Impact of anthropometric parameters on outcomes in Asians with metabolic dysfunction-associated fatty liver disease.

BACKGROUND: We examined the incidence and predictors of clinical outcomes in metabolic dysfunction-associated fatty liver disease (MAFLD), focusing on anthropometric parameters. METHODS: Adult patients with MAFLD were identified in nationwide databases and a hospital cohort. Primary endpoints were atherosclerotic cardiovascular disease (ASCVD) and advanced fibrosis. Logistic and Cox regression analyses were used to analyse the association between anthropometric parameters and endpoints. RESULTS: In total, 4407 of 15 256 (28.9%) and 6274 of 25 784 subjects (24.3%) had MAFLD in the nationwide database; of these, 403 (9.2%) and 437 (7.0%) subjects were of lean/normal weight, respectively. Compared to the overweight/obese group, the lean/normal weight group had a significantly lower muscle mass (15.0 vs. 18.9 kg) and handgrip strength (31.9 vs. 35.1 kg) and had a higher ASCVD risk (9.0% vs. 6.3% and 15.9% vs. 8.5%; Ps < 0.001). Sarcopenia (odds ratio [OR], 6.66; 95% confidence interval [CI], 1.79-24.80) and handgrip strength (OR, 0.92; 95% CI, 0.86-0.97; Ps = 0.005) were associated with the ASCVD risk in the lean/normal weight group. In a hospital cohort (n = 1363), the ASCVD risk was significantly higher in the lean/normal weight group than in the overweight/obese group (median follow-up, 39.1 months). Muscle mass was inversely correlated with the ASCVD risk (hazard ratio [HR], 0.72; 95% CI, 0.56-0.94), while visceral adiposity was associated with advanced fibrosis (HR, 1.36; 95% CI, 1.10-1.69; Ps < 0.05). CONCLUSIONS: Muscle mass/strength was significantly associated with the ASCVD risk in patients with MAFLD. Visceral adiposity was an independent predictor of advanced fibrosis.

Five-year on-treatment variables-based PPACS model predicts subsequent hepatocellular carcinoma in entecavir/tenofovir-treated patients.

Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long-term potent antiviral therapy, models predicting HCC after 5 years of therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4-fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore, Platelet counts and Prothrombin time at 5 years, Age at baseline and Sex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time-dependent area under the curve of 0.80 (95% confidence interval, 0.75-0.85) at 8-year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (https://ppacs.shinyapps.io/shiny_app_up/).

Diabetic MAFLD is associated with increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis patients.

Metabolic dysfunction-associated fatty liver disease (MAFLD) can coexist with chronic viral hepatitis. MAFLD is a heterogeneous disease because the diagnostic criteria include various metabolic traits. We aimed to identify patients at high risk of poor long-term outcomes based on MAFLD subgroups in chronic viral hepatitis patients. We evaluated 63 273 chronic hepatitis B and C patients. Patient with a fatty liver index ≥30 was defined to have hepatic steatosis. MAFLD was defined as the presence of hepatic steatosis with any one of the following three conditions, overweight/obesity, type 2 diabetes or ≥2 metabolic risk factors. The prevalence of MAFLD was 38.4% (n = 24 290). During a median 8.8-year follow-up, 1839 HCCs and 2258 deaths were documented in MAFLD patients. Among MAFLD patients, diabetes could identify patients at high risk of HCC and mortality, whereas overweight/obesity and metabolic risk factors did not. Compared with non-MAFLD patients, risk of HCC and mortality was significantly higher in diabetic MAFLD patients (adjusted hazard ratio [aHR] = 1.34, 95% confidence interval [CI] = 1.26-1.43 for HCC; aHR = 1.15, 95% CI = 1.08-1.22 for mortality). Risk of HCC and mortality was significantly higher in diabetic MAFLD patients (aHR = 1.40, 95% CI = 1.26-1.55 for HCC; aHR = 1.77, 95% CI = 1.63-1.93 for mortality) compared with non-diabetic MAFLD patients. Diabetic MAFLD is associated with increased risk of HCC and mortality among chronic viral hepatitis patients. Our findings highlight the need for close surveillance and effective treatment for these high-risk patients to reduce HCC and mortality in patients with chronic viral hepatitis.

