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Alcohol-associated liver disease (ALD) represents one of the deadliest yet preventable consequences of excessive alcohol use. It represents 5.1 % of the global burden of disease, mainly involving the productive-age population (15-44 years) and leading to an increased mortality risk from traffic road injuries, suicide, violence, cardiovascular disease, neoplasms, and liver disease, among others, accounting for 5.3 % of global deaths. Daily alcohol consumption, binge drinking (BD), and heavy episodic drinking (HED) are the patterns associated with a higher risk of developing ALD. The escalating global burden of ALD, even exceeding what was predicted, is the result of a complex interaction between the lack of public policies that regulate alcohol consumption, low awareness of the scope of the disease, late referral to specialists, underuse of available medications, insufficient funds allocated to ALD research, and non-predictable events such as the COVID-19 pandemic, where increases of up to 477 % in online alcohol sales were registered in the United States. Early diagnosis, referral, and treatment are pivotal to achieving the therapeutic goal in patients with alcohol use disorder (AUD) and ALD, where complete alcohol abstinence and prevention of alcohol relapse are expected to enhance overall survival. This can be achieved through a combination of cognitive behavioral, motivational enhancement and pharmacological therapy. Furthermore, the appropriate use of available pharmacological therapy and implementation of public policies that comprehensively address this disease will make a real difference.

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Innate immunity contributes effectively to the development of Alcohol-Associated liver disease (ALD). Particularly, human studies and murine models of ALD have shown that Complement activation plays an important role during the initial and later stages of ALD. The Complement System may contribute to the pathogenesis of this disease since it has been shown that ethanol-derived metabolic products activate the Complement cascade on liver membranes, leading to hepatocellular damage. However, studies evaluating the plasma levels of Complement proteins in ALD patients present contradictory results in some cases, and do not establish a well-marked role for each Complement component. The impairment of leukocyte chemoattractant activity observed in these patients may contribute to the susceptibility to bacterial infections in the latter stages of the disease. On the other hand, murine models of ALD have provided more detailed insights into the mechanisms that link the Complement System to the pathogenesis of the disease. It has been observed that Classical pathway can be activated via C1q binding to apoptotic cells in the liver and contributes to the development of hepatic inflammation. C3 contributes to the accumulation of triglycerides in the liver and in adipose tissue, while C5 seems to be involved with inflammation and liver injury after chronic ethanol consumption. In this review, we present a compendium of studies evaluating the role of Complement in human and murine models of ALD. We also discuss potential therapies to human ALD, highlighting the use of Complement inhibitors.

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In recent years, knowledge on the biology and pathobiology of extracellular vesicles (EVs) has exploded. EVs are submicron membrane-bound structures secreted from different cell types containing a wide variety of bioactive molecules (e.g., proteins, lipids, and nucleic acids (coding and non-coding RNA) and mitochondrial DNA). EVs have important functions in cell-to-cell communication and are found in a wide variety of tissues and body fluids. Better delineation of EV structures and advances in the isolation and characterization of their cargo have allowed the diagnostic and therapeutic implications of these particles to be explored. In the field of liver diseases, EVs are emerging as key players in the pathogenesis of both nonalcoholic liver disease (NAFLD) and alcoholic liver disease (ALD), the most prevalent liver diseases worldwide, and their complications, including development of hepatocellular carcinoma. In these diseases, stressed/damaged hepatocytes release large quantities of EVs that contribute to the occurrence of inflammation, fibrogenesis, and angiogenesis, which are key pathobiological processes in liver disease progression. Moreover, the specific molecular signatures of released EVs in biofluids have allowed EVs to be considered as promising candidates to serve as disease biomarkers. Additionally, different experimental studies have shown that EVs may have potential for therapeutic use as a liver-specific delivery method of different agents, taking advantage of their hepatocellular uptake through interactions with specific receptors. In this review, we focused on the most recent findings concerning the role of EVs as new structures mediating autocrine and paracrine intercellular communication in both ALD and NAFLD, as well as their potential use as biomarkers of disease severity and progression. Emerging therapeutic applications of EVs in these liver diseases were also examined, along with the potential for successful transition from bench to clinic.

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Objective: Alcoholic liver disease (ALD) is among the leading causes of death from liver disease. Among the factors involved in its pathogenesis are inflammation and increased intestinal permeability. The aim of this study was to assess the effect of Lactobacillus rhamnosus GG (LGG) on hepatic lipid accumulation, activation of inflammasomes, and gut permeability markers in experimental model of ALD with zebrafish.Methods: An experiment was conducted to assess the effective LGG dose capable of promoting intestinal colonization. Animals were divided into three groups (n = 64/group): ethanol group (E), ethanol + probiotic group (EP), and control group (C). Groups E and EP were exposed to 0.5% ethanol concentration for 28 days. At the end of this period, animals were euthanized, and livers were collected for Oil Red staining and assessment of the inflammasome system. Intestines were collected for evaluation of gut permeability markers.Results: The dose of 1.55 × 106 UFC LGG/fish/d promoted intestinal colonization. Group EP presented lower hepatic lipid accumulation, lower il-1ß expression, and higher cldn15a expression when compared to group E.Conclusions: Supplementation with LGG was protective for hepatic steatosis in ALD model. In addition, LGG influenced the modulation of the inflammatory response and markers of gut permeability, improving the gut barrier structure.

