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.

Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation.

BACKGROUND AIMS: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood. APPROACH RESULTS: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced-ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1ß release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1ß release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1ß production, and steatohepatitis in a murine model of AH. CONCLUSIONS: Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.

Interaction Between Alcohol Consumption and PNPLA3 Variant in the Prevalence of Hepatic Steatosis in the US Population.

BACKGROUND & AIMS: To our knowledge, the interaction between alcohol consumption and PNPLA3 genotype on hepatic steatosis has not been explored in a representative sample. To examine the interaction between alcohol consumption and PNPLA3 genotype on hepatic steatosis in the US adult population. METHODS: Cross-sectional study of 4,674 adult participants of the Third National Health and Nutrition Examination Survey, Phase 2 (1991-1994) with data on PNPLA3 genotype, self-reported alcohol consumption, ultrasound-defined hepatic steatosis and socio-demographic characteristics. RESULTS: In 1991-1994 in the U.S. population, the weighted allele frequency of the G (risk) allele of the rs738409 at PNPLA3 was 25.4%. We confirmed both a J shaped association between alcohol consumption and hepatic steatosis among those with the CC genotype of PNPLA3, and a higher prevalence of hepatic steatosis among those with PNPLA3 gene G variant. We found evidence of an interaction of PNPLA3 G allele presence on the association between moderate alcohol consumption and hepatic steatosis on both the multiplicative (relative prevalence ratio [RPR]=1.95, 95% confidence interval [CI] 1.04-3.65) and additive scales (relative excess risk due to interaction=0.49, 95% CI 0.13-0.85). Compared to never drinkers, moderate alcohol drinking was associated with a 48% decreased risk of hepatic steatosis only among those without PNPLA3 G allele (PR=0.52, 95% CI 0.26-1.05), with no association among those with at least one copy of the PNPLA3 G allele (PR=1.02, 95% CI 0.68-1.54). CONCLUSIONS: Our results suggest that a highly common and strong genetic susceptibility to liver disease is modifiable by the level of alcohol consumption. Keeping alcohol consumption low may offset genetic predisposition to liver disease.

Keratin-18: Diagnostic, Prognostic, and Theragnostic for Alcohol-Associated Hepatitis.

ABSTRACT: It is still sometimes difficult to differentiate alcohol-associated hepatitis (AH) from other liver problems. In this edition of AJG, Atkinson et al. showed that keratin-18 (intermediate filament protein) is a promising biomarker for predicting histological severity of AH, defining the type of hepatocyte death (necrosis vs apoptosis), predicting 90-day mortality, and predicting the response to corticosteroid therapy in severe AH. The authors conclude that K18 is diagnostic, prognostic, and may be a theragnostic marker for prednisolone therapy and note that "serum K18 estimation should be adopted into routine clinical practice." We agree.

Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute.

The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management. Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH). Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever. Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections. Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI). Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate. Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment. Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate. Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF. Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest. Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting. Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high. Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid.

Alcoholic hepatitis: current trends in management.

PURPOSE OF REVIEW: Alcohol consumption is increasing globally, as are complications of alcohol-related liver disease, including the most severe manifestation, alcoholic hepatitis. Despite the increased prevalence, many patients hospitalized with alcoholic hepatitis are either not diagnosed or inadequately treated leading to significant morbidity and high mortality rates. The purpose of this review is to discuss current challenges in the diagnosis and management of this frequently fatal condition. RECENT FINDINGS: Recent studies and meta-analyses have improved our understanding of both the evaluation and treatment of alcoholic hepatitis including the diagnostic criteria, appropriate use of glucocorticoids and other therapeutic modalities including novel disease-specific therapeutic agents and indications for considering liver transplantation. SUMMARY: Glucocorticoid therapy and enteral nutrition represent the best options for reducing short-term mortality in patients with the severe form of acute alcoholic hepatitis. The efficacy of other medications such as pentoxifylline as currently used does not support a role for use outside clinical trials. While the current management options for alcoholic hepatitis remain insufficient, improvements in diagnosis, determining prognosis and severity and the potential role of novel treatments provides encouragement that outcomes from this devastating condition will improve.

