End-stage Alcoholic Liver Disease Research Articles

When Should Patients With Less Than 6 Months Sobriety Be Transplanted?

Alcoholic liver disease (ALD) and alcohol-induced deaths have increased dramatically over the last 2 decades. Patients are often referred to liver transplant programs critically ill with a life expectancy of less than 6 months. Historically, less than 6 months sobriety has been an absolute contraindication for transplant listing as ALD is stigmatized as a choice, as patients are responsible for their condition because they did not stop drinking. It has been recommended that 6 months of sobriety should not be considered the determining factor for access to transplantation. However, changing years of clinical practice involves developing new protocols, finding available resources, reworking systems, transforming team, and institutional culture. Steps taken by a large, urban, academic liver transplant program to develop a program for patients with end stage ALD with less than 6 months of sobriety are outlined.

Personality traits and cognition as predictors of long-term quality of life after transplantation for alcoholic liver disease

IntroductionLiver transplantation (LT) is a crucial treatment for end-stage alcoholic liver disease, the most common liver disease in developed countries. Personality traits and cognition, a relatively stable characteristics, are known to be significantly associated with quality of life (QoL). However, how they impact QoL in long-term LT survivors is unclear.ObjectivesThe study aimed to assess the associations between personality traits and cognition and their impact on the QoL in long-term LT survivors.MethodsFirst time LT recipients due to end-stage alcohol liver disease without long-term complications were consecutively included during standard outpatient care. Sociodemographic and clinical data was collected. Personality traits were assessed using 50-item International Personality Item Pool of the Five-factor model (IPIP), cognition using Mini Mental State Examination (MMSE), and QoL using EuroQoL-5D (EQ-5D) questionnaire.ResultsEighty-three participants were included (mean age 62.9±7.03y, 90.6% male). Median MMSE score was 27±2.00, and median years since LT 5±2.91. Significant positive associations were found between IPIP dimensions Extraversion (B=0.297, p<0.01), Agreeableness (B=0.384, p<0.01), Conscientiousness (B=0.511, p<0.01), and Emotional stability (B=0.432, p<0.01) with EQ-5D visual analogue scale (EQ VAS). IPIP dimension Conscientiousness (B=0.338, p<0.01) and Emotional Stability (B=0. 379, p<0.01) were significantly associated with descriptive dimension of EQ-5D (EQ-5D-3L). MMSE score was significantly associated with QoL (EQ-VAS B=0.291, p<0.01; EQ-5D-3L B=0.283, p<0.05, respectively). However, MMSE score was not shown to be a statistically significant predictor of QoL, whereas Consciousness was a significant predictor of EQ-VAS (β 1.404, t 3.125), and Emotional stability of EQ-5D-3L (β 0.011, t 2.132).ConclusionsSome personality traits predicted QoL in long-term LT survivors. Therefore, assessment of personality traits should be considered as a part of pre-LT evaluation within a regular psychiatric clearance evaluation.Disclosure of InterestS. Medved: None Declared, B. Aukst Margetić: None Declared, A. Ražić Pavičić: None Declared, T. Filipec Kanižaj : None Declared, V. Medved Grant / Research support from: This work was done as a part of the “Genetic Background of End Stage Alcoholic Liver Disease and Liver Transplantation” study supported by the University of Zagreb, Croatia grant 2017 and 2018.

Mechano-structural alteration in proximal femora of individuals with alcoholic liver disease: Implications for increased bone fragility.

