interleukin-8 and Liver-Cirrhosis--Alcoholic

(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21−65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8.

Topics: Adult; Aged; Biomarkers; Humans; Interleukin-8; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Middle Aged; Young Adult

We examined 74 patients with acute decompensation of alcoholic liver cirrhosis: 34 (45.9%) with bacterial infection (group 1) and 40 (54.1%) without bacterial infection (group 2). The degree and index of acute-on-chronic liver failure (ACLF) were determined using an on-line CLIF-C ACLF Calculator and the levels of cytokeratin-18 fragments, TNFα, IL-1β, IL-4, IL-6, and IL-8. In group 1, AST, cytokeratin-18, TNFα, IL-1β, IL-6, degree and score of ACLF were significantly higher than in group 2. ACLF developed in 18 (52.9%) patients in group 1 and in 11 (27.5%) (p<0.05) patients in group 2. Within 1 month, 10 (29.4%) patients of group 1 and 2 (5%) patients of group 2 died (p<0.05). Patients with bacterial infection showed a more severe course of alcoholic liver cirrhosis and ACLF than those without bacterial infection.

Topics: Acute-On-Chronic Liver Failure; Adult; Aspartate Aminotransferases; Bacterial Infections; Biomarkers; Case-Control Studies; Female; Humans; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Keratin-18; Liver; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Prognosis; Severity of Illness Index; Survival Analysis; Tumor Necrosis Factor-alpha

Platelet-derived growth factor (PDGF) promotes liver collagen deposition, acting on hepatic stellate cells. Despite this, low serum PDGF levels were reported in chronic hepatitis C or B infection, although some studies yield the opposite result. Since PDGF may be related not only to fibrosis but also with vascular, neuronal or muscle disease, it is important to analyze its behavior in alcoholics.. In total, 17 controls and 62 alcoholic patients consecutively admitted to the hospitalization unit of the Internal Medicine Service were included. We determined serum levels of PDGF C, routine laboratory evaluation, tumor necrosis factor-α, interleukin (IL)-6 and IL-8 and malondialdehyde (MDA) levels. We analyzed the relationships between PDGF and liver function, ethanol intake and inflammatory reaction by both univariate and multivariate analysis to discern which variables PDGF levels depend on.. Serum PDGF levels were significantly lower among patients (675 ± 466 pg/ml) than among controls (1074 ± 337 pg/ml; Z = 3.70; P < 0.001), and even lower among cirrhotics (549 ± 412 among cirrhotics vs 778 ± 487 among non-cirrhotics; Z = 2.33; P = 0.02). PDGF levels showed a direct correlation with prothrombin activity (ρ = 0.50; P < 0.001), platelet count (ρ = 0.44; P < 0.001) and inverse ones with bilirubin (ρ = -0.39; P = 0.002), IL-6 (ρ = -0.33; P = 0.016), IL-8 (ρ = -0.47; P < 0.001), and MDA levels (ρ = -0.44; P < 0.001). By multivariate analysis, only prothrombin activity and platelet count were independently related to PDGF.. PDGF-C levels are decreased in alcoholics, especially among cirrhotics. Multivariate analysis discloses that only prothrombin activity and platelet count are independently related to PDGF-C levels.

Topics: Alcohol Drinking; Alcoholism; Case-Control Studies; Female; Humans; Interleukin-6; Interleukin-8; Liver Cirrhosis, Alcoholic; Liver Function Tests; Lymphokines; Male; Malondialdehyde; Middle Aged; Platelet-Derived Growth Factor; Tumor Necrosis Factor-alpha

