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ABSTRACT Purpose Recent research (Li et al. 2021) suggests an upregulated expression and activation of H1 receptors on macrophages in the tumor microenvironment, and concomitant H1‐antihistamine use is associated with improved overall survival in patients with lung and skin cancers receiving immunotherapy. Therefore, we retrospectively evaluated the impacts of H1‐antihistamine use in cancer patients during immunotherapy. Methods All patients who had received at least one dose of immune checkpoint inhibitors (ICIs) from July 1, 2014 to October 31, 2019 were identified from Hong Kong's territory‐wide database, with this date defined as the baseline. A 1‐month landmark analysis was conducted with follow–for up to 6 months, including an exposure period of 1 month before and after the baseline date. Patients were grouped according to the types of primary cancer and the percentages of daily H1‐antihistamine usage within the exposure period. The primary outcome was overall survival. Results A total of 1740 (65.1% male, mean age 61.9 years) were included in the landmark analysis, of which 529 (30.4%) and 307 (17.6%) had primary lung and liver malignancies. The multivariable Cox regression model estimated statistically significant improvement in overall survival of intermediate use in patients with primary lung malignancies (adjusted hazard ratio [aHR] 0.223, 95% confidence interval [CI] 0.052–0.958, p = 0.044), but not with primary liver maligancies. Similar frequency‐dependent effects were identified in Kaplan–Meier analysis. Conclusion The benefits of adjunctive use of H1‐antihistamines may be generation‐ and tumor‐dependent. Further clinical and mechanistic studies are required to confirm the findings.

Introduction and Objectives: Patients increasingly use social media to share and access health-related information and experiences. This study employed social media listening to gain patient-centric insights into metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). Materials and Method: Publicly available social media data was collected between November 4th, 2020, and November 4th, 2022, about MASLD from eight countries: Brazil, China, France, Germany, Japan, South Korea, Spain, and the United Kingdom. The analysis involved capturing patient conversations on their journey stages (causes-risk factors, symptoms, diagnosis, and treatment), unmet needs, and impact on patient's quality of life (QoL) from various social media platforms to gain insights associated with MASLD. Results: A total of 1600 patient-centric posts were analyzed. The patient journey was the most prevalent topic (92 %) mentioned, followed by comorbidities (38 %) and interactions with HCPs (26 %, health care professionals). Key causes discussed included unhealthy diet (39 %) and overweight/obese (32 %), while the most mentioned symptoms were fatigue (20 %) and pain or abdominal discomfort (20 %). Ultrasound (n=170/553, 31 %) was the most used diagnosis, followed by blood tests (n=130/553, 24 %) and liver function tests (n=91/553, 16 %). Lifestyle management techniques were mainly the standard of care, followed by treatment (n=270/1061, 25 %) and follow-ups with HCPs (n=133/1061, 13 %). Over half (54 %) of the QoL discussion (n=104/192) focused on patients’ comorbidities, and 27 % on disease severity, indicating that having MASLD in moderate to severe form with comorbidities significantly affects patients’ quality of life. An emotional analysis revealed that patients were worried and frustrated about their condition but were also hopeful and determined to improve their health. Nearly 38 % of the posts mentioned that patients were emotionally affected by negative feelings, especially those with multiple comorbidities. Lack of access to knowledgeable HCPs and treatment options were the most frequently discussed unmet needs. Conclusions: This analysis of NAFLD patient experiences introduces a unique approach for deriving insights into patients' experiences and their impact on QoL. These insights have the potential to complement conventional methods and foster patient-centric research.

Background & Aims: Alcohol-associated liver disease (ALD) burden has been rising globally, fueled by increases in high-risk alcohol use following the coronavirus disease 2019 (COVID-19) pandemic. We evaluated trends in annual incidence of alcohol-associated hepatitis (AH) before and following the onset of the COVID-19 pandemic across two geographically distinct populations in the USA and Hong Kong. Methods: Using US national Veterans Affairs (VA) data and Hong Kong territory-wide data, trends in annual incidence of AH were evaluated from 2000 to 2023. AH was identified using a combination of International Classification of Diseases (ICD)-9/10 diagnostic codes, laboratory data, and available alcohol use data. Results: Among the VA data, annual incidence of AH rose steadily from 39.4 to 53.7 per 100,000 persons (2010–2020), then declined to 36.2 per 100,000 persons in 2023. Annual AH incidence was substantially lower in Hong Kong, but demonstrated similar trends, peaking at 0.28 per 100,000 persons during the first year of the pandemic. Among both cohorts, incidence of AH was significantly higher in men vs. women, but particularly for the VA cohort, the increase in AH incidence was more rapid in women. Among both cohorts, the highest incidence of AH in 2023 was among the 40–49-year age group (VA: 72.7 per 100,000 persons; Hong Kong: 1.89 per 100,000 persons). Conclusions: We provide a comprehensive analysis of epidemiological trends in AH incidence across two distinct populations, highlighting the need for continued awareness of targeted interventions to curb unhealthy alcohol use and its complications. Impact and implications:: Alcohol-associated hepatitis (AH) is a severe complication of high-risk alcohol use associated with significant morbidity and mortality. Increasing alcohol use fueled by the COVID-19 pandemic has led to parallel increases in alcohol-related comorbidities. The current study provides a comprehensive analysis of trends in the incidence of AH across two distinct world regions before and following the onset of the COVID-19 pandemic. Better identification of epidemiological trends in AH incidence as well as highlighting populations most affected can help target public health resources and health system interventions to address the dangers of high-risk alcohol use more effectively.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population. Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD, progress in drug development for this condition remains limited. This review highlights the potential of drug-target Mendelian randomisation (MR), a study design that leverages human genetics and genomics, for the discovery, repositioning and safety assessment of drug targets in MASLD. We summarised key aspects of designing and appraising a drug-target MR study, discussing its inherent assumptions and considerations for instrument selection. Furthermore, we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets, repositing existing drug targets, informing adjunctive treatments and addressing issues in paediatric MASLD.

