Severity Of Alcoholic Hepatitis Research Articles

The landscape of inpatient admissions for alcoholic hepatitis in the era of early liver transplantation

Introduction and ObjectivesLiver transplant (LT) is a recent option available in the United States (US) to treat those with severe, refractory alcoholic hepatitis (AH). We examined changes in clinical characteristics of patients admitted with AH and tracked hospital outcomes as practice changes involving LT have shifted. Materials and MethodsUsing the National Inpatient Sample, we performed a cross-sectional analysis of patients admitted with AH during the years 2016–2020 in the US. Differences in clinical characteristics over time were assessed. To compare outcomes between 2016–2017 (when LT was less common) and 2018–2020 (when LT was more common), we conducted linear and logistic regression. Propensity-score matching was used to compare outcomes between patients with and without LT. ResultsFrom 2016–2017 to 2018–2020, patients admitted with AH tended to have a higher frequency of infection (p = 0.006), hepatorenal syndrome (<0.001), and ascites (<0.001). Hospital costs and length of stay (LOS) were highest in transplant hospitals, and costs rose over time in both non-transplant (NT) teaching and non-teaching hospitals (p < 0.001). Mortality decreased in NT teaching hospitals [aOR 0.7 (95% CI: 0.6–0.8)] and slightly decreased in NT non-teaching hospitals [aOR 0.7 (95% CI: 0.5–1.0)]. In the propensity-matched cohort involving LT versus non-LT patients, there was a 10% absolute reduction in-hospital mortality, but this came at a higher cost (p < 0.001) and length of stay (p < 0.001). ConclusionsThe severity of AH has been increasing over time, yet mortality has declined after adjusting for severity of disease. Patients who underwent LT survived; however, the healthcare burden of LT is substantial.

Mitochondrial respiratory chain activity is associated with severity, corticosteroid response and prognosis of alcoholic hepatitis.

Little is known about the extent of mitochondrial respiratory chain (MRC) activity dysfunction in patients with alcoholic hepatitis (AH). We aimed to assess the hepatic MRC activity in AH patients and its potential impact on the severity and prognosis of this life-threatening liver disease. MRC complexes were measured in liver biopsies of 98 AH patients (non-severe, 17; severe, 81) and in 12 histologically normal livers (NL). Severity was assessed according to Maddrey's Index and MELD score. Corticosteroid response rate and cumulative mortality were also evaluated. The activity of the five MRC complexes was markedly decreased in the liver of AH patients compared with that of NL subjects, being significantly lower in patients with severe AH than in those with non-severe AH. There was a negative correlation between the activity of all MRC complexes and the severity of AH. Interestingly, only complex I and III activities showed a significant positive correlation with the corticosteroid response rate and a significant negative correlation with the mortality rate at all-time points studied. In a multivariate regression analysis, besides the MELD score and the corticosteroid response rate, complex I activity was significantly associated with 3-month mortality (OR=6.03; p= 0.034) and complex III activity with 6-month mortality (OR=4.70; p= 0.041) in AH patients. Our results indicate that MRC activity is markedly decreased in the liver of AH patients, and, particularly, the impairment of MRC complexes I and III activity appears to have a significant impact on the clinical outcomes of patients with AH.

Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis.

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there is no efficacious treatment aiding most patients. AH manifests differently in individuals, with some patients showing debilitating symptoms more so than others. Previous studies showed significant metabolic dysregulation associated with AH. Therefore, we sought to analyze how the activity of metabolic pathways differed in the liver of patients with varying degrees of AH severity. We utilized a genome-scale metabolic modeling approach that allowed for integration of a generic human cellular metabolic model with specific RNA-seq data corresponding to healthy and multiple liver disease states to predict the metabolic fluxes within each disease state. Additionally, we performed a systems-level analysis of the transcriptomic data and predicted metabolic flux data to identify the regulatory and functional differences in liver metabolism with increasing severity of AH. Our results provide unique insights into the sequential dysregulation of the solute transport mechanisms underlying the glutathione metabolic pathway with increasing AH disease severity. We propose targeting of the solute transporters in the glutathione pathway to mimic the flux activity of the healthy liver state as a potential therapeutic intervention for AH.

