Alcohol-associated Cirrhosis Research Articles

Alcohol as a risk factor for mortality in liver transplant patients in Sweden

Objectives Liver transplantation (LT) is the only available cure for end-stage liver disease and one of the best treatment options for hepatocellular carcinomas (HCC). Patients with known alcohol-associated cirrhosis (AC) are routinely assessed for alcohol dependence or abuse before LT. Patients with other liver diseases than AC may consume alcohol both before and after LT. The aim of this study was to assess the effects of alcohol drinking before and after LT on patient and graft survival regardless of the etiology of liver disease. Materials and Methods Between April 2012 and December 2015, 200 LT-recipients were interviewed using the Lifetime Drinking History and the Addiction Severity Index questionnaire. Patients were categorized as having AC, n = 24, HCC and/or hepatitis C cirrhosis (HCV), n = 69 or other liver diseases, n = 107. Patients were monitored and interviewed by transplantation-independent staff for two years after LT with questions regarding their alcohol consumption. Patient and graft survival data were retrieved in October 2019. Results Patients with AC had an increased hazard ratio (HR) for death after LT (crude HR: 4.05, 95% CI: 1.07–15.33, p = 0.04) and for graft loss adjusted for age and gender (adjusted HR: 3.24, 95% CI 1.08–9.77, p = 0.04) compared to the other patients in the cohort. There was no significant effect of the volume of alcohol consumed before or after LT on graft loss or overall survival. Conclusion Patients transplanted for AC have a worse prognosis, but we found no correlation between alcohol consumed before or after LT and graft or patient survival.

Differentiating between liver diseases by applying multiclass machine learning approaches to transcriptomics of liver tissue or blood-based samples

Background & AimsLiver disease carries significant healthcare burden and frequently requires a combination of blood tests, imaging, and invasive liver biopsy to diagnose. Distinguishing between inflammatory liver diseases, which may have similar clinical presentations, is particularly challenging. In this study, we implemented a machine learning pipeline for the identification of diagnostic gene expression biomarkers across several alcohol-associated and non-alcohol-associated liver diseases, using either liver tissue or blood-based samples.MethodsWe collected peripheral blood mononuclear cells (PBMCs) and liver tissue samples from participants with alcohol-associated hepatitis (AH), alcohol-associated cirrhosis (AC), non-alcohol-associated fatty liver disease, chronic HCV infection, and healthy controls. We performed RNA sequencing (RNA-seq) on 137 PBMC samples and 67 liver tissue samples. Using gene expression data, we implemented a machine learning feature selection and classification pipeline to identify diagnostic biomarkers which distinguish between the liver disease groups. The liver tissue results were validated using a public independent RNA-seq dataset. The biomarkers were computationally validated for biological relevance using pathway analysis tools.ResultsUtilizing liver tissue RNA-seq data, we distinguished between AH, AC, and healthy conditions with overall accuracies of 90% in our dataset, and 82% in the independent dataset, with 33 genes. Distinguishing 4 liver conditions and healthy controls yielded 91% overall accuracy in our liver tissue dataset with 39 genes, and 75% overall accuracy in our PBMC dataset with 75 genes.ConclusionsOur machine learning pipeline was effective at identifying a small set of diagnostic gene biomarkers and classifying several liver diseases using RNA-seq data from liver tissue and PBMCs. The methodologies implemented and genes identified in this study may facilitate future efforts toward a liquid biopsy diagnostic for liver diseases.Lay summaryDistinguishing between inflammatory liver diseases without multiple tests can be challenging due to their clinically similar characteristics. To lay the groundwork for the development of a non-invasive blood-based diagnostic across a range of liver diseases, we compared samples from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, and non-alcohol-associated fatty liver disease. We used a machine learning computational approach to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to discover a small set of gene biomarkers for effective diagnosis of these liver diseases.

Cirrhotic Cardiomyopathy: The Interplay Between Liver and Heart.