Changes in liver stiffness values assessed using transient elastography in chronic hepatitis B patients treated with tenofovir disoproxil fumarate: a prospective observational study.

BACKGROUND/AIMS: Regression of liver fibrosis during antiviral therapy in chronic hepatitis B (CHB) patients has been demonstrated, but data on the influence of long-term treatment with tenofovir disoproxil fumarate (TDF) on liver stiffness (LS) measured by transient elastography are scarce. We aimed to investigate the changes in LS values during the 144-week TDF therapy in treatment-naïve CHB patients. METHODS: This prospective observational study was conducted from April 2015 to July 2020 at CHA Bundang Medical Center. Laboratory tests and LS measurements were performed at baseline and repeated at weeks 12, 24, 48, 96, and 144. A significant decline in LS was defined as ≥ 30% decrease in LS value at week 96 from baseline. RESULTS: A total of 48 treatment-naïve CHB patients initiating TDF therapy were screened, and 36 patients were included in the final analysis (median age, 46 [interquartile range, 34.5-55.8] years; 19 men [52.8%]). During TDF therapy, the median LS values decreased from 13.8 kPa at baseline to 8.7 kPa, 6.5 kPa, and 6.4 kPa at weeks 48, 96, and 144, respectively (all P < 0.001). At week 96, virological and biochemical responses were achieved in 34 (94.4%) patients and 20 (76.9%) patients, respectively. Moreover, 21 of 36 (58.3%) patients showed a significant decline in LS value. A higher baseline LS value was a single independent predictor for the reduction in LS value at week 96 from baseline (P < 0.001). CONCLUSIONS: During the 144-week TDF therapy, LS values declined significantly in treatment-naïve CHB patients.

Increased PRL-1 in BM-derived MSCs triggers anaerobic metabolism via mitochondria in a cholestatic rat model.

Mesenchymal stem cell (MSC) therapy in chronic liver disease is associated with mitochondrial anaerobic metabolism. Phosphatase of regenerating liver-1 (PRL-1), known as protein tyrosine phosphatase type 4A, member 1 (PTP4A1), plays a critical role in liver regeneration. However, its therapeutic mechanism remains obscure. The aim of this study was to establish genetically modified bone marrow (BM)-MSCs overexpressing PRL-1 (BM-MSCsPRL-1) and to investigate their therapeutic effects on mitochondrial anaerobic metabolism in a bile duct ligation (BDL)-injured cholestatic rat model. BM-MSCsPRL-1 were generated with lentiviral and nonviral gene delivery systems and characterized. Compared with naive cells, BM-MSCsPRL-1 showed an improved antioxidant capacity and mitochondrial dynamics and decreased cellular senescence. In particular, mitochondrial respiration in BM-MSCsPRL-1 generated using the nonviral system was significantly increased as well as mtDNA copy number and total ATP production. Moreover, transplantation of BM-MSCsPRL-1 generated using the nonviral system had predominantly antifibrotic effects and restored hepatic function in a BDL rat model. Decreased cytoplasmic lactate and increased mitochondrial lactate upon the administration of BM-MSCsPRL-1 indicated significant alterations in mtDNA copy number and ATP production, activating anaerobic metabolism. In conclusion, BM-MSCsPRL-1 generated by a nonviral gene delivery system enhanced anaerobic mitochondrial metabolism in a cholestatic rat model, improving hepatic function.

Predictive biomarkers of survival in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab treatment.

