Incidence Of Cirrhosis Research Articles

Clinicopathological Features of Hepatocellular Carcinoma with Metabolic Risk Factors.

This study aims to explore the pathological characteristics of metabolic-related hepatocellular carcinoma (HCC) and its correlation with metabolic factors. Fifty-one patients with liver cancer of unknown causes were enrolled. Biopsy of the liver and staining of the liver tissues with hematoxylin-eosin as well as special and immunohistochemical stains were performed. The histological subtypes of HCC were diagnosed based on the WHO Classification of Malignant Hepatocellular Tumors. The NAFLD activity score system was adopted for assessing the surrounding non-neoplastic liver tissues. Of the total, 42 (82.4%) patients were diagnosed with HCC, 32 had metabolic risk factors, 20 patients met the diagnostic criteria of the metabolic-associated fatty liver disease (MAFLD)-related HCC, and 40.6% (13/32) had liver cirrhosis. The incidence of cirrhosis (p = 0.033) and diabetes mellitus type 2 (p = 0.036) in patients with MAFLD-related HCC was notably higher than that in HCC patients with only metabolic risk factors. Among the 32 HCC cases with metabolic risk factors, trabecular type was the most prevalent, followed by steatohepatitis type, scirrhous type, solid type, pseudoglandular type, clear-cell type, and macrotrabecular type. The degree of tumor cells' swelling and ballooning was found to be positively related to the degree of fibrosis in the surrounding liver tissues (p = 0.011) as well as the proportion of cirrhosis (p = 0.004). Moreover, the degree of fibrosis in the surrounding liver tissues showed a negative correlation with the levels of serum cholesterol (p = 0.002), low-density lipoprotein (p = 0.002), ApoA1 (p = 0.009), ApoB (p = 0.022), total protein (p = 0.015), WBC count (p = 0.006), and PLT count (p = 0.015). Pathological characteristics of the tumor and adjacent non-neoplastic liver tissues of HCC with metabolic risk factors were found to be correlated with metabolic abnormalities.

Progression to cirrhosis is similar among all ages in nonalcoholic fatty liver disease, but liver-related events increase with age.

NAFLD is increasingly common among young people. Whether NAFLD carries a more benign course in younger adults is not known. We aimed to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression across age groups. We conducted a retrospective study of adults with NAFLD seen within Michigan Medicine, a tertiary care center, between 2010 and 2021. NAFLD was defined by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases. Cirrhosis was determined by validated International Classification of Diseases-9/10 codes or imaging. Fine-Gray competing risk models were generated, with incident cirrhosis and liver-related events (LREs) as the primary outcomes and death without cirrhosis or LREs as a competing risk. The primary predictor was the age category. We included 31,505 patients with NAFLD, with 8,252 aged 18 to younger than 40, 15,035 aged 40 to younger than 60, and 8,218 aged 60 years or older years at diagnosis. Compared with older patients, young adults more often had obesity, higher ALT, and high-risk PNPLA3 alleles, and fewer had prevalent cirrhosis, hypertension, hyperlipidemia, and diabetes. The 10-year risk of incident cirrhosis was similar between ages (3.4% in age 18 to <40 vs 3.7% in age 40 to <60 vs 4.7% in age ≥60; p = 0.058). Predictors of LREs were advancing age and diabetes, with a significantly higher 10-year risk of LREs in the oldest age group (0.2% in age 18 to <40 vs 0.7% in age 40 to <60 vs 1.1% in age ≥60; p = 0.008). While the baseline prevalence of cirrhosis was higher among older adults, the rate of NAFLD progression to cirrhosis was similar in young and older adults. Older patients were more likely to have LREs.

