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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a global prevalence estimated at approximately 25%. NAFLD is also the leading cause of liver cirrhosis, hepatocellular carcinoma, and death. Additionally, the risk of cardiovascular disease increases with greater NAFLD severity. The liver- and cardiovascular disease-related mortality incident rate ratios among the NAFLD population were 0.77 and 4.79 per 1,000 person-years, respectively. We intend to discuss the risk factors associated with NAFLD in terms of development and progression. Obesity or higher body mass index is closely associated with NAFLD in a dose-dependent manner, but growing evidence suggests that central obesity plays a more important role in the development of NAFLD. Saturated fat and fructose have been reported to be closely related to NAFLD. Fructose intake promotes lipogenesis and impairs mitochondria fat oxidation. The presence of type 2 diabetes is the most powerful predictive risk factor for hepatic fibrosis in patients with NAFLD. Single nucleotide polymorphism is not only associated with the prevalence of NAFLD but also associated with increased liver disease mortality. Obstructive sleep apnea, intestinal dysbiosis, and sarcopenia are associated with the development of NAFLD

The global burden of chronic liver disease (CLD) is substantial. Due to the limited indication of and accessibility to antiviral therapy in viral hepatitis and lack of effective pharmacological treatment in nonalcoholic fatty liver disease, the beneficial effects of antidiabetics and non–antidiabetics in clinical practice have been continuously investigated in patients with CLD. In this narrative review, we focused on non-antidiabetic drugs, including ursodeoxycholic acid, silymarin, dimethyl4,4’-dimethoxy-5,6,5’,6’-dimethylenedixoybiphenyl-2,2’-dicarboxylate, L-ornithine L-aspartate, branched chain amino acids, statin, probiotics, vitamin E, and aspirin, and summarized their beneficial effects in CLD. Based on the antioxidant, anti-inflammatory properties, and regulatory functions in glucose or lipid metabolism, several non–antidiabetic drugs have shown beneficial effects in improving liver histology, aminotransferase level, and metabolic parameters and reducing risks of hepatocellular carcinoma and mortality, without significant safety concerns, in patients with CLD. Although the effect as the centerpiece management in patients with CLD is not robust, the use of these non-antidiabetic drugs might be potentially beneficial as an adjuvant or combined treatment strategy.

There are several reports on the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the prevalence of advanced hepatic fibrosis in MAFLD is largely unknown. We aimed to evaluate the prevalence of advanced fibrosis in MAFLD.A total of 6775 subjects from nationwide 13 health check-up centres were included in this cross-sectional study. Fatty liver was evaluated using ultrasonography. Significant (≥F2) and advanced (≥F3) hepatic fibrosis were defined by MRE thresholds of 3.0 kPa (range: 2.99-3.65 kPa) and 3.6 kPa (range: 3.4-3.9 kPa) respectively. The sex- and age-standardized prevalence of MAFLD and hepatic fibrosis was estimated.The sex- and age-standardized prevalence of MAFLD was 33.9%. The prevalence of obesity (BMI ≥25 kg/mThe sex- and age-standardized prevalence of advanced fibrosis was 3.0% (range: 2.6-4.6%) in subjects with MAFLD.

Aims Fibrosis-4 index (FIB-4) and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) are the two most widely used non-invasive tools for screening of advanced fibrosis in subjects with NAFLD. Since metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a new category of fatty liver disease, we aimed to compare the diagnostic performance of FIB-4 and NFS in subjects with MAFLD and in various subgroups. Methods This study was designed as cross-sectional study. Data from 6,775 subjects who underwent magnetic resonance elastography (MRE) and abdominal ultrasonography at the same time during a health check-up at 13 various health check-up centers were retrospectively reviewed. Advanced fibrosis was defined as an MRE value of ≥3.6 kPa. Results The area under the receiver operating characteristic curves (AUROCs) of FIB-4 and NFS for diagnosing advanced fibrosis were similar in subjects with MAFLD. However, the AUROC of NFS was lower than that of FIB-4 in the diabetic subgroup of MAFLD (0.809 in FIB-4 vs. 0.717 in NFS, P = 0.002). The performances of both FIB-4 and NFS were poor in the subgroup of MAFLD with significant alcohol intake. Conclusions The overall diagnostic performance of FIB-4 and NFS for diagnosing advanced fibrosis did not differ among subjects with MAFLD. However, the performance of NFS was lower in the diabetes subgroup of MAFLD. The diagnostic performance of FIB-4 was better for fibrosis in various subgroups of MAFLD. This article is protected by copyright. All rights reserved.

Although universal vaccination has been administered to toddlers, South Korea has had periodic nationwide outbreaks of acute hepatitis A since the late 2000s. We examined the chronological changes in the seroprevalence of anti-hepatitis A virus (HAV) immunoglobulin G (IgG) over the past 15 years (2005-2019). We retrospectively collected data from 45,632 subjects who underwent anti-HAV IgG testing without evidence of acute HAV infection at four centers in the capital area of South Korea between January 2005 and December 2019. The seroprevalence of anti-HAV IgG was analyzed according to age and compared among seven age groups and five time periods. Additionally, age-period-cohort analyses were used to identify the age, period, and cohort effects of the seroprevalence of anti-HAV IgG. The mean age of the enrolled subjects was 39.2 ± 19.2 years, and the average anti-HAV IgG positivity rate was 66.4%. During the 15 years, the seroprevalence of anti-HAV IgG in people aged 0 to 19 years significantly increased over time (P .001). In people aged 20 to 29 years, the seroprevalence slightly decreased to that of the early 2010s (31.3% in 2005-2007 to 19.7% in 2011-2013) but rebounded to 39.5% in 2017 to 2019. In contrast, the seroprevalence of anti-HAV IgG in those aged 30 to 49 years decreased over time (P .001). The seroprevalence of anti-HAV IgG in those aged 20 to 39 years in 2017 to 2019 was still less than 40%. In addition, the seroprevalence of anti-HAV IgG in people aged 50 to 59 years has recently decreased. Since the introduction of the universal vaccination, the seroprevalence of anti-HAV IgG in children and young adults has gradually increased. However, the seroprevalence of anti-HAV IgG in people in their 20s remains low, and the seroprevalence of anti-HAV IgG in people in their 30s and 40s is gradually decreasing. Therefore, a new strategy for HAV vaccination is needed for those in their 20s to 40s.

Background and aimThe current cut-offs for fibrosis-4 (FIB-4) and non-alcoholic fatty liver disease fibrosis score (NFS) are suboptimal for screening because of low accuracy and high false-negative rates in average-risk populations. This study aimed to reappraisal the performance of FIB-4 and NFS in such average-risk populations.MethodsThis is a cross-sectional study, which retrospectively reviewed the magnetic resonance elastography (MRE) data of 8,522 subjects. Individuals with history of significant alcohol consumption and those with positive viral serologic markers were excluded. Finally, 6,215 average-risk individuals were analyzed.ResultsThe area under the receiver operating characteristic curves (AUROCs) of FIB-4 for the diagnosis of advanced hepatic fibrosis was higher than that in the NFS especially in the metabolically healthy. The AUROCs of FIB-4 for in the average-risk population was also higher than that in the NFS (0.840 in FIB-4 vs. 0.798, P = 0.036). However, the sensitivity of FIB-4 and NFS was low (69.6 and 61.4%, respectively) in applying the current cut-off of FIB-4 [1.3 (2.0)] and NFS [-1.455 (0.12)]. At cut-off of FIB-4 at 1.0, sensitivity (90.2%), and negative predictive value (99.7%) were improved.ConclusionThe diagnostic performance of FIB-4 was better than that of NFS for screening hepatic fibrosis in average-risk populations. It is recommended to use FIB-4 rather than NFS, when screening for hepatic fibrosis in general population.

Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR

Background and aimNon-alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction. This study aims to develop biomarkers for assessing mitochondrial dysfunction in patients with NAFLD.MethodsMitochondrion-associated transcriptome analysis was performed. Peripheral blood mononuclear cells obtained from patients with NAFLD (69) and healthy controls (19) were used to determine the mitochondrial DNA (mtDNA) copy number. A mitochondrial inhibition substrate test (ATP assay) was performed in HepG2 cells using the patient serum.ResultsHepatic mRNA transcriptome analysis showed that the gene expression related to mitochondrial functions (mitochondrial fusion, apoptotic signal, and mitochondrial envelope) increased in patients with steatohepatitis, but not in those with NAFL. Gene set enrichment analysis revealed that the upregulated expression of genes is related to the pathways of the tricarboxylic (TCA) cycle and deoxyribonucleic acid (DNA) replication in patients with steatohepatitis, but not in healthy controls. The mtDNA copy number in the peripheral blood mononuclear cells was 1.28-fold lower in patients with NAFLD than that in healthy controls (P P ConclusionThe mitochondrial copy number of peripheral blood mononuclear cells and mitochondrial ATP inhibition substrate can be used as biomarkers for assessing the mitochondrial dysfunction in patients with NAFLD.

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization’s goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan–Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03–1.57% among noncirrhotic males and 2.57–6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients. To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups. In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p

Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.

Background/Aims: This study examined the risk factors associated with mortality in cirrhotic patients hospitalized with variceal bleeding, and evaluated the effects of acute-on-chronic liver failure (ACLF) on the prognosis of these patients.Methods: This study was retrospectively conducted on patients registered in the Korean acute-on-chronic liver failure study cohort, and on 474 consecutive cirrhotic patients hospitalized with variceal bleeding from January 2013 to December 2013 at 21 university hospitals. ACLF was defined as described by the European Association for the Study of Liver-Chronic Liver Failure Consortium.Results: Among a total of 474 patients, 61 patients were diagnosed with ACLF. The cumulative overall survival (OS) rate was lower in the patients with ACLF than in those without (PPPP

