Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy.

The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.

Convolutional Neural Networks for Optical Discrimination Between Histological Types of Colorectal Polyps Based on White Light Endoscopic Images.

The objective of this study was to compare different convolutional neural networks (CNNs), as employed in a Python-produced deep learning process, used on white light images of colorectal polyps acquired during the process of a colonoscopy, in order to estimate the accuracy of the optical recognition of particular histologic types of polyps. The TensorFlow framework was used for Inception V3, ResNet50, DenseNet121, and NasNetLarge, which were trained with 924 images, drawn from 86 patients.

Treatment of portal vein thrombosis in cirrhosis: a multicenter real life cοhort study.

BACKGROUND: Portal vein thrombosis (PVT) is a common complication of cirrhosis and can be a cause or consequence of liver disease progression. It is unclear whether PVT treatment is affecting clinical outcomes in cirrhotics. METHODS: This is a multicenter study of cirrhotics with PVT, initially retrospectively and thereafter prospectively registered in a data base. We studied the impact of PVT treatment on this population for efficacy, safety and the impact on survival. In survival analysis Mantel-Cox and Wilcoxon-Breslow-Gehan tests were used. A P value of <0.05, was considered significant. For statistical computations the STATA 12.1 was used. RESULTS: Seventy-six patients were included (76% decompensated, median MELD score 12 and Child-Pugh score 7), 47% with concomitant HCC. Fifty-one patients with PVT were treated with Vitamin-K antagonists or Low-Molecular-Weight Heparin. Patients were followed up for at least 6 months after PVT diagnosis, or until death or transplantation. PV patency after 6 months was not statistically different between patients receiving or not anticoagulation (complete-partial recanalization 27.4% of treated vs. 20% of untreated, P=0.21). Median survival was statistically worse between patients treated with anticoagulation than those untreated (10 vs. 15 months, P=0.036). Less portal hypertensive bleeding and less decompensation rates were found in treated cirrhotics vs. untreated (45.8% vs. 54.2%, P=0.003 and 78% vs. 80.9%, P=0.78, respectively). Patients with HCC had worse survival when treated vs. untreated (P=0.047). CONCLUSIONS: In our cohort of cirrhotics with PVT, treatment was feasible with acceptable side effects, but without meaningful clinical benefits.

Iron as a therapeutic target in chronic liver disease.

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

Enzymes of Fibrosis in Chronic Liver Disease.

Introduction: Liver fibrosis has been extensively studied at the cellular and molecular level, but very few data exist on the final enzymatic stages of collagen synthesis (prolyl hydroxylase, PH) and degradation (matrix metalloproteinases, MMPs), particularly in primary biliary cholangitis (PBC). Aim: We studied enzyme activities in liver tissue from patients with chronic liver diseases and compared them to normal livers. Patients: Eighteen patients with PBC of early and late stages (Ludwig's classification) and seven on treatment with ursodeoxycholate (UDCA) were studied and compared to 34 patients with alcoholic liver disease (ALD), 25 patients with chronic viral liver disease and five normal biopsies. Sera were available from a total of 140 patients. Methods: The tritiated water released from the tritiated proline was measured in PH assessment. 14C intact and heat-denatured collagen substrates were used to measure collagenase and gelatinases, respectively. 3H Elastin was the substrate for elastase. In serum, ELISAs were used for MMP-1, TIMP-1, and TIMP-2 measurements while MMP-2 and MMP-9 were estimated by zymography. Results: PH was significantly increased in early and late PBC. Collagenase was reduced only in the late stages (p < 0.01), where the ratio PH/collagenase was increased. UDCA treatment restored values to almost normal. Gelatinases were reduced in late stages (p < 0.05). In contrast to PBC and ALD fibrosis, collagen synthesis is not increased in viral fibrosis. The balance shifted towards collagen deposition due to reduced degradation. Interestingly, gelatinolytic activity is not impaired in ALD. Elastase was similar to controls in all diseases studied. TIMP-1 was reduced in early PBC and viral and alcoholic hepatitis and cirrhosis (p < 0.001). Conclusions: (1) There is evidence that collagen synthesis increases in the early stages of PBC, but the collagenolytic mechanism may compensate for the increased synthesis. (2) In viral disease, fibrosis may be due to decreased degradation rather than increased synthesis. (3) The final biochemical stages of liver fibrosis may be quantitatively different according to underlying etiology.