THU-422 - PNPLA3 GG genotype is associated with higher incidence of cirrhosis and liver-related events among patients with non-alcoholic fatty liver disease

THU-422 - PNPLA3 GG genotype is associated with higher incidence of cirrhosis and liver-related events among patients with non-alcoholic fatty liver disease

LBP-30-YI - A new risk model outperforms FIB-4 when predicting incident cirrhosis in the general population: a cohort study of 504,000 persons

LBP-30-YI - A new risk model outperforms FIB-4 when predicting incident cirrhosis in the general population: a cohort study of 504,000 persons

Associations of Race and Ethnicity with Hepatocellular Carcinoma, Decompensation, and Mortality in US Veterans with Cirrhosis.

Among patients with cirrhosis, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology. US Veterans diagnosed with cirrhosis from 2001 to 2014 (n = 120,992), due to hepatitis C virus (HCV; n = 55,814), alcohol-associated liver disease (ALD; n = 36,323), hepatitis B virus (HBV; n = 1,972), nonalcoholic fatty liver disease (NAFLD; n = 17,789), or other (n = 9,094), were followed through 2020 for incident HCC (n = 10,242), cirrhosis decompensation (n = 27,887), and mortality (n = 81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). Compared with non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR, 1.32; 95% CI, 1.24-1.41) and by cirrhosis etiology, particularly for ALD- (aHR, 1.63; 95% CI, 1.42-1.87) and NAFLD-cirrhosis (aHR, 1.76; 95% CI, 1.41-2.20), whereas non-Hispanic Black patients had lower HCC risk in ALD- (aHR, 0.79; 95% CI, 0.63-0.98) and NAFLD-cirrhosis (aHR, 0.54; 95% CI, 0.33-0.89). Asian patients had higher HCC risk (aHR, 1.70; 95% CI, 1.29-2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR, 0.71; 95% CI, 0.68-0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared with non-Hispanic White patients. Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality. Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for patients with cirrhosis.

TBX5 Variants are Associated with Susceptibility to and the Incidence of Liver Cirrhosis and Hepatocellular Carcinoma in the Chinese Population: A Multicenter and Follow-Up Study.

Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) are progressions affected by genetic predispositions, and persistent hepatitis B virus infection also demonstrates genetic susceptibility. All HBV-related outcomes have been compared in parallel to identify risk polymorphism in HBV progression. The multiple-stage association study filtered and validated the risk SNPs for HBV progression and explored their association with persistent infection, with a total of 8906 subjects in China from three sites. Cox proportional hazards models and Kaplan-Meier Log rank tests were used to determine the time to the progressive event in relation to the risk SNPs. Rs3825214 in TBX5 replicated a specific association with LC and HCC in 4 progression cohorts and was not related to persistent infection, naivety to HBV infection and natural clearance in 3 persistent cohorts. In combined samples, rs3825214 was associated with an increased risk of LC (P<0.001; OR = 1.98) and HCC (P<0.001; OR = 1.68). The results of bioinformatics analysis indicated that rs3825214 genotypes change RNA structure and intron excision ratio. In the follow-up of 571 hospital-based persistent HBV infection patients, ninety-three (16.29%) developed LC, and seventy-four (12.96%) progressed to HCC at a median follow-up of 5.1 years. Rs3825214 was associated with HCC and LC events in Cox proportional hazards models (P<0.001). We identified and confirmed that genetic variants in TBX5 are significantly associated with susceptibility to and the incidence of LC and HCC.

Global, regional, and national burdens of cirrhosis in children and adolescents aged under 19 years from 1990 to 2019

Background & aimsCirrhosis was the leading cause of morbidity and mortality in adults, but data on the burden and trends were sparse in children and adolescents. We aimed to assess the trends in 204 countries and territories over the past 30 years in children and adolescents aged 0–19 years.MethodsData on cirrhosis was collected by the Global Burden of Disease (GBD) 2019 database from 1990 to 2019. We reported on the number, rates, and average annual percentage changes (AAPCs) of incidence and disability-adjusted life-years (DALYs) of cirrhosis at global, regional, and national level.ResultsGlobally, the incident numbers of cirrhosis in children and adolescents increased from 204,767 in 1990 to 241,364 in 2019, an increase of 17.9%, with an AAPC 0.13(0.10 to 0.16). Prevalence (AAPC = − 2.27[− 2.39 to − 2.15]), mortality (AAPC = − 1.68 [− 1.86 to − 1.5]), and DALYs rate (AAPC = − 1.72[− 1.88 to − 1.56]) of cirrhosis have decreased significantly. Cirrhosis incident rates varied between different ages. Cirrhosis caused by alcohol use (AAPC = 1[0.8 to 1.1]; incidence cases increased 48%), hepatitis C (AAPC = 0.4 [0.4 to 0.5]), NAFLD (AAPC = 0.5 [0.3 to 0.6]) have been increasing, while only hepatitis B (− 0.3[− 0.4 to − 0.2]) decreasing. Incidence cases of cirrhosis were increased in low (101.6%) and low-middle sociodemographic index (SDI 21.1%) areas, while decreasing in middle and above SDI areas. At the regional level, the largest increases count was observed in Sub-Saharan Africa.ConclusionsGlobal incidence rate of cirrhosis has been increasing, while the DALYs rate has been decreasing in children and adolescents. Morbidity of cirrhosis caused by hepatitis B declined, while hepatitis C, NAFLD, and alcohol use increased.

CME Exam 2: PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis

CME Exam 2: PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis

The care cascade for hepatitis C virus and prognosis of chronic hepatitis C patients treated with antiviral agents in a tertiary hospital

BackgroundSome studies have analyzed the frequency of HCV RNA testing and actual treatment among anti-HCV positive patients in Korea, which has a low prevalence of HCV infection. This study aimed to analyze the diagnosis process, treatment results, and prognosis according to care cascade in patients who are anti-HCV positive.MethodsThree thousand two hundred fifty-three anti-HCV positive patients presented to a tertiary hospital between January 2005 and December 2020. The number of patients who underwent HCV RNA testing, treatment, and proportion of sustained virologic response (SVR) according to the type of antivirals was investigated. We investigated the cumulative incidence of hepatocellular carcinoma (HCC) and liver cirrhosis.ResultsOf a total of 3,253 people, 1,177 (36.2%) underwent HCV RNA testing and 858 (72.9%) were positive for HCV RNA. 494 (57.6%) of HCV RNA positive patients received antiviral treatment, and 443 (89.7%) of initiated hepatitis C treatment experienced SVR. Of the 421 treated patients, 16 (14.2%) developed HCC. The cumulative incidence of HCC at 15 years was significantly different according to the presence of liver cirrhosis (10/83, 29.5% vs. 6/338, 10.8%, p < 0.001). The cumulative incidences of HCC or liver cirrhosis did not show significant differences according to the presence of SVR12 (14/388, 13.2% vs. 2/33, 52.5%, p = 0.084, 21/319, 15.0%, vs. 3/22, 28.7%, p = 0.051).ConclusionsOwing to the introduction of direct-acting antivirals, high SVR12 was achieved, but the proportion of anti-HCV positive patients who received HCV RNA testing and treatment was not high. HCC surveillance after SVR12 is recommended for chronic hepatitis C patients with cirrhosis.

Does metabolic syndrome affect perioperative outcomes in patients undergoing robotic hepatectomy? A propensity score-matched analysis.