Связь между полиморфизмом rs4073 гена интерлейкина-8, содержанием интерлейкина-8 и развитием алкогольного гепатита

To study the interrelations between the rs4073 polymorphism of the IL-8 gene, IL-8 serum levels and severity of alcoholic hepatitis (AH).

Obesity Is Associated With Higher odds of Hepatorenal syndrome in Patients Admitted With Alcoholic Hepatitis: Analysis of the National Inpatient Sample (2016–2017)

Introduction: Obesity is a significant independent risk factor for the development of liver disease. There is some available data suggesting worse outcomes of alcoholic hepatitis (AH) in obese patients however, national sample data supporting these findings are scarce. The aim of our study was to study the severity of AH in patients with concurrent obesity thus we analyzed data from the national inpatient sample. Methods: We queried the National Inpatient Sample (NIS) 2016 and 2017 database. The NIS was searched for hospitalization of adult patients with alcoholic hepatitis as a principal diagnosis with and without Obesity (BMI = 30 and above) as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality while the secondary outcomes were severe sepsis with shock, hospital length of stay (LOS), NSTEMI, hepatorenal syndrome (HRS) and bleeding esophageal varices (BEV) development. STATA software was used for analysis. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders. Results: There were over 71 million discharges in the combined 2016 and 2017 NIS database. Out of 32,584 adult AH hospitalizations, 3,720 (11.4%) had a concomitant diagnosis of obesity. There were no differences between mean age, sex and race in both groups of patients. Patients with AH and concurrent obesity had no significant difference in inpatient mortality (aOR= 0.74, P = 0.272, CI = 0.438 -1.261) however, they were found to have higher odds of developing HRS (aOR = 1.54, P= 0.020, CI= 1.069 -2.209) and lower odds of developing BEV(aOR 0.22, P= 0.008, CI= 0.070 -0.670). Patients with AH and concurrent obesity were also found to have similar odds of developing NSTEMI (aOR = 2.29, P= 0.180, CI= 0.680 - 7.762), severe sepsis with shock (aOR = 0.97%, P= 0.945, CI= 0.486 -1.954) and a 0.5 day mean increase in LOS (P =0.045, CI = 0.011 - 0.987) when compared to those without obesity. Conclusion: In conclusion, patients with obesity admitted with AH have higher odds of developing HRS, lower odds of developing BEV and no statistically significant difference in mortality, development of NSTEMI and severe sepsis with septic shock. It is important to identify these patients at higher risk and provide better surveillance to prevent the development of HRS.

Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis

Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. We found significant associations between AH risk and the risk alleles of rs738409 (p=0.0081) and HP (p=0.0371), but not rs72613567 (p=0.3132), rs58542926 (p=0.2180), or rs641738 (p=0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR=1.59 (95% CI: 1.15-2.22), p=0.0055] and HP*2 [OR=1.38 (95% CI: 1.04-1.82), p=0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p=0.0921). PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.

Gender-related disparities in the frequencies of PD-1 and PD-L1 positive peripheral blood T and B lymphocytes in patients with alcohol-related liver disease: a single center pilot study.

BackgroundExposure to excessive alcohol consumption dysregulates immune signaling. The programed cell death 1 (PD-1) receptor and its ligand PD-L1 play a critical role in the protection against immune-mediated tissue damage. The aim of our study was evaluation of the PD-1/PDL-1 expression on peripheral T and B lymphocytes, its correlation with markers of inflammation and the severity of liver dysfunction in the course of alcohol-related liver disease (ALD).Material and MethodsFifty-six inpatients with ALD (38 males, 18 females, aged 49.23 ± 10.66) were prospectively enrolled and assigned to subgroups based on their: (1) gender, (2) severity of liver dysfunction (Child-Pugh, MELD scores, mDF), (3) presence of ALD complications, and followed for 30 days. Twenty-five age- and gender-matched healthy volunteers served as the control group. Flow cytometric analysis of the PD-1/PD-L1 expression on peripheral lymphocyte subsets were performed.ResultsGeneral frequencies of PD-1/PD-L1 positive T and B subsets did not differ between the ALD and control group. When patients were analyzed based on their gender, significantly higher frequencies of PD1/PD-L1 positive B cells in ALD females compared to controls were observed. ALD females presented with significantly higher frequencies of PD-1+ and PD-L1+ B cells, as well as PD-L1+ all T cell subsets in comparison with ALD males. The same gender pattern of the PD-1/PDL1 expression was found in the subgroups with mDF > 32 and MELD > 20. No correlations of PD-1+ and PD-L1+ lymphocyte percentages with mDF, CTP and MELD scores, nor with complications of ALD were observed. Significant correlations of PD-L1 positive B cell frequencies with conventional markers of inflammation were found.ConclusionsGender-related differences in the frequencies of PD-1/PD-L1 positive T and B cells were observed in patients with ALD. Upregulation of PD-1+/PD-L1+ lymphocytes paralleled both the severity of alcoholic hepatitis and liver dysfunction in ALD females.

THU097 - The development and severity of alcoholic hepatitis is associated with decreased intestinal microbiome-derived secondary bile acid isoursodeoxycholic acid

THU097 - The development and severity of alcoholic hepatitis is associated with decreased intestinal microbiome-derived secondary bile acid isoursodeoxycholic acid

Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope.

Alcohol use disorder is associated with a wide array of hepatic pathologies ranging from steatosis to alcoholic-related cirrhosis (AC), alcoholic hepatitis (AH), or hepatocellular carcinoma (HCC). Biomarkers are categorized into two main categories: biomarkers associated with alcohol consumption and biomarkers of alcoholic liver disease (ALD). No ideal biomarker has been identified to quantify the degree of hepatocyte death or severity of AH, even though numerous biomarkers have been associated with AH. This review provides information of some of the novel and latest biomarkers that are being investigated and have shown a substantial association with the degree and severity of liver injury and inflammation. Importantly, they can be measured noninvasively. In this manuscript, we consolidate the present understanding and prospects of these biomarkers; and their application in assessing the severity and progression of the alcoholic liver disease (ALD). We also review current and upcoming management options for AH.

Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis.

Severe alcoholic hepatitis (SAH) has high mortality. Dysregulated lipid transport and metabolism in liver/macrophages contributes to disease pathophysiology. Paraoxonase/arylesterase 1 (PON1), a liver‐specific enzyme, inhibits oxidation of phospholipids and prevents lipid‐mediated oxidative damage. However, its functional contribution in macrophage‐mediated hepatic injury warrants elucidation. Plasma proteome of patients with SAH (n = 20), alcoholic cirrhosis (n = 20), and healthy controls was analyzed. Dysregulated pathways were identified, validated, and correlated with severity and outcomes in 200 patients with SAH. Tohoku‐Hospital‐Pediatrics‐1 (THP1)‐derived macrophages were treated with plasma from study groups in the presence/absence of recombinant PON1 and the phenotype; intracellular lipid bodies and linked functions were evaluated. In patients with SAH, 208 proteins were >1.5 fold differentially regulated (32 up‐regulated and 176 down‐regulated; P < 0.01).Validation studies confirmed lower levels of lipid transporter proteins (Pon1, apolipoprotein [Apo]B, ApoA1, ApoA2, and ApoC3; P < 0.01). Low PON1 levels inversely correlated with severity and mortality (r2 > 0.3; hazard ratio, 0.91; P < 0.01) and predicted nonsurvivors (area under the receiver operating characteristic curve, 0.86; cut‐off, <18 μg/mL; log rank, <0.01). Low PON1 levels corroborated with increased oxidized low‐density lipoprotein levels, intracellular lipid bodies, lipid uptake, lipid metabolism, biosynthesis, and alternative macrophage activation genes in nonsurvivors (P < 0.01). Importantly, in vitro recombinant PON1 treatment on THP1 macrophages reversed these changes (P < 0.01), specifically by alteration in expression of clusters of differentiation 36 (CD36) and adenosine triphosphate‐binding cassette subfamily A1 (ABCA1) receptor on macrophages. Conclusion: Lipid transport proteins contribute to the pathogenesis of SAH, and low PON1 levels inversely correlate with the severity of alcoholic hepatitis and 28‐day mortality. Restitution of circulating PON1 may be beneficial and needs therapeutic evaluation in patients with SAH.

The Impact of Previous Acute Decompensation on the Long-Term Prognosis of Alcoholic Hepatitis in Cirrhotic Patients.

Recurrent episodes of liver injury may either waste hepatic reserve or induce tolerance to further injury. We aimed to investigate whether the previous acute decompensation (AD) in liver cirrhosis (LC) affects the long-term transplant-free survival of patients with alcoholic hepatitis (AH). The survival data of 894 alcoholic LC cohort who had been admitted with acute deterioration in 21 academic hospitals in Korea were prospectively followed up. Enrolled patients were divided into three groups: Group 1, without AH; group 2, with nonsevere AH; and group 3, with severe AH. Although the baseline liver function was not different between the groups with or without previous AD, it was a significant predictor of poor long-term outcomes. The presence of previous AD negatively affected long-term overall survival (HR 1.62, 95% C.I. 1.20–2.18, p = 0.002) in groups 1 and 2 as a whole, independent of the Model for End-stage Liver Disease score. The three-month conditional survival was significantly worse in group 3 for up to 12 months in the presence of previous AD (p < 0.05). We concluded that not only the severity of AH, but also the prior AD is an important predictor of long-term outcomes in alcoholic LC patients with acute deterioration.

Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis.

Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7days to assess "response". To assess the prognostic and therapeutic implications of baseline neutrophil-to-lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis. Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the receiver operating curve (AUC) analysis was performed. Kaplan-Meier analysis was used to assess survival. Log-rank test and odds ratio (OR) were used for comparative analysis. Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90-day outcome (0.660), but was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety-day survival was not affected by prednisolone treatment if NLR < 5 or > 8 but mortality was reduced with prednisolone treatment when the NLR was 5-8 (21.0% cf. 34.5%; P=0.012). Prednisolone treatment increased the chance of Lille response if the NLR was ≥5 (56.5% cf. 41.1%: P=0.01; OR 1.86) but increased the risk of day 7 infection (17.3% cf. 7.4%: P=0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P=0.008; OR 3.46) if the NLR was>8. Incorporation of NLR into a modified Glasgow alcoholic hepatitis score (mGAHS) improved the AUC to 0.783 and 0.739 for 28-day and 90-day outcome, respectively. The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5-8). The mGAHS has a good predictive value for 28- and 90-day outcomes.

318 – Haptoglobin 2 Allele is Associated with Increased Risk and Severity of Alcoholic Hepatitis

318 – Haptoglobin 2 Allele is Associated with Increased Risk and Severity of Alcoholic Hepatitis

Metabolomics Discloses a New Non-invasive Method for the Diagnosis and Prognosis of Patients with Alcoholic Hepatitis

Introduction and aims. Alcoholic hepatitis is the most severe manifestation of alcoholic liver disease. Unfortunately, there are still some unresolved issues in the diagnosis and management of this disease, such as the need of histological diagnosis, an accurate prognostic stratification, and the development of novel targeted therapies. The present study aimed at addressing these issues by means of metabolomics, a novel high-throughput approach useful in other liver diseases.Material and methods. 64 patients with biopsy-proven alcoholic hepatitis were included and compared with 26 patients with decompensated alcoholic cirrhosis without superimposed alcoholic hepatitis, which was ruled out by liver biopsy.Results. The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000).Conclusions. Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies.

Sarcopenia Is Increased in Females and Associated With Severity of Alcoholic Hepatitis and Increased Hospital Stay

Sarcopenia Is Increased in Females and Associated With Severity of Alcoholic Hepatitis and Increased Hospital Stay

Relative Adrenal Insufficiency in Patients with Alcoholic Hepatitis

Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with high morbidity and mortality. Treatment with steroids is known to decrease short-term mortality in severe AH patients. Hence, we hypothesize that adrenal insufficiency can be associated with severe AH and affects prognosis. The aim of this study was (1) to evaluate relative adrenal insufficiency (RAI) in patients with AH and (2) to Compare RAI with the severity of AH. Newly diagnosed cases of AH hospitalized in SMS Medical College and Hospital, Department of Gastroenterology were, enrolled. All patients of AH were classified as mild and severe AH on the basis of Maddrey discriminant function (DF). After baseline serum cortisol, 25 IU ACTH (Adreno Corticotrophic Hormone) was injected intramuscularly and blood sample was collected after 1 h and assessed for serum cortisol. RAI was defined as <7 μg increase in the cortisol level from baseline. RAI was compared with severity of AH. Of 120 patients of AH, 58 patients fulfilled the inclusion criteria, in which 48 patients were diagnosed as severe AH and 10 patients were diagnosed as mild AH. In patients with severe AH, the baseline mean serum cortisol level was significantly high as compared with mild AH; 26 patients (54.16 %) of 48 patients with severe AH showed RAI (P≤0.001).Whereas in patients with mild AH, none of patients showed RAI. RAI also showed negative correlation with DF. There was no difference in RAI with respect to acute kidney injury (AKI). RAI is a common entity in patients with severe AH, and it is related with the severity of disease.

Metabolomics Discloses a New Non-invasive Method for the Diagnosis and Prognosis of Patients with Alcoholic Hepatitis

Introduction and Aims: Alcoholic hepatitis is the most severe manifestation of alcoholic liver disease. Unfortunately, there are still some unresolved issues in the diagnosis and management of this disease, such as the need of histological diagnosis, an accurate prognostic stratification, and the development of novel targeted therapies. The present study aimed at addressing these issues by means of metabolomics, a novel high-throughput approach useful in other liver diseases. Methods: 64 patients with biopsy-proven alcoholic hepatitis were included and compared with 26 patients with decompensated alcoholic cirrhosis without superimposed alcoholic hepatitis, which was ruled out by liver biopsy. Results: The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000). Conclusions: Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies.

SAT-455 - The bile acid biome and its relationship to the development and severity of alcoholic hepatitis

SAT-455 - The bile acid biome and its relationship to the development and severity of alcoholic hepatitis

Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients.

These results implicate pyroptosis induced by the CASP11/4-GSDMD pathway in the pathogenesis of AH. (Hepatology 2018;67:1737-1753).

Relative Adrenal Insufficiency in Alcoholic Hepatitis

Background and Aim: Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with high morbidity and mortality. The pathogenesis of alcoholic hepatitis is complex and involve oxidative stress, gut dysbiosis, and dysregulation of the innate and adaptive immune system similar to sepsis. It has been reported that adrenal insufficiency is common in sepsis. Further treatment with steroids decreases mortality in such patients. We hypothesize that adrenal insufficiency is associated with severe alcoholic hepatitis and affects prognosis. Methods: 50 patients of alcoholic hepatitis were included in study. As per ACTH stimulation protocol the criteria to diagnose relative adrenal insufficiency rise of serum cortisol less than 7 after 1 h of inj ACTH. After a baseline 8 AM cortisol sample, inj ACTH 25 IU was injected intramuscularly and blood sample was collected after 1 h for estimation of serum cortisol. Results: In our study it was observed that out of 50 patients of alcoholic hepatitis; 7 patients (14%) had DF < 32 and 43 patients (86%) had DF > 32. Patients with DF < 32 had baseline mean serum cortisol level 9.02 μm/dl and post ACTH mean serum cortisol level was 24.12 μm/dl. Patients with DF > 32 had baseline mean serum cortisol level of 18.9 μm/dl and post-ACTH mean serum cortisol levels was 22.6 μm/dl. None of the patients with DF < 32 had evidence of relative adrenal insufficiency while 24 patients (55.8%) out of 43 patients with DF > 32; had <7 rise in serum cortisol level suggestive of relative adrenal insufficiency. Conclusion: Relative adrenal insufficiency was observed in patients with alcoholic hepatitis and it correlated with severity of AH. The cause of relative adrenal insufficiency is still not known and it may be multifactorial in etiology and may have therapeutic and prognostic implications. The authors have none to declare.