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Alcohol-related liver disease (ALD) encompasses a spectrum of diseases caused by excessive alcohol consumption. ALD includes hepatic steatosis, steatohepatitis, variable degrees of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH), the latter being the most severe acute form of the disease. Severe AH is associated with high mortality (reaching up to 30%–50%) at 90 days. The cornerstone of ALD, and particularly AH, treatment continues to be abstinence, accompanied by support measures such as nutritional supplementation and management of alcohol withdrawal syndrome (AWS). In severe AH with model for end-stage liver disease (MELD) score ≥21, corticosteroids can be used, especially MELD score between 25 and 39, where the highest benefit is achieved. Other key aspects of treatment include the early identification of infections and their associated management and the proper identification of potential candidates for liver transplantation. The development of new therapies based on the pathophysiology and mechanisms of liver injury are underway. This includes the modulation and management of the innate immune response, gut dysbiosis, bacterial translocation, and bacteria-derived products from the intestine. These hold promise for the future of AH treatment.

In hepatorenal syndrome-acute kidney injury (HRS-AKI), accurate and early diagnosis is crucial. HRS is a severe condition seen in advanced cirrhosis, requiring prompt recognition and proper management to enhance patient outcomes. Diagnosis of HRS-AKI relies on serum creatinine elevations, similar to other AKI cases in cirrhosis. However, distinguishing HRS-AKI from other renal impairments in these patients can be challenging. Biomarkers and clinical criteria aid in diagnosis and guide treatment. The management of HRS-AKI initially involves improving the haemodynamic profile using albumin and vasoconstrictors like terlipressin, a synthetic vasopressin analogue. Despite some reports linking terlipressin to increased adverse events compared with norepinephrine, it remains the preferred choice in HRS-AKI and acute-on-chronic liver failure due to its faster, stronger response and improved survival. Additional therapies like midodrine (alpha-1 adrenergic agonist), octreotide (somatostatin analogue) and transjugular intrahepatic portosystemic shunt are proposed as adjuvant treatments for HRS-AKI, aiming to improve vasoconstriction and renal blood flow. However, these adjunctive therapies cannot replace the definitive treatment for HRS-AKI—liver transplantation (LT). In cases unresponsive to medical management, LT is the only option to restore liver function and improve renal outcomes. Current evidence favours combined liver and kidney transplantation (CLKT) in certain situations. This review aims to evaluate the present evidence and recommendations on AKI in patients with cirrhosis, the pathophysiology of HRS-AKI, different treatments and indications for LT and CLKT. Understanding the complexities of managing HRS-AKI is crucial for optimising patient care and achieving better outcomes in this challenging clinical setting.

Introduction and Objectives: Acute-on-chronic liver failure (ACLF) is associated with reduced short-term survival, and liver transplantation is frequently the only therapeutic option. Nonetheless, the post-transplantation prognosis seems to be worse in ACLF patients. Materials and Methods: The databases of two university centers were retrospectively evaluated, and adult patients with cirrhosis who underwent transplantation between 2013 and 2020 were included. One-year survival of patients with ACLF was compared to that of patients without ACLF. Variables associated with mortality were identified. Results: A total of 428 patients were evaluated, and 303 met the inclusion criteria; 57.1% were male, the mean age was 57.1 ± 10.2 years, 75 patients had ACLF, and 228 did not. The main etiologies of ACLF were NASH (36.6%), alcoholic liver disease (13.9%), primary biliary cholangitis (8.6%) and autoimmune hepatitis (7.9%). Mechanical ventilation, renal replacement therapy, the use of vasopressors and the requirement of blood product transfusion during liver transplantation were significantly more frequent in ACLF patients. Among those recipients without and with ACLF, survival at 1, 3 and 5 years was 91.2% vs. 74.7%, 89.1% vs. 72.6% and 88.3% vs. 72.6%, respectively (p=0.001). Among pre-transplantation variables, only the presence of ACLF was independently associated with survival (HR 3.2, 95% CI: 1.46-7.11). Post-transplantation variables independently associated with survival were renal replacement therapy (HR 2.8, 95% CI: 1.1-6.8) and fungal infections (HR 3.26, 95% CI: 1.07-9.9). Conclusions: ACLF is an independent predictor of one-year post-transplantation survival. Importantly, transplant recipients with ACLF require the use of more resources than patients without ACLF.

