RACIAL AND ETHNIC DISPARITIES IN LIVER TRANSPLANTATION FOR ALCOHOL-ASSOCIATED LIVER DISEASES IN THE UNITED STATES

Background and Aims: Mitochondrial damage-associated molecular patterns(DAMPs) share structural similarity with bacteria and may trigger potent immune response. We have recently demonstrated that mitochondrial DNA is a major component of mitochondrial DAMPs which directly drives liver disease progression. Here, we aimed to investigate circulating mtDNAs and its potential significance as a disease biomarker in patients with alcoholic liver disease (ALD).
Methods: We retrospectively analyzed serum and plasma samples from 43 patients admitted with ALD to Beth Israel Deaconess Medical Centre. Absolute copy number of cell-free mitochondrial DNA was measured using novel inhouse high sensitivity digital droplet polymerase chain reaction assay via amplification of two different mtDNA regions (DL, hND1). The relationship between multiple clinically relevant serum markers and serum and plasma DL and hND1 (as well as their averages) was assessed using linear regression analysis.
Results: The P-values and the correlation coefficients revealed that ALT, ALP, Triglycerides, lipoprotein-Z, lipoprotein-X, and apolipoprotein b were significantly associated with average plasma and serum DL and hND1. Average plasma DL and hND1 correlates better with ALT (r² =0.31, P < 0.001) and ALP (r²=0.29, P < 0.001), while average serum DL and hND1 correlates better with Triglycerides (r² =0.38, P = 0.001), lipoprotein-Z (r² =0.17, P = 0.005), and apolipoprotein b (r² =0.13, P = 0.01) . There was no significant correlation between AST, Z-index and average plasma and serum DL and hND1.
Conclusion: We developed novel ddPCR assay for circulating mtDNA and showed that elevated plasma and serum mtDNA levels correlate with parameters of alcohol-related liver injury and lipid metabolism in patients with AH. mtDNA may be a promising new disease biomarker in patients with alcoholic liver disease, supporting larger, prospective validation studies.

Background:
Alcohol recidivism occurs frequently in survivors with alcohol associated hepatitis (AAH) but recurrent AAH has not been described. We aimed to describe the incidence, clinical characteristics and outcomes associated with recurrent AAH.

Methods:
Patients hospitalized with AAH from 2010-2020 at a tertiary referral healthcare system in the US [11 hospitals, 1 liver transplant (LT) center] were followed until death, transplant, date of last follow up, or end of study (12/31/2021). AAH was defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcoholic Hepatitis Consortium [heavy alcohol use >6 months, with <60 days of abstinence before onset of jaundice (>3 mg/dL); AST/ALT ratio >1.5 with AST >50 IU/mL] and severe AAH was defined according to Model for End-stage Liver Disease Score (MELD) >20. Recurrent AAH was defined by meeting NIAAA criteria for AAH >6 months from index AAH plus interim normalization of total bilirubin or >50% improvement in nadir total bilirubin after index and before recurrent AAH hospitalization. Cox-regression analysis was performed to identify risk factors associated with recurrent AAH.

Results:
1,602 patients with AAH were hospitalized during the study period [89% white, 61% male, 59% severe AH, median MELD score 22 (interquartile range (IQR) 18, 28)]. 90-day mortality was 24% (n=390). At 6 months, 58% (n=925) were alive without a transplant and were examined for recurrent AAH. Incident recurrent AAH was 13% (n=123) and the nadir median (IQR) total bilirubin between index and recurrent AAH was 1.2 (1.2, 1.9) mg/dL. Comparisons of patient characteristics at the time of index AAH hospitalization between patients with recurrent AAH and non-recurrent AAH can be found in the Table. Patients with recurrent AAH were significantly younger (p=0.012), but there were no significant differences between the two groups for sex, insurance type, psychiatric co-morbidities, severity of AAH, corticosteroid use, and severity of hospitalization course. Accordingly, only age was associated with recurrent AAH [hazards ratio 0.98 (95%CI 0.96-0.99)].

At the time of recurrent AAH hospitalization, mean MELD score was 23 + 7, 54% (n=66) had severe AAH, of which 33% (n=22) were treated with corticosteroids. The proportion of patients with a day-4 Lille score <0.45 was lower at 50% compared to index AAH at 72% despite comparable median (IQR) MELD scores at time of corticosteroid initiation [index 26 (24, 33) vs. recurrent 26 (23, 31)]. 90-day mortality was 23% (n=28).

Conclusions:
Recurrent AAH occurs in 1 of 10 survivors of AAH and has similar 90-day mortality rates to index AAH. Younger age and not the severity of index AAH or hospitalization course is associated with recurrent AAH. Prospective studies investigating liver- and non-liver-related risk factors are needed to design effective interventions to prevent recurrence.

Introduction: Females develop alcohol-associated liver disease with less exposure to alcohol than males. However, whether there are gender differences in the clinical course and severity of alcohol-associated liver disease is less clear. Recent studies show an alarming increase in the incidence of alcohol use and alcohol-associated liver disease in females. This study aimed to assess if there are gender differences in severity, outcomes, and healthcare utilization for patients hospitalized for alcohol-associated hepatitis (AH).
Methods: This retrospective cohort study included encounters with specific ICD codes for alcohol-related hepatitis hospitalized at our institution between 1/1/2012 and 4/1/2021. We obtained demographic and clinical data, including liver decompensation, mortality, length of stay (LOS), steroid and N-acetylcysteine (NAC) treatment, pressor use and mechanical ventilation. We compared data between males and females using t-test for continuous variables and chi-square analysis for categorical variables.
Results: Of 1386 subjects, 511 were female and 875 were male. Both genders had similar baseline characteristics with an average age of 45 and 47 for females and males, respectively, an average body mass index of 29, and predominantly Caucasian, Non-Hispanic ethnicity. Mortality was higher for females (9.4%) than for males (8.5%) (p<0.001). The average LOS was the same for both genders at 8.4 days. Females had a higher incidence of norepinephrine administration than males (p<0.045). There were no gender differences for mechanical ventilation, discriminant function (mean 48.9 in females versus 47.4 in males), bacteremia, hepatorenal syndrome, spontaneous bacterial peritonitis, pneumonia, or administration of steroids or NAC. Males had increased incidence of esophageal variceal bleed (11 vs. 9%, p<0.001). A higher percentage of females developed sepsis (p<0.022) and urinary tract infection (UTI) (p<0.001).
Discussion: Our study shows that females admitted for alcohol-related hepatitis at our institution have a higher incidence of sepsis, UTI, norepinephrine administration, and mortality. Although the mortality difference is modest, it appears that males and females may experience different complications from AH, with females having a higher incidence of complications from infections, notably sepsis and UTI. Rodent studies have shown higher levels of endotoxin, increased gut permeability to endotoxin in females and demonstrated that estrogen sensitizes Kupffer cells to endotoxin-mediated liver injury. Whether this translates to a higher pro-inflammatory milieu and infection risk in women with AH needs further exploration. Future studies are warranted to assess the clinical significance of gender differences in alcohol-associated hepatitis to further improve care for this worsening healthcare problem.

INTRODUCTION: While liver transplantation (LT) has been increasing for alcohol-associated liver diseases (ALD) in recent years, there has been growing concerns of racial/ethnic disparities in ALD LT practices across the entire care continuum. Studies have shown ethnic minorities have a lower probability of undergoing LT, and Black patients have a significantly higher risk of post-LT graft failure and death. Previous studies have primarily focused on Black-White disparities. Along with this, due to the changes in LT practice in the direct-acting antiviral era, the older literature may not apply to the emerging ALD LT landscape. Assessment of ALD LT outcomes is needed to understand the current extent of racial/ethnic disparities and assess for opportunities to narrow the disparity gap. The objectives of our study were to: 1) characterize latest practices and outcomes in LT for AH and AAC and 2) describe the extent of racial and ethnic disparities in LT waitlist and post-LT outcomes.

METHODS: Using UNOS data (2015 through 2021), we evaluated LT frequency, waitlist mortality, and graft survival among US adults with ALD (alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AAC)) stratified by race and ethnicity. We used adjusted competing-risk regression analysis to evaluate waitlist outcomes, Kaplan-Meier analysis to illustrate graft survival, and Cox proportional hazards modeling to identify factors associated with graft survival.

RESULTS: We found significant racial/ethnic disparities exist for ALD LT outcomes in the U.S. There were 1,211 AH and 26,526 AAC new LT waitlist additions, with 970 AH and 15,522 AAC LTs performed. Compared with non-Hispanic whites (NHWs) with AAC, higher hazards of waitlist death were observed for Hispanic (SHR=1.23, 95%CI:1.16-1.32), non-Hispanic Black (NHB) (subdistribution hazard ratio (SHR)=1.14, 95%CI:1.01-1.29), Asian (SHR=1.22, 95%CI:1.01-1.47), and American Indian/Alaskan Native (AIAN) (SHR=1.42, 95%CI:1.15-1.76) candidates. Similarly, significantly higher graft failures were observed in NHB (HR=1.32, 95%CI:1.09-1.61) and AIAN (HR=1.65, 95%CI:1.15-2.38) patients with AAC than NHWs. We did not observe differences in waitlist or post-LT outcomes by race or ethnicity in AH, although analyses were limited by small subgroups.

CONCLUSION: Further exploration of prevailing hypotheses, such as pharmacokinetic nuances in immunosuppression among racial/ethnic groups, psychosocial challenges, and barriers to care, for these disparities is still required. Future studies are needed to help identify determinants for LT disparities in ALD that can inform intervention strategies.