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.

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

Beneficial effects of LRP6-CRISPR on prevention of alcohol-related liver injury surpassed fecal microbiota transplant in a rat model.

Alcohol intake can modify gut microbiota composition, increase gut permeability, and promote liver fibrogenesis. LRP6 is a signal transmembrane protein and a co-receptor for the canonical Wnt signaling pathway. This study compared the curative effect of LRP6-CRISPR on alcohol-related liver injury with that of traditional fecal microbiota transplant (FMT) and investigated the alteration of the gut microbiome following the treatment. A rat model of alcohol-related liver injury was established and injected with lentiviral vectors expressing LRP6-CRISPR or administered with fecal filtrate from healthy rats, with healthy rat served as the control. Liver tissues of rats were examined by HE staining, Sirius staining, and Oil red O staining, respectively. The expression of LRP6 and fibrosis biomarkers were tested by PCR. The fecal sample of rats was collected and examined by 16S rRNA sequencing. Our data indicated that LRP6-CRISPR was more efficient in the prevention of alcohol-related liver injury than FMT. Microbiome analysis showed that alcohol-related liver injury related to gut microbiota dysbiosis, while treatment with LRP6-CRISPR or FMT increased gut microflora diversity and improved gut symbiosis. Further, bacteria specific to the disease stages were identified. Genera Romboutsia, Escherichia-Shigella, Pseudomonas, Turicibacter, and Helicobacter were prevalent in the intestine of rats with alcohol-related liver injury, while the domination of Lactobacillus was found in rats treated with LRP6-CRISPR or FMT. Besides, Lactobacillus and genera belonging to family Lachnospiraceae, Bacteroidales S24-7 group, and Ruminococcaceae were enriched in healthy rats. LRP6-CRISPR and FMT have beneficial effects on the prevention of alcohol-related liver injury, and correspondently, both treatments altered the disrupted gut microflora to a healthy one.

Gender Disparities in Alcohol Use Disorder Treatment Among Privately Insured Patients with Alcohol-Associated Cirrhosis.

BACKGROUND: The burden of alcohol-associated cirrhosis (AC) is high, and though alcohol cessation improves mortality, many patients fail to engage in alcohol use disorder (AUD) treatment and continue drinking. Our aim was to determine rates, predictors, and outcomes of AUD treatment utilization in AC patients with private insurance. METHODS: We collected data from persons with AC (diagnosed by ICD-9/ICD-10 codes), aged 18 to 64 years, enrolled in the Truven MarketScan Commercial Claims and Encounters database (2009 to 2016). We determined rates and predictors of substance abuse treatment visits as well as rates of alcohol relapse prevention medication prescriptions, weighted to the national employer-sponsored insured population. Effects of AUD treatment utilization on decompensation rates were calculated using proportional hazards regression with propensity score adjustment. RESULTS: A total of 66,053 AC patients were identified, 32% were female, and mean age at diagnosis was 54.5 years. About 72% had insurance coverage for substance abuse treatment. Overall, AUD treatment utilization rates were low, with only 10% receiving a face-to-face mental health or substance abuse visit and only 0.8% receiving a Food and Drug Administration (FDA)-approved relapse prevention medication within 1 year of index diagnosis. Women were less likely to receive a face-to-face visit (hazard ratio [HR] 0.84, p < 0.001) or an FDA-approved relapse prevention medication (0.89, p = 0.05) than men. AC patients who had a clinic visit for AUD treatment or used FDA-approved relapse medication showed decreased risk of decompensation at 1 year (HR 0.85, p < 0.001 for either). CONCLUSIONS: AUD treatment utilization is associated with lower decompensation rates among privately insured patients with AC. Women were less likely to utilize AUD treatment visits. Efforts to reduce gender-specific barriers to treatment are urgently needed to improve outcomes.

Opportunities to Prevent Alcoholic Liver Cirrhosis in High-Risk Populations: A Systematic Review With Meta-Analysis.