Background & Aims: This study used the Global Burden of Disease data (2010–2021) to analyze the rates and trends of point prevalence, annual incidence, and years lived with disability (YLDs) for metabolic dysfunction-associated steatotic liver disease (MASLD) in 204 countries. Methods: Total numbers and age-standardized rates per 100,000 population for MASLD prevalence, annual incidence, and YLDs were compared across regions and countries by age, sex, and sociodemographic index (SDI). Smoothing spline models were used to evaluate the relationship between the burden of MASLD and SDI. Estimates were reported with uncertainty intervals (UI). Results: Globally, in 2021, the age-standardized rates per 100,000 population of point prevalence of MASLD were 15,018.1 cases (95% UI 13,756.5–16,361.4), annual incidence rates were 608.5 cases (598.8–617.7), and YLDs were 0.5 (0.3–0.8) years. MASLD point prevalence was higher in men than women (15,731.4 vs. 14,310.6 cases per 100,000 population). Prevalence peaked at ages 45–49 for men and 50–54 for women. Kuwait (32,312.2 cases per 100,000 people; 95% UI: 29,947.1–34,839.0), Egypt (31,668.8 cases per 100,000 people; 95% UI: 29,272.5–34,224.7), and Qatar (31,327.5 cases per 100,000 people; 95% UI: 29,078.5–33,790.9) had the highest prevalence rates in 2021. The largest increases in age-standardized point prevalence estimates from 2010 to 2021 were in China (16.9%, 95% UI 14.7%–18.9%), Sudan (13.3%, 95% UI 9.8%–16.7%) and India (13.2%, 95% UI 12.0%–14.4%). MASLD incidence varied with SDI, peaking at moderate SDI levels. Conclusions: MASLD is a global health concern, with the highest prevalence reported in Kuwait, Egypt, and Qatar. Raising awareness about risk factors and prevention is essential in every country, especially in China, Sudan and India, where disease incidence and prevalence are rapidly increasing. Impact and implications: This research provides a comprehensive analysis of the global burden of MASLD, highlighting its rising prevalence and incidence, particularly in countries with varying sociodemographic indices. The findings are significant for both clinicians and policymakers, as they offer critical insights into the regional disparities in MASLD burden, which can inform targeted prevention and intervention strategies. However, the study’s reliance on modeling and available data suggests cautious interpretation, and further research is needed to validate these findings in clinical and real-world settings.

Hepatitis B surface antigen (HBsAg) seroclearance is considered the functional cure and the optimal treatment endpoint for chronic hepatitis B (CHB). Patients with CHB who cleared HBsAg generally have a favorable clinical course with minimal risk of developing hepatocellular carcinoma (HCC) or cirrhotic complications. Nevertheless, a minority of patients still develop HCC despite HBsAg seroclearance. While patients with liver cirrhosis are still recommended for HCC surveillance, whether other non-cirrhotic patients who achieved HBsAg seroclearance should remain on HCC surveillance remains unclear. This review provides an overview of the incidence of HBsAg seroclearance, the factors associated with the occurrence of HBsAg seroclearance, the durability of HBsAg seroclearance, the risk of developing HCC after HBsAg seroclearance, the risk factors associated with HCC development after HBsAg seroclearance, the role of HCC risk scores, and the implications on HCC surveillance. Existing HCC risk scores have a reasonably good performance in patients after HBsAg seroclearance. In the era of artificial intelligence, future HCC risk prediction models based on artificial intelligence and longitudinal clinical data may further improve the prediction accuracy to establish a foundation of a risk score-based HCC surveillance strategy. As different novel hepatitis B virus (HBV) antiviral agents aiming at HBsAg seroclearance are under active development, new knowledge is anticipated on the natural history and HCC risk prediction of patients treated with new HBV drugs.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p

Background/Aims Chronic hepatitis B (CHB) and fatty liver (FL) often co-exist, but natural history data of this dual condition (CHB-FL) are sparse. Via a systematic review, conventional meta-analysis (MA) and individual patient-level data MA (IPDMA), we compared liver-related outcomes and mortality between CHB-FL and CHB-no FL patients. Methods We searched 4 databases from inception to December 2021 and pooled study-level estimates using a random-effects model for conventional MA. For IPDMA, we evaluated outcomes after balancing the two study groups with inverse probability treatment weighting (IPTW) on age, sex, cirrhosis, diabetes, ALT, HBeAg, HBV DNA, and antiviral treatment. Results We screened 2,157 articles and included 19 eligible studies (17,955 patients: 11,908 CHB-no FL; 6,047 CHB-FL) in conventional MA, which found severe heterogeneity (I2=88–95%) and no significant differences in HCC, cirrhosis, mortality, or HBsAg seroclearance incidence (P=0.27–0.93). IPDMA included 13,262 patients: 8,625 CHB-no FL and 4,637 CHB-FL patients who differed in several characteristics. The IPTW cohort included 6,955 CHB-no FL and 3,346 CHB-FL well-matched patients. CHB-FL patients (vs. CHB-no FL) had significantly lower HCC, cirrhosis, mortality and higher HBsAg seroclearance incidence (all P≤0.002), with consistent results in subgroups. CHB-FL diagnosed by liver biopsy had a higher 10-year cumulative HCC incidence than CHB-FL diagnosed with non-invasive methods (63.6% vs. 4.3%, P

