Hepatocellular Carcinoma Incidence in Alcohol-Associated Cirrhosis: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Alcohol is one of the leading causes of hepatocellular carcinoma (HCC). However, pooled estimates of HCC incidence in alcohol-associated cirrhosis have not been evaluated systematically. We performed a pooled analysis of time-to-event data to provide robust estimates for the incidence of HCC in alcohol-associated cirrhosis. METHODS: Medline, Embase, Cochrane Central Register, Scopus, and Web of Science were searched from inception to August 2021. Individual patient data were reconstructed from published Kaplan-Meier curves, and a pooled analysis of cumulative HCC incidence was performed using a random-effects model. RESULTS: We screened 5022 articles and included 18 studies (148,333 patients). In the pooled analysis, the cumulative incidence of HCC in alcohol-associated cirrhosis at 1, 5, and 10 years among studies that accounted for the competing risk of death without HCC was 1%, 3%, and 9%, respectively. A secondary analysis by traditional meta-analysis determined that the HCC incidence rate was higher in cohorts enrolled in a HCC surveillance program (18.6 vs 4.8 per 1000 person-years; P = .001) vs those who were not enrolled in a surveillance program. Meta-regression showed that diabetes, smoking, variceal bleeding, and hepatic decompensation were associated with a higher risk of HCC. CONCLUSIONS: Our analysis determined that the 5- and 10- year cumulative risk of HCC in alcohol-associated cirrhosis was 3% and 9%, respectively, with a higher incidence in cohorts that were enrolled in a HCC surveillance program. These data should be validated further in large prospective studies, and may have important implications for HCC screening and surveillance among patients with alcohol-associated cirrhosis.

Global treatment rate and barriers to direct-acting antiviral therapy: A systematic review and meta-analysis of 146 studies and 1 760 352 hepatitis C virus patients.

BACKGROUND: Global data on the treatment rate with direct-acting antivirals (DAAs) for chronic hepatitis C (CHC) are sparse. We aimed to evaluate the CHC treatment rate and barriers to treatment in the DAA era. METHODS: We searched PubMed, EMBASE and Cochrane from inception to 5 August 2021, for relevant articles. Patients treated with DAAs without interferon (IFN) therapy were categorized as IFN-free DAAs. Patients receiving DAA with IFN or unclear IFN status were categorized as DAA/IFN. RESULTS: We identified and analysed data from 146 studies (1 760 352 CHC patients). DAA/IFN treatment rate was 16.0% (95% CI: 9.9-23.3, 49 studies, 886 535 patients). IFN-free DAA treatment rate was 52.3% (95% CI: 46.2-58.4, 123 studies, 1 276 754 patients): 45.4% in North America, 64.2% in South America (1 study), 90.4% in Africa (most data from Egypt), 54.4% in Europe, 60.7% in Australia and 60.5% in Asia, (p < .0001); 49% with hepatitis B co-infection and 32.3% with hepatocellular carcinoma (HCC). Treatment was not a priority in 22.8% of patients in Europe and 16.7% in Australia, compared to only 4.8% in North America and 2.1% in Asia (p < .0001). Poor adherence to clinical follow-up was the cause of no treatment in 74.7% of patients in Australia, 37.0% in North America, 7.9% in Europe and 14.3% in Asia (p < .0001). CONCLUSION: Though a marked improvement from IFN/DAA, the treatment rate with IFN-free DAA remains suboptimal (52.3% overall, 32.3% in HCC patients). Non-adherence to clinical follow-up and lack of disease awareness were treatment barriers.

The Global Burden of Early-Onset Biliary Tract Cancer: Insight From the Global Burden of Disease Study 2019.

Backgrounds/objectives: The escalating incidence of early-onset gastrointestinal cancers is becoming a primary global health concern. Biliary tract cancer (BTC) has been relatively understudied in this regard. We conducted an epidemiological study regarding the burden of this condition. Methods: We utilized data from the Global Burden of Disease Study 2019 to investigate the temporal trends in early-onset BTC (EOBTC), encompassing the estimation of frequencies and age-standardized rates (ASRs) of EOBTC incidence, mortality, and disability-adjusted life-years (DALYs), from 2010 to 2019. Results: EOBTC constituted nearly 7%of all BTC cases worldwide. The incidence rates of EOBTC decreased significantly in most regions, except in the Eastern Mediterranean (annual percentage change +1.04 %), where the incidence is rising. Stratified by the sociodemographic index (SDI), countries with low middle SDI (annual percentage change +0.5 %) show increasing incidence of EOBTC. The ASR of death and DALYs decreased in most regions. The ASR of EOBTC-related death and disability attributable to high body mass index increased in most regions, with the highest increase in Southeast Asia and low, middle SDI strata. Conclusions: There was a reduction in the burden of EOBTC globally, except for Eastern Mediterranean countries and low-middle SDI countries.

