Alcoholic-related Liver Disease Research Articles

JNK/MAPK pathway regulation by BEX2 gene silencing in alcoholic hepatitis mice: Effects on oxidative stress.

Alcoholic hepatitis (AH) is a severe alcoholic-related liver disease that is a leading cause of morbidity and mortality, for which effective treatments are lacking. Brain-expressed X-linked gene 2 (BEX2) has been implicated in various diseases, but its association with AH has received limited attention. Thus, this study investigated BEX2's impact on the progression of AH by affecting the c-Jun NH2-terminal kinase/mitogen-activated protein kinase (JNK/MAPK) pathway. Microarray dataset GSE28619 from the Gene Expression Omnibus database was used to identify differentially expressed genes in AH. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), Western blot analysis, and flow cytometry were used to measure various factors in the liver tissue of AH mice. BEX2 expression was significantly upregulated in the model. BEX2 gene silencing increased the levels of glutathione peroxidase and superoxide dismutase while decreasing malondialdehyde content; phosphorylation of JNK, c-JUN, and p38MAPK; apoptosis rate; and the extent of JNK/MAPK pathway activation. These findings provide valuable insights into the mechanisms underlying AH development and highlight the potential role of BEX2 gene expression as a promising therapeutic target for AH.

Zonal expression of StARD1 and oxidative stress in alcoholic-related liver disease

Alcoholic-related liver disease (ALD) is one of the leading causes of chronic liver disease and morbidity. Unfortunately, the pathogenesis of ALD is still incompletely understood. StARD1 has emerged as a key player in other etiologies of chronic liver disease, and alcohol-induced liver injury exhibits zonal distribution. Here, we report that StARD1 is predominantly expressed in perivenous (PV) zone of liver sections from mice-fed chronic and acute-on-chronic ALD models compared to periportal (PP) area and is observed as early as 10 days of alcohol feeding. Ethanol and chemical hypoxia induced the expression of StARD1 in isolated primary mouse hepatocytes. The zonal-dependent expression of StARD1 resulted in the accumulation of cholesterol in mitochondria and increased lipid peroxidation in PV hepatocytes compared to PP hepatocytes, effects that were abrogated in PV hepatocytes upon hepatocyte-specific Stard1 KO mice. Transmission electron microscopy indicated differential glycogen and lipid droplets content between PP and PV areas, and alcohol feeding decreased glycogen content in both areas while increased lipid droplets content preferentially in PV zone. Moreover, transmission electron microscopy revealed that mitochondria from PV zone exhibited reduced length with respect to PP area, and alcohol feeding increased mitochondrial number, particularly, in PV zone. Extracellular flux analysis indicated lower maximal respiration and spared respiratory capacity in control PV hepatocytes that were reversed upon alcohol feeding. These findings reveal a differential morphology and functional activity of mitochondria between PP and PV hepatocytes following alcohol feeding and that StARD1 may play a key role in the zonal-dependent liver injury characteristic of ALD.

FRI-458 - Evaluation of histological differences between cirrhosis due to alcoholic-related liver disease and non-alcoholic steatohepatitis using automated fibrosis phenotyping of liver histology

FRI-458 - Evaluation of histological differences between cirrhosis due to alcoholic-related liver disease and non-alcoholic steatohepatitis using automated fibrosis phenotyping of liver histology

Impaired lower limb muscle mass, quality and function in end stage liver disease: A cross-sectional study.

