Natural Autoantibodies Negatively Correlate with Hepatocellular Carcinoma Incidence in Cirrhosis.

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.