The treatment of multidrug-resistant (MDR) chronic hepatitis B (CHB) is challenging. Herein, we report a multicenter prospective cohort study for the evaluation of tenofovir disoproxil fumarate (TDF)-based therapy for MDR CHB in a real-life setting. The inclusion criteria comprised patients with resistance to more than two nucleos(t)ide analogue (NA) classes and hepatitis B virus (HBV) DNA level of ≥200 IU/mL. The primary end-point was virologic response (VR), defined as undetectable HBV DNA (

Acute pancreatitis (AP) severity is determined by associated organ failure (OF). However, enzymatic erosion of peripancreatic vessels can lead to life-threatening hemoperitoneum in clinically non-severe AP without OF. We herein report a case of unexpected hemoperitoneum which developed in a patient with clinically resolving AP without OF. A 36-year-old woman with alcohol use disorder presented with resolving epigastric pain and sustained abdominal distension of 2 weeks’ duration. Ranson’s score on admission was 1 and Computed tomography (CT) revealed non-necrotic AP with peripancreatic fluid collection. She showed sudden hypotension with an abrupt decrease in serum hemoglobin within 24 hours after admission. She was suspected to have an acute hemoperitoneum associated with venous bleeding from AP based on repeated CT. Venous bleeding from the splenic branch was ligated during surgery. The possibility of bleeding at the pancreatic bed should be considered even if the pancreatitis is not severe.

With the wide use of potent and safe nucloes(t-)ide analogues (NAs) treatment, patient-centered care is getting important. Intensive care for comorbidity has gain utmost importance in care of aging chronic hepatitis B (CHB) patients with life-long antiviral treatment. Linkage to care of patients with CHB is essential for the goal of hepatitis B virus (HBV) eradication. As long-term suppression of HBV DNA replication does not prevent hepatocellular carcinoma (HCC), prevention of HCC is another challenge for NAs treatment. There is a possibility of hepatocarcinogenesis in the immune-tolerant phase and risk of loss of patients during active monitoring seeking the time point for antiviral treatment initiation. Initiation of NAs treatment from the immune-tolerant phase would improve the linkage to care. However, universal recommendation is premature and evidence for cost-effectiveness needs to be accumulated. Early initiation of NAs in the evidence of significant disease progression, either HBV associated or comorbidity associated, would be a better strategy to reduce the risk of HCC in patients located in the gray zone.

The purpose of this study was to investigate the proportion of subjects with metabolic dysfunction-associated fatty liver disease (MAFLD) and to assess the degree of hepatic fibrosis and cardiovascular risk in metabolically healthy MAFLD subjects.A total of 6740 subjects who underwent both magnetic resonance elastography and abdominal ultrasound were included in this study. Significant (≥3.0 kPa) and advanced (≥3.6 kPa) hepatic fibrosis were evaluated by magnetic resonance elastography. The metabolic unhealthy status among subjects with MAFLD was defined as the presence of diabetes or 2 or more metabolic risk abnormalities.The prevalence of MAFLD among the health examination cohort was 44.5% (3002 of 6740). A total of 26.6% (800 of 3002) of MAFLD subjects were metabolically healthy (≤1 risk factors and no diabetes), and 56.3% of MAFLD subjects (1691 of 3002) did not have metabolic syndrome. Hepatic fibrosis burden and cardiovascular risk were significantly higher in the metabolic unhealthy MAFLD group than in the healthy control group. However, the prevalence of significant (5.8% vs 4.3%; P = .099) and advanced hepatic fibrosis (0.8% vs 0.7%; P = .934) did not differ between the metabolically healthy MAFLD and healthy control groups. The prevalence of carotid artery plaque in the metabolically healthy MAFLD (32.7% vs 30.7%; P = .453) group was not different from that in the healthy control group.Contrary to the definition of MAFLD, a non-negligible number of metabolically healthy individuals are included in the MAFLD group. The metabolic healthy MAFLD group showed a comparable fibrosis burden and prevalence of carotid artery plaque compared with the healthy control group.

Serum-based noninvasive tests (NITs) have been widely used to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). However, the diagnostic efficacy of NITs across ranges of age, body mass index (BMI), and presence of type 2 diabetes (T2DM) may vary and have not been well-characterized.We analyzed 1489 patients with biopsy-proven NAFLD from 6 centers in Japan, Taiwan, and Korea. Using histology as the gold standard, we compared the areas under the receiver operating characteristic (AUROCs) of Fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), and the new Hepamet fibrosis score (HFS), with a focus on performance in subgroups as stratified by age, BMI, and the presence of T2DM.By histology, 44.0% of the overall cohort (655/1489) had F2-4, and 20.6% (307/1489) had F3-4 fibrosis. FIB-4 had the highest AUROCs for both F2-4 (0.701 vs NFS 0.676 and HFS 0.682, P = .001) and F3-4 (0.767 vs NFS 0.736 and HFS 0.752, P = .002). However, for F3-4 fibrosis, the AUROCs of all 3 NITs were generally higher in older (60 years), nonobese (BMI25 kg/mFIB-4 had higher diagnostic efficacy for F3-4 than NFS or HFS, but this varied greatly by age, BMI, and T2DM, with better performance in older, nonobese, and nondiabetic patients. However, all NITs including FIB-4 had unacceptably poor performance in young or obese diabetic patients.

Previous studies have shown that ultrasonography has high specificity (80%-100%) but low sensitivity (50%-70%) in diagnosing fatty liver; sensitivity is especially low for mild steatosis. In this study, we aimed to reappraise the diagnostic performance of B-mode ultrasonography (B-USG) for fatty liver disease.We performed a retrospective, multinational, multicenter, cross-sectional, observational study (6 referral centers from 3 nations). We included 5,056 participants who underwent both B-USG and magnetic resonance proton density fat fraction (MRI-PDFF) within a 6-month period. The diagnostic performance of B-USG was compared with that of MRI-PDFF as a reference standard for fatty liver diagnosis, using sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and area under the receiver operating characteristic curve (AUC).B-USG showed a sensitivity of 83.4%, specificity of 81.0%, and AUC of 0.822 in diagnosing mild liver steatosis (6.5% ≤MRI-PDFF ≤14%). The sensitivity, specificity, and AUC in diagnosing the presence of fatty liver disease (MRI-PDFF ≥6.5%) were 83.4%, 81.0%, and 0.822, respectively. The mean PDFF of B-USG-diagnosed nonfatty liver differed significantly from that of diagnosed mild liver steatosis (3.5% ± 2.8% vs 8.5% ± 5.0%, P0.001). The interinstitutional variability of B-USG in diagnosing fatty liver was similar in diagnostic accuracy among the 6 centers (range, 82.8%-88.6%, P = 0.416).B-USG was an effective, objective method to detect mild liver steatosis using MRI-PDFF as comparison, regardless of the etiologies and comorbidities.

Background & Aims Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. Methods The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. Results A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26–0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28–0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28–0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00–1.67). Conclusions This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

Several models have recently been developed to predict risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Our aims were to develop and validate an artificial intelligence-assisted prediction model of HCC risk.Using a gradient-boosting machine (GBM) algorithm, a model was developed using 6,051 patients with CHB who received entecavir or tenofovir therapy from 4 hospitals in Korea. Two external validation cohorts were independently established: Korean (5,817 patients from 14 Korean centers) and Caucasian (1,640 from 11 Western centers) PAGE-B cohorts. The primary outcome was HCC development.In the derivation cohort and the 2 validation cohorts, cirrhosis was present in 26.9%-50.2% of patients at baseline. A model using 10 parameters at baseline was derived and showed good predictive performance (c-index 0.79). This model showed significantly better discrimination than previous models (PAGE-B, modified PAGE-B, REACH-B, and CU-HCC) in both the Korean (c-index 0.79 vs. 0.64-0.74; all p0.001) and Caucasian validation cohorts (c-index 0.81 vs. 0.57-0.79; all p0.05 except modified PAGE-B, p = 0.42). A calibration plot showed a satisfactory calibration function. When the patients were grouped into 4 risk groups, the minimal-risk group (11.2% of the Korean cohort and 8.8% of the Caucasian cohort) had a less than 0.5% risk of HCC during 8 years of follow-up.This GBM-based model provides the best predictive power for HCC risk in Korean and Caucasian patients with CHB treated with entecavir or tenofovir.Risk scores have been developed to predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. We developed and validated a new risk prediction model using machine learning algorithms in 13,508 antiviral-treated patients with chronic hepatitis B. Our new model, based on 10 common baseline characteristics, demonstrated superior performance in risk stratification compared with previous risk scores. This model also identified a group of patients at minimal risk of developing HCC, who could be indicated for less intensive HCC surveillance.

Background & AIMS Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. Methods We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. Results The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. Conclusion There is great variability in CHB disease progression rates even among “lower-risk” populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Background & aims There are currently several prediction models for hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) receiving oral antiviral therapy. However, most models are based on pre-treatment clinical parameters. The current study aimed to develop a novel and practical prediction model for HCC by using both pre- and post-treatment parameters in this population. Methods We included two treatment-naive CHB cohorts who were initiated on oral antiviral therapies: the derivation cohort (n=1,480, Korea prospective SAINT cohort) and the validation cohort (n=426, the US retrospective Stanford Bay cohort). We employed logistic regression, decision tree, lasso regression, support vector machine, and random forest algorithms to develop the HCC prediction model and selected the most optimal method. Results We evaluated both pre-treatment and the 12-month clinical parameters on-treatment and found the 12-month on-treatment values to have superior HCC prediction performance. The lasso logistic regression algorithm using the presence of cirrhosis at baseline and alpha-fetoprotein and platelet at 12 months showed the best performance (AUROC=0.843 in the derivation cohort. The model performed well in the external validation cohort (AUROC=0.844) and better than other existing prediction models including the APA, PAGE-B, and GAG models (AUROC=0.769 to 0.818). Conclusions We provided a simple-to-use HCC prediction model based on presence of cirrhosis at baseline and two objective laboratory markers (AFP and platelets) measured 12 months after antiviral initiation. The model is highly accurate with excellent validation in an external cohort from a different country (AUROC 0.844). (Clinical trial number: KCT0003487).

Background Chronic hepatitis B is the most common cause of liver cirrhosis in South Korea. However, alcoholic liver disease has shown an increasing trend. Although the clinical implications surrounding liver cirrhosis have been changing over the years, few studies have recently examined cirrhosis epidemiology. Therefore, we aimed to investigate changes in liver cirrhosis etiology and severity in Korea. Methods We retrospectively reviewed 16,888 records of cirrhotic patients from six tertiary hospitals in Korea from 2008 to 2017. Continuous and non-continuous variables were processed via linear and Poisson regression, expressed as beta (B) coefficients and as exponentiated values of coefficients (Exp[B]), respectively. Results Chronic hepatitis B showed a decreasing trend (Exp[B] = 0.975, P < 0.001), whereas alcohol showed an increasing trend (Exp[B] = 1.013, P = 0.003), occupying the most common etiology in 2017. The Child-Turcotte-Pugh (CTP) score and decompensated liver cirrhosis prevalence did not change over the 10-year period. The incidence of variceal bleeding, severe ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis significantly decreased from 12.3% to 7.7%, 7.8% to 4.1%, 1.0% to 0.5%, and 1.9% to 1.1%, respectively (P < 0.05 for all). In the subgroup analysis, the chronic hepatitis B group showed improving CTP scores (B = −0.025, P < 0.001) and decreasing decompensated liver cirrhosis rates (Exp[B] = 0.977, P = 0.016), whereas the alcohol group demonstrated increasing CTP class C (Exp[B] = 1.031, P = 0.005) and model for end-stage liver disease scores (B = 0.081, P = 0.005) over 10 years. Conclusion The chronic hepatitis B group exhibited improved results, whereas the alcohol group still presented poor liver functions and outcomes. Future national policies and systematic approaches addressing the incidence, prevention, and treatment of alcoholic liver cirrhosis are indispensable., Graphical Abstract

BACKGROUND AND AIM Stem cell treatments using scaffolds for liver disease have been well studied. However, macro-encapsulation of mesenchymal stem cells (MSCs) to minimize or inhibit stem cell homing has not been evaluated. Here, we conducted a proof-of-concept study using MSCs macro-encapsulated in poly lactic-co-glycolic acid in liver disease models. METHODS Poly lactic-co-glycolic acid semipermeable membranes (surface pore size up to 40 μm) were used as the macro-encapsulation system. Macro-encapsulated pouches were loaded with MSCs and sealed. Each pouch was implanted in the subcutaneous region of the dorsum or interlobular space of the liver. Acute liver injury was induced using thioacetamide intraperitoneal injection thrice a week. For the chronic liver fibrosis model, thioacetamide dose was gradually increased, starting from 100 to 400 mg/kg over 16 weeks (thrice a week). RESULTS In the acute liver injury model, the treated groups showed decreased liver inflammation and necrosis compared with the control. Hepatic fibrosis decreased in the treated group in the chronic liver fibrosis model compared with that in the control group. Encapsulated MSCs exhibited changed cell morphology and characteristics after implantation, showing increased periodic acid-Schiff staining and CYP2E1 expression. Migration and homing of MSCs into the liver was not observed. Under hypoxic conditions, macro-encapsulated MSCs secreted more growth hormones, including vascular endothelial growth factor, platelet-derived growth factor, angiopoietin-2, and placental growth factor, than monolayered MSCs in vitro. CONCLUSIONS Macro-encapsulated MSCs attenuate hepatic inflammation and fibrosis by upregulating hypoxia-induced growth hormone secretion in liver disease models.

Context Large-scale clinical trials on the hepatotoxicity of ulipristal acetate (UPA) are lacking. Objective This work aimed to determine the incidence of liver disease with UPA vs gonadotropin-releasing hormone (GnRH) agonists. Methods A retrospective cohort study was conducted in South Korea of women with uterine fibroids from the Korean Health Insurance Data 2010 to 2018. Women with uterine fibroids were divided into 2 treatment groups: the UPA (5 mg/day) and GnRH agonist groups. Main outcome measures included the presence or absence of severe liver disease, mild liver disease, and liver transplantation. Results Among the patients with uterine fibroids,17 207 patients were treated with GnRH agonists and 20 926 patients with UPA. After 1:1 propensity score matching for each group, there were 11 445 individuals. Neither group had a liver transplantation case. In the conditional logistic regression analysis, the incidence of total liver diseases (relative risk [RR] 1.111; 95% CI, 1.015-1.216) and mild liver diseases (RR 1.094; 95% CI, 1-1.196) was higher in the UPA group than in the GnRH agonist group, but that of severe liver diseases (RR 0.07; 95% CI, 0.001-4.412) and toxic liver disease (RR 1.256; 95% CI, 0.845-1.867) did not differ between the groups. Conclusion The incidence of severe liver disease, hepatic failure, and toxic liver disease was not different between the UPA and GnRH agonist groups. However, the incidence of mild liver disease was higher in the UPA group than in the GnRH agonist group. The incidence of hepatic damage with UPA was very low.

Despite HCV cure, patients remain at risk for HCC, but risk factor data for HCC following SVR are limited for Asian patients.To address this gap, we analyzed 5814 patients (5646 SVR, 168 non-SVR) from the Real-World Evidence from the Asia Liver Consortium for HCV (REAL-C) who did not have HCC or a history of HCC at baseline (pre-DAA treatment) and did not develop HCC within 6 months of baseline. To assess the effect of SVR on HCC incidence, we used 1:4 propensity score matching [(PSM), age, sex, baseline cirrhosis, and baseline AFP] to balance the SVR and non-SVR groups.In the PSM cohort (160 non-SVR and 612 SVR), the HCC incidence rate per 100 person years was higher in the non-SVR compared to the SVR group (5.26 vs. 1.94, p 0.001). Achieving SVR was independently associated with decreased HCC risk (adjusted HR [aHR]: 0.41, p = 0.002). Next, we stratified the SVR cohort of 5646 patients to cirrhotic and noncirrhotic subgroups. Among cirrhotic SVR patients, aged ≥ 60, having an albumin bilirubin grade (ALBI) of 2 or 3 (aHR: 2.5, p 0.001), and baseline AFP ≥ 10 ng/mL (aHR: 1.6, p = 0.001) were associated with higher HCC risk, while among the non-cirrhotic SVR group, only baseline AFP ≥ 10 ng/mL was significant (aHR: 4.26, p = 0.005).Achieving SVR decreases HCC risk; however, among East Asians, patients with elevated pretreatment AFP remained at risk. Pretreatment AFP, an easily obtained serum marker, may provide both prognostic and surveillance value for HCC in East Asian patients who obtained SVR.

Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions.We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria.Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment.Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

Goals: We aimed to investigate significant factors influencing the long-term prognosis of patients who survived acute-on-chronic liver failure (ACLF). Background: The mortality of ACLF is predominantly affected by the organ failure severity. However, long-term outcomes of patients who survive ACLF are not known. Study: A cohort of 1084 cirrhotic patients who survived for more than 3 months following acute deterioration of liver function was prospectively followed. ACLF was defined by the European Association for the Study of the Liver Chronic Liver Failure Consortium definition. Results: The mean follow-up duration was 19.4±9.9 months. In the subgroup of patients without previous acute decompensation (AD), ACLF occurrence did not affect long-term outcomes. However, in patients with previous AD, ACLF negatively affected long-term transplant-free survival even after overcoming ACLF (hazard ratio, 2.00, P=0.012). Previous AD was the significant predictive factor of long-term mortality and was independent of the Model for End-stage Liver Disease score in these ACLF-surviving patients. Organ failure severity did not affect transplant-free survival in patients who survived an ACLF episode. Conclusions: A prior history of AD is the most important factor affecting long-term outcomes following an ACLF episode regardless of Model for End-stage Liver Disease score. Prevention of a first AD episode may improve the long-term transplant-free survival of liver cirrhosis patients.

We read the commentary by Francque and Wong1 with great interest. They pointed out that metabolic dysfunction could be the main factor associated with an increased risk of hepatic fibrosis among lean patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear whether the definition of metabolic dysfunction would also fit lean patients, who are less likely to have metabolic risks.2 Herein, we evaluated the fibrosis burden in lean patients with NAFLD according to the presence of each metabolic dysfunction component. We analysed participants in a community-based cohort, all of whom have undergone magnetic resonance elastography (MRE) for their health check-up (N=6775, 100% single ethnic Korean). Fatty liver was diagnosed by ultrasonography. The prevalence of NAFLD and lean (body mass index

Background and Aim The aim of this study was to validate the Chronic Liver Failure-Sequential Organ Failure Assessment score (CLIF-SOFAs), CLIF consortium organ failure score (CLIF-C OFs), CLIF-C acute-on-chronic liver failure score (CLIF-C ACLFs), and CLIF-C acute decompensation score (CLIF-C ADs) in Korean chronic liver disease patients with acute deterioration. Methods ACLF was defined by either the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) or CLIF-C criteria. The diagnostic performances for short-term mortality were compared by the area under the receiver operating characteristics (AUROC) curve. Results Among a total of 1470 patients, 252 patients were diagnosed with ACLF according to the CLIF-C (197 patients) or AARC definition (95 patients). As the ACLF grades increased, the survival rates became significantly lower. The AUROCs of the CLIF-SOFAs, CLIF-C OFs and CLIF-C ACLFs were significantly higher than those of the Child-Pugh, Model for End-stage Liver Disease (MELD), and MELD-Na scores in ACLF patients according to the CLIF-C definition (all P

Linkage-to-care rate of chronic hepatitis B (CHB) is less well characterized. We aimed to evaluate the proportion, characteristics of CHB patients who are linked to care. We retrospectively analyzed insurance reimbursement claims data provided by the Korean National Health Insurance Service. CHB patients who had at least two clinic or hospital visits that were associated with a CHB diagnostic code during 2002–2006 were included. Those without a history of malignancy at baseline were followed up until 2018. Mean follow-up period was 14.5 ± 2.9 years. Among the participants, 553,085 patients (35.8%) were found to be linked to care. The rates were lower in men than women (35.7% vs. 36.0%, p = 0.006). By age, it was highest for the 40′s age group at 44.8% and lowest at 29.4% for the 20′s age group (All p &lt, 0.0001). The linkage-to-care rate was higher in rural area than metropolitan area (p &lt, 0.0001). The 15-year cumulative incidence of hepatocellular carcinoma and overall survival rates among linked-to-care CHB patients were 18.2% and 93.8%, respectively. Two thirds of CHB patients were not linked to care. Those who are male, dwelling in metropolitan areas, and not in life transition periods need to be targeted to improve the linkage-to-care rate in Korea.

Recently, the classification of fatty liver and the definition for non-alcoholic fatty liver disease (NAFLD) have been challenged. Herein, we aim to evaluate the burden of hepatic fibrosis in the missed and added populations following the proposal of the new definition of metabolic dysfunction-associated fatty liver (MAFLD) in a health check-up cohort. A total of 6775 subjects underwent both magnetic resonance elastography (MRE) and an abdominal ultrasound at 13 nationwide health check-up centers in Korea. Significant and advanced hepatic fibrosis was defined as ≥3.0 kPa and ≥3.6 kPa in the MRE test, respectively. The prevalence of sonographic fatty liver (FL) was 47.4%. Among the subjects with sonographic FL, 77.3% and 94% are compatible with NAFLD and with the new MAFLD definitions, respectively. Moreover, 72% of FL cases belong to both the NAFLD and MAFLD definitions, whereas 1.4% is compatible with neither. The population compatible with the MAFLD definition has the following coexisting liver diseases: alcohol-related (71.9%), hepatitis B (23.9%), hepatitis C (0.4%), and both alcohol and viral hepatitis (2.8%). The prevalence of significant and advanced hepatic fibrosis is considerable in the MAFLD-only group. However, the prevalence of significant and advanced hepatic fibrosis is similar in the NAFLD-only group, and neither the NAFLD nor MAFLD group compared to healthy controls. The added population (MAFLD-only group), according to the new MAFLD definition, has a higher metabolic and fibrosis burden when compared to those in the missed population (NAFLD-only group).

Hepatitis A virus is one of the most frequent causes of foodborne infection, which is closely associated with sanitary conditions and hygienic practices. The clinical spectrum of acute hepatitis A is wide, ranging from mild case without any noticeable symptoms to severe case with acute liver failure leading to mortality. The severity and outcome are highly correlated with age at infection. In developing countries, most people are infected in early childhood without significant symptom. Ironically, in area where sanitary condition has improved rapidly, adults who do not have immunity for viral hepatitis A (VH-A) in early childhood is accumulating. Adults without immunity are exposed to risks of symptomatic disease and large outbreaks in society. In Korea, where hygiene has improved rapidly, acute hepatitis A is a significant health burden that needs to be managed with nationwide health policy. The incidence of symptomatic VH-A has increased since 2000 and peaked in 2009. Korea has designated hepatitis A as a group 1 nationally notifiable infectious disease in 2001. Since 2001, mandatory surveillance system has been established to detect every single case of acute hepatitis A. Universal, nationwide vaccination program for newborns was introduced in 2015. In this review, we will present the current epidemiologic status of viral hepatitis A, and evaluate the effectiveness of the current nationwide strategies for the control of viral hepatitis A in Korea. Furthermore, we presented some action proposals that can help eliminate viral hepatitis A, which is a significant health burden in Korea.

Background/Aims Sorafenib is the first approved systemic treatment for advanced hepatocellular carcinoma (HCC). However, its clinical utility is limited, especially in Asian countries. Several reports have suggested the survival benefits of hepatic arterial infusion chemotherapy (HAIC) for advanced HCC with main portal vein tumor thrombosis (PVTT). This study aimed to compare the efficacy of sorafenib-based therapy with that of HAIC-based therapy for advanced HCC with main PVTT. Methods Advanced HCC patients with main PVTT treated with sorafenib or HAIC between 2008 and 2016 at Korea University Medical Center were included. We evaluated overall survival (OS), time-to-progression (TTP), and the disease control rate (DCR). Results Seventy-three patients were treated with sorafenib (n=35) or HAIC (n=38). Baseline characteristics were not significantly different between groups, except the presence of solid organ metastasis (46% vs 5.3%, p

