McClain, Craig J.

INTRODUCTION: Alcohol-associated hepatitis (AH) is a severe condition with high short-term mortality. Identifying key predictors of poor outcomes is critical for guiding therapeutic strategies. Mean arterial pressure (MAP), a key determinant of tissue perfusion and systemic hemodynamics, may play a pivotal role in prognosis. METHODS: We analyzed a multicenter, prospective cohort of 323 patients hospitalized with AH, with validation in an independent cohort of 290 patients. Survival was evaluated using Kaplan-Meier curves and compared with the log-rank (Mantel-Cox) test. Cox proportional hazards models were used to estimate hazard ratios for mortality, adjusted for Model for end stage liver disease score. Mechanistic insights were explored through assessment of cardiovascular biomarkers. RESULTS: A baseline MAP <80 mm Hg was associated with significantly higher mortality at both 28 days (27.3% vs 8.0%) and 90 days (40.3% vs 15.6%; P < 0.001 for both). This association persisted after adjusting for Model for end stage liver disease score, age, and baseline hepatic encephalopathy. The incidence of infections during follow-up was similar across MAP groups (27.6% vs 22.8%), but acute kidney injury occurred more frequently in the MAP <80 mm Hg group (62% vs 38%, P < 0.001). In the validation cohort, patients with MAP <80 mm Hg also demonstrated significantly lower 28-day transplant-free survival. Although B-type natriuretic peptide and plasma renin levels were altered in patients with AH, they did not correlate with MAP values. DISCUSSION: A baseline MAP <80 mm Hg is an independent predictor of short-term and mid-term mortality in patients with AH. Strategies aimed at restoring hemodynamic stability may improve outcomes in this high-risk population.

Abstract Background Recurrent alcohol use is a major determinant of liver‐related outcomes in patients recovering from alcohol‐associated hepatitis (AH). However, the timing and predictors of return to drinking (RTD) are not well‐studied. Methods We analyzed alcohol use among patients with AH enrolled in two AlcHepNet multicenter studies: a Phase 2b randomized controlled trial and a prospective observational study. TimeLine FollowBack (TLFB) assessed drinking at each visit. RTD was defined as any alcohol use since the previous visit. The cumulative incidence of RTD was evaluated using the Fine–Gray method, with death as a competing risk. Factors associated with RTD were evaluated using univariate and multivariate Cox regression. Results Among 518 patients alive at Day 28, RTD occurred in 7.7%, 21.7%, and 30.8% at 30, 90, and 180 days, respectively. Patients with moderate AH (mAH, MELD 11–19, n = 103) had a higher RTD incidence at 180 days than those with severe AH (sAH, MELD ≥20, n = 415) (44.3% vs. 27.5%; p = 0.01). RTD was associated with higher AUDIT scores, family history of alcohol use disorder (AUD), lower education, greater alcohol use at baseline, lower MELD scores, and less ascites (all p ≤ 0.01). In multivariable analysis, >20 drinking days in the prior month was associated with increased risk of RTD (HR: 3.46, 95% CI: 2.21–5.39), whereas college education or higher was protective (HR: 0.53, 95% CI: 0.32–0.88). Conclusion RTD occurred in 22% of AH patients within 90 days postrecovery, highlighting the need for early AUD interventions. Frequent drinking days at baseline and lower education were strongly linked to early RTD.

Background & Aims: The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes do not capture the added risk of return to drinking. We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH. Approach & Results: A cohort of 1127 participants: 712 AH patients, 256 heavy drinking controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6 months at 8 United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, HE, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking. Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p <0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p <0.05). College education and higher ALP were associated with lower mortality. Heavy drinking controls had low mortality (n=3; 1.2%). Conclusions: This large observational study showed a high incidence of composite liver and alcohol-use events within 6 months, reiterating the need for early interventions.

Background: How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown. Methods: We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome. Results: Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]). Conclusions: The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.