Cardiac vascular dysfunction was described years ago in alcohol-associated liver cirrhosis and recently became known as cirrhotic cardiomyopathy (CCM) in 2005. Cirrhotic cardiomyopathy is a specific cardiac dysfunction estimated to be prevalent in half of the liver cirrhosis patient population; it comprises a triad of impaired myocardial contractile responses to stress (systolic dysfunction), inadequate ventricular relaxation, and electrophysiological abnormalities. This review describes the various pathophysiological mechanisms connecting liver cirrhosis to the alterations seen in CCM and briefly mentions the role of the cardiovascular system in connecting the pathophysiology of hepatorenal syndrome (HRS). Insertion of the transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation exacerbates the underlying cardiac dysfunction leading to signs and symptoms of heart failure. This article also focuses on the clinical importance of diagnosing CCM and the limitations existing around traditional diagnostic criteria based on transmitral flow parameters. It highlights newer parameters proposed by the Cirrhotic Cardiomyopathy Consortium to obtain a diagnosis of CCM. Liver transplantation is the only treatment available to cure CCM.

Heterogeneity in Center Practices in Liver Transplantation for Alcohol-Associated Liver Disease in the United States.

Alcohol-related liver disease (ALD) is now the leading indication for liver transplantation (LT) in the United States (US). It remains unclear how centers are managing the medical and psychosocial issues associated with these patients. We conducted a web-based survey of LT centers in the United States to identify center-level details on peri-LT management of ALD and related issues. Of the 117 adult LT centers, 100 responses (85.5%) were collected, representing all Organ Procurement and Transplantation Network regions. For alcohol-associated cirrhosis, 70.0% of the centers reported no minimum sobriety requirement while 21.0% required 6 months of sobriety. LT for severe alcohol-associated hepatitis was performed at 85.0% of the centers. Monitoring protocols for pre-LT and post-LT alcohol use varied among centers. Our findings highlight a change in center attitudes toward LT for ALD, particularly for severe alcohol-associated hepatitis.

Association of Previous Gastric Bypass Surgery and Patient Outcomes in Alcohol-Associated Cirrhosis Hospitalizations.

Roux-En-Y gastric bypass (RYGB) is associated with risk of alcohol use disorder. The impact of RYGB among patients with alcohol-associated liver disease (ALD) remains unknown. A retrospective cohort from National Inpatient Sample (01/2006-09/2015) database on 421,156 admissions with alcohol-associated cirrhosis (AC) was stratified for non-primary discharge diagnosis of previous RYGB. Admissions with RYGB (cases) were matched 1:3 to without RYGB (controls) based on propensity score on demographics, calendar year, socioeconomic status (insurance and zip code income quartile), obesity, diabetes, anxiety, and alcohol use disorder. Primary outcome was concomitant discharge diagnosis of alcoholic hepatitis (AH) or development of acute on chronic liver failure (ACLF). Of 10,168 admissions (mean age 49 yrs., 75% females, 79% whites), cases (N = 2542) vs. controls had higher prevalence of concomitant AH (18.8 vs. 17%, P = 0.032), hepatic encephalopathy (31 vs. 25%), infection (28 vs. 24%), and grade 3 ACLF (13 vs. 5%), P < 0.001. Conditional logistic regression models showed higher odds for AH, hepatic encephalopathy, and infection among cases. In-hospital mortality of 6.3% (43% in ACLF) was lower in cases, but similar in the sub-cohorts of AH (N = 1768) or ACLF (N = 768). Results were similar in a sensitivity analysis of matched cohort of 2016 hospitalizations (504 cases) with primary discharge diagnosis of AC. Among patients with AC, previous RYGB is associated with increased likelihood of concomitant AH, hepatic encephalopathy, and infection, but similar in-hospital mortality. Prospective studies are needed to validate, determine causality, and understand mechanisms of these findings among patients with alcohol-associated cirrhosis.