Alcoholic Hepatitis: Risk Factors, Pathogenesis, and Approach to Treatment.

BACKGROUND: Alcoholic hepatitis (AH) is an inflammatory disorder of the liver characterized clinically by jaundice, hepatomegaly, and abdominal pain, and histologically by macrovesicular steatosis and necroinflammation. METHODS: This clinical review will cover what is known about the pathogenesis, clinical presentation, current treatments, and novel therapies for AH. RESULTS: The pathogenesis and treatment of AH remain areas of active research. Although abstinence is the cornerstone of therapy for all stages of alcoholic liver disease, corticosteroids have shown modest short-term benefits in treatment of severe AH. CONCLUSIONS: Improved understanding of the pathogenesis of AH has expanded the range of potential treatments for this devastating disease. Several novel therapies are also currently in various stages of testing through clinical trials.

Endoscopic suturing for transoral outlet reduction increases weight loss after Roux-en-Y gastric bypass surgery.

BACKGROUND & AIMS: Weight regain or insufficient loss after Roux-en-Y gastric bypass (RYGB) is common. This is partially attributable to dilatation of the gastrojejunostomy (GJ), which diminishes the restrictive capacity of RYGB. Endoluminal interventions for GJ reduction are being explored as alternatives to revision surgery. We performed a randomized, blinded, sham-controlled trial to evaluate weight loss after sutured transoral outlet reduction (TORe). METHODS: Patients with weight regain or inadequate loss after RYGB and GJ diameter greater than 2 cm were assigned randomly to groups that underwent TORe (n = 50) or a sham procedure (controls, n = 27). Intraoperative performance, safety, weight loss, and clinical outcomes were assessed. RESULTS: Subjects who received TORe had a significantly greater mean percentage weight loss from baseline (3.5%; 95% confidence interval, 1.8%-5.3%) than controls (0.4%; 95% confidence interval, 2.3% weight gain to 3.0% weight loss) (P = .021), using a last observation carried forward intent-to-treat analysis. As-treated analysis also showed greater mean percentage weight loss in the TORe group than controls (3.9% and 0.2%, respectively; P = .014). Weight loss or stabilization was achieved in 96% subjects receiving TORe and 78% of controls (P = .019). The TORe group had reduced systolic and diastolic blood pressure (P < .001) and a trend toward improved metabolic indices. In addition, 85% of the TORe group reported compliance with the healthy lifestyle eating program, compared with 53.8% of controls; 83% of TORe subjects said they would undergo the procedure again, and 78% said they would recommend the procedure to a friend. The groups had similar frequencies of adverse events. CONCLUSIONS: A multicenter randomized trial provides Level I evidence that TORe reduces weight regain after RYGB. These results were achieved using a superficial suction-based device; greater levels of weight loss could be achieved with newer, full-thickness suturing devices. TORe is one approach to avoid weight regain; a longitudinal multidisciplinary approach with dietary counseling and behavioral changes are required for long-term results. ClinicalTrials.gov identifier: NCT00394212.

Absorption and peak blood alcohol concentration after drinking beer, wine, or spirits.

