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Background and Aims We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol‐associated hepatitis (AH) pathogenesis and their prognostic significance. Approach and Results Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR‐30b‐5p, miR‐20a‐5p, miR‐146a‐5p, and miR‐26b‐5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell‐cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 (RRM2), cyclin D1 (CCND1), cyclin D2 (CCND2), MYC proto‐oncogene (MYC), and phorbol‐12‐myristate‐13‐acetate‐induced protein 1 (PMAIP1). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR‐26b‐5p and miR‐30b‐5p inhibited the 3′‐UTR (untranslated region) luciferase activity of RRM2 and CCND2, and miR‐20a‐5p reduced the 3′‐UTR luciferase activity of CCND1 and CCND2. During a median follow‐up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End‐Stage Liver Disease (MELD), and serum miR‐30b‐5p, miR‐20a‐5p, miR‐146a‐5p, and miR‐26b‐5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR‐20a‐5p, miR‐146a‐5p, and miR‐26b‐5p predicted mortality. Conclusions Patients with AH attempt to deal with hepatocyte injury by down‐regulating specific miRNAs and up‐regulating genes responsible for DNA synthesis and cell‐cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short‐term mortality in AH patients.

Background and Aims Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. Approach and Results Inpatients with cirrhosis from 11 North American Consortium of End‐stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis‐free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor–adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3‐dihydroxy‐5‐methylthio‐4‐pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8‐methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor–adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched‐chain amino‐acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. Conclusions Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Background and Aims Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF‐Ag) and C‐reactive protein (CRP) are simple, broadly available markers of these processes. Approach and Results We determined whether addition of vWF‐Ag and CRP to the Model for End‐Stage Liver Disease‐Sodium (MELD‐Na) score improves risk stratification of patients awaiting LT. CRP and vWF‐Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD‐Na, and mortality on the waiting list were recorded. Prediction of 3‐month waiting list mortality was assessed by receiver operating characteristics curve (ROC‐AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF‐Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF‐Ag and CRP both improved the predictive value of MELD‐Na for 3‐month waitlist mortality and showed the highest predictive value when combined (AUC: MELD‐Na, 0.764; MELD‐Na + CRP, 0.790; MELD‐Na + vWF, 0.803; MELD‐Na + CRP + vWF‐Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD‐Na, 0.677; MELD‐Na + CRP + vWF‐Ag, 0.882). vWF‐Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. Conclusions The addition of vWF‐Ag and CRP—reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT—to the MELD‐Na score improves prediction of waitlist mortality. Using the vWFAg‐CRP‐MELD‐Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Abstract Context. —Impairment of venous outflow manifests as zone 3 sinusoidal dilatation and congestion (SDC) in liver biopsy. However, the finding of SDC is not specific for venous outflow impairment. Objectives. —To determine the specificity of SDC in liver biopsies for venous outflow impairment and to seek an explanation for SDC in patients without clinical or radiologic features of venous outflow impairment. Design. —Liver biopsies from 51 patients with sinusoidal dilatation were reviewed. Biopsies from transplant recipients, patients with cirrhosis, and patients with hepatic neoplasms (primary or metastatic) were not included. Clinical records were reviewed for laboratory tests and final clinicopathologic diagnosis. Results. —Thirty-four patients (66.7%) had confirmed venous outflow impairment. Of the 17 cases (33.3%) without clinical and/or radiologic evidence of venous outflow impairment, vascular causes were present in 5 cases (9.8%; nodular regenerative hyperplasia in 2 cases and portal vein thrombosis, congenital absence of the portal vein, and sickle cell anemia in 1 case each). Systemic inflammatory disorders were identified in 6 patients (11.8%). These included 2 cases of Castleman disease and 1 each of sarcoidosis, Crohn disease, rheumatoid arthritis, and Still disease. Three patients (5.9%) had tumors without direct involvement of the liver (1 case each of Hodgkin lymphoma, renal cell carcinoma, and pancreatic serous pseudopapillary tumor). In the remaining 3 patients, SDC was identified in wedge liver biopsies performed at the time of surgery, including gastric bypass surgery, cholecystectomy, and splenectomy. No other disease association was apparent in these cases. Conclusion. —Sinusoidal dilatation and congestion in liver biopsy is associated with venous outflow impairment in two thirds of the cases. In the absence of clinical and/or radiological evidence of venous outflow, diagnostic considerations include other vascular conditions, such as portal vein insufficiency and nodular regenerative hyperplasia. Sinusoidal dilatation and congestion can also occur in the setting of systemic inflammatory diseases, granulomatous disorders, and neoplasms, as well as in wedge biopsies obtained during abdominal surgery.