Identifying Alcohol Use Disorder in Patients With Cirrhosis Reduces 30-Days Readmission Rate.

Readmission is frequent among patients with cirrhosis and is a complex multifactorial process. To examine the association of alcohol use disorder (AUD) and risk of readmission in patients with alcohol-associated cirrhosis. National Readmission Dataset (2016-2017) was used to extract a retrospective cohort of 53,348 patients with primary or secondary discharge diagnosis code of alcohol-associated cirrhosis with their first admission (26,674 patients with vs. propensity matched 26,674 without a primary or secondary discharge diagnosis code of AUD). Readmission within 30-day was lower (43.9 vs. 48%, P< 0.001) among patients identified to have AUD at the time of discharge. In a conditional logistic regression model, a diagnosis of AUD was associated with 15% reduced odds of 30-day readmission, 0.85 (0.83-0.88). Furthermore, the reason for readmission among patients identified vs. not identified to have AUD was less likely to be liver disease complication. The findings remained similar in a matched cohort of patients where the AUD diagnosis at discharge was listed as one of the secondary diagnoses only. Although, our study findings suggest that identification of AUD at the time of discharge among patients hospitalized for alcohol-associated cirrhosis reduces the risk of 30-day readmission, unavailable information on patient counseling, referral for mental health specialist and treatment received for AUD limit the causality assessment. Future studies are needed overcoming the inherent limitations of the database to establish the role of identification and treatment of AUD in reducing readmission and liver decompensation in patients with alcohol-associated cirrhosis.

Alterations in hepatic albumin phosphorylation in patients with alcohol‐associated hepatitis and cirrhosis

BackgroundAlcohol‐associated liver disease (ALD) encompasses a range of disease states including alcohol‐associated hepatitis (AH) and cirrhosis (AC), two severe clinical manifestations with high mortality due to compromised liver function. One key function of the liver is to synthesize and secrete albumin (ALBU), which plays a critical role in maintaining overall homeostasis. Hypoalbuminemia is a common feature of AH and AC; however, the contributing mechanisms are not established. Recently, S82‐ALBU phosphorylation via FA20A/C was shown to be required for hepatocellular release of ALBU. In this study, we hypothesized that hypoalbuminemia in AH and AC may occur in part due to hepatocellular retention secondary to compromised ALBU phosphorylation.MethodsProteomic and phosphoproteomic analyses were conducted using LC/MS/MS on liver biopsy samples from AH patients (n=34), AC patients (n=10), and non‐ALD controls (n=10). Further, AH patients were stratified by MELD score (Model for End‐stage Liver Disease) as follows: AH1 (MELD 17‐20), AH2 (21‐25), AH3 (26‐29), and AH4 (30‐37). Significantly changed proteins were correlated with MELD and compared between non‐surviving and surviving AH patients. One‐way ANOVA was used for comparisons between three groups (parametric), unpaired Student’s t‐test was used for two groups (parametric), and Pearson’s correlation was used for regression analysis. A p&lt;0.05 was considered statistically significant.ResultsExpression of hepatic ALBU was elevated in AH and AC patients relative to non‐ALD controls and was positively associated with MELD in AH patients. Among AH severity groups, liver ALBU was further elevated from AH3 to AH4. We further observed that pS82‐ALBU, and its allosteric regulator FA20A (molecules involved in ALBU release), were reduced in AH and AC relative to non‐ALD controls. This would suggest that one mechanism of increased expression of hepatic ALBU may be due to inhibition of its release. These results for AH were confirmed in an independent cohort.ConclusionThis study demonstrated that hepatic ALBU levels are elevated in AH and AC, likely due to the loss of pS82 phosphorylation by FA20A/C, compromising hepatocellular ALBU release. Altered ALBU phosphorylation and subsequent release could be a key pathogenic mechanism of hypoalbuminemia in AH and AC. Further studies are warranted to test this hypothesis.

