Steroid responsiveness in alcohol-associated hepatitis is linked to glucocorticoid metabolism, mitochondrial repair, and heat shock proteins.

BACKGROUND: Alcohol-associated hepatitis (AH) is one of the clinical presentations of alcohol-associated liver disease. AH has poor prognosis, and corticosteroids remain the mainstay of drug therapy. However, ~40% of patients do not respond to this treatment, and the mechanisms underlying the altered response to corticosteroids are not understood. The current study aimed to identify changes in hepatic protein expression associated with responsiveness to corticosteroids and prognosis in patients with AH. METHODS: Patients with AH were enrolled based on the National Institute on Alcohol Abuse and Alcoholism inclusion criteria for acute AH and further confirmed by a diagnostic liver biopsy. Proteomic analysis was conducted on liver samples acquired from patients with AH grouped as nonresponders (AH-NR, n = 7) and responders (AH-R, n = 14) to corticosteroids, and nonalcohol-associated liver disease controls (n = 10). The definition of responders was based on the clinical prognostic model, the Lille Score, where a score < 0.45 classified patients as AH-R and a score > 0.45 as AH-NR. Primary outcomes used to assess steroid response were Lille Score (eg, improved liver function) and survival at 24 weeks. RESULTS: Reduced levels of the glucocorticoid receptor and its transcriptional co-activator, glucocorticoid modulatory element-binding protein 2, were observed in the hepatic proteome of AH-NR versus AH-R. The corticosteroid metabolizing enzyme, 11-beta-hydroxysteroid dehydrogenase 1, was increased in AH-NR versus AH-R along with elevated mitochondrial DNA repair enzymes, while several proteins of the heat shock pathway were reduced. Analysis of differentially expressed proteins in AH-NR who survived 24 weeks relative to AH-NR nonsurvivors revealed several protein expression changes, including increased levels of acute phase proteins, elevated coagulation factors, and reduced mast cell markers. CONCLUSIONS: This study identified hepatic proteomic changes that may predict responsiveness to corticosteroids and mortality in patients with AH.

Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis.

BACKGROUND & AIMS: Severe alcohol-associated hepatitis (SAH) is associated with high 90-day mortality. Glucocorticoid therapy for 28 days improves 30- but not 90-day survival. We assessed the efficacy and safety of a combination of anakinra, an IL-1 antagonist, plus zinc (A+Z) compared to prednisone using the Day-7 Lille score as a stopping rule in patients with SAH. METHODS: In this phase IIb double-blind randomized trial in adults with SAH and MELD scores of 20-35, participants were randomized to receive either daily anakinra 100 mg subcutaneously for 14 days plus daily zinc sulfate 220 mg orally for 90 days, or daily prednisone 40 mg orally for 30 days. Prednisone or prednisone placebo was stopped if Day-7 Lille score was >0.45. All study drugs were stopped for uncontrolled infection or ≥5 point increase in MELD score. The primary endpoint was overall survival at 90 days. RESULTS: Seventy-three participants were randomized to prednisone and 74 to A+Z. The trial was stopped early after a prespecified interim analysis showed prednisone was associated with higher 90-day overall survival (90% vs. 70%; hazard ratio for death = 0.34, 95% CI 0.14-0.83, p = 0.018) and transplant-free survival (88% vs. 64%; hazard ratio for transplant or death = 0.30, 95% CI 0.13-0.69, p = 0.004) than A+Z. Acute kidney injury was more frequent with A+Z (45%) than prednisone (22%) (p = 0.001), but rates of infection were similar (31% in A+Z vs. 27% in prednisone, p = 0.389). CONCLUSIONS: Participants with SAH treated with prednisone using the Day-7 Lille score as a stopping rule had significantly higher overall and transplant-free 90-day survival and lower incidence of acute kidney injury than those treated with A+Z. IMPACT AND IMPLICATIONS: There is no approved treatment for severe alcohol-associated hepatitis (SAH). In this double-blind randomized trial, patients with SAH treated with prednisone using the Lille stopping rule on Day 7 had higher 90-day overall and transplant-free survival and lower rates of acute kidney injury compared to patients treated with a combination of anakinra and zinc. The data support continued use of glucocorticoids for patients with SAH, with treatment discontinuation for those with a Lille score >0.45 on Day 7. TRIAL REGISTRATION: NCT04072822.