BACKGROUND: Since atezolizumab plus bevacizumab (ATE+BEV) regimen for patients with unresectable hepatocellular carcinoma (HCC) was released quite recently, real-world data are lacking. We evaluated efficacy, safety, and predictive biomarkers for survival in patients receiving ATE+BEV. METHODS: Between 2020 and 2021, HCC patients receiving ATE+BEV at academic teaching hospitals were recruited. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors (version 1.1.). RESULTS: Among 121 patients enrolled, the median age was 63 years, with male predominance (82.6%). Complete response, partial response, stable disease, and progressive disease were identified in 2.5%, 26.4%, 54.5%, and 16.6%, respectively. Patients with alpha-fetoprotein and des-gamma-carboxy prothrombin (DCP) response, defined as ≥30% and ≥50% decreases, respectively, at the first response evaluation relative to baseline, and those with neutrophil-to-lymphocyte ratio (NLR) <2.5, had significantly higher objective response rates (42.6% vs. 21.5%, 50.0% vs. 26.2%, and 39.0% vs. 19.4%, respectively; all p < 0.05). During follow-up, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 5.7 months. Multivariable analyses showed that macrovascular invasion (adjusted hazard ratio [aHR] 2.541; p = 0.017), DCP ≥186 mAU/ml (aHR 5.102; p < 0.001), NLR ≥2.5 (aHR 3.584; p = 0.001), and an NLR decrease ≥10% at the first response (aHR 0.305; p = 0.002) were independent predictors of OS, and DCP ≥186 mAU (aHR 2.311; p = 0.002) and NLR ≥2.5 (aHR 1.938; p = 0.012) were independent predictors of PFS. Grade ≥3 treatment-related adverse events (AEs) occurred in 33 (27.3%) patients. CONCLUSION: ATE+BEV showed favorable efficacy and safety. Baseline high DCP and NLR may be useful prognostic predictors for OS and PFS.

Gamma-glutamyl transpeptidase dynamics as a biomarker for advanced fibrosis in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: It is unclear whether changes in lipid profile and liver biochemistry are associated with advanced fibrosis. METHODS: Patients diagnosed with non-alcoholic fatty liver disease (NAFLD) between 2009 and 2017 were included. The changes in blood tests were calculated as follows: [(value at 6 months - value at baseline)/value at baseline] × 100. The endpoint was advanced fibrosis determined by the NAFLD fibrosis score, calculated every year from diagnosis until 2019. Cox proportional hazards models were used to identify factors predicting advanced fibrosis. RESULTS: After a median follow-up of 31.7 (19.4-50.8) months, advanced fibrosis occurred in 64 (6.3%) of 1021 patients. Gamma-glutamyl transpeptidase (GGT) levels (72.9 vs 51.1 IU/L; P = 0.23) and ΔGGT (+6.0% vs -6.9%; P = 0.06) were higher in the advanced fibrosis group. ΔGGT (hazard ratio [HR] 1.03; P < 0.001) was significantly associated with advanced fibrosis after adjusting for age and platelet count. The positive ΔGGT group showed a higher incidence of advanced fibrosis and the 1-standard deviation increment in ΔGGT showed a significant association with advanced fibrosis both in statin users (HR, 1.35) and in non-users (HR, 1.31; Ps < 0.05). The restricted cubic spline model identified a positive correlation between ΔGGT and the NAFLD fibrosis scores (P < 0.001). ΔGGT showed sensitivity of 64.2%, specificity of 52.6%, and negative predictive value of 98.3% in predicting advanced fibrosis. CONCLUSIONS: ΔGGT calculated at 6 months following NAFLD diagnosis is associated with advanced fibrosis.

Atezolizumab/Bevacizumab vs. Lenvatinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: A Real-World, Multi-Center Study.

Lenvatinib (LENV) and atezolizumab/bevacizumab (ATE/BEV) have been approved as first-line regimens for the treatment of unresectable hepatocellular carcinoma (HCC). We aimed to compare their clinical efficacy and safety. Patients receiving ATE/BEV (n = 86) or LENV (n = 146) as first-line treatment were recruited from three academic hospitals in Korea. Overall survival (OS), progression-free survival (PFS), and radiological response were assessed according to the Response Evaluation Criteria in Solid Tumors. Clinical features of the two groups were balanced through propensity score (PS) matching with a 1:1 ratio and inverse probability of treatment weighting (IPTW) analyses. The median age was 62 years, with male predominance (83.6%). There was no significant difference in the objective response rate between the ATE/BEV and LENV groups (32.6% vs. 31.5%; p = 0.868). Neither median OS (not reached vs. 12.8 months; p = 0.357) nor PFS (5.7 vs. 6.0 months; p = 0.738) was different between ATE/BEV and LENV groups. PS-matched and IPTW analyses yielded comparable results in terms of OS and PFS (all p > 0.05). Grade ≥ 3 adverse events occurred in 42.8% and 21.9% of patients in the ATE/BEV and LENV groups, respectively (p = 0.141). The two first-line therapy regimens for unresectable HCC had comparable clinical efficacy and safety in real-world practice settings. Further studies with a larger sample size and longer follow-up are needed to validate these results.