Background & Aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. Results: A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20–33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732–0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713–0.775; p = 0.042) and Maddrey’s discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691–0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723–0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727–0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724–0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708–0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687–0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805–0.883). Conclusions: MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Impact and implications: Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

Introduction and Objectives: Alcohol consumption is among the five main factors responsible for the burden of disease and mortality. It is associated with changes in serum bile acids, and in recent years, extracellular vesicles (EV´s) and their Cargo have shown special interest in various lines of research due to their role in intercellular communication. This study aimed to characterize the serum levels of bile acids, changes in their composition, extracellular vesicles and their cargo in alcohol-associated liver disease (ALD). Materials and Methods: Prospective cohort, years 2019-2021. They were divided into four groups; control group, alcohol-associated hepatitis (AH), alcohol-related cirrhosis, and alcohol use disorder (AUD). Measurement of serum bile acids and C4 was performed through Liquid Chromatography /Tandem Mass Spectrometry, serum measurement of FGF19 and the serum concentration of extracellular vesicles through NTA (nanoparticle tracking analysis) and their cargo of bile acids. Results: A greater concentration of total bile acids was measured in the AUD group (1366.28 ng/ml) compared to the control group (552.42 ng/ml) (p = 0.003). The concentration of chenodeoxycholic acid is higher in the group of patients with AH (734.23 ng/ml) (p=0.04). The EV´s concentration is higher in the HA groups (1.292 E^11 ± 6.4E^10 particles/ml) and in AUD (9.9E^10+ 4.9E^ particles/ml) (p=0.005). It was possible to analyze the Cargo of BA in exosomes with proportional differences between the groups. Conclusions: Serum bile acids, both in concentration and composition, are modified in patients with AUD and HA, respectively; both present a higher concentration of exosomes, which could be a hepato-specific, dynamic and potentially prognostic biomarker in subjects with ALD.

Introduction and Objectives: The long-term impact of alcohol-related public health policies (PHP) on the burden of liver disease is unclear. This study aimed to assess the association between alcohol-related PHP and alcohol-related health consequences; 2. To develop an instrument to quantify the establishment of alcohol-related PHP in each country. Materials and Methods: We performed an ecological multi-national study including 169 countries. We recorded socio-demographic data and the presence of alcohol-related PHP in each country from the WHO Global Information System of Alcohol and Health (GISAH) in 2010. Data on alcohol-related health consequences was collected from the Global Burden of Disease database (between 2010-2019). We classified the WHO categories into five domains to design an instrument with criteria for a low, moderate, and strong establishment of PHP. We estimated an incidence rate ratio (IRR) using multilevel generalized linear models with a Poisson family distribution. The models were adjusted by population size, age structure, and gross domestic product. We also estimated a preparedness index using multiple correspondence analysis. Results: The table summarizes the final instrument. We included 169 countries; the median preparedness index was 54 [34.9-76.8]. The preparedness index was associated with lower alcohol-associated liver disease (ALD) mortality (IRR:0.25, 95%CI: 0.06-1.09, p=0.064), cancer mortality (IRR:0.22, 95%CI: 0.05-0.97, p=0.046), hepatocellular carcinoma (HCC) mortality (IRR:0.20, 95%CI: 0.04-0.95, p=0.043), and cardiovascular mortality (IRR:0.15, 95%CI: 0.04-0.61, p=0.008). There was also a trend to lower alcohol use disorder prevalence (IRR:0.25, 95%CI: 0.06-1.09, p=0.064). The highest linear associations were observed in the Americas and Africa, while Europe exhibits a nonlinear association. Conclusions: The preparedness index on alcohol policies is a valuable instrument to assess the establishment and strength of PHP. Those countries with a higher number of PHP had lower mortality due to ALD, cancer, HCC, and cardiovascular diseases. Our results strongly encourage the development and implementation of PHP on alcohol consumption worldwide.