BACKGROUND: Alcoholic liver cirrhosis is preventable and caused by heavy drinking. Few in the general population may be at risk and interventions targeting individuals at high risk may be a more feasible opportunity for prevention than interventions targeting the whole population. METHODS: We conducted a systematic review to identify opportunities to prevent alcoholic liver cirrhosis in high-risk populations. Following MOOSE guidelines, we included observational studies published between 1980 and 2017. Prospective studies of alcohol-problem cohorts were included to investigate whether alcohol-problem cohorts qualify as high-risk populations for alcoholic liver cirrhosis. Studies on the alcohol amount consumed by alcoholic liver cirrhosis patients were included to compare with the amount consumed by the general population. Moreover, studies on alcohol-related healthcare contacts prior to alcoholic liver cirrhosis diagnosis were included to identify opportunities to offer prevention interventions. Of 7198 screened references, 38 studies (N = 120,928) were included. RESULTS: Alcohol-problem cohorts qualified as high-risk populations with an incidence of alcoholic liver cirrhosis ranging from 7 to 16% after 8-12 years. The alcohol amount consumed by alcoholic liver cirrhosis patients was high compared to the general population. For example, 45% (95%CI 34, 56) of alcoholic liver cirrhosis patients were drinking >110 g alcohol/day. Finally, there were opportunities to reach alcoholic liver cirrhosis patients prior to diagnosis; 40-61% of alcoholic liver cirrhosis patients had a previous alcohol-related healthcare contact. CONCLUSIONS: We conclude that alcohol-problem cohorts are high-risk populations for alcoholic liver cirrhosis and there seems to be opportunities to reach later alcoholic liver cirrhosis cases with preventive interventions in healthcare settings.

Betaine treatment decreased oxidative stress, inflammation, and stellate cell activation in rats with alcoholic liver fibrosis.

The aim of this study was to investigate the effect of betaine (BET) on alcoholic liver fibrosis in rats. Fibrosis was experimentally generated with ethanol plus carbon tetrachloride (ETH+CCl4) treatment. Rats were treated with ETH (5% v/v in drinking water) for 14 weeks. CCl4 was administered intraperitoneally (i.p.) 0.2mL/kg twice a week to rats in the last 6 weeks with/without commercial food containing BET (2% w/w). Serum hepatic damage markers, tumor necrosis factor-α, hepatic triglyceride (TG) and hydroxyproline (HYP) levels, and oxidative stress parameters were measured together with histopathologic observations. In addition, α-smooth muscle-actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and type I collagen (COL1A1) protein expressions were assayed immunohistochemically to evaluate stellate cell (HSC) activation. mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were also determined. BET treatment diminished TG and HYP levels; prooxidant status and fibrotic changes; α-SMA, COL1A1 and TGF-ß protein expressions; MMP-2, TIMP-1 and TIMP-2 mRNA expressions in the liver of fibrotic rats. In conclusion, these results indicate that the antifibrotic effect of BET may be related to its suppressive effects on oxidant and inflammatory processes together with HSC activation in alcoholic liver fibrosis.

Survey of alcohol-related cirrhosis at a tertiary care center in North East India.

BACKGROUND: Alcohol use is increasing in North East India and is important to estimate the influence of these changes in the epidemiology of alcohol related cirrhosis. METHODS: Among 1000 consecutive patients of cirrhosis, diagnosed by a combination of clinical, radiological and/or histopathological features, etiology was established by history of significant alcohol abuse, determining viral and autoimmune markers and by metabolic screening. Patients not confirmed to be cirrhotic were excluded from the study. All cases were studied to determine clinical features, complications, disease prognosis, and mortality. Alcoholic cirrhotics were then compared with nonalcohol etiology. RESULTS: 72.2 % alcoholic cirrhosis were compared with 27.8 % patients of nonalcohol etiology and alcoholic cirrhotics were younger (45 + 9.4 years vs. 47.9 + 12.5 years), predominantly males (M/F ratio 37:1 vs. 1.8:1) with significantly high incidence of jaundice (38.5 % vs. 30.5 %), night blindness (14.4 % vs. 3.6 %), ascites (76.3 % vs. 69.1 %), upper gastrointestinal bleed (46.4 % vs. 34.5 %), and hepatic encephalopathy (24.1 % vs. 10.4 %). Biochemical parameters that were significantly higher in alcoholics were mean bilirubin (4.7 + 8.7 vs. 3.1 + 4.7 mg/dL), AST/ALT ratio (2.03 vs. 1.4), gamma-glutaryl transaminase levels (209.7 + 37.9 vs. 93.9 + 14 IU/mL), and serum ammonia (75.1 + 55.7 vs. 52.1 + 45.4 mg/dL). Mean model for end-stage liver disease, scores, and Child C disease was significantly higher in alcoholics (18.6 + 7.7 vs. 15.6 + 6.4) and (54.1 % vs. 37 %), respectively, representing advanced disease at presentation. Mortality within 1 month was significantly higher among alcoholic cirrhosis (9.8 % vs. 3.2 %). CONCLUSION: Thus, alcoholic cirrhosis is of major concern in North East India as majority patients are in most productive age group and presented with advanced disease. Short-term mortality was high among alcoholic cirrhotics. Proper education and legislation are essential to mitigate the consequences of this disease.

EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1.

Hepatic stellate cells (HSCs) activation represents an essential event during alcoholic liver fibrosis (ALF). Previous studies have demonstrated that the rat HSCs could be significantly activated after exposure to 200 µmol/L acetaldehyde for 48 h, and the cAMP/PKA signaling pathways were also dramatically upregulated in activated HSCs isolated from alcoholic fibrotic rat liver. Exchange protein activated by cAMP (EPAC) is a family of guanine nucleotide exchange factors (GEFs) for the small Ras-like GTPases Rap, and is being considered as a vital mediator of cAMP signaling in parallel with the principal cAMP target protein kinase A (PKA). Our data showed that both cAMP/PKA and cAMP/EPAC signaling pathways were involved in acetaldehyde-induced HSCs. Acetaldehyde could reduce the expression of EPAC1 while enhancing the expression of EPAC2. The cAMP analog Me-cAMP, which stimulates the EPAC/Rap1 pathway, could significantly decrease the proliferation and collagen synthesis of acetaldehyde-induced HSCs. Furthermore, depletion of EPAC2, but not EPAC1, prevented the activation of HSC measured as the production of α-SMA and collagen type I and III, indicating that EPAC1 appears to have protective effects on acetaldehyde-induced HSCs. Curiously, activation of PKA or EPAC perhaps has opposite effects on the synthesis of collagen and α-SMA: EPAC activation by Me-cAMP increased the levels of GTP-bound (activated) Rap1 while PKA activation by Phe-cAMP had no significant effects on such binding. These results suggested that EPAC activation could inhibit the activation and proliferation of acetaldehyde-induced HSCs via Rap1.

Alcohol-attributable healthcare attendances up to 10 years prior to diagnosis of alcoholic cirrhosis: a population based case-control study.

BACKGROUND & AIMS: Cirrhosis because of alcohol could be avoided if drinking behaviour could be altered earlier in the disease course. Our aim was to quantify the burden of morbidities in patients prior to alcoholic cirrhosis diagnosis, as this may inform the earlier identification of people at high risk for targeted interventions. METHODS: We carried out a case-control study using 2479 incident cases of alcoholic cirrhosis and 24 790 controls identified from 357 primary and secondary care centres in England. We assessed the prevalence of morbidities that are partly attributable to alcohol (namely malignant neoplasms, diabetes, epilepsy, injuries, cardiovascular and digestive diseases) prior to alcoholic cirrhosis diagnosis. We compared prevalence in cases to the control population and used logistic regression to derive odds ratios (95% CI). RESULTS: Fifty-eight per cent of cases compared to 29% of controls had had at least one alcohol-attributable condition before cirrhosis diagnosis. The most frequent conditions (proportion in cases vs. controls) were intentional injuries (35.9% vs. 11.9%) and cardiovascular diseases (23.2% vs. 15.6%), followed by diabetes (12.8% vs. 5.3%), digestive diseases (6.1% vs. 1.2%) and epilepsy (5.0% vs. 1.1%). The strongest association with alcoholic cirrhosis was found for digestive diseases [OR 5.4 (4.4-6.7)], epilepsy [OR: 4.4 (3.5-5.5)] and injuries [OR: 4.0 (3.7-4.4)] particularly among those aged 18-44 years. CONCLUSION: These data highlight the high burden of other alcohol-attributable conditions in patients prior to alcoholic cirrhosis diagnosis. Reviewing those consistently presenting with any of these conditions more closely could help practitioners reduce/avoid the long-term consequences of development of alcoholic liver disease.

