Alcoholic Hepatitis Group Research Articles

Influence of Nanosized Cerium Dioxide on Metabolic Changes of the Liver under Conditions of Chronic Alcoholic Hepatitis

Background: Alcoholic liver disease is one of the most common diseases in the world, leading to oxidative stress and inflammation. Antioxidants can protect against oxidative stress and resolve inflammation. The purpose of this work is to study the effect of nanosized cerium dioxide on the liver of rats under conditions of chronic alcohol hepatitis modeling. Methods: The study was conducted on 24 male Wistar rats, divided into I – control; II – nanosized cerium dioxide group (1mg/kg); III – chronic alcoholic hepatitis group; and IV – received nanosized cerium dioxide during chronic alcoholic hepatitis modeling. Indicators of pro- and antioxidant balance, NO-cycle, and markers of extracellular matrix metabolism were studied in the liver. Results: Usage of NCD during chronic alcoholic hepatitis decreased the concentration of peroxynitrite by 1.25 times, oxidatively modified proteins decreased by 3.82 times, sialic acids decreased by 1.86 times, and oxyproline decreased by 1.57 times. Conclusions: Intragastric administration of nanosized cerium dioxide at a dose of 1mg/kg for the correction of metabolic changes in the liver of rats under conditions of chronic alcohol intoxication limits ethanol-induced protein damage, peroxynitrite production and reduces collagenolysis and catabolism of non-collagenous proteins of extracellular matrix of the liver.

Influence of doxorubicin on the extracellular matrix of the liver of rats under conditions of chronic alcoholic hepatitis

The liver has a high regenerative potential that is dependent on many factors, in particular adenosine monophosphate kinase signaling, however, long-term alteration, such as daily alcohol consumption, turns regeneration into a chronic disease such as fibrosis, the end stage of which is cirrhosis. Hepatic extracellular matrix proteins are important triggers of enhanced stellate cell function during the progression of liver fibrosis. The experiments were performed on Wistar rats divided into four groups: control group; doxorubicin injection group (1.25 mg/kg); chronic alcohol hepatitis group; injection of doxorubicin during alcoholic hepatitis group, where we studied the total concentration of glycosaminoglycans, concentration of heparin-heparan, keratan-dermatan and chondroitin fractions of glycosaminoglycans, free oxyproline and sialic acids in the liver tissue homogenate. Cells with Mallory-Denk bodies were present in the liver of rats from the alcohol hepatitis group, which consisted of tangled balls of intermediate filaments and showed eosinophilia in the cytoplasm of degenerative hepatocytes. There were also necrotic changes in cells. Sinusoidal capillaries were locally dilated. In the central sections of the liver lobules of rats injected with doxorubicin against the background of chronic alcoholic hepatitis, the central veins were expanded, their endothelium was thinned. Sinusoidal capillaries were locally expanded, there were no blood cells in their lumens. The nuclei of the vast majority of hepatocytes were in a state of karyopyknosis, karyorrhexis, and karyolysis. Mallory-Denk bodies were present in the cytoplasm of cells. Administration of doxorubicin to animals with chronic alcoholic hepatitis leads to an increase in the total concentration of glycosaminoglycans, the concentration of chondroitin sulfates, a decrease in the heparin-heparan fraction of glycosaminoglycans and no changes in concentration of the keratan-dermatan fraction in the liver of rats compared to the control group. In the group of rats injected with doxorubicin against the background of chronic alcoholic hepatitis, the concentrations of total glycosaminoglycans, heparin-heparan fraction, and chondroitin fraction significantly increased, and the content of the keratan-dermatan fraction of glycosaminoglycans significantly decreased compared to animals with chronic alcoholic hepatitis. In rats injected with doxorubicin against the background of chronic alcoholic hepatitis, the content of free oxyproline decreased by 1.25 times, sialic acids – by 1.36 times, compared to the group of animals with chronic alcoholic hepatitis. Administration of ethanol or doxorubicin in combination with ethanol to rats causes morphological changes in the liver that are characteristic of chronic alcoholic hepatitis. Administration of doxorubicin to rats leads to degenerative morphological changes in the liver lobules. The administration of doxorubicin prevents alcohol-induced collagenolysis and the breakdown of glycoproteins, but increases the breakdown of proteoglycans due to an increase in the content of chondroitin and heparin-heparan fractions.