Real-World Utilization of Corticosteroids in Severe Alcoholic Hepatitis: Eligibility, Response, and Outcomes.

Background and Objectives: Alcoholic hepatitis (AH) poses a medical challenge, causing moderately severe to life-threatening episodes with high short- and long-term mortality. This study aimed to explore real-world corticosteroid utilization in severe AH, response predictors, and patient outcomes. Materials and Methods: We conducted a retrospective study on patients admitted for severe AH, defined as a Maddrey Discriminant Function score equal to or above 32, at a tertiary care center. We reviewed patients' medical observation charts to identify corticosteroid prescriptions, reasons for ineligibility, and response rates. Responders were defined based on the Lille score, and predictors of non-response were identified. Short-term (one-month) and long-term (one-year) mortality rates were calculated according to treatment and response. Results: Out of 310 patients enrolled with severe AH, 59% received corticosteroids, achieving a response rate of 75.4%. The reasons for not administering corticosteroids were as follows: uncontrolled infections (27.6%), renal dysfunction (20.4%), gastrointestinal bleeding (18.9%), acute pancreatitis (7.1%), uncontrolled diabetes (3.1%), and other or unknown causes (22.8%). The overall 1-month mortality rate was 12.2%, higher in non-responders (35.3%) and patients who did not receive corticosteroids (13.4%) compared to responders (3.6%). The overall 1-year mortality rate was 62.5%, similar between patients who did not receive corticosteroids (78.7%) and non-responders (77.7%) and higher compared to responders (42.8%). Predictive factors for non-response included older age (OR = 1.05, 95%CI: 1.01-1.08), concomitant cirrhosis (OR= 2.11, 95% CI: 1.064-4.20), MELD scores exceeding 30 (OR = 2.42, 95% CI: 1.21-4.80), severe hypoalbuminemia (OR = 2.46, 95%CI: 1.12-5.37), and increased serum creatinine (OR = 1.5, 95% CI: 1.1-2.03). Among the prognostic scores, MELD 3.0 score exhibited superior efficacy for short-term (AUC = 0.734, 95% CI 0.656-0.811) and long-term mortality (AUC = 0.777, 95% CI: 0.724-0.830) compared to alternative scoring systems. Conclusions: Low eligibility rate and poor prognosis underscore the need for effective therapies. Our findings contribute to refining risk stratification and early prediction of non-response, aiding clinicians in identifying more beneficial therapies.

Prothrombin time predicts steroid response in severe alcohol-related hepatitis.

BACKGROUND AND AIMS: Alcohol-related hepatitis (AH) is the most severe form of acute alcohol-related liver disease. Maddrey's discriminant function ≥32 defines the severe form of AH, which is associated with a high mortality. Steroid therapy represents the main medical treatment that may reduce short-term mortality. Lille score at day 7 assesses the therapeutic response to steroid therapy. At present, no parameters able to predict the response to steroid therapy have been highlighted. The aim of the present study was to evaluate if baseline prothrombin time (BPT) could predict the response to steroid in severe AH (sAH). METHODS: Patients consecutively admitted in two Italian Liver Units, from 2017 to 2022, suffering from sAH were included. Data were collected prospectively. In order to evaluate if BPT could predict steroid response, we assessed the correlation between BPT using the Lille score at day 7. RESULTS: A total of 52 patients received steroid treatment were enrolled in the study. The response to therapy was assessed by Lille score at day 7. Responders were 34 patients (65%), non-responders 18 patients (34%). BPT significantly predicted the steroid response (p < .001). The likelihood of not responding to the steroid therapy was significantly higher in patients with higher BPT (OR = 2.954). CONCLUSIONS: BPT value predicted steroid response in patients with sAH. BPT could quickly identify non-responder patients to steroid therapy, reducing the risk of infections and it could allow the early evaluation for liver transplantation.

Safety, Pharmacokinetics, and Efficacy Signals of Larsucosterol (DUR-928) in Alcohol-Associated Hepatitis.

INTRODUCTION: This study is to evaluate the safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without US Food and Drug Administration-approved therapies. METHODS: This phase 2a, multicenter, open-label, dose escalation study evaluated the safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed subjects with AH. Based on the model for end-stage liver disease (MELD) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150 mg and were followed up for 28 days. Efficacy signals from a subgroup of subjects with severe AH were compared with those from 2 matched arms of those with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study. RESULTS: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the subjects with severe AH were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to day 7 and day 28, and MELD scores were reduced at day 28. The efficacy signals compared favorably with those from 2 matched groups treated with SOC. Lille scores at day 7 were <0.45 in 16 of the 18 (89%) subjects with day 7 samples. Lille scores from 8 subjects with severe AH who received 30 or 90 mg larsucosterol (doses used in phase 2b trial) were statistically significantly lower ( P < 0.01) than those from subjects with severe AH treated with SOC from the contemporaneous study. DISCUSSION: Larsucosterol was well tolerated at all 3 doses in subjects with AH without safety concerns. Data from this pilot study showed promising efficacy signals in subjects with AH. Larsucosterol is being evaluated in a phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.

Severity of Acute Portal Hypertension Determines the Clinical Outcomes in Severe Alcoholic Hepatitis.

BACKGROUND: Severe alcohol-associated hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) has high mortality. Severe hepatic inflammation and ongoing hepatocellular cell death lead to rapid rise in portal pressure, a hyperdynamic circulation that might precipitate infections and organ failures. METHODS: Consecutive SAH patients were classified based on baseline HVPG measurement as 6to < 12 mmHg, 12to < 20 mmHg, and ≥ 20 mmHg. We analyzed portal hypertension severity in relation to fibrosis stage, ACLF at presentation, response to prednisolone, severity scores(MELD and Maddrey's Discriminant Function, mDF), and 90-day mortality. RESULTS: Of 819 SAH patients (94.6% ACLF, 85.4% histological cirrhosis, median MELD and mDF scores 25 and 66, respectively), 250(30.5%) had HVPG ≥ 20 mmHg. Patients with HVPG ≥ 20 mmHg more often had large esophageal varices (25.2%vs.13.2%; p-0.001), higher baseline MELD (27.1 ± 5.6vs.25.3 ± 5.2; p-0.001), and mDF(76.1 ± 16vs.68.4 ± 15.1; p-0.01) scores. No patient without ACLF had HVPG ≥ 20 mmHg. Moreover, during hospital course these patients had higher incidence of variceal bleed (17.2%vs.8.8%; p-0.001), acute kidney injury (36.4%vs.25.3%; p-0.001), and spontaneous bacterial peritonitis (6.4%vs.3.5%; p-0.05). Of 412(50.3%) eligible patients treated with prednisolone, 69.2% showed response at day 7(Lille's score < 0.45). 90-day mortality was 27.6%; and baseline MELD > 25.5[HR 1.78], HVPG ≥ 20 mmHg [HR 1.86], the presence of HE[HR 1.63], and prednisolone ineligibility due to sepsis[HR 1.27] were independent predictors. Mortality was unrelated to varices grade, variceal bleed, and histological cirrhosis. Repeat HVPG performed in 114(19.2%) patients after a median of 5.2 months showed significant decrease (3.6 mmHg; p-0.001) which correlated with improvement in MELD score(13points; p-0.05). CONCLUSION: Development of ACLF and complications in SAH are likely a result of acute rise in HVPG. "High-risk" SAH are SAH patients with HVPG ≥ 20 mmHg in the presence of ascites. Understanding the drivers for acute rise in portal pressure in SAH ACLF might help introduction of newer therapies.

