Protective role of 17ß-estradiol in alcohol-associated liver fibrosis is mediated by suppression of integrin signaling.

BACKGROUND: Alcohol-associated liver disease is a complex disease regulated by genetic and environmental factors such as diet and sex. The combination of high-fat diet and alcohol consumption has synergistic effects on liver disease progression. Female sex hormones are known to protect females from liver disease induced by high-fat diet. In contrast, they promote alcohol-mediated liver injury. We aimed to define the role of female sex hormones on liver disease induced by a combination of high-fat diet and alcohol. METHODS: Wild-type and protein arginine methyltransferase (Prmt)6 knockout female mice were subjected to gonadectomy (ovariectomy, OVX) or sham surgeries and then fed western diet and alcohol in the drinking water. RESULTS: We found that female sex hormones protected mice from western diet/alcohol-induced weight gain, liver steatosis, injury, and fibrosis. Our data suggest that these changes are, in part, mediated by estrogen-mediated induction of arginine methyltransferase PRMT6. Liver proteome changes induced by OVX strongly correlated with changes induced by Prmt6 knockout. Using Prmt6 knockout mice, we confirmed that OVX-mediated weight gain, steatosis, and injury are PRMT6 dependent, while OVX-induced liver fibrosis is PRMT6 independent. Proteomic and gene expression analyses revealed that estrogen signaling suppressed the expression of several components of the integrin pathway, thus reducing integrin-mediated proinflammatory (Tnf, Il6) and profibrotic (Tgfb1, Col1a1) gene expression independent of PRMT6 levels. Integrin signaling inhibition using Arg-Gly-Asp peptides reduced proinflammatory and profibrotic gene expression in mice, suggesting that integrin suppression by estrogen is protective against fibrosis development. CONCLUSIONS: Taken together, estrogen signaling protects mice from liver disease induced by a combination of alcohol and high-fat diet through upregulation of Prmt6 and suppression of integrin signaling.

Dysregulation of innate cell types in the hepatic immune microenvironment of alcoholic liver cirrhosis.

Introduction: The risk of alcoholic cirrhosis increases in a dose- and time-dependent manner with alcohol consumption and ethanol metabolism in the liver. Currently, no effective antifibrotic therapies are available. We aimed to obtain a better understanding of the cellular and molecular mechanisms involved in the pathogenesis of liver cirrhosis. Methods: We performed single-cell RNA-sequencing to analyze immune cells from the liver tissue and peripheral blood form patients with alcoholic cirrhosis and healthy controls to profile the transcriptomes of more than 100,000 single human cells and yield molecular definitions for non-parenchymal cell types. In addition, we performed single-cell RNA-sequencing analysis to reveal the immune microenvironment related to alcoholic liver cirrhosis. Hematoxylin and eosin, Immunofluorescence staining and Flow cytometric analysis were employed to study the difference between tissues and cells with or without alcoholic cirrhosis. Results: We identified a fibrosis-associated M1 subpopulation of macrophages that expands in liver fibrosis, differentiates from circulating monocytes, and is pro-fibrogenic. We also define mucosal-associated invariant T (MAIT) cells that expand in alcoholic cirrhosis and are topographically restricted to the fibrotic niche. Multilineage modeling of ligand and receptor interactions between the fibrosis-associated macrophages, MAIT, and NK cells revealed the intra-fibrotic activity of several pro-fibrogenic pathways, including responses to cytokines and antigen processing and presentation, natural killer cell-mediated cytotoxicity, cell adhesion molecules, Th1/Th2/Th17 cell differentiation, IL-17 signaling pathway, and Toll-like receptor signaling pathway. Discussion: Our work dissects unanticipated aspects of the cellular and molecular basis of human organ alcoholic fibrosis at the single-cell level and provides a conceptual framework for the discovery of rational therapeutic targets in liver alcoholic cirrhosis.

CD73 aggravates alcohol-related liver fibrosis by promoting autophagy mediated activation of hepatic stellate cells through AMPK/AKT/mTOR signaling pathway.

CD73 is a membrane-bound glycoprotein that can dephosphorylate AMP to adenosine. Increasing evidence has shown that CD73 is involved in the occurrence and development of liver fibrosis. However, the potential mechanism by which CD73 affects the progression of alcohol-related liver fibrosis (ALF) remains unknown. This study aimed to examine the role and mechanism of CD73 in autophagy in HSC-T6 cells and its role in ALF in mice that treated with alcohol plus CCl4. We found that CD73 knockout reduced serum alanine aminotransferase and aspartate aminotransferase levels and decreased liver injury and collagen deposition. Furthermore, autophagy-related indicators were downregulated in the liver fibrosis tissues of CD73-/- (EtOH + CCl4) mice. In vitro, the expression of CD73 and autophagy increased in activated HSC-T6 cells. Autophagy inhibitor, 3-methyladenine, reduced autophagy and activation of acetaldehyde-induced HSC-T6 cells. When using CD73-siRNA, autophagy in HSC-T6 cells was found to be downregulated. However, the CD73 plasmid increased the activation and autophagy of hepatic stellate cells (HSCs). In addition, CD73 induced autophagy through the AMPK/AKT/mTOR pathway, which is characterized by an increase in the ratio of P-AMPKα/AMPKα and a decrease in the ratio of P-AKT/AKT and P-mTOR/mTOR. Our study found that CD73 promotes HSCs activation by regulating autophagy through the AMPK/AKT/mTOR signaling pathway.

Epidemic characteristics of alcohol-related liver disease in Asia from 2000 to 2020: A systematic review and meta-analysis.

BACKGROUND AND AIMS: To systematically summarize the prevalence of alcohol-related liver disease (ALD) and the alcohol-attributable proportions of liver cirrhosis and hepatocellular carcinoma (HCC) cases in Asia. METHODS: The Embase, PubMed, Web of Science, Cochrane, CINAHL, WanfangMed and China National Knowledge Infrastructure databases were searched from 01 January 2000 to 01 December 2021 for reports of ALD prevalence and alcohol-attributable proportions of liver cirrhosis/HCC in Asian populations. Study characteristics were extracted, and meta-analyses were conducted. RESULTS: Our literature search identified 13 studies reporting the ALD prevalence, 62 studies reporting the alcohol-attributable proportion of liver cirrhosis and 34 studies reporting the alcohol-attributable proportion of HCC. The overall prevalence of ALD was 4.81% (95% confidence interval [CI] 3.67%, 6.09%). The ALD prevalence was higher in men (7.80% [95% CI 5.70%, 10.19%]) than in women (0.88% [95% CI 0.35%, 1.64%]) and increased significantly over time from 3.82% (95% CI 2.74%, 5.07%) between 2000 and 2010 to 6.62% (95% CI 4.97%, 8.50%) between 2011 and 2020. Among 469 640 cases of liver cirrhosis, the pooled alcohol-attributable proportion was 12.57% (95% CI 10.20%, 15.16%). Among 82 615 HCC cases, the pooled alcohol-attributable proportion was 8.30% (95% CI 6.10%,11.21%). Significant regional differences were observed in alcohol-attributable proportions of liver cirrhosis and HCC. CONCLUSIONS: The prevalence of ALD and the proportions of alcohol-related liver cirrhosis and HCC in Asia are lower than those in western populations. However, a gradual increasing trend was observed over the last 21 years. ALD is likely to emerge as a leading cause of chronic liver disease in Asia.

Role of Bacterial Infection in the Development of Acute Liver Failure in Patients with Decompensated Alcoholic Liver Cirrhosis.

We examined 74 patients with acute decompensation of alcoholic liver cirrhosis: 34 (45.9%) with bacterial infection (group 1) and 40 (54.1%) without bacterial infection (group 2). The degree and index of acute-on-chronic liver failure (ACLF) were determined using an on-line CLIF-C ACLF Calculator and the levels of cytokeratin-18 fragments, TNFα, IL-1ß, IL-4, IL-6, and IL-8. In group 1, AST, cytokeratin-18, TNFα, IL-1ß, IL-6, degree and score of ACLF were significantly higher than in group 2. ACLF developed in 18 (52.9%) patients in group 1 and in 11 (27.5%) (p<0.05) patients in group 2. Within 1 month, 10 (29.4%) patients of group 1 and 2 (5%) patients of group 2 died (p<0.05). Patients with bacterial infection showed a more severe course of alcoholic liver cirrhosis and ACLF than those without bacterial infection.

Second-harmonic generation (SHG) microscopy and hepatic venous pressure gradient-based validation of a novel histological staging system for alcoholic hepatitis.