Metabolic syndrome is a known risk factor for postoperative complications after general surgical procedures. Literature analyzing perioperative outcomes of patients with metabolic syndrome undergoing a minimally invasive hepatectomy is limited. We sought to investigate if metabolic syndrome significantly impacts the perioperative course and outcomes of patients undergoing robotic hepatectomy. With IRB, we prospectively followed patients who underwent robotic hepatectomy from 2016 through 2020. A 1:1 propensity score-matched (PSM) analysis was applied to patients with and without metabolic syndrome. Demographic and clinical data were analyzed for those cohorts before and after PSM. Metabolic syndrome was defined as BMI ≥ 28.8kg/m2, diabetes, and hypertension. A total of 272 patients underwent robotic hepatectomy, 39 (14%) of whom had metabolic syndrome. After performing PSM, we ended up with 74 patients, 37 in each cohort, 28% of them had liver cirrhosis. Patients with metabolic syndrome had higher BMI (34 ± 5.6 vs. 28 ± 5.9kg/m2, p < 0.001) and MELD scores (10 ± 4.5 vs. 8 ± 3.2, p < 0.001) compared to patients without metabolic syndrome. Additionally, patients with metabolic syndrome had an increased incidence of liver cirrhosis (33% vs. 9%, p = 0.0002). Following PSM, BMI (34 ± 5.7 vs. 26 ± 4.4kg/m2, p < 0.001) was the only preoperative variables associated with metabolic syndrome. There were no statistical differences before and after PSM between patients with and without metabolic syndrome in terms of intraoperative metrics including operative time, blood loss, conversion to 'open,' and intraoperative complications. All postoperative outcomes metrics before and after PSM did not correlate with the presence or absence of metabolic syndrome. Metabolic syndrome had no impact on intra- or postoperative metrics, complications, or outcomes after robotic hepatectomy. We believe that the robotic approach may mitigate the adverse effects of metabolic syndrome for patients undergoing robotic hepatectomy.

Characteristics of microbiome-derived metabolomics according to the progression of alcoholic liver disease.

The prevalence and severity of alcoholic liver disease (ALD) are increasing. The incidence of alcohol-related cirrhosis has risen up to 2.5%. This study aimed to identify novel metabolite mechanisms involved in the development of ALD in patients. The use of gut microbiome-derived metabolites is increasing in targeted therapies. Identifying metabolic compounds is challenging due to the complex patterns that have long-term effects on ALD. We investigated the specific metabolite signatures in ALD patients. This study included 247 patients (heathy control, HC: n = 62, alcoholic fatty liver, AFL; n = 25, alcoholic hepatitis, AH; n = 80, and alcoholic cirrhosis, AC, n = 80) identified, and stool samples were collected. 16S rRNA sequencing and metabolomics were performed with MiSeq sequencer and liquid chromatography coupled to time-of-flight-mass spectrometry (LC-TOF-MS), respectively. The untargeted metabolites in AFL, AH, and AC samples were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Metabolic network classifiers were used to predict the pathway expression of the AFL, AH, and AC stages. The relative abundance of Proteobacteria was increased and the abundance of Bacteroides was decreased in ALD samples (p = 0.001) compared with that in HC samples. Fusobacteria levels were higher in AH samples (p = 0.0001) than in HC samples. Untargeted metabolomics was applied to quantitatively screen 103 metabolites from each stool sample. Indole-3-propionic acid levels are significantly lower in AH and AC (vs. HC, p = 0.001). Indole-3-lactic acid (ILA: p = 0.04) levels were increased in AC samples. AC group showed an increase in indole-3-lactic acid (vs. HC, p = 0.040) level. Compared with that in HC samples, the levels of short-chain fatty acids (SCFAs: acetic acid, butyric acid, propionic acid, iso-butyric acid, and iso-valeric acid) and bile acids (lithocholic acids) were significantly decreased in AC. The pathways of linoleic acid metabolism, indole compounds, histidine metabolism, fatty acid degradation, and glutamate metabolism were closely associated with ALD metabolism. This study identified that microbial metabolic dysbiosis is associated with ALD-related metabolic dysfunction. The SCFAs, bile acids, and indole compounds were depleted during ALD progression. Clinicaltrials.gov, number NCT04339725.

Model-based hypothesis tests for the causal mediation of semi-competing risks.