Hepatic Protein and Phosphoprotein Signatures of Alcohol-Associated Cirrhosis and Hepatitis

Alcohol-associated liver disease is a global health care burden, with alcohol-associated cirrhosis (AC) and alcohol-associated hepatitis (AH) being two clinical manifestations with poor prognosis. The limited efficacy of standard of care for AC and AH highlights a need for therapeutic targets and strategies. The current study aimed to address this need through the identification of hepatic proteome and phosphoproteome signatures of AC and AH. Proteomic and phosphoproteomic analyses were conducted on explant liver tissue (test cohort) and liver biopsies (validation cohort) from patients with AH. Changes in protein expression across AH severity and similarities and differences in AH and AC hepatic proteome were analyzed. Significant alterations in multiple proteins involved in various biological processes were observed in both AC and AH, including elevated expression of transcription factors involved in fibrogenesis (eg, Yes1-associated transcriptional regulator). Another finding was elevated levels of hepatic albumin (ALBU) concomitant with diminished ALBU phosphorylation, which may prevent ALBU release, leading to hypoalbuminemia. Furthermore, altered expression of proteins related to neutrophil function and chemotaxis, including elevated myeloperoxidase, cathelicidin antimicrobial peptide, complement C3, and complement C5 were observed in early AH, which declined at later stages. Finally, a loss in expression of mitochondria proteins, including enzymes responsible for the synthesis of cardiolipin was observed. The current study identified hepatic protein signatures of AC and AH as well as AH severity, which may facilitate the development of therapeutic strategies.

Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids.

Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD.

Stearic acid prevent alcohol-induced liver damage by regulating the gut microbiota

The pathological characteristics of alcohol-associated liver damage (ALD) mainly include liver lipid accumulation, which subsequently leads to alcohol-associated steatohepatitis, fibrosis and cirrhosis. Dietary factors such as alcohol and fat may contribute to the development of ALD. A chronic alcohol-fed mouse model was used to investigate the effect of fatty acids in Jinhua ham on ALD. The fatty acids in Jinhua ham could prevent the occurrence of ALD from chronic alcohol consumption. In addition, the fatty acids in Jinhua ham with liver protective activity were long-chain saturated fatty acids (LCSFAs), including palmitic acid and stearic acid. In contrast, long-chain polyunsaturated fatty acids aggravated the pathogenesis of ALD. Furthermore, the mechanism underlying the prevention of ALD by fatty acids in Jinhua ham was ascribed to increasing relative abundances of Akkermansia muciniphila and Lactobacillus in the gut, which were beneficial to regulating intestinal homeostasis, ameliorating intestinal barrier dysfunction and reducing alcohol-associated hepatitis and oxidative stress damage. This study demonstrated that dietary supplementation with saturated fatty acids could prevent or mitigate ALD by regulating the gut microbiota (GM) and improving the intestinal barrier, while provided a more affordable dietary intervention strategy for the prevention of ALD.

Relationship Between Etiology of Cirrhosis and Survival Among Patients Hospitalized in Intensive Care Units

ObjectiveTo determine short-term outcomes of patients with alcohol-associated cirrhosis (ALC) admitted to the intensive care unit (ICU) compared with other etiologies of liver disease. In addition, we investigate whether quick sequential organ failure assessment accurately predicts presence of sepsis and in-hospital mortality in critically ill patients with various etiologies of cirrhosis. MethodsA retrospective cohort of 1174 consecutive patients with cirrhosis admitted to the ICU between January of 2006 and December of 2015 was analyzed. Outcomes of interest included survival rates within the ICU, post-ICU in-hospital, or at 30 days post-ICU discharge. ResultsFive hundred seventy-eight patients were found to have ALC with 596 in the non-ALC group. There was no significant difference in ICU mortality rates in ALC versus non-ALC cohorts (10.2% vs 11.7%, P=.40). However, patients with ALC had significantly higher post-ICU in-hospital death (10.0% vs 6.5%, P=.04) as well as higher mortality at 30-day post-ICU discharge (18.7% vs 11.2%, P<.001). Sustained alcohol abstinence did not offer survival advantage over nonabstinence. The predictive power for quick sequential organ failure assessment for sepsis and in-hospital mortality for patients with cirrhosis was limited. ConclusionCritically ill patients with ALC have decreased survival after ICU discharge compared with patients with other etiologies of cirrhosis, independent of alcohol abstinence.