Malnutrition, defined as deficiency, excess, or imbalance of nutrients, is a common complication in patients with liver disease, especially those with cirrhosis. Malnutrition may present as an isolated micronutrient deficiency, such as zinc deficiency, and it commonly presents as frailty and/or sarcopenia in patients with advanced liver disease. Patients with cirrhosis and/or alcohol-associated hepatitis should be assessed for malnutrition because it adversely affects patient outcomes including mortality, as well as waitlist and posttransplant outcomes among liver transplant candidates. The prevalence of malnutrition varies based on the method of assessment and disease severity, being higher in those with advanced liver disease. Among stable outpatients with cirrhosis, counseling should be done to eat small frequent meals, a night-time snack between 7 PM and 10 PM, and 2 or more cups of coffee daily. In selected patients with metabolic dysfunction-associated steatohepatitis, vitamin E 800 IU/d should be provided. Among hospitalized patients with cirrhosis, nutritional supplementation preferably by enteral route should be implemented in those with poor oral intake of daily requirements of proteins and/or calories. Protein intake should not be restricted including patients with decompensated cirrhosis and hepatic encephalopathy. A vegetable source of protein seems to be better tolerated than an animal source of protein in patients with hepatic encephalopathy. Branched chain amino acids augment the efficacy of lactulose and rifaximin in the treatment of hepatic encephalopathy. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the auspices of the American College of Gastroenterology Practice Parameters Committee.

Background and Aims: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. Approach and Results: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p=0.001). AKI phenotypes were similar between the 2 treatment arms (p=0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p=0.035). At baseline, urine-neutrophil-gelatinase–associated lipocalin levels were similar between participants who developed AKI in both treatment arms (p=0.319). However, day 7 and 14 urine-neutrophil-gelatinase–associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI (p=0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p=0.005). Conclusions: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z–treated participants with AKI had higher urine-neutrophil-gelatinase–associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

Abstract Alcohol‐associated liver disease (ALD) is emerging worldwide as the leading cause of liver‐related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol‐associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient‐selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long‐term outcomes in patients with ALD.

Conventional resuscitation (CR) from hemorrhagic shock (HS) results in gut and liver hypoperfusion, organ and cellular edema, and vital organ injury. Adjunct direct peritoneal resuscitation (DPR) with dialysate prevents gut vasoconstriction, hypoperfusion, and injury. We hypothesized that DPR might also improve hepatocellular edema, inflammation, and injury. Anesthetized male SD rats were assigned to groups ( n = 8/group): 1) sham (no HS); 2) HS (40% MAP/60 min) + intravenous fluid conventional resuscitation [CR; shed blood + 2 vol saline (SAL)/30 min]; 3) HS+CR+DPR (30 ml ip 2.5% glucose dialysate); or 4) HS+CR+SAL (30 ml ip saline). Histopathology showed lung and liver injury in HS+CR and HS+CR+SAL up to 24-h postresuscitation (post-RES) that was not in shams and which was prevented by adjunct DPR. Wet-to-dry weight ratios in HS+CR revealed organ edema formation that was prevented by adjunct DPR. HS+CR and HS+CR+SAL had 34% mortality by 24-h post-RES, which was absent with DPR (0%). Liver IFN-γ and IL-6 levels were elevated in CR compared with DPR or shams. TNF-α mRNA was upregulated in CR/sham and DPR/sham. IL-17 was downregulated in DPR/sham. CXCL10 mRNA was upregulated in CR/sham but downregulated in DPR/sham. Despite restored central hemodynamic performance after CR of HS, liver blood flow was compromised up to 24 h post-RES, and the addition of DPR restores and maintains liver perfusion at 24-h post-RES. DPR prevented liver injury, histological damage, and edema formation compared with CR alone. DPR provided a mitigating anti-inflammatory dampening of the systemic inflammatory response. In all, these effects likely account for improved survivorship in the DPR-treated group.