Analyzing the causal mediation of semi-competing risks has become important in medical research. Semi-competing risks refers to a scenario wherein an intermediate event may be censored by a primary event but not vice versa. Causal mediation analyses decompose the effect of an exposure on the primary outcome into an indirect (mediation) effect: an effect mediated through a mediator, and a direct effect: an effect not through the mediator. Here we proposed a model-based testing procedure to examine the indirect effect of the exposure on the primary event through the intermediate event. Under the counterfactual outcome framework, we defined a causal mediation effect using counting process. To assess statistical evidence for the mediation effect, we proposed two tests: an intersection-union test (IUT) and a weighted log-rank test (WLR). The test statistic was developed from a semi-parametric estimator of the mediation effect using a Cox proportional hazards model for the primary event and a series of logistic regression models for the intermediate event. We built a connection between the IUT and WLR. Asymptotic properties of the two tests were derived, and the IUT was determined to be a size [Formula: see text] test and statistically more powerful than the WLR. In numerical simulations, both the model-based IUT and WLR can properly adjust for confounding covariates, and the Type I error rates of the proposed methods are well protected, with the IUT being more powerful than the WLR. Our methods demonstrate the strongly significant effects of hepatitis B or C on the risk of liver cancer mediated through liver cirrhosis incidence in a prospective cohort study. The proposed method is also applicable to surrogate endpoint analyses in clinical trials.

A256 INCIDENCE OF CIRRHOSIS AMONG RECENT IMMIGRANTS AND REFUGEES TO ONTARIO, CANADA : A POPULATION-BASED COHORT STUDY

Abstract Background The burden of cirrhosis is increasing in North America where a significant proportion of the population (~20%) is comprised of recent immigrants and refugees. However, the incidence of cirrhosis among this population has not been described. Purpose The aim of this study was to describe the incidence of cirrhosis among recent immigrants and refugees to Ontario, Canada stratified by cirrhosis etiology and region of origin and compare incidence rates to those of Canadian-born and long-term residents. Method This is a population-based cohort study from Ontario, Canada from 2000-2017 using healthcare data housed at ICES. Individuals with incident cirrhosis using a 5-year lookback were identified along with cirrhosis etiology using validated algorithms. Recent immigrants and refugees to Ontario (since 1985) and their World Bank region of origin were defined based on linkage to the Immigration, Refugees, and Citizenship Canada’s Permanent Resident database. Adjusted incidence rates of cirrhosis by immigration status, etiology, and region of origin were calculated and differences in rates were compared between recent immigrants and refugees to long-term residents (born in Canada or arriving before 1985) using age and sex adjusted Poisson regression to calculate rate ratios (RR). Result(s) In total, n=25,054 recent immigrants/refugees with incident cirrhosis were identified. 59% were male, median age was 49 years (IQR 39-61), 99% resided in urban areas and 31% resided in neighbourhoods of the lowest income quintile. The most common regions of origin were East Asia and Pacific (n=8,121; 32%), South Asia (n=5,576; 22%), Europe and Central Asia (n=4,454; 18%) and Latin America/Caribbean (n=3,216; 13%). The majority had NAFLD cirrhosis (n=13,972; 55%), followed by HBV (n=4,648; 19%), ALD (n=2,957; 12%), and HCV (n=2,635; 11%). Cirrhosis incidence stratified by etiology varied by region of origin, with HBV highest among the East Asia and Pacific and Sub-Saharan Africa cohort (Figure 1b), HCV among Sub-Saharan Africa and South Asia (Figure 1c), ALD among European/Central Asia and South Asia (Figure 1d), and NAFLD among the Latin America/Caribbean, Middle East/North Africa, and South Asian populations (Figure 1e). When comparing age and sex adjusted incidence of cirrhosis by etiology and immigration status, rates were lower among recent immigrants/refugees for all causes compared to long-term residents (all RR &amp;lt;1.0; Figure 1a,c-f) with the exception of HBV where it was over 4-fold higher (Figure 1b). Image Conclusion(s) Rates of HBV cirrhosis are substantially higher among migrants to Ontario while rates of all other causes of cirrhosis are lower, likely explained by the healthy immigrant effect. NAFLD has emerged as the most common etiology of cirrhosis among migrants with rates approaching those of Canadian-born and long-term residents. These data add to our understanding of the evolving epidemiology of cirrhosis and the contribution of other etiologies outside of viral hepatitis among immigrants. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Comment on: Textbook Outcomes Following Open Live Donor Right Hepatectomy and Open Right Hepatic Lobectomy for Cancer in 686 Patients: Re-Defining the Benchmark.

