A consistent feature of chronic liver diseases and the hallmark of pathologic repair is the so-called ductular reaction. This is a histological abnormality characterized by an expansion of dysmorphic cholangiocytes inside and around portal spaces infiltrated by inflammatory, mesenchymal, and vascular cells. The ductular reaction is a highly regulated response based on the reactivation of morphogenetic signaling mechanisms and a complex crosstalk among a multitude of cell types. The nature and mechanism of these exchanges determine the difference between healthy regenerative liver repair and pathological repair. An orchestrated signaling among cell types directs mesenchymal cells to deposit a specific extracellular matrix with distinct physical and biochemical properties defined as portal fibrosis. Progression of fibrosis leads to vast architectural and vascular changes known as liver cirrhosis. The signals regulating the ecology of this microenvironment are just beginning to be addressed. Contrary to the tumor microenvironment, immune modulation inside this \"benign\" microenvironment is scarcely known. One of the reasons is that both the ductular reaction and portal fibrosis have been primarily considered a manifestation of cholestatic liver disease, whereas this phenomenon is also present, albeit with distinctive features, in all chronic human liver diseases. Novel human-derived cellular models and progress in \"omics\" technologies are increasing our knowledge at a fast pace. Most importantly, this knowledge is on the edge of generating new diagnostic and therapeutic advances. Here, we will critically review the latest advances, in terms of mechanisms, pathophysiology, and treatment prospects. In addition, we will delineate future avenues of research including innovative translational opportunities.

Alcohol-associated liver disease is highly prevalent worldwide, with alcohol-associated hepatitis as a severe form characterized by substantial morbidity, mortality, and economic burden. Gut bacterial dysbiosis has been linked to progression of alcohol-associated hepatitis. Fecal cytolysin secreted by the pathobiont Enterococcus faecalis (E. faecalis) is associated with increased mortality in patients with alcohol-associated hepatitis. Although gelatinase is considered a virulence factor in E. faecalis, its prevalence and impact on alcohol-associated hepatitis patient outcomes remains unclear. In this study, 20 out of 65 (30.8%) patients with alcohol-associated hepatitis tested positive for gelatinase in their stool. There were no significant differences in 30-day and 90-day mortality between gelatinase-positive and gelatinase-negative patients (p=0.97 and p=0.48, respectively). Fecal gelatinase had a low discriminative ability for 30-day mortality (area under the curve [AUC] 0.50 vs fibrosis-4 Index (FIB-4) 0.75) and 90-day mortality compared with other established liver disease markers (AUC 0.57 vs FIB-4 0.79 or \'age, serum bilirubin, INR, and serum creatinine\' (ABIC) score 0.78). Furthermore, fecal gelatinase was not an important feature for 30-day or 90-day mortality per random forest analysis. Finally, gelatinase-positive patients with alcohol-associated hepatitis did not exhibit more severe liver disease compared with gelatinase-negative patients. In conclusion, fecal gelatinase does not predict mortality or disease severity in patients with alcohol-associated hepatitis from our cohort.

UNASSIGNED: Thrombocytopenia is present in up to 76% of patients with chronic liver disease, and lower platelet counts (PCs) are associated with greater severity of portal hypertension. In this study, we assess the relationship of PC in patients with a clinical diagnosis of severe alcoholic hepatitis (SAH) with clinical severity and response to corticosteroid (CS) therapy.
UNASSIGNED: Clinical characteristics, treatment, and hospital outcomes for patients admitted with SAH were analyzed from an electronic health record system. Patients were categorized based on admission PC (k/uL) into 5 categories: <50, 50-99, 100-149, 150-199, and ≥200. Frequency of complications (acute kidney injury, ascites, and hepatic encephalopathy), length of stay, and admission to an intensive care unit were analyzed across PC categories. Characteristics of patients who did and did not receive at least 4 days of CS therapy were compared.
UNASSIGNED: Among 159 patients, 15 (9.4%) were in the PC < 50 category, 42 (26.4%) in PC 50-99, 51 (32%) in PC 100-149, 23 (14.5%) in PC 150-199, and 28 (17.6%) in PC ≥ 200. A higher admission PC was associated with greater white blood cell count, absolute neutrophil count, and total bilirubin (P < .05). Patients with higher PC on admission were more likely to receive steroids. PC was inversely associated with Lille score at treatment day 4 (P < .05).
UNASSIGNED: A higher PC in SAH was associated with a greater inflammatory response and total bilirubin. Patients with a higher PC were more likely to receive CS and have a favorable treatment response.

OBJECTIVE: The aim of the present study is to elucidate the mechanism of CYP2E1 induction as a causative factor of alcoholic hepatitis (AH) and its relationship with inflammation.
BACKGROUND: Chronic alcohol consumption induces CYP2E1, which is involved in the development of alcoholic hepatitis (AH). However, the mechanisms underlying the induction of CYP2E1 by alcohol remain unclear. Therefore, we herein investigated the induction of drug-metabolizing enzymes, particularly CYP2E1, by hydrogen peroxide (H2O2), the concentration of which is elevated under inflammatory conditions.
OBJECTIVE: The mechanisms underlying the induction of CYP2E1 by H2O2 were examined with a focus on Keap1, a target factor of H2O2.
METHODS: We assessed changes in the expression of drug-metabolizing enzymes in the human hepatoma cell line, Hep3B, following treatment with H2O2, and evaluated changes in the expression of the NFkB-related factor RelA(p65) after the knockdown of Keap1, a regulator of Nrf2 expression by reactive oxygen species. We also performed a promoter analysis using the upstream region of the CYP2E1 gene. We herein used the GSE89632 series for non-alcoholic hepatitis (NASH) and the GSE28619 series for AH.
RESULTS: The induction of CYP2E1 by H2O2 was significantly stronger than that of other drugmetabolizing enzymes. On the other hand, the knockdown of Keap1, a target of H2O2, markedly increased RelA(p65), an NFkB factor. Furthermore, the overexpression of RelA(p65) strongly induced the expression of CYP2E1. Four candidate p65-binding sequences were identified upstream of the CYP2E1 gene, and promoter activity assays showed that the third sequence was responsive to the overexpression of RelA(p65). We used the GSE89632 series for NASH and the GSE28619 series for AH in the present study. The expression of CYP2E1 mRNA in the liver was significantly lower in AH patients than in HC patients, but was similar in HC patients and NASH patients.
CONCLUSIONS: We herein demonstrated that the expression of CYP2E1 was induced by H2O2. The overexpression of RelA(p65) also induced CYP2E1 mRNA expression, whereas H2O2 did not after the knockdown of RelA. These results suggest that H2O2 acts on Keap1 to upregulate RelA (p65) in the NFkB system. One of the mechanisms underlying the induction of CYP2E1 was dependent on the H2O2-Keap1-RelA axis. The results of the database analysis revealed that the expression of CYP2E1 in the liver was significantly lower in AHH patients than in NASH patients, suggesting that CYP2E1 is not the main cause of AH; however, CYP2E1 may exacerbate the pathogenesis of AH.

UNASSIGNED: Alcoholic hepatitis (AH) represents a severe manifestation of alcoholic liver disease (ALD) associated with a wide severity spectrum. ALD is linked to nutritional deficiencies, with the gravity of malnutrition escalating as alcohol abuse and ALD progress. This study aims to delve into the impact of malnutrition on the clinical trajectory of AH.
UNASSIGNED: We identified adult patients admitted with AH using the National Readmission Database (NRD) 2016-2020. We further classified AH patients based on the severity of malnutrition. We compared the outcomes of AH hospitalizations using a multivariate regression model.
UNASSIGNED: We included 82,367 AH patients, of whom 15,693 (19.00%) had malnutrition. 4,243 (5.15%) patients exhibited mild to moderate malnutrition, 5,862 (7.07%) patients had severe malnutrition, and 5,588 (6.78%) patients had unspecified severity of malnutrition. We found that adjusted in-hospital mortality due to AH was higher in patients with malnutrition, corresponding to the severity of malnutrition (adjusted odds ratio [aOR] 1.62 and 3.14 in mild-moderate malnutrition and severe malnutrition, respectively; p < .01). Additionally, patients with malnutrition had progressively elevated odds of septic shock, vasopressor requirement, mechanical ventilation, and intensive care unit (ICU) admission with escalating intensity of malnutrition. Liver-related complications, such as spontaneous bacterial peritonitis, coagulopathy, hepatorenal syndrome, and hepatic encephalopathy, were also found to have an increased likelihood in the presence of malnutrition. Furthermore, resource utilization showed a progressive increase with increasing severity of malnutrition.
UNASSIGNED: Our findings indicate that malnutrition is a common comorbidity in AH patients, with varying degrees of severity, which correlates with higher mortality rates, emphasizing the critical role of nutritional status in the prognosis of AH. These findings underscore the importance of addressing and managing malnutrition in patients with AH, not only for its potential contribution to mortality but also because of its association with a spectrum of complications and increased healthcare resource utilization.