BACKGROUND: Both the amount and the rate of absorption of ethanol (EtOH) from alcoholic beverages are key determinants of the peak blood alcohol concentration (BAC) and exposure of organs other than gut and liver. Previous studies suggest EtOH is absorbed more rapidly in the fasting than in the postprandial state. The concentration of EtOH and the type of beverage may determine gastric emptying/absorption of EtOH. METHODS: The pharmacokinetics of EtOH were measured in 15 healthy men after consumption of 0.5 g of EtOH/kg body weight. During this 3-session crossover study, subjects consumed in separate sessions, beer (5.1% v/v), white wine (12.5% v/v), or vodka/tonic (20% v/v) over 20 minutes following an overnight fast. BAC was measured by gas chromatography at multiple points after consumption. RESULTS: Peak BAC (Cmax ) was significantly higher (p < 0.001) after vodka/tonic (77.4 ± 17.0 mg/dl) than after wine (61.7 ± 10.8 mg/dl) or beer (50.3 ± 9.8 mg/dl) and was significantly higher (p < 0.001) after wine than beer. The time to Cmax occurred significantly earlier (p < 0.01) after vodka/tonic (36 ± 10 minutes) compared to wine (54 ± 14 minutes) or beer (62 ± 23 minutes). Six subjects exceeded a Cmax of 80 mg/dl after vodka/tonic, but none exceeded this limit after beer or wine. The area under the concentration-time curve (AUC) was significantly greater after drinking vodka/tonic (p < 0.001) than after wine or beer. Comparison of AUCs indicated the relative bioavailability of EtOH was lower after drinking beer. CONCLUSIONS: Findings indicate that BAC is higher after drinking vodka/tonic than beer or wine after fasting. A binge pattern is significantly more likely to result in BAC above 80 mg/dl after drinking vodka/tonic than beer or wine. Men drinking on an empty stomach should know BAC will vary depending on beverage type and the rate and amount of EtOH.

Brief alcohol interventions are underutilized in persons with nonalcohol-associated chronic liver diseases.

BACKGROUND: Brief alcohol interventions use patient-provider communication to promote alcohol cessation. We characterized the receipt of this intervention in chronic liver disease (CLD). METHODS: We surveyed patients with CLD for weekly drinking patterns and examined associations with patient-provider communication receipt. RESULTS: Among 840 participants, 82.1% and 56.5% reported ≥1 standard drink weekly and excessive alcohol consumption, respectively. Patient-provider communication was lower in noncirrhotic (adjusted odds ratio:0.34, 95% CI: 0.22-0.54) and nonalcohol-associated CLD (adjusted odds ratio: 0.22, 95% CI: 0.15-0.34) among individuals drinking ≥1 standard drink weekly, and similarly in noncirrhotic CLD (adjusted odds ratio: 0.45, 95% CI: 0.21-0.95) among those with excessive drinking. CONCLUSIONS: Brief alcohol interventions are underutilized in noncirrhotic and nonalcohol-associated CLD.

Racial and ethnic disparities in alcohol-associated liver disease in the United States: A systematic review and meta-analysis.

BACKGROUND: Alcohol-associated liver disease (ALD), encompassing alcohol-associated hepatitis and alcohol-associated cirrhosis, is rising in the United States. Racial and ethnic disparities are evident within ALD; however, the precise nature of these disparities is poorly defined. METHODS: We conducted a search of the PubMed/MEDLINE and EMBASE databases to identify studies published from inception through September 2023 that reported ALD incidence, prevalence, and mortality within the United States, stratified by race and ethnicity. We calculated pooled prevalence and incidence by race and ethnicity, including risk ratios and ORs for ALD pooled prevalence and alcohol-associated hepatitis/alcohol-associated cirrhosis pooled proportions, and OR for ALD mortality using the DerSimonian and Laird method for random-effect models. RESULTS: We identified 25 relevant studies (16 for quantitative meta-analysis), comprising 76,867,544 patients. ALD prevalence was highest in Hispanic (4.5%), followed by White (3.1%) and Black (1.4%) individuals. Pooled risk ratios of ALD prevalence were 1.64 (95% CI: 1.12-2.39) for Hispanic and 0.59 (95% CI: 0.35-0.87) for Black compared to White individuals. Mortality among those with ALD did not significantly differ between White and Hispanic (OR: 1.54, 95% CI: 0.9-2.5; I2=0%), Black (OR: 1.2, 95% CI: 0.8-1.6; I2=0%), or Native American (OR: 2.41, 95% CI: 0.9-2.9) individuals, while there was a significant difference between White and Asian (OR: 0.1; 95% CI: 0.03-0.5) individuals. Most data were cross-sectional and assessed to be of poor or fair quality. CONCLUSIONS: Differences were observed in ALD epidemiology, including higher prevalence among Hispanic and lower prevalence among Black individuals, although there were smaller differences in ALD mortality. Differences in ALD prevalence and prognosis remain poorly defined based on existing data, highlighting a need for higher-quality epidemiological studies in this area.

