Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Alcohol-Associated Liver Disease Mortality Rates by Race Before and During the COVID-19 Pandemic in the US.

This cross-sectional study examines the national- and state-level age-adjusted mortality rates for alcohol-associated liver disease in 4 racial groups, with a focus on the American Indian or Alaska Native population.

Actionable Solutions to Achieve Health Equity in Chronic Liver Disease.

There are well-described racial and ethnic disparities in the burden of chronic liver diseases. Hispanic persons are at highest risk for developing nonalcoholic fatty liver disease, the fastest growing cause of liver disease. Hepatitis B disproportionately affects persons of Asian or African descent. The highest rates of hepatitis C occur in American Indian and Alaskan Native populations. In addition to disparities in disease burden, there are also marked racial and ethnic disparities in access to treatments, including liver transplantation. Disparities also exist by gender and geography, especially in alcohol-related liver disease. To achieve health equity, we must address the root causes that drive these inequities. Understanding the role that social determinants of health play in the disparate health outcomes that are currently observed is critically important. We must forge and/or strengthen collaborations between patients, community members, other key stakeholders, health care providers, health care institutions, professional societies, and legislative bodies. Herein, we provide a high-level review of current disparities in chronic liver disease and describe actionable strategies that have potential to bridge gaps, improve quality, and promote equity in liver care.

Equitable Access to Liver Transplant: Bridging the Gaps in the Social Determinants of Health.

The COVID-19 pandemic and social justice movement have highlighted the impact of social determinants of health (SDOH) and structural racism in the United States on both access to care and patient outcomes. With the evaluation for liver transplantation being a highly subjective process, there are multiple ways for SDOH to place vulnerable patients at a disadvantage. This policy corner focuses on three different methods to reverse the deleterious effects of SDOH-identify and reduce implicit bias, expand and optimize telemedicine, and improve community outreach.

Waitlist mortality and transplant free survival in Hispanic patients listed for liver transplant using the UNOS database.

INTRODUCTION AND OBJECTIVES: After the implementation of "Share 35", several concerns arose such as the potential to increase travel distance, costs, and decreased liver availability. These elements could have a negative impact on waitlist outcomes among ethnic minorities. We aimed to determine waitlist survival after the implementation of the Share 35 policy in non-Hispanic white and Hispanic patients. MATERIALS AND METHODS: We identified non-Hispanic whites and Hispanics who were listed for liver transplantation from June 18th, 2013 to June 18, 2018. We excluded pediatric patients, patients with acute hepatic necrosis, re-transplants, multiorgan transplant, living donor, and exception cases. The primary outcome was death or removal from the waitlist due to clinical deterioration. We used competing risk analysis to compare waitlist survival between the two groups. RESULTS: There were 23,340 non-Hispanic whites and 4938 Hispanics listed for transplant. On competing risk analysis, Hispanic patients had a higher risk of being removed from the waitlist for death or clinical deterioration compared to their counterpart (SHR 1.23, 95% CI 1.13-1.34; P < 0.001). CONCLUSION: After the implementation of Share 35, disparities are still present and continue to negatively impact outcomes in minority populations especially Hispanic patients.

Modest alcohol intake not associated with significant hepatic steatosis or more severe liver disease among patients with diabetes mellitus.

