The long‐term clinical impact of low‐level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change ...in therapy. A retrospective cohort of 875 treatment‐naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 65.5%, cirrhosis = 443 50.6%) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow‐up (range 1.0‐8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28‐3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34‐3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. Conclusion: LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335–343).
Background and Aims
Statins have pleiotropic effects that may include chemoprevention. Several observational studies have suggested that statins may prevent hepatocellular carcinoma (HCC), but they ...have not yet been fully studied in patients with chronic hepatitis B virus (HBV) infections.
Approach and Results
A hospital‐based retrospective cohort of 7,713 chronic HBV‐infected individuals between January 2008 and December 2012 were analyzed. The primary outcome was the development of HCC. Patients who used statins for at least 28 cumulative defined daily doses during the follow‐up period were defined as statin users (n = 713). The association between the use of statin and the incidence of HCC was analyzed using the multivariable Cox regression model with time‐dependent covariates. During a median follow‐up of 7.2 years (min‐max: 0.5‐9.9), HCC newly developed in 702 patients (9.1%). Statin use was associated with a lower risk of HCC (adjusted hazard ratio = 0.36, 95% confidence interval: 0.19‐0.68, adjusted for age, sex, cirrhosis, diabetes, hypertension, serum alanine aminotransferase, cholesterol, HBV DNA level, antiviral treatment, and antiplatelet therapy). The observed benefit of the statin use was dose‐dependent (adjusted hazard ratio 95% confidence interval, 0.63 0.31‐1.29; 0.51 0.21‐1.25; 0.32 0.07,1.36; and 0.17 0.06, 0.48 for patients with statin use of 28‐365, 366‐730, 731‐1095, and more than 1,095 cumulative defined daily doses, respectively). In subgroup analysis, the association between statin use and reduced risk of HCC was observed in all prespecified subgroups analyzed.
Conclusion
Statin use was associated with a reduced risk of HCC development in chronic HBV‐infected patients, suggesting that statins may have a chemopreventive role in this population. These findings warrant a prospective evaluation.
Summary
Background
Anti‐viral therapy is not indicated for patients with chronic hepatitis B (CHB) in the immune‐tolerant phase.
Aims
To investigate the cumulative incidence of phase change and ...hepatocellular carcinoma (HCC) and independent predictors for phase change in patients with CHB in immune‐tolerant phase.
Methods
In total, 946 patients in immune‐tolerant phase, defined as hepatitis B e antigen positivity, HBV‐DNA >20 000 IU/mL and alanine aminotransferase (ALT) ≤40 IU/L, between 1989 and 2017 were enrolled from eight institutes.
Results
The mean age of study population (429 men and 517 women) was 36.7 years. The mean ALT and HBV‐DNA levels were 24.6 IU/L and 8.50 log10 IU/mL, respectively. Of the study population, 476 (50.3%) patients remained in immune‐tolerant phase throughout the study period (median: 63.6 months). The cumulative incidence rates of phase change and HCC at 10 years were 70.7% and 1.7%, respectively. Multivariate analyses revealed that HBV‐DNA level >107 IU/mL was associated independently with a reduced risk of phase change (hazard ratio HR = 0.734, P = 0.008), whereas a high ALT level, above the cut‐off recommended in the Korean Association for the Study of the Liver guidelines (34 IU/L for men and 30 IU/L for women), was associated independently with a greater risk of phase change (HR = 1.885, P < 0.001).
Conclusions
The criterion of HBV‐DNA level > 107 IU/mL may be useful to define immune‐tolerant phase. In addition, an extremely low risk of HCC development was observed in patients with CHB in immune‐tolerant phase.
Background & Aims
The Baveno VI and the expanded Baveno VI criteria were proposed to help identify patients who could safely avoid screening endoscopies for clinically significant varices among ...patients with compensated advanced chronic liver disease. However, these criteria require cross‐validation, especially in Asian populations where the aetiologies of liver disease are different.