Modest alcohol intake and mortality in individuals with elevated alanine aminotransferase levels: a nationwide cohort study

BackgroundAlanine aminotransferase (ALT) levels are widely used to screen liver disease, and many asymptomatic individuals show elevated ALT levels. As elevated ALT level indicates liver injury, even a small amount of alcohol intake may be harmful in subjects with elevated ALT levels, but there is limited evidence of the effect of light to moderate amount of alcohol intake in this subgroup.MethodsA cohort of 367,612 men and women without established liver diseases (including chronic viral hepatitis, alcohol-associated liver disease, cirrhosis, liver transplantation, or rare forms of liver disease) who underwent at least 1 health screening exam between 2009 and 2015 were assessed for liver-related and all-cause mortality. Elevated ALT levels were defined as ≥ 34 U/L for men and 25 U/L for women.ResultsIn participants with normal ALT levels, the fully-adjusted hazard ratios (95% CI) for liver-related mortality comparing light and moderate drinkers to non-drinkers were 0.73 (0.51–1.05), and 1.06 (0.73–1.52), respectively. In participants with elevated ALT levels, the corresponding hazard ratios were 1.57 (1.08–2.28), and 2.09 (CI 1.46–2.99), respectively (p value for alcohol intake by ALT interaction < 0.01). For all-cause mortality, the fully-adjusted hazard ratios comparing light and moderate drinkers to non-drinkers in participants with normal ALT levels were 0.72 (0.66–0.77), and 0.89 (0.82–0.97), respectively. In participants with elevated ALT levels, the corresponding hazard ratios were 0.93 (0.81–1.08), and 1.31 (1.14–1.50), respectively (p value for alcohol intake by ALT interaction < 0.01).ConclusionsSmall amounts of alcohol intake were associated with increased liver-related and all-cause mortality among individuals with elevated ALT levels. Subjects with elevated ALT levels should be advised complete abstinence from alcohol.

Soluble CD137 is a novel serum marker of liver cirrhosis in patients with hepatitis C and alcohol‐associated disease etiology

Defective T-cell functions play a role in the persistence of HCV infection. Activated T cells express CD137, which costimulates antivirus T-cell responses, and this activity is antagonized by soluble CD137 (sCD137). Here, we show that in sera of 81 patients with chronic HCV, sCD137 levels did not correlate with measures of viral infection, and did not decline after virus eradication using direct-acting antivirals. Thus, serum sCD137 was similar in patients infected with HCV and in uninfected controls. Of note, in HCV patients with liver cirrhosis and patients with mostly alcohol-associated liver cirrhosis, sCD137 was increased. A negative association of sCD137 and albumin existed in both cohorts. sCD137 concentrations were similar in hepatic and portal vein blood excluding the liver as the origin of higher levels. Recombinant sCD137 reduced Th1 and Th2 but not Th17 cell polarization in vitro, and accordingly lowered IFN-γ, TNF, and IL-13 in cell media. Serum sCD137 is associated with inflammatory states, and positively correlated with serum TNF in cirrhotic HCV patients following virus eradication. Our study argues against a role of sCD137 in HCV infection and suggests a function of sCD137 in liver cirrhosis, which yet has to be defined.

