Sex and Race-Ethnic Disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis of 40,166 Individuals.

BACKGROUND: To overcome the limitations of the term "non-alcoholic fatty liver disease" (NAFLD), the term metabolic-associated steatotic liver disease (MASLD) was introduced. While epidemiologic studies have been conducted on MASLD, there is limited evidence on its associated sex and ethnic variations. AIMS: This study assesses the differences across sex and race-ethnicity on the prevalence, associated risk factors and adverse outcomes in individuals with MASLD. METHODS: Data retrieved from the National Health and Nutrition Examination Survey between 1999 to 2018 was analyzed. Prevalence, clinical characteristics, and outcomes were evaluated according to sex and race-ethnicity. Adverse outcomes and mortality events were analyzed using multivariate analyses. RESULTS: Of 40,166 individuals included, 37.63% had MASLD. There was a significant increase in MASLD prevalence from 1999 to 2018 among Mexican Americans (Annual Percentage Change [APC] + 1.889%, p < 0.001), other Hispanics (APC + 1.661%, p = 0.013), NH Whites (APC + 1.084%, p = 0.018), NH Blacks (APC + 1.108%, p = 0.007), and females (APC + 0.879%, p = 0.030), but not males. Females with MASLD were at lower risk of all-cause (HR: 0.766, 95%CI 0.711 to 0.825, p < 0.001), cardiovascular disease-related (CVD) (SHR: 0.802, 95% CI 0.698 to 0.922, p = 0.002) and cancer-related mortality (SHR: 0.760, 95% CI 0.662 to 0.873, p < 0.001). Significantly, NH Blacks have the highest risk of all-cause and CVD-related mortality followed by NH Whites then Mexican Americans. CONCLUSION: There has been an increase in prevalence in most race-ethnicities over time. While the change in definition shows no significant differences in previous associations found in NAFLD, the increased mortality in NH Whites relative to Mexican Americans remains to be explored.

Sex-based Disparities in Liver Transplantation for Hepatocellular Carcinoma and the Impact of the Growing Burden of NASH.

Background: The cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC. Methods: Data were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men. Results: A total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P < 0.01), followed by alcohol-associated liver disease. NASH overtook chronic hepatitis C as the leading cause of liver disease in 2020 and 2022 among waitlisted women and men with HCC, respectively. Female patients with HCC spent a significantly longer time on the LT waitlist compared with male patients (ß: 8.73; 95% confidence interval [CI], 2.91-14.54). Female patients with HCC from alcohol-associated liver disease also have a lower probability of receiving LT (subdistribution hazard ratio: 0.90; 95% CI, 0.82-0.99). Among transplant recipients with NASH HCC, female sex was associated with lower posttransplant mortality compared with male sex (hazard ratio: 0.79; 95% CI, 0.70-0.89; P < 0.01). Conclusions: Women have a significantly longer waitlist duration compared with men. NASH is now the leading cause of liver disease among both female and male LT candidates and recipients with HCC.

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.

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.

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.

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.

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.

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.

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.

Global Epidemiology of Cirrhosis: Changing Etiological Basis and Comparable Burden of Nonalcoholic Steatohepatitis between Males and Females.

INTRODUCTION: The etiology of liver diseases has changed significantly, but its impact on the comparative burden of cirrhosis between males and females is unclear. We estimated sex differences in the burden of cirrhosis across 204 countries and territories from 2010 to 2019. METHODS: We analyzed temporal trends in the burden of cirrhosis using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age-standardized rates (ASRs) of cirrhosis incidence, death, and disability-adjusted life-years (DALYs) by sex, region, country, and etiology. RESULTS: In 2019, the frequency of incident cases, deaths, and DALYs due to cirrhosis was 1,206,125, 969,068, and 31,781,079 in males versus 845,429, 502,944, and 14,408,336 in females, respectively. From 2010 to 2019, the frequency of cirrhosis deaths increased by 9% in males and 12% in females. Incidence ASRs remained stable in males but increased in females, while death ASRs declined in both. Death ASRs for both sexes declined in all regions, except in the Americas where they remained stable. In 2019, alcohol was the leading cause of cirrhosis deaths in males, and hepatitis C in females. Death ASRs declined for all etiologies in both sexes, except in nonalcoholic steatohepatitis (NASH). The ratio of female-to-male incidence ASRs in 2019 was lowest in alcohol(0.5), and highest in NASH(1.3), while the ratio of female-to-male death ASRs was lowest in alcohol(0.3) and highest in NASH(0.8). CONCLUSION: The global burden of cirrhosis is higher in males. However, incidence and death ASRs from NASH cirrhosis in females are comparable to that of males.