Past, Present, and Future Therapies for Alcohol-associated Hepatitis.

PURPOSE: Alcohol-associated hepatitis (AH) is a unique presentation of cholestatic steatohepatitis with liver dysfunction and malaise preceded by heavy alcohol intake. Although AH exists on a spectrum, in its most severe form, 28-day mortality approaches 50%. Clinical trials of therapeutic interventions over the last 50 years have yielded few durable therapies, none of which convey benefit beyond the short term. METHODS: A qualitative systematic review was performed via searches of PubMed, the International Clinical Trials Registry Platform, and ClinicalTrials.gov for therapeutic interventions for AH. FINDINGS: Prior to 2005, clinical trial results for AH were identified within PubMed. From 2005 to the present, trials were well catalogued within online registries and included information regarding trial status (eg, complete, terminated, actively enrolling). Most clinical trials for AH have used existing medications broadly targeting pathogenic themes of AH (eg, inflammation, cell death) in an off-label manner. The trend of initially promising pilot studies answered by larger trials showing lack of efficacy or safety signals have ended the hopes of many new therapeutics. The emergence of theragnostics to identify patients who may benefit from existing therapies and trials of agents with novel mechanisms of action, including epigenetic modifications and hyaluronic acid signaling targeted to AH pathogenesis, are currently under investigation. IMPLICATIONS: This review of AH treatments details the historical interventions and clinical trials that have led to the current treatment algorithm and active studies shaping the therapeutic pipeline for AH.

In severe alcohol-related hepatitis, acute kidney injury is prevalent, associated with mortality independent of liver disease severity, and can be predicted using IL-8 and micro-RNAs.

BACKGROUND: The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain. AIMS: We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date. METHODS: Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0-AKI. Survival was compared by Kaplan-Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; biomarkers by AUROC analyses. RESULTS: D0-AKI was present in 198/1051 (19%) participants; incident AKI developed in a further 119/571 (21%) with available data. Participants with D0-AKI had higher 90-day mortality than those without (32% vs. 25%, p = 0.008), as did participants with incident AKI compared to those without D0-AKI or incident AKI (47% vs. 25%, p < 0.001). Incident AKI was associated with D90 mortality adjusted for age and discriminant function (AHR 2.15, 1.56-2.97, p < 0.001); D0-AKI was not. Prednisolone therapy reduced incident AKI (AOR 0.55, 0.36-0.85, p = 0.007) but not mortality. D0 bilirubin and IL-8 combined, miR-6826-5p, and miR-6811-3p predicted incident AKI (AUROCs 0.726, 0.821, 0.770, p < 0.01). CONCLUSIONS: Incident AKI is associated with 90-day mortality independent of liver function. Prednisolone therapy was associated with reduced incident AKI. IL-8 and several miRNAs are potential biomarkers to predict AKI. Novel therapies to prevent incident AKI should be evaluated in AH to reduce mortality.

Granulocyte colony stimulating factor in decompensated cirrhosis, acute alcoholic hepatitis, and acute-on-chronic liver failure: A comprehensive meta-analysis of randomized controlled trials.