What is the central question of this study? To what extent does musculoskeletal impairment occur (i.e., muscle mass, quality and function) in patients with end stage liver disease (ESLD) by comparison to a healthy age/sex-matched control group? What is the main finding and its importance? Muscle mass, quality and function are impaired in patients with ESLD (compared to age/sex matched controls). Importantly, greater impairments were seen in lower limb compared to arm and trunk muscle groups. These findings may suggest that there should be greater consideration of muscle health in functionally relevant lower limb muscle groups. Sarcopenia is associated with reduced quality of life and increased mortality in patients with end stage liver disease (ESLD). Historically, sarcopenia identification in ESLD utilised L3 skeletal muscle index (SMI). There are few data on muscle quality and function within lower limb muscle groups with high functional relevance. The aim of this prospective case-control study was to evaluate the quadriceps muscle in patients with ESLD. Muscle mass and quality were evaluated using MRI (quadriceps anatomical cross sectional area (ACSA), quadriceps volume index, L3 SMI, quadriceps intermuscular adipose tissue (IMAT)), mid-arm muscle circumference (MAMC) and ultrasonography (vastus lateralis (VL) thickness and quadriceps ACSA). Muscle strength/function was assessed by handgrip strength, peak quadriceps isokinetic torque and chair rise time. Thirty-nine patients with ESLD (55 years, 61% male, 48% alcoholic related liver disease (ArLD), 71% Child-Pugh B/C) and 18 age/sex-matched healthy control participants (HC) were studied. Quadriceps mass was significantly reduced in ESLD versus HC (-17%), but L3 SMI and MAMC were unchanged. Quadriceps IMAT percentage was increased in ESLD (+103%). Handgrip strength (-15%), peak isokinetic torque (-29%), and chair rise time (+56%) were impaired in ESLD. Ultrasound measures of VL thickness (r=0.56, r=0.57, r=0.42) and quadriceps ACSA (r=0.98, r=0.86, r=0.67) correlated to MRI quadriceps ACSA, quadriceps volume and L3 SMI, respectively. Quadriceps muscle mass, quality, and function were impaired in patients with ESLD, whereas conventional assessments of muscle (L3 SMI and MAMC) highlighted no differences between ESLD and HC. Full evaluation of lower limb muscle health is essential in ESLD in order to accurately assess sarcopenia and target future interventions.

Histomorphological Changes in Pancreas and Liver among Chronic AlcoholicsAn Autopsy Study

Introduction: The clinical and pathological association between pancreatitis and alcohol abuse is well recognised, however the concurrence of prevalence of alcoholic related pancreatitis and liver disease is less well studied. Aim: To evaluate frequency of histomorphological changes in pancreas and liver among patients with history of alcohol abuse and observe the prevalence of coexistence between chronic pancreatitis and liver cirrhosis. Materials and Methods: This was observational cross-sectional study conducted in Department of Pathology at Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India, from July 2013 to July 2018. The study included 1917 autopsies and 107 cases with a documented history of chronic alcohol abuse. Haematoxylin and Eosin (H&E) staining was done on all sections and special stain like Masson’s trichrome was performed as per indication. Gross and microscopy were studied under variable defined parameters. Data was entered in Microsoft Excel sheets. Results: Histomorphologically, 12 cases (11.21%) were diagnosed as pancreatitis; 10 cases (9.34%) were of acute pancreatitis and two cases (1.86%) were of chronic pancreatitis. Total 21 cases were diagnosed as liver cirrhosis. The most dominant pattern of fibrosis seen in pancreatitis was perilobular and interlobular periductal fibrosis. The frequency of pancreatitis (14.28%) and pancreatic fibrosis (38.09%) was found to be more in cirrhotics. Chronic pancreatitis was commonly seen in cirrhotics than in non cirrhotics. Similarly, liver cirrhosis was more commonly observed in cases of chronic pancreatitis. Conclusion: The frequency of histomorphological changes seen in pancreas and liver was observed considerably among patients giving history of alcohol abuse. The prevalence of co-existence of chronic pancreatitis and liver cirrhosis was 50%.

Alcoholic liver disease: A registry view on comorbidities and disease prediction.

Alcoholic-related liver disease (ALD) is the cause of more than half of all liver-related deaths. Sustained excess drinking causes fatty liver and alcohol-related steatohepatitis, which may progress to alcoholic liver fibrosis (ALF) and eventually to alcohol-related liver cirrhosis (ALC). Unfortunately, it is difficult to identify patients with early-stage ALD, as these are largely asymptomatic. Consequently, the majority of ALD patients are only diagnosed by the time ALD has reached decompensated cirrhosis, a symptomatic phase marked by the development of complications as bleeding and ascites. The main goal of this study is to discover relevant upstream diagnoses helping to understand the development of ALD, and to highlight meaningful downstream diagnoses that represent its progression to liver failure. Here, we use data from the Danish health registries covering the entire population of Denmark during nineteen years (1996–2014), to examine if it is possible to identify patients likely to develop ALF or ALC based on their past medical history. To this end, we explore a knowledge discovery approach by using high-dimensional statistical and machine learning techniques to extract and analyze data from the Danish National Patient Registry. Consistent with the late diagnoses of ALD, we find that ALC is the most common form of ALD in the registry data and that ALC patients have a strong over-representation of diagnoses associated with liver dysfunction. By contrast, we identify a small number of patients diagnosed with ALF who appear to be much less sick than those with ALC. We perform a matched case–control study using the group of patients with ALC as cases and their matched patients with non-ALD as controls. Machine learning models (SVM, RF, LightGBM and NaiveBayes) trained and tested on the set of ALC patients achieve a high performance for data classification (AUC = 0.89). When testing the same trained models on the small set of ALF patients, their performance unsurprisingly drops a lot (AUC = 0.67 for NaiveBayes). The statistical and machine learning results underscore small groups of upstream and downstream comorbidities that accurately detect ALC patients and show promise in prediction of ALF. Some of these groups are conditions either caused by alcohol or caused by malnutrition associated with alcohol-overuse. Others are comorbidities either related to trauma and life-style or to complications to cirrhosis, such as oesophageal varices. Our findings highlight the potential of this approach to uncover knowledge in registry data related to ALD.