BACKGROUND: The effect of modest alcohol intake on prevalence of significant hepatic steatosis and severity of liver disease in patients with type 2 diabetes mellitus (T2DM) is unclear. METHODS: This is a cross-sectional study on T2DM patients. Modest alcohol intake was defined as alcohol intake ≤ 21 units/week in men and ≤ 14 units/week in women. Significant hepatic steatosis was diagnosed on the basis of controlled attenuation parameter > 263 dB/m, while advanced fibrosis was diagnosed on the basis of liver stiffness measurement ≥ 9.6 kPa using M probe or ≥ 9.3 kPa using XL probe. Patients with liver stiffness measurement ≥ 8.0 kPa were offered liver biopsy. RESULTS: Five hundred fifty-seven patients underwent transient elastography, and 71 patients underwent liver biopsy. The prevalence of modest drinking was 16.5%. Modest drinking was equally prevalent among ethnic Indians and Chinese at 22.9% and 23.3%, respectively, but uncommon among ethnic Malays at 1.7%. Modest drinkers were more likely to be male, smoked, and had significantly lower glycated hemoglobin, total cholesterol, low-density lipoprotein cholesterol, alkaline phosphatase, and platelet count. There was no significant difference in the prevalence of significant hepatic steatosis or advanced fibrosis based on transient elastography and steatohepatitis or advanced fibrosis between modest drinkers and nondrinkers. The prevalence of significant hepatic steatosis was higher among ethnic Malays and Indians compared with ethnic Chinese, but the Chinese did not have a lower prevalence of more severe liver disease. CONCLUSION: Modest alcohol intake is not associated with higher prevalence of significant hepatic steatosis or more severe liver disease among patients with T2DM.

Interleukin-6 gene polymorphisms and susceptibility to liver diseases: A meta-analysis.

BACKGROUND: Several studies have explored the associations between interleukin-6 (IL-6) gene polymorphisms and the susceptibility to liver diseases, however, results remain ambiguous. The goal of this study was to conduct a meta-analysis to provide more credible evidence. METHODS: Studies identified in the PubMed, Cochrane Library, and EMBASE databases were used to perform a meta-analysis via the STATA software. Pooled odds ratios (OR) were calculated under fixed- and random-effects models to estimate the potential genetic associations. RESULTS: Twenty-five case-control studies involving 5813 cases and 5298 controls were included in this meta-analysis. Overall, the pooled results suggested that rs1800795 polymorphism was significantly associated with the risk of liver diseases in heterozygote (GC vs CC; OR = 1.57) and dominant (GG+GC vs CC: OR = 1.47) models; rs1800796 polymorphism was significantly associated with the susceptibility to liver diseases in heterozygote (GG vs GC; OR = 0.58) and recessive (GG vs GC+CC: OR = 0.68) models; rs1800797 polymorphism was significantly associated with genetic predisposition to liver diseases in homozygote (GG vs AA: OR = 1.63), heterozygote (GA vs AA; OR = 1.53) and dominant (GG + GA vs AA: OR = 1.61) models. A similar conclusion was found in the HBV, HCV, HCC, NASH and alcoholic liver disease of all ethnic populations for rs1800795; HBV and Asian subgroups for rs1800796; HCV and non-Asian subgroups for rs1800797. However, IL-6 rs2069837 and rs2066992 polymorphisms did not exhibit significant associations with the risk of liver diseases under any genetic models. CONCLUSION: This meta-analysis suggests that patients carrying G (rs1800795), C (rs1800796) or G (rs1800797) allele or genotypes of IL-6 may be more likely to suffer from liver diseases, which was ethnic-dependent.

Gender, Race and Disease Etiology Predict De Novo Malignancy Risk After Liver Transplantation: Insights for Future Individualized Cancer Screening Guidance.

BACKGROUND: Malignancy after liver transplant (LT) is a leading cause of mortality, but data is limited. The aim of this study was to identify patients at higher risk for de novo malignancies after LT in a large multicenter database. METHODS: The Scientific Registry of Transplant Recipients database comprising all 108 412 LT recipients across the United States between 1987 and March 2015 was analyzed with a median follow-up of 6.95 years. Potential risk factors for malignancies after LT were assessed using Cox regression analysis for the outcome of time to first malignancy. RESULTS: Mean age 51.9 ± 10.8 years, 64.6% male, 74.5% white, and 15.8% with previous malignancy. Malignancies during follow-up were 4,483 (41.3%) skin, 1519 (14.0%) hematologic, and 4842 (44.7%) solid organ. The 10-year probability of de novo malignancy was 11.5% (11.3-11.8%). On multivariable analysis, age by decade (hazard ratio [HR], 1.52; P < 0.001), male sex (HR, 1.28; P < 0.001), white race (compared with other races: HR, 1.45-2.04; P < 0.001), multiorgan transplant (HR, 1.35; P < 0.001), previous malignancy (HR, 1.34; P < 0.001), and alcoholic liver disease, autoimmune, nonalcoholic steatohepatitis (HR, 1.35; P < 0.001), and primary sclerosing cholangitis pre-LT (compared with hepatitis C virus, P < 0.001) were associated with higher risk of post-LT malignancy, but type of immunosuppression was not (P = NS). CONCLUSIONS: This large data set demonstrates the effects of ethnicity/race and etiologies of liver disease, particularly nonalcoholic steatohepatitis as additional risk factors for cancer after LT. Patients with these high-risk characteristics should be more regularly and diligently screened.

Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2018.

BACKGROUND & AIMS: Estimates of disease burden can inform national health priorities for research, clinical care, and policy. We aimed to estimate health care use and spending among gastrointestinal (GI) (including luminal, liver, and pancreatic) diseases in the United States. METHODS: We estimated health care use and spending based on the most currently available administrative claims from commercial and Medicare Supplemental plans, data from the GI Quality Improvement Consortium Registry, and national databases. RESULTS: In 2015, annual health care expenditures for gastrointestinal diseases totaled $135.9 billion. Hepatitis ($23.3 billion), esophageal disorders ($18.1 billion), biliary tract disease ($10.3 billion), abdominal pain ($10.2 billion), and inflammatory bowel disease ($7.2 billion) were the most expensive. Yearly, there were more than 54.4 million ambulatory visits with a primary diagnosis for a GI disease, 3.0 million hospital admissions, and 540,500 all-cause 30-day readmissions. There were 266,600 new cases of GI cancers diagnosed and 144,300 cancer deaths. Each year, there were 97,700 deaths from non-malignant GI diseases. An estimated 11.0 million colonoscopies, 6.1 million upper endoscopies, 313,000 flexible sigmoidoscopies, 178,400 upper endoscopic ultrasound examinations, and 169,500 endoscopic retrograde cholangiopancreatography procedures were performed annually. Among average-risk persons aged 50-75 years who underwent colonoscopy, 34.6% had 1 or more adenomatous polyps, 4.7% had 1 or more advanced adenomatous polyps, and 5.7% had 1 or more serrated polyps removed. CONCLUSIONS: GI diseases contribute substantially to health care use in the United States. Total expenditures for GI diseases are $135.9 billion annually-greater than for other common diseases. Expenditures are likely to continue increasing.

Risk factors for liver disease among adults of Mexican descent in the United States and Mexico.

AIM: To compare the prevalence of chronic liver disease (CLD) risk factors in a representative sample of Mexican-Americans born in the United States (US) or Mexico, to a sample of adults in Mexico. METHODS: Data for Mexican-Americans in the US were obtained from the 1999-2014 National Health and Nutrition Examination Survey (NHANES), which includes persons of Mexican origin living in the US (n = 4274). The NHANES sample was restricted to Mexican-American participants who were 20 years and older, born in the US or Mexico, not pregnant or breastfeeding, and with medical insurance. The data in Mexico were obtained from the 2004-2013 Health Worker Cohort Study in Cuernavaca, Mexico (n = 9485). The following known risk factors for liver disease/cancer were evaluated: elevated aminotransferase levels (elevated alanine aminotransferase was defined as > 40 IU/L for males and females; elevated aspartate aminotransferase was defined as > 40 IU/L for males and females), infection with hepatitis B or hepatitis C, metabolic syndrome, high total cholesterol, diabetes, obesity, abdominal obesity, and heavy alcohol use. The main independent variables for this study classified individuals by country of residence (i.e., Mexico vs the US) and place of birth (i.e., US-born vs Mexico-born). Regression analyses were used to investigate CLD risk factors. RESULTS: After adjusting for socio-demographic characteristics, Mexican-American males were more likely to be obese, diabetic, heavy/binge drinkers or have abdominal obesity than males in Mexico. The adjusted multivariate results for females also indicate that Mexican-American females were significantly more likely to be obese, diabetic, be heavy/binge drinkers or have abdominal obesity than Mexican females. The prevalence ratios and prevalence differences mirror the multivariate analysis findings for the aforementioned risk factors, showing a greater risk among US-born as compared to Mexico-born Mexican-Americans. CONCLUSION: In this study, Mexican-Americans in the US had more risk factors for CLD than their counterparts in Mexico. These findings can be used to design and implement more effective health promotion policies and programs to address the specific factors that put Mexicans at higher risk of developing CLD in both countries.