The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity.

The HCC constitutes one of the most frequent cancers, with a non-decreasing trend in disease mortality despite advances in systemic therapy and surgery. This trend is fueled by the rise of an obesity wave which is prominent the Western populations and has reshaped the etiologic landscape of HCC. Interest in the nucleotide-binding domain leucine-rich repeat containing (NLR) family member NLRP3 has recently been revived since it would appear that, by generating inflammasomes, it participates in several physiologic processes and its dysfunction leads to disease. The NLRP3 inflammasome has been studied in depth, and its influence in HCC pathogenesis has been extensively documented during the past quinquennial. Since inflammation comprises a major regulator of carcinogenesis, it is of paramount importance an attempt to evaluate the contribution of the NLRP3 inflammasome to the generation and management of HCC. The aim of this review was to examine the literature in order to determine the impact of the NLRP3 inflammasome on, and present a hypothesis about its input in, HCC.

Nutritional Assessment of Greek Liver Cirrhosis Patients: Mini Nutritional Assessment Predicts Mortality.

Malnutrition is highly prevalent in liver cirrhosis (LC). It increases as the severity of the disease progresses and it is related to poor survival. The objectives of the study were the nutritional assessment of Greek LC patients, using various nutritional assessment and screening tools, and the comparison of their predictive value for mortality. In total, 137 (77 male) consecutive LC patients (median age: 67 years) were assessed with subjective global assessment (SGA) and mini nutritional assessment (MNA) questionnaires, anthropometrics, handgrip strength (HGS) tests, and bioelectric impedance analysis (BIA), in comparison to a control group of 148 healthy people. Disease severity was assessed using the model for end-stage liver disease (MELD) scores. Patients were followed up for a median of 19 months. Survival curves were calculated using the Kaplan-Meier method. In total, 60% and 43% of patients were of adequate nutritional status by SGA and MNA, respectively, which was confirmed by most anthropometric measurements. MNA and SGA scores correlated significantly with anthropometrics and BIA-derived parameters. Besides the MELD score, mid-arm circumference (MAC), triceps skinfold (TSF), BIA's phase angle (Pha), and MNA predicted mortality in cirrhotic patients. The nutritional assessment demonstrated an unexpectedly high prevalence of well-nourished LC patients. MNA was a strong predictor of mortality.

Hepatitis C virus: A critical approach to who really needs treatment.

Introduction of effective drugs in the treatment of hepatitis C virus (HCV) infection has prompted the World Health Organization to declare a global eradication target by 2030. Propositions have been made to screen the general population and treat all HCV carriers irrespective of the disease status. A year ago the new severe acute respiratory syndrome coronavirus 2 virus appeared causing a worldwide pandemic of coronavirus disease 2019 disease. Huge financial resources were redirected, and the pandemic became the first priority in every country. In this review, we examined the feasibility of the World Health Organization elimination program and the actual natural course of HCV infection. We also identified and analyzed certain comorbidity factors that may aggravate the progress of HCV and some marginalized subpopulations with characteristics favoring HCV dissemination. Alcohol consumption, HIV coinfection and the presence of components of metabolic syndrome including obesity, hyperuricemia and overt diabetes were comorbidities mostly responsible for increased liver-related morbidity and mortality of HCV. We also examined the significance of special subpopulations like people who inject drugs and males having sex with males. Finally, we proposed a different micro-elimination screening and treatment program that can be implemented in all countries irrespective of income. We suggest that screening and treatment of HCV carriers should be limited only in these particular groups.

