Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.

BACKGROUND AND AIMS: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.

The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

Renal Replacement Therapy for Acute Kidney Injury in Severe Alcohol-Associated Hepatitis as a Bridge to Transplant or Recovery.

BACKGROUND: Acute kidney injury is seen in approximately 30% of patients with severe alcohol-associated hepatitis (AH) and is associated with increased mortality. Controversy exists surrounding initiation of renal replacement therapy (RRT) in these patients, as most are ineligible for early transplantation. AIMS: The primary aim was to identify predictors of survival and identify patients who may benefit from RRT as a bridge to transplant or recovery. METHODS: A retrospective multicenter cohort of adult patients with AH, who received RRT, was developed, including patients from two North American and one European liver transplant centers. RESULTS: Fifty-five patients were included. Survival was 26/55 (47.3%) at 30 days, 17/55 (30.9%) at 3 months, and 15/55 (27.2%) at 6 months. Of those who survived 6 months, 2/15 (13.3%) received simultaneous liver and kidney transplantation, 11/15 (73.3%) had spontaneous recovery of kidney function, and 2/15 (13.3%) remained on RRT. Of patients who survived at least 3 months, 8/17 (47%) completed addiction treatment. Predictors of mortality were pre-RRT MELD (OR 1.10, 1.02-1.19) and pre-RRT MELD-Na (OR 1.14, 1.03-1.27). Pre-RRT MELD-Na < 35 was associated with lower 6-month mortality (OR 0.23, 0.06 - 0.81). Of patients with pre-RRT MELD-Na < 35, 50% survived 6 months compared to 18% of patients with pre-RRT MELD-Na ≥ 35. CONCLUSIONS: Although RRT has a limited role in patients with decompensated cirrhosis, ineligible for transplant, it may be used in select patients with AH. This may allow for spontaneous recovery with alcohol abstinence or completion of addiction treatment prior to transplant.

Early liver transplantation for acute alcoholic hepatitis: We can't say no.

In patients with severe alcoholic hepatitis who are not responding to medical therapy, it is detrimental to postpone the decision to list a patient as there are no therapeutic alternatives. Early transplantation of patients with severe alcoholic hepatitis, using a restrictive selection process, has increasingly been used in the last decade with acceptable relapse rates. Indeed, early transplantation has gained the support of a growing number of experts from different countries, as shown by the European, American and Latin American recommendations. However, there is still great heterogeneity in its application between countries and even between centres within the same country.

Blood Biomarkers of Intestinal Epithelium Damage Regenerating Islet-derived Protein 3α and Trefoil Factor 3 Are Persistently Elevated in Patients with Alcoholic Hepatitis.

BACKGROUND: Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). METHODS: Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. RESULTS: At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. CONCLUSIONS: Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.

Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro-RNA 155 in Alcoholic Liver Disease.

Cellular homeostais, that is normally maintained through autophagy, is disrupted in alcoholic liver disease (ALD). Because autophagy and exosome biogenesis share common elements, we hypothesized that increased exosome production in ALD may be linked to disruption of autophagic function. We found impaired autophagy both in ALD and alcoholic hepatitis (AH) mouse models and human livers with ALD as indicated by increased hepatic p62 and LC3-II levels. Alcohol reduced autophagy flux in vivo in chloroquine-treated mice as well as in vitro in hepatocytes and macrophages treated with bafilomycin A. Our results revealed that alcohol targets multiple steps in the autophagy pathway. Alcohol-related decrease in mechanistic target of rapamycin (mTOR) and Ras homolog enriched in brain (Rheb), that initiate autophagy, correlated with increased Beclin1 and autophagy-related protein 7 (Atg7), proteins involved in phagophore-autophagosome formation, in ALD. We found that alcohol disrupted autophagy function at the lysosomal level through decreased lysosomal-associated membrane protein 1 (LAMP1) and lysosomal-associated membrane protein 2 (LAMP2) in livers with ALD. We identified that micro-RNA 155 (miR-155), that is increased by alcohol, targets mTOR, Rheb, LAMP1, and LAMP2 in the authophagy pathway. Consistent with this, miR-155-deficient mice were protected from alcohol-induced disruption of autophagy and showed attenuated exosome production. Mechanistically, down-regulation of LAMP1 or LAMP2 increased exosome release in hepatocytes and macrophages in the presence and absence of alcohol. These results suggested that the alcohol-induced increase in exosome production was linked to disruption of autophagy and impaired autophagosome and lysosome function. Conclusion: Alcohol affects multiple genes in the autophagy pathway and impairs autophagic flux at the lysosome level in ALD. Inhibition of LAMP1 and LAMP2 promotes exosome release in ALD. We identified miR-155 as a mediator of alcohol-related regulation of autophagy and exosome production in hepatocytes and macrophages.

Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis.

Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.

Persistent Hyperactivation of Endothelial Cells in Patients with Alcoholic Hepatitis.

BACKGROUND: Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up-regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM-1, VCAM-1, and VEGF-A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH. METHODS: ELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6-month follow-up, and 18 AH patients and 25 HDC at 12-month follow-up. RESULTS: At baseline, the 4 soluble markers were significantly up-regulated in AH patients compared with HDC and HC, whereas only sVCAM-1 was elevated in HDC relative to HC. At follow-ups, plasma levels of CD146, VCAM-1, and VEGF-A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors. CONCLUSIONS: The levels of soluble CD146, ICAM-1, VCAM-1, and VEGF-A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.

Current trials and novel therapeutic targets for alcoholic hepatitis.

Alcoholic hepatitis is a clinical syndrome in which patients present with acute-on-chronic liver failure and a high risk of short-term mortality. The current treatment of alcoholic hepatitis is suboptimal. Results recently published from the STOPAH study have improved our understanding of how best to design clinical trials for this condition. Although emerging data on liver transplantation for patients with alcoholic hepatitis are encouraging, less than 2% of these patients qualify. Clearly, there is an unmet need for novel treatments to improve the survival of these patients. Changes in the gut microbiota, inflammatory and cytokine signalling, oxidative stress and mitochondrial dysfunction, and abnormalities in the hepatic regenerative capacity alone or in combination contribute to the pathology of alcoholic hepatitis. In this chapter, we will describe the novel therapeutic agents targeting various pathways in the pathophysiology of alcoholic hepatitis. Specifically, we will describe the ongoing clinical trials in which some of these agents are being studied.

Modification Patterns of Urinary Albumin Correlates With Serum Albumin and Outcome in Severe Alcoholic Hepatitis.

BACKGROUND AND AIMS: Albumin modifications and deranged functions are well documented in serum of severe alcoholic hepatitis (SAH). We investigated whether urinary albumin (u-Alb) can serve as surrogate marker of circulatory albumin phenotype, functionality, and could predict outcome in SAH patients. PATIENTS AND METHODS: Baseline serum and urine samples from 100 SAH, 20 alcoholic cirrhosis, and 20 healthy controls were subjected to u-Alb, ischemia modified albumin (IMA), IMA to albumin ratio (IMAr), advanced oxidation protein products, advanced glycation end-products, albumin-binding capacity determination. In addition, SAH urinary samples were also analyzed at day 4 and day 7 to predict nonresponse to corticosteroid therapy. RESULTS: Urine and serum levels of IMA, advanced oxidation protein products and advanced glycation end-products were higher (P<0.05) in SAH versus alcoholic cirrhosis and healthy controls. IMAr was low in urine but high in serum of SAH (P<0.05). Albumin-binding capacity was lower (P<0.05) in both urinary and serum albumin of SAH. Urinary and serum albumin parameters showed direct correlation, whereas IMAr showed inverse correlation (cc>0.2, P<0.05). Baseline u-Alb level was significantly higher in SAH, and was correlated directly with corticosteroid treatment outcome and 12-month mortality in SAH. Baseline u-Alb showed an area under the receivers operating curve analysis of 0.7 and a hazard ratio of 1.23 for prediction of 12-month mortality in SAH. Baseline u-Alb level >9.0 mg/dL was associated with reduced 12-month survival in SAH (log rank <0.01). CONCLUSIONS: u-Alb modifications are reflective of serum albumin modifications. Further baseline u-Alb levels could be exploited to predict steroid response and mortality in SAH patients.

Grand Rounds: Alcoholic Hepatitis.