Changes in general and central fatness are associated with hepatocellular carcinoma: A Korean nationwide longitudinal study.

We investigated the impact of short-term changes in general and central fatness on the risk of hepatocellular carcinoma (HCC) in a large, population-based cohort. We screened 7 221 479 subjects who underwent health examinations provided by the National Health Insurance Service of South Korea in 2009 and 2011. In total, 6 789 472 subjects were included in the final analysis. General fatness was defined as a body mass index (BMI) ≥25 kg/m2 , and central fatness was defined as a waist circumference (WC) ≥90 cm in men and ≥85 cm in women. Subjects were classified according to the change in body fatness between 2009 and 2011, as follows: (a) persistent no fatness as no fatness in both 2009 and 2011, (b) reversed fatness as fatness in 2009, but no fatness in 2011, (c) incident fatness as no fatness in 2009, but fatness in 2011 or (d) persistent fatness as fatness in both 2009 and 2011. During a median 6.4-year follow-up, we documented 9952 HCC cases. Compared to subjects with a persistent no general fatness, the risk of HCC significantly increased in those with incident (adjusted hazard ratio [aHR] = 1.10, 95% confidence interval [CI] = 1.01-1.20) and persistent (aHR = 1.28, 95% CI = 1.23-1.34) general fatness. Compared to subjects with persistent no central fatness, those with incident and persistent central fatness showed a significantly increased risk of HCC (aHR = 1.19, 95% CI = 1.11-1.27 and aHR = 1.33, 95% CI = 1.26-1.40, respectively). Taken together, these findings indicate the importance of strategies for preventing and reversing body fatness to reduce the incidence of HCC.

Increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis with concurrent fatty liver.

BACKGROUND: Population-based data are lacking regarding whether fatty liver is a risk factor for hepatocellular carcinoma (HCC) and mortality in patients with chronic viral hepatitis. AIM: To investigate the association of fatty liver with HCC incidence and mortality in patients with chronic viral hepatitis using a nationwide cohort METHODS: We included 57,385 patients with chronic hepatitis B (CHB) or chronic hepatitis C (CHC) who underwent health examinations. The patients were divided into three groups: no fatty liver, fatty liver index (FLI) <30, grade 1 (G1) fatty liver: 30≤ FLI <60, and grade 2 (G2) fatty liver: FLI >60. RESULTS: During a median 8.4-year follow-up, we documented 3496 HCC cases and 4146 deaths. Compared to patients with no fatty liver (n = 35,018), the risk of HCC was significantly higher in patients with G1 fatty liver (n = 14,544) (adjusted hazard ratio [aHR] = 1.50, 95% confidence interval [CI] = 1.38-1.64) and G2 fatty liver (n = 7,823) (aHR = 1.88, 95% CI = 1.67-2.12). The risk of mortality was significantly higher in patients with G1 fatty liver (aHR = 1.53, 95% CI = 1.41-1.66) and G2 fatty liver (aHR = 2.16, 95% CI = 1.94-2.42) compared to patients with no fatty liver. CONCLUSIONS: Concurrent fatty liver was associated with a higher risk of HCC and mortality in patients with chronic viral hepatitis. Our results suggest the importance of management of fatty liver to reduce the risks of HCC and mortality in patients with chronic viral hepatitis.

Cirrhosis, Age, and Liver Stiffness-Based Models Predict Hepatocellular Carcinoma in Asian Patients with Chronic Hepatitis B.

