Alcohol-related Hepatitis Research Articles

SIRS criteria versus qSOFA score in patients with severe alcohol-related hepatitis.

Severe alcohol-related hepatitis (sAH) is a potentially life-threatening complication of alcohol-related liver disease. SIRS criteria have been related to disease severity and may be a prognostic factor. Recently, qSOFA has been shown to be more prognostically accurate than SIRS in other inflammatory conditions. To determine whether qSOFA is a better prognostic score than SIRS criteria in sAH. We included 62 consecutive patients admitted for sAH, defined by modified Maddrey DF ≥32. MELD-Na, SIRS criteria and qSOFA score were calculated. Survival at 180 days was assessed. Twenty-four patients (38.7%) died after 180days. Three or more SIRS criteria and two or more qSOFA criteria were associated with 180-day mortality (LR=12.09, p=0.001; LR=4.81, p=0.028, respectively). Patients with MELD-Na >30 points died during follow-up more frequently (LR=5.997; p=0.014). SIRS respiratory criterion (B=5.113; p=0.023) and qSOFA respiratory criterion (B=5.985; p=0.05), bilirubin (>10mg/dL; LR=5.43, p=0.006), creatinine (>1mg/dL; B=5.885, p=0.015) and hyponatraemia (LR=5.75, p=0.018) were associated with mortality. Cox Regression model revealed that only SIRS and MELD-Na were independent prognostic factors. SIRS criteria seem to be more useful for patients with sAH, as well as MELD-Na. In contrast, qSOFA has no independent prognostic value in patients with sAH.

S179 Jaundice in Alcohol-related Hepatitis: How Biliary We Need to Go?

S179 Jaundice in Alcohol-related Hepatitis: How Biliary We Need to Go?

IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab

Background and aimShort-term mortality in alcohol-related hepatitis (AH) is high and no current therapy results in durable benefit. A role for IL-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. MethodsParticipants with biopsy-confirmed AH and discriminant function ≥32 but MELD ≤27 were randomly allocated 1:1 to receive either CAN 3mg/kg or placebo (PBO). Liver biopsies were taken before, and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analysed by modified Intention-To-Treat (mITT). ResultsFifty-seven participants were randomised: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data was evaluable from 48 participants. In CAN-treated participants, 14/24 (58%) demonstrated histological improvement compared to 10/24 (42%) in the PBO group (p=0.25). There was no improvement in prognostic scores of liver function. Four of the 55 participants (7%) died within 90 days; 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post-hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (p=0.04). ConclusionCAN therapy in severe AH participants with MELD≤27 did not alter biochemical or clinical outcomes compared to PBO. Non-significant histological improvements did not translate into clinical benefit.

GS-010 Early liver transplantation for severe alcohol-related hepatitis: long-term data of the french-belgian controlled study (QuickTrans)

GS-010 Early liver transplantation for severe alcohol-related hepatitis: long-term data of the french-belgian controlled study (QuickTrans)

Workup and management of liver transplantation in alcohol-related liver disease.

Alcohol-related liver disease (ALD) represents the most common indication for liver transplantation (LT) worldwide. Outcomes of LT for ALD are comparable with those of LT for other etiologies; however, ALD is still considered a controversial indication for LT, mainly because it is considered a self-inflicted disease with a high risk of return to alcohol use after LT. Pre-LT evaluation criteria have changed over time, with a progressive re-evaluation of the required pre-transplant duration of abstinence. Despite the fact that some transplant programs still require 6months of abstinence in order to consider a patient suitable for LT, there is increasing evidence that a pre-transplant abstinence period of <6months can be considered for well-selected patients. Early LT for severe alcohol-related hepatitis that has not responded to medical therapy has been shown to be an effective therapeutic option with high survival benefit when performed within strict and well-recognized criteria. However, high variability in LT access exists for these patients due to the presence of social and medical stigma. A psycho-social assessment, together with an evaluation by an addiction specialist, should be mandatory in patients with ALD who are potential candidates for LT in order to assess the risk of post-transplant return to alcohol use and to ensure good long-term outcomes. Finally, before LT, attention should be paid to the presence of other potential comorbidities (i.e., cardiovascular and neurological diseases), which could represent a potential contraindication to LT. Similarly, after LT, patients should be adequately monitored for the development of cardiovascular events and screened for "de novo" tumors, although standardized protocols for this monitoring do not exist at this time.