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

Summary: Background: Currently, assessment of candidate pharmacotherapies in patients with non-alcoholic steatohepatitis (NASH) involves invasive liver biopsy. Non-invasive scores, such as the FibroScan-aspartate aminotransferase (FAST) score, are used to identify candidates for therapy, but their ability to assess disease progression or treatment effect is unknown. We aimed to assess the association between FAST score and histological endpoints. Methods: We conducted a post-hoc analysis using data from a prior randomised, double-blind, placebo-controlled, phase 2b trial at 143 sites across 16 countries. Patients (aged 18–75 years) with biopsy-confirmed NASH, fibrosis stage 1–3, and a Non-alcoholic fatty liver disease Activity Score (NAS) ≥4 were enrolled between January 2017 and September 2018, and randomly assigned to receive once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg or placebo for 72 weeks. A subgroup analysis of patients with FAST score and histological data in the pooled semaglutide treatment and placebo arms at baseline and week 72 was performed. The original trial is registered at ClinicalTrials.gov, NCT02970942. Findings: A total of 122 patients were included in this post-hoc analysis (93 received semaglutide and 29 received placebo). FAST score reduction was associated with achieving the primary endpoint of NASH resolution without worsening of fibrosis in the pooled semaglutide group (area under the receiver operating curve 0.69; 95% confidence interval [CI] 0.58, 0.81). Mean FAST score reduction from baseline to week 72 was greatest in patients who met the primary endpoint vs those who did not in both the semaglutide (−0.40 [95% CI –0.84, 0.04] vs −0.22 [95% CI –0.74, 0.30] points; p = 0.002) and placebo groups (−0.25 [95% CI –0.72, 0.23] vs 0.00 [95% CI –0.50, 0.50] points; p = 0.047). Similarly, mean reductions in FAST score at week 72 were greater in those with NAS improvement vs those without in the semaglutide and placebo groups (≥1 point, −0.36 [95% CI –0.82, 0.11] vs −0.08 [95% CI –0.53, 0.38] points [p

Abstract. Background:. Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. Methods:. Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). Results:. A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69–1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension (P

Background & Aims: We aimed to evaluate the impact of oesophageal varices (OV) and their evolution on the risk of complications of compensated advanced chronic liver disease (cACLD) caused by non-alcoholic fatty liver disease (NAFLD). We also assessed the accuracy of non-invasive scores for predicting the development of complications and for identifying patients at low risk of high-risk OV. Methods: We performed a retrospective assessment of 629 patients with NAFLD-related cACLD who had baseline and follow-up oesophagogastroduodenoscopy and clinical follow-up to record decompensation, portal vein thrombosis (PVT), and hepatocellular carcinoma. Results: Small and large OV were observed at baseline in 30 and 15.9% of patients, respectively. The 4-year incidence of OV from absence at baseline, and that of progression from small to large OV were 16.3 and 22.4%, respectively. Diabetes and a ≥5% increase in BMI were associated with OV progression. Multivariate Cox regression revealed that small (hazard ratio [HR] 2.24, 95% CI 1.47–3.41) and large (HR 3.86, 95% CI 2.34–6.39) OV were independently associated with decompensation. When considering OV status and trajectories, small (HR 2.65, 95% CI 1.39–5.05) and large (HR 4.90, 95% CI 2.49–9.63) OV at baseline and/or follow-up were independently associated with decompensation compared with the absence of OV at baseline and/or follow-up. The presence of either small (HR 2.8, 95% CI 1.16–6.74) or large (HR 5.29, 95% CI 1.96–14.2) OV was also independently associated with incident PVT. Conclusion: In NAFLD-related cACLD, the presence, severity, and evolution of OV stratify the risk of developing decompensation and PVT. Impact and implications: Portal hypertension is the main driver of liver decompensation in chronic liver diseases, and its non-invasive markers can help risk prediction. The presence, severity, and progression of oesophageal varices stratify the risk of complications of non-alcoholic fatty liver disease. Easily obtainable laboratory values and liver stiffness measurement can identify patients at low risk for whom endoscopy may be withheld, and can also stratify the risk of liver-related complications.

Background & Aims: The latest Baveno VII consensus has provided guidance for identifying patients who have truly recompensated from those with hepatic decompensation. This study aimed to evaluate patients’ transplant-free survival in three different stages of cirrhosis. Methods: All patients with chronic HBV infection and liver cirrhosis treated with oral nucleos(t)ide analogues from March 2006 to December 2022 were identified from a territory-wide database in Hong Kong. Patients with follow-up duration of

Abstract. For the detection of steatosis, quantitative ultrasound imaging techniques have achieved great progress in past years. Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis. Some blood biomarkers correlate with non-alcoholic steatohepatitis, but the accuracy is modest. Regarding liver fibrosis, liver stiffness measurement by transient elastography (TE) has high accuracy and is widely used across the world. Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability. Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response. This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease (NAFLD). Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict the prognosis. Further studies are needed to determine the role of the tests as monitoring tools. We cannot overemphasize the importance of context in selecting appropriate tests.

Background/Aims We aimed to determine the association between blood urea level and incident cirrhosis, hepatic decompensation, and hepatocellular carcinoma in chronic liver disease (CLD) patients. Methods The association between blood urea level and liver fibrosis/liver-related events were evaluated on continuous scale with restricted cubic spline curves based on generalized additive model or Cox proportional hazards models. Then, the above associations were evaluated by urea level within intervals. Results Among 4,282 patients who had undergone liver stiffness measurement (LSM) by transient elastography, baseline urea level had a U-shaped association with LSM and hepatic decompensation development after a median follow-up of 5.5 years. Compared to patients with urea of 3.6–9.9 mmol/L, those with urea ≤3.5 mmol/L (adjusted hazard ratio [aHR], 4.15; 95% confidence interval [CI], 1.68–10.24) and ≥10 mmol/L (aHR, 5.22; 95% CI, 1.86–14.67) had higher risk of hepatic decompensation. Patients with urea ≤3.5 mmol/L also had higher risk of incident cirrhosis (aHR, 3.24; 95% CI, 1.50–6.98). The association between low urea level and incident cirrhosis and hepatic decompensation was consistently observed in subgroups by age, gender, albumin level, and comorbidities. The U-shaped relationship between urea level and LSM was validated in another population screening study (n=917). Likewise, urea ≤3.5 mmol/L was associated with a higher risk of incident cirrhosis in a territory-wide cohort of 12,476 patients with nonalcoholic fatty liver disease at a median follow-up of 9.9 years (aHR, 1.27; 95% CI, 1.03–1.57). Conclusions We identified a U-shaped relationship between the urea level and liver fibrosis/incident cirrhosis/hepatic decompensation in patients with CLD.