Although increased hip fracture risk is noted in patients with alcoholic liver disease (ALD), their femoral microstructural and mechanical properties were not investigated previously. The present study aimed to analyze the associations between subregional deteriorations in femoral mechano-structural properties and clinical imaging findings to explain increased femoral fracture risk among ALD patients. This study analyzed proximal femora of 33 male cadaveric donors, divided into ALD (n=13, 57±13years) and age-matched control group (n=20, 54±13years). After pathohistological verification of ALD stage, DXA and HSA measurements of the proximal femora were performed, followed by micro-CT and Vickers microindentation of the superolateral neck, inferomedial neck, and intertrochanteric region. Bone mineral density and cross sectional area of the femoral neck were deteriorated in ALD donors, compared with healthy controls (p<0.05). Significant ALD-induced degradation of trabecular and cortical microstructure and Vickers microhardness reduction were noted in the analyzed femoral regions (p<0.05). Still, the most prominent ALD-induced mechano-structural deterioration was noted in intertrochanteric region. Additionally, more severe bone alterations were observed in individuals with an irreversible stage of ALD, alcoholic liver cirrhosis (ALC), than in those with an initial ALD stage, fatty liver disease. Observed osteodensitometric and mechano-structural changes illuminate the basis for increased femoral fracture risk in ALD patients. Additionally, our data suggest bone strength reduction that may result in increased susceptibility to intertrochanteric femoral fracture in men with ALD. Thus, femoral fracture risk assessment should be advised for all ALD patients, especially in those with ALC.

A Phase II Dose Escalation Study of Intraarterial (Hepatic) Adult Human Bone Marrow Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells (Stempeucel®) in Patients with Alcoholic Liver Cirrhosis

Background: Alcoholic liver cirrhosis is an end-stage alcoholic liver disease with a poor prognosis. The definitive treatment of alcoholic liver cirrhosis is orthotopic liver transplantation, which is expensive, requires long-term immunosuppression and is limited by the supply of organs. Being an unmet medical need, cell therapy is under investigation for alcoholic liver cirrhosis. Aims: This study was designed primarily for assessing the safety and feasibility of administering stempeucel® through the hepatic artery in alcoholic liver cirrhosis and secondarily to assess possible efficacy and dose-response. Methods: Sixty patients with alcoholic cirrhosis (18-65 years/Child-Pugh class B or C/Model for End-Stage Liver Disease score of minimum 10) were planned to be included in 6 groups: 2.5 million cells/kg Body Weight (2.5M Cell) and respective control (2.5M Control); 5 million cells/kg Body Weight (5M Cell) and respective control (5M Control); 7.5 million cells/kg Body Weight (5M Cell) and respective control (7.5M Control) with 10 patients in each group. Cell groups received stempeucel® administered via hepatic artery by catheterization through the femoral artery (Seldinger technique) and Standard Protocol of Care. The control group received Standard Protocol of Care. Patients were followed up at 1 week, 1 month, 3 months and 6 months. Efficacy evaluations included liver function test, Model for End-Stage Liver Disease score, Child-Pugh score, Short Form-36 questionnaire, liver stiffness using Fibroscan (Transient Elastography), and liver volume using Computerized Tomography scan. Results: Stempeucel® injection was well tolerated. Common treatment-emergent adverse events were gastrointestinal disorders, general disorders and administration site conditions and infections and infestations. Most of the treatment-emergent adverse events were unrelated / remotely related to stempeucel®. Thirty serious adverse events occurred in 10 patients (3 in 2.5M Cell, 5 in 5M Cell and one each in control groups). Three patients died due to SAEs: Two in 2.5M and one in 5M Cell group, none were related to stempeucel®. Statistically significant improvement was seen in 2.5M group compared to the control group in Short Form-36 score: bodily pain, mental component summary, vitality and social functioning. Conclusion: Stempeucel® was safe, well-tolerated and subjective improvement in Short Form-36 (bodily pain, mental component summary, vitality and social functioning and mental health) score was seen in the 2.5M cell group.

Characteristics of Psychosocial Factors in Liver Transplantation Candidates with Alcoholic Liver Disease before Transplantation: A Retrospective Study in a Single Center in Taiwan.