OBJECTIVES: Predicting hepatocellular carcinoma (HCC) in patients with chronic hepatitis B who received long-term therapy with potent nucleos(t)ide analogs is of utmost importance to refine the strategy for HCC surveillance. METHODS: We conducted a multicenter retrospective cohort study to validate the CAGE-B and SAGE-B scores, HCC prediction models developed for Caucasian patients receiving entecavir (ETV) or tenofovir (TFV) for >5 years. Consecutive patients who started ETV or TFV at two hospitals in Korea from January 2009 to December 2015 were identified. The prediction scores were calculated, and model performance was assessed using receiver operating characteristics (ROC) curves. RESULTS: Among 1557 patients included, 57 (3.7%) patients had HCC during a median follow-up of 93 (95% confidence interval, 73-119) months. In the entire cohort, CAGE-B predicted HCC with an area under the ROC curve of 0.78 (95% CI, 0.72-0.84). Models that have "liver cirrhosis" in the calculation, such as AASL (0.79 (0.72-0.85)), CU-HCC (0.77 (0.72-0.82)), and GAG-HCC (0.79 (0.74-0.85)), showed accuracy similar to that of CAGE-B (p > 0.05); however, models without "liver cirrhosis", including SAGE-B (0.71 (0.65-0.78)), showed a lower predictive ability than CAGE-B. CAGE-B performed well in subgroups of patients treated without treatment modification (0.81 (0.73-0.88)) and of male sex (0.79 (0.71-0.86)). CONCLUSIONS: This study validated the clinical usefulness of the CAGE-B score in a large number of Asian patients treated with long-term ETV or TFV. The results could provide the basis for the reappraisal of HCC surveillance strategies and encourage future prospective validation studies with liver stiffness measurements.

Increased Phosphatase of Regenerating Liver-1 by Placental Stem Cells Promotes Hepatic Regeneration in a Bile-Duct-Ligated Rat Model.

Phosphatase of regenerating liver-1 (PRL-1) controls various cellular processes and liver regeneration. However, the roles of PRL-1 in liver regeneration induced by chorionic-plate-derived mesenchymal stem cells (CP-MSCs) transplantation remain unknown. Here, we found that increased PRL-1 expression by CP-MSC transplantation enhanced liver regeneration in a bile duct ligation (BDL) rat model by promoting the migration and proliferation of hepatocytes. Engrafted CP-MSCs promoted liver function via enhanced hepatocyte proliferation through increased PRL-1 expression in vivo and in vitro. Moreover, higher increased expression of PRL-1 regulated CP-MSC migration into BDL-injured rat liver through enhancement of migration-related signals by increasing Rho family proteins. The dual effects of PRL-1 on proliferation of hepatocytes and migration of CP-MSCs were substantially reduced when PRL-1 was silenced with siRNA-PRL-1 treatment. These findings suggest that PRL-1 may serve as a multifunctional enhancer for therapeutic applications of CP-MSC transplantation.

Prognostic Value of Alpha-Fetoprotein in Patients Who Achieve a Complete Response to Transarterial Chemoembolization for Hepatocellular Carcinoma.

PURPOSE: Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC. MATERIALS AND METHODS: Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR. RESULTS: Among the recruited patients, 569 (63.9%) with naïve HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all p=0.001). CONCLUSION: High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE.

Dynamics of liver stiffness-based risk prediction model during antiviral therapy in patients with chronic hepatitis B.

OBJECTIVE: The liver stiffness-based risk prediction models predict hepatocellular carcinoma (HCC) development. We investigated the influence of antiviral therapy (AVT) on liver stiffness-based risk prediction model in patients with chronic hepatitis B (CHB). METHODS: Patients with CHB who initiated AVT were retrospectively recruited from 13 referral Korean institutes. The modified risk estimation for hepatocellular carcinoma in chronic hepatitis B (mREACH-B) model was selected for the analysis. RESULTS: Between 2007 and 2015, 1034 patients with CHB were recruited. The mean age of the study population (639 men and 395 women) was 46.8 years. During AVT, the mREACH-B score significantly decreased from the baseline to 3 years of AVT (mean 9.21 → 7.46, P < 0.05) and was maintained until 5 years of AVT (mean 7.23, P > 0.05). The proportion of high-risk patients (mREACH-B score ≥11) was significantly reduced from the baseline to 2 years of AVT (36.4% → 16.4%, P < 0.001) and was maintained until 5 years of AVT (12.2%, P > 0.05). The mREACH-B scores at baseline and 1 year of AVT independently predicted HCC development (hazard ratio = 1.209-1.224) (all P < 0.05). The cumulative incidence rate of HCC was significantly different at 5 years of AVT among risk groups (high vs. high-intermediate vs. low-intermediate vs. low) from baseline (4.5% vs. 3.2% vs. 1.5% vs. 0.8%) and 1 year (11.8% vs. 4.6% vs. 1.8% vs. 0.6%) (all P < 0.05, log-rank tests). CONCLUSIONS: The mREACH-B score was dynamically changed during AVT. Thus, repeated assessment of the mREACH-B score is required to predict the changing risk of HCC development in patients with CHB undergoing AVT.