Alcohol Consumption and Chronic Liver Disease Mortality in New Mexico and the United States, 1999-2013.

OBJECTIVE: Current chronic liver disease (CLD) mortality surveillance methods may not adequately capture data on all causes of CLD mortality. The objective of this study was to calculate and compare CLD death rates in New Mexico and the United States by using both an expanded definition of CLD and estimates of the fractional impact of alcohol on CLD deaths. METHODS: We defined CLD mortality as deaths due to alcoholic liver disease, cirrhosis, viral hepatitis, and other liver conditions. We estimated alcohol-attributable CLD deaths by using national and state alcohol-attributable fractions from the Centers for Disease Control and Prevention's Alcohol-Related Disease Impact application. We classified causes of CLD death as being alcohol-attributable, non-alcohol-attributable, or hepatitis C. We calculated average annual age-adjusted CLD death rates during five 3-year periods from 1999 through 2013, and we stratified those rates by sex, age, and race/ethnicity. RESULTS: By cause of death, CLD death rates were highest for alcohol-attributable CLD. By sex and race/ethnicity, CLD death rates per 100 000 population increased from 1999-2001 to 2011-2013 among American Indian men in New Mexico (67.4-90.6) and the United States (38.9-49.4), American Indian women in New Mexico (48.4-63.0) and the United States (27.5-39.5), Hispanic men in New Mexico (48.6-52.0), Hispanic women in New Mexico (16.9-24.0) and the United States (12.8-13.1), non-Hispanic white men in New Mexico (17.4-21.3) and the United States (15.9-18.4), and non-Hispanic white women in New Mexico (9.7-11.6) and the United States (7.6-9.7). CLD death rates decreased among Hispanic men in the United States (30.5-27.4). CONCLUSIONS: An expanded CLD definition and alcohol-attributable fractions can be used to create comprehensive data on CLD mortality. When stratified by CLD cause and demographic characteristics, these data may help states and jurisdictions improve CLD prevention programs.

Assessment of serum bile acid profiles as biomarkers of liver injury and liver disease in humans.

To assess the potential of individual bile acids (IBA) and their profiles as mechanistic biomarkers of liver injury for humans in real world situations, we interrogated samples collected under minimum controlled conditions (ie subjects were not fasted). Total bile acids (TBA) have been considered to be biomarkers of liver injury for decades, and more recently, monitoring of IBA has been proposed for differentiation of variety of etiologies of liver injury. We established a LC-MS/MS methodology to analyze nine IBA, generated reference ranges, and examined effects of age, gender, and ethnicity for each IBA. Furthermore, we evaluated the ability of IBA and their profiles to detect hepatic injury in subjects with a broad range of liver impairments. To date, our study utilized the largest total cohort of samples (N = 645) that were divided into 2 groups, healthy or liver impaired, to evaluate IBA as biomarkers. The TBA serum levels in the Asian ethnic group trended higher when compared to other ethnic groups, and the serum concentrations of IBA, such as glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), chenodeoxycholic acid (CDCA), and taurochenoxycholic acid (TCDCA) were significantly increased. To our knowledge, this report is the first to describe ethnic differences in serum concentrations of IBAs. In patients with hepatic impairments, with the exception of deoxycholic acid (DCA), the concentrations of IBAs were significantly elevated when compared with healthy subjects. The conjugated bile acids displayed greater differences between healthy subjects and subjects with hepatic impairments than non-conjugated bile acids. Furthermore, the subjects with hepatic impairments exhibited distinct profiles (signatures) of IBAs that clustered subjects according the nature of their liver impairments. Although additional studies are needed, our data suggested that the analysis of IBA has the potential to become useful for differentiation of various forms of liver injury.

