Changing global epidemiology of chronic hepatitis C virus-related outcomes from 2010 to 2019: cirrhosis is the growing burden of hepatitis C virus-related disease.

BACKGROUND: Chronic infection with hepatitis C virus (HCV) has a long-term impact on hepatic consequences. A comprehensive evaluation of the global burden of HCV-related health outcomes can help to develop a global HCV prevention and treatment program. METHODS: We used the 2019 Global Burden of Disease (GBD) Study to comprehensively investigate burden and temporal trends in incidence, mortality and disability-adjusted life-years (DALYs) of HCV-related diseases, including liver cancer and cirrhosis and other liver diseases across 264 countries and territories from 2010 to 2019. RESULTS: Globally, there were 152 225 incident cases, 141 811 deaths and approximately 2.9 million DALYs because of HCV-related liver cancer, and 551 668 incident cases, 395 022 deaths and about 12.2 million DALYs because of HCV-related cirrhosis in 2019. Worldwide, during the 2010-2019 period, liver cancer incidence declined, however, there was a 62% increase in cirrhosis incidence. In 2019, the Eastern Mediterranean was the region with the highest rates of incidence and mortality of both liver cancer and cirrhosis. Africa was the region with the fastest-growing trend of incidence of cirrhosis in the 2010-2019 period [annual percentage change (APC) = 2.09, 95% confidence interval (CI): 1.93-2.25], followed by the Western Pacific region (APC = 1.17, 95% CI: 1.09-1.22). Americas were the only region observing increased trends in liver cancer and cirrhosis mortality (APC = 0.70 and 0.12, respectively). We identified three patterns of temporal trends of mortality rates of liver cancer and cirrhosis in countries that reported HCV treatment rates. CONCLUSION: Urgent measures are required for diagnosis, treatment and research on HCV-related cirrhosis at global, regional and country levels, particularly in Africa, the Western Pacific and the Eastern Mediterranean.

Incidence of liver cancer in young adults according to the global burden of disease database 2019.

OBJECTIVE: The worldwide burden of cancer is increasing in younger populations. However, the epidemiology of primary liver cancer remains understudied in young adults compared to other cancer forms. METHODS: This study analyzed data from the Global Burden of Disease (GBD) study between 2010 and 2019 to assess the age-standardized incidence, mortality, and disability-adjusted life years (DALYs) associated with primary liver cancer in the young (15-49 y), stratified by region, nation, sociodemographic index, and sex. RESULTS: The study found a global estimate of 78,299 primary liver cancer cases, 60,602 deaths, and 2.90 million DALYs in the young population. The Western Pacific region exhibited the highest burden in 2019, showing the most significant increase compared to other regions between 2010-2019. More than half of countries worldwide have undergone an increase in primary liver cancer incidence rates in young adults. Around 12.51% of deaths due to primary liver cancer occur in young individuals. Throughout the study period, there was a significant decline in primary liver cancer mortality due to most etiologies, except for metabolic dysfunction-associated steatotic liver disease (MASLD)-attributable primary liver cancer (annual percentage change [APC] +0.87%, 95% confidence interval 0.70-1.05%) and alcohol-attributable primary liver cancer (APC +0.21%, 95% confidence interval 0.01-0.42%). Limitations of the GBD database include reliance on the quality of primary data and possible underestimation of alcohol consumption. CONCLUSION: Over the past decade, there has been a marked increase in the burden of primary liver cancer, especially that originating from steatotic liver disease. This trend calls for the development of urgent and comprehensive strategies to mitigate this rising burden globally.

Global and regional burden of alcohol-associated liver disease and alcohol use disorder in the elderly.