The silent burden of non-alcoholic fatty liver disease in the elderly: A global burden of disease analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a significant health threat worldwide. The growing trend towards an aging population, along with an alarming rise in obesity and diabetes, may have significant implications for the burden of NAFLD. AIM: To assess the impact of NAFLD on the elderly. METHODS: We utilised data from the Global Burden of Disease study between 2010 and 2019 to conduct a comprehensive analysis of the prevalence, mortality, and disability-adjusted life years (DALYs) associated with NAFLD in the elderly (65-89 years), stratified by region, nation, sociodemographic Index and sex. RESULTS: Globally, there were an estimated 228 million cases, 87,230 deaths and 1.46 million DALYs attributed to NAFLD in the elderly. Geographically, the Western Pacific region had the highest burden of NAFLD in the elderly. From 2010 to 2019, there was an increasing prevalence rate in all areas, with the most pronounced change observed in the Western Pacific region (annual percentage change (APC) +0.95%, p < 0.001). Over the study period, there was a more rapid increase in NAFLD prevalence in men (APC +0.74%, p < 0.001) than in women (APC +0.63%, p < 0.001). In most regions, death and DALYs rates have declined, with the exception of the Americas, where there was a slight increase (APC +0.25%, p = 0.002 and 0.38%, p < 0.001, respectively). CONCLUSION: Over the past decade, the burden of NAFLD in the elderly has been increasing, necessitating immediate and inclusive measures to tackle the rising burden.

Clinical Course, Immunogenicity, and Efficacy of BNT162b2 mRNA Vaccination Against SARS-CoV-2 Infection in Liver Transplant Recipients.

Background: Immunocompromised individuals have been excluded from landmark studies of messenger RNA vaccinations for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). In such patients, the response to vaccination may be blunted and may wane more quickly compared with immunocompetent patients. We studied the factors associated with decreased antibody response to SARS-CoV-2 vaccination and risk factors for subsequent breakthrough infections in liver transplant (LT) patients undergoing coronavirus disease 2019 vaccination with at least 2 doses of messenger RNA vaccine from April 28, 2021, to April 28, 2022. Methods: All LT recipients received at least 2 doses of the BNT162b2 (Pfizer BioNTech) vaccine 21 d apart. We measured the antibody response against the SARS-CoV-2 spike protein using the Roche Elecsys immunoassay to the receptor-binding domain of the SARS-CoV-2 spike protein, and the presence of neutralizing antibodies was measured by the surrogate virus neutralization test (cPass) before first and second doses of vaccination and also between 2 and 3 mo after the second dose of vaccination. Results: Ninety-three LT recipients who received 2 doses of BNT162b2 were included in the analysis. The mean time from LT was 110 ± 154 mo. After 2-dose vaccination, 38.7% of LT recipients (36/93) were vaccine nonresponders on the cPass assay compared with 20.4% (19/93) on the Roche S assay. On multivariable analysis, increased age and increased tacrolimus trough were found to be associated with poor neutralizing antibody response (P = 0.038 and 0.022, respectively). The use of antimetabolite therapy in conjunction with tacrolimus approached statistical significance (odds ratio 0.21; 95% confidence interval, 0.180-3.72; P = 0.062). Breakthrough infection occurred in 18 of 88 LT recipients (20.4%). Female gender was independently associated with breakthrough infections (P < 0.001). Conclusions: Among LT recipients, older age and higher tacrolimus trough levels were associated with poorer immune response to 2-dose SARS-CoV-2 vaccination. Further studies are needed to assess variables associated with breakthrough infections and, hence, who should be prioritized for booster vaccination.

Patterns in Cancer Incidence Among People Younger Than 50 Years in the US, 2010 to 2019.