Racial and Ethnic Disparities in Liver Transplantation for Alcohol-associated Liver Diseases in the United States.

BACKGROUND: Emerging data suggest disparities exist in liver transplantation (LT) for alcohol-associated liver disease (ALD). As the incidence of ALD increases, we aimed to characterize recent trends in ALD LT frequency and outcomes, including racial and ethnic disparities. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network 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: There were 1211 AH and 26 526 AAC new LT waitlist additions, with 970 AH and 15 522 AAC LTs performed. Compared with non-Hispanic White patients (NHWs) with AAC, higher hazards of waitlist death were observed for Hispanic (subdistribution hazard ratio [SHR] = 1.23, 95% confidence interval [CI]: 1.16-1.32), Asian (SHR = 1.22, 95% CI:1. 01-1.47), and American Indian/Alaskan Native (SHR = 1.42, 95% CI: 1.15-1.76) candidates. Similarly, significantly higher graft failures were observed in non-Hispanic Black (HR = 1.32, 95% CI: 1.09-1.61) and American Indian/Alaskan Native (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. CONCLUSIONS: Significant racial and ethnic disparities exist for ALD LT frequency and outcomes in the United States. Compared with NHWs, racial and ethnic minorities with AAC experience increased risk of waitlist mortality and graft failure. Efforts are needed to identify determinants for LT disparities in ALD that can inform intervention strategies.

Proteomics identifies complement protein signatures in patients with alcohol-associated hepatitis.

Diagnostic challenges continue to impede development of effective therapies for successful management of alcohol-associated hepatitis (AH), creating an unmet need to identify noninvasive biomarkers for AH. In murine models, complement contributes to ethanol-induced liver injury. Therefore, we hypothesized that complement proteins could be rational diagnostic/prognostic biomarkers in AH. Here, we performed a comparative analysis of data derived from human hepatic and serum proteome to identify and characterize complement protein signatures in severe AH (sAH). The quantity of multiple complement proteins was perturbed in liver and serum proteome of patients with sAH. Multiple complement proteins differentiated patients with sAH from those with alcohol cirrhosis (AC) or alcohol use disorder (AUD) and healthy controls (HCs). Serum collectin 11 and C1q binding protein were strongly associated with sAH and exhibited good discriminatory performance among patients with sAH, AC, or AUD and HCs. Furthermore, complement component receptor 1-like protein was negatively associated with pro-inflammatory cytokines. Additionally, lower serum MBL associated serine protease 1 and coagulation factor II independently predicted 90-day mortality. In summary, meta-analysis of proteomic profiles from liver and circulation revealed complement protein signatures of sAH, highlighting a complex perturbation of complement and identifying potential diagnostic and prognostic biomarkers for patients with sAH.

Designing clinical trials to address alcohol use and alcohol-associated liver disease: an expert panel Consensus Statement.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions.

A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy.