New considerations for colorectal cancer screening based on the demographic profile of colorectal cancer in a Greek population.

Colorectal cancer screening has long been recommended for middle age and older individuals. Recent evidence indicates increasing incidence and mortality among young adults. Therefore, the present study re-examined the current recommendations using an asymptomatic average-risk population screened by colonoscopy. A total of 716 participants of a wide age range were prospectively enrolled in an open-access endoscopic screening program based on self-referral. Comparisons between different age, gender and location groups, and receiver operating characteristic curves (ROC) curves for best age selection for detection of lesions were employed. Increased incidence of advanced lesions was observed in adults <50 years old. Although the polyp size was <1 cm in 85% of the cohort, a significant number of participants harbored advanced lesions. A disturbing incidence of lesions in women 30-49 years was located mainly in the left colon. One-third of the important pathology resides exclusively in the right colon. ROC curves demonstrated that with the current starting age of screening at 50 years, 92% of polyps and 95% of adenomas could be detected by colonoscopy, but a number of potential precancerous lesions will appear at an earlier age and therefore will be missed. The present study supported the notion that it is critical to reduce screening initiation below the currently accepted age of 50 years. Colonoscopy is a suitable method for addressing the increased prevalence of proximal lesions and the meticulous resection of smaller polyps.

Spontaneous bacterial peritonitis: a prospective Greek multicenter study of its epidemiology, microbiology, and outcomes.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is an ominous complication of decompensated cirrhosis. This study aimed to assess several epidemiological, clinical, microbiological and outcome characteristics in Greek patients with SBP, as no solid representative nationwide data of this type was available. METHODS: During a 3-year period, 77 consecutive patients with SBP (61 male; median age: 67 years; model for end-stage liver disease [MELD] score: 20), diagnosed and followed in 5 tertiary liver units, were prospectively recruited and studied. Various prognostic factors for disease outcome were studied. RESULTS: Thirty-eight patients had alcohol-related cirrhosis, 17 viral hepatitis, 6 non-alcoholic steatohepatitis, 6 autoimmune liver diseases, and 10 cryptogenic cirrhosis. Hepatocellular carcinoma (HCC) was present in 23 (29.9%), whereas 10 (13%) had portal vein thrombosis. The first SBP episode at baseline was community-acquired in 53 (68.8%), while in 24 (31.1%) was hospital-acquired, with predominant symptoms abdominal pain and encephalopathy. A positive ascitic culture was documented in 36% of patients in the initial episode, with almost equal gram (+) and gram (-) pathogens, including 3 multidrug-resistant pathogens. Significant factors for 6-month survival were: higher MELD score, previous b-blocker use, lower serum albumin, higher lactate on admission and need for vasopressors, while factors for 12-month survival were MELD score and lactate. For overall survival, higher MELD score and lactate along with HCC presence were negative predictive factors. CONCLUSIONS: MELD score, lactate, albumin, HCC and treatment with vasopressors were predictive of survival in SBP patients. In hospital-acquired SBP the prevalence of difficult-to-treat pathogens was higher.

Autophagy in liver diseases.

Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.

Impact of Silymarin in individuals with nonalcoholic fatty liver disease: A systematic review and meta-analysis.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting a significant proportion of the general population. Recently, randomized clinical trials have been conducted examining the efficacy of silymarin in individuals with NAFLD, with conflicting results. The aim of this meta-analysis was to evaluate the efficacy of silymarin in the treatment of NAFLD by examining changes in liver biochemistry, body mass index, and liver histology. METHODS: We searched major electronic databases PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, as well as gray-literature sources, up to June 2020 for randomized clinical trials examining the efficacy of treatment with silymarin in individuals with NAFLD compared to placebo. The primary outcomes were changes in the mean values of transaminases (alanine aminotransferase and aspartate aminotransferase). Secondary outcomes included changes in body mass index and liver histology. Quality analysis was performed with the risk-of-bias tool 2.0. We synthesized results using weighted mean differences for continuous outcomes, along with 95% confidence intervals. RESULTS: In the meta-analysis, eight randomized clinical trials were included. A cutoff level of 0.05 was considered to provide statistically significant results. Silymarin treatment led to a statistically significant greater reduction in the levels of transaminases compared to placebo, irrespective of weight loss. CONCLUSIONS: Silymarin seems to be effective in reducing transaminase levels in individuals with NAFLD. Despite the statistical benefits, we call attention to potential flaws related to the quality of the included studies. Further well-designed studies should be carried out to examine whether this reduction in transaminase levels corresponds to histologic improvement.

Comparative evaluation of ALBI, MELD, and Child-Pugh scores in prognosis of cirrhosis: is ALBI the new alternative?

BACKGROUND: The existence of reliable prognostic indices is of paramount importance in the management of cirrhosis. Both the model for end-stage liver disease (MELD) score and the older Child-Pugh (CP) scores are widely used. The albumin-bilirubin (ALBI) score, initially used in hepatocellular carcinoma, has not been thoroughly investigated in cirrhosis. The aim of this study was to compare the prognostic accuracy of ALBI, MELD, MELD with sodium (MELD-Na), CP, and the corrected for creatinine CP scores in a genetically homogeneous Cretan cirrhotic population. METHODS: One hundred ninety-five outpatients or hospitalized cirrhotics (127 male, median age 66 years) were studied over a period of 2 years and ALBI, platelet-albumin-bilirubin, MELD, MELD-Na, CP score, and 2 types of modified CP score (CP-I and CP-II) with serum creatinine were calculated and correlated with survival. RESULTS: ALBI had an optimum balance between sensitivity and specificity (area under the curve 0.704, 95% confidence interval [CI] 0.630-0.778) compared to the other scores. In the multivariate analysis, the only factors independently associated with death were the ALBI score (hazard ratio [HR] 2.51, 95%CI 1.69-3.73; P<0.001), the MELD-Na score (HR 1.04, 95%CI 1.00-1.09; P=0.045), and age (HR 1.05, 95%CI 1.03-1.07; P<0.001). When only decompensated cirrhosis was evaluated, the multivariate analysis showed that the ALBI score (HR 3.03; 95%CI 1.92-4.78; P<0.001), and age (HR 1.05, 95%CI 1.03-1.07; P<0.001) were independently associated with death. CONCLUSION: ALBI score might be a better prognostic indicator of mortality in cirrhosis and given its simplicity could substitute for the CP, MELD, and MELD-Na scores.

Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis.

BACKGROUND: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. METHODS: COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. RESULTS: COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. CONCLUSIONS: Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor's stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.

Association of smoking with liver fibrosis and mortality in primary biliary cholangitis.

BACKGROUND: The outcome of primary biliary cholangitis (PBC) is affected by both genetic and environmental factors. OBJECTIVE: The aim of this study was to study the effect of smoking on liver histology and mortality in a genetically homogeneous population having PBC. PATIENTS AND METHODS: Smoking and drinking habits at diagnosis (based on standard criteria) were recorded in 171 Cretan patients with PBC (163 women). A total of 148 patients had a liver biopsy. Odds ratios were calculated with logistic regression analysis. Kaplan-Meier curves were used for mortality estimation. RESULTS: Smoking was associated with alcohol consumption of more than 20 g/day [adjusted odds ratio (AOR)=2.20, 95% CI: 1.029-4.099], severe steatosis (AOR=5.31, 95% CI: 2.019-9.919), and fibrosis stage F3-F4 (AOR=1.21, 95% CI: 1.015-3.031). Heavy smoking, years of passive smoking, and serious necroinflammatiοn were independent factors associated with advanced fibrosis after adjustment for sex, age, BMI, and alcohol consumption in multivariate analysis. For every pack-year increase in smoking intensity, there was a 3.2 times higher likelihood of advanced fibrosis (95% CI: 2.018-6.294). Increased mortality was found in smokers with advanced PBC. CONCLUSION: There is an association between smoking, whether active or passive, and advanced fibrosis in PBC. Mortality is increased in smokers with advanced disease at presentation.

Biomarkers for primary biliary cholangitis: current perspectives.

Primary biliary cholangitis (PBC) is a chronic progressive cholestatic disease characterized by destruction of small- and medium-sized intrahepatic bile ducts. It is no longer a rare disease, since many new asymptomatic cases are incidentally identified. Liver biopsy is diagnostically critical but not always feasible or practical to be performed. Many potential, noninvasive, markers have been proposed to replace liver biopsy and further provide the assessment of disease severity and ultimate prognosis. In this review, we evaluated serum biomarkers proposed for diagnosis, extent of fibrosis, disease prognosis and attempts for early prediction of treatment response. Older biochemical and immunological markers are presented along with recent reports including the role of microRNAs and promising results based on proteomics and metabolomics.

Angiodrastic Chemokines in Colorectal Cancer: Clinicopathological Correlations.

AIM: To study the expression of angiodrastic chemokines in colorectal tumors and correlate findings with clinicopathological parameters and survival. METHODS: The proangiogenic factor VEGF, the angiogenic chemokines CXCL8 and CXCL6, and the angiostatic chemokine CXCL4 were measured by ELISA in tumor and normal tissue of 35 stage II and III patients and correlated with the histopathology markers Ki67, p53, p21, bcl2, EGFR, and MLH1 and 5-year survival. The Wilcoxon and chi-square tests were used for statistical comparisons. RESULTS: There was a significant increase of CXCL6 (p = 0.005) and VEGF (p = 0.003) in cancerous tissue compared to normal. Patients with lower levels of CXCL8 and CXCL4 lived significantly longer. Patients with loss of EGFR expression had higher levels of CXCL8 while p21 loss was associated with higher levels of CXCL6. Chemokine levels were not correlated with TNM or Dukes classification. Strong expression of p53 was accompanied by decreased survival. CONCLUSIONS: (1) The angiogenic factors CXCL6 and VEGF are increased in colorectal cancer tissue with no association with the clinical stage of the disease or survival. (2) However, increased levels of tissue CXCL8 and CXCL4 are associated with poor survival. (3) Strong expression of p53 is found in patients with poor survival.

Portal vein thrombosis in cirrhosis: diagnosis, natural history, and therapeutic challenges.

Portal vein thrombosis (PVT) is a frequent complication in cirrhosis and its prevalence increases with disease severity. Several factors are involved in the development and progression of PVT. The challenge for the management of PVT is the precise evaluation of the bleeding risk as opposed to life-threatening extension of thrombosis. Nevertheless, the impact on the progression and outcome of liver disease is unclear. A critical evaluation of the available data discloses that treating PVT in cirrhotics is safe and effective. However, there are open issues, such as which anticoagulant could represent a safer therapeutic option, and when and for how long this treatment should be administered to cirrhotic patients with PVT.

GABAA receptor polymorphisms in alcohol use disorder in the GWAS era.

Alcohol use disorder (AUD) is a chronic, relapsing, neuro-psychiatric illness of high prevalence and with a serious public health impact worldwide. It is complex and polygenic, with a heritability of about 50%, and influenced by environmental causal heterogeneity. Risk factors associated with its etiology have a genetic component. GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in mammalian brain. GABAA receptors are believed to mediate some of the physiological and behavioral actions of alcohol. In this critical review, relevant genetic terms and type and methodology of the genetic studies are briefly explained. Postulated candidate genes that encode subunits of GABAA receptors, with all the reported SNPs, are presented. Genetic studies and meta-analyses examining polymorphisms of the GABAA receptor and their association with AUD predisposition are presented. The data are critically examined with reference to recent GWAS studies that failed to show relations between GABAA receptors and AUD. Restrictions and perspectives of the different findings are discussed.