Inflammation is the key driver of liver fibrosis progression in non-alcoholic fatty liver disease (NAFLD). Unfortunately, it is often challenging to assess inflammation in NAFLD due to its dynamic nature and poor correlation with liver biochemical markers. Liver histology keeps its role as the standard tool, yet it is well-known for substantial sampling, intraobserver, and interobserver variability. Serum proinflammatory cytokines and apoptotic markers, namely cytokeratin-18, are well-studied with reasonable accuracy, whereas serum metabolomics and lipidomics have been adopted in some commercially available diagnostic models. Ultrasound and computed tomography imaging techniques are attractive due to their wide availability; yet their accuracies may not be comparable with magnetic resonance imaging-based tools. Machine learning and deep learning models, be they supervised or unsupervised learning, are promising tools to identify various subtypes of NAFLD, including those with dominating liver inflammation, contributing to sustainable care pathways for NAFLD.

Summary: Background: There is a growing number of trials examining the effectiveness of pharmacotherapies for obesity, however, little is known about placebo and nocebo effect in these trials. Hence, we sought to examine the effect of placebo in obesity trials, to better understand the potential factors affecting clinical endpoints in them. Methods: Medline, Embase, and Cochrane CENTRAL were searched for articles examining weight-loss RCTs examining patients with overweight or obesity in placebo-controlled arms from inception till 25 June 2022. This paper was registered online with PROSPERO (CRD42022302482). A single arm meta-analysis of proportions was used to estimate the primary outcomes, ≥5%, ≥10%, and ≥15% total weight loss – and the adverse effects that patients experienced during the trial. A meta-analysis of means was used to estimate the pooled mean differences of the secondary outcomes including, body weight measurements, lipid levels, glycemic indices, and blood pressure over time. Findings: A total of 63 papers involving 20,454 patients and 69 trials were included. The proportion of patients that had ≥5%, ≥10%, and ≥15% weight loss was 20·4% (CI:16·1% to 25·0%), 8·3% (CI:6·1% to 10·9%), and 6·2% (CI:3·8% to 9·7%), respectively. Analysis by duration of trials showed stepwise increase in proportion of patients with ≥5% and ≥10% weight loss with increasing duration of study. Analysis of secondary outcomes found modest improvement in all analyses. The pooled average rate of overall AEs, serious AEs, and discontinuation was 73·7% (CI:68·0% to 79·0%), 3·4% (CI:2·4% to 4·5%), and 5·2% (CI:4·0% to 6·5%), respectively. In psychiatric complications, the pooled rates of anxiety and depression were 2·7% (CI:1·8% to 3·7%) and 2·5 (CI:1·7% to 3·3%). Interpretation: Our meta-analysis of placebo-treated participants in weight-loss RCTs indicate a significant placebo and nocebo effect. These findings are important to quantify their effect and may inform the design of future RCTs. Funding: This research did not receive additional support from organizations beyond the authors’ academic institutions.

Background/Aims Serum fibrosis scores comprised of common laboratory tests have high utility to assess severity of liver fibrosis. We aimed to derive and validate a hepatocellular carcinoma (HCC) risk score based on serum fibrosis scores to predict HCC in treatment-naïve chronic hepatitis B (CHB) patients. Methods Fifteen thousand one hundred eighty-seven treatment-naïve adult CHB patients were identified to form the training cohort in this retrospective study. Individual fibrosis score was included to construct a new HCC prediction score. The score was externally validated in an independent treatment-naïve Korean CHB cohort. Results 180/15,187 patients (1.2%) in training cohort and 47/4,286 patients (1.1%) in validation cohort developed HCC during a mean follow-up of 52 and 50 months, respectively. The newly developed HCC risk score, Liang score, is composed of gender, age, hepatitis B virus DNA, fibrosis-4 (FIB-4) index, and ranges from 0 to 22. Area under the time-dependent receiver operating characteristic curve of Liang score was 0.79 (95% confidence interval, 0.70–0.89). A cutoff value of nine provided an extremely high negative predictive value of 99.9% and high sensitivity of 90.0% at 5 years in the validation cohort. Patients with Liang score ≤9 had HCC incidence

The benefit of colonoscopy and/or polypectomy for colorectal cancer (CRC) prevention in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. We aimed to estimate the incidence rate of CRC in patients with NAFLD who had and had not undergone colonoscopy. We conducted a retrospective territory‐wide cohort study for patients aged over 40 years with NAFLD identified with the International Classification of Diseases, Ninth Revision, Clinical Modification codes between January 1, 2000, and December 31, 2014. Patients were followed until CRC diagnosis, death, or December 31, 2017. We estimated CRC incidence and standardized incidence ratio (SIR) using the general population of Hong Kong as reference. We included 8,351 patients with NAFLD in the final analysis (median age, 56.2 years; interquartile ratio [IQR], 49.2‐65.3 years; 45.4% male; median follow‐up, 7.4 years; IQR, 5.4‐9.6 years). Compared with the general population, patients with NAFLD who had not undergone colonoscopy had a higher incidence of CRC (SIR, 2.20; 95% confidence interval [CI], 1.64‐2.88; P 2.67) had a significantly higher risk of CRC after adjusting for demographic and metabolic factors. Conclusion: Patients with NAFLD who had undergone colonoscopy had a lower incidence of CRC than the general population, especially among those aged ≥50 years or with DM. A high FIB‐4 index was associated with a higher risk of CRC.