BACKGROUND: GCSF may improve the prognosis of severe liver disease by promoting liver regeneration and immune restoration. Our Aim was to investigate its controversial efficacy in decompensated cirrhosis, acute alcoholic hepatitis (AAH), or acute-on-chronic liver failure (ACLF) through meta-analysis. METHODS: Meta-analysis of proportions (random effect model) including 19 RCTs (1287 patients from 16 Asian and 3 European studies including 487 ACLF, 231 AAH and 569 cirrhotic patients) evaluating survival at day-28, day-90, 6 months, one year, and/or occurrence of sepsis as major outcomes. RESULTS: In patients with decompensated cirrhosis, G-CSF administration was associated with a reduction in the weight-adjusted risk of mortality of 9% at day-90 (OR=0.33; 95%CI: 0.18-0.58; p = 0.0002), 16% at 6 months (OR=0.31; 95%CI: 0.15-0.62; p = 0.0009), 26% at one year (OR=0.21; 95%CI:0.12-0.38, p<0.0001) and a weight-adjusted 28% risk reduction for sepsis (OR=0.28; 95%CI: 0.16-0.49; p<0.0001). Only Asian studies were positive. In AAH, G-CSF was associated with an 18% reduction in weight-adjusted mortality risk at day-28 (OR=0.31; 95%CI:0.11-0.83, p = 0.021), 32% at day-90 (OR=0.20; 95%CI:0.09-0.46, p<0.0001) and a weight-adjusted 42% risk reduction for sepsis (OR=0.17; 95%CI: 0.08-0.38; p<0.0001). Only Asian studies, in which corticosteroids were not given systematically in case of severe AAH, were positive. In patients with ACLF, the results on mortality at day-28 were heterogeneous, and GCSF had no beneficial effect on sepsis or survival at day-90. CONCLUSION: G-CSF may be effective in patients with decompensated cirrhosis or AAH by reducing the occurrence of sepsis and mortality. Further meta-analyses of individual data, or new, powerful and methodologically flawless therapeutic trials, are warranted to confirm these results, which harbor wide divergences between Asian and European RCTs.

A multicenter double-blind, placebo-controlled randomized trial to evaluate the safety and efficacy of bovine colostrum in the treatment of severe alcoholic hepatitis (SAH).

BACKGROUND: Severe alcoholic hepatitis (SAH) is associated with high mortality. Numerous studies and meta-analysis have reported that corticosteroids reduce the 28-day mortality in SAH, but not the 6-month mortality. Therefore, newer treatments for SAH need to be studied. A pilot study from our group had recently treated ten patients with SAH with bovine colostrum (BC) [20 g thrice in a day for 8 weeks] and prednisolone. This therapy improved the biological functions and 3-month mortality. However, as more and more data showed the failure of corticosteroids to improve the 3- and 6-month mortality, especially in patients with high mDF and MELD scores, we planned this trial to study the safety and efficacy of BC (without corticosteroids) in the treatment of SAH. METHOD: This is a multicenter, parallel, double-blind, randomized (1:1) placebo-controlled trial, which will enroll 174 patients with SAH from 5 academic centers in the India. Patients will receive freeze-dried BC or placebo by random 1:1 allocation for 4 weeks. The primary outcome measure is survival at 3 months. The secondary outcome measures are survival at 1 month, change in mDF and MELD scores, change in endotoxin and cytokines (alpha TNF, IL6, and IL8) levels, number of episodes of sepsis [pneumonia, spontaneous bacterial peritonitis (SBP), cellulitis, urinary tract infection (UTI)] from baseline to 4 weeks. DISCUSSION: This study will evaluate the safety and efficacy of bovine colostrum in improving the survival of patients with SAH. TRIAL REGISTRATION: ClinicalTrials.gov NCT02473341. Prospectively registered on June 16, 2015.

Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial.

Importance: The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear. Objective: To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone. Design, Setting, and Participants: Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019. Intervention: Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147). Main Outcome and Measures: The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days. Results: Among 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, -4.7% [95% CI, -14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% [95% CI, -23.0% to -0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group). Conclusion and Relevance: In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis. Trial Registration: ClinicalTrials.gov Identifier: NCT02281929.

[Principles of treatment of different forms of alcoholic liver disease: A review].

The review considers the principles of treatment of various forms of alcoholic liver disease from the point of view of the evidence base and clinical recommendations. The main therapy for severe alcoholic hepatitis is systemic glucocorticosteroids, their effect on survival is increased by the addition of antioxidants (N-acetylcysteine, ademethionine). The effect of ademetionine on the life expectancy of patients with alcoholic cirrhosis of Child-Pugh class A and B has been proven. The treatment of patients with mild forms of alcoholic liver disease is not well developed, and the evidence base for most of the drugs used is modest.

IgY antibodies against cytolysin reduce ethanol-induced liver disease in mice.