Liver transplantation (LT) is an essential treatment for end-stage alcoholic liver disease (ALD). The patients’ psychosocial condition plays a vital role in post-transplantation prognosis. A survey of the candidates’ psychosocial wellbeing is necessary before LT. This study aims to investigate the psychosocial characteristics, including the depression degree, family function, alcohol use duration, and alcohol abstinence period, of LT candidates with ALD. In addition, 451 candidates for LT due to ALD were enrolled. They received psychosocial evaluations, including depression scale (Hamilton depression rating scale) and family functioning assessment (adaptability, partnership, growth, affection, resolve (APGAR) index). The test scores were analyzed according to age, alcohol use duration, and alcohol abstinence period. The Hamilton depression rating scale (HAM-D) score and the family APGAR index score differentiated significantly according to the age, alcohol use duration, and abstinence period of the LT candidates. The patients with shorter alcohol use duration tended to have more severe depressive symptoms and poorer family support. The younger patients showed a significantly shorter abstinence period, more severe depression, and poorer family functioning than older patients. The younger ALD patients and patients with shorter alcohol use duration showed an increased severity of depression before transplantation. They need more mental health care over time.

Corrigendum: Leptin Expression and Gene Methylation Patterns in Alcohol-Dependent Patients with Ethyltoxic Cirrhosis—Normalization After Liver Transplantation and Implications for Future Research

Aims Liver transplantation is the only curative treatment available for patients with end-stage alcoholic liver disease. As different studies showed a significant association between leptin plasma levels, gene methylation patterns and the extent of craving in alcohol-dependent patients, we investigated the effect of liver transplantation on leptin expression and promoter methylation. Short summary The present study shows that in alcohol-dependent patients with liver cirrhosis leptin is significantly higher before liver transplantation and decreases significantly after transplantation. Alcohol-dependent patients on the waiting list had significantly higher leptin promoter methylation values than patients who underwent liver transplantation for other reasons than alcoholic liver disease. Methods Only plasma of 118 and peripheral blood mononuclear cells of 121 patients were used: healthy controls (C, n = 24/22), alcohol-dependent patients without ethyltoxic liver cirrhosis (AD, n = 24/22), patients after liver transplantation for other reasons than ethyltoxic liver cirrhosis (C-Tx, n = 18/21), alcohol-dependent patients suffering from ethyltoxic liver cirrhosis on the transplantation waiting list (Pre-Tx, n = 30/28) and patients with prior ethyltoxic liver cirrhosis after liver transplantation (Post-Tx, n = 22/28). Results Leptin protein was significantly elevated in the pre-transplantation cohort when compared to post-transplantation and alcohol-dependent cohorts. Furthermore, leptin promoter methylation was higher in ethyltoxic patients before transplantation compared to non-ethyltoxic patients after transplantation, but not when compared to ethyltoxic patients after transplantation. C-Tx had lower methylation values than all other groups except for Post-Tx. Conclusions Our study outlines the role of leptin protein levels as a marker for AD-related liver damage, contrasting it from AD without severe liver damage. With regard to the results of the methylation analysis, inflammation of the liver appears to cause mechanisms of leptin regulation to deviate from transcriptional regulation. Our data also suggest that leptin regulation is altered in ethyltoxic liver disease when compared to liver cirrhosis caused by other pathologies.

Leptin Expression and Gene Methylation Patterns in Alcohol-Dependent Patients with Ethyltoxic Cirrhosis-Normalization After Liver Transplantation and Implications for Future Research.