Patient‐reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo‐controlled study of selonsertib, firsocostat, or cilofexor, alone or in two‐drug combinations (NCT03449446). PROs included Short Form 36 (SF‐36), Chronic Liver Disease Questionnaire (CLDQ)‐NASH, EuroQol Five Dimension (EQ‐5D), Work Productivity and Impairment (WPAI), and 5‐D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF‐36 and Fatigue and Worry of CLDQ‐NASH were significantly lower in patients with cirrhosis (total CLDQ‐NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P

Abstract Liver stiffness measurement (LSM) by transient elastography (TE) is a non-invasive assessment for diagnosing and staging liver fibrosis in non-alcoholic fatty liver disease (NAFLD). Evidence on its role as a longitudinal monitoring tool is lacking. This study aims to evaluate the role of TE in monitoring NAFLD improvement following bariatric surgery. This study prospectively recruited 101 morbidly obese patients undergoing laparoscopic bariatric surgery for intraoperative liver biopsy. Thirty-seven patients of the cohort received perioperative TE. Postoperative anthropometric, biochemical and LSM data were collected annually for 5 years. In 101 patients receiving liver biopsy (mean age 40.0 ± 10.3 years, mean body-mass-index (BMI) 40.0 ± 5.7 kg/m2), NASH and liver fibrosis were diagnosed in 42 (41.6%) and 48 (47.5%) patients respectively. There were 29 (28.7%) stage 1, 11 (10.9%) stage 2, 7 (6.9%) stage 3, and 1 (1.0%) stage 4 fibrosis. In 37 patients receiving TE (mean age 38.9 ± 10.8 years, mean BMI 41.1 ± 5.6 kg/m2), the percentages of total weight loss were 21.1 ± 7.6% at 1 year, 19.7 ± 8.3% at 3 years, and 17.1 ± 7.0% at 5 years after surgery. The mean LSM reduced significantly from 9.8 ± 4.6 kPa at baseline to 6.9 ± 3.4 kPa at 1 year, 7.3 ± 3.0 kPa at 3 years, and 6.8 ± 2.6 kPa at 5 years (P = 0.002). Using pre-defined LSM cut-offs, the rates of significant fibrosis, advanced fibrosis and cirrhosis being ruled out at 5 years improved from baseline values of 43.7 to 87.5% (P

Fatigue and pruritus are common in patients with chronic liver diseases of all etiologies, but clinical awareness is mostly restricted to those with cholestatic liver diseases. We assessed the impact of fatigue and pruritus on patient‐reported outcomes (PROs) of patients with advanced nonalcoholic steatohepatitis (NASH). Specifically, PROs (Short Form–36, Chronic Liver Disease Questionnaire–NASH, Euro‐Qol 5 Dimension, and Work Productivity and Activity Impairment instruments) were assessed at baseline in patients with histologically confirmed bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH enrolled in STELLAR 3 and 4. Presence of fatigue and pruritus were indicated by a score of 4 or less on the respective items of the Chronic Liver Disease Questionnaire–NASH (scale range, 1‐7). Among the included 1,669 patients with advanced NASH (mean age = 58 ± 9 years, 48% F3, 42% with psychiatric comorbidities), 33% and 27% had fatigue and pruritus, respectively. Patients with NASH with fatigue were younger, more likely to be female, cirrhotic, and diabetic, and had higher body mass index and more comorbidities (all P

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta‐analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound‐detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random‐effects mixed model and upper threshold (95th‐percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal‐weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study‐level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal‐weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). Conclusion: We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound‐detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice.

Abstract Background Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancers. We aimed to evaluate the incidence and prognostic impact of hepatic adverse events (AEs) in a territory‐wide cohort of patients who received ICIs. Methods Patients were identified from a territory‐wide database who received ICIs in 2014‐2018. Hepatic AEs were defined as any elevation of liver biochemistries including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels. Hepatic AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results Total of 1480 patients were identified (mean age 60 years, male 65.5%) and the commonest malignancies being lung cancer (39.6%), liver cancer (16.5%), and gastrointestinal cancer (10.0%). Grade 1‐2 and grade 3‐4 hepatic AEs occurred in 41.3% and 14.9% of patients during ICI treatment, respectively. Patients with liver cancer had the highest rate of hepatic AEs (grade 1‐2:54.1%; grade 3‐4:32.8%). Among 711 patients with hepatic AEs, 383 (53.9%) had raised ALT/AST only, and 328 (46.1%) had concomitant raised ALT/AST and bilirubin levels. In the whole cohort, median overall survival of patients without any hepatic AEs, grade 1‐2 and grade 3‐4 hepatic AEs during ICI treatment was 9.0 months, 7.2 months, and 3.3 months (P

Abstract Background Because of high-risk behaviours, sedentary lifestyle and side effects of medications, psychiatric patients are at risk of viral hepatitis, alcohol-related liver disease and non-alcoholic fatty liver disease. We aimed to study the incidence of hepatocellular carcinoma (HCC) and cirrhotic complications in psychiatric patients. Methods We identified consecutive adult patients in all public hospitals and clinics in Hong Kong with psychiatric diagnoses between year 2003 and 2007 using the Clinical Data Analysis and Reporting System, which represents in-patient and out-patient data of approximately 80% of the 7.4-million local population. The patients were followed for liver-related events (HCC and cirrhotic complications) and deaths until December 2017. Age- and sex-standardized incidence ratio (SIR) of HCC in psychiatric patients to the general population was estimated by Poisson model. Results We included 105,763 psychiatric patients without prior liver-related events in the final analysis. During a median (interquartile range) follow-up of 12.4 (11.0–13.7) years, 1461 (1.4%) patients developed liver-related events; 472 (0.4%) patients developed HCC. Compared with the general population, psychiatric patients had increased incidence of HCC (SIR 1.42, 95% confidence interval [CI] 1.28–1.57, P

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Although it has become one of the leading causes of cirrhosis and hepatocellular carcinoma in the Western world, the proportion of NAFLD patients developing these complications is rather small. Therefore, current guidelines recommend non-invasive tests for the initial assessment of NAFLD. Among the available non-invasive tests, transient elastography by FibroScan® (Echosens, Paris, France) is commonly used by hepatologists in Europe and Asia, and the machine has been introduced to the United States in 2013 with rapid adoption. Transient elastography measures liver stiffness and the controlled attenuation parameter simultaneously and can serve as a one-stop examination for both liver steatosis and fibrosis. Liver stiffness measurement also correlates with clinical outcomes and can be used to select patients for varices screening. Although obesity is a common reason for measurement failures, the development of the XL probe allows successful measurements in the majority of obese patients. This article reviews the performance and limitations of transient elastography in NAFLD and highlights its clinical applications. We also discuss the reliability criteria for transient elastography examination and factors associated with false-positive liver stiffness measurements.

Background & Aims: Accurate hepatocellular carcinoma (HCC) risk prediction facilitates appropriate surveillance strategy and reduces cancer mortality. We aimed to derive and validate novel machine learning models to predict HCC in a territory-wide cohort of patients with chronic viral hepatitis (CVH) using data from the Hospital Authority Data Collaboration Lab (HADCL). Methods: This was a territory-wide, retrospective, observational, cohort study of patients with CVH in Hong Kong in 2000–2018 identified from HADCL based on viral markers, diagnosis codes, and antiviral treatment for chronic hepatitis B and/or C. The cohort was randomly split into training and validation cohorts in a 7:3 ratio. Five popular machine learning methods, namely, logistic regression, ridge regression, AdaBoost, decision tree, and random forest, were performed and compared to find the best prediction model. Results: A total of 124,006 patients with CVH with complete data were included to build the models. In the training cohort (n = 86,804; 6,821 HCC), ridge regression (area under the receiver operating characteristic curve [AUROC] 0.842), decision tree (0.952), and random forest (0.992) performed the best. In the validation cohort (n = 37,202; 2,875 HCC), ridge regression (AUROC 0.844) and random forest (0.837) maintained their accuracy, which was significantly higher than those of HCC risk scores: CU-HCC (0.672), GAG-HCC (0.745), REACH-B (0.671), PAGE-B (0.748), and REAL-B (0.712) scores. The low cut-off (0.07) of HCC ridge score (HCC-RS) achieved 90.0% sensitivity and 98.6% negative predictive value (NPV) in the validation cohort. The high cut-off (0.15) of HCC-RS achieved high specificity (90.0%) and NPV (95.6%); 31.1% of patients remained indeterminate. Conclusions: HCC-RS from the ridge regression machine learning model accurately predicted HCC in patients with CVH. These machine learning models may be developed as built-in functional keys or calculators in electronic health systems to reduce cancer mortality. Lay summary: Novel machine learning models generated accurate risk scores for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. HCC ridge score was consistently more accurate than existing HCC risk scores. These models may be incorporated into electronic medical health systems to develop appropriate cancer surveillance strategies and reduce cancer death.

Introduction Small molecule inhibitors of the terminal step in intrahepatic triglyceride synthesis (diacylglycerol acyltransferase 2 inhibitor (DGAT2i, PF-06865571, ervogastat)) and upstream blockade of de novo lipogenesis via acetyl-coenzyme A carboxylase inhibitor (ACCi, PF-05221304, clesacostat) showed promise in reducing hepatic steatosis in early clinical trials. This study assesses efficacy and safety of these metabolic interventions to resolve non-alcoholic steatohepatitis (NASH) with fibrosis.Methods and analysis This phase II, randomised, dose-ranging, dose-finding study evaluates DGAT2i 25–300 mg two times per day (BID) or 150–300 mg once a day, DGAT2i 150–300 mg BID+ACCi 5–10 mg BID coadministration or matching placebo in a planned 450 adults with biopsy-confirmed NASH and liver fibrosis stages 2–3 from approximately 220 sites in 11 countries across North America, Europe and Asia. A triage approach including double-confirmation via non-invasive markers is included prior to screening/baseline liver biopsy. On confirmation of histological diagnosis, participants enter a ≥6-week run-in period, then a 48-week double-blind, double-dummy dosing period. The primary endpoint is the proportion of participants achieving histological NASH resolution without worsening fibrosis, ≥1 stage improvement in fibrosis without worsening NASH, or both, assessed by central pathologists. Other endpoints include assessment of hepatic steatosis (imaging substudy), overall safety and tolerability, and evaluation of blood-based biomarkers and quantitative ultrasound parameters over time.Ethics and dissemination Metabolic Interventions to Resolve NASH with fibrosis (MIRNA) is conducted in accordance with the Declaration of Helsinki and Council for International Organisations of Medical Sciences (CIOMS) International Ethical Guidelines, International Council on Harmonisation Good Clinical Practice guidelines, applicable laws and regulations, including privacy laws. Local independent review board/ethics committees (IRB/ECs) review/approve the protocol, any amendments, informed consent and other forms. Participants provide written informed consent. Details of all IRB/ECs, as well as results, will be published in a peer-reviewed journal and publicly disclosed through ClinicalTrials.gov, EudraCT, and/or www.pfizer.com and other public registries as per applicable local laws/regulations.Trial registration number NCT04321031.