P-30 IMPACT OF PUBLIC HEALTH POLICIES ON ALCOHOL-ASSOCIATED LIVER DISEASE IN LATIN AMERICA: AN ECOLOGICAL MULTI-NATIONAL STUDY

Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality in Latin-America, yet the impact of public health policies (PHP) on alcohol consumption and liver disease is unknown. To assess the association between alcohol PHP, alcohol consumption, and cirrhosis in Latin-American countries. We performed an ecological multi-national study including 20 countries in Latin-America (628,466,088 inhabitants). We obtained country-level socio-demographic information from the World Bank Open Data source. Alcohol-related PHP data for countries in Latin-America were obtained from the World Health Organization (WHO) Global Information System of Alcohol and Health (GISAH). We used a fixed-effects model to estimate proportions and multiple linear regression models to examine the association between the number of PHP and outcomes (alcohol intake, and deaths due to cirrhosis & traffic injuries). The prevalence of obesity was 27% and 26.1% among males and females, respectively. The estimated alcohol per capita consumption (APC) among the population 15 years old was 6.8 liters of pure alcohol (5.6 recorded and 1.2 unrecorded). The countries with the highest APC were Uruguay (10.8 liters), Argentina (9.8 liters), and Chile (9.3 liters). The overall prevalence of alcohol use disorders (AUD) was 4.9%. ALD was the main cause of cirrhosis in 64.7% of males and 40.0% of females. A total of 19 (95%) countries have at least one alcohol-related PHP on alcohol. The most frequent PHP were: limiting drinking age (95%), tax control (90%), alcohol and driving (90%), and government monitoring systems (90%)(Table). A higher number of alcohol-related PHP was associated with a lower odds of AUD (OR 0.83, 95%CI:0.73-0.94; p=0.004), lower mortality due to ALD (OR 0.18, 95%CI:0.07-0.46, p<0.001), and lower mortality due to alcohol-attributable road traffic injuries (OR 0.84, 95%CI:0.71-0.98; p=0.028). Our study demonstrates that countries with more alcohol-related PHP have lower alcohol per capita consumption, alcohol-associated cirrhosis, and deadly alcohol-attributable road traffic injuries. These results highlight the value of alcohol control policies in all countries to reduce the burden of excessive alcohol consumption.

Test-Retest Reliability and Consistency of HVPG and Impact on Trial Design: A Study in 289 Patients from 20 Randomized Controlled Trials.

Portal hypertension (PH) is a major driver for cirrhosis complications. Portal pressure is estimated in practice by the HVPG. The assessment of HVPG changes has been used for drug development in PH. This study aimed at quantifying the test-retest reliability and consistency of HVPG in the specific context of randomized controlled trials (RCTs) for the treatment of PH in cirrhosis and its impact on power calculations for trial design. We conducted a search of published RCTs in patients with cirrhosis reporting individual patient-level data of HVPG at baseline and after an intervention, which included a placebo or an untreated control arm. Baseline and follow-up HVPGs in the control groups were extracted after digitizing the plots. We assessed reliability and consistency and the potential impact of study characteristics. We retrieved a total of 289 before and after HVPG measurements in the placebo/untreated groups from 20 RCTs. The time span between the two HVPG measurements ranged between 20minutes and 730days. Pre-/post-HVPG variability was lower in studies including only compensated patients; therefore, modeled sample size calculations for trials in compensated cirrhosis were lower than for decompensated cirrhosis. A higher proportion of alcohol-associated cirrhosis and unicentric trials was associated with lower differences between baseline and follow-up measurements. The smallest detectable difference in an individual was 26% and 30% in compensated and decompensated patients, respectively. The test-retest reliability of HVPG is overall excellent. Within-individual variance was higher in studies including higher proportions of decompensated patients. These findings should be taken into account when performing power analysis for trials based on the effects on HVPG or when considering HVPG as a tool to guide therapy of PH.

Clinical Course and Risk Factors for Infection in Severe Forms of Alcohol-Associated Liver Disease.