Liver transplantation is the only curative treatment available for patients with end-stage alcoholic liver disease. As different studies showed a significant association between leptin plasma levels, gene methylation patterns and the extent of craving in alcohol-dependent patients, we investigated the effect of liver transplantation on leptin expression and promoter methylation. The present study shows that in alcohol-dependent patients with liver cirrhosis leptin is significantly higher before liver transplantation and decreases significantly after transplantation. Alcohol-dependent patients on the waiting list had significantly higher leptin promoter methylation values than patients who underwent liver transplantation for other reasons than alcoholic liver disease. Only plasma of 118 and peripheral blood mononuclear cells of 121 patients were used: healthy controls (C, n = 24/22), alcohol-dependent patients without ethyltoxic liver cirrhosis (AD, n = 24/22), patients after liver transplantation for other reasons than ethyltoxic liver cirrhosis (C-Tx, n = 18/21), alcohol-dependent patients suffering from ethyltoxic liver cirrhosis on the transplantation waiting list (Pre-Tx, n = 30/28) and patients with prior ethyltoxic liver cirrhosis after liver transplantation (Post-Tx, n = 22/28). Leptin protein was significantly elevated in the pre-transplantation cohort when compared to post-transplantation and alcohol-dependent cohorts. Furthermore, leptin promoter methylation was higher in ethyltoxic patients before transplantation compared to non-ethyltoxic patients after transplantation, but not when compared to ethyltoxic patients after transplantation. C-Tx had lower methylation values than all other groups except for Post-Tx. Our study outlines the role of leptin protein levels as a marker for AD-related liver damage, contrasting it from AD without severe liver damage. With regard to the results of the methylation analysis, inflammation of the liver appears to cause mechanisms of leptin regulation to deviate from transcriptional regulation. Our data also suggest that leptin regulation is altered in ethyltoxic liver disease when compared to liver cirrhosis caused by other pathologies.

Liver Transplantation in Patients with Alcoholic Liver Disease: A Retrospective Study.

Alcoholic liver disease (ALD) is the most common liver disease in the Western World. Liver transplantation (LT) is the treatment for end-stage ALD. However, many transplant centers are still reluctant to transplant these patients because of the risk of alcohol relapse, recurrence of the primary liver disease and associated post-transplant complications. We examined survival rate, prevalence of primary liver disease recurrence, re-transplantation and post-transplant complications among transplanted patients for alcoholic cirrhosis compared with those transplanted for viral cirrhosis. data about patients transplanted for alcoholic and viral cirrhosis at the Gemelli Hospital from January 1995 to April 2016 were retrospectively collected. Survival rate was evaluated according to the Kaplan-Meier method. Recurrence was defined as histological evidence of primary liver disease. Data on the onset of complication, causes of death and graft failure after liver transplant were analyzed. There was no statistically significant difference regarding survival rate between the two groups. Only patients transplanted for viral cirrhosis presented with primary liver disease recurrence. There was a higher rate of cancer development in patients transplanted for alcoholic cirrhosis. Cancer was the major cause of death in this population. Risk factors associated with the onset of cancer were a high MELD score at the transplant time and smoking after transplantation. ALD is a good indication for LT. Patients transplanted for alcoholic cirrhosis should receive regular cancer screening and should be advised against smoking. No difference was found between patients transplanted for alcoholic cirrhosis and viral cirrhosis in term of survival rate. Only patients transplanted for viral cirrhosis presented primary liver disease recurrence. A higher rate of cancer development was found in patients transplanted for alcoholic cirrohosis. This complication was associated with post-trasplant smoking.

Liver transplantation in patients with alcoholic liver disease: A retrospective study

Introduction: Alcoholic liver disease is the most common liver disease in the Western World. Alcohol abstinence represents the gold standard for its treatment. When liver function fails to improve in spite of alcohol abstinence, liver transplantation is the treatment of for end-stage alcoholic liver disease; however, many transplant centers are still reluctant to transplant these group of patients because of the risk of alcohol relapse, recurrence of the primary liver disease and associated post transplant complications.

Reluctance to Accept Alcohol Treatment by Alcoholic Liver Disease Transplant Patients: A Qualitative Study.