Influence of birth origin and risk factor profile on hepatitis B mortality: Philadelphia, PA 2003-2013.

PURPOSE: Chronic hepatitis B virus (HBV) affects specific subpopulations in the United States, including individuals born in HBV-endemic countries and persons engaging in high-risk behaviors. METHODS: The 2003-2013 HBV registry data and surveillance investigations for Philadelphia, PA were matched to death certificate data to examine demographic, risk factor, and cause of death characteristics among HBV-infected populations. Bivariate analysis compared investigated foreign-born (FB) and US-born chronic HBV individuals. Multivariable logistic regression assessed associations between HBV-status, birth origin, demographic information, and liver-related death. RESULTS: Of 773 investigated HBV-infected individuals, 159 were US-born and 614 were FB and of primarily non-Hispanic Asian descent. Behavioral risk factors were more often reported by US-born individuals. HBV-infected FB decedents were twice as likely as US-born decedents to have a liver-related cause of death, whereas HIV/AIDS and drug overdose were more likely causes of death among those born in the United States. CONCLUSIONS: There are two HBV-infected populations in Philadelphia: 1) FB individuals most likely infected at birth or during early childhood and 2) US-born individuals with behaviors suggestive of risk-related HBV acquisition. These findings illustrate the need for both FB and US-born individuals with ongoing risk behaviors to receive routine HBV screening, vaccination if indicated, and medical care for outcomes of chronic HBV infection.

The Epidemic of Despair Among White Americans: Trends in the Leading Causes of Premature Death, 1999-2015.

OBJECTIVES: To evaluate trends in premature death rates by cause of death, age, race, and urbanization level in the United States. METHODS: We calculated cause-specific death rates using the Compressed Mortality File, National Center for Health Statistics data for adults aged 25 to 64 years in 2 time periods: 1999 to 2001 and 2013 to 2015. We defined 48 subpopulations by 10-year age groups, race/ethnicity, and county urbanization level (large urban, suburban, small or medium metropolitan, and rural). RESULTS: The age-adjusted premature death rates for all adults declined by 8% between 1999 to 2001 and 2013 to 2015, with decreases in 39 of the 48 subpopulations. Most decreases in death rates were attributable to HIV, cardiovascular disease, and cancer. All 9 subpopulations with increased death rates were non-Hispanic Whites, largely outside large urban areas. Most increases in death rates were attributable to suicide, poisoning, and liver disease. CONCLUSIONS: The unfavorable recent trends in premature death rate among non-Hispanic Whites outside large urban areas were primarily caused by self-destructive health behaviors likely related to underlying social and economic factors in these communities.

Epidemiology and outcomes of hypoglycemia in patients with advanced diabetic kidney disease on dialysis: A national cohort study.

BACKGROUND: Patients with advanced diabetic kidney disease (DKD) behave differently to diabetic patients without kidney disease. We aimed to investigate the associations of hypoglycemia and outcomes after initiation of dialysis in patients with advanced DKD on dialysis. METHODS: Using National Health Insurance Research Database, 20,845 advanced DKD patients beginning long-term dialysis between 2002 and 2006 were enrolled. We investigated the incidence of severe hypoglycemia episodes before initiation of dialysis. Patients were followed from date of first dialysis to death, end of dialysis, or 2008. Main outcomes measured were all-cause mortality, myocardial infarction (MI), and subsequent severe hypoglycemic episodes after dialysis. RESULTS: 19.18% patients had at least one hypoglycemia episode during 1-year period before initiation of dialysis. Advanced DKD patients with higher adapted Diabetes Complications Severity Index (aDCSI) scores were associated with more frequent hypoglycemia (P for trend < 0.001). Mortality and subsequent severe hypoglycemia after dialysis both increased with number of hypoglycemic episodes. Compared to those who had no hypoglycemic episodes, those who had one had a 15% higher risk of death and a 2.3-fold higher risk of subsequent severe hypoglycemia. Those with two or more episodes had a 19% higher risk of death and a 3.9-fold higher risk of subsequent severe hypoglycemia. However, previous severe hypoglycemia was not correlated with risk of MI after dialysis. CONCLUSIONS: The rate of severe hypoglycemia was high in advanced DKD patients. Patients with higher aDCSI scores tended to have more hypoglycemic episodes. Hypoglycemic episodes were associated with subsequent hypoglycemia and mortality after initiation of dialysis. We studied the associations and further study is needed to establish cause. In addition, more attention is needed for hypoglycemia prevention in advanced DKD patients, especially for those at risk patients.