Infection is a major driver of mortality in patients with advanced alcohol-associated liver disease (ALD). The epidemiology and clinical course of patients infected with life-threatening forms of ALD, including severe alcohol-associated hepatitis (sAH) and decompensated alcohol-associated cirrhosis (DAC), and specific risk factors for infection remain mostly unknown. In this observational study, we assessed all infectious episodes occurring within a 90-day period from diagnosis in all consecutive patients with biopsy-proven sAH (modified Maddrey's discriminant function ≥ 32, Model for End-Stage Liver Disease [MELD] ≥ 18) and DAC (MELD ≥ 18) without alcohol-associated hepatitis in our tertiary hospital between 2003 and 2016. A total of 207 patients were included: 139 with sAH and 68 with DAC. One hundred seventeen (84%) patients with sAH and 41 (60%) patients with DAC experienced at least one infection episode at 90days (P<0.001). In multivariable analysis, factors associated with the development of infection were the presence of sAH and baseline MELD score. Bacterial infections represented the most common infection in the two groups, and only the MELD score was independently associated with the occurrence of bacterial infection. In both groups, pneumonia was the most prevalent bacterial infection, and gram-negative bacilli were the main pathogens. Invasive fungal infections (IFI) occurred in 20 (14.5%) patients with sAH and 3 (4.5%) with patients with DAC (P<0.05). Multivariable regression showed that younger age, higher MELD, and corticosteroid therapy were independently associated with IFI. The 90-day cumulative incidence of death in patients infected with sAH and patients infected with DAC was 46% and 41.5%, respectively (P=0.43). Patients with sAH are more susceptible to develop infection than those with DAC. In life-threatening forms of ALD, patients who were infected share a similar mortality rate. Corticosteroid treatment, not sAH, seems to be the main risk factor triggering IFI.

Combination of Model for End-Stage Liver Disease and Lactate Predicts Death in Patients Treated With Salvage Transjugular Intrahepatic Portosystemic Shunt for Refractory Variceal Bleeding.

Data about the prognosis of salvage transjugular intrahepatic portosystemic shunt (TIPS) using covered stents for refractory variceal bleeding caused by portal hypertension are scarce. We aimed to assess survival and to identify predictors of mortality in these patients. One hundred sixty-four patients with cirrhosis from five centers treated with salvage TIPS between 2007 and 2017 were retrospectively divided into a derivation cohort (83 patients) and a validation cohort (81 patients). Comparisons were performed using the Mann-Whitney and Fischer's exact test. Six-week overall survival (OS) was correlated with variables on the day of the TIPS using Kaplan-Meier curves with log-rank test and univariate/multivariate analyses using the Cox model. Eighty-three patients were included in the derivation cohort (male, 78%; age, 55years, alcohol-associated cirrhosis, 88%; Model for End-Stage Liver Disease [MELD], 19 [15-27]; arterial lactate, 3.7mmol/L [2.0-8.3]). Six-week OS rate was 58%. At multivariate analysis, the MELD score (OR, 1.064; 95% CI, 1.005-1.126; P=0.028) and arterial lactate (OR, 1.063; 95% CI, 1.013-1.114; P=0.032) were associated with 6-week OS. Six-week OS rates were 100% in patients with arterial lactate ≤2.5mmol/L and MELD score≤15 and 5% in patients with lactate ≥12mmol/L and/or MELD score≥30. The 81 patients of the validation cohort had similar MELD and arterial lactate level but lower creatinine level (94vs 106µmol/L, P=0.008); 6-week OS was 67%. Six-week OS rates were 86% in patients with arterial lactate ≤2.5mmol/L and MELD score≤15 and 10% for patients with lactate ≥12mmol/L and/or MELD score≥30. In the overall cohort, rebleeding rate was 15.8% at 6weeks, and the acute-on-chronic liver failure grade (OR, 1.699; 95% CI, 1.056-1.663; P=0.040) was independently associated with rebleeding. After salvage TIPS, 6-week mortality remains high and can be predicted by MELD score and lactate. Survival rate at 6weeks was >85% in patients with arterial lactate ≤2.5mmol/L and MELD score≤15, while mortality was >90% for lactate ≥12mmol/L and/or MELD score≥30.