Introduction and Objectives: there are different variables in patients with alcohol associated liver disease (ALD) and enlisted patients for liver transplant (LT), such as ethnicity, that determine health disparities in access, morbidity and mortality. This study aimed to assess and measure the impact of ethnicity in ALD and patients enlisted for LT. Materials and Methods: we conducted a retrospective study using U.S databases, the National Health and Nutrition Examination Survey (NHANES) and the United Network for Organ Sharing (UNOS) from 2011 to 2018. We created a multivariate model analyzing the clinical characteristics of the interviewed patients for NHANES. Alcohol consumption and ethnicity were self-reported. We also created a competing risks model for time to LT in enlisted patients. Results: of the 39,156 interviewed patients, 17.1% identified as Hispanic. In this group, the prevalence of ALD was 9.0% and the average consumption of pure alcohol was 2.3 L/year. The multivariate-adjusted model showed that Hispanics were independently associated with a higher risk of ALD (OR 1.30; 95%CI: 1.05-1.60, p=0.018). Of the enlisted patients, 13.6% were Hispanic. White ethnicity, lower age, male sex, higher MELD score, renal failure, lower BMI, higher education and private insurance were associated with a higher rate of LT. Hispanics were independently associated with a lower LT (HR 0.80; 95%CI: 0.74-0.87, p

Introduction and Objectives: Although most cases of HCC occur in patients with advanced liver disease and there are effective screening methods, health policies aimed at preventing and detecting HCC are not often on the agenda of government initiatives and policies. This study aimed to explore HCC-related population-wide public health policies, treatment availability, epidemiological surveillance, and awareness campaigns in the Americas. Materials and Methods: We conducted a 43-item survey about HCC among experts from 12 countries. Questions were classified into four categories: policies and civil society (18 questions), clinical guidelines (5 questions), epidemiology (7 questions), and care management (13 questions). The survey was administered using an electronic form in May 2022. Data was collected in a spreadsheet, revised by two independent reviewers, and contrasted with governmental institutions. Results: We obtained 22 responses from 15 out of the 18 countries targeted. A total of 7 (47%) countries had a written national cancer strategy or action plan. Only 4 (27%) countries had a specific written national HCC strategy or action plan, including Argentina, Brazil, Mexico, and the United States. These same four countries also had national clinical guidelines on HCC. HCC is managed by various providers, including Hepatologists (80%), Oncologists (80%), Gastroenterologists (60%), Surgeons (47%), and Palliative medicine (20%). There were important differences in the availability of treatments among countries in the Americas (Figure). Of note, 60% of countries had liver transplantation available for HCC, but only 67% of them had this therapy outside the capital city. Nine (60%) countries had a national disease registry that included HCC. However, only Brazil (7%) had governmental funded awareness campaigns on HCC prevention or screening. Conclusions: Implementation of public health policies on HCC is scarce in the Americas. Important differences in treatments were observed across countries, especially in curative therapies. Our results strongly encourage developing public health policies on HCC in the Americas.

Introduction and Objectives: Alcohol-associated hepatitis (AH) is a severe entity associated with high mortality. Corticosteroids might be used in cases with severe disease and several dynamic models can predict mortality and response to corticosteroids in AH patients. However, there is no consensus on the best of them. This study aimed to evaluate dynamic models to predict response to corticosteroid treatment based on short-term mortality in patients with severe AH based on a worldwide cohort. Materials and Methods: A retrospective cohort study of patients with severe AH (between 2009 – 2019). We included patients who received corticosteroid treatment and calculated the Lille model of day 4 (Lille-4), day 7 (Lille-7) (cut-off value ≥0.45), and the Trajectory of Serum Bilirubin (TSB)(cut-off value ≥0.8 of the ratio between bilirubin at admission and day 7) to predict mortality. We estimated up to 30-day survival using Kaplan-Meier curves, and we performed multivariable analyzes using Cox regression. Specifically, we constructed two models to compare Lille-4 vs. TSB and Lille-7 vs. TSB, adjusting by well-known clinical variables associated with higher mortality in AH (age, sex, and creatinine at admission). Results: 1,066 patients were included (30 centers, 10 countries), age 47.7 ± 10.9 years, 30% women. The MELD score on admission was 25 [21-30]. Responders were considered by Lille-4 49.1%, Lille-7 46.6%, and TSB 55.4%. In the first Cox regression, we observed that Lille-4 and TSB predicted 30-day mortality (HR 3.0, 95%CI: 1.7-5.1; p