Cirrhosis represents a state of functional immune paresis with increased infection risk.. To investigate polymorphonuclear (PMN) leukocyte and monocyte function in ambulatory cirrhotics, and their potential relation with cirrhosis etiology or patient outcome.. Consecutive ambulatory cirrhotics without current or recent (<1 month) infection or acute decompensation were prospectively enrolled in 2013 and followed for a median time of 20 months until death, transplant or end of 2014. Oxidative burst and phagocytosis of circulating PMNs and monocytes were investigated at baseline and after in vitro Escherichia coli stimulation. Seventeen healthy blood donors served as controls. Baseline clinical and laboratory data as well as follow-up data on the development of cirrhosis complications, including acute-on-chronic liver failure (ACLF), and bacterial infections were collected.. Sixty patients were included (70 % male, median age 63 years, 52 % with alcoholic cirrhosis). Compared to controls, cirrhotics showed increased resting and stimulated burst as well as reduced phagocytosis of PMNs, and increased stimulated monocyte burst (p < 0.05 for all). Alcoholic etiology was not related to PMN or monocyte dysfunction (p > 0.05 for all). In Cox regression analysis, increased stimulated monocyte and PMN burst were independent predictors of sepsis, severe sepsis and ACLF occurrence. Also, increased stimulated monocyte burst was associated with worse transplant-free survival (p < 0.05 for all).. Stimulated PMN and monocyte oxidative burst are increased in ambulatory cirrhotics without acute decompensation. In turn, these changes are associated to sepsis and ACLF occurrence.

Topics: Acute-On-Chronic Liver Failure; Aged; Ambulatory Care; Bacterial Infections; Case-Control Studies; Cytokines; Disease Progression; Escherichia coli; Female; Humans; Interleukin-6; Interleukin-8; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Monocytes; Neutrophils; Phagocytosis; Prognosis; Prospective Studies; Respiratory Burst; Sepsis; Sweden; Tumor Necrosis Factor-alpha

Preliminary data suggest that polymorphisms in cytokine genes may be involved in the genetic predisposition to alcoholic liver cirrhosis or alcohol use disorders. We thus analyze the association between these diseases and the following polymorphisms: -33T>C IL4, -174 G>C IL6, -251 T>A IL8 and 1188 A>C IL12B.. 258 male alcoholics (161 without liver disease and 97 with liver cirrhosis) and 101 healthy controls were genotyped for the above mentioned polymorphisms. We examined the relationship between genotype and allele frequencies and the presence of disease, as well as the correlation with combinations of putative pro-inflammatory genotypes. Haplotypes were inferred using the expectation-maximization algorithm and haplotype frequencies were compared.. We found no statistically significant association between any of these polymorphisms or the combinations of pro-inflammatory polymorphisms and the risk of alcoholic liver cirrhosis or alcohol abuse or dependence. Haplotype analysis of the IL4 and IL12B polymorphisms did not show any statistical relationship either.. Our results do not support the hypothesis that the analyzed polymorphisms confer differences in alcoholic liver cirrhosis or alcohol use disorders susceptibility.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Gene Frequency; Genetic Predisposition to Disease; Humans; Interleukin-12; Interleukin-4; Interleukin-6; Interleukin-8; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Polymorphism, Genetic

The influence of the immune system on the development of alcoholic liver disease has recently been the object of attention. However, the connection between alcohol consumption, altered immune response, and development of changes in the liver has not been fully explained. The aim of the present study was to evaluate serum IL-8 concentration in patients with chronic alcoholic liver disease.. 85 patients with different types of ALD and 35 healthy subjects were enrolled in the study. Serum IL-8 concentration was evaluated with the ELISA immunoenzymatic method. IL-8 in liver tissue was measured by the indirect immunofluorescence method.. There was a significant correlation between IL-8 concentration and AST, ALP, GGT, total bilirubin and albumin levels in blood serum. A significantly higher concentration of IL-8 was seen in all the groups of ALD patients. The highest values were found in patients with chronic alcoholic hepatitis, and the lowest in those with fatty liver. Significantly higher values were found in patients with ascites or encephalopathy in comparison to those without any features of portal hypertension and/or insufficiency of the liver cells. A high concentration of the tested cytokine is a disadvantageous prognostic factor in patients with ALD.. IL-8 appears to be an important factor in liver pathology in patients with ALD, especially in the development of the inflammatory process.