BACKGROUND: We performed the first multiple dose study of remimazolam designed to assess both the feasibility of maintaining suitable sedation during colonoscopy and reversing the sedative effects of remimazolam with flumazenil. METHODS: Healthy volunteers received fentanyl followed by remimazolam for sedation during colonoscopy. Three dose groups of 15 volunteers each received remimazolam in increasing initial doses, plus top-up doses to maintain sedation for a 30-minute period. In a separate double-blind crossover part of the trial, 6 volunteers were sedated with a single high dose of remimazolam, followed by flumazenil or placebo to reverse the sedation. RESULTS: Successful sedation that was adequate for colonoscopy was achieved in >70% of subjects. After the procedure, subjects rapidly recovered to fully alert, with a median of <10 minutes overall. Failures were due to the inability to sedate or adverse events, with 1 subject failing due to hypotension (arterial blood pressure 80/40) and low SpO2 (<90%). There were no serious adverse events reported, and no events that were unexpected with the combination of a benzodiazepine and fentanyl. The study also showed that sedation was rapidly reversible (1.0 minutes flumazenil vs 10.5 minutes placebo) without resedation. CONCLUSIONS: Remimazolam has the attributes of a sedative drug, with success rates comparable with recent studies of other drugs. Remimazolam provided adequate sedation in 33 of 44 subjects undergoing colonoscopy, and its sedative effects were easily reversed with flumazenil.

Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis.

Background: Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1ß receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods: Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions: The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.

The Practice of Retransplantation for Recurrent Alcohol-associated Liver Disease in the United States Is Uncommon With Acceptable Outcomes.

Alcohol-associated liver disease (ALD) is the leading indication for liver transplantation (LT) in the United States. Alcohol use disorder relapse can lead to graft failure and the need for liver retransplantation (re-LT). Despite the rising incidence of LT for ALD, the practice of re-LT for recurrent ALD is not well understood. We aimed to define the practice of re-LT for recurrent ALD during the last 20 y. METHODS: Using the US national transplant registry, adults who underwent re-LT for recurrent ALD were compared with LT recipients who died from recurrent ALD and propensity score-matched re-LT recipients with non-ALD indications. All groups had at least 1-y survival of their primary graft. Kaplan-Meier analysis was used to calculate 1- and 5-y survivals. RESULTS: Between 2000 and 2020, 74 re-LTs were performed for recurrent ALD (1.0% of all re-LTs). There was an increase in recurrent ALD re-LT practice from 2017 to 2020 versus 2014 to 2016 (20 versus 2). At the time of re-LT, patients with recurrent ALD had a significant decrease in body mass index (median 25.1 versus 28.8 kg/m2; P < 0.001) versus the index LT. Patient and graft survivals were similar between patients who underwent re-LT for ALD and non-ALD (56.4% versus 56.9% 5-y graft survival, P = 0.96; 62.8% versus 59.0% 5-y patient survival, P = 0.58). CONCLUSIONS: The practice of re-LT for recurrent ALD is uncommon in the United States. Graft and patient survivals seem to be acceptable and support the occasional practice of re-LT for recurrent ALD should the patient be deemed an appropriate candidate.

Should the reorganization of addiction-related research across all the National Institutes of Health be structural?--The devil is truly in the details.

The recent proposal to dissolve the National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse and create a new institute for substance use, abuse, and addiction will require significant effort by the staff of both institutes, the Advisory Councils, and outside experts to overcome complex challenges that could threaten its success. Although integration of the grants portfolios can be achieved, harmonization of goals and policies related to legal use of alcohol versus illegal consumption of drugs will present serious challenges. Consolidating the infrastructure of the 2 existing institutes would entail avoiding encroachment on grant funding. A new institute for substance use, abuse, and addiction would require an enormous amount of cooperation from other institutes as the portfolios of research on alcohol, tobacco, and other drug abuse should logically be transferred to the new institute. In the near term, a structural reorganization would be less efficient and more costly than the individual institutes are currently. Increasing efficiency and reducing costs over time will necessitate careful strategic planning. Success in this difficult task would be made easier and less costly by first implementing carefully placed building blocks of increasing functional reorganization. The newly created institute should increase opportunities for specialization within disorders of addiction, attract new leadership, and build a novel strategic plan that will energize scientists and staff and incorporate ideas of stakeholders to advance the public good in preventing and treating alcohol, tobacco, and all addictions. Attention must be paid to the devil in the details.