Response to Paik et al. on the disease burden of NAFLD.

Chew and Ng et al. recently reported on the global burden of metabolic disease by utilizing estimates from the Global Burden of Disease (GBD) study. Herein, they respond to critical points highlighted by Paik et al. regarding the limitations of the GBD database as well as the definitions employed in the study.

Meta-analysis: Chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin.

BACKGROUND: Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks. AIM: To examine by an updated meta-analysis the association between these medications and HCC risk. METHODS: Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model. RESULTS: Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37-0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27-0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31-1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I2  = 0%). CONCLUSION: Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.

Meta-analysis: Prevalence of significant or advanced fibrosis in adults with alpha-1-antitrypsin deficiency.

BACKGROUND: The prevalence of liver fibrosis detected by non-invasive imaging in alpha-1-antitrypsin (AAT) deficiency has not been systematically assessed. AIMS: We conducted a systematic review and meta-analysis to determine the prevalence of significant fibrosis and advanced fibrosis in AAT deficiency based on non-invasive imaging. METHODS: Medline and Embase electronic databases were searched for studies from inception to 13 November 2022 that provided data for the prevalence of fibrosis in adults with AAT deficiency. A generalised linear mixed model with Clopper-Pearson intervals was used to pool single-arm outcomes. RESULTS: Of the 214 records identified, 8 studies were included. Five studies assessed fibrosis using vibration-controlled transient elastography. The prevalence of significant fibrosis (defined as ≥7.1 kPA) in Z homozygosity, Z heterozygosity and non-carrier status was 22.10% (five studies, 95% CI: 17.07-28.12), 9.24% (three studies, 95% CI: 4.68-17.45) and 5.38% (one study, 95% CI: 3.27-8.73), respectively, p < 0.0001, and the prevalence of advanced fibrosis (defined as ≥9.5 kPa) was 8.13% (five studies, 95% CI: 4.60-13.96), 2.96% (three studies, 95% CI: 1.49-5.81) and 1.08% (one study, 95% CI: 0.35-3.28), respectively, p = 0.003. There were limited data regarding the use of magnetic resonance elastography or acoustic radiation force impulse to assess for fibrosis. CONCLUSION: More than one in five adult individuals with AAT deficiency and Z homozygosity harbour significant fibrosis, and nearly 1 in 10 harbours advanced fibrosis. The risk of fibrosis increases incrementally with the frequency of Pi*Z mutations.

Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer.

Liver cancer epidemiology is changing due to increasing alcohol consumption, rising prevalence of obesity, and advances in hepatitis B virus (HBV) and hepatitis C virus (HCV) treatment. However, the impact of these changes on global liver cancer burden remains unclear. We estimated global and regional temporal trends in the burden of liver cancer and the contributions of various liver disease etiologies using the methodology framework of the Global Burden of Disease study. Between 2010 and 2019, there was a 25% increase in liver cancer deaths. Age-standardized death rates (ASDRs) increased only in the Americas and remained stable or fell in all other regions. Between 2010 and 2019, non-alcoholic steatohepatitis (NASH) and alcohol had the fastest growing ASDRs, while HCV and HBV declined. Urgent measures are required at a global level to tackle underlying metabolic risk factors and slow the growing burden of NASH-associated liver cancer, especially in the Americas.

Delayed coloanal anastomosis as a stoma-sparing alternative to immediate coloanal anastomosis: A systematic review and meta-analysis.