Validation of risk prediction scores for hepatocellular carcinoma in patients with chronic hepatitis B treated with entecavir or tenofovir.

Several prediction scores for the early detection of hepatocellular carcinoma (HCC) are available. We validated the predictive accuracy of age, albumin, sex, liver cirrhosis (AASL), RESCUE-B, PAGE-B and modified PAGE-B (mPAGE-B) scores in chronic hepatitis B (CHB) patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF). Between 2007 and 2014, 3171 patients were recruited (1645, ETV; 1517, TDF). The predictive accuracy of each prediction score was assessed. The mean age of the study population (1977 men; 1194 women) was 48.8 years. Liver cirrhosis was present in 1040 (32.8%) patients. During follow-up (median, 58.2 months), 280 (8.8%) patients developed HCC; these patients were significantly older; more likely to be male; had significantly higher proportions of liver cirrhosis, hypertension and diabetes; and had significantly higher values for the four risk scores than those who did not develop HCC (all P < .05). Older age (hazard ratio [HR] = 1.048), male sex (HR = 2.142), liver cirrhosis (HR = 3.144) and prolonged prothrombin time (HR = 2.589) were independently associated with an increased risk of HCC (all P < .05), whereas a higher platelet count (HR = 0.996) was independently associated with a decreased risk of HCC (P < .05). The predictive accuracy of AASL score was the highest for 3- and 5-year HCC predictions (areas under the curve [AUCs] = 0.818 and 0.816, respectively), followed by RESCUE-B, PAGE-B and mPAGE-B scores (AUC = 0.780-0.815 and 0.769-0.814, respectively). In conclusion, four HCC prediction scores were assessed in Korean CHB patients treated with ETV or TDF. The AASL score showed the highest predictive accuracy.

Upregulation of C-Reactive Protein by Placenta-Derived Mesenchymal Stem Cells Promotes Angiogenesis in A Rat Model with Cirrhotic Liver.

BACKGROUND AND OBJECTIVES: Liver cirrhosis is accompanied by abnormal vascular shunts. The Wnt pathway is essential for endothelial cell survival and proliferation. C-reactive protein (CRP), which is produced by hepatocyte, activates angiogenesis in cardiovascular diseases. METHODS AND RESULTS: The expression of CRP in CCl4-injured rat livers was detected using qRT-PCR and Western blotting after transplantation of placenta-derived mesenchymal stem cells (PD-MSCs) into rats. To determine whether CRP functions in hepatic regeneration by promoting angiogenesis through the Wnt pathway, we detected VEGF and ß-catenin in liver tissues and BrdU and ß-catenin in hepatocytes by immunofluorescence. The expression levels of CRP, Wnt pathway-related and angiogenic factors were increased in CCl4-injured and PD-MSCs transplanted rat livers. In vitro, the expression levels of Wnt signaling and angiogenic factors were decreased in siRNA-CRP-transfected rat hepatocytes. CONCLUSIONS: CRP upregulation by PD-MSCs participates in vascular remodeling to promote liver regeneration via the Wnt signaling pathway during hepatic failure.

Hepatocellular carcinoma and death and transplantation in chronic hepatitis B treated with entecavir or tenofovir disoproxil fumarate.

Conflicting results have been reported regarding which of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is associated with better outcomes. Chronic hepatitis B patients who started ETV or TDF between 2010 and 2015 were analysed. The primary outcomes were hepatocellular carcinoma and death and transplantation. The impact of the treatment on the primary outcomes was analysed using Cox proportional hazards models in the entire and propensity score-matched cohorts. A total of 404 patients (180 and 224 in the ETV and TDF groups, respectively) were analysed. The median duration of follow-up was significantly longer in the ETV group (64.0 vs. 49.1 months; P < 0.001). Virological response (79.4% vs. 68.4%; P = 0.018) and sustained virological suppression (59.7% vs. 45.2%; P = 0.005) were significantly higher in the TDF group. TDF was associated with lower hepatocellular carcinoma [hazard ratio (HR) 0.31, 95% confidence interval (95% CI), 0.12‒0.79; P = 0.014]; however, statistical significance was not reached after adjusting sustained virological suppression using propensity score matching (HR 0.36, 95% CI 0.12‒1.14; P = 0.08). Death and transplantation was comparable. In conclusion, the impact of TDF on the lower hepatocellular carcinoma was blunted after adjusting sustained virological suppression. Further comparison in a larger number of patients who show sustained virological suppression over a longer period of time is needed.