Alcoholic-related liver disease: pathogenesis, management and future therapeutic developments.

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies.

Predictive models of mortality and hospital readmission of patients with decompensated liver cirrhosis

IntroductionComplications of cirrhosis are one the major causes of hospital admission associated with high morbimortality rates and social and economic charges.The aims of this study were to evaluate hospital readmission and mortality rates and predictive factors for hospital readmission and mortality. MethodsPatients with decompensated cirrhosis admitted to our institution between 2008–2014 were retrospectively analyzed. ResultsIncluded 427 admissions from 177 patients with cirrhosis with mean age of 59.0 ± 12.3 years. The major cause was alcoholic-related liver disease and the median duration of admission was 9.0 days (IQR 6.0–14.0).During the follow-up period,there were 250 readmissions from 95 patients, with a median of 58 (IQR27-134) days for readmission, representing 58.5% of the total number of admissions.The 180-day mortality rate was 35.0%.In the multivariate analysis, ascites, smoking and MELD Na were associated with 180-day mortality. Creatinine, albumin, esophageal variceal bleeding, previous variceal banding, lactulose, rifaximin and proton pump inhibitors use were independently associated with need of readmission. Based on regression analysis, two models were calculated to predict 180-day mortality (AUROC 0.74 (0.682−0.794)) and need for readmission(AUROC 0.821 (0.781−0.861)), p < 0.001. ConclusionThe readmission rate and mortality of cirrhotic patients are still very high and it is a priority to determine preventable risk factors to improve patient outcome.Two models were created to predict 180-day mortality(AUROC 0.74) and need for readmission(AUROC 0.821), that could guide the management of the patients at the time of admission.

Co-stimulation of LPAR1 and S1PR1/3 increases the transplantation efficacy of human mesenchymal stem cells in drug-induced and alcoholic liver diseases

BackgroundOne of the major obstacles facing stem cell therapy is the limited number of functional stem cells available after transplantation due to the harsh microenvironment surrounding the damaged tissue. The aim of this study was to delineate the mechanistic involvement of lysophosphatidic acid receptors (LPARs) and sphingosine-1-phosphate receptors (S1PRs) in the regulation of anti-stress and transplantation efficacy of stem cells.MethodsHuman adipose-derived mesenchymal stem cells (hADMSCs) were treated with chemical toxin or ethanol to induce cell stress. Lysophosphatidic acid (LPA) and/or sphingosine-1-phosphate (S1P) were co-treated to examine their protective effects and mechanisms on stem cell damage. Acute liver failure and alcoholic liver disease murine models were also established to test the transplantation efficacy of hADMSCs with or without LPA/S1P pre-incubation.ResultsCo-stimulation of LPAR1 by LPA and S1PR1/3 by S1P synergistically enhanced the anti-stress ability of hADMSCs induced by chemical or ethanol incubation in vitro. Downstream pathways involved in this process included the Gi protein (but not the G12/13 proteins), the RAS/ERK pathway, and the PI3K/Akt pathway. Upon cell injury, the nuclear translocation of nuclear factor-kappa B (NF-κB) was promoted to facilitate the activation of downstream pro-inflammatory gene transcription, which was ameliorated by co-treatment with LPA and/or S1P. Increased secretion of interleukin (IL)-10 from stem cells by LPA and/or S1P seemed to be one of the major protective mechanisms since blocking IL-10 expression significantly aggravated stress-induced cell damage. In a drug-induced acute liver failure model and a chronic alcoholic liver disease model, pre-conditioning with LPA and/or S1P significantly enhanced the survival ratio and the therapeutic efficacy of hADMSCs in mice, including ameliorating histological damage, oxidative stress, inflammation, fibrosis, lipid metabolism dysfunction, and enhancing alcohol metabolizing enzyme activity. Importantly, supplementing LPA and/or S1P did not alter the basic characteristics of the hADMSCs nor induce tumour formation after cell transplantation.ConclusionsCo-use of LPA and S1P represents a novel and safe strategy to enhance stem cell transplantation efficacy for future drug- and alcoholic-related liver disease therapies.

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice.

Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis±IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

Outcomes after index hospital admission for decompensated alcohol-related cirrhosis versus severe alcoholic hepatitis: a retrospective cohort study

BackgroundWe have previously described outcomes in severe alcoholic hepatitis, identifying abstinence after hospital discharge as the only independent predictor of long-term survival. The outcome of patients presenting with other forms of decompensated alcohol-related liver disease is unknown. Our aim was to assess predictors of inpatient and long-term survival in patients admitted with decompensated alcohol-related cirrhosis compared with those with severe alcoholic hepatitis. MethodsA retrospective case-note review was performed for all index hospital admissions with alcoholic-related liver disease between April 1, 2005, and Dec 31, 2011. Patients with decompensated alcohol-related cirrhosis (Child-Pugh score ≥7 and bilirubin <80 mmol/L) were compared with a previously studied cohort with severe alcoholic hepatitis admitted over the same time period (discriminant function ≥32, corroborated by biopsy results where available). Predictors of inpatient survival were determined using binary logistic regression, and the Kaplan-Meier method was used to estimate long-term survival. Findings177 patients were studied (73 decompensated alcohol-related cirrhosis, 104 severe alcoholic hepatitis). In decompensated alcohol-related cirrhosis, the independent determinants of inpatient mortality were hospital-acquired infection (odds ratio 20·2, 95% CI 3·5–118; p=0·001) and hepatic encephalopathy (9·3, 1·8–47; p=0·007). Overall median survival was similar in both groups (26 months [IQR 12·8–39·2] in decompensated alcohol-related cirrhosis vs 23 [10·6–35·4] in severe alcoholic hepatitis, p=0·872) with similar abstinence rates at last follow-up (41·1% vs 34·6%, p=0·431). In severe alcoholic hepatitis, abstinence at last follow-up was the only predictor of survival (3 year survival 75·2% in abstainers vs 33·2% in continued drinkers, p=0·012). However, in decompensated alcohol-related cirrhosis, abstinence did not predict long-term survival (median survival 36 months [IQR 22·3–49·7] in abstainers vs 38 [9·9–66·1] in continued drinkers, p=0·949). InterpretationInpatient mortality in decompensated alcohol-related liver disease was predicted by hospital-acquired infection and hepatic encephalopathy. Long-term survival in decompensated alcohol-related cirrhosis did not significantly improve with abstinence, which is in contrast to severe alcoholic hepatitis, and this suggests a reduced scope for disease reversibility thereby mandating earlier assessment for liver transplantation. FundingNone.

Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease.

BackgroundFew studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting.MethodsIn this retrospective study, all patients who underwent a liver biopsy 1984–2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine.ResultsA total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01).ConclusionsPatients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.

S16 * ALCOHOLIC LIVER DISEASE AND LIVER TRANSPLANTATION * S16.3 * RELAPSE OF HARMFUL DRINKING IN LIVER-TRANSPLANTED ALCOHOLICS: RISK STRATIFICATION AND CHALLENGE TO THE 6-MONTH RULE