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

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). 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. 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). 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.

Circulating myeloid populations have prognostic utility in alcohol-related liver disease.

Alcohol-related liver disease (ARLD) accounts for over one third of all deaths from liver conditions, and mortality from alcohol-related liver disease has increased nearly five-fold over the last 30 years. Severe alcohol-related hepatitis almost always occurs in patients with a background of chronic liver disease with extensive fibrosis or cirrhosis, can precipitate 'acute on chronic' liver failure and has a high short-term mortality. Patients with alcohol-related liverdisease have impaired immune responses, and increased susceptibility to infections, thus prompt diagnosis of infection and careful patient management is required. The identification of early and non-invasive diagnostic and prognostic biomarkers in ARLD remains an unresolved challenge. Easily calculated predictors of infection and mortality are required for use in patients who often exhibit variable symptoms and disease severity and may not always present in a specialized gastroenterology unit. We have used a simple haematological analyser to rapidly measure circulating myeloid cell parameters across the ARLD spectrum. We demonstrate for the first time that immature granulocyte (IG) counts correlate with markers of disease severity, and our data suggests that elevated counts are associated with increased short-term mortality and risk of infection. Other myeloid populations such as eosinophils and basophils also show promise. Thus IG count has the potential to serve alongside established markers such as neutrophil: lymphocyte ratio as a simply calculated predictor of mortality and risk of infectious complications in patients with alcohol-related hepatitis. This would allow identification of patients who may require more intensive management.

Hepatic TRPC3 loss contributes to chronic alcohol consumption-induced hepatic steatosis and liver injury in mice

Abstract Emerging evidence discloses the involvement of calcium channel protein in the pathological process of liver diseases. Transient receptor potential cation channel subfamily C member 3 (TRPC3), a ubiquitously expressed non-selective cation channel protein, controls proliferation, inflammation, and immune response via operating calcium influx in various organs. However, our understanding on the biofunction of hepatic TRPC3 is still limited. The present study aims to clarify the role and potential mechanism(s) of TRPC3 in alcohol-associated liver disease (ALD). We recently found that TRPC3 expression plays an important role in the disease process of ALD. Alcohol exposure led to a significant reduction of hepatic TRPC3 in patients with alcohol-related hepatitis (AH) and ALD models. Antioxidants (N-acetylcysteine and mitoquinone) intervention improved alcohol-induced suppression of TRPC3 via a miR-339-5p-involved mechanism. TRPC3 loss robustly aggravated the alcohol-induced hepatic steatosis and liver injury in mouse liver; this was associated with the suppression of Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2)/AMP-activated protein kinase (AMPK) and dysregulation of genes related to lipid metabolism. TRPC3 loss also enhanced hepatic inflammation and early fibrosis-like change in mice. Replenishing hepatic TRPC3 effectively reversed chronic alcohol-induced detrimental alterations in ALD mice. Briefly, chronic alcohol exposure-induced TRPC3 reduction contributes to the pathological development of ALD via suppression of the CAMKK2/AMPK pathway. Oxidative stress-stimulated miR-339-5p upregulation contributes to alcohol-reduced TRPC3. TRPC3 is the requisite and a potential target to defend alcohol consumption-caused ALD.

Positive Predictive Value of Cirrhosis and Chronic Pancreatitis Diagnoses in Individuals with Alcohol Use Disorder: A Single-Center Study.