COMPARISON OF CXCL-8 and IFN-γ PRODUCTION IN ACUTE AND CHRONIC STAGES OF LIVER DISEASE

Hepatitis C virus and alcoholism are the main causes of Chronic Liver Disease. (1) The increase of CXCL-8 has been correlated with mortality in alcoholic hepatitis (AH), while in Chronic Hepatitis C (CHC) with the disease severity. (2) The IFN-γ has an anti-viral and anti-fibrotic function. There are few comparative studies in patients regarding the production of these mediators and their possible implication in liver damage. The objective is to evaluate the concentrations of CXCL-8 and IFN-γ in the serum of AH, alcoholic cirrhosis (CiOH) and CHC patients. A multicenter cross-sectional study was carried out. Four participant groups were included: AH, CiOH, CHC and control group (CT). For the quantification of CXCL-8 and IFN-γ a multiple suspension array assay (Milliplex®-MERCK©) was used. Statistical analysis was performed by the SPSS V.22 software using Mann-Whitney-U-test. A p-value<0.05 was considered statistically significant. Values were expressed as median (Q3, Q1). 110 individuals were included: AH (10), CiOH (25), CHC (25) and CT (50). In CXCL-8 quantification, significant differences were detected in AH vs. CT, CiOH vs. CT, CHC vs. CT, CiOH vs. AH and CHC vs. AH (p≤0.001). While in IFN-γ, the differences were detected in AH vs. CT, CiOH vs. CT, CHC vs. CT, CiOH vs. AH and CHC vs. AH (p≤0.001). Differences were detected in both molecules when comparing the chronic stages (CiOH and CHC) with the acute stage (HA), while no differences were found when comparing both chronic stages. The highest CXCL-8 concentration corresponds to AH, reflecting its importance in prognosis and mortality. (2) The increase of IFN-γ in CiOH and CHC may have a role in the regulation of fibrogenesis because of its anti-fibrotic function. The deregulation of mediators such as IL-8 and IFN-γ promotes systemic inflammation in both acute and chronic stages, being greater in AH. This may indicate an association with the susceptibility to persistent respiratory and gastrointestinal diseases. The authors declare that there is no conflict of interest. This work was partially financed by CONACyT SALUD-2016-272579 (GRG) and PAPIIT- UNAM TA200515 (GRG).

Clinical diagnosis of alcoholic hepatitis in Tongliao City, Inner Mongolia

Objective: To explore the current status of alcoholic hepatitis diagnosis by clinicians' in China. Methods: Clinical data of inpatients confirmed with alcohol-associated liver disease diagnosed at Tongliao Infectious Disease Hospital of Inner Mongolia from June 1, 2018 to May 31, 2019 were retrospectively analyzed. The consistency of clinical diagnosis of alcoholic hepatitis was judged according to the diagnostic criteria recommended by the National Institute of Alcohol Abuse and Alcoholism (USA), and then the alcoholic hepatitis severity assessment model recommended by international guidelines, including Maddrey discriminant function, Model for end-stage liver disease, and Glasgow alcoholic hepatitis score and ABIC scores (age, total bilirubin, international normalized ratio and creatinine) were applied to evaluate this group of cases. Results: Among 79 cases with alcohol-associated liver disease, 75 were males and 4 were females, age ranged between 27~75 (51.1±8.8) years. Alcohol consumption varied from 60 g/d to 600g/d, with an average consumption of 148.8 ± 76.6 g/d. The alcohol consumption duration ranged from 4 to 50 [average (23.9 ± 9.6)] years. According to the initial discharge diagnosis, there were 47 and 32 cases in alcoholic hepatitis and alcoholic liver cirrhosis group, respectively. The mean erythrocyte volume, serum alanine aminotransferase, aspartate aminotransferase and total bilirubin were increased in alcoholic liver cirrhosis than alcoholic hepatitis group, while albumin and total cholesterol were lowered in alcoholic liver cirrhosis than alcoholic hepatitis group, and coagulation indexes were significantly extended. Alpha-fetoprotein of both groups were in the normal range; however, it was significantly higher in the alcoholic hepatitis group than the alcoholic cirrhosis group. The 10 cases in the alcoholic cirrhosis group met the definition and diagnosis of alcoholic hepatitis defined by the National Institute of Alcohol Abuse and Alcoholism (USA), but there was no case in the alcoholic hepatitis group. Among the 10 diagnosed cases of alcoholic hepatitis, 5, 6, 1 and 3 cases met the diagnostic criteria of Maddrey discriminant function, Model for end-stage liver disease, Glasgow alcoholic hepatitis score, and ABIC score for severe alcoholic hepatitis, respectively. The Maddrey discriminant function, ABIC score, and Glasgow alcoholic hepatitis score within the Model for end-stage liver disease scores> 20 points had 5, 1, and 3 cases, respectively. Conclusion: Alcoholic hepatitis is over-diagnosed by clinicians. Alcoholic hepatitis patients have the base of liver cirrhosis who meet the diagnostic criteria of National Institute of Alcohol Abuse and Alcoholism (USA). Patients with Model for end-stage liver disease score > 20 points have good consistency with Maddrey discriminant function score ≥ 32 points, and both can be used to evaluate the alcoholic hepatitis patient clinical severity.

Comparison of 1-Year Morbidity Following Liver Transplant for Acute Alcoholic Hepatitis Versus Alcoholic Cirrhosis.

With limited data on the morbidity profile of liver transplant as therapy for alcoholic hepatitis, we compared 30-day and 1-year morbidity in liver transplant recipients with alcoholic hepatitis versus alcoholic cirrhosis. We retrospectively reviewed 38 perioperative variables in patients with alcoholic hepatitis (n = 15) and with alcoholic cirrhosis (n = 46). Multivariable analysis was performed to identify factors independently associated with outcomes. Patients with alcoholic hepatitis were younger (43 vs 58 years; P = .001), with higher pretransplant Model for End-Stage Liver Disease scores (36 vs 29; P = .009) and worse Karnofsky scores (20 vs 50; P < .001). All patients with alcoholic hepatitis received standard criteria deceased donor grafts; however, in the alcoholic cirrhosis group, 64% received standard criteria deceased, 11% living, 11% after cardiac death, 9% extended criteria, and 2% split graft donor organ donations (P > .05). The alcoholic hepatitis group had higher degree of steatosis on explant (P < .005), and the alcoholic cirrhosis group had higher 30-day reoperation rate (P = .001); however, 1-year interventions, vascular and biliary complications, graft and patient survival, and all other variables were similar (P > .05). Rates of alcohol relapse, 1-year infection, and 1-year rejection were higher but not significant (P > .05) in the alcoholic hepatitis group. Thirty-day reoperation (odds ratio of 82.63; 95% CI, 8.02-3338.96; P = .002) and Karnofsky scores (odds ratio of 1.18; 95% CI, 1.08-1.36; P = .006) remained significant on multivariate analysis. Our results showed significant differences between our patient groups, including worse functional status in the alcoholic hepatitis group but significantly higher 30-day reoperation rates and more variable grafts in the alcoholic cirrhosis group, although both groups had similar overall 1-year complication and survival rates. Although not significant, patients with alcoholic hepatitis had higher alcohol relapse and 1-year infection and rejection rates. A larger cohort is necessary to confirm the strength of these findings.

The Diagnostic Value of Autoantibodies to Asialoglycoprotein Receptor Combined with Antinuclear Antibody in Autoimmune Hepatitis.

This study aimed to analyze the combined diagnostic value of autoantibodies to asialoglycoprotein receptor (anti-ASGPR) and antinuclear antibody (ANA) for autoimmune hepatitis (AIH), and to further explore the role of anti-ASGPR in autoimmune hepatitis. According to the clinical diagnosis, the patients were divided into AIH group, viral hepatitis group, alcoholic hepatitis group, fatty liver group, and normal group, then the four groups were compared with the normal group, and the sensitivity and specificity of Anti-ASGPR, ANA and their combination in the diagnosis of AIH were analyzed. Then AIH patients were divided into anti-ASGPR positive group and negative group. The two groups were compared regarding the difference of biochemical and immunological indicators. Only the positive rate of anti-ASGPR and ANA in the AIH group and normal disease group were statistically significant (p < 0.05); in the AIH group, the positive rate of anti-ASGPR and ANA was 63.16% and 71.93%, respectively, the sensitivity and specificity of anti-ASGPR and ANA in parallel were 87.72% and 79.02%, respec-tively, and the Youden index was 0.6674. AIH patients with anti-ASGPR positive had higher levels of immunoglobin G (IgG), alanine aminotransferase (ALT), interleukin-6 (IL-6), interleukin-10 (IL-10), and lower complement C3 than AIH patients with anti-ASGPR negative. The combined positive of anti-ASGPR and ANA in serum has diagnostic value for AIH, and anti-ASGPR may be related to the disease activity, inflammatory reaction, and pathogenesis of AIH.