Introduction and Objectives: Severe alcohol-associated hepatitis (AH) is an entity with high morbidity and mortality; however, data in Latin America is limited. We aimed to characterize patients hospitalized for AH in a multinational cohort in Latin America. Materials and Methods: Multicenter prospective cohort study. We included patients admitted with severe AH between 2015-2022. Sociodemographic and clinical information was recorded. The analysis included survival analysis using Kaplan-Meier curves. This study was approved by the institutional ethics committee. Results: 470 patients from 24 centers (8 countries: Mexico, Chile, Argentina, Brazil, Peru, Bolivia, Colombia, and Ecuador) were included. Age 49.8 ± 10.6 years, 85.6% of men and 45% had a previous diagnosis of cirrhosis. Median MELD at admission was 26.9 [22-32] points. 26.5% met SIRS criteria and 34.3% had an acute kidney injury (AKI) on admission. Only 36.8% of patients were treated with corticosteroids. Survival at 30 days was 75.0% (95%CI: 70.1-79.3%) and 62.8% (95%CI: 57.1-68.0%) at 90 days. A total of 191 (45.8%) patients presented infections, 31.4% at admission and 24.9% during hospitalization. The most frequent locations of community-acquired infections were respiratory (33.5%), urinary (32.1%), spontaneous bacterial peritonitis (14.9%), and skin (10.5%), while the most frequent pathogens were Escherichia coli (40%), Klebsiella pneumoniae (12%), and Enterococcus (6%). The presence of infection at admission was associated with a decreased survival at 90-days (66.9% versus 48.1%, p=0.0002). AKI at admission was also associated with decreased survival at 90-days (86.8% versus 51.3%, p

Introduction and Objectives: Acute-on-chronic liver failure (ACLF) is a severe clinical entity with organ failures and high short-term mortality. To Date, few ACLF reports have been published in Latin America. This study aimed to characterize patients with ACLF, identifying triggers, organ failure, and survival at 30, 90, and 180 days compared to patients with decompensated cirrhosis without ACLF. Materials and Methods: Retrospective study of decompensated cirrhotic patients hospitalized (between 2017-2019) in three centers in Chile. We evaluated transplant-free survival using Kaplan-Meier curves and Cox-regression. Results: 398 patients were included, a median age of 65.3±11.7-year-old, 50.5% female, 91 (22.9%) presented ACLF (8% ACLF-1, 6.3% ACLF-2, 8.6% ACLF-3); 6.6% underwent liver transplantation. ACLF patients were younger (63.6 vs. 66.0 years; p=0.045), had higher MELD-Na scores (27 [23-32] vs. 17 [13-23]; p

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Despite the proven economic importance of Aloe vera, studies of saline stress and its effects on the biochemistry and mineral content in tissues of this plant are scarce. The objective of this study was to grow Aloe under NaCl stress of 0, 30, 60, 90 and 120 mM and compare: (1) proline, total protein, and enzyme phosphoenolpyruvate carboxylase (PEP-case) in chlorenchyma and parenchyma tissues, and (2) ion content (Na, K, Ca, Mg, Cl, Fe, P. N, Zn, B, Mn, and Cu) in roots, stems, leaves and sprouts. Proline and PEP-case increased as salinity increased in both parenchyma and chlorenchyma, while total protein increased in parenchyma and decreased in chlorenchyma, although at similar salt concentrations total protein was always higher in chlorenchyma. As salinity increased Na and Cl ions increased in roots, stems, leaves, while K decreased only significantly in sprouts. Salinity increases typically caused mineral content in tissue to decrease, or not change significantly. In roots, as salinity increased Mg decreased, while all other minerals failed to show a specific trend. In stems, the mineral concentrations that changed were Fe and P which increased with salinity while Cu decreased. In leaves, Mg, Mn, N, and B decreased with salinity, while Cu increased. In sprouts, the minerals that decreased with increasing salinity were Mg, Mn, and Cu. Zinc did not exhibit a trend in any of the tissues. The increase in protein, proline and PEP-case activity, as well as the absorption and accumulation of cations under moderate NaCl stress caused osmotic adjustment which kept the plant healthy. These results suggest that Aloe may be a viable crop for soil irrigated with hard water or affected by salinity at least at concentrations used in the present study.