Although accuracy of diagnosis codes for cirrhosis and chronic pancreatitis (CP) has been evaluated in multiple studies, none have focused on patients with alcohol use disorders (AUD). We evaluated the positive predictive value (PPV) for a verified diagnosis of cirrhosis and CP in AUD patients treated at a tertiary care center. We performed a detailed review of electronic health records for AUD patients assigned ICD-9 or 10 codes for alcoholic cirrhosis (ALC) (n = 199), CP (n = 200), or both (n = 200). We calculated PPV for a verified diagnosis of cirrhosis and CP and performed multivariable regression analysis to assess the impact of relevant factors on PPV for a verified diagnosis. PPV of cirrhosis was 81.2% (95% CI 77.0 to 84.9%) which increased to 87.5% (95% CI 83.8 to 90.6%) if the definition was relaxed to include alcohol-related hepatitis. PPV of CP was 54.5% (95% CI 49.5 to 59.5%) which increased to 78% (95% CI 73.6 to 82.0%) when recurrent acute pancreatitis was included in the definition. In multivariable analyses, the odds of a verified diagnosis were significantly higher in individuals aged 65+ years for both cirrhosis (OR 12.23, 95% CI 2.19 to 68.42) and CP (OR 8.84, 95% CI 2.7 to 28.93) and in ever smokers for CP (OR 1.95, 95% CI 1.05 to 3.65). PPV for diagnosis codes in AUD patients is high for a verified diagnosis of cirrhosis but only modest for CP. While administrative datasets can provide reliable information for cirrhosis, future studies should focus on ways to boost the diagnostic validity of administrative datasets for CP.

Single-center experience with early liver transplantation for acute alcohol-related hepatitis-Limitations of the SALT score and directions for future study.

Alcohol-related liver disease (ALD) is the leading indication for liver transplantation worldwide. Since Mathurin etal. described their experience in providing early liver transplantation for patients with ALD in 2011, other centers have followed suit with generally favorable survival outcomes. This patient population poses a unique clinical challenge given the expedited nature of the evaluation and the lack of any significant sobriety period prior to transplantation. The SALT (Sustained Alcohol Use Post-Liver Transplant) score is a standardized psychometric tool increasingly used to help stratify the risk of relapse and guide listing decisions for these challenging clinical situations. In 2018, our center introduced a protocol for early liver transplantation for acute alcohol-related hepatitis (AAH). In this article, we offer a retrospective review of 26 patients transplanted between May 2018 and May 2021, including at least 1-year follow-up, and compare outcomes to initial SALT scores; we further identify additional factors that may impact post-transplant success. As transplant committees continue to weigh the ethical dilemma of denying lifesaving treatment against the obligation to remain stewards of a limited resource, we aim to contribute to a more nuanced understanding of risk regarding early transplantation for ALD.

Low sphingolipid levels predict poor survival in patients with alcohol-related liver disease

Alcohol-related hepatitis (AH) and alcohol-related cirrhosis are grave conditions with poor prognoses. Altered hepatic lipid metabolism can impact disease development and varies between different alcohol-related liver diseases. Therefore, we aimed to investigate lipidomics and metabolomics at various stages of alcohol-related liver diseases and their correlation with survival. Patients with newly diagnosed alcohol-related cirrhosis, who currently used alcohol (ALC-A), stable outpatients with decompensated alcohol-related cirrhosis with at least 8 weeks of alcohol abstinence (ALC), and patients with AH, were compared with each other and with healthy controls (HC). Circulating lipids and metabolites were analysed using HPLC and mass spectrometry. Forty patients with ALC, 95 with ALC-A, 30 with AH, and 42 HC provided plasma. Lipid levels changed according to disease severity, with generally lower levels in AH and cirrhosis than in the HC group; this was most pronounced for AH, followed by ALC-A. Nine out of 10 free fatty acids differed between cirrhosis groups by relative increases of 0.12-0.66 in ALC compared with the ALC-A group (p <0.0005). For metabolomics, total bile acids increased by 19.7, 31.3, and 80.4 in the ALC, ALC-A, and AH groups, respectively, compared with HC (all p <0.0001). Low sphingolipid ([d42:1] and [d41:1]) levels could not predict 180-day mortality (AUC= 0.73, p= 0.95 and AUC= 0.73, p= 0.95) more accurately than the model for end-stage liver disease score (AUC= 0.71), but did predict 90-day mortality (AUC d42:1= 0.922, AUC d41:1= 0.893; pd42:1= 0.005, pd41:1= 0.007) more accurately than the MELD score AUCMELD= 0.70, pMELD= 0.19). Alcohol-related severe liver disease is characterised by low lipid levels progressing with severity of liver disease, especially low sphingomyelins, which also associate to poor prognoses. Lipidomics has the potential to diagnose and risk stratify patients with liver diseases. Lipidomics differed between patients with alcohol-related hepatitis and alcohol-related cirrhosis with and without recent alcohol use. Furthermore, lipidomics could predict short-term mortality and might be suitable as a prognostic tool in the future. Scientific Ethics Committee of the Capital Region of Denmark, journal no. H-21013476.