Background & Aims: Alcohol-associated liver diseases (ALDs) and alcohol use disorder (AUD) pose a global health risk. AUD is underrecognized in the elderly, and the burden of AUD complications, including ALD, may increase with aging populations and rising alcohol intake. However, there is a lack of epidemiological evidence on AUD and ALD in the elderly. Methods: Using the Global Burden of Disease Study 2019, we analyzed the prevalence, mortality, disability-adjusted life years (DALYs), age-standardized rates (ASRs), and temporal change from 2000 to 2019 of ALD and AUD in the overall population and the elderly (65-89 years). The findings were categorized by sex, region, nation, and sociodemographic index. Results: The prevalence rates of ALD in the elderly were higher than those in adolescents and young adults, whereas AUD levels were lower than those in adolescents and young adults. In 2019, there were 9.39 million cases (8.69% of cases in the overall population) of AUD, 3.23 million cases (21.8% of cases in the overall population) of alcohol-associated cirrhosis, and 68,468 cases (51.27% of cases in the overall population) of liver cancer from alcohol among the elderly. ASRs of the prevalence of ALD and AUD in the elderly increased in most regions; on the contrary, ASRs of death and DALYs decreased in most regions. Nevertheless, ASRs of death and DALYs from liver cancer from alcohol increased in many areas. Conclusions: Our findings highlighted the increased prevalence of ALD in the elderly, with a burden of AUD comparable with that in the overall population. Public health strategies on ALD and AUD targeting the elderly are urgently needed. Impact and implications: The burden of alcohol-associated liver disease (ALD) and alcohol use disorder (AUD) is increasing. Advances in healthcare and education have resulted in a remarkable spike in life expectancy and a consequential population aging. Nevertheless, little is known about the epidemiology of ALD and AUD in the elderly. Our study indicates the increasing burden of ALD and AUD in the elderly population, necessitating early detection, intervention, and tailored care to the unique needs and complexities faced by older individuals grappling with these conditions.

Metabolic Syndrome and Metabolic Dysfunction-Associated Steatotic Liver Disease in Premenopausal Women: Global Trends and Projections to 2040.

OBJECTIVE: To quantify the burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and related metabolic disorders in premenopausal women. PATIENTS AND METHODS: Between 2010 and 2019, global evaluations of prevalence, mortality, disability-adjusted life years (DALYs), and their age-standardized rate (ASR) were conducted for metabolic conditions such as MASLD, type 2 diabetes mellitus, dyslipidemia, hypertension (HTN), obesity, and polycystic ovarian syndrome. Subgroup assessments were conducted according to geographical regions and the sociodemographic index. The predictive models were established to estimate mortality and DALYs through 2040. RESULTS: In 2019, the most significant ASR of deaths was found in HTN (11.37; 9.52 to 13.45), followed by obesity (10.49; 7.57 to 13.64). In contrast, the greatest ASR of DALYs was attributed to obesity (816.13; 581.41 to 1073.32), followed by HTN (634.73; 536.75 to 744.77). The mortality rates for dyslipidemia (-0.55%) and HTN (-0.72%) have been decreasing over time, but there has been an increase in obesity (+0.58%), type 2 diabetes mellitus (+0.85%), and MASLD (+0.51%). Lower sociodemographic index countries exhibit a higher disability-to-prevalence ratio. In 2040, obesity is predicted to cause the most deaths (+41.59% from 2019). CONCLUSION: The escalating impact of metabolic syndrome, the rising trends in death rates linked to obesity, and the disparities based on region and socioeconomic status in premenopausal women underscore the alarming increase in the global burden of metabolic syndrome.

The Global Burden of Alcohol-associated Cirrhosis and Cancer in Young and Middle-aged Adults.

Alcohol is a substance that impacts premature mortality and morbidity.1 The liver is invariably subjected to the impact of alcohol, which can result in cirrhosis and cancer. Alcohol also has detrimental effects that extend beyond the liver. While traditionally associated with advanced age, emerging data reported a rising burden of cancers and alcohol-associated liver disease in the young.1-3 Thus, the primary objective was to evaluate the trend of alcohol-associated cirrhosis and cancer in young and middle-aged adults (aged 15-49) utilizing the Global Burden of Disease Study (GBD) 2019.4 We chose the age group less than 50 years old based on the definition of early-onset cancer and the inherent selection of the age group in the GBD database.4-6 The detailed methods are provided in the Supplementary Appendix. Briefly, data were sourced from population-based cancer registries, vital registration systems, or verbal autopsy studies. Verbal autopsy is a well-established approach for monitoring health, providing valuable information on mortality patterns and the reasons behind deaths in areas lacking robust medical death certification processes. The researchers employed the Cause of Death Ensemble model to estimate the burden linked to cancer and cirrhosis associated with alcohol use.