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy.

The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.

Validation of the CAMD Score in Patients With Chronic Hepatitis B Virus Infection Receiving Antiviral Therapy.

BACKGROUND & AIMS: Researchers previously developed a scoring system to determine the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection, based on the presence of cirrhosis, patient age, male sex, and diabetes (called the CAMD scoring system). We validated the CAMD scoring system and compared its performance with that of other risk assessment models in an independent cohort. METHODS: We followed up 3277 patients with chronic HBV infection (mean age, 48.7 y; 62.6% male; 32.4% with cirrhosis) who were treated with entecavir (n = 1725) or tenofovir (n = 1552) as the first-line antiviral agent in 4 academic teaching hospitals in the Republic of Korea. The primary outcome was development of HCC. We evaluated the ability of the CAMD, PAGE-B, and mPAGE-B scoring systems to identify patients who would develop HCC using integrated area under the curve (iAUC) analysis. RESULTS: Over a median follow-up period of 58.2 months, 8.9% of the patients developed HCC. Patients who developed HCC were older, more likely to be male, and had higher proportions of cirrhosis and diabetes than patients who did not develop HCC (all P < .05). CAMD scores identified patients who developed HCC with an iAUC of 0.790, mPAGE-B scores with an iAUC of 0.769, and PAGE-B scores with an iAUC of 0.760. The 5-year cumulative risks of HCC were 1.3% in patients with low CAMD scores (<8), 8.0% in patients with intermediate CAMD scores (8-13), and 24.3% in patients with high CAMD scores (>13) (P < .001 for comparison of low- vs intermediate-score groups and between intermediate- vs high-score groups). The predicted and observed probabilities of HCC had excellent agreement. CONCLUSIONS: We validated the CAMD scoring system in determining the risk of HCC in patients with chronic HBV treatment receiving entecavir or tenofovir treatment. Validation was performed in a cohort of patients in the Republic of Korea, where most patients have genotype C2 HBV infection.

Fibrosis-4, aspartate transaminase-to-platelet ratio index, and gamma-glutamyl transpeptidase-to-platelet ratio for risk assessment of hepatocellular carcinoma in chronic hepatitis B patients: comparison with liver biopsy.

BACKGROUND AND AIMS: It is well known that hepatocellular carcinoma (HCC) develops as a consequence of hepatic fibrosis progression. Thus, early identification of advanced liver fibrosis is very important. This study evaluated the prognostic value of FIB-4, the aspartate transaminase to-platelet ratio index (APRI), and the gamma-glutamyl transpeptidase-toplatelet ratio (GPR) for predicting HCC development using histological fibrosis stage as a reference in Asian chronic hepatitis B (CHB) patients. METHODS: A total of 444 CHB patients who underwent liver biopsy and serological tests for determining noninvasive serum fibrosis markers were enrolled. All patients were followed to monitor HCC development. RESULTS: The histological fibrosis stage showed best performance in predicting HCC development at 5 (area under the receiver operating characteristic curve [AUROC] = 0.783) and 7 years (AUROC = 0.766), followed by FIB-4 (AUROC = 0.753 at 5 years, 0.698 at 7 years), APRI (AUROC = 0.658 at 5 years, 0.572 at 7 years), and GPR (AUROC = 0.638 at 5 years, 0.603 at 7 years). When we classified risk groups according to the histological fibrosis stage (F4 vs. F0-3) and FIB-4 (FIB-4 ≥ 3.25 vs. FIB-4 < 3.25), patients in the high-risk group were found to have a significantly higher probability of developing HCC than those in the low-risk group (P=0.005 and 0.022, respectively, log-rank test). CONCLUSION: Our study demonstrated that FIB-4 is useful for the noninvasive prediction of HCC development, while APRI and GPR were less useful.