Alcohol y salud: ¿Alcohol y salud?: revisión bibliográfica / Alcohol and health: alcohol and health?: review of the literature

El consumo excesivo de bebidas alcohólicas constituye un serio problema sanitario y social. En los últimos años se han destacado sus propiedades anticancerosas, antioxidantes y protectoras contra la enfermedad cardíaca coronaria, lo que ha generado controversias entre beneficios y perjuicios de su consumo. Los efectos tóxicos sobre el sistema nervioso central lideran el cuadro de la intoxicación aguda, mientras que los efectos del consumo crónico afectan prácticamente todo el organismo, alterando numerosas funciones aún en etapas tempranas de la vida. Los profesionales de las ciencias de la salud tienen un rol clave en la prevención de los daños producidos por este hábito tan difundido.

Instrumento para avaliação da qualidade do Time de Resposta Rápida em um hospital universitário público / Instrument for assessing the quality of the Rapid Response Team at a university public hospital / Instrumento para la evaluación de la calidad del Equipo de Respuesta Rápida en un hospital universitario público

O artigo descreve a construção de um questionário para avaliação da qualidade do atendimento de um Time de Resposta Rápida, em Hospital Universitário de Londrina-PR, fundamentado no modelo conceitual de Donabedian (estrutura-processoresultado). A coleta de dados ocorreu no mês de março de 2012 e o processo de adequação do questionário foi desenvolvido com a aplicação da Técnica Delphi com a participação de 15 especialistas. Ao término do estudo obteve-se um questionário com 37 enunciados, sendo alcançado índice de concordância final na pesquisa com valores superiores a 80% para todos os conceitos. Espera-se que as contribuições do grupo de especialistas tornem o instrumento confiável e seja aplicado em outros serviços semelhantes. Aplicações futuras deste instrumento poderão trazer subsídios para melhor avaliação da qualidade dos serviços de equipes de Resposta Rápida.

The paper describes the construction of a questionnaire to assess the quality of care of a Rapid Response Team at the University Hospital of Londrina, based on the conceptual model of Donabedian (structure-process-outcome). Data collection occurred in March 2012 and the process of adjusting the questionnaire was developed with the application of the Delphi technique involving 15 experts. At the end of the study the questionnaire contained 37 statements, achieving final compliance level higher than 80% in all concepts. It is hoped that the contributions of the expert group produce a more reliable questionnaire to be applied in other similar services. Future applications of this instrument may provide information to better assess the quality of teams of Rapid Response services.

El artículo describe la construcción de un cuestionario para la evaluación de la calidad de la atención de un Equipo de Respuesta Rápida en un Hospital Universitario de Londrina, Paraná, basado en el modelo conceptual de Donabedian (estructura-procesoresultado). La recolección de datos ocurrió durante el mes de marzo de 2012 y el proceso de ajuste del cuestionario fue desarrollado por medio de la Técnica Delphi con la participación de 15 especialistas. Al término del estudio se obtuvo un cuestionario con 37 enunciados, alcanzándose un índice de concordancia final en la investigación con valores superiores al 80% para todos los conceptos. Se espera que las contribuciones del grupo de especialistas afiancen la confiabilidad del instrumento y que el cuestionario sea utilizado en otros servicios semejantes. Las aplicaciones futuras podrán traer subsidios para evaluar mejor la calidad de los servicios de los equipos de Respuesta Rápida.

[Effect of curcumin on antioxidant function in the mice with acute alcoholic liver injury].

OBJECTIVE: To study the effect of curcumin on antioxidant function in the mice with acute alcoholic liver injury. METHODS: 50 male KM mices were randomly divided into 5 groups according to the weight, i. e. the normal control group, model control group, and curcumin low-dose group, middle-dose group, high-dose group (50, 100 and 200 mg/kg BW). After a 14-day administration, the relative liver weight, the content of MDA, the activity of SOD, GSH-Px, T-AOC in the liver tissue and the content of serum AST, ALT were determined. RESULTS: Compared with the normal control group, all indexes of model control group were significantly different (P < 0.05). The content of serum AST and ALT at high-dose group were significantly decreased compared with model control group (P < 0.05). Meanwhile, the activity of SOD, GSH-Px and T-AOC in the liver tissue were increased significantly (P < 0.05), and the content of MDA decreased significantly (P < 0.05). CONCLUSION: Curcumin can improve the antioxidant activity of the mice with acute alcoholism, and has good protective effects on acute alcoholic liver injury in mice.

[Primary and secondary prevention of alcoholic liver cirrhosis].

Alcohol--is the main causative factor of cirrhosis among the population in Russia. The primary prevention must be focused on exception of consumption of heavy doses of alcohol hepatitis and B vaccination. There are no healthy doses of alcohol. Secondary prevention means the use of the hepatoprotectors. List of hepatoprotectors and also amount of money spent to the purchase of these hepatoprotectors increase constantly. But, unfortunately, alongside with it, increases the mortality from hepatic disorders. Effectiveness of the most hepatoprotectors (such as Essential phospholipids, milk thistle) equals to the effectiveness of placebo.

Hepatopoietin Cn reduces ethanol-induced hepatoxicity via sphingosine kinase 1 and sphingosine 1-phosphate receptors.

The hepatic growth factor hepatopoietin Cn (HPPCn) prevents liver injury induced by carbon tetrachloride in rats. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase (SphK). S1P and S1P receptors (S1PRs) are involved in liver fibrogenesis and oxidative injury. This work sought to understand the mechanism by which SphK/S1P/S1PRs are involved in the protective effects of HPPCn on ethanol-induced liver injury and fibrosis. Transgenic mice with liver-specific overexpression of HPPCn (HPPCn(liver) (+/+)) were generated. Two ethanol feeding protocols were used to assess the protective effect of HPPCn on acute and chronic liver injury in mice. Specific inhibitors of S1PR1, S1PR2 and S1PR3 and siRNA were used to examine the roles of S1PRs in hepatic stellate cell (HSC) activation and hepatocyte apoptosis. Increased HPPCn expression in transgenic mice attenuated fibrosis induced by ethanol and carbon tetrachloride (CCl4). Treatment with recombinant human HPPCn prevented human hepatocyte apoptosis and HSC activation. JTE-013 or S1PR2-siRNA attenuated the effect of HPPCn on HSC activation induced by tumour necrosis factor-α (TNF-α). Consistent with the effect of N,N-dimethylsphingosine (DMS), suramin or S1PR3-siRNA treatment blocked HPPCn-induced Erk1/2 phosphorylation in human hepatocytes. This study demonstrated that HPPCn attenuated oxidative injury and fibrosis induced by ethanol feeding and that the SphK1/S1P/S1PRs signalling pathway contributes to the protective effect of HPPCn on hepatocyte apoptosis and HSC activation.

Protective effect of genistein isolated from Hydrocotyle sibthorpioides on hepatic injury and fibrosis induced by chronic alcohol in rats.

This study examined the effect of genistein isolated from Hydrocotyle sibthorpioides on chronic alcohol-induced hepatic injury and fibrosis. Rats underwent intragastric administration of alcohol (5.0-9.5g/kg) once a day for 24 weeks. A subset of rats were also intragastrically treated with genistein (0.5, 1 or 2mg/kg) once a day. Genistein significantly decreased the plasma alcohol concentration, inhibited the activities of alanine and aspartate aminotransferases and decreased levels of inflammatory mediators, including interleukin 6, tumor necrosis factor-α and myeloperoxidase, via down-regulation of nuclear factor-κB. Moreover, genistein effectively inhibited collagen deposition and reduced pathological tissue damage as determined by hepatic fibrosis biomarkers, such as total hyaluronic acid, laminin, and type III collagen. Mechanistically, studies showed that genistein markedly reduced lipid peroxidation, recruited the anti-oxidative defense system, inhibited CYP2El activity, promoted extracellular matrix degradation by modulating the levels of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-2, induced HSC apoptosis by down-regulating B-cell lymphoma 2 mRNA, and inhibited the expression of α-smooth muscle actin and transforming growth factor ß(1) proteins. In conclusion, genistein exerts a preventative effect to ameliorate developing liver injury and even liver fibrosis induced by chronic alcohol administration in rats.

Inhibition of apoptosis protects mice from ethanol-mediated acceleration of early markers of CCl4 -induced fibrosis but not steatosis or inflammation.