Alcoholic liver diesease (ALD) is still the most frequent and lethal complication in chronic alcoholism. Primary treatment modalities are abstinence, agents that suppress inflammation, anticytokine therapy and nutritional support, among others. For alcoholic liver cirrhosis, transplantation is an accepted option but requires careful consideration of alcohol history and future prognosis resp treatment options. Although there is a relationship between the lemgth of sobriety and future abstience, the present methods to predict future drinking are inexact. Approximately 20% of patients return to harmful drinking after transplantation (Lucey, 2011). Compared with other patient groups, relapse rates in patients with ALD are low. A number of other clinical variables apart from length of abstinence (Tandon et al. , 2008) may predict outcome as alcohol research shows. This may include alcohol-associated symptoms, previous treatments and psychopathological symptoms including cogntion and history of suicide attempts. In general, DSM-IV-Tr alcoholism criteria appear to have greater utility for predicting survival differences beyond pathophysiologically defined alcoholic liver failure (Rowley et al. , 2010). Implications for diagnosis and treatment are discussed. REFERENCES Lucey M (2011) Liver transplantaion in patients with alcoholic liver disease. Liver Transpl , doi. 10.1002/lt.22330. Rowley AA, Hong BA, Chapmna W et al. (2010) The psychiatric disgnosis of alcohol abuse and the medical diagnosis of alcoholic related liver disease: effect on liver transplant survival. J Clin Psychol Med Settings 17 :195–202. Tandon P, Goodman KJ, Ka MM et al. (2009) A shorter duration of pre-transplant abstinence predicts problem drinking after liver transplantation. Am J Gastroenterol 104 :1700–1706. # S16.4 EARLY LIVER TRANSPLANTATION AS A RESCUE OPTION FOR PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS NON-RESPONSIVE TO THERAPY: A CHANGE OF PARADIGMS? {#article-title-2} Although liver transplantation (LT) for alcoholic liver disease has a favorable outcome, it remains controversial in the eyes of the public. To ration organs, most programs require a 6-month period of abstinence prior to evaluation of alcoholic patients, which is presumed to: (a) permit patients to recover from liver failure; (b) identify subsets of patients likely to maintain abstinence after LT. Acute alcoholic hepatitis (AAH) is the most severe form of alcoholic liver disease. In its severe form (defined by a discriminant function ≥32), the risk of dying within 2 months is 40–50%. A recent analysis of individual data from five randomized controlled studies evaluating corticosteroids in severe AAH patients demonstrated a better short-term survival in the group of patients treated by steroids. The so-called Lille model enables clinicians to identify early on those patients unlikely to respond to medical management. Using this approach, strict application of the 6-month rule may be unfair to such patients, since 70–80% of them die prior to the end of the sobriety period. Alternative therapies, such as pentoxifylline or MARS therapy, have been demonstrated to be inefficient in patients non-responsive to corticosteroids. The recent French and Belgian pilot experience in highly selected patients showed that early LT clearly improves 6-month survival of patients with severe AAH refractory to medical management. In this preliminary experience, the relapse rate was limited and occurred late after LT. This approach opens new perspectives for such patients, but will need a drastic selection of candidate patients by expert centers. These encouraging results must be confirmed by other groups. REFERENCES Lucey M, Mathurin P, Morgan TR (2009) Alcoholic hepatitis. N Engl J Med 360 :2758–2769. Mathurin P, O'Grady J, Carithers RL et al. (2011) Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 60 :255–260. Louvet A, Naveau S, Abdelnour M et al. (2007) The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 45 :1348–1354. Louvet A, Diaz E, Dharancy S et al. (2008) Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J Hepatol 48 :465–470. Moreno C, Duclos-Vallee JC, Castel H et al. (2010) Early transplantation improves survival of non-responders to corticosteroids in severe alcoholic hepatitis: a challenge to the 6 month rule of abstinence. Am J Transplant A398.

The Psychiatric Diagnosis of Alcohol Abuse and the Medical Diagnosis of Alcoholic Related Liver Disease: Effects on Liver Transplant Survival

The present study investigated whether differing diagnostic criteria for alcoholism used by mental health professionals versus hepatologists lead to different outcomes in predicting liver transplant survival as determined by the medical record and without a priori judgments. This was in contrast to past studies, particularly in the liver transplant literature, demonstrating comparable survival rates between alcoholics and non-alcoholics that have typically employed a diagnosis of Alcoholic Liver Disease (ALD), which does not capture the salient maladaptive behavioral and interpersonal features associated with DSM-IV-TR diagnoses of Alcohol Abuse (AA) and Alcohol Dependence (AD). A series of survival analyses were conducted using data culled from the psychological and medical records of 358 first-time liver transplant recipients at Barnes-Jewish Hospital in St. Louis, Missouri. The primary outcome investigated was liver graft survival following transplant surgery. Follow-up times varied from 0 days to 13 years, depending on the time of transplant and length of graft survival, with a median follow-up time of 6.2 years. Diagnoses of AA and AD predicted significantly poorer survival rates, while diagnoses of ALD did not. DSM-IV-TR alcoholism criteria appear to have greater utility for predicting survival differences beyond pathophysiologically defined alcoholic liver failure.

LONG TERM RESULTS OF LIVER TRANSPLANTATION FOR ALCOHOLIC RELATED LIVER DISEASE UNDER TACROLIMUS

765 Results of liver transplantation (Ltx) for alcohol related liver disease have been quite satisfactory in short term. Aim of the present study is to examine the results of patient/graft survival and evaluate the causes of graft loss and death in long term. Material: Between Sept. 89 and Dec. 92, 188 adults received primary Ltx under tacrolimus for alcoholic related end stage liver disease. These were 132 (70%) male and 56 (30%) female; mean age 51.0±10.1 (median 51.5; range 25.9 to 75.0) 31 (16%) patients had associated other diagnosis (13-non A non B hepatitis, 10- hepatocellular carcinoma, 4 - autoimmune hepatitis, 3 hepatic B and 1 - cholangiocarcinoma). All patients were followed until April 98. Mean follow-up 7.1 ± 0.9 (mean 7.2; range 5.4 to 8.6) years. 96 (51% were 1 cu bound (UNOS 2A 67 (35.6%) non ICU bound hospitalized (UNOS 2B) and 25 (13.3%) patients came from home (UNOS-3). Results: During the follow up period 23 patients received second Ltx (hepatic artery thrombosis 12, primary non-function 8, portal vein thrombosis, biliary stricture 1, HCV - 1,) and 3 patients received 3rd Ltx. 77 patients died. Commonest cause of late death was denovo cancers accounted 10 cases; 13% of all deaths and 28, 9% of deaths beyond 2 years. (Oropharyngeal - 5, lung - 3, renal -1, unknown primary -1). Patient and graft survival for different UNOS status is shown in the (table). Rate of recidivism is currently evaluated.TableConclusion: overall patients survival and graft survival in long term for alcoholic related end stage liver disease has remained satisfactory with 7 year patient survival of 60% and graft survival of 57%. Rate of recidivism leading to graft loss has fortunately remained low because of prior rehabilitation. Commonest cause of late death, beyond two years, is denovo cancer (mainly oropharyngeal and pulmonary) and demands thorough screening for early detection to improve long term survival.

Personality disorder as a contraindication for liver transplantation in alcoholic cirrhosis.

Severe personality disorder has been proposed as a contraindication for liver transplantation. Seventy-three subjects with alcoholic-related liver disease were evaluated for personality disorder and followed for 6 months. The subjects with severe personality disorder had higher rates of divorce, higher rates of comorbid drug abuse or dependence, lower Weschler Adult Inventory Scale IQ estimates, and higher scores on indicators of emotional impairment. Personality disorder was not associated with a higher rate of return to alcohol use during the follow-up period. Three subjects with personality disorder underwent liver transplantation without behavioral or substance abuse complications. This study does not support routine exclusion of subjects based solely on a diagnosis of a severe personality disorder.

Tumor necrosis factor and alcoholic liver disease.

Increased levels of hepatic and serum tumor necrosis factor (TNF) have been documented in animal models of alcoholic liver disease and in human alcoholic liver disease. This dysregulated TNF metabolism has been postulated to play a role in many of the metabolic complications and the liver injury of alcoholic liver disease. One potential therapy for alcoholic liver disease may be agents that downregulate TNF production or block TNF activity. Indeed, agents such as prostaglandins and glucocorticoids (both inhibit TNF production) have been used in both human liver disease and experimental models of liver injury, and anti-TNF antibody has recently been shown to attenuate the hepatotoxicity in an animal model of alcoholic-related liver disease. In this study, we demonstrate that a simple ex vivo system can be used to initially assess potential efficacy of anticytokine agents when administered to humans. Both prednisone and a prostaglandin analog were effective in downregulating TNF and interleukin-8 production. The liver is normally resistant to TNF cytotoxicity. Sensitivity to TNF cytotoxicity is thought to occur when there is inadequate production of hepatic protective factors. In this study, we showed that, when patients with acute alcoholic hepatitis were matched with trauma patients for serum levels of interleukin-6, they had similar depressions in the negative acute phase protein, albumin, but markedly different increases in the major acute phase protein, C reactive protein. Patients with alcoholic hepatitis had a very blunted response. We also showed that inhibiting activation of the redox sensitive transcription factor NFkappaB sensitizes to TNF-induced hepatocyte death in vitro. This transcription factor is important for the production of both cytokines and many acute phase protective factors. Several hepatic protective factors are induced by TNF. One possible mechanism for liver injury in alcoholic hepatitis may be inadequate generation of hepatic protective factors. Our future understanding of mechanisms of alcoholic liver disease will involve understanding the balance between noxious and protective factors in the liver, and this should lead to rational therapy for this disease process.