Chronic hepatitis B baseline viral load and on-treatment liver cancer risk: A multinational cohort study of HBeAg-positive patients.

BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.

Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis B.

BACKGROUND & AIMS: The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB). METHODS: Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching. RESULTS: A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n = 39,897 [96.1%]) and TDF (n = 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1-58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56-1.73, p = 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11-2.93, p = 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%-3.4%) vs. 2.6% (1.9%-3.5%), 6.4% (5.0%-8.2%) vs. 4.7% (3.8%-6.0%), and 10.2% (8.3%-12.6%) vs. 6.8% (5.4%-8.5%), respectively. CONCLUSIONS: The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities. IMPACT AND IMPLICATIONS: Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities.

A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance. METHODS: A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from six centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n = 944), internal validation (n = 1,102), and external validation (n = 2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death. RESULTS: During a median follow-up of 55.2 (IQR 30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. The model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and seven variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all p <0.001; area under the receiver-operating characteristic curve: 0.86 vs. 0.62-0.72, all p <0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all p <0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test p >0.05) and these results were reproduced in the internal and external validation cohorts. CONCLUSION: This novel machine learning model consisting of seven variables provides reliable risk prediction of LROs after HBsAg seroclearance that can be used for personalized surveillance. IMPACT AND IMPLICATIONS: Using large-scale multinational data, we developed a machine learning model to predict the risk of liver-related outcomes (i.e., hepatocellular carcinoma, decompensation, and liver-related death) after the functional cure of chronic hepatitis B (CHB). The new model named PLAN-B-CURE was constructed using seven variables (age, sex, alcohol consumption, diabetes, cirrhosis, serum albumin, and platelet count) and a gradient boosting machine algorithm, and it demonstrated significantly better predictive accuracy than previous models in both the training and validation cohorts. The inclusion of diabetes and significant alcohol intake as model inputs suggests the importance of metabolic risk factor management after the functional cure of CHB. Using seven readily available clinical factors, PLAN-B-CURE, the first machine learning-based model for risk prediction after the functional cure of CHB, may serve as a basis for individualized risk stratification.

A Liver Stiffness-Based Etiology-Independent Machine Learning Algorithm to Predict Hepatocellular Carcinoma.

BACKGROUND & AIMS: The existing hepatocellular carcinoma (HCC) risk scores have modest accuracy, and most are specific to chronic hepatitis B infection. In this study, we developed and validated a liver stiffness-based machine learning algorithm (ML) for prediction and risk stratification of HCC in various chronic liver diseases (CLDs). METHODS: MLs were trained for prediction of HCC in 5155 adult patients with various CLDs in Korea and further tested in 2 prospective cohorts from Hong Kong (HK) (N = 2732) and Europe (N = 2384). Model performance was assessed according to Harrell's C-index and time-dependent receiver operating characteristic (ROC) curve. RESULTS: We developed the SMART-HCC score, a liver stiffness-based ML HCC risk score, with liver stiffness measurement ranked as the most important among 9 clinical features. The Harrell's C-index of the SMART-HCC score in HK and Europe validation cohorts were 0.89 (95% confidence interval, 0.85-0.92) and 0.91 (95% confidence interval, 0.87-0.95), respectively. The area under ROC curves of the SMART-HCC score for HCC in 5 years was ≥0.89 in both validation cohorts. The performance of SMART-HCC score was significantly better than existing HCC risk scores including aMAP score, Toronto HCC risk index, and 7 hepatitis B-related risk scores. Using dual cutoffs of 0.043 and 0.080, the annual HCC incidence was 0.09%-0.11% for low-risk group and 2.54%-4.64% for high-risk group in the HK and Europe validation cohorts. CONCLUSIONS: The SMART-HCC score is a useful machine learning-based tool for clinicians to stratify HCC risk in patients with CLDs.

Role of Early On-Treatment Serum HBV RNA Declines in Predicting Hepatocellular Carcinoma Risk in Patients With Chronic Hepatitis B.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk prediction models established in patients with chronic hepatitis B receiving a nucleos(t)ide analogue (NA) rarely include viral factors because of mediocre predictability of traditional viral markers. Here, we investigate the role of serum hepatitis B virus (HBV) RNA, a novel biomarker, in predicting HCC risk in NA-treated patients. METHODS: A total of 1374 NA-treated patients were enrolled from 2 prospective chronic hepatitis B cohorts. Serum HBV RNA was detected at baseline, year 1, 2 and 3 of treatment. Cox proportional-hazard model was used to investigate the association of HBV RNA kinetics with HCC risk. RESULTS: After a median follow-up of 5.4 years, 76 patients developed HCC. HBV RNA declines at year 1 (adjusted hazard ratio, 0.70, P = .009) and 2 (adjusted hazard ratio, 0.71; P = .016) were independently associated with HCC risk. Patients with less HBV RNA decline at year 1 (≤0.4 log10 copies/mL) or 2 (≤0.6 log10 copies/mL) had 2.22- and 2.09-folds higher HCC risk, respectively, than those with more declines. When incorporating these early on-treatment HBV RNA declines into existing HCC risk scores, including PAGE-B (age, sex, and platelets), modified PAGE-B (mPAGE-B) (age, sex, platelets, and albumin), and aMAP (age, sex, platelets, and albumin-bilirubin score) score, they could enhance their predictive performance (ie, C-index 0.814 vs 0.78 [model (PAGE-B + year-1 HBV RNA decline) vs PAGE-B score based on baseline parameters]). CONCLUSIONS: Serum HBV RNA declines at year 1 and 2 were significantly associated with on-treatment HCC risk. Incorporating early on-treatment HBV RNA declines into HCC risk prediction models can be useful tools to guide appropriate surveillance strategies in NA-treated patients.

Baseline Viral Load and On-treatment Hepatocellular Carcinoma Risk in Chronic Hepatitis B: A Multinational Cohort Study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk persists in patients with chronic hepatitis B (CHB) despite antiviral therapy. The relationship between pre-treatment baseline hepatitis B virus (HBV) viral load and HCC risk during antiviral treatment remains uncertain. METHODS: This multinational cohort study aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in 20,826 noncirrhotic, hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with baseline HBV DNA levels ≥2000 IU/mL (3.30 log10 IU/mL) who initiated entecavir or tenofovir treatment. The primary outcome was on-treatment HCC incidence, stratified by baseline HBV viral load as a categorical variable. RESULTS: In total, 663 patients developed HCC over a median follow-up of 4.1 years, with an incidence rate of 0.81 per 100 person-years (95% confidence interval [CI], 0.75-0.87). Baseline HBV viral load was significantly associated with HCC risk in a non-linear parabolic pattern, independent of other factors. Patients with baseline viral load between 6.00 and 7.00 log10 IU/mL had the highest on-treatment HCC risk (adjusted hazard ratio, 4.28; 95% CI, 2.15-8.52; P < .0001) compared with those with baseline viral load ≥8.00 log10 IU/mL, who exhibited the lowest HCC risk. CONCLUSION: Baseline viral load showed a significant, non-linear, parabolic association with HCC risk during antiviral treatment in noncirrhotic patients with CHB. Early initiation of antiviral treatment based on HBV viral load may help prevent irreversible HCC risk accumulation in patients with CHB.

Dynamic Changes in ELF Score Predict Hepatocellular Carcinoma in Chronic Hepatitis B Patients Receiving Antiviral Treatment.

Enhanced liver fibrosis (ELF) score is a noninvasive assessment for liver fibrosis. We aimed to evaluate the performance of changes in ELF score 3 years apart in combination with liver stiffness measurement (LSM)-hepatocellular carcinoma (HCC) score to predict HCC in chronic hepatitis B (CHB) patients. This is a prospective cohort study. Patients who underwent transient elastography (TE) examinations and at intermediate or high risk of HCC defined by LSM-HCC score were invited to repeat the examination about 3 years later. Their serum samples at these two time points were retrieved to assess the ELF score changes. The primary endpoint was HCC. There were 445 CHB patients (males: 73.9%; mean age: 51.6 ± 10.3 years) who received two TE examinations and ELF scores. Among them, 252 (56.6%) and 193 (43.4%) patients were at intermediate and high HCC risk at first assessment defined by LSM-HCC score, respectively. Kaplan-Meier analysis showed that the changes in ELF score could stratify the HCC risk in both intermediate- and high-risk patients defined by LSM-HCC score (p < 0.001 for intermediate-risk group; p = 0.011 for high-risk group). Patients remained having mild or moderate fibrosis at both assessments had the lowest risk of HCC (4.0%), followed by patients with fibrosis regressed (11.3%; p = 0.014) during a mean follow-up of 163 months. Patients remained having or progressed to severe fibrosis were at highest risk of HCC (>20%). Consistent findings were demonstrated in patients at both intermediate and high risk of HCC defined by LSM-HCC score. Dynamic changes in ELF score provided additional value to LSM-HCC score for stratifying HCC risk in CHB patients.

Geographical similarity and differences in the burden and genetic predisposition of NAFLD.

NAFLD has become a major public health problem for more than 2 decades with a growing prevalence in parallel with the epidemic of obesity and type 2 diabetes (T2D). The disease burden of NAFLD differs across geographical regions and ethnicities. Variations in prevalence of metabolic diseases, extent of urban-rural divide, dietary habits, lifestyles, and the prevalence of NAFLD risk and protective alleles can contribute to such differences. The rise in NAFLD has led to a remarkable increase in the number of cases of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver-related mortality related to NAFLD. Moreover, NAFLD is associated with multiple extrahepatic manifestations. Most of them are risk factors for the progression of liver fibrosis and thus worsen the prognosis of NAFLD. All these comorbidities and complications affect the quality of life in subjects with NAFLD. Given the huge and growing size of the population with NAFLD, it is expected that patients, healthcare systems, and the economy will suffer from the ongoing burden related to NAFLD. In this review, we examine the disease burden of NAFLD across geographical areas and ethnicities, together with the distribution of some well-known genetic variants for NAFLD. We also describe some special populations including patients with T2D, lean patients, the pediatric population, and patients with concomitant liver diseases. We discuss extrahepatic outcomes, patient-reported outcomes, and economic burden related to NAFLD.

Duration of type 2 diabetes and liver-related events in nonalcoholic fatty liver disease: A landmark analysis.

BACKGROUND AND AIMS: We aimed to determine the impact of the duration of type 2 diabetes (T2D) on the risk of liver-related events and all-cause mortality in patients with NAFLD. APPROACH AND RESULTS: We conducted a territory-wide cohort study of adult patients with NAFLD diagnosed between January 1, 2000, and July 31, 2021, in Hong Kong. T2D was defined by the use of any antidiabetic agents, laboratory tests, and/or diagnosis codes. The primary endpoint was liver-related events, defined as a composite endpoint of HCC and cirrhotic complications. To conduct a more granular assessment of the duration of T2D, we employed landmark analysis in four different ages of interest (biological age of 40, 50, 60, and 70 years). By multivariable analysis with adjustment of non-liver-related deaths, compared with patients without diabetes at age 60 (incidence rate of liver-related events: 0.70 per 1,000 person-years), the adjusted subdistribution HR (SHR) of liver-related events was 2.51 (95% CI: 1.32-4.77; incidence rate: 2.26 per 1,000 person-years) in patients with T2D duration < 5 years, 3.16 (95% CI: 1.59-6.31; incidence rate: 2.54 per 1,000 person-years) in those with T2D duration of 6-10 years, and 6.20 (95% CI: 2.62-14.65; incidence rate: 4.17 per 1000 person-years) in those with T2D duration more than 10 years. A similar association between the duration of T2D and all-cause mortality was also observed. CONCLUSIONS: Longer duration of T2D is significantly associated with a higher risk of liver-related events and all-cause mortality in patients with NAFLD.

Age and the relative importance of liver-related deaths in nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: It is unclear if the leading causes of death in patients with NAFLD differ by age. We aimed to investigate if the relative importance of liver-related deaths is lower and overshadowed by cardiovascular and cancer-related deaths in the elderly population. APPROACH AND RESULTS: We conducted a territory-wide retrospective cohort study of adult patients with NAFLD between 2000 and 2021 in Hong Kong. The outcomes of interest were all-cause and cause-specific mortality. Age groups at death were studied at 10-year intervals. During 662,471 person-years of follow-up of 30,943 patients with NAFLD, there were 2097 deaths. The top three causes of death were pneumonia, extrahepatic cancer, and cardiovascular diseases. Liver disease was the sixth leading cause of death in patients aged 70-79 and 80-89 years, accounting for 5.1% and 5.9% of deaths, respectively, but only accounted for 3% or fewer of the deaths in the other age groups. Nonetheless, liver disease was the leading cause of death in patients with NAFLD-related cirrhosis, accounting for 36.8% of all deaths. The incidence of liver-related death was higher in men younger than age 70 but higher in women afterwards. The incidence of liver-related death in women increased from 0.62 to 7.14 per 10,000 person-years from age 60-69 to 70-79 years. CONCLUSION: The relative importance of liver-related death increases with age in patients with NAFLD, especially among women. In patients with cirrhosis, liver disease is the leading cause of death.

AI-powered prediction of HCC recurrence after surgical resection: Personalised intervention opportunities using patient-specific risk factors.

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence following surgical resection remains a significant clinical challenge, necessitating reliable predictive models to guide personalised interventions. In this study, we sought to harness the power of artificial intelligence (AI) to develop a robust predictive model for HCC recurrence using comprehensive clinical datasets. METHODS: Leveraging data from 958 patients across multiple centres in Australia and Hong Kong, we employed a multilayer perceptron (MLP) as the optimal classifier for model generation. RESULTS: Through rigorous internal cross-validation, including a cohort from the Chinese University of Hong Kong (CUHK), our AI model successfully identified specific pre-surgical risk factors associated with HCC recurrence. These factors encompassed hepatic synthetic function, liver disease aetiology, ethnicity and modifiable metabolic risk factors, collectively contributing to the predictive synergy of our model. Notably, our model exhibited high accuracy during cross-validation (.857 ± .023) and testing on the CUHK cohort (.835), with a notable degree of confidence in predicting HCC recurrence within accurately classified patient cohorts. To facilitate clinical application, we developed an online AI digital tool capable of real-time prediction of HCC recurrence risk, demonstrating acceptable accuracy at the individual patient level. CONCLUSION: Our findings underscore the potential of AI-driven predictive models in facilitating personalised risk stratification and targeted interventions to mitigate HCC recurrence by identifying modifiable risk factors unique to each patient. This model aims to aid clinicians in devising strategies to disrupt the underlying carcinogenic network driving recurrence.

Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Machine-learning model comprising five clinical indices and liver stiffness measurement can accurately identify MASLD-related liver fibrosis.

BACKGROUND & AIMS: aMAP score, as a hepatocellular carcinoma risk score, is proven to be associated with the degree of chronic hepatitis B-related liver fibrosis. We aimed to evaluate the ability of aMAP score for metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD)-related fibrosis diagnosis and establish a machine-learning (ML) model to improve the diagnostic performance. METHODS: A total of 946 biopsy-proved MASLD patients from China and the United States were included in the analysis. The aMAP score, demographic/clinical indices and liver stiffness measurement (LSM) were included in seven ML algorithms to build fibrosis diagnostic models in the training set (N = 703). The performance of ML models was evaluated in the external validation set (N = 125). RESULTS: The AUROCs of aMAP versus fibrosis-4 index (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) in cirrhosis and advanced fibrosis were (0.850 vs. 0.857 [P = 0.734], 0.735 [P = 0.001]) and (0.759 vs. 0.795 [P = 0.027], 0.709 [P = 0.049]). When using dual cut-off values, aMAP had a smaller uncertainty area and higher accuracy (26.9%, 86.6%) than FIB-4 (37.3%, 85.0%) and APRI (59.0%, 77.3%) in cirrhosis diagnosis. The seven ML models performed satisfactorily in most cases. In the validation set, the ML model comprising LSM and 5 indices (including age, sex, platelets, albumin and total bilirubin used in aMAP calculator), built by logistic regression algorithm (called LSM-plus model), exhibited excellent performance. In cirrhosis and advanced fibrosis detection, the LSM-plus model had higher accuracy (96.8%, 91.2%) than LSM alone (86.4%, 67.2%) and Agile score (76.0%, 83.2%), respectively. Additionally, the LSM-plus model also displayed high specificity (cirrhosis: 98.3%; advanced fibrosis: 92.6%) with satisfactory AUROC (0.932, 0.875, respectively) and sensitivity (88.9%, 82.4%, respectively). CONCLUSIONS: The aMAP score is capable of diagnosing MASLD-related fibrosis. The LSM-plus model could accurately identify MASLD-related cirrhosis and advanced fibrosis.