Objectives To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes.Design Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021.Setting All public health facilities in Hong Kong.Participants 1220 patients with diabetes who were admitted for confirmed COVID-19.Primary and secondary outcome measures Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death.Results In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p

Abstract Background and Aims Metformin is an oral anti‐hyperglycemic recommended by the American Diabetes Association (ADA) as a preferred initial pharmacologic agent for type 2 diabetes. Metabolic acidosis is a rare yet severe side effect of it. We examined the association of metformin use and dosage on the risk of metabolic acidosis in diabetic patients with different degrees of chronic hepatitis B (CHB)‐related cirrhosis and chronic kidney disease (CKD). Methods Metabolic acidosis was defined by blood pH ≤7.35, together with lactate >5 mmol/L or arterial bicarbonate ≤18 mmol/L or venous bicarbonate ≤21 mmol/L, and/or diagnosis codes. Child‐Pugh class and CKD stage were included in the model as time‐dependent covariates. Age, gender, comorbidities, and use of relevant medications were adjusted as covariates. Maximum daily dose of metformin was classified into ≤1000 mg and >1000 mg. Results We identified 4431 diabetic patients with CHB‐related cirrhosis between 2000 and 2017 from a territory‐wide database in Hong Kong. The risk of metabolic acidosis increased with Child‐Pugh class B and C cirrhosis regardless of CKD stage (adjusted subdistribution hazard ratio [aSHR] ranged from 3.50 to 86.16). Metformin use was associated with a higher risk in patients with Child‐Pugh class B or C cirrhosis and stage 3A CKD or above (aSHR ranged from 1.55 to 2.46). In stage 4/5 CKD, a daily dose of metformin ≤1000 mg was still associated with a higher risk of metabolic acidosis regardless of the severity of cirrhosis (aSHR ranged from 2.45 to 3.92). Conclusion In conclusion, patients with Child‐Pugh class B cirrhosis or above were at a higher risk of metabolic acidosis. Metformin further increased the risk in patients with Child‐Pugh class B cirrhosis or above and stage 3A CKD or above. Dose adjustment in stage 4/5 CKD did not reduce the risk of metabolic acidosis.

Background & Aims: Antiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to report the secular trend in antiviral treatment uptake from 2007–2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival. Methods: A 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment (i.e. no NA), patients receiving NAs after their first HCC treatment (i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment (i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs). Results: The uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70–3.44; p

Introduction and aim: Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free water excretion, but its efficacy and safety in cirrhotic patients remain unclear. Material and Methods: We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multi-center prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. Results: Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). Conclusion: In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.

Background and rationale for the study. Limited studies have aimed to define the cut-offs of XL probe (XL cut-offs) for different stages of liver fibrosis, whereas those of M probe (M cut-offs) may not be applicable to XL probe. We aimed to derive appropriate XL cut-offs in overweight patients. Patients with liver stiffness measurement (LSM) by both probes were recruited. XL cut-offs probe for corresponding M cut-offs were derived from an exploratory cohort, and subsequently validated in a subgroup patients also underwent liver biopsy. The diagnostic accuracy of XL cut-offs to diagnose advanced fibrosis was evaluated.Results. Total 517 patients (63% male, mean age 58) who had reliable LSM by both probes were included in the exploratory cohort. There was a strong correlation between the LSM by M probe (LSM-M) and LSM by XL probe (LSM-XL) (r2 = 0.89, p < 0.001). A decision tree using LSM-XL was learnt to predict the 3 categories of LSM-M (< 6.0kPa, 6.0–11.9kPa and ≥ 12.0kPa), and XL cut-offs at 4.8kPa and 10.7kPa were identified. These cut-offs were subsequently validated in a cohort of 147 patients who underwent liver biopsy. The overall accuracy was 89% among 62 patients whose LSM-XL < 4.8kPa or ≥ 10.7kPa. These cut-offs would have avoided under-staging of fibrosis among patients with body mass index (BMI) > 25–30 kg/m2 but not > 30 kg/m2.Conclusions. XL cut-offs at 4.8kPa and 10.7kPa were the best estimates of 6.0kPa and 12.0kPa of M probe for patients with BMI > 25–30 kg/m2. Patients with BMI > 30 kg/m2 might use M probe cut-offs for XL probe.

Background. Probiotics have profound effect on nonalcoholic steatohepatitis (NASH) in animal models. We aimed to test the hypothesis that probiotics treatment was superior to usual care in reducing liver fat in NASH patients.Material and methods. Patients with histology-proven NASH were randomized to receive probiotics (n = 10) or usual care (n = 10) for 6 months. The Lepicol probiotic formula contained Lactobacillus plantarum, Lactobacillus deslbrueckii, Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum. The primary endpoint was change in intrahepatic triglyceride content (IHTG), as measured by proton-magnetic resonance spectroscopy, from baseline to month 6. Secondary endpoints included changes in liver biochemistry and metabolic profile.Results. IHTG decreased from 22.6 ± 8.2% to 14.9 ± 7.0% in the probiotic group (P = 0.034) but remained static in the usual care group (16.9 ± 6.1% to 16.0 ± 6.6%; P = 0.55). Six subjects in the probiotic group had IHTG reduced by more than 30% from baseline, compared to 2 subjects in the usual care group (p = 0.17). The probiotic group also had greater reduction in serum aspartate aminotransferase level (P = 0.008). On the other hand, the use of probiotics was not associated with changes in body mass index, waist circumference, glucose and lipid levels.Conclusions. Probiotics treatment may reduce liver fat and AST level in NASH patients. The therapeutic potential of probiotics in NASH should be tested in larger studies.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer deaths in men. Due to differences in the prevalence of viral hepatitis, the incidence of HCC in low and middle income countries is much higher than that of high income countries. Strategies to limit the impact of HCC include primary prevention against new cases of viral hepatitis, secondary prevention of HCC in susceptible individuals, and early HCC detection. Universal hepatitis B vaccination has resulted in dramatic reduction in incident cases of chronic hepatitis B and HCC in children and adolescents, and the full effect is expected in the next 20 years. The key hurdle for universal vaccination is the cost and the accessibility in low and middle income countries. Randomized controlled trials and meta-analyses showed that successful treatment of chronic hepatitis B and C can reduce the risk of HCC and cirrhotic complications. HCC surveillance by regular ultrasound examination and alpha fetoprotein testing leads to early cancer detection and offers the opportunity for curative treatment. Since all these measures are costly and require manpower and infrastructure support, the implementation should rely on the liaison among healthcare providers and policymakers. The cost-effectiveness of various strategies should also be studied based on local situations.