BACKGROUND AND AIMS: Patients with severe alcohol-associated hepatitis have high morbidity and mortality. Novel therapeutic approaches are urgently needed. The aims of our study were to confirm the predictive value of cytolysin-positive Enterococcus faecalis ( E. faecalis ) for mortality in patients with alcohol-associated hepatitis and to assess the protective effect of specific chicken immunoglobulin Y (IgY) antibodies against cytolysin in vitro and in a microbiota-humanized mouse model of ethanol-induced liver disease. APPROACH AND RESULTS: We investigated a multicenter cohort of 26 subjects with alcohol-associated hepatitis and confirmed our previous findings that the presence of fecal cytolysin-positive E. faecalis predicted 180-day mortality in those patients. After combining this smaller cohort with our previously published multicenter cohort, the presence of fecal cytolysin has a better diagnostic area under the curve, better other accuracy measures, and a higher odds ratio to predict death in patients with alcohol-associated hepatitis than other commonly used liver disease models. In a precision medicine approach, we generated IgY antibodies against cytolysin from hyperimmunized chickens. Neutralizing IgY antibodies against cytolysin reduced cytolysin-induced cell death in primary mouse hepatocytes. The oral administration of IgY antibodies against cytolysin decreased ethanol-induced liver disease in gnotobiotic mice colonized with stool from cytolysin-positive patients with alcohol-associated hepatitis. CONCLUSIONS: E. faecalis cytolysin is an important mortality predictor in alcohol-associated hepatitis patients, and its targeted neutralization through specific antibodies improves ethanol-induced liver disease in microbiota-humanized mice.

Subclinical versus advanced forms of alcohol-related liver disease: Need for early detection.

Alcohol-related liver disease (ALD) consists of a wide spectrum of clinical manifestations and pathological features, ranging from asymptomatic patients to decompensated cirrhosis and hepatocellular carcinoma. Patients with heavy alcohol intake and advanced fibrosis often develop a subacute form of liver failure called alcohol-induced hepatitis (AH). Globally, most patients with ALD are identified at late stages of the disease, limiting therapeutic interventions. Thus, there is a need for early detection of ALD patients, which is lacking in most countries. The identification of alcohol misuse is hampered by the existence of alcohol underreporting by many patients. There are useful biomarkers that can detect recent alcohol use. Moreover, there are several non-invasive techniques to assess the presence of advanced fibrosis among patients with alcohol misuse, which could identify patients at high risk of liver related events or early death. In this review, we discuss differences between early stages of ALD and AH as the cornerstone of advanced forms. A global overview of epidemiological, anthropometric, clinical, analytical, histological, and molecular differences is summarized in this article. We propose that campaigns aimed at identifying patients with subclinical forms can prevent the development of life-threatening forms.

Fecal microbiota transplantation compared with prednisolone in severe alcoholic hepatitis patients: a randomized trial.

BACKGROUND: Severe alcoholic hepatitis (SAH) has high 90-day mortality. Prednisolone therapy has shown modest survival benefits over placebo at 28 but not 90 days. Fecal microbial transplantation (FMT) has shown promise in these patients. We compared the efficacy and safety of the two therapies in SAH patients. METHODS: Steroid eligible SAH patients were randomized in an open-label study to prednisolone (n = 60) 40 mg/day for 28 days (assessed at day-7 for continuation) or healthy donor FMT (n = 60) through naso-duodenal tube, daily for seven days. Primary outcome of study was day-90 survival. RESULTS: Patients in prednisolone and FMT arms were comparable at baseline (discriminant function score 65 ± 16.2 and 68 ± 14, MELD score 17.1 and 16.5, respectively). Of 120 patients, 112 [prednisolone-57; FMT-55] completed trial. As per intention-to-treat analysis, 90-day survival was achieved by 56.6% (34/60) patients in prednisolone and 75% (45/60) in FMT group (p = 0.044, FMT HR = 0.528, 95%CI 0.279-0.998). Secondary outcome of 28-day survival [78.33% (47/60) and 88.33% (53/60) (p = 0.243, FMT HR = 0.535, 95%CI 0.213-1.34)] with comparable severity scores over time between both arms. Infections accounted for 11 (19.3%) and 2 (3.6%) deaths in prednisolone and FMT groups, respectively (p = 0.01). Path-tracing showed a slow establishment of microbiota and alpha diversity (Shannon index) improvement by day-28 (p = 0.029). FMT resulted in 23 new taxa by day-28, reduction from baseline in pathogenic taxa [Campylobacter (19-fold, p = 0.035), anaerobes (Parcubacteria, Weisella and Leuconostocaceae)], and increase of Alphaproteobacteria [~ sevenfold, p = 0.047] and Thaumarcheota (known ammonia oxidizer, p = 0.06). Lachnospiraceae (p = 0.008), Prevotella and Viellonella communities in gut favored survival (p < 0.05). CONCLUSION: In severe alcoholic hepatitis, FMT is safe and improves 90-day survival and reduces infections by favorably modulating microbial communities. It can be a useful alternative to prednisolone therapy.