Disparities among ethnic groups in mortality and outcomes among adults with MASLD: A multicenter study.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease and 10%-20% occurs in lean individuals. There is little data in the literature regarding outcomes in an ethnically-diverse patient populations with MASLD. Thus, we aim to investigate the natural history and ethnic disparities of MASLD patients in a diverse population, and stratified by body mass index categories. METHODS: We conducted a retrospective multicenter study on patients with MASLD at the Banner Health System from 2012 to 2022. Main outcomes included mortality and incidence of cirrhosis, cardiovascular disease, diabetes mellitus (DM), liver-related events (LREs), and cancer. We used competing risk and Cox proportional hazard regression analysis for outcome modelling. RESULTS: A total of 51 452 (cross-sectional cohort) and 37 027 (longitudinal cohort) patients were identified with 9.6% lean. The cohort was 63.33% European ancestry, 27.96% Hispanic ancestry, 3.45% African ancestry, and 2.31% Native American/Alaskan ancestry. Median follow-up was 45.8 months. After adjusting for confounders, compared to European individuals, Hispanic and Native American/Alaskan patients had higher prevalence of cirrhosis and DM, and individuals of Hispanic, African, and Native American/Alaskan ancestry had higher mortality and incidence of LREs and DM. Lean patients had higher mortality and incidence of LREs compared with non-lean patients. CONCLUSION: Native American/Alaskan, Hispanic, and African patients had higher mortality and incidence of LREs and DM compared with European patients. Further studies to explore the underlying disparities and intervention to prevent LREs in lean patients, particularly several ethnic groups, may improve clinical outcomes.

Upper limit of normal ALT levels in health and metabolic diseases: Pooled analysis of 423,355 individuals with bootstrap modelling.

INTRODUCTION: Given the global rise in obesity-related metabolic diseases, the upper limit of normal (ULN) alanine aminotransferase (ALT) in individuals with and without metabolic diseases may have changed. We performed a meta-analysis combined with bootstrap modelling to estimate the ALT ULN levels for individuals with and without metabolic diseases. METHODS AND RESULTS: Two separate searches of the PubMed, Embase and Cochrane databases were performed, one to identify healthy individuals which yielded 12 articles (349,367 individuals); another to include those with potential metabolic diseases but without known liver disease which yielded 35 articles (232,388 individuals). We estimated the mean ALT using a random-effects mixed model and the ULN level (95th-percentile value) via a bootstrap model with 10,000 resamples. In individuals without metabolic diseases and known liver disease, the ALT ULN levels were 32 U/L overall; 36 U/L in males and 28 U/L in females. In analyses that included individuals with metabolic diseases, the ALT ULN levels were 40 U/L among the overweight/obese (29 U/L if normal weight) and 36 U/L among those with type 2 diabetes mellitus (T2DM) (33 U/L if no T2DM). On meta-regression of study-level factors, body mass index (coefficient 1.49, 95% CI 0.11-2.86, p = 0.03), high-density lipoprotein (coefficient -0.47, 95% CI -0.85-(-0.08), p = 0.02) and triglycerides (coefficient 0.19, 95% CI 0.12-0.25, p < 0.0001) correlated with ALT. CONCLUSION: We provide expected ranges of ALT ULN levels for individuals without known liver disease without metabolic diseases and those with or without T2DM and/or are normal weight or overweight/obese. These data may have implications for clinical care and screening.

Meta-analysis: Prevalence and impact of alcohol abstinence in alcohol-associated cirrhosis.

BACKGROUND: Although alcohol abstinence may be an effective intervention for alcohol-associated cirrhosis, its association with prognosis has not been systematically assessed or quantified. AIMS: To determine the prevalence of alcohol abstinence, factors associated with alcohol abstinence and the impact of abstinence on morbidity and overall survival in people with alcohol-associated cirrhosis. METHODS: We searched Medline and Embase from inception to 15 April 2023 for prospective and retrospective cohort studies describing alcohol abstinence in people with known alcohol-associated cirrhosis. Meta-analysis of proportions for pooled estimates was performed. The method of inverse variance, employing a random-effects model, was used to pool the hazard ratio (HR) comparing outcomes of abstinent against non-abstinent individuals with alcohol-associated cirrhosis. RESULTS: We included 19 studies involving 18,833 people with alcohol-associated cirrhosis. The prevalence of alcohol abstinence was 53.8% (CI: 44.6%-62.7%). Over a mean follow-up duration of 48.6 months, individuals who continued to consume alcohol had significantly lower overall survival compared to those who were abstinent (HR: 0.611, 95% CI: 0.506-0.738). These findings remained consistent in sensitivity/subgroup analysis for the presence of decompensation, study design and studies that assessed abstinence throughout follow-up. Alcohol abstinence was associated with a significantly lower risk of hepatic decompensation (HR: 0.612, 95% CI: 0.473-0.792). CONCLUSIONS: Alcohol abstinence is associated with substantial improvement in overall survival in alcohol-associated cirrhosis. However, only half of the individuals with known alcohol-associated cirrhosis are abstinent.