A 33-year-old Caucasian male was admitted to hospital with recent onset of jaundice of 2-3 weeks duration. He reported heavy use of alcohol for the last 10 years with the last drink a day prior to the onset of symptoms. At admission, he was alert and oriented to time, place, and person, and was deeply jaundiced. His laboratory profile can be summarised as follows: haemoglobin 12.1 g/dl, white blood cell count 18,700 with 81% neutrophils, serum bilirubin 33 (direct 22) mg/dl, aspartate aminotransferase 147 IU/L, alanine aminotransferase 62 IU/L, alkaline phosphatase 117 IU/L, serum albumin 2.8 gm/dl, serum creatinine 0.6 mg/dl, prothrombin time 18.3 (control 14.5) seconds, and international normalized ratio 1.48. He was diagnosed with severe alcoholic hepatitis (Maddrey discriminant function score of 50) and treated with prednisolone for 28 days with symptomatic and biochemical improvement. His Lille score at seven days was 0.4, and his serum bilirubin had decreased to 3.5 mg/dl at the end of treatment. He was also seen by the addiction team during hospitalisation; he agreed to follow through on recommendations. He was dismissed after completing a three-week inpatient rehabilitation programme but relapsed to alcohol use three months later, and was readmitted with alcohol withdrawal. He was readmitted two months later (about six months from the first episode) for a second episode of severe alcoholic hepatitis. At admission, his model for end-stage liver disease score was 32 and he was treated again with corticosteroids. His Lille score at seven days was 0.6 and steroids were discontinued. The hospital course was complicated by spontaneous bacterial peritonitis and pneumonia with development of acute kidney injury. He continued to worsen, developing multiorgan failure. After a course of one month, the family's preference was for him to receive comfort measures. This scenario raises several questions.

Application of prognostic scores in the STOPAH trial: Discriminant function is no longer the optimal scoring system in alcoholic hepatitis.

BACKGROUND & AIMS: 'Static' prognostic models in alcoholic hepatitis, using data from a single time point, include the discriminant function (DF), Glasgow alcoholic hepatitis score (GAHS), the age, serum bilirubin, international normalized ratio and serum creatinine (ABIC) score and the model of end-stage liver disease (MELD). 'Dynamic' scores, incorporating evolution of bilirubin at seven days, include the Lille score. The aim of this study was to assess these scores' performance in patients from the STOPAH trial. METHODS: Predictive performance of scores was assessed by area under the receiver operating curve (AUC). The effect of different therapeutic strategies upon survival was assessed by Kaplan-Meier analysis and tested using the log-rank test. RESULTS: A total of 1,068 patients were studied. The AUCs for the DF were significantly lower than for MELD, ABIC and GAHS for both 28- and 90-day outcomes: 90-day values were 0.670, 0.704, 0.726 and 0.713, respectively. 'Dynamic' scores and change in 'static' scores by Day 7 had similar AUCs. Patients with consistently low 'static' scores had low 28-day mortalities that were not improved with prednisolone (MELD <25: 8.6%; ABIC <6.71: 6.6%; GAHS <9: 5.9%). In patients with high 'static' scores without gastrointestinal bleeding or sepsis, prednisolone reduced 28-day mortality (MELD: 22.2% vs. 28.9%, p = 0.13; ABIC 14.6% vs. 21%, p = 0.02; GAHS 21% vs. 29.3%, p = 0.04). Overall mortality from treating all patients with a DF ≥32 and Lille assessment (90-day mortality 26.8%) was greater than combining newer 'static' and 'dynamic' scores (90-day mortality: MELD/Lille 21.8%; ABIC/Lille 23.7%; GAHS/Lille 20.6%). CONCLUSION: MELD, ABIC and GAHS are superior to the DF in alcoholic hepatitis. Consistently low scores have a favourable outcome not improved with prednisolone. Combined baseline 'static' and Day 7 scores reduce the number of patients exposed to corticosteroids and improve 90-day outcome. LAY SUMMARY: Alcoholic hepatitis is a life-threatening condition. Several scores exist to determine the outcome of these patients as well as to identify those who may benefit from treatment. This study looked at the performance of existing scores in patients who had been recruited to the largest alcoholic hepatitis clinical trial: STOPAH. 'Static' scores are calculable at the start of assessment. The three newer static scores (ABIC, GAHS and MELD) were shown to be superior to the oldest score (DF). ABIC and GAHS could also identify patients who had a survival benefit 28 days after starting prednisolone treatment. 'Dynamic' scores relate to the change in disease over the first week of treatment. Combination of the 'static' scores 'with the 'dynamic' scores or change in 'static' scores allowed identification of patients who could benefit from prednisolone up to 90 days.

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION: AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).

Adherence to Appropriate Nutrition in Acute Alcoholic Hepatitis is Low.