Topics: Ascites; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Fatty Liver, Alcoholic; Female; Fluorescent Antibody Technique, Indirect; Hepatic Encephalopathy; Hepatitis, Alcoholic; Humans; Interleukin-8; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Male; Prognosis

Endotoxin plays an important role in the initiation and aggravation of alcoholic liver disease. In this study, we evaluated plasma endotoxin levels and serum concentrations of cytokines and lipopolysaccharide binding protein (LBP) during the acute and recovery phase of patients with alcoholic hepatitis; we also explored the prognostic factors associated with a fatal outcome.. Fourteen patients, consisting of eight patients with alcoholic hepatitis (AH), five cirrhotics with superimposed AH (LC+AH), and one patient with severe alcoholic hepatitis (SAH), were studied. Among these, two with LC+AH died of hepatic failure.. Plasma endotoxin levels in the acute phase were higher in patients with AH (184.4 +/- 159.4 pg/ml) and LC+AH (206.9 +/- 174.9 pg/ml) than in healthy subjects (10.4 +/- 5.5 pg/ml, p < 0.001). In particular, in one patient with SAH and one of two nonsurvivors, plasma endotoxin levels were markedly high relative to the other cases. In most survivors, plasma endotoxin levels decreased in the recovery phase, whereas they further increased at the terminal stage in one of two nonsurvivors. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were significantly higher in patients with AH and LC+AH as compared with healthy subjects. These levels were especially high in nonsurvivors and in one patient with SAH. IL-10 increased in two nonsurvivors, one patient with SAH, and one with LC+AH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in nonsurvivors, IL-6 remained high, and IL-8 and IL-10 further increased. Tumor necrosis factor-alpha levels were below the detection limit throughout the course in all patients. Serum lipopolysaccharide binding protein (LBP) generally was elevated in the acute phase and decreased in the recovery phase in all survivors, but in one of the nonsurvivors, LBP was elevated markedly at the terminal stage. In the acute phase, plasma endotoxin levels were correlated positively with white blood cell counts, neutrophil counts, and serum IL-8. IL-8 was correlated positively with neutrophil counts and negatively with serum cholinesterase, hepaplastin test, and serum albumin levels. IL-6 was correlated positively with white blood cell and neutrophil counts, C-reactive protein, and serum total bilirubin and negatively with hepaplastin test and serum total protein levels. Serum LBP was correlated positively with white blood cell and neutrophil counts.. Endotoxemia and related elevation of IL-8 may play an important role in the activation and migration of neutrophils in patients with alcoholic hepatitis. Marked elevation of inflammatory cytokines, IL-6 and IL-8, are related to severity and poor prognosis of alcoholic hepatitis. Serum LBP may serve as an index of inflammatory reaction in alcoholics.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Adult; Aged; C-Reactive Protein; Carrier Proteins; Cytokines; Endotoxins; Female; Hepatitis, Alcoholic; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Count; Liver; Liver Cirrhosis, Alcoholic; Male; Membrane Glycoproteins; Middle Aged; Neutrophils; Tumor Necrosis Factor-alpha