Alcoholic hepatitis (AH) lacks specific histological staging. A novel fibrosis staging that encompasses perisinusoidal fibrosis and cirrhosis sub-stages, substantiated by Hepatic venous pressure gradient (HVPG) and automated fibrosis quantification, is imperative. To correlate novel histological staging system of AH with second-harmonic generation microscopy (SHG)-based q-fibrosis, HVPG, and activated hepatic stellate cells (HSCs). Liver biopsies of AH (n = 175) were staged semi-quantitatively as F0, F1, F2, F3A and F3B and Laennec substages of cirrhosis 4A, 4B and 4C. Stages were correlated with SHG q-fibrosis parameters, HVPG and HSCs. Mean age 41.2 ± 9.4 years, 96.6% males, bilirubin 20.58 ± 8.0 mg/dl and Maddrey's discriminant function 78.9 ± 36.7 displayed advanced fibrosis in 98.6%. With increasing histological stages, an increase in q-fibrosis indices and mean HVPG (p < 0.0001) were recorded; stage 4C showed the most significant difference from other stages (p < 0.000). Stages 3A and 3B were comparable with the stages 4A and 4B, respectively, for q-fibrosis (p = 1) and HVPG (p = 1). HSCs (> 30%) were significantly higher in stage 3 (75%) compared with 4 (49%) and 2 (59%), p = 0.018. Overall agreement for histological staging was excellent for all stages (0.82). SHG quantified fibrosis and HVPG corroborates the novel histological staging of AH. Expansive PCF matches with collagen content and clinical severity to early sub-stages of cirrhosis. This highlights the need for an accurate quantification and inclusion of PCF as a separate stage. SHG-based quantification can be a useful adjunct to histological fibrosis staging systems.

miRNA expression profiles in liver grafts of HCV and HIV/HCV-infected recipients, 6 months after liver transplantation.

In hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infected patients, HIV enhances HCV replication and liver damage. Several microRNAs (miRNAs), active in pro-fibrotic and inflammatory pathways, have been implicated in the pathogenesis of this phenomenon. However, these miRNAs have been tested only in explanted cirrhotic livers, when the liver damage has become chronic and irreversible. No data are available on the early phase of viral infection, such as early after liver transplantation (LT). In the present study, the expression of miR-101, miR-122, miR-155, miR-192, miR-200c, miR-338, and miR-532 was determined by quantitative real-time polymerase chain reaction in liver biopsies of HCV (n = 19) and HCV/HIV-infected (n = 20) LT recipients, as well as in a control group (n = 18) of noninfected patients, transplanted for alcoholic cirrhosis. The timing of liver biopsy was 6 months post-LT. None of the patients was treated with direct-acting anti-HCV drugs. All co-infected recipients had suppressed HIV viral load. Grading and staging were assessed according to the Ishak Classification. HCV and HIV viral load were measured in the sera. miR-101 (p = .03), miR-122 (p = .012), and miR-192 (p = .038) were significantly downregulated in HCV/HIV co-infected and HCV mono-infected recipients when compared with noninfected recipients, and such downregulation was more pronounced in co-infected ones. Moreover, in co-infected recipients but not in mono-infected ones, miR-101 inversely correlated with the peripheral HCV-RNA levels (r = .41, p = .04) and miR-122 inversely correlated with peripheral HCV-RNA levels (r = .49, p = .03) and with the histological grading (r = .51, p = .02).  In conclusion, as early as 6 months after LT, the presence of HIV-HCV co-infection enhanced a significant downregulation of certain miRNAs that showed a direct correlation with HCV viral load and liver inflammation.

Point shear wave elastography predicts fibrosis severity and steatohepatitis in alcohol-related liver disease.

BACKGROUND: Point shear wave elastography (pSWE) is a convenient noninvasive tool for assessing liver fibrosis in chronic liver disease. However, there is little information on the correlation between pSWE and the histological findings of alcohol-related liver disease (ALD). Thus, we investigated the diagnostic performance of pSWE in discriminating the fibrosis stage of patients with ALD. METHODS: A total of 251 Korean patients with ALD were prospectively enrolled. The diagnostic performance of pSWE was evaluated on the basis of histological fibrosis severity according to Kleiner/Brunt et al.'s criteria and the Laennec classification. RESULTS: Median liver stiffness on pSWE significantly increased as liver fibrosis stage increased (p < 0.001). Liver stiffness measurement proved to be an excellent diagnostic indicator in the evaluation of a ≥ F2 stage (area under the receiver operating characteristics curve [AUROC] 0.93; cutoff > 1.46 m/s), ≥ F3 stage (AUROC 0.90; cutoff > 1.47 m/s), and F4 stage (AUROC 0.91; cutoff > 1.66 m/s). Compared with noninvasive serum fibrosis tests, pSWE had the highest AUROC for predicting ≥ F2, ≥ F3, and = F4 stages and the highest Obuchowski index (0.931 ± 0.007; all p < 0.001). The AUROC for discriminating steatohepatitis from simple steatosis was 0.93 (> 1.49 m/s) and the AUROC for discriminating cirrhosis with steatohepatitis from cirrhosis without steatohepatitis was 0.92 (> 2.52 m/s). CONCLUSION: pSWE not only gives an accurate indication of liver fibrosis stage in ALD, but also can allow patients with severe alcoholic steatohepatitis to begin corticosteroid treatment without exposing them to the risks of liver biopsy. CLINICAL TRIAL REGISTRATION: Clincialtrials.gov Identifier NCT01943318.

Portal vein thrombosis prevalence and mortality among alcoholic cirrhosis in a nationwide inpatient cohort.

OBJECTIVES: Portal vein thrombosis is commonly associated with cirrhosis. The effect of alcoholic cirrhosis on portal vein thrombosis prevalence and mortality has not been well studied. METHODS: We conducted a retrospective cohort study utilizing the 2000-2014 National Inpatient Sample Database. We included patients older than 18 years with decompensated cirrhosis without a history of liver transplantation or hepatocellular carcinoma. We further identified patients with alcoholic cirrhosis vs. non-alcoholic cirrhosis. Primary outcomes included the risk and mortality of portal vein thrombosis in alcoholic cirrhosis. Secondary outcomes included trends of portal vein thrombosis prevalence and mortality in alcoholic cirrhosis, implications of portal vein thrombosis on complications in alcoholic cirrhosis vs. non-alcoholic cirrhosis, and risk of venous thromboembolism in alcoholic cirrhosis. RESULTS: Among 1 892 271 patients with decompensated alcoholic cirrhosis, portal vein thrombosis prevalence was 1.3%. Alcoholic cirrhosis was associated with lower risk of portal vein thrombosis (odds ratio 0.76, P < 0.001) and venous thromboembolism (odds ratio 0.69, P < 0.001) compared to non-alcoholic cirrhosis. Portal vein thrombosis contributed to increased mortality (odds ratio 1.19, P < 0.001) in alcoholic cirrhosis. Portal vein thrombosis prevalence among alcoholic cirrhosis increased while mortality declined during the study period. CONCLUSION: Thrombotic events including portal vein thrombosis and venous thromboembolism were found in less frequent association with alcoholic cirrhosis compared with non-alcoholic cirrhosis. Despite this, the higher in-hospital mortality found among portal vein thrombosis with alcoholic cirrhosis should prompt careful consideration of management.

Cardiac Dysfunction in Patients with Liver Cirrhosis.

BACKGROUND: The clinical picture in cirrhosis is dominated by the classical complications such as ascites, bleeding varices, portal hypertension and encephalopathy. Cardiac dysfunction in patients with cirrhosis, which contributes significantly to the morbidity and, mortality though prevalent, is less studied and not widely recognized entity since it is largely asymptomatic at rest, with overt heart failure seen mainly during pharmacological stress, transjugular intrahepatic portosystemic shunt, liver transplantation. METHODS: It is a cross sectional study done on patients admitted in wards or attending to outpatient department of Liver unit, Bir Hospital, between May 2015 to May 2016. Diagnosis of cirrhosis was based on clinical examination, lab parameters, ultrasound examination, endoscopy and/or liver biopsy. Cirrhotic patients after assessing the exclusion criteria were recruited for the study. Child Pugh and model for end stage liver disease scores were calculated to assess the liver function. Cardiac function was evaluated by resting pulse, mean arterial pressure, electrocardiography, and 2 dimensional echocardiography. RESULTS: Diastolic dysfunction was seen in 61.9%(48) and was more common in alcoholic group (63.2% Vs 58.6%). Systolic dysfunction was seen in 6.6% of alcoholic patients only. 51.4% had cirrhotic cardiomyopathy according to the criteria (proposed by World congress of gastroenterology in 2005). Prolonged QTc of >0.44 seconds was noted in 79%, mainly in child pugh C, with model for end stage liver disease score >10. CONCLUSIONS: Cardiac dysfunction is prevalent with sizeable number of patients with cirrhosis especially in the form of diastolic dysfunction independent of etiology. QTc prolongation might be an early indicator of cardiac dysfunction and is directly correlated with child pugh and model for end stage liver disease scores.