The incidence of adverse outcome in donors after living donor liver transplantation: A meta-analysis of 60,829 donors.

The scarcity of liver grafts has prompted developments in living donor liver transplantations (LDLT), with previous literature illustrating similar outcomes in recipients compared to deceased donor transplants. However, significant concerns regarding living donor morbidity and mortality have yet to be examined comprehensively. This study aims to provide estimates of the incidence of various outcomes in living liver donors. In this meta-analysis, Medline and Embase were searched from inception to July 2022 for articles assessing the incidence of outcomes in LDLT donors. Complications in the included studies were classified into respective organ systems. Analysis of incidence was conducted using a generalized linear mixed model with Clopper-Pearson intervals. Eighty-seven articles involving 60,829 living liver donors were included. The overall pooled incidence of complications in LDLT donors was 24.7% (CI: 21.6%-28.1%). The incidence of minor complications was 17.3% (CI: 14.7%-20.3%), while the incidence of major complications was lower at 5.5% (CI: 4.5%-6.7%). The overall incidence of donor mortality was 0.06% (CI: 0.0%-0.1%) in 49,027 individuals. Psychological complications (7.6%, CI: 4.9%-11.5%) were the most common among LDLT donors, followed by wound-related (5.2%, CI: 4.4%-6.2%) and respiratory complications (4.9%, CI: 3.8%-6.3%). Conversely, cardiovascular complications had the lowest incidence among the subgroups at 0.8% (CI: 0.4%-1.3%). This study presents the incidence of post-LDLT outcomes in living liver donors, illustrating significant psychological, wound-related, and respiratory complications. While significant advancements in recent decades have contributed towards decreased morbidity in living donors, our findings call for targeted measures and continued efforts to ensure the safety and quality of life of liver donors post-LDLT.

Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies.

BACKGROUND & AIMS: The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted. METHODS: To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated. RESULTS: One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD. CONCLUSIONS: The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.

Donor Diabetes and Steatosis Affects Recipient Survival Following Liver Transplantation Based on Etiology of Liver Cirrhosis.

BACKGROUND: Liver transplantation (LT) offers patients with decompensated cirrhosis the best chance at long-term survival. With the rising prevalence of diabetes, further clarity is needed on the impact of receiving a liver allograft from a donor with diabetes on post-LT outcomes. This study aims to evaluate the impact of donor diabetes on clinical outcomes after LT. METHODS: This is a retrospective analysis of the United Network for Organ Sharing registry data of LT recipients from January 1, 2000, to December 31, 2021. Outcomes analysis was performed using Cox proportional model for all-cause mortality and graft failure. Confounding was reduced by coarsened exact matching causal inference analysis. RESULTS: Of 66 960 donors identified, 7178 (10.7%) had diabetes. Trend analysis revealed a longitudinal increase in the prevalence of donor diabetes ( P < 0.001). Importantly, donor diabetes was associated with increased all-cause mortality (hazard ratio [HR]: 1.13; 95% confidence interval [CI], 1.07-1.19; P < 0.001) and graft failure (HR: 1.16; 95% CI, 1.11-1.22; P < 0.001). Receiving donor organ with diabetes reduced graft survival in patients who received LT for nonalcoholic steatohepatitis cirrhosis (HR: 1.26; 95% CI, 1.13-1.41; P < 0.001) but not other etiologies of cirrhosis. CONCLUSIONS: Donor diabetes was associated with worse outcomes post-LT, particularly in patients receiving LT for nonalcoholic steatohepatitis cirrhosis. Future studies are needed to better understand the mechanism underlying this association to develop better risk stratification and clinical practice to improve the outcomes of the transplanted patients.

Rising global burden of cancer attributable to high BMI from 2010 to 2019.

BACKGROUND: High body mass index (BMI) is a major risk factor for cancer development, but its impact on the global burden of cancer remains unclear. METHODS: We estimated global and regional temporal trends in the burden of cancer attributable to high BMI, and the contributions of various cancer types using the framework of the Global Burden of Disease Study. RESULTS: From 2010 to 2019, there was a 35 % increase in deaths and a 34 % increase in disability-adjusted life-years from cancers attributable to high BMI. The age-standardized death rates for cancer attributable to high BMI increased over the study period (annual percentage change [APC] +0.48 %, 95 % CI 0.22 to 0.74 %). The greatest number of deaths from cancer attributable to high BMI occurred in Europe, but the fastest-growing age-standardized death rates and disability-adjusted life-years occurred in Southeast Asia. Liver cancer was the fastest-growing cause of cancer mortality (APC: 1.37 %, 95 % CI 1.25 to 1.49 %) attributable to high BMI. CONCLUSION: The global burden of cancer-related deaths attributable to high BMI has increased substantially from 2010 to 2019. The greatest increase in age-standardized death rates occurred in Southeast Asia, and liver cancer is the fastest-growing cause of cancer mortality attributable to high BMI. Urgent and sustained measures are required at a global and regional level to reverse these trends and slow the growing burden of cancer attributed to high BMI.

Proton Pump Inhibitors Increases Longitudinal Risk of Mortality, Decompensation, and Infection in Cirrhosis: A Meta-Analysis.

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) are frequently prescribed to cirrhotic patients, but there is limited longitudinal evidence regarding their effects. This study aimed to assess the impact of PPIs on adverse events in cirrhotic patients. METHODS: A comprehensive search was conducted using the Medline and Embase databases to identify relevant articles. Pooled hazard ratios (HRs) using DerSimonian and Laird random-effects model were calculated to evaluate the risk of adverse events such as long-term mortality, hepatic decompensation, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and overall infection in cirrhotic patients with PPI use. RESULTS: The analysis included 28 studies with 260,854 cirrhotic patients. The prevalence of PPI use among cirrhotic patients was 55.93%. The use of PPIs was not significantly associated with short-term mortality in cirrhotic patients. However, long-term mortality (HR 1.321, 95% CI 1.103-1.581, P = 0.002), decompensation (HR 1.646, 95% CI 1.477-1.835, P < 0.001), HE (HR 1.968, 95% CI 1.372-2.822, P < 0.001), SBP (HR 1.751, 95% CI 1.649-1.859, P < 0.001), and infection (HR 1.370, 95% CI 1.148-1.634, P < 0.001) were significantly associated with PPI use. Sensitivity analysis with prospective studies yielded similar results. CONCLUSION: PPIs should be reserved for appropriate indications at lowest effective dose for cirrhotic patients due to the potential harm.

From Shadows to Spotlight: Exploring the Escalating Burden of Alcohol-Associated Liver Disease and Alcohol Use Disorder in Young Women.

INTRODUCTION: The burden of alcohol-related complications is considerable, particularly alcohol-associated liver disease and alcohol use disorder (AUD). However, there are deficiencies in comprehensive epidemiological research focusing on these issues, especially among young women who display higher susceptibility to such complications compared with their male counterparts. We thus aimed to determine the global burden of these conditions in this vulnerable group. METHODS: Leveraging data from the Global Burden of Disease Study 2019, we analyzed the prevalence, mortality, and disability-adjusted life years of alcohol-associated cirrhosis (AC), liver cancer from alcohol, and AUD in young women. The findings were categorized by region, nation, and sociodemographic index. RESULTS: The highest age-standardized prevalence rates were observed in AUD (895.96 [95% uncertainty interval (UI) 722.6-1,103.58]), followed by AC (65.33 [95% UI 48.37-86.49]) and liver cancer from alcohol (0.13 [95% UI 0.09-0.19]) per 100,000 people. The highest age-standardized mortality rates were observed in AC (0.75 [95% UI 0.55-0.97]), followed by AUD (0.48 [95% UI 0.43-0.53]) and liver cancer from alcohol (0.06 [95% UI 0.04-0.09]). The highest burdens of AC and AUD were observed in Central Europe, whereas the high-income Asia Pacific had the highest burden of liver cancer from alcohol. DISCUSSION: Throughout the past decade, the trend of AUD varied among regions while the impact of alcohol-associated liver disease has increased, requiring urgent public health strategy to mitigate these complications, particularly in female patients in Europe and the Asia-Pacific region.

Cardiovascular Health Metrics Differ Between Individuals With and Without Cancer.