BackgroundLiver transplantation (LT) is the optimum treatment for patients with end-stage alcoholic liver disease (ALD). However, despite a recognized risk of relapse to harmful drinking, ALD transplant patients are reluctant to use speciality alcohol treatment to support their abstinence, even when offered within the LT context. This study aimed to understand and identify factors contributing to alcohol treatment reluctance by ALD patients undergoing transplantation.MethodsWe conducted an in-depth qualitative study of ALD transplant patients. Minimally structured face-to-face interviews explored participants' alcohol-related experiences and their reasons for not using alcohol treatment during the course of their transplantation. Thematic analysis was used to analyze and interpret interview data to understand treatment reluctance based on participants' experiences.ResultsFive major themes were identified among 3 subgroups of patients (pretransplant and posttransplant abstainers and posttransplant relapsers): (i) the “contract” of mandatory abstinence, (ii) the “gap in the program” involving the lack of candour between patient and staff about alcohol-related matters and the lack of addiction services, (iii) a preference by participants to self-manage their alcohol use disorder, (iv) social support as a facilitator of abstinence and the risk of relapse when social support is diminished, and (v) the fear of stigmatization. Each of these factors were dynamically interrelated and differed slightly for each subgroup.ConclusionsThe LT services may benefit from the inclusion of integrated specialist addiction services in their model of care. Such an approach may enhance the acceptability of alcohol treatment and reduce the risk of relapse among ALD transplant participants, especially for those whose social supports have diminished.

The Reluctance of Liver Transplant Participants with Alcoholic Liver Disease to Participate in Treatment for Their Alcohol Use Disorder: An Issue of Treatment Matching?

ABSTRACTLiver transplantation (LT) has increased the survival for participants with end-stage alcoholic liver disease (ALD), however more than 50% of ALD transplant patients return to alcohol use after LT. Despite medical referral and a number of clinical trials of standard alcohol interventions, participants who are ALD transplant patients are reluctant to use specialist alcohol programs to support their required abstinence. The aim of this study was to identify those factors contributing to treatment reluctance by participants who are ALD transplant patients. The authors conducted a prospective case-control study comparing 40 ALD transplant patients matched for age and sex with 40 alcohol treatment seekers on a number of demographic and clinical predictors associated with treatment seeking. The authors found that lengthy abstinence and a progressive stage of change profile by participants who are ALD transplant patients contributed toward alcohol treatment being perceived as unwarranted or not needed. Furthermore, the ALD group differed significantly to those who would typically utilize alcohol treatment on a number of other clinical variables suggesting that standard alcohol interventions are not well tailored to the ALD transplant population. Two major barriers to help seeking among ALD transplant patients included the potential for stigma and limited access to alcohol services. Based on these findings, an individualized stepped-care alcohol treatment approach taking into account the clinical characteristics and needs of ALD transplant participants is required. Alcohol treatment needs to be integrated with the medical transplant program and is recommended for responsiveness to the ongoing psychological and social needs of those at risk of relapsing.

Management of alcohol recurrence before and after liver transplantation

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide and can lead to steatosis, steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The primary effective treatment for patients with ALD is total alcohol abstinence, although sometimes impossible, liver transplant (LT) is the gold standard treatment for end-stage ALD, which represents the second most common diagnosis among patients undergoing this procedure. Liver transplant in ALD has better results than those for other etiologies. The alcohol consumption recidivism after LT is frequent and 10% to 15% of these resume heavy drinking with consequences to the new liver. The "6-month rule" of abstinence is an arbitrary threshold used in many transplant centers and has never been shown to affect survival after LT. The optimal abstinence period in pre-transplant remains unclear. The patients in the pre- and post-transplant period need evaluation of a multidisciplinary team, as psychiatrist, addiction specialists, including counselling and attendance to support groups. The impact of alcohol relapse on post-transplant outcomes is not entirely clear but is worse with continuing heavy drinking, with poorer survival beyond the fifth post-transplant year malignancy and cardiovascular disease and not recurrent liver failure. Acute alcoholic hepatitis, in careful selected cases, should be transplanted and have comparable survival outcomes. Prevention of alcoholic recidivism has proved to be the most important treatment after liver transplantation.