We read the article by Dogeas et al1 with great interest. This study used a prospective database to compare textbook outcomes (TO) rates between right hepatectomy (RH) for live donor purposes and RH for malignancy. The author found that the TO rates of RH for live donor purposes (92.2%) were significantly higher than that for malignancy (53.7%) and considered that these indicators represented a new benchmark for “real world” TO after open RH. Despite inspiring and thought-provoking, we have the following comments. First, in our experience, in the real world, regardless of the type of hepatectomy, the most common cause is hepatocellular carcinoma. However, among cancer patients in this study, the most common pathology was colorectal cancer liver metastases, accounting for 58.4% (184 patients). This also means that cirrhosis has a very low proportion of cancer patients, only 5.4% (17 patients). In fact, there may be a higher incidence of cirrhosis in all cancer patients who underwent RH. Although cirrhosis was only confirmed as an independent risk factor associated with a lower TO rate of hepatocellular carcinoma hepatectomy in our previous study,2 we still believe that cirrhosis may strongly affect the TO rate in all cases of hepatectomy. Therefore, it is reasonable to wonder whether the TO rate in the tumor patients in this study can be viewed as a new benchmark for the “real world” and whether independent factors associated with not achieving TO can be applied to all RH cancer patients. Second, this study noted that the live donor RH people had higher TO rates, as they were younger, healthier, and thinner, but logistic regression analysis showed no significant association between body mass index (BMI) and TO rates. The study did not mention the grouping method of BMI in the methods section. If BMI is analyzed as a continuous variable, it is likely to obtain negative results that BMI is not related to TO rates. However, high BMI often means that body obesity, while low BMI means body malnutrition or cachexia. Consequently, appropriate BMI grouping may directly determine the results of the study. We wanted to know how the authors analyzed of the association between BMI and TO rates. Third, TO rates were compared between RH for live donor purposes and RH for malignancy in this study. However, direct comparisons between the 2 groups may not be statistically appropriate due to the large difference between the 2 groups. Therefore, we believe that some statistical methods, such as propensity score matching or inverse probability of treatment weighting, should be used first to balance the baseline data between the 2 groups, perhaps to make the 2 groups more comparable. Although balancing may not have changed the final results of this study, we still believe that balancing the baselines of the 2 groups and then comparing them can make the results of this study more solid. Finally, we are still very appreciative of Dogeas et al1 for the new benchmark for “real world” TO after RH. We hold the belief that these findings will contribute to the further improvement and development of liver surgery.

Higher mortality among lean patients with non-alcoholic fatty liver disease despite fewer metabolic comorbidities.