Importance: Emerging data suggest that the incidence of early-onset cancers, defined as cancers diagnosed in people younger than 50 years, is increasing, but updated data are limited. Objective: To characterize the patterns in the incidence of early-onset cancers in the US from 2010 to 2019 and provide granular data on the cancers with the fastest-growing incidence rates. Design, Setting, and Participants: This population-based cohort study analyzed data from 17 National Cancer Institute Surveillance, Epidemiology, and End Results registries from January 1, 2010, to December 31, 2019. Age-standardized incidence rates per 100 000 people were extracted for early-onset cancers, with rates age adjusted to the US standard population. A total of 562 145 patients with early-onset cancer between 2010 and 2019 were identified and included. Data were analyzed from October 16, 2022, to May 23, 2023. Main Outcomes and Measures: Primary outcomes were incidence rates and descriptive epidemiological data for people younger than 50 years with cancer. The annual percentage change (APC) of the age-standardized incidence rate was estimated using the Joinpoint regression program. Results: Among 562 145 patients (324 138 [57.7%] aged 40-49 years; 351 120 [62.5%] female) with early-onset cancer, 4565 (0.8%) were American Indian or Alaska Native, 54 876 (9.8%) were Asian or Pacific Islander, 61 048 (10.9%) were Black, 118 099 (21.0%) were Hispanic, 314 610 (56.0%) were White, and 8947 (1.6%) were of unknown race and/or ethnicity. From 2010 to 2019, the age-standardized incidence rate of early-onset cancers increased overall (APC, 0.28%; 95% CI, 0.09%-0.47%; P = .01) and in female individuals (APC, 0.67%; 95% CI, 0.39%-0.94%; P = .001) but decreased in male individuals (APC, -0.37%; 95% CI, -0.51% to -0.22%; P < .001). In contrast, the age-standardized incidence rate of cancers in individuals aged 50 years and older decreased over the study period (APC, -0.87%; 95% CI, -1.06% to -0.67%; P < .001). In 2019, the highest number of incident cases of early-onset cancer were in the breast (n = 12 649). From 2010 to 2019, gastrointestinal cancers had the fastest-growing incidence rates among all early-onset cancer groups (APC, 2.16%; 95% CI, 1.66%-2.67%; P < .001). Among gastrointestinal cancers, those with the fastest-growing incidence rates were in the appendix (APC, 15.61%; 95% CI, 9.21%-22.38%; P < .001), intrahepatic bile duct (APC, 8.12%; 95% CI, 4.94%-11.39%; P < .001), and pancreas (APC, 2.53%; 95% CI, 1.69%-3.38%; P < .001). Conclusions and Relevance: In this cohort study, the incidence rates of early-onset cancer increased from 2010 to 2019. Although breast cancer had the highest number of incident cases, gastrointestinal cancers had the fastest-growing incidence rates among all early-onset cancers. These data may be useful for the development of surveillance strategies and funding priorities.

Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. METHODS: MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. RESULTS: 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I2=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I2=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I2=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2-F4), while 14.95% (95% CI 11.03% to 19.95%, I2=99.00%) had advanced fibrosis (F3-F4). CONCLUSION: This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO REGISTRATION NUMBER: CRD42022360251.

Hepatic, Extra-hepatic Outcomes and Causes of Mortality in NAFLD - An Umbrella Overview of Systematic Review of Meta-Analysis.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. While the prevalence, impact, and causes of mortality have been described in various meta-analyses, a systematic all-encompassing umbrella review has yet to be conducted to consolidate the evidence on outcomes associated with NAFLD. Methods: Search was conducted on Medline and Embase for meta-analysis investigating associated complications and causes of mortality in NAFLD patients. Summary estimates were presented with original units, sample size, and I2 for heterogeneity. The Assessment of Multiple Systematic Reviews 2 was employed for article selection. Results: 25 meta-analyses were included in the present review. NAFLD increased the risks of systemic complications, including cardiovascular diseases, systemic malignancies, diabetes, and chronic kidney disease. Regarding hepatic outcomes, the incidence of hepatocellular carcinoma in NAFLD was 2.39 per 100 person years (CI: 1.40 to 4.08). Individuals with NAFLD were also found to have an increased likelihood of cholangiocarcinoma (OR: 1.88, CI: 1.25 to 2.83) and gallstone disease (OR: 1.55, CI: 1.31 to 1.82) compared to individuals without NAFLD. NAFLD was associated with a higher risk of fatal and non-fatal CVD events (HR: 1.45, CI: 1.31 to 1.61) compared to individuals without NAFLD. Coronary heart disease and subclinical and clinical coronary heart disease were also significantly elevated in NAFLD individuals compared to individuals without NAFLD. Additionally, NAFLD was associated with an increased risk of all-cause mortality (HR: 1.34, CI: 1.17 to 1.54) and cardiovascular (HR: 1.30, CI: 1.08 to 1.56) but not cancer-related mortality. Conclusion: The study summarizes high-level evidence from published meta-analyses to provide a much-needed update on the outcomes in patients with NAFLD. The significant systemic burden associated with NAFLD and impending fatty liver epidemic requires prompt action from multidisciplinary providers, policy providers, and stakeholders to reduce the burden of NAFLD.

Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma.

The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.

Natural history of NASH cirrhosis in liver transplant waitlist registrants.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) cirrhosis is rapidly growing as an indication for liver transplant(ation) (LT). However, the natural history of NASH cirrhosis among LT waitlist registrants has not been established. The present study aimed to define the natural history of NASH cirrhosis using the Scientific Registry of Transplant Recipients database. METHODS: The study cohort comprised patients registered on the LT waitlist between 1/1/2016 to 12/31/2021. The primary outcomes included probability of LT and waitlist mortality, comparing NASH (n = 8,120) vs. non-NASH (n = 21,409) cirrhosis. RESULTS: Patients with NASH cirrhosis were listed with lower model for end-stage liver disease (MELD) scores despite bearing a greater burden of portal hypertension, especially at lower MELD scores. The overall transplant probability in LT waitlist registrants with NASH [vs. non-NASH] cirrhosis was significantly lower at 90 days (HR 0.873, p <0.001) and 1 year (HR 0.867, p <0.001); this was even more pronounced in patients with MELD scores >30 (HR 0.705 at 90 days and HR 0.672 at 1 year, p <0.001 for both). Serum creatinine was the key contributor to MELD score increases leading to LT among LT waitlist registrants with NASH cirrhosis, while bilirubin was in patients with non-NASH cirrhosis. Finally, waitlist mortality at 90 days (HR 1.15, p <0.001) and 1 year (1.25, p <0.001) was significantly higher in patients with NASH cirrhosis compared to those with non-NASH cirrhosis. These differences were more pronounced in patients with lower MELD scores at the time of LT waitlist registration. CONCLUSIONS: LT waitlist registrants with NASH cirrhosis are less likely to receive a transplant compared to patients with non-NASH cirrhosis. Serum creatinine was the major contributor to MELD score increases leading to LT in patients with NASH cirrhosis. IMPACT AND IMPLICATIONS: This study provides important insights into the distinct natural history of non-alcoholic steatohepatitis (NASH) cirrhosis among liver transplant (LT) waitlist registrants, revealing that patients with NASH cirrhosis face lower odds of transplantation and higher waitlist mortality than those with non-NASH cirrhosis. Our study underscores the significance of serum creatinine as a crucial contributor to model for end-stage liver disease (MELD) score in patients with NASH cirrhosis. These findings have substantial implications, emphasizing the need for ongoing evaluation and refinement of the MELD score to more accurately capture mortality risk in patients with NASH cirrhosis on the LT waitlist. Moreover, the study highlights the importance of further research investigating the impact of the implementation of MELD 3.0 across the US on the natural history of NASH cirrhosis.

Quality Assessment of Ultrasound and Magnetic Resonance Imaging for Hepatocellular Carcinoma Surveillance: A Systematic Review and Meta-Analysis.

INTRODUCTION: To achieve early detection and curative treatment options, surveillance imaging for hepatocellular carcinoma (HCC) must remain of quality and without substantial limitations in liver visualization. However, the prevalence of limited liver visualization during HCC surveillance imaging has not been systematically assessed. Utilizing a systematic review and meta-analytic approach, we aimed to determine the prevalence of limited liver visualization during HCC surveillance imaging. METHODS: MEDLINE and Embase electronic databases were searched to identify published data on liver visualization limitations of HCC surveillance imaging. An analysis of proportions was pooled using a generalized linear mixed model with Clopper-Pearson intervals. Risk factors were analysed using a generalized mixed model with a logit link and inverse variance weightage. RESULTS: Of 683 records, 10 studies (7,131 patients) met inclusion criteria. Seven studies provided data on liver visualization limitations on ultrasound (US) surveillance exams: prevalence of limited liver visualization was 48.9% (95% CI: 23.5-74.9%) in the overall analysis and 59.2% (95% CI: 24.2-86.9%) in a sensitivity analysis for cirrhotic patients. Meta-regression determined that non-alcoholic fatty liver disease was associated with limited liver visualization on US. Four studies provided data for liver visualization limitations in abbreviated magnetic resonance imaging (aMRI), with inadequate visualization ranging from 5.8% to 19.0%. One study provided data for complete MRI and none for computed tomography. CONCLUSION: A substantial proportion of US exams performed for HCC surveillance provide limited liver visualization, especially in cirrhosis, which may hinder detection of small observations. Alternative surveillance strategies including aMRI may be appropriate for patients with limited US visualization.