Incidence and long‐term survival of patients with de novo head and neck carcinoma after liver transplantation

Liver transplant recipients have an increased risk of developing de novo malignancies. We conducted a prospective evaluation of clinicopathological data and predictors for overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) after liver transplantation (1988 to 2010). Thirty-three of 2040 patients who underwent liver transplantation (1.6%) developed de novo HNSCC. The incidence of HNSCC in liver transplant recipients with end-stage alcoholic liver disease (26) was 5%. After a median follow-up of 9 years, 1-year, 3-year, and 5-year OS rates were 74%, 47%, and 34%, respectively. Tumor size, cervical lymph node metastases, tumor site, and therapy (surgery only vs surgery and adjuvant radiotherapy [RT]/chemoradiotherapy [CRT] vs RT/CRT only; p < .0001) were significantly associated with OS in univariate analysis. However, surgery only predicted OS independently in multivariate analysis. Early diagnosis and surgical treatment of de novo HNSCC are crucial to the outcome. HNSCC risk should be taken into close consideration during posttransplantation follow-up examinations, especially among patients with a positive history of smoking and alcohol consumption.

Assessing and treating alcohol relapse risk in liver transplantation candidates.

In Europe between 30 and 50% of all liver transplantations (LTX) are done within the context of chronic end-stage alcoholic liver disease (ALD). However, post-operatively 20-25% of these patients lapse or relapse into heavy alcohol use. Thus, assessment of alcohol relapse risk before enlisting and therapeutic follow-up during and after LTX is of utmost importance. However, as yet there are enormous differences between European countries and between transplant centers, with regard to the assessment methods and criteria and the implementation of therapeutic follow-up. Only the so-called '6-month abstinence' rule is widely used. However, there are not much scientific data validating its use in predicting relapse. Thus, there is a clear need of a more homogeneous approach, which was the focus of a symposium of the European Federation of Addiction Societies during the 14th conference of the European Society for Biomedical Research on Alcoholism, 2013 (ESBRA), entitled 'Liver transplantation: A European perspective'. In a follow-up on this symposium, the authors aim to sum up the evidence of psychiatric assessment criteria and psychiatric treatment interventions relevant in the context of patient selection and patient follow-up within ALD transplantation procedures. Based upon these findings, we propose elements of a procedure that can serve as a first step toward a model of good practice regarding addiction-specialist input within the pre- and post-transplantation period.

Addiction specialist's role in liver transplantation procedures for alcoholic liver disease.

Although liver transplantation (LT) is performed increasingly for patients with end-stage alcoholic liver disease (ALD), the topic remains controversial. Traditionally, the role of an addiction specialist focused on the screening and identification of patients with a high risk on relapse in heavy alcohol use. These patients were in many cases subsequently excluded from a further LT procedure. Recently, awareness is growing that not only screening of patients but also offering treatment, helping patients regain and maintain abstinence is essential, opening up a broader role for the addiction specialist (team) within the whole of the transplant procedure. Within this context, high-risk assessment is proposed to be an indication of increasing addiction treatment intensity, instead of being an exclusion criterion. In this review we present an overview regarding the state of the art on alcohol relapse assessment and treatment in patients with alcohol use disorders, both with and without ALD. Screening, treatment and monitoring is suggested as central roles for the addiction specialist (team) integrated within transplant centers.

Alcoholic liver disease: a synopsis of the Charles Lieber's Memorial Symposia 2009-2012.

This paper is based upon the 'Charles Lieber Satellite Symposia' organized by Manuela G. Neuman at each of the 2009-2012 Research Society on Alcoholism (RSA) Annual Meetings. The presentations represent a broad spectrum dealing with alcoholic liver disease (ALD). In addition, a literature search (2008-2013) in the discussed area was performed in order to obtain updated data. The presentations are focused on genetic polymorphisms of ethanol metabolizing enzymes and the role of cytochrome P4502E1 (CYP2E1) in ALD. In addition, alcohol-mediated hepatocarcinogenesis, immune response to alcohol and fibrogenesis in alcoholic hepatitis as well as its co-morbidities with chronic viral hepatitis infections in the presence or absence of human deficiency virus are discussed. Finally, emphasis was led on alcohol and drug interactions as well as liver transplantation for end-stage ALD.

Lower Recidivism Rates with Good Post-Transplant Outcome in Alcoholic Liver Disease: Experience from a Large Volume Living Donor Liver Transplant Center

Introduction: End-stage Alcoholic Liver Disease (ALD) is one of the leading indications of liver transplantation (LT). Post-transplant recidivism is a major factor influencing the long-term outcome in these patients.