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.

The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain. 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. 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. 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). 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.

Quality standards for the management of alcohol-related liver disease: consensus recommendations from the British Association for the Study of the Liver and British Society of Gastroenterology ARLD special interest group

ObjectiveAlcohol-related liver disease (ALD) is the most common cause of liver-related ill health and liver-related deaths in the UK, and deaths from ALD have doubled in the last decade. The...

Mechanisms and treatment approaches for ACLF.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.

Advances and Controversies in Acute Alcohol-Related Hepatitis: From Medical Therapy to Liver Transplantation.

Alcohol-related hepatitis (AH) is a clinical syndrome characterized by recent-onset jaundice in the context of alcohol consumption. In patients with severe AH "unresponsive" to steroid therapy, mortality rates exceed 70% within six months. According to European and American guidelines, liver transplantation (LT) may be considered in highly selected patients who do not respond to medical therapy. The aim of this narrative review is to summarize current knowledge from medical therapy to liver transplantation in acute alcohol-related hepatitis. Due to the impossibility to guarantee six-month abstinence, LT for AH is controversial. Principal concerns are related to organ scarcity in the subset of stigma of "alcohol use disorder" (AUD) and the risk of relapse to alcohol use after LT. Return to alcohol use after LT is a complex issue that cannot be assessed as a yes/no variable with heterogeneous results among studies. In conclusion, present data indicate that well-selected patients have excellent outcomes, with survival rates of up to 100% at 24 and 36 months after LT. Behavioral therapy, ongoing psychological support, and strong family support seem essential to improve long-term outcomes after LT and reduce the risk in relapse of alcohol use.

Development of severe alcohol related liver disease over four decades in Iceland: impact of increased access and use of alcohol

Objective Limited data exist on the association between per capita alcohol consumption and incidence of alcohol related liver disease (ARLD). The aims were to analyse this relationship and assess prevalence of ARLD in Iceland and among patients treated for alcohol use disorder (AUD) and its impact on outcomes. Methods A retrospective study on all patients diagnosed with severe ARLD: alcohol related cirrhosis (ARC) and alcohol related hepatitis (ARH) in Iceland 1984–2020. Medical records were scrutinized for clinical features, severity of ARLD, proportion undergoing treatment for AUD, data on abstinence and long-term outcomes. Results A total of 314 patients, males 76%, median age 56 years, fulfilled the predetermined criteria for ARLD. Median MELD was 17, 73% with Child-Pugh B/C and 70/314 (22%) who had ARH. Incidence of ARLD increased from 0.77 cases per 100 000 inhabitants annually 1984–2000 to 6.1 per 100 000 in 2016–2020. Per capita alcohol consumption increased from 4.3 Liters to 7.5 L in in the same time periods. Overall 220/314 (70%) with ARLD had undergone treatment for AUD. Of all individuals who had AUD treatment during the study period (n = 21.845), 1% were diagnosed with ARLD. Patients who underwent treatment for AUD after the ARLD diagnosis had better prognosis than those who had treatment prior to ARLD diagnosis (hazard ratio 2.5 [95% CI 1.3–5.0]). Conclusions The incidence of ARLD increased 8-fold during the study period coinciding with 74% increase in per capita alcohol consumption. Patients with prior diagnosis of AUD had worse prognosis that needs special attention.

Alcohol-related hepatitis admissions decline in 2021 after a 2020 surge attributed to the COVID-19 pandemic.

We previously investigated the impact of the COVID-19 pandemic on alcohol-related liver disease (ARLD), finding that admissions for alcoholic hepatitis (AH) increased by 50% in the summer of 2020 compared to the same period in 2016-2019. We have now expanded our analysis to consider full years' data and evaluate how rates changed in 2021. We also sought to identify factors associated with ICU admissions, need for dialysis, liver transplant evaluations, and death. Using retrospective data, we identified patients admitted to our four Detroit, Michigan area hospitals for acute ARLD for three periods pre-COVID (2016-February 2020), early COVID (June-December 2020), and late COVID (2021). Clustered logistic regression was performed to study rates of AH admissions across the three eras, where the patient was defined as the cluster and the analysis accounted for multiple encounters per cluster. A similar regression approach, univariate followed by multivariable analysis, was also used to study associations between patient characteristics and outcomes during hospitalization for AH. AH-related admissions declined significantly from the early COVID to late COVID eras (OR 0.68, 95% CL 0.52, 0.88), returning to levels similar to that of the pre- COVID period (OR 1.18, 95% CL 0.96, 1.47). In multivariable analysis, baseline MELD score was associated with ICU admission, initiation of dialysis, transplant evaluation, and death while hospitalized for AH. Female patients were at almost twice the risk of death during admission compared to male patients (aOR 1.81, 95% CL 1.1, 2.98). Increasing age was associated with slightly lower odds of transplant (aOR 0.97, 95% CL 0.94, 1) and higher odds of death (aOR 1.03, 95% CL 1.01. 1.06). After a spike in AH-related admissions during the first summer of the COVID-19 pandemic, rates declined significantly in 2021, returning to pre-pandemic levels.

Impact of COVID-19 pandemic on alcohol-related hepatitis admissions: Analysis of nationwide data 2016-2020

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic was a public health crisis affecting medical, social, and psychological wellness. In a previous study, we reported a rise in alcohol-related hepatitis (ARH) cases between 2019 and 2020 in the central valley of California. Our goal in the current study was to assess the impact of COVID-19 on ARH at a national level. Materials and methodsWe used data from the 2016 to 2020 National Inpatient Sample. All adult patients diagnosed with ARH (ICD10 K70.1 and K70.4) were included. Information was collected regarding patient demographics, hospital characteristics, and severity of hospitalization. We analyzed the annual percentage changes (PC) between 2016-2019 and 2019-2020 to assess the impact of COVID-19 on hospitalizations. Multivariate logistic regression analysis was performed to identify factors associated with increased ARH admissions between 2016 and 2020. ResultsA total of 823,145 patients were admitted with ARH. The total number of cases increased from 146,370 in 2016 to 168,970 in 2019 (annual percentage change (PC) 5.1%), while the cases increased to 190,770 in 2020 (PC 12.4%). The PC in women was 6.6% between 2016 and 2019, which increased to 14.2% between 2019 and 2020. In men, PC increased by 4.4% between 2016 and 2019 to 12.2% between 2019 and 2020. On multivariate analysis, after adjusting for patient demographics and hospital characteristics, there was 46% increased odds of admission with ARH in 2020, compared to 2016. The total number of deaths increased from 8725 in 2016 to 9190 in 2019 (PC 1.7%), while the total number of deaths increased to 11,455 in 2020 (PC 24.6%). ConclusionsA sharp rise in the cases of ARH between 2019 and 2020 was noted, which aligned with the COVID-19 pandemic. Not only did total hospitalization increase, but an increase in mortality was also noted, reflecting higher severity in the patients admitted during the COVID-19 pandemic.

FRI-438 - Epidemic within pandemic: alcohol-related hepatitis and COVID-19

FRI-438 - Epidemic within pandemic: alcohol-related hepatitis and COVID-19

TOP-095 - A systematic review of interventions for alcohol use disorder in patients with cirrhosis or alcohol-related hepatitis

TOP-095 - A systematic review of interventions for alcohol use disorder in patients with cirrhosis or alcohol-related hepatitis