Background & Aims Studies to evaluate risks of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with the nucelos(t)ide analogues entecavir or tenofovir have produced contradictory results. These differences are likely to be the result of censored data, insufficient observation periods, and different observation periods for patients treated with different drugs. We aimed to compare the incidence of HCC development between patients treated with oral entecavir or tenofovir and followed up for the same time periods. Methods We performed a retrospective study, collecting data from 1560 treatment-naive patients with chronic HBV infection who were first treated with entecavir (n = 753) or tenofovir (n = 807) from 2011 through 2015 at 9 academic hospitals in Korea. Clinical outcomes were recorded over a mean time period of 4.7 ± 1.0 years, from 92.4% of patients treated with tenofovir and 92.7% of patients treated with entecavir. Results Thirty-four patients in the entecavir group (4.5%) and 45 patients in the tenofovir group (5.6%) developed HCC during the follow-up period. The incidence of HCC did not differ significantly between groups, even in a 516-pair propensity score–matched population. Conclusions In a retrospective study of 1560 treatment-naive patients with chronic HBV infection, the incidence of HCC did not differ significantly between patients treated with entecavir vs tenofovir over the same observation period. Clinical trial: KCT0003487.

The burden of minimal hepatic encephalopathy (MHE) is significant, but no universal criteria for diagnosis have been established. We aimed to validate the Korean Stroop Test for MHE screening. Chronic hepatitis B-related liver cirrhosis patients were recruited prospectively from 13 centers. The Korean Stroop Test consisted of two Stroop-off states (color and word) and two Stroop-on states (inhibition and switching). Accuracy adjusted psychomotor speed (rate correct score) of these tests were analyzed. Sex- and age- adjusted rate correct scores of these tests were rated as the Korean Stroop Score (K-Stroop score). MHE was diagnosed when Portosystemic Encephalopathy Syndrome Test (PHES) scores were below −4. A total of 220 liver cirrhosis patients and 376 healthy controls were enrolled. Prevalence of MHE was 20.6% in cirrhosis patients. Rate correct scores and the K-Stroop score showed significant differences between healthy controls, cirrhosis patients without MHE, and cirrhosis patients with MHE. The rate correct score of the K-Stroop score was 0.74 (95% Confidence Interval: 0.66–0.83, P

Background & Aim Although the ideal end point for antiviral treatment in patients with chronic hepatitis B (CHB) is loss of HBsAg, the typical clinical end points are HBeAg seroconversion in HBeAg-positive patients and long-term DNA suppression in HBeAg-negative patients. We evaluated the long-term antiviral response after cessation of lamivudine treatment in CHB patients. Methods A total of 157 patients who had discontinued lamivudine between 1997 and 2014 were enrolled (97 HBeAg-positive and 60 HBeAg-negative CHB patients). The long-term durability of the antiviral response (viralogical relapse; HBV DNA ≥ 104 copies/mL) and the clinical course of these patients were analyzed retrospectively. Results In HBeAg-positive patients, the mean follow-up period after discontinuation was 72.3 months. The cumulative probabilities of virological relapse at 1, 12, 24, 48, 60, 96, and 120 months were 10.3%, 40.2%, 55.6%, 62.8%, 65.9%, 67.0%, and 67.0%, respectively. In HBeAg-negative patients, the cumulative probabilities of a virological relapse at 1, 12, 24, 48, 60, 96, and 120 months were 25.0%, 35.0%, 41.7%, 43.3%, 43.3%, 46.7%, and 48.3%, respectively. Younger age [HR 1.732, 95% CI: 1.058–2.835, p = 0.02] was predictive of non-virological relapse in HBeAg-positive patients. And achievement of undetectable HBV DNA level within 3 months of treatment discontinuation was associated with decreased rate of virological relapse [HR 0.159, 95% CI: 0.069–0.367 p

The aim of this study was to validate the chronic liver failure-sequential organ failure assessment score (CLIF-SOFAs), CLIF consortium organ failure score (CLIF-C OFs), CLIF-C acute-on-chronic liver failure score (CLIF-C ACLFs), and CLIF-C acute decompensation score in Korean chronic liver disease patients with acute deterioration.Acute-on-chronic liver failure was defined by either the Asian Pacific Association for the study of the Liver ACLF Research Consortium (AARC) or CLIF-C criteria. The diagnostic performances for short-term mortality were compared by the area under the receiver operating characteristic curve.Among a total of 1470 patients, 252 patients were diagnosed with ACLF according to the CLIF-C (197 patients) or AARC definition (95 patients). As the ACLF grades increased, the survival rates became significantly lower. The areas under the receiver operating characteristic of the CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs were significantly higher than those of the Child-Pugh, model for end-stage liver disease, and model for end-stage liver disease-Na scores in ACLF patients according to the CLIF-C definition (all P 0.05), but there were no significant differences in patients without ACLF or in patients with ACLF according to the AARC definition. The CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs had higher specificities with a fixed sensitivity than liver specific scores in ACLF patients according to the CLIF-C definition, but not in ACLF patients according to the AARC definition.The CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs are useful scoring systems that provide accurate information on prognosis in patients with ACLF according to the CLIF-C definition, but not the AARC definition.