Acute alcoholic hepatitis, end stage alcoholic liver disease and liver transplantation: an Italian position statement.

Alcoholic liver disease encompasses a broad spectrum of diseases ranging from steatosis steatohepatitis, fibrosis, and cirrhosis to hepatocellular carcinoma. Forty-four per cent of all deaths from cirrhosis are attributed to alcohol. Alcoholic liver disease is the second most common diagnosis among patients undergoing liver transplantation (LT). The vast majority of transplant programmes (85%) require 6 mo of abstinence prior to transplantation; commonly referred to as the "6-mo rule". Both in the case of progressive end-stage liver disease (ESLD) and in the case of severe acute alcoholic hepatitis (AAH), not responding to medical therapy, there is a lack of evidence to support a 6-mo sobriety period. It is necessary to identify other risk factors that could be associated with the resumption of alcohol drinking. The "Group of Italian Regions" suggests that: in a case of ESLD with model for end-stage liver disease < 19 a 6-mo abstinence period is required; in a case of ESLD, a 3-mo sober period before LT may be more ideal than a 6-mo period, in selected patients; and in a case of severe AAH, not responding to medical therapies (up to 70% of patients die within 6 mo), LT is mandatory, even without achieving abstinence. The multidisciplinary transplant team must include an addiction specialist/hepato-alcohologist. Patients have to participate in self-help groups.

Treatment of alcoholic liver disease

Alcoholic liver disease (ALD) remains a major cause of liver-related mortality in the US and worldwide. The correct diagnosis of ALD can usually be made on a clinical basis in conjunction with blood tests, and a liver biopsy is not usually required. Abstinence is the hallmark of therapy for ALD, and nutritional therapy is the first line of therapeutic intervention. The role of steroids in patients with moderate to severe alcoholic hepatitis is gaining increasing acceptance, with the caveat that patients be evaluated for the effectiveness of therapy at 1 week. Pentoxifylline appears to be especially effective in ALD patients with renal dysfunction/hepatorenal syndrome. Biologics such as specific anti-TNFs have been disappointing and should probably not be used outside of the clinical trial setting. Transplantation is effective in patients with end-stage ALD who have stopped drinking (usually for ≥6 months), and both long-term graft and patient survival are excellent.

NFκB, cytokines, TLR 3 and 7 expression in human end‐stage HCV and alcoholic liver disease

Conflicting observations exist concerning the role of nuclear factor kappa B (NFjB) in alcoholic liver disease (ALD) in animal models. To date no studies have examined this aspect in human liver tissue. We here assessed cytokines and toll-like receptors (TLRs) expressions in conjunction with NFkappaB activation in non-active end-stage human ALD compared with normal livers and hepatitis C virus (HCV) related end-stage disease. mRNA and protein expression were examined by quantitative PCR and Western blotting, DNA-binding by electrophoretic mobility shift assays and NFkappaB sub-cellular localization by immunofluorescent staining of livers. NFkappaB mRNA and protein expression as well as strong DNA-binding were preserved in ALD but significantly down-regulated in HCV compared with normal livers. P50 immunofluorescence was found in hepatocytes and bile ducts in ALD and normal livers, whereas a shift was observed in p65 staining from non-parenchymal cells in normal livers to hepatocytes in ALD. NFkappaB responsive genes mRNA levels IkBalpha and interleukin 6 were significantly higher in ALD compared with HCV. Tumour necrosis factor alpha (TNFalpha), TLRs 3 and 7 mRNA were up-regulated in ALD and HCV compared with normal liver with TNFalpha and TLR7 being the highest in HCV. Strong induction of interferon beta was found in HCV but not in ALD or normal liver tissue. Persistent NFkappaB activation together with high pro-inflammatory cytokine expression and upregulation of TLR3 and TLR7 is associated with end-stage ALD in humans and could contribute to disease progression even in absence of alcohol intake.