Nonalcoholic fatty liver disease (NAFLD) has been associated with reduced growth hormone levels and signaling. Such hormonal changes also occur in metabolic acidosis. Since mild metabolic acidosis can be diet induced, diet-induced acid load may constitute a nutritional factor with possible influence on NAFLD development. This study explored whether a higher diet-induced acid load is associated with an increased likelihood of NAFLD. Apparently healthy Chinese adults (330 male, 463 female) aged 19-72 years were recruited through population screening between 2008 and 2010 in a cross-sectional population-based study in Hong Kong. Estimated net endogenous acid production (NEAP) was calculated using Frassetto's method and potential renal acid load (PRAL) was calculated using Remer's method based on dietary data from a food frequency questionnaire. NAFLD was defined as intrahepatic triglyceride content at >5% by proton-magnetic resonance spectroscopy. Possible advanced fibrosis was defined as liver stiffness at >7.9 kPa by transient elastography. Multivariate logistic regression models were used to examine the association between each measure of dietary acid load and prevalent NAFLD or possible advanced fibrosis with adjustment for potential anthropometric and lifestyle factors. 220 subjects (27.7%) were diagnosed with NAFLD. Estimated NEAP was positively associated with the likelihood of having NAFLD after adjustment for age, sex, body mass index, current drinker status and the presence of metabolic syndrome [OR (95% CI) = 1.25 (1.02-1.52), p = 0.022]. The association was slightly attenuated but remained significant when the model was further adjusted for other dietary variables. No association between PRAL and NAFLD prevalence was observed. Both estimated NEAP and PRAL were not associated with the presence of possible advance fibrosis. Our findings suggest that there may be a modest association between diet-induced acid load and NAFLD. More studies are needed to ascertain the link between diet-induced acid load and NAFLD and to investigate the underlying mechanisms.

Dietary pattern analysis is an alternative approach to examine the association between diet and nonalcoholic fatty liver disease (NAFLD). This study examined the association of two diet-quality scores, namely Diet Quality Index-International (DQI-I) and Mediterranean Diet Score (MDS) with NAFLD prevalence. Apparently healthy Chinese adults (332 male, 465 female) aged 18 years or above were recruited through a population screening between 2008 and 2010 in a cross-sectional population-based study in Hong Kong. DQI-I and MDS, as well as major food group and nutrient intakes were calculated based on dietary data from a food frequency questionnaire. NAFLD was defined as intrahepatic triglyceride content at ≥5% by proton-magnetic resonance spectroscopy. Multivariate logistic regression models were used to examine the association between each diet-quality score or dietary component and prevalent NAFLD with adjustment for potential lifestyle, metabolic and genetic factors. A total of 220 subjects (27.6%) were diagnosed with NAFLD. DQI-I but not MDS was associated with the prevalence of NAFLD. A 10-unit decrease in DQI-I was associated with 24% increase in the likelihood of having NAFLD in the age and sex adjusted model (95% CI: 1.06-1.45, p = 0.009), and the association remained significant when the model was further adjusted for other lifestyle factors, metabolic and genetic factors [OR: 1.26 (95% CI: 1.03-1.54), p = 0.027]. Multivariate regression analyses showed an inverse association of the intake of vegetables and legumes, fruits and dried fruits, as well as vitamin C with the NAFLD prevalence (p

The human gut microbiota has profound influence on host metabolism and immunity. This study characterized the fecal microbiota in patients with nonalcoholic steatohepatitis (NASH). The relationship between microbiota changes and changes in hepatic steatosis was also studied.Fecal microbiota of histology-proven NASH patients and healthy controls was analyzed by 16S ribosomal RNA pyrosequencing. NASH patients were from a previously reported randomized trial on probiotic treatment. Proton-magnetic resonance spectroscopy was performed to monitor changes in intrahepatic triglyceride content (IHTG).A total of 420,344 16S sequences with acceptable quality were obtained from 16 NASH patients and 22 controls. NASH patients had lower fecal abundance of Faecalibacterium and Anaerosporobacter but higher abundance of Parabacteroides and Allisonella. Partial least-square discriminant analysis yielded a model of 10 genera that discriminated NASH patients from controls. At month 6, 6 of 7 patients in the probiotic group and 4 of 9 patients in the usual care group had improvement in IHTG (P=0.15). Improvement in IHTG was associated with a reduction in the abundance of Firmicutes (R(2)=0.4820, P=0.0028) and increase in Bacteroidetes (R(2)=0.4366, P=0.0053). This was accompanied by corresponding changes at the class, order and genus levels. In contrast, bacterial biodiversity did not differ between NASH patients and controls, and did not change with probiotic treatment.NASH patients have fecal dysbiosis, and changes in microbiota correlate with improvement in hepatic steatosis. Further studies are required to investigate the mechanism underlying the interaction between gut microbes and the liver.

BACKGROUND: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. METHODS: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. RESULTS: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. CONCLUSION: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis.

Recent 16S ribosomal RNA gene (rRNA) molecular profiling of the stomach mucosa revealed a surprising complexity of microbiota. Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID) use are two main contributors to gastritis and peptic ulcer. However, little is known about the association between other members of the stomach microbiota and gastric diseases. In this study, cloning and sequencing of the 16S rRNA was used to profile the stomach microbiota from normal and gastritis patients. One hundred and thirty three phylotypes from eight bacterial phyla were identified. The stomach microbiota was found to be closely adhered to the mucosa. Eleven Streptococcus phylotypes were successfully cultivated from the biopsies. One to two genera represented a majority of clones within any of the identified phyla. We further developed two real-time quantitative PCR assays to quantify the relative abundance of the Firmicutes phylum and the Streptococcus genus. Significantly higher abundance of the Firmicutes phylum and the Streptococcus genus within the Firmicutes phylum was observed in patients with antral gastritis, compared with normal controls. This study suggests that the genus taxon level can largely represent much higher taxa such as the phylum. The clinical relevance and the mechanism underlying the altered microbiota composition in gastritis require further functional studies.