Miguel Ángel y el hígado de Noé: ¿Una lección secreta de anatomía? / Michelangelo and Noah's liver: a hidden anatomy lesson?

Miguel Ángel Buonarroti (1475 - 1564) es considerando uno de los más grandes artistas de la historia. Estudió en detalle la anatomía humana a través de la disección de cadáveres, práctica hasta entonces relegada por motivos religiosos. Desde que en el año 1990 el médico Frank Lynn Meshberger publicara su interpretación del fresco "La Creación de Adán" basada en la neuroanatomía, en donde comparaba la imagen de Dios con la de una sección sagital del cerebro humano, muchos autores han encontrado diversas referencias anatómicas ocultas en la obra de Miguel Ángel. En el presente trabajo exponemos el hallazgo de una inédita lección de anatomía hepática oculta en el fresco La Embriaguez de Noé de la Capilla Sixtina.

Michelangelo Buonarroti (1475 - 1564) is considered one of the greatest artists in history. He studied in detail the human anatomy through corpses dissection, practice until then relegated for religious reasons. Since the physician Frank Lynn Meshberger published in 1990 his interpretation of the fresco "The Creation of Adam" based on neuroanatomy, where he compared the image of God with a sagittal section of the human brain, many authors have found various hidden anatomical references in the work of Michelangelo. In the present paper we expose the finding of a hidden lesson on liver anatomy in the fresco The Drunkenness of Noah of the Sistine Chapel.

ECM1 Prevents Activation of Transforming Growth Factor ß, Hepatic Stellate Cells, and Fibrogenesis in Mice.

BACKGROUND & AIMS: Activation of TGFB (transforming growth factor ß) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Natural history of histologically proven alcohol-related liver disease: A systematic review.

BACKGROUND & AIMS: To date, studies into the natural history of alcohol-related liver disease (ALD) have lacked long-term follow-up, large numbers of participants, or both. We performed a systematic review to summarise studies that describe the natural history of histologically proven ALD. METHODS: PubMed and Medline were searched for relevant studies according to pre-specified criteria. Data were extracted to describe the prevalence of ALD, histological progression of disease and mortality. Single-proportion meta-analysis was used to combine data from studies regarding rates of progression or mortality. RESULTS: Thirty-seven studies were included, reporting data from 7,528 participants. Amongst cohorts of hazardous drinkers, on average 15% had normal histological appearance, 27% had hepatic steatosis, 24% had steatohepatitis and 26% had cirrhosis. The annualised rates of progression of pre-cirrhotic disease to cirrhosis were 1% (0-8%) for patients with normal histology, 3% (2-4%) for hepatic steatosis, 10% (6-17%) for steatohepatitis and 8% (3-19%) for fibrosis. Annualised mortality was 6% (4-7%) in patients with steatosis and 8% (5-13%) in cirrhosis. In patients with steatohepatitis on biopsy a marked difference was seen between inpatient cohorts (annual mortality 15%, 8-26%) and mixed cohorts of inpatients and outpatients (annual mortality 5%, 2-10%). Only in steatosis did non-liver-related mortality exceed liver-specific causes of mortality (5% per year vs. 1% per year). CONCLUSIONS: These data confirm the observation that alcohol-related hepatic steatohepatitis requiring admission to hospital is the most dangerous subtype of ALD. Alcohol-related steatosis is not a benign condition as it is associated with significant risk of mortality. LAY SUMMARY: Knowledge of the natural history of a disease allows clinicians and patients to understand the risks that are associated with a medical condition. In this study we systematically gathered all the published data regarding the natural history of alcohol-related liver disease in people who had a liver biopsy. We used this data to define the prevalence of the disease, the annual risk of progression to cirrhosis and the annual risk of death at each stage of the disease.