Non-alcoholic fatty liver disease (NAFLD) can develop in individuals who are not overweight. Whether lean persons with NAFLD have lower mortality and lower incidence of cirrhosis, cardiovascular diseases (CVD), diabetes mellitus (DM) and cancer than overweight/obese persons with NAFLD remains inconclusive. We compared mortality and incidence of cirrhosis, CVD, DM and cancer between lean versus non-lean persons with NAFLD. This is a retrospective study of adults with NAFLD in a single centre from 2012 to 2021. Primary outcomes were mortality and new diagnosis of cirrhosis, CVD, DM and cancer. Outcomes were modelled using competing risk analysis and Cox proportional hazards regression analysis. A total of 18,594 and 13,420 patients were identified for cross-sectional and longitudinal analysis respectively: approximately 11% lean, 25% overweight, 28% class 1 obesity and 35% class 2-3 obesity. The median age was 51.0 years, 54.6% were women. The median follow-up was 49.3months. Lean patients had lower prevalence of metabolic diseases at baseline and lower incidence of cirrhosis and DM than non-lean patients and no difference in CVD, any cancer or obesity-related cancer during follow-up. However, lean patients had significantly higher mortality with incidence per 1000 person-years of 16.67, 10.11, 7.37 and 8.99, respectively, in lean, overweight, obesity class 1 and obesity class 2-3 groups respectively. Lean patients with NAFLD had higher mortality despite lower incidence of cirrhosis and DM, and similar incidence of CVD and cancer and merit similar if not more attention as non-lean patients with NAFLD.

Incidence of Cirrhosis Among Recent Immigrants and Refugees to Ontario, Canada.

The epidemiology of cirrhosis among immigrants to North America has not been described. Using population-level data from Ontario, Canada, recent immigrant and refugees with incident cirrhosis were identified and stratified by World Bank region of origin and cirrhosis etiology. Incidence rates were described based on region of origin and etiology and compared with those in Canadian-born/long-term residents. A total of 25,054 immigrants/refugees were identified with rates of cirrhosis lower compared with those in Canadian-born/long-term residents for all etiologies except hepatitis B virus likely explained by the healthy immigrant effect. Nonalcoholic fatty liver disease was the most common etiology of cirrhosis among immigrants and refugees.

PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis

Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

The burden of liver cirrhosis and underlying etiologies: results from the Global Burden of Disease Study 2019.

Liver cirrhosis and other chronic liver diseases are major health concerns. [corrected]. Herein, we aimed to estimate the incidence, prevalence, and mortality of liver cirrhosis and other chronic liver diseases (collectively referred to as liver cirrhosis in this paper) [corrected] caused by specific etiologies for 204 countries and territories. The data were retrieved from the Global Burden of Disease Study 2019. The age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), age-standardized death rate, and estimated annual percentage changes were used to estimate the trends in incidence, prevalence, and mortality of liver cirrhosis by sex, region, country, and etiology between 2009 and 2019. From 2009 to 2019, the incident cases of liver cirrhosis increased by 16.7%, from 1.8 million (95% uncertainty interval: 1.5-2.1) to 2.1 million (1.7-2.5), and the prevalent cases increased from 1378.3 million (1275.1-1498.8) to 1691.0 million (1560.9-1845.5). Liver cirrhosis contributed to nearly 1.5 million (1.4-1.6) deaths in 2019, nearly 0.2 million more than in 2009. However, the age-standardized death rate fell from 20.71 (19.79-21.65) per 100,000 population in 2009 to 18.00 (16.80-19.31) per 100,000 population in 2019. In terms of sex, males showed higher ASIR, ASPR, and age-standardized death rate than females. Among the etiologies, the ASIR and ASPR of NAFLD increased markedly, and there was also a modest increase in ASIR and ASPR for HCV and alcohol use. In contrast, the ASIR and ASPR of HBV decreased considerably. Our finding suggests an increasing burden of liver cirrhosis worldwide but a declining attributed death. A high prevalence and still rising trend of NAFLD and alcohol use-etiology were found in patients with cirrhosis globally, although variation was found between regions/countries. These data indicate that efforts to reduce the associated burden need to be improved.

Rising incidence, progression and changing patterns of liver disease in Wales 1999-2019.