The protective effect of puerarin-loaded mesoporous silicon nanoparticles on alcoholic hepatitis through mTOR-mediated autophagy pathway.

Puerarin, a bioactive flavone compound isolated from Pueraria (Wild.), provides hepatoprotection by anti-inflammatory, anti-alcoholism, and regulating mechanistic target of rapamycin (mTOR). Building evidence suggests that the activation of mTOR reduces liver injuries associated with alcohol consumption and metabolism. However, the poor water solubility, low bioavailability, and short half-life of puerarin hinder its clinical application. The utility of mesoporous silicon nanoparticles (MSNs) can improve traditional Chinese medicine limitations. Stober methods were used to fabricate MSNs@Pue, and the size, zeta potentials and drug encapsulation efficiency were characterized by a series of analytical methods. IVIS Imaging System demonstrated liver-targeted bio-distribution, and then high-throughput sequencing, immunoproteomics and ultrastructure methods indicated autophagy related protective mechanism, followed by curative effect evaluation for the treatment efficacy. An acute-on chronic ethanol-drinking according to Gao-binge model induced alcoholic hepatitis (AH) pathology and resulted in hepatic hyper-autophagy, which was improved with MSNs@Pue administration (puerarin: 30 mM, 42 mg/kg; intravenously [i.v.]). Ethanol-fed mice were found to have increased expression of autophagy-related proteins (Atg3, Atg7, LC3 and p62). In contrast, MSNs@Pue administration significantly decreased the expression of these proteins and alleviated fatty droplets infiltration in damaged liver. Furthermore, acute-on-chronic ethanol feeding also resulted in the activiation of ERK activation and mTOR expression, which were reversed with MSNs@Pue administration and better than the usage of puerarin alone. Results point to MSNs@Pue mediated ERK/mTOR signaling pathway activation as a possible protective strategy to improve AH, which provides a strategy and evidence for treating liver disease using an MSN delivery system.

Liver regeneration as treatment target for severe alcoholic hepatitis.

Severe alcoholic hepatitis (AH) is a distinct entity in the spectrum of alcohol-related liver disease, with limited treatment options and high mortality. Supportive medical care with corticosteroids in selected patients is the only currently available treatment option, often with poor outcomes. Based on the insights into the pathogenetic mechanisms of AH, which are mostly obtained from animal studies, several new treatment options are being explored. Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target. Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor (G-CSF) on liver regeneration and immunomodulation in animal models, several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH. Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH, these effects were not confirmed by a recently published multicenter randomized trial, suggesting that other options should rather be pursued. Stem cell transplantation represents another option for improving liver regeneration, but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing, with established lack of efficacy in patients with compensated cirrhosis. In this review, we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration. The lack of high-quality studies and evidence is a major obstacle in further treatment development. New insights into the pathogenesis of not only liver injury, but also liver regeneration processes are mandatory for the development of new treatment options. A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing, and data obtained from animal studies are essential for future research.