Successful definitive concurrent chemoradiotherapy in a patient with esophageal cancer and Child-Pugh B cirrhosis of the liver.

This case report demonstrates successful concurrent chemoradiotherapy for esophageal cancer without severe adverse events in a patient with cirrhotic disease. A 63-year-old Japanese male with alcoholic liver cirrhosis was referred to our hospital for treatment of superficial esophageal cancer. Endoscopic submucosal dissection was performed and the patient was diagnosed as having squamous cell carcinoma of the esophagus that was pathologically staged as pT1bN0M0. When a superficial tumor involves the submucosa, esophagectomy is usually recommended. However, the patient was at high risk of perioperative morbidity and mortality because of impaired liver function. As an alternative to esophagectomy, the patient received concurrent chemoradiotherapy, comprising nedaplatin 64 mg/m2 on days 1 and 34 and S-1 80 mg/body orally on days 1-14 and 34-47 with concurrent radiotherapy of 50 Gy in daily fractions of 2 Gy. He has shown no signs of recurrence in the 30 months since his treatment.

Fibrosis and alcohol-related liver disease.

Histological fibrosis stage is one of the most important prognostic factors in compensated and decompensated alcohol-related liver disease (ALD). Morphological assessment of fibrosis is useful for patient stratification, enabling individualised management, and for evaluation of treatment effects in clinical studies. In contrast to most chronic liver diseases where fibrosis is portal-based, fatty liver disease (FLD) of alcoholic or non-alcoholic aetiology (NAFLD) is associated with a centrilobular pattern of injury which leads to perivenular fibrosis and/or pericellular fibrosis. Progression of FLD drives expansive pericellular fibrosis, linking vascular structures and paving the way for the development of cirrhosis. At the cirrhotic stage, ongoing tissue damage leads to increasing fibrosis severity due to parenchymal loss and proliferation of fibrous scars. Histologic fibrosis staging systems have been devised, based on topography and the extent of fibrosis, for most chronic liver diseases. The utility of histological staging is reflected in different risks associated with individual fibrosis stages which cannot be reliably distinguished by non-invasive fibrosis assessment. In contrast to NAFLD, ALD-specific staging systems that enable the standardised prognostication required for clinical management and trials are lacking. Although morphological similarities between NAFLD and ALD exist, differences in clinical and histological features may substantially limit the utility of established NAFLD-specific staging systems for prognostication in ALD. This review summarises morphological features of fibrosis in ALD and compares them to other chronic liver diseases, particularly NAFLD. ALD-related fibrosis is examined in the context of pathogenetic mechanisms of fibrosis progression, regression and clinical settings that need to be considered in future prognostically relevant ALD staging approaches.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Histopathology of Alcohol-Related Liver Diseases.

Excessive alcohol consumption can lead to a spectrum of liver histopathology, including steatosis, steatohepatitis, foamy degeneration, fatty liver with cholestasis, and cirrhosis. Although variability in sampling and pathologist interpretation are of some concern, liver biopsy remains the gold standard for distinguishing between steatohepatitis and noninflammatory histologic patterns of injury that can also cause the clinical syndrome of alcohol-related hepatitis. Liver biopsy is not routinely recommended to ascertain a diagnosis of alcohol-related liver disease in patients with an uncertain alcohol history, because the histologic features of alcohol-related liver diseases can be found in other diseases, including nonalcoholic steatohepatitis and drug-induced liver injury.

[Ascending Colon Variceal Bleeding in Cirrhotic Patient with Emergent Endoscopic Variceal Obturation with N-butyl-2-cyanoacrylate].

Ectopic varices are rare among patients with portal hypertension, especially in the ascending colon. It is difficult to evaluate massive lower gastrointestinal bleeding in patients with liver cirrhosis by colonoscopy due to hemodynamic instability and poor bowel preparation. In Korea, there has only been one case report about ascending colon variceal bleeding, in which hemostasis was performed by venous coil embolization. We report another rare case of ascending colon variceal bleeding in a patient with alcoholic cirrhosis, who was successfully treated via two sessions of N-butyl-2-cyanoacrylate injection through colonoscopy. This case suggests that the careful endoscopic approach and hemostasis with glue injection might be an option for treating massive bleeding in the lower gastrointestinal varix.