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Chronic alcohol consumption is a major cause of liver disease. The term alcoholic liver disease (ALD) refers to a spectrum of mild to severe disorders including steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. With limited therapeutic options, stem cell therapy offers significant potential for these patients. In this article, we review the pathophysiologic features of ALD and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), based on their potential to differentiate into hepatocytes, their immunomodulatory properties, their potential to promote residual hepatocyte regeneration, and their capacity to inhibit hepatic stellate cells. The perfect match between ALD pathogenesis and MSC therapeutic mechanisms, together with encouraging, available preclinical data, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage ALD onset and progression.

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Excessive alcohol consumption is an important cause of preventable morbidity and mortality. We have to bealert to chronic alcohol usage or abuse. Simple tests (AUDIT, CAGE) can be applied quickly on outpatientcare. We highlight advances in understanding the immune and molecular mechanisms; there is disruptionof the intestinal barrier with bacterial translocation, as well as endotoxins which activate the liver’s innateimmunity, causing apoptosis, necrosis, inflammation and fibrosis. Alcoholic hepatitis is most common inpatients between 40 and 60 years of age, preferably male with jaundice, fever, ascites, hepatomegaly. Thediagnosis is confirmed with a history of alcoholic consumption, mild to moderate AST and ALT values,a AST/ALT ratio > 2, hyperbilirrubinemia and prolonged prothrombin time. There are scores to evaluatethe severity and the need of corticoid therapy, such as modified Maddrey discriminating function andMELD score. Lille score assesses the response to treatment in the seventh day. The risks and benefits ofliver biopsy should be evaluated individually. The cornerstone of treatment remains alcohol abstinence.Nutritional management must be carefully monitored. Proteins requirements are standardized based onweight. The use of corticoids with 40 mg of prednisolone each day is the most widely accepted therapy,indicated on patients with MMDF higher than 32 or MELD score higher than 21. If Lille score is higherthan 0.45 at the seven day under corticoid therapy, treatment must be interrupted. The use of pentoxifyllinewould only be effective for prevention of hepatorenal syndrome...

El consumo excesivo de alcohol es una causa importante de morbimortalidad prevenible. Debemos estaratentos en detectar a pacientes con dependencia o abuso crónico de alcohol. Test sencillos (AUDIT, CAGE)pueden aplicarse rápidamente en consulta ambulatoria. Destacamos avances en el conocimiento moleculare inmunológico, existe disrupción de la barrera intestinal con translocación bacteriana y endotoxinas conactivación del sistema inmune innato del hígado, produciendo apoptosis celular, necrosis e inflamación yfibrosis. La hepatitis alcohólica se presenta principalmente en pacientes entre 40 y 60 años, preferentementeen varones con ictericia, fiebre, ascitis, hepatomegalia. El diagnóstico se confirma con antecedentes deingesta alcohólica, GOT y GPT elevadas en forma leve o moderada, relación GOT/GPT mayor de 2, hiperbilirrubinemiay tiempo de protrombina prolongado. Existen scores para evaluar la gravedad y necesidad demanejo con corticoides como función discriminante de Maddrey modificada y MELD. El puntaje de Lilleevalúa respuesta del tratamiento al séptimo día. El riesgo/beneficio de la biopsia hepática se evalúa caso acaso. La piedra angular del tratamiento sigue siendo la abstinencia. Manejo nutricional debe ser riguroso.Requerimientos proteicos están estandarizados por peso. La terapia con corticoides (prednisolona 40 mg/día) es la más ampliamente aceptada, con indicación en pacientes con FDMm mayor a 32 o MELD mayora 21. Si el puntaje de Lille es mayor de 0,45 a los 7 días con corticoides, deben suspenderse. Pentoxifilinasólo tendría efecto en prevenir el desarrollo de síndrome hepatorrenal (SHR). Hay nuevas terapias enevaluación, como el uso de G-CSF...

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Treatment of alcoholic liver disease is for the most part based on the stage of the disease and the pathogenic event that is being targeted. The primary treatment modalities that are considered in the treatment of alcoholic liver disease include abstinence, agents that suppress inflammation, anticytokine therapy, nutritional support, modifiers of alcohol metabolism, anti-oxidants, and inhibitors of hepatic fibrosis. Future therapeutic options include exploration of new pathways such as the patatin-like phospholipase domain containing 3 protein (PNPLA-3).

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Alcohol use disorders and alcohol dependency affect millions of individuals worldwide. The impact of these facts lies in the elevated social and economic costs. Alcoholic liver disease is caused by acute and chronic exposure to ethanol which promotes oxidative stress and inflammatory response. Chronic consumption of ethanol implies liver steatosis, which is the first morphological change in the liver, followed by liver fibrosis and cirrhosis. This review comprises a broad approach of alcohol use disorders, and a more specific assessment of the pathophysiologic molecular basis, and genetics, as well as clinical presentation and current modalities of treatment for alcoholic liver disease.

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The prevalence and incidence of alcoholic liver disease are constantly evolving. Alcoholic liver disease has a wide clinical spectrum. It may progress to cirrhosis and to end-stage liver disease requiring liver transplantation. The histological manifestations range from steatosis without inflammation to liver cell injury and ultimately to fibrosis and cirrhosis. In some cases, the histological manifestation is steatohepatitis, morphologically characterized by inflammation and necrosis. Currently, although there are no specific tests to establish a diagnosis of steatohepatitis, some serological, radiological, or laboratory tests may be useful. Liver biopsy is useful in confirming a suspected diagnosis and in assessing the extent of parenchymal damage. This review synthesizes the main aspects of the epidemiology, pathogenesis, morphological characteristics, diagnosis, treatment, and prognosis of alcoholic liver disease.

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