BACKGROUND: The role of serum biomarkers in the surveillance of hepatocellular carcinoma (HCC) is controversial. OBJECTIVE: We assessed the diagnostic performances of alpha-fetoprotein (AFP) and protein-induced by vitamin-K-absence/antagonist-II (PIV

BACKGROUND: The time-related variability of HCC biomarkers has not been investigated so far. OBJECTIVE: To assess the changes of alpha-fetoprotein (AFP) and protein induced by vitamin-K absence/antagonist-II (PIVKA-II) in patients with HCC (HCC+) as compared to patients without HCC (HCC-). METHODS: AFP and PIVKA-II were measured by a single laboratory using an automated chemiluminescent-enzyme-immunoassay (Fujirebio Inc., Tokyo, Japan) in 1163 sera of 418 cirrhotics (31.1% HBV, 58.6% HCV, 10.3% non-viral etiology) undergoing ultrasound HCC surveillance. The mean (range) number of effective time-points available for analysis was 2.8 (2.0 to 3.0); 124 patients with HCC were matched with 294 who remained HCC free for at least 12 months after the last specimen. AFP and PIVKA-II changes were estimated over time by means of a random-effect generalized least squares (RE-GLS) regression model under the missingness at random assumption. RESULTS: Patients with and without HCC had comparable chronic liver disease etiology and staging. AFP/PIVKA-II median (25th; 75th percentile) values at the latest time-point were 4.2 (2.6; 8.6) ng/mL/32 (25; 42) mAU/mL in HCC- and 8.4 (4.4; 32.1) ng/mL/66 (32; 192) mAU/mL in HCC+ (p< 0.001). Log10AFP and log10PIVKA-II time-changes differed in HCC+ and HCC- patients. In HCC+ patients, both log10AFP and log10PIVKA-II showed an increasing trend over time. In HCC- patients, log10PIVKA-II variations were minimal as compared to log10AFP variations. The percent increase of log10AFP at 6 months vs. baseline was 11% (95%CI 5 to 17%) and 5% (95%CI 1 to 8%) for log10PIVKA-II in HCC+vs. HCC- patients. CONCLUSIONS: The present retrospective study of the biological variability of AFP and PIVKA-II suggests that their time-related changes may serve as potential predictors of HCC. This topic needs to be addressed by longitudinal studies.

Aims: Insulin resistance (IR) plays a pivotal role in the pathogenesis of Metabolic dysfunction‐Associated Fatty Liver Disease (MAFLD), which can progress to liver fibrosis. We examined the relationship of different IR scores with markers of MAFLD severity in obese individuals.Materials and Methods: In this retrospective observational study, 346 non‐diabetic, overweight/obese individuals with newly diagnosed MAFLD (age 50.2 ± 13.3 years, 34% females, BMI 30.8 ± 4.4 kg/m²) underwent liver stiffness (LS) and controlled attenuation parameter (CAP) measurements by Fibroscan® to assess liver fibrosis and steatosis. Biochemical data were collected to calculate surrogate markers of IR (Homoeostasis model assessment ‐ insulin resistance index [HOMA‐IR], triglyceride‐glucose index, triglyceride by HDL ratio), liver fibrosis (Nonalcoholic Fatty Liver Diseases fibrosis score, fibrosis‐4 score, Aspartate aminotransferase to platelet ratio index) and steatosis (fatty liver index, hepatic steatosis index).Results: All three IR scores were associated with CAP, while only HOMA‐IR positively correlated with LS (r = 0.275, p < 0.0001), independent of age and sex, BMI, transaminases, and fibrosis markers. Insulin‐resistant individuals (HOMA‐IR >2.5, n = 165) had higher liver enzymes, CAP and LS, with a 4‐fold increased risk of severe liver disease (LS >9.7 kPa, OR 4.42[1.95–10.01], p = 0.0002). Among HOMA‐IR components, fasting plasma insulin (FPI) was independently associated with LS (r = 0.270, p < 0.0001). ROC AUC for HOMA‐IR and FPI to predict severe liver disease were virtually identical (0.748 and 0.758, respectively).Conclusions: HOMA‐IR is independently associated with non‐invasive markers of MAFLD severity in overweight/obese individuals. This relationship is largely mediated by hyperinsulinemia, regardless of BMI. Measuring insulin levels in MAFLD individuals might be useful to identify those at risk of liver fibrosis.

Optimal scoring system for clinical prognostic factors in patients with unresectable hepatocellular carcinoma (HCC) is currently uncertain. We aimed to develop and externally validate an easy to use tool, particularly for this population, and named it the “unresectable hepatocellular carcinoma prognostic index” (UHPI). We evaluated the data of patients with treatment‐naive unresectable HCC who were diagnosed in the training center from 2010 to 2019 (n = 209). A simple prognostic model was developed by assigning points for each covariate in proportion to the beta coefficients in the Cox multivariable model. Predictive performance and distinction ability of the UHPI were further evaluated in an independent European validation cohort (n = 147) and compared with 11 other available models. A simple scoring system was derived, assigning 0.5/1/2 scores for six independent covariates including, the Child‐Pugh score, Eastern Cooperative Oncology Group performance status, maximum tumor size, vascular invasion or extrahepatic metastasis, lymph node involvement, and alpha‐fetoprotein. The UHPI score, ranging from 0 to 6, showed superior performance in prognosis prediction and outperformed 11 other staging or prognostic models, giving the highest homogeneity (c‐index, 6‐month and 1‐year area under the receiver operator characteristic curves), lowest Akaike information criterion, and –2 log‐likelihood ratio values. The UHPI score allocated well the risk of patients with unresectable HCC for mortality within the first year, using two cut‐off values (low‐risk, 2). Conclusion: The UHPI score can predict prognosis better than other systems in subjects with unresectable HCC and can be used in clinical practice or trials to estimate the 6‐month and 1‐year survival probabilities for this group.