INCIDENCE, CLINICAL CHARACTERISTICS AND OUTCOMES ASSOCIATED WITH RECURRENT ALCOHOL ASSOCIATED HEPATITIS: A MULTICENTER STUDY

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.