Malnutrition is a common cause of impeding recovery in patients with acute alcoholic hepatitis (AAH). Previous reports have shown that appropriate nutritional supplementation reduce short and long-term mortality in patients with AAH. Despite these clear recommendations, the element of nutrition in AAH is often neglected. We designed a quality improvement project to evaluate and improve compliance with appropriate nutrition in patients presenting with AAH at our institution. Patients admitted with AAH between December 2015 to December 2016 were included. Our primary outcome was compliance with appropriate nutrition. Secondary outcomes included nutrition consultation and hepatology consultation. A total of fifty-four patients were included. Nine of the 53 patients (17%) received high calorie and high protein diets. Hepatology was consulted in 72% (38/53) of the patients, and 21% (8/38) of these patients received appropriate nutrition as compared to only 8.3% (1/12) in whom hepatology was not consulted. Nutrition was consulted in 55% (29/53) of these patients and 67% (19/28) of those patients received appropriate nutrition. In conclusion, our compliance of appropriate nutrition in AAH is low. Our initial investigation suggests that hepatology and nutrition consultation improved compliance with appropriate nutrition. The next step will be to implement protocolized care for appropriate nutrition in AAH by incorporating consultation of hepatology and nutrition services, assess the effect on adherence to appropriate nutrition, and determine the impact on patient outcomes.

Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.

OBJECTIVE: In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection. DESIGN: Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon-γ (IFN-γ) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy. RESULTS: MOB, production of superoxide and bacterial killing in response to Escherichia coli were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90 days. Expression of the gp91 phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN-γ stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7 days in vivo prednisolone therapy. CONCLUSIONS: Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.

Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute.

The purpose of this clinical practice update is to review diagnostic criteria for severe acute alcoholic hepatitis and to determine the current best practices for this life-threatening condition. The best practices in this review are based on clinical trials, systematic reviews including meta-analysis and expert opinion to develop an approach to diagnosis and management. Best Practice Advice 1: Abstinence from drinking alcohol is the cornerstone of treatment for alcohol hepatitis (AH). Best Practice Advice 2: Patients with jaundice and suspected AH should have cultures of blood, urine, and ascites, if present, to determine the presence of bacterial infections regardless of whether they have fever. Best Practice Advice 3: Patients with AH who have jaundice should be admitted to the hospital to encourage abstinence, restore adequate nutrition, and exclude serious infections. Best Practice Advice 4: Imaging of the liver is warranted as part of the evaluation, but caution should be used in administering iodinated contrast dye, as it increases the risk of acute kidney injury (AKI). Best Practice Advice 5: Patients with AH require a diet with 1-1.5 g protein and 30-40 kcal/kg body weight for adequate recovery. If the patient is unable to eat because of anorexia or altered mental status, a feeding tube should be considered for enteral feeding. Parenteral nutrition alone is inadequate. Best Practice Advice 6: Severity and prognosis of AH should be evaluated using Maddrey Discriminant Function (MDF), Model for End-Stage Liver Disease (MELD), age, bilirubin, international normalized ratio, and creatinine (ABIC), or Glasgow scoring systems. Current treatments are based on this assessment. Best Practice Advice 7: Presence of systemic inflammatory response syndrome (SIRS) on admission is associated with an increased risk of multi-organ failure (MOF) syndrome. Development of MOF, usually due to infections developing after initial diagnosis of AH, is associated with a very high mortality rate. Best Practice Advice 8: Nephrotoxic drugs, including diuretics, should be avoided or used sparingly in patients with AH, since AKI is an early manifestation of MOF. Best Practice Advice 9: Patients with MDF > 32 or MELD score > 20 without a contraindication to glucocorticoid, such as hepatitis B viral infection, tuberculosis, or other serious infectious diseases, may be treated with methylprednisolone 32 mg daily, but the appropriate duration of treatment remains a subject of controversy. Methylprednisolone does not improve survival beyond 28 days, and the benefits for < 28 days are modest. Best Practice Advice 10: Patients with a contraindication to glucocorticoids may be treated with pentoxifylline 400 mg three times daily with meals. Data regarding the efficacy are conflicting. Best Practice Advice 11: Patients with severe AH, particularly those with a MELD score > 26 with good insight into their alcohol use disorder and good social support should be referred for evaluation for liver transplantation, as the 90-day mortality rate is very high. Best Practice Advice 12: Patients with mild to moderate AH defined by a MELD score < 20 and MDF < 32 should be referred for abstinence counseling and prescribed a high protein diet supplemented with B vitamins and folic acid.

Intensive Enteral Nutrition Is Ineffective for Patients With Severe Alcoholic Hepatitis Treated With Corticosteroids.

BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a life-threatening disease for which adequate oral nutritional support is recommended. We performed a randomized controlled trial to determine whether the combination of corticosteroid and intensive enteral nutrition therapy is more effective than corticosteroid therapy alone in patients with severe AH. METHODS: We enrolled 136 heavy consumers of alcohol (age, 18-75 y) with recent onset of jaundice and biopsy-proven severe AH in our study, performed at 18 hospitals in Belgium and 2 in France, from February 2010 through February 2013. Subjects were assigned randomly (1:1) to groups that received either intensive enteral nutrition plus methylprednisolone or conventional nutrition plus methylprednisolone (controls). In the intensive enteral nutrition group, enteral nutrition was given via feeding tube for 14 days. The primary end point was patient survival for 6 months. RESULTS: In an intention-to-treat analysis, we found no significant difference between groups in 6-month cumulative mortality: 44.4% of patients died in the intensive enteral nutrition group (95% confidence interval [CI], 32.2%-55.9%) and 52.1% of controls died (95% CI, 39.4%-63.4%) (P = .406). The enteral feeding tube was withdrawn prematurely from 48.5% of patients, and serious adverse events considered to be related to enteral nutrition occurred in 5 patients. Regardless of group, a greater proportion of patients with a daily calorie intake less than 21.5 kcal/kg/day died (65.8%; 95% CI, 48.8-78.4) than patients with a higher intake of calories (33.1%; 95% CI, 23.1%-43.4%) (P < .001). CONCLUSIONS: In a randomized trial of patients with severe AH treated with corticosteroids, we found that intensive enteral nutrition was difficult to implement and did not increase survival. However, low daily energy intake was associated with greater mortality, so adequate nutritional intake should be a main goal for treatment. ClinicalTrials.gov number: NCT01801332.

Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice.

BACKGROUND & AIMS: Inflammation and impaired hepatocyte regeneration contribute to liver failure in alcoholic hepatitis (AH). Interleukin (IL)-1 is a key inflammatory cytokine in the pathobiology of AH. The role of IL-1 in liver regeneration in the recovery phase of alcohol-induced liver injury is unknown. METHODS: In this study, we tested IL-1 receptor antagonist to block IL-1 signalling in a mouse model of acute-on-chronic liver injury on liver inflammation and hepatocyte regeneration in AH. RESULTS: We observed that inhibition of IL-1 signalling decreased liver inflammation and neutrophil infiltration, and resulted in enhanced regeneration of hepatocytes and increased rate of recovery from liver injury in AH. CONCLUSION: Our novel findings suggest that IL-1 drives sustained liver inflammation and impaired hepatocyte regeneration even after cessation of ethanol exposure.

Association between alcohol consumption and serum paraoxonase and arylesterase activities: a cross-sectional study within the Bavarian population.

High alcohol consumption is an important risk factor for chronic disease and liver degeneration. Paraoxonase (PON1) and arylesterase (AE) are functions of the enzyme paraoxonase, which is synthesised by the liver. Paraoxonase circulates in plasma bound to HDL and hydrolyses lipid peroxides, protecting lipoproteins against oxidative modification. It has been shown that excessive alcohol consumption leads to a reduction of serum PON1 and AE activities; however, studies investigating the association with low and moderate alcohol consumption are scarce. We investigated the cross-sectional association between alcohol consumption and serum activities of PON1 and AE using data from the population-based Bavarian Food Consumption Survey II survey. PON1 and AE activities were quantified in serum samples of 566 male and female study participants (aged 18-80 years), and dietary intake including alcohol consumption was estimated from three 24-h dietary recalls. The association between alcohol consumption and PON1 and AE activities was analysed using linear regression, adjusted for age, sex and socio-economic status. There was no strong association between alcohol consumption and enzymatic activities of PON1 and AE in the Bavarian population. PON1 activity was seen to be lowest in non-drinkers (0 g/d) and highest in people who consumed 15·1-30 g of alcohol/d. AE activity increased across alcohol consumption categories, with a mean maximum difference of 14 U/ml (P for linear trend 0·04). These associations were attenuated after adjustment for blood concentrations of HDL. The results of this study do not support the hypothesis that alcohol consumption is related to important alterations in PON1 and AE activities.

Alcoholic hepatitis: How far are we and where are we going?

 The burden of alcoholic liver disease continues to be a major public health problem worldwide. The spectrum of disease ranges from fatty liver to cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis (AH) is a type of acute-on-chronic liver failure and the most severe form of alcoholic liver disease. Severe AH carries a poor short-term prognosis and its management is still challenging, with scarce advances in the last decades. Corticosteroids are still the first line of therapy in severe cases. Unfortunately, many patients do not respond and novel targeted therapies are urgently needed. Liver transplantation has shown extraordinary results in non-responders to corticosteroids however; its applicability is very low. This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis.