/PD-L1, LAG-3, TIGIT, and soluble CD14/CD163, offer promise for refining HCC risk stratification and improving early detection. Integrating these biomarkers into existing surveillance protocols could enhance screening efficacy, particularly in high-risk populations such as the elderly and immunocompromised. Current guidelines recommend biannual ultrasound and alpha-fetoprotein testing for cirrhotic patients, but adherence remains suboptimal, and late diagnoses are common. A personalized approach combining clinical risk factors, immune markers, and patient demographics may improve surveillance outcomes. Future research should focus on validating immune biomarkers in large cohorts, exploring novel therapeutic targets like LAG-3 and TIGIT, and developing tools to quantify immune dysfunction for risk stratification. By addressing immune dysregulation as a critical factor in HCC development, this review highlights the potential for improved HCC screening adherence and early detection for better patient outcomes through immune-based strategies.

Autoimmune hepatitis (AIH) is an immune-mediated liver condition marked by progressive inflammation, piecemeal necrosis, and eventual cirrhosis. Prednisone has long served as the foundational AIH therapy. However, its prolonged use warrants closer evaluation regarding long-term outcomes. Among cirrhotic patients, the combination of chronic inflammatory and tumor-promoting changes may synergize to compromise immunity increasing susceptibility to hepatocellular carcinoma (HCC). In this context, adding immunosuppressive burden of corticosteroids may influence cancer risk in ways not well investigated. We investigated the effect of dose-dependent prednisone exposure on HCC risk in AIH-cirrhosis patients. We conducted a retrospective analysis of 121 adults with AIH-cirrhosis evaluated at Cedars-Sinai. Patients were categorized based on prednisone exposure: (≥7.5 mg/day for ≥6 months following cirrhosis diagnosis) exposure vs subthreshold exposure (with or without alternative therapies). The primary outcome was the HCC incidence rate and hazard ratio derived from Cox proportional hazards models. Secondary outcomes included HCC incidence using multivariable models adjusted per demographics and disease severity. In unadjusted time-to-event analysis, prednisone use shortened HCC-free survival, the results indicated HCC developed in 25.4% of the prednisone group vs 9.7% of controls (P = .030). Multivariable analysis adjusted per age, gender, ethnicity, Child-Turcotte-Pugh, and alpha-fetoprotein confirmed prednisone as an independent risk factor (adjusted hazard ratio: 3.36; P = .040). The study findings suggested that prolonged prednisone exposure in patients with AIH-cirrhosis independently contributes to HCC development. This association appears to be supported by mechanistic pathways, driven by prednisone's dose-dependent immunosuppressive and metabolic effects, disrupting immune surveillance, promoting hepatic fibrosis, and oncogenic pathways.

INTRODUCTION: Several emerging modalities are available for hepatocellular carcinoma (HCC) surveillance; however, patient preferences for surveillance tests—particularly across key subgroups such as race/ethnicity, income, and education level—are poorly characterized. METHODS: We conducted a choice-based conjoint survey among patients with cirrhosis and chronic hepatitis B undergoing HCC surveillance (from 2022 to 2024) at 7 centers in the United States. Participants were presented with 15 scenarios, where they chose between surveillance modalities based on test attributes. RESULTS: We included 649 patients, with a median age of 60 years, 51% male, 60% White, 10% Black, and 20% Hispanic. The cohort reflected substantial socioeconomic variation including 12% with Medicaid and 38% with Medicare. The highest priority attribute was surveillance benefits (42.9%; 95% confidence interval [CI] 40.6%–45.1%), followed by financial harms (19.4%; 95% CI 18.1%–20.7%). Patients placed less priority on test logistics (12.3%; 95% CI 11.5%–13.2%), test location (9.2%; 95% CI 8.5%–10.0%), test duration (8.3%; 95% CI 7.8%–8.7%), and physical harms (7.9%; 95% CI 7.2%–8.6%). In subgroup analyses, Black participants placed significantly lower importance on surveillance benefits and higher importance on financial harms ( P < 0.001) and test duration ( P = 0.001) compared with White participants. Hispanic participants also prioritized financial harms more than non-Hispanic participants ( P < 0.001), a pattern consistent with cost-related concerns seen across other lower socioeconomic status (SES) subgroups. Lower SES individuals with below a high school education ( P = 0.01), Medicaid insurance ( P = 0.001), and income below $25,000 ( P < 0.001) assigned greater importance to financial harms and less to surveillance benefits. DISCUSSION: Patients with undergoing HCC surveillance prioritize surveillance test sensitivity; however, results vary by race, ethnicity, and SES. Improving access by reducing financial and logistical barriers through shared decision-making may enhance surveillance, particularly when modalities present with similar effectiveness.

Chronic inflammation is an established driver of tumorigenesis across multiple organs, including the liver. Yet, the precise mechanisms linking persistent inflammatory signaling to tumorigenesis remain unclear. While classic tumor immunology focuses on immune-mediated tumor eradication, in hepatocellular carcinoma (HCC), growing evidence highlights a paradoxical immune capacity to foster malignant growth. HCC is a major health burden, most often arising in the setting of chronic inflammatory liver disease and cirrhosis. Nonetheless, some HCC cases occur in patients lacking cirrhosis or its traditional triggers, underscoring gaps in our mechanistic understanding. The immune system orchestrates a highly regulated defense network; however, neoplastic cells can subvert this network by sculpting an immune-modulating milieu that mimics protective inflammation while promoting tumor survival and expansion. In HCC, immune influences are bidirectional and stage dependent. As liver disease evolves to cirrhosis, the interplay among the inflammatory response, immune response, cirrhosis-associated immune dysfunction syndrome, and the tumor microenvironment becomes increasingly intricate. This review delineates these overlapping but distinct processes, dissects their individual contributions to HCC pathogenesis, and highlights immune-cell compositional changes across disease stages. We contrast protective immune-inflammatory responses that contain early chronic liver injury with the pro-tumorigenic environment characteristic of cirrhosis. Finally, we propose that mapping stage-specific biomarker signatures could transform inflammatory staging into a precision modality, informing immune-based prevention strategies and guiding individualized systemic therapies for HCC.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer death, and existing HCC risk stratification models in cirrhosis poorly identify patients at the highest risk. We evaluated whether baseline antinuclear antibody (ANA) status is independently associated with incident HCC and whether adding ANA improves risk prediction. We conducted a single-center, retrospective cohort of adults (age ≥18 years) with established cirrhosis and clinically obtained ANA testing within 12 months of cirrhosis diagnosis. Follow-up began at the cirrhosis index date; the primary outcome was incident HCC. Associations were assessed using cause-specific Cox models with prespecified clinical covariates. We compared discrimination for a clinical model with and without ANA and performed inverse-probability–weighted and immunologic (IgG/neutrophil-to-lymphocyte ratio) sensitivity analyses in complete cases. Among 1,023 participants [mean age 53.7 years (SD 10.9); 57% male], 102 developed incident HCC over a median 4.7 years of follow-up. HCC incidence was lower in ANA-positive versus ANA-negative patients (1.10 vs. 3.73 per 100 person-years; log-rank P < 0.001). ANA positivity was associated with lower HCC risk in multivariable models (HR, 0.32; 95% CI, 0.20–0.52). Adding ANA improved discrimination (C-index 0.727–0.750) and model fit (likelihood-ratio P < 0.001). Findings were consistent in weighted and laboratory-complete sensitivity analyses. In cirrhosis, baseline ANA positivity is independently associated with lower incident HCC risk and provides incremental prognostic information beyond routine clinical factors. Prospective validation and mechanistic studies are warranted. Significance: Natural autoantibodies (ANA) are routinely measured, inexpensive, and widely accessible, yet their prognostic value in cirrhosis is not used for HCC risk stratification. In this retrospective cohort, baseline ANA positivity was independently associated with lower incident HCC risk and improved model discrimination beyond clinical factors. These findings support repurposing a common clinical test to refine individualized surveillance intensity and motivate prospective validation and mechanistic studies.