Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease.

BACKGROUND & AIMS: Patients with alcoholic liver disease (ALD) display inflammation of the subcutaneous adipose tissue (SAT) which correlates with liver lesions. We examined macrophage markers and polarization in the SAT of alcoholic patients and adipokine expression according to liver inflammation; we studied the consequences of alcohol withdrawal. PATIENTS AND METHODS: Forty-seven patients with ALD were prospectively included. SAT and blood samples were collected at inclusion and after 1 week of alcohol withdrawal. Pro-inflammatory cytokines/chemokines, inflammasome components and products, adipokine expression levels, macrophage markers and polarization in liver and SAT samples were assessed by RT-PCR arrays. RESULTS: mRNA expression level of chemokines (IL8, semaphorin 7A) correlated with hepatic steatosis in both liver and SAT. Liver expression of inflammasome components (IL1ß, IL18, caspase-1) and SAT IL6 and CCL2 correlated with liver damage. In patients with mild ALD, 1 week of alcohol withdrawal was sufficient to decrease expression level of total macrophage markers in the adipose tissue, to orient adipose tissue macrophages (ATM) towards an anti-inflammatory M2 phenotype and to decrease the mRNA expression of cytokines/chemokines (IL18, CCL2, osteopontin, semaphorin 7A). In patients with severe ALD, 1 week of abstinence was also associated with an increase in CCL18 expression. CONCLUSIONS: In alcoholic patients, upregulation of chemotactic factors in the liver and SAT is an early event that begins as early as the steatosis stage. The inflammasome pathway is upregulated in the liver of patients with ALD. One week of alcohol withdrawal alleviates macrophage infiltration in SAT and orients ATM towards a M2 anti-inflammatory phenotype; this implicates alcohol in adipose tissue inflammation (ClinicalTrials.gov NCT00388323).

The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease.

BACKGROUND: Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFß expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F ≥ 2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F ≥ 2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury. CONCLUSION/SIGNIFICANCE: OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.

Harmful effect of adipose tissue on liver lesions in patients with alcoholic liver disease.

BACKGROUND & AIMS: Adipose tissue is an important source of cytokines. Excess weight is an independent risk factor for steatosis, acute alcoholic hepatitis (AAH), and cirrhosis in patients with alcoholic liver disease (ALD). In this study, we investigated the role of adipose tissue in human ALD. PATIENTS AND METHODS: Fifty patients with ALD underwent liver and abdominal subcutaneous adipose tissue biopsies and supplied blood samples for the investigation of cytokine gene expression and secretion, as well as liver histology. RESULTS: The levels of TNF-alpha and IL-10 in adipose tissue were higher in patients with AAH. IL-10 level in adipose tissue was also correlated with fibrosis score. TNF-alpha gene expression in adipose tissue was correlated with Maddrey score, blood C-reactive protein (CRP) concentration and liver IL-6 concentration. IL-6 production levels in the liver were higher in patients with AAH and correlated with AAH score, liver histological lesions, liver TNF-alpha concentration, Maddrey score, and blood CRP concentration. Plasma concentrations of soluble forms of TNF-receptor were correlated with inflammatory lesions in the liver, Maddrey score and fibrosis score. CONCLUSION: In patients with ALD, inflammation occurs not only in the liver, but also in the adipose tissue. Adipose tissue inflammation is correlated with the severity of pathological features in the liver. Our findings may account for the harmful interactions between body mass index, AAH, fibrosis, and cirrhosis in alcoholic patients.

Acute hepatitis E infection associated with a false-positive serology against Epstein-Barr virus.

Hepatitis E virus is a major cause of acute viral hepatitis. The diagnosis of acute viral hepatitis E is based essentially on antibodies and hepatitis E virus RNA. We describe herein a case of acute hepatitis E associated with a false-positive serology for Epstein-Barr virus (EBV). This case report suggests that anti-viral capsid antigen IgM must be interpreted with caution in acute E hepatitis. When positive, EBV RNA polymerase chain reaction can be useful as a false positivity of anti-viral capsid antigen IgM and can be misinterpreted as an acute infection. EBV false positivity was probably related to polyclonal stimulation of the immune system, favoured by hepatitis E.

Chronic ethanol consumption lessens the gain of body weight, liver triglycerides, and diabetes in obese ob/ob mice.

Clinical studies suggest that moderate alcohol consumption can have beneficial effects, in particular regarding cardiovascular events, insulin resistance, and type 2 diabetes. In this study, lean and obese diabetic ob/ob mice were submitted or not to chronic ethanol intake via the drinking water for 6 months, which was associated with moderate levels of plasma ethanol. Plasma levels of alanine aminotransferase and aspartate aminotransferase were not increased by alcohol intake. Ethanol consumption progressively reduced the gain of body weight in ob/ob mice, but not in lean mice, and this was observed despite higher calorie intake. Increased plasma free fatty acids and glycerol in ethanol-treated ob/ob mice suggested peripheral lipolysis. Glycemia and insulinemia were significantly reduced, whereas adiponectinemia was increased in ethanol-treated ob/ob mice. Liver weight and triglycerides were significantly decreased in ethanol-treated ob/ob mice, and this was associated with less microvesicular steatosis. Hepatic levels of AMP-activated protein kinase and the phosphorylated form of acetyl-CoA carboxylase were higher in ethanol-treated ob/ob mice, suggesting better fatty acid oxidation. However, hepatic mRNA expression of several lipogenic genes was not reduced by ethanol consumption. Finally, mild oxidative stress was noticed in the liver of ethanol-treated mice, regardless of their genotype. Hence, our data are in keeping with clinical studies suggesting that moderate ethanol intake can have beneficial effects on type 2 diabetes and insulin sensitivity, at least in part through increased levels of plasma adiponectin. However, further studies are needed to determine whether long-term drinking of light-to-moderate amounts of ethanol is safe for the liver.

Predictive factors for pure steatosis in alcoholic patients.

BACKGROUND: Bearing in mind the mechanisms involved in nonalcoholic fatty liver disease, this study aims to verify whether metabolic syndrome or its various individual components are independent predictive factors for steatosis > or =10% in alcoholic patients. METHODS: This study included 281 consecutive alcoholic patients with abnormal liver tests and either normal liver histology or steatosis <10% (n = 119) or steatosis > or =10% (n = 162). Logistic regression analysis was used to study the relationship between metabolic syndrome components and various risk factors and the presence of steatosis > or =10%. We assessed apolipoprotein A1 (ApoA-1) levels, a major protein component of plasma high-density lipoprotein (HDL), rather than HDL-cholesterol levels. RESULTS: Plasma ApoA-1 levels (p < 0.01), body mass index (BMI) (p < 0.01), and waist circumference (p < 0.05) were significantly higher in patients with steatosis > or =10% than in patients with normal liver histology or steatosis <10%. A higher percentage of patients with steatosis > or =10% had high blood pressure (p = 0.003) than patients with normal liver histology or steatosis <10%. In the logistic regression, ApoA-1 [odds ratio (OR) = 1.57 (1.10-2.22)], BMI [OR = 1.10 (1.01-1.23)], and high blood pressure [OR = 1.84 (1.10-3.06)] were positively and independently correlated with the presence of steatosis > or =10%. In the multivariate regression high blood pressure was independently and positively correlated with steatosis score (r = 0.55 +/- 0.26; p < 0.05). On the other hand, when the presence of high blood pressure was the dependent variable, the presence of steatosis > or =10% positively and independently correlated with it [OR = 1.82 (1.05-3.15)]. CONCLUSION: In alcoholic patients without fibrosis, ApoA-1, BMI, and high blood pressure on the next morning after the admission were predictive of steatosis > or =10%. High blood pressure was the only metabolic syndrome component associated with the presence of alcoholic steatosis >/=10% and was not correlated with other metabolic syndrome components. These findings suggest that steatosis mechanisms are different in alcoholic and nonalcoholic fatty liver.

Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease.

FibroTest has been validated as a biomarker of fibrosis in patients with chronic viral hepatitis, with a similar prognostic value as biopsy. The aim of the study was to compare the diagnostic and prognostic values of FibroTest versus the recently patented biomarkers, FibrometerA, and Hepascore. A total of 218 consecutive patients with ALD and available liver biopsy examination were included. Biomarkers were compared using univariate area under the ROC curves (AUROC) and multivariate analysis (logistic regression and Cox). The median follow-up was 8.2 years. Eighty-five patients died, including 42 deaths related to liver complications. The diagnostic values of FibrometerA and Hepascore did not differ from that of FibroTest for advanced fibrosis (all AUROC = 0.83 +/- 0.03) and cirrhosis (FibroTest and FibrometerA = 0.94 +/- 0.02, Hepascore = 0.92 +/- 0.02), and were significantly greater than those of nonpatented biomarkers (APRI, Forns, FIB4; P < 0.01). In multivariate analysis the most significant was FibroTest (P = 0.001), without independent diagnostic value for FibrometerA (P = 0.19), and Hepascore (P = 0.40). The prognostic values of FibroTest (AUROC for survival or non liver disease-related death = 0.79 +/- 0.04), FibrometerA (0.80 +/- 0.04), Hepascore (0.78 +/- 0.04), did not differ from that of biopsy fibrosis staging (0.77 +/- 0.04). In multivariate analysis the most significant were FibroTest (P = 0.004) and biopsy (P = 0.03), without independent prognostic values for FibrometerA (P = 0.41) and Hepascore (P = 0.28). In patients with alcoholic liver disease, FibrometerA and Hepascore did not improve the diagnostic and prognostic values of FibroTest.