Liver disease incidence and hence demand on hepatology services is increasing. To describe trends in incidence and natural history of liver diseases in Wales to inform effective provision of hepatology services. The registry is populated by International Classification of Diseases-10 (ICD-10) code diagnoses for residents derived from mortality data and inpatient/day case activity between 1999-2019. Pseudo-anonymised linkage of: (1) Causative diagnoses; (2) Cirrhosis; (3) Portal hypertension; (4) Decompensation; and (5) Liver cancer diagnoses enabled tracking liver disease progression. The population of Wales in 2019 was 3.1 million. Between 1999 and 2019 73054 individuals were diagnosed with a hepatic disorder, including 18633 diagnosed with cirrhosis, 10965 with liver decompensation and 2316 with hepatocellular carcinoma (HCC). Over 21 years the incidence of liver diseases increased 3.6 fold, predominantly driven by a 10 fold increase in non-alcoholic fatty liver disease (NAFLD); the leading cause of liver disease from 2014. The incidence of cirrhosis, decompensation, HCC, and all-cause mortality tripled. Liver-related mortality doubled. Alcohol-related liver disease (ArLD), autoimmune liver disease and congestive hepatopathy were associated with the highest rates of decompensation and all-cause mortality. A 10 fold increase in NAFLD incidence is driving a 3.6 fold increase in liver disease in Wales over 21 years. Liver-related morbidity and mortality rose more slowly reflecting the lower progression rate in NAFLD. Incidence of ArLD remained stable but was associated with the highest rates of liver-related and all-cause mortality.

The Evolution of Iron-Related Comorbidities and Hospitalization in Patients with Hemochromatosis: An Analysis of the Nationwide Inpatient Sample.

Hemochromatosis, either hereditary hemochromatosis (HH) or secondary hemochromatosis, consists of the accumulation of iron in the liver, heart, and other organs. It leads to end-organ damage in a proportion of affected subjects. Although liver-related morbidity (cirrhosis and hepatocellular carcinoma [HCC]) and mortality are well established, the frequency of these complications remains controversial. The aim of this study is to examine the rate of hospitalization and the incidence of iron overload-related comorbidities in patients with hemochromatosis between the years of 2002 and 2010. We queried the Nationwide Inpatient Sample (NIS) database from the year 2002 to 2010. We included adults (age ≥18 years) and used the ICD-CM 9 code 275.0x to identify hospitalized patients with a diagnosis of hemochromatosis. Data analysis for this study was generated using SAS software version 9.4. A total of 168,614 hospitalized patients between 2002 and 2010 had a diagnosis of hemochromatosis. The majority were males (57%) with a median age of 54 years (37-68), with a predominance of white patients (63.3%) followed by black (26.8%). The rate of hospitalization among patients with hemochromatosis increased by 79% between the years 2002 and 2010 (34.5/100,000 in 2002 vs 61.4/100,000 in 2010). The main associated diagnoses were diabetes mellitus (20.2%), cardiac disease, including arrhythmias (14%) and cardiomyopathy (dilated 3.8%; peri-, endo-, myocarditis 1.3%), liver cirrhosis (8.6%), HCC (1.6%), and acute liver failure (0.81%). Of note, HCC was associated with cirrhosis in 1188 patients (43% of HCC patients) and male sex (87%). Diagnostic biopsies were performed in 6023 (3.6%) of those patients and liver transplant was performed in 881 (0.5%). In-hospital mortality occurred in 3638 (2.16%) patients. In this large database study, we found a rising trend in hospitalization for hemochromatosis, possibly due to the increased recognition of this entity and billing for the condition. The incidence of cirrhosis in hemochromatosis was found to be similar to other studies (8.6% vs 9%). However, the rate of HCC was lower than previous reports (1.6% vs 2.2%-14.9%), and only 43% of HCC was associated with cirrhosis. This raises important pathophysiologic questions regarding the impact of iron overload in HCC. There has been an increase in the rate of hospitalization for patients with a diagnosis of hemochromatosis. This may be related to an increased recognition of hemochromatosis as the underlying etiology for conditions such as diabetes, cardiomyopathy, cirrhosis, and HCC. Further prospective studies are needed to clarify the burden of liver disease in HH and secondary iron overload.