Physician-Patient Communication is Associated With Hepatocellular Carcinoma Screening in Chronic Liver Disease Patients.

BACKGROUND: Patients with chronic liver disease are at high risk for developing liver cancer. Factors associated with screening awareness and doctor-patient communication regarding liver cancer were examined. STUDY: Four hundred sixty-seven patients with chronic liver disease at a tertiary-care clinic participated in a phone survey regarding awareness of cancer screening, doctor-patient communication, and health behaviors. Medical records were retrospectively reviewed for data on liver disease etiology and dates of liver imaging tests. RESULTS: Seventy-nine percent of patients reported awareness of liver cancer screening, and 50% reported talking to their doctor about liver cancer. Patients with higher education, abstinence from alcohol, and liver cirrhosis were more likely to be aware of liver cancer screening (P=0.06, 0.005, <0.0001). Whites, patients with higher education, and those with cirrhosis were more likely to talk to their doctor about liver cancer (P=0.006; P=0.09, <0.0001). Awareness of liver cancer screening (79%) was similar to that of colorectal cancer screening (85%), lower than breast cancer screening (91%), and higher than prostate cancer screening (66%). Patients who were aware of liver cancer screening and reported talking to their doctor about liver cancer were significantly more likely to receive consistent liver surveillance (odds ratio, 4.81; 95% confidence interval, 2.62-8.84 and odds ratio, 1.97; 95% confidence interval, 1.19-3.28, respectively). CONCLUSIONS: Our study demonstrates the importance of effective physician communication with chronic liver disease patients on the risks of developing liver cancer and the importance of regular screening, especially among nonwhites and patients with lower education.

Ectopic Fat Depots and Coronary Artery Calcium in South Asians Compared With Other Racial/Ethnic Groups.

BACKGROUND: South Asians have a low body mass index and high prevalence of cardiovascular disease (CVD) relative to other racial/ethnic groups. Radiographically detected ectopic fat distribution is better associated with CVD than body mass index. We assessed whether differences in ectopic fat depots explained differences in the prevalence/severity of coronary artery calcium (CAC), a predictor of incident CVD events, among South Asians compared with other racial/ethnic groups. METHODS AND RESULTS: We examined the associations of radiographically detected visceral, intermuscular, intrahepatic, and pericardial fat with CAC among adults without baseline CVD. We compared 803 South Asians in the Mediators of Atherosclerosis in South Asians Living in America to 4 racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis: 2622 whites, 1893 blacks, 1496 Latinos, and 803 Chinese Americans. We adjusted for body mass index and known CVD risk factors. South Asians had the highest intrahepatic fat and lowest pericardial fat volume (PFV). There was a positive graded association between ectopic fat and higher CAC scores in all the groups with the strongest associations observed with PFV. PFV was independently associated with CAC severity in South Asians (P=0.01) and blacks (P=0.05) and borderline in whites (P=0.06). PFV partially explained the higher CAC burden in South Asians compared with blacks, but not the other racial/ethnic groups. CONCLUSIONS: Differences in PFV explain a small fraction of the higher CAC burden in South Asians. Our findings suggest that ectopic fat depots may not explain the elevated CAC risk in South Asians.