Methods
A total of 1035 patients, including 282 patients with compensated advanced chronic liver disease of different aetiology, were analysed. The compensated advanced chronic liver disease was defined by liver stiffness measurement ≥10 kPa, Child‐Pugh class A and absence of prior liver decompensation. High‐risk varix was defined as a grade ≥2 oesophageal varix, any varix with a red colour sign or gastric varices.
Results
High‐risk varixs were present in 19.5% (55/282 patients) with compensated advanced chronic liver disease. Among compensated advanced chronic liver disease patients, the expanded criteria could spare more endoscopies (51.7%) than the original criteria (27.6%). However, the expanded criteria missed a greater number of high‐risk varixs (6.8%) than the original criteria (3.8%). When stratified according to liver disease aetiology, the negative predictive values for the original Baveno VI criteria were 0.92, 1.00, 1.00 and 1.00, and the negative predictive values for the expanded criteria were 0.92, 0.96, 0.92 and 0.93 for hepatitis B, hepatitis C, alcohol and non‐alcoholic fatty liver disease, respectively. High‐risk varixs were rarely detected in patients without compensated advanced chronic liver disease (1.1%, 8/753 patients).
Conclusions
In this Asian cohort study, the Baveno VI criteria were able to identify who could safely avoid screening endoscopy. The expanded Baveno VI criteria could spare more endoscopies but also could increase the odds of missing a high‐risk varix.
Cancer cachexia affects quality of life, response to chemotherapy, and survival in many advanced cancer patients. The aim of this study was to evaluate the prognostic value of pretreatment cachexia ...index (CXI) in patients with advanced hepatocellular carcinoma (HCC) treated with systematic chemotherapy. Patients with advanced HCC treated with lenvatinib therapy between October 2018 and October 2020 were retrospectively studied. The CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil-to-lymphocyte ratio). The association with treatment response and early adverse events within the first two months of lenvatinib therapy was investigated. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method with log-rank test. Multivariable Cox regression was used to identify the predictors of survival. A total of 116 patients (median age: 60, male: 84.5% ) with calculated CXI. They divided into two groups: high CXI (≥ 53, n = 82) and low CXI (< 53, n = 34). Patients with low CXI had a significantly lower disease control rate (61.8% vs. 89.0%, p = 0.001) and a shorter median OS (8.0 95% CI 6.2-9.8 vs. 12.3 95% CI 10.1-14.4 months, p = 0.002) than those with high CXI. In multivariable analysis, low CXI was independently associated with shorter OS (HR: 2.07, 95% CI: 1.17-3.65, p = 0.01) and PFS (HR: 1.84, 95% CI: 1.09-3.09, p = 0.02). Of note, during the first two months of lenvatinib therapy, anorexia (41.2% vs. 22.0%, p = 0.04) developed more frequently among patients with low CXI than those with high CXI. The CXI may be a clinically useful index for predicting poor treatment response and prognosis in patients with advanced HCC undergoing lenvatinib treatment.
Given the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT ...improves patient outcome is limited.
We performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396).
In the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval CI; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR 95% CI = 0.67 0.56-0.80). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml).
MDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations.
Background and Aims
Breastfeeding has multiple effects on maternal health outcomes. However, the effect of breastfeeding on NAFLD in parous women remains unclear.