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with impaired renal function, and both diseases often occur alongside other metabolic disorders. However, the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear. The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients. METHODS: All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study. Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase (FAST), Agile 3+ and Agile 4 scores. Impaired renal function and chronic kidney disease (CKD) were defined by an estimated glomerular filtration rate (eGFR) with value of < 90 mL/min/1.73 m2 and < 60 mL/min/1.73 m2, respectively, as estimated by the CKD-Epidemiology Collaboration (CKD-EPI) equation. RESULTS: Among 529 included NAFLD patients, the prevalence rates of impaired renal function and CKD were 37.4% and 4.9%, respectively. In multivariate analysis, a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+ and Agile 4 scores were independent risk factors for CKD (P< 0.05). Furthermore, increased fasting plasma glucose (FPG) and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome (P< 0.05). Compared with patients with normoglycemia, those with prediabetes [FPG ≥ 5.6 mmol/L or hemoglobin A1c (HbA1c) ≥ 5.7%] were more likely to have impaired renal function (P< 0.05). CONCLUSIONS: Agile 3+ and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD. Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Clinical care pathway to detect advanced liver disease in patients with type 2 diabetes through automated fibrosis score calculation and electronic reminder messages: a randomised controlled trial.

OBJECTIVE: We aimed to test the hypothesis that automated fibrosis score calculation and electronic reminder messages could increase the detection of advanced liver disease in patients with type 2 diabetes. DESIGN: In this pragmatic randomised controlled trial at five general medical or diabetes clinics in Hong Kong and Malaysia, we randomly assigned patients in a 1:1 ratio to the intervention group with Fibrosis-4 index and aspartate aminotransferase-to-platelet ratio index automatically calculated based on routine blood tests, followed by electronic reminder messages to alert clinicians of abnormal results, or the control group with usual care. The primary outcome was the proportion of patients with increased fibrosis scores who received appropriate care (referred for hepatology care or specific fibrosis assessment) within 1 year. RESULTS: Between May 2020 and Oct 2021, 1379 patients were screened, of whom 533 and 528 were assigned to the intervention and control groups, respectively. A total of 55 out of 165 (33.3%) patients with increased fibrosis scores in the intervention group received appropriate care, compared with 4 of 131 (3.1%) patients in the control group (difference 30.2% (95% CI 22.4% to 38%); p<0.001). Overall, 11 out of 533 (2.1%) patients in the intervention group and 1 out of 528 (0.2%) patients in the control group were confirmed to have advanced liver disease (difference 1.9% (95% CI 0.61% to 3.5%); p=0.006). CONCLUSION: Automated fibrosis score calculation and electronic reminders can increase referral of patients with type 2 diabetes and abnormal fibrosis scores at non-hepatology settings. TRIAL REGISTRATION NUMBER: NCT04241575.

Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalization in Community Coronavirus Disease 2019 Patients (COVID-19).

BACKGROUND: We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and deaths in a real-world cohort of nonhospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a territory-wide retrospective cohort study in Hong Kong. Nonhospitalized COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2022 were identified. Patients hospitalized on the day of the first clinic appointment or used both oral antivirals were excluded. The primary endpoint was hospitalization. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death. RESULTS: Of 93 883 patients, 83 154 (88.6%), 5808 (6.2%), and 4921 (5.2%) were oral antiviral nonusers, molnupiravir users, and nirmatrelvir/ritonavir users, respectively. Compared with nonusers, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year. Molnupiravir users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1931 (2.1%) patients were hospitalized and 225 (0.2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0.79; 95% confidence interval [CI], 0.65-0.95; P = .011) but not molnupiravir use (weighted hazard ratio 1.17; 95% CI, 0.99-1.39; P = .062) was associated with a reduced risk of hospitalization than nonusers. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared with nonusers. CONCLUSION: Use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalization in real-world nonhospitalized patients with COVID-19.

Changing epidemiology, global trends and implications for outcomes of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease globally and is currently estimated to affect 38% of the global population. Only a minority of patients with NAFLD will progress to cirrhosis or hepatocellular carcinoma, but from this vast population the total number of patients who are at risk of such severe outcomes is increasing. Worryingly, individuals are increasingly being affected by NAFLD at an earlier age, meaning there is more time for them to develop severe complications. With considerable changes in dietary composition and urbanisation, alongside the growth in obesity and type 2 diabetes in the global population, in particular in developing countries, the global proportion of persons affected by NAFLD is projected to increase further. Yet, there are large geographical discrepancies in the prevalence rates of NAFLD and its inflammatory component non-alcoholic steatohepatitis (NASH). Such differences are partly related to differing socio-economic milieus, but also to genetic predisposition. In this narrative review, we discuss recent changes in the epidemiology of NAFLD and NASH from regional and global perspectives, as well as in special populations. We also discuss the potential consequences of these changes on hepatic and extrahepatic events.

Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss.

BACKGROUND & AIMS: We examined the long-term incidence of hepatocellular carcinoma (HCC) and hepatic decompensation among chronic hepatitis B (CHB) patients who have achieved hepatitis B surface antigen (HBsAg) seroclearance. METHODS: All adult CHB-monoinfected patients who cleared HBsAg between January 2000 and December 2020 were identified using a territory-wide database in Hong Kong. Patients who underwent liver transplantation and/or developed HCC before HBsAg seroclearance or less than 6 months follow-up were excluded. The primary and secondary endpoints were HCC and hepatic decompensation respectively. RESULTS: We identified 9,769 patients with CHB who achieved HBsAg seroclearance (mean age 57 years, 60.0% male, 13.2% cirrhosis); most had compensated liver function at HBsAg loss. At a median (25th-75th percentile) follow-up of 4.6 (2.2-8.4) years, 106 (1.1%) patients developed HCC. Patients who developed HCC were older, more likely to be male and have cirrhosis, and had higher alanine aminotransferase and lower platelets at the time of HBsAg loss than patients without HCC. The cumulative incidence of HCC remained steady 0-7 and 8-12 years after HBsAg loss (p = 0.898) (crude annual incidence drop: -0.04%, 95% CI -0.13% to 0.04%, p = 0.265). Moreover, 124/9,640 (1.3%) patients developed hepatic decompensation. The growth in cumulative incidence of hepatic decompensation decelerated 8-12 years after HBsAg loss (p = 0.009) (crude annual incidence drop: -0.23%, 95% CI -0.40% to -0.06%, p = 0.012). In multivariable analysis, HBsAg loss for over 7 years was associated with a reduced risk of hepatic decompensation (adjusted subdistribution hazard ratio [aSHR] 0.55, 95% CI 0.31-0.97, p = 0.039) but not HCC (aSHR 1.35, 95% CI 0.83-2.19, p = 0.230). CONCLUSION: HCC risk persists in patients after HBsAg loss, whereas the risk of hepatic decompensation decreases over time. IMPACT AND IMPLICATIONS: Patients with chronic hepatitis B (CHB) still have a non-negligible risk of hepatocellular carcinoma (HCC) after 12 years of HBsAg seroclearance, especially among those with cirrhosis. The risk of developing hepatic decompensation decreases over time after HBsAg seroclearance. In clinical practice, although patients with CHB who cleared HBsAg have a more favourable clinical outcome than those who remain chronically infected, long-term HCC surveillance would still be necessary for patients with cirrhosis and other high-risk subgroups after HBsAg seroclearance.