BACKGROUND: Although individuals with cancer experience high rates of cardiovascular morbidity, there are limited data on the potential differences in cardiovascular health (CVH) metrics between individuals with and without cancer. METHODS AND RESULTS: The National Health and Nutrition Examination Survey between 2015 and 2020 was queried to evaluate the prevalence of health metrics that comprise the American Heart Association Life's Essential 8 construct of cardiovascular health among adult individuals with and without cancer in the United States. Health metric scores were also evaluated according to important patient demographics including age, sex, race and ethnicity, and socioeconomic status. Among 4370 participants representing >180 million US adults, 9.4% had a history of cancer. Individuals with cancer had lower overall cardiovascular health scores (67.1 versus 69.1, P<0.001) compared with individuals without cancer. Among individual components of the cardiovascular health score, those with cancer had better health scores on key behaviors including physical activity, diet, and sleep compared with those without cancer, although variation was noted based on age. Higher scores on these modifiable health behaviors among those with cancer compared with those without cancer were noted in older individuals, in White individuals compared with other races and ethnicities, and in individuals with higher socioeconomic status. CONCLUSIONS: We highlight important variations in simple cardiovascular health metrics among individuals with cancer compared with individuals without cancer and demonstrate differences among health metrics based on age, race and ethnicity, and socioeconomic status. These findings may explain ongoing racial, ethnic, and socioeconomic status disparities in the cancer population and provide a framework for optimizing cardiovascular health among individuals with cancer.

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials.

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I2 ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.

Foregut bypass vs. restrictive bariatric procedures for nonalcoholic fatty liver disease: a meta-analysis of 3,355 individuals.

Background: Bariatric surgery represents an important treatment option for severely obese patients with nonalcoholic fatty liver disease (NAFLD). However, there remains inadequate data regarding the effects of different bariatric procedures on various NAFLD parameters, especially for histological outcomes. Thus, this meta-analysis aimed to compare the effects of restrictive bariatric procedures and foregut bypass on the metabolic, biochemical, and histological parameters for patients with NAFLD. Methods: Medline and Embase were searched for articles relating to bariatric procedures and NAFLD. Pairwise meta-analysis was conducted to compare efficacy of bariatric procedures pre- vs. post-procedure with subgroup analysis to further compare restrictive against foregut bypass procedures. Results: Thirty-one articles involving 3,355 patients who underwent restrictive bariatric procedures (n=1,460) and foregut bypass (n=1,895) were included. Both foregut bypass (P<0.01) and restrictive procedures (P=0.03) significantly increased odds of fibrosis resolution. Compared to restrictive procedures, foregut bypass resulted in a borderline non-significant decrease in fibrosis score (P=0.06) and significantly lower steatosis score (P<0.001). For metabolic parameters, foregut bypass significantly lowered body mass index (P=0.003) and low-density lipoprotein (P=0.008) compared to restrictive procedures. No significant differences were observed between both procedures for aspartate aminotransferase (P=0.17) and alkaline phosphatase (P=0.61). However, foregut bypass resulted in significantly lower gamma-glutamyl transferase than restrictive procedures (P=0.01) while restrictive procedures resulted in significantly lower alanine transaminase than foregut bypass (P=0.02). Conclusions: The significant histological and metabolic advantages and comparable improvements in biochemical outcomes support the choice of foregut bypass over restrictive bariatric procedures in NAFLD management.

Impact of Pretransplant Diabetes on Outcomes After Liver Transplantation: An Updated Meta-analysis With Systematic Review.

BACKGROUND: Preliver transplant diabetes mellitus (pre-LT DM) is a common comorbidity in LT recipients associated with poorer post-transplant survival. However, its relationship with other important outcomes, including cardiovascular and renal outcomes, remains unclear. This meta-analysis aims to provide an updated analysis of the impact of pre-LT DM on key post-LT outcomes. METHODS: A search was conducted in Medline and Embase databases for articles comparing the post-transplant outcomes between patients with and without pre-LT DM. Pairwise analysis using random effects with hazard ratios (HRs) was used to assess the longitudinal post-LT impacts of pre-LT DM. In the absence of HR, pooled odds ratios analysis was conducted for secondary outcomes. RESULTS: Forty-two studies involving 77,615 LT recipients were included in this analysis. The pooled prevalence of pre-LT DM amongst LT recipients was 24.79%. Pre-LT DM was associated with significantly lower overall survival (HR, 0.65; 95% confidence interval, 0.52-0.81; P<0.01) and significantly increased cardiovascular disease-related mortality (HR, 1.78; 95% confidence interval, 1.11-2.85; P=0.03). Meta-regression of other patient characteristics identified Asian ethnicity and hypertension to be significant predictors of worse overall survival, whereas African-American ethnicity was associated with significantly improved overall survival in patients with pre-LT DM. Further analysis of secondary outcomes revealed pre-LT DM to be a significant predictor of post-LT cardiovascular events and end-stage renal disease. CONCLUSIONS: The present study illustrates the impact of pre-LT DM on post-LT survival, and cardiovascular and renal outcomes and provides a sound basis for revision of preoperative management of pre-LT DM.