BACKGROUND: Recent clinical trials have demonstrated favorable outcomes associated with trans-anal colonic pull-through for rectal resection followed by delayed coloanal anastomoses (DCA), resulting in a resurgence in popularity of the technique. This meta-analysis aims to review existing literature to evaluate the postoperative complications associated with DCA, and to make comparisons with immediate coloanal anastomoses (ICA) after colorectal resection to assess the suitability of DCA as an alternative form of surgical treatment. METHODS: Medline and Embase databases were reviewed from inception until 31 July 2020 in accordance with PRISMA guidelines. Single-arm studies that involved patients undergoing DCA for benign or malignant causes were selected, and meta-analysis of proportions was conducted to determine the prevalence of postoperative complications following DCA. Comparative studies comparing postoperative outcomes between DCA and ICA were also included for comparative meta-analysis. RESULTS: Patients undergoing DCA were significantly less likely to require diverting stoma construction as compared to ICA (odds ratio [OR] = 0.04; confidence interval [CI]: 0.02-0.07; P < 0.001). Overall postoperative morbidity (OR = 0.50; 95% CI: 0.23-1.12; P = 0.09) and mortality (OR = 0.49, 95% CI: 0.12-1.98; P = 0.32) was comparable between DCA and ICA groups. No significant differences in perioperative complications, such as anastomotic leakage (OR = 0.42; 95% CI: 0.11-1.64; P = 0.21), postoperative ileus, pelvic abscesses, or sepsis, were noted between DCA and ICA. CONCLUSION: Our study shows no differences in complications or functional outcomes between DCA and ICA. Pooled analysis expectedly revealed a lower rate of diverting stoma in patients undergoing DCA. DCA is thus a safe alternative to current surgical practices where avoidance of a stoma is desired.

Meta-Analysis of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Left Main Narrowing.

Randomized controlled trials (RCTs) comparing percutaneous coronary intervention (PCI) with drug-eluting stents and coronary artery bypass grafting (CABG) for patients with left main coronary artery disease (LMCAD) have reported conflicting results. We performed a systematic review up to May 23, 2021, and 1-stage reconstructed individual patient data meta-analysis (IPDMA) to compare outcomes between both groups. The primary outcome was 10-year all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, and unplanned revascularization at 5 years. We performed individual patient data meta-analysis using published Kaplan-Meier curves to provide individual data points in coordinates and numbers at risk were used to increase the calibration accuracy of the reconstructed data. Shared frailty model or, when proportionality assumptions were not met, a restricted mean survival time model were fitted to compare outcomes between treatment groups. Of 583 articles retrieved, 5 RCTs were included. A total of 4,595 patients from these 5 RCTs were randomly assigned to PCI (n = 2,297) or CABG (n = 2,298). The cumulative 10-year all-cause mortality after PCI and CABG was 12.0% versus 10.6%, respectively (hazard ratio [HR] 1.093, 95% confidence interval [CI] 0.925 to 1.292; p = 0.296). PCI conferred similar time-to-MI (restricted mean survival time ratio 1.006, 95% CI 0.992 to 1.021, p=0.391) and stroke (restricted mean survival time ratio 1.005, 95% CI 0.998 to 1.013, p = 0.133) at 5 years. Unplanned revascularization was more frequent after PCI than CABG (HR 1.807, 95% CI 1.524 to 2.144, p <0.001) at 5 years. This meta-analysis using reconstructed participant-level time-to-event data showed no statistically significant difference in cumulative 10-year all-cause mortality between PCI versus CABG in the treatment of LMCAD.

A Meta-Analysis on the Rate of Hepatocellular Carcinoma Recurrence after Liver Transplant and Associations to Etiology, Alpha-Fetoprotein, Income and Ethnicity.

Hepatocellular carcinoma (HCC) recurrence after liver transplant is associated with a poor prognosis and significantly increases morbidity and mortality among liver transplant patients. Therefore, this meta-analysis aims to evaluate the overall prevalence of HCC recurrence following liver transplant. Medline and Embase databases were searched, and a meta-analysis of proportions was conducted. Observational studies reporting the prevalence of recurrent hepatocellular carcinoma (HCC) after liver transplant were included, with the analysis being stratified by adherence to Milan criteria, ethnicity, socio-economic status, alpha fetoprotein (AFP) levels, living donor vs. deceased donor, and the underlying aetiology of the liver disease. A meta-regression on the date of the study completion was also performed. Of a total 40,495 patients, 3888 developed an HCC recurrence. The overall prevalence of recurrent HCC was 13% (CI: 0.12-0.15). Patients beyond the Milan criteria (MC) were more likely to recur than patients within MC. Asian populations had the greatest prevalence of HCC recurrence (19%; CI: 0.15-0.24) when compared to Western (12%; CI: 0.11-0.13) and Latin American populations (11%; CI: 0.09-0.14). The prevalence of recurrent HCC was the highest in patients infected with hepatitis B virus (HBV) (18%; CI: 0.11-0.27) compared to other aetiologies. A higher AFP also resulted in an increased recurrence. This highlights interesting differences based on ethnicity, income, and aetiology, and further studies are needed to determine the reasons for the disparity.