Although altered cytokine homeostasis has been implicated in the pathogenesis of both alcoholic liver and pancreas diseases, the serum cytokine pattern characteristic of concomitant alcoholic liver cirrhosis and pancreatitis has not been examined. In this paper we examine the serum levels of proinflammatory cytokines, such as IL-6, IL-8, TNF-alpha, and also antiinflammatory ones, such as IL-10 and TGF-beta, in 22 patients with alcoholic liver cirrhosis and 28 patients with chronic pancreatitis and compare them with those detected in the sera of 14 patients with concomitant alcoholic cirrhosis and pancreatitis. All patients were heavy alcohol drinkers, consuming more than 70 g of pure alcohol per day for at least 5 years. The control group consisted of 33 age- and sex-matched healthy subjects receiving an annual health examination. They were not addicted to alcohol and confirmed to be free of major cardiopulmonary, gastrointestinal and hepatobiliary-pancreatic diseases. The results indicated that the cytokine pattern in the sera of patients with concomitant liver cirrhosis and pancreatitis was characterized by increased levels of two proinflammatory cytokines: TNF-alpha, the concentration of which seemed to be influenced by both liver and pancreas injury, and IL-6, which seemed to be rather connected with pancreas injury. Increased levels of IL-8, which were detected in the sera of patients with cirrhosis, pancreatitis and concomitant cirrhosis and pancreatitis, were rather connected with exacerbation of the disease processes which occurred only in some of the patients. No significant changes in the levels of IL-10 or TGF-beta were detected in the sera of patients with chronic pancreatitis and concomitant cirrhosis and pancreatitis, while in patients with cirrhosis significantly decreased levels of IL-10 were found. A significant imbalance between proinflammatory/antiinflammatory signals was especially characteristic of alcoholic cirrhosis and concomitant cirrhosis with pancreatitis.

Topics: Adult; Alcohol Drinking; Cytokines; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Pancreatitis; Tumor Necrosis Factor-alpha

Neutrophil cytotoxity and activated macrophages have been implicated in the pathogenesis of alcohol-induced liver disease. The aim of this study was to relate plasma levels of neopterin, a marker of activation of the cellular immune system, and IL-8, a neutrophil chemotactic factor, with severity of liver disease and prognosis in patients with alcohol-induced cirrhosis.. Plasma concentrations of neopterin and IL-8 were assessed in 81 patients with alcohol-induced cirrhosis admitted to the Department of Medicine B, Bispebjerg Hospital, Copenhagen, Denmark, and in 16 healthy controls. After a median follow-up period of 5 years, mortality and death causes were registered. The patients were divided into groups according to the major contributing cause of death: infection, upper gastrointestinal bleeding or hepatic coma.. Neopterin and IL-8 levels were increased in the cirrhosis patients, but not significantly related to Child-Pugh classification. Five-year mortality was 67%. High neopterin levels (>upper quartile) were an independent predictor of death (p=0.01, Log rank and p<0.02, Cox). High IL-8 levels (>upper quartile) were of no significant prognostic value for overall mortality. Causes of death related mortality were as follows (Log rank): Neopterin; p=0.009, p=0.84 and p=0.94, and IL-8; p=0.36, p=0.002 and p=0.27, respectively, according to infection, bleeding and coma as causes of death.. Neopterin and IL-8 plasma levels are raised in patients with alcohol-induced cirrhosis, and are predictive of mortality associated with infections and upper gastrointestinal bleeding, respectively.

Topics: Cause of Death; Follow-Up Studies; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Humans; Interleukin-8; Liver Cirrhosis, Alcoholic; Neopterin; Pneumonia; Prognosis; Prospective Studies; Survival Analysis; Survival Rate

Alcoholic liver disease is associated with three histologically distinct processes: steatosis (parenchymal fat accumulation), alcoholic hepatitis (characterized by parenchymal infiltration by neutrophil polymorphs), and alcoholic cirrhosis (in which chronic inflammation and fibrosis dominate). Chemokines are cytokines that promote subset-specific leukoycte recruitment to tissues and could therefore play a crucial role in determining which leukocyte subsets are recruited to the liver in alcoholic liver disease. This paper reports that chemokine expression is increased in the liver of patients with alcoholic liver disease and, moreover, that distinct patterns of chemokine expression are associated with the different inflammatory responses to alcohol. Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were all detected in the parenchyma at sites of inflammation in alcoholic hepatitis, whereas in alcoholic cirrhosis, chemokines were restricted to inflammatory cells and endothelium in the fibrous septa and portal tracts. In alcoholic hepatitis, chemokine transcription was localized to sinusoidal cells, leukocytes, and fibroblasts in areas of parenchymal inflammation, but hepatocytes, despite staining strongly for chemokine protein, were negative. In alcoholic cirrhosis, chemokine mRNA was detected in portal tract endothelium, leukocytes, and fibroblasts. Thus, alcoholic hepatitis and alcoholic cirrhosis are associated with distinct patterns of chemokine expression that are likely to be important factors in determining whether a patient develops acute parenchymal inflammation and alcoholic hepatitis, or chronic septal inflammation and alcoholic cirrhosis.

Topics: Chemokine CCL2; Chemokine CCL4; Chemokines; Gene Expression; Hepatitis, Alcoholic; Humans; Immunoenzyme Techniques; In Situ Hybridization; Interleukin-8; Leukocytes; Liver Cirrhosis, Alcoholic; Macrophage Inflammatory Proteins; RNA, Messenger; Tumor Necrosis Factor-alpha

The increased frequency of autoantibodies and B cell non-Hodgkins lymphoma (B-NHL) in hepatitis C virus (HCV) infection suggests dysregulated humoral immunity. Soluble CD23 (sCD23) is involved in B cell activation and proliferation and the serum levels are raised in autoimmune diseases and B cell lymphoproliferative disease. We compared the serum levels of sCD23 in patients with HCV infection with those in patients with alcoholic cirrhosis (AC) and in healthy controls. Serum levels of interleukin (IL) 8, IL10, granulocyte macrophage-colony stimulating factor, and interferon-gamma were assessed simultaneously to check for generalized nonspecific immune stimulation. In contrast to the essentially normal serum levels of these latter cytokines, the levels of sCD23 were raised in the patients with HCV compared to those with AC and the normal controls (medians 34.0, 10.1, and 11.1 arbitrary units, respectively; HCV vs AC P < 0.0004, HCV vs controls P < 0.0001, AC vs controls P > 0.8). These results confirm HCV-induced humoral immune dysregulation and invite comparison with primary Sjögrens syndrome and Epstein-Barr virus infection, both of which are also associated with raised levels of serum sCD23, autoantibodies, and B-NHL.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatitis C; Humans; Interferon-gamma; Interleukin-10; Interleukin-8; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Receptors, IgE

Acute alcoholic hepatitis is characterized by a unique degree of liver neutrophil infiltration, often accompanied by marked peripheral neutrophilia in the absence of demonstrable bacterial or fungal infection. In this study we assayed plasma and tissue levels of a potent neutrophil activator and chemotaxin, interleukin-8, in patients with a spectrum of alcoholic liver diseases and in normal and diseased control subjects. Levels of circulating interleukin-8 were undetectable in normal subjects but highly elevated in patients with alcoholic hepatitis, particularly in those who died (geometric mean = 600 ng/L; confidence interval = 323 to 1,120 vs. geometric mean = 184 ng/L; confidence interval = 114 to 309 in survivors). Levels correlated with biochemical indicators of severe disease (bilirubin: R = 0.38; international prothrombin ratio: R = 0.28; white blood cell count: R = 0.35; creatinine: R = 0.34) and with tumor necrosis factor-alpha (R = 0.43) and soluble tumor necrosis factor receptors (p55; R = 0.59). In contrast, moderate elevations in the levels of circulating interleukin-8 were seen in alcoholic cirrhosis (geometric mean = 93 ng/L; confidence interval = 40 to 213) and in alcoholic patients undergoing alcohol withdrawal (geometric mean = 137 ng/L; confidence interval = 72 to 259). Levels in nonalcoholic inflammatory liver disease were comparatively low (geometric mean = 17 ng/L; confidence interval = 10 to 29).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Autoimmune Diseases; Female; Hepatic Encephalopathy; Hepatitis; Hepatitis, Alcoholic; Humans; Immunohistochemistry; Interleukin-8; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Male; Neutrophils; Prospective Studies; Tumor Necrosis Factor-alpha