A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis.

Bacterial translocation drives liver disease progression. We investigated whether functional genetic variants in toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, affect the risk for hepatocellular carcinoma (HCC). Healthy controls (n=212), patients with alcohol abuse without liver disease (n=382), and patients from a discovery cohort of alcohol-associated cirrhosis (n=372 including 79 HCC cases), a validation cohort of alcohol-associated cirrhosis (n=355 including 132 HCC cases), and a cohort of cirrhosis due to nonalcoholic steatohepatitis (NASH) (n=145 including 62 HCC cases) were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients' sera and supernatants of flagellin-stimulated healthy monocytes. Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33%), controls with alcohol abuse (34%), and patients with alcohol-associated cirrhosis in the discovery (28%), validation (33%), and NASH cohort (31%). The TT genotype was enriched in patients with versus without HCC in the discovery, validation, and NASH cohort (41% vs 25%; 39% vs 29%; 40% vs 24%; p<.05 each). This genotype remained a risk factor for HCC (OR=1.9; p=.01) after multivariate correction for age, gender, diabetes, and carriage of the PNPLA3 148M variant. Interleukin-8 induction in monocytes from healthy controls and serum levels of interleukin-8 and CXCL1 from cirrhotic patients with the TT genotype were significantly increased versus C allele carriers. The TLR5 rs5744174 polymorphism, affecting immune response to flagellin, is linked to occurrence of HCC in cirrhosis caused by steatohepatitis.

Liver Stiffness by Transient Elastography to Detect Porto‐Sinusoidal Vascular Liver Disease With Portal Hypertension

Porto-sinusoidal vascular liver disease (PSVD) is a rare cause of portal hypertension. PSVD is still often misdiagnosed as cirrhosis, emphasizing the need to improve PSVD diagnosis strategies. Data on liver stiffness measurement using transient elastography (TE-LSM) in PSVD are limited. The aim of this study was to evaluate the accuracy of TE-LSM to discriminate PSVD from cirrhosis in patients with signs of portal hypertension. Retrospective multicenter study comparing TE-LSM in patients with PSVD, according to Vascular Liver Disease Interest Group criteria, with patients with compensated biopsy-proven cirrhosis associated with alcohol (n=117), HCV infection (n=110), or NAFLD (n=46). All patients had at least one sign of portal hypertension among gastroesophageal varices, splenomegaly, portosystemic collaterals, history of ascites, or platelet count < 150 × 109 /L. The 77 patients with PSVD included in the test cohort had lower median TE-LSM (7.9 kPa) than the patients with alcohol-associated, HCV-related, and NAFLD-related cirrhosis (33.8, 18.2, and 33.6kPa, respectively; P<0.001). When compared with cirrhosis, a cutoff value of 10kPa had a specificity of 97% for the diagnosis of PSVD with a 85% positive predictive value. A cutoff value of 20kPa had a sensitivity of 94% for ruling out PSVD with a 97% negative predictive value. Of the patients, 94% were well-classified. Even better results were obtained in a validation cohort including 78 patients with PSVD. This study including a total of 155 patients with PSVD and 273 patients with cirrhosis demonstrates that TE-LSM<10kPa strongly suggests PSVD in patients with signs of portal hypertension. Conversely, when TE-LSM is >20kPa, PSVD is highly unlikely.

Diagnosis and Treatment of Alcohol-Associated Liver Disease: A Patient-Friendly Summary of the 2019 AASLD Guidelines.

Diagnosis and Treatment of Alcohol-Associated Liver Disease: A Patient-Friendly Summary of the 2019 AASLD Guidelines.