BACKGROUND: Correlative evidence indicates that apoptosis is associated with the progression of alcoholic liver disease. If apoptosis contributes to ethanol (EtOH)-induced steatohepatitis and/or fibrosis, then mice deficient in Bid, a key pro-apoptotic Bcl-2 family member, or mice treated with a pan-caspase inhibitor (VX166) should be resistant to EtOH-induced liver injury. METHODS: This hypothesis was tested in mice using a model of chronic, heavy EtOH-induced liver injury, as well as in a model in which moderate EtOH feeding accelerated the appearance of early markers of hepatic fibrosis in response to acute carbon tetrachloride (CCl(4) ) exposure. RESULTS: Chronic EtOH feeding to mice increased TUNEL- and cytokeratin-18-positive cells in the liver, as well as the expression of receptor-interacting protein kinase 3 (RIP3), a marker of necroptosis. In this model, Bid-/- mice or wild-type mice treated with VX166 were protected from EtOH-induced apoptosis, but not EtOH-induced RIP3 expression. Bid deficiency or inhibition of caspase activity did not protect mice from EtOH-induced increases in plasma alanine and aspartate amino transferase activity, steatosis, or mRNA expression of some inflammatory cytokines. Moderate EtOH feeding to mice enhanced the response of mice to acute CCl(4) exposure, resulting in increased expression of α-smooth muscle actin and accumulation of extracellular matrix protein. VX166-treatment attenuated EtOH-mediated acceleration of these early indicators of CCl(4) -induced hepatic fibrosis, decreasing the expression of α-smooth muscle actin, and the accumulation of extracellular matrix protein. CONCLUSIONS: EtOH-induced apoptosis of hepatocytes was mediated by Bid. Apoptosis played a critical role in the accelerating the appearance of early markers of CCl(4) -induced fibrosis by moderate EtOH but did not contribute to EtOH-induced hepatocyte injury, steatosis, or expression of mRNA for some inflammatory cytokines.

Epidemiology-based risk assessment using the benchmark dose/margin of exposure approach: the example of ethanol and liver cirrhosis.

BACKGROUND: A novel approach to derive a threshold dose with respect to alcohol-related harm, the benchmark dose (BMD) methodology, is introduced to provide a basis for evidence-based drinking guidelines. This study is the first to calculate a BMD for alcohol exposure using epidemiological cohort data. With this BMD we will be able to calculate the margin of exposure (MOE) for alcohol consumption, which can be used for comparative risk assessment and applied to setting public health policy. METHODS: Benchmark dose-response modelling of epidemiological data gathered during a recent systematic review and meta-analysis of alcohol consumption as a risk factor for liver cirrhosis morbidity and mortality. RESULTS: For a benchmark response (BMR) of 1.5%, the resulting BMD values were 30.9 g/day for males and 29.7 g/day for females; the corresponding lower one-sided confidence values were 25.7 and 27.2 g/day, respectively. The intake scenario for the Canadian population resulted in an MOE of 1.23. Intake scenarios for individuals as based on the Canadian drinking guidelines led to MOE values between 0.96 and 1.91. Using an uncertainty factor of 10, the acceptable daily intake for alcohol would be 2.6 g/day. CONCLUSIONS: The BMD approach was feasible in developing evidence-based guidelines for low-risk drinking. As our calculated MOEs result around unity (i.e. 1) for moderate drinking, it is evident that the current guidelines correspond very well to low risk on the dose-response curve. The BMD methodology therefore validates current guidelines. The results again highlight the health risk associated with alcohol consumption.

On measurement of avoidable and unavoidable cost of alcohol: an application of method for estimating costs due to prior consumption.

This study estimates the avoidable and unavoidable costs of alcohol-related, liver cirrhosis inpatient care, controlling for the lag structure and period of decline in disease risk. Lag structures with different lengths are applied to the exposure to risk from alcohol consumption, which allows for differentiation between avoidable and unavoidable cases due to prior consumption. A lag length of 20 (men) and 23 (women) years (expected remaining life years) gives a total cost of 592 million SEK. Given alcohol consumption is reduced to zero, 72% of cost could potentially be avoided. It is important to account for the length and structure of the risk decline following a consumption change as this substantially affects the estimates.