Approach and Results
A total of ...6,893 Korean parous women aged 30‐50 years who participated in the Korean National Health and Nutrition Examination Survey were assessed for the association between breastfeeding and NAFLD. Duration of lactation was calculated by dividing the total lactation period by the number of breastfed children. NAFLD was defined by the hepatic steatosis index. Of 6,893 women, 1,049 (15.2%) had NAFLD. Prevalence of NAFLD was 18.3%, 14.3%, 12.3%, 14.4%, and 15.8% in women with a breastfeeding period of <1, ≥1‐<3, ≥3‐<6, ≥6‐<12, and ≥12 months, respectively. In a fully adjusted model, breastfeeding (≥1 month) was associated with reduced NAFLD prevalence (OR, 0.67; 95% CI, 0.51‐0.89) after adjusting for metabolic, socioeconomic, and maternal risk factors. Fully adjusted ORs (95% CI) decreased with an increase of breastfeeding duration: 0.74 (0.49‐1.11), 0.70 (0.47‐1.05), 0.67 (0.48‐0.94), and 0.64 (0.46‐0.89) for women with ≥1‐<3, ≥3‐<6, ≥6‐<12, and ≥12 months of breastfeeding duration, respectively, compared to women with <1 month of breastfeeding duration. Such an association was also observed in all predefined subgroups without interaction.
Conclusions
Breastfeeding showed a protective effect against NAFLD in later life of parous women, suggesting a maternal benefit of breastfeeding on NAFLD.
Hepatic myofibroblasts are activated in response to chronic liver injury of any etiology to produce a fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of ...fibrotic liver diseases is unresolved. To identify distinct populations of myofibroblasts and quantify their contribution to hepatic fibrosis of two different etiologies, collagen-α1(I)-GFP mice were subjected to hepatotoxic (carbon tetrachloride; CCl ₄) or cholestatic (bile duct ligation; BDL) liver injury. All myofibroblasts were purified by flow cytometry of GFP ⁺ cells and then different subsets identified by phenotyping. Liver resident activated hepatic stellate cells (aHSCs) and activated portal fibroblasts (aPFs) are the major source (>95%) of fibrogenic myofibroblasts in these models of liver fibrosis in mice. As previously reported using other methodologies, hepatic stellate cells (HSCs) are the major source of myofibroblasts (>87%) in CCl ₄ liver injury. However, aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of injury (5 d BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and contribute to the myofibroblast population (14 and 20 d BDL). Unlike aHSCs, aPFs respond to stimulation with taurocholic acid and IL-25 by induction of collagen-α1(I) and IL-13, respectively. Furthermore, BDL-activated PFs express high levels of collagen type I and provide stimulatory signals to HSCs. Gene expression analysis identified several novel markers of aPFs, including a mesothelial-specific marker mesothelin. PFs may play a critical role in the pathogenesis of cholestatic liver fibrosis and, therefore, serve as an attractive target for antifibrotic therapy.
Background and Aims
Baveno VII consensus introduced the non‐invasive criteria of clinically significant portal hypertension (CSPH) using liver stiffness measurement (LSM). We evaluated the usefulness ...of the Baveno VII criteria to predict the risk of decompensation in patients with compensated advanced chronic liver disease (cACLD).
Methods
We conducted a retrospective cohort study of 1966 patients with cACLD. Patients were categorized into four groups (CSPH excluded (n = 619), grey zone (low risk of CSPH (n = 699), high risk of CSPH (n = 207)), and CSPH included (n = 441)) according to Baveno VII consensus. The risk of events was estimated using a Fine and Gray competing risk regression analysis, with liver transplantation and death as competing events. We calculated standardized hazard ratios (sHR) to assess the relative risk of decompensation.
Results
Among 1966 patients, 178 developed decompensations over a median follow‐up of 3.06 (IQR: 1.03–6.00) years. Patients with CSPH had the highest decompensation risk, followed by the grey zone high‐risk group, grey zone low‐risk group, and those without CSPH with 3‐year cumulative risks of 22%, 12%, 3.3%, and 1.4% respectively (p < .001). Compared to CSPH excluded group, CSPH included group (sHR: 8.00, 95% CI: 4.00–16.0), grey zone high‐risk group (sHR: 6.57, 95% CI: 3.16–13.6), grey zone low‐risk group (sHR: 2.15, 95% CI: 1.04–4.41) had significantly higher risk of decompensation (Gray's test p < .01).
Conclusion
Non‐invasive diagnosis of CSPH according to the Baveno VII criteria can stratify the risk of decompensation.