An unusual anatomical variation known as \"beaver tail liver\" occurs when the liver\'s left lobe spreads laterally until it touches the spleen. It is also known as a sliver liver, saber-shaped liver, or flax-like liver. We are talking about a 34-year-old man, a chronic alcoholic in this case, who had complaints of upper abdominal pain, persistent vomiting, and abdominal palpation elicited tenderness in the upper abdomen. Also, he had hepatosplenomegaly. On further investigation, he was diagnosed with alcoholic hepatitis, and on computed tomography, there was enlargement of the left lobe of the liver, which was beaver tail liver. This case report aimed to present a detailed account of a patient presenting with upper abdominal pain and clinical suspicion of acute pancreatitis. On imaging, there was a beaver tail liver. This unusual morphology can be an incidental finding during imaging studies or surgical procedures, often posing diagnostic challenges and considerations for clinicians.

BACKGROUND: Low-volume plasma exchange (PLEX) and low-dose steroid improve survival in severe alcoholic hepatitis. We aimed to compare one-year survival of very severe alcoholic hepatitis (VSAH) patients treated with centrifugal PLEX (cPLEX), membrane PLEX (mPLEX) or standard medical treatment (SMT).
METHODS: We retrospectively analyzed survival in consecutive VSAH patients treated at our department from November 2017 to September 2021. PLEX patients received low-volume PLEX along with low-dose steroid (tab. prednisolone 10 mg or 20 mg daily). To adjust for baseline differences between the three treatment (cPLEX, mPLEX or SMT) groups, propensity score (PS) matching was done. Acute-on-chronic liver failure (ACLF) was defined as per European Association for the Study of the Liver (EASL). The primary study outcome was one-year transplant-free survival of PS-matched VSAH patients treated with cPLEX compared to SMT.
RESULTS: Of 101 PLEX-eligible VSAH patients, 30 patients were treated with cPLEX, 21 with mPLEX and 50 with SMT. On comparing 30 PS-matched patients each in the cPLEX group vs. the SMT group, transplant-free survival in the cPLEX group was 86.7% at one month, 70% at three months and 52.4% at one year and in the SMT group was 33.3% at one month, 23.3% at three months and 16.7% at one year with hazard ratio (HR [95% CI]) in favor of the cPLEX group (0.29 [0.15-0.56], p < 0.001). Total 21 patients each (PS-matched) in cPLEX and mPLEX groups were compared and one-year survival was better with cPLEX (0.33 [0.16-0.69], p = 0.001). The sub-group analysis of VSAH (PS-matched cohort) patients with ACLF also showed better survival with cPLEX compared to SMT (0.38 [0.17-0.83], p = 0.003) and compared to mPLEX (0.43 [0.17-0.95], p = 0.03).
CONCLUSIONS: Better one-year transplant-free survival was noted among PS-matched VSAH patients treated with cPLEX (and low-dose steroid) compared to SMT (without steroid).

BACKGROUND: Alcoholic hepatitis (AH) is a serious complication of alcohol consumption with high morbidity and mortality, particularly in the United States where alcohol-related liver diseases rank as one of the leading causes of preventable death. Our study aims to analyze the morbidity and mortality of AH across racial groups and project hospitalization trends up to 2028, thereby informing public health initiatives.
METHODS: We conducted a cross-sectional study utilizing data from the Nationwide Inpatient Sample (NIS) spanning 2012 to 2021. The study population comprised hospitalizations identified using specific ICD-9-CM and ICD-10-CM codes for AH. We assessed hospitalizations, in-hospital mortality rates, length of stay (LOS), and morbidities related to alcoholic hepatitis adjusting for sociodemographic factors and hospital characteristics. Statistical analyses were performed using Stata and R software, employing logistic and linear regression analyses, and SARIMA models for forecasting.
RESULTS: Our results indicated a predominantly White cohort (68%), with a notable increase in AH hospitalizations among Hispanics (129.1% from 2012 to 2021). Racial disparities were observed in inpatient mortality, liver transplant accessibility, and the occurrence of in-hospital complications. The study forecasts a continued rise in hospitalizations across all racial groups, with Hispanics experiencing the sharpest increase.
CONCLUSIONS: Our study reveals a disproportionate rise in the AH burden among Hispanics with projections indicating a persistent upward trend through 2028. These findings highlight the need for targeted public health strategies and improved healthcare access to mitigate the increasing AH burden and address disparities in care and outcomes.

This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5-7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory-Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient\'s hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis.

Acute hepatitis can result from a wide variety of noninfectious causes that include, but are not limited to, drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis, primary biliary cholangitis), or as a result of indirect insult secondary to biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock, or metastatic disease. In clinical settings, these causes are not uncommon to overlap with each other or are masked by obviously visible causes in medical history. We reported our scenario of a patient who has a heavy history of alcohol use and presented with alcohol withdrawal symptoms and a marked elevation of liver enzymes. Interestingly, further investigations suggested Wilson\'s disease could be an underlying culprit of acute hepatitis in this patient. This case again emphasized that Wilson\'s disease can be masked under multiple causes and various scenarios, which alerts clinicians that a broad approach should be made for every case of acute hepatitis.