Identification of key genes, MicroRNAs and potentially regulated pathways in alcoholic hepatitis by integrative analysis

Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease associated with high mortality. Current pharmacological treatment options are not fully effective, and novel target therapies are urgently needed. Until now, key genes, miRNAs and potential signaling pathways in AH remain unclear. Here, we integrated mRNA and miRNA expression profiles to reveal 1411 differentially expressed genes (DEG) and 69 differentially expressed miRNAs (DEM) in AH. And then 51 overlapping genes were identified by compared with miRNA target genes and DEGs, which named as consistent expression genes (CEGs). Pathway analysis showed that CEGs were mainly enriched in PI3K-Akt signaling pathway, MicroRNAs in cancer, FoxO signaling pathway, TNF signaling pathway and P53 signaling pathway. A total of 8 hub genes，FOS, FOXO1, SIRT1, ESR1, BCL2L11, CDK1, CCNB1 and CDKN1A, were screened using protein-protein interaction network analysis. In the regulatory network of miRNA and hub genes, a total of five miRNAs, miR-29c, miR-92b, miR-132, miR-221, miR-222, were identified as key miRNAs. Among them, miR-132 has been shown to target SIRT1, FOXO1, CDKN1A and BCL2L11, and miR-92b targets SIRT1 and BCL2L11. miR-221 and miR-222 both target FOS, ESR1, and BCL2L11. In addition, miR-29c is one of the major down-regulated miRNAs in AH, targeting FOS. Western blot analysis showed that SIRT1 and FoxO1 were expressed at low levels (P < 0.05) and CDK1 was highly expressed in the AH group (P < 0.05). The other five proteins were not significantly different between the two groups (P > 0.05). RT-PCR results showed that miR-132 was significantly higher in the AH group than in the normal group (P < 0.05), while miR-29c was lower than the normal group (P < 0.05), and the other three miRNAs were not significantly different between the two groups (P > 0.05). Therefore, SIRT1, FOXO1, CDK1, miR-132 and miR-29c are involved in the regulation of FoxO and P53 signaling pathways, cell cycle and other biological processes, which may play a key role in the pathogenesis of AH.

Good outcome of living donor liver transplantation for severe alcoholic hepatitis not responding to medical management: A single center experience of 39 patients.

There are limited data on outcomes of living donor liver transplantation (LDLT) for patients with severe alcoholic hepatitis. The study included LDLT recipients for severe alcoholic hepatitis (n=39) who did not improve with medical treatment and compared their outcomes with patients who underwent LDLT for alcoholic liver disease (n=461). The diagnosis of severe alcoholic hepatitis was based on both clinical and explants data. No patients had psychiatric contraindications for liver transplant and all had good family support. The data are shown as number, mean (SD), or median (25-75 interquartile range). All transplant recipients were males, aged 42±8 years. The patients with alcoholic hepatitis were abstinent for a duration of 4±1.8monthsat the time of LDLT. All patients underwent LDLT with a graft to recipient weight ratio of 0.95±0.17. The post-transplant ICU and hospital stay were 5.4±1.3 and 17.6±8.4 days, respectively. When patients with alcoholic hepatitis (n=39) were compared to patients who underwent LDLT for alcoholic liver disease without alcoholic hepatitis (n=461), patients with alcoholic hepatitis were significantly younger (43.2±8.5 vs. 48.2±9.1 years, p=0.001) and had higher Child's (10.9±1.5 vs. 9.8±1.8) and MELD scores (22.1±4.5 vs. 18.4±5.9, p=0.000). Post-operative infections were also significantly more common in the alcoholic hepatitis group (71.7% vs. 51.6%, p=0.018). Fungal infections developed in 23% of alcoholic hepatitis patients as compared to 14% in the rest of the alcoholic patients (p=0.247). Six recipients (15.7%) died at a median follow-up of 28 (6-37) months due to infections, and five (12.8%) patients had relapse of alcohol drinking. Survival was not different between the two groups. Living donor liver transplantation can be successfully performed with good survival for patients with severe alcoholic hepatitis.

Transplantation for acute alcoholic hepatitis.

Transplantation for acute alcoholic hepatitis.

Serum Interleukin-12 Levels in Alcoholic Liver Disease

Interleukin (IL)-12 is a proinflammatory cytokine produced by antigen-presenting cells upon stimulation by diverse stimuli. This study aimed to explore the relationship between IL-12 serum levels and different stages of alcoholic liver disease, alcoholic intake status and abstinence from alcohol. A total of 35 healthy controls without alcohol consumption and 94 patients with alcoholic liver disease (17 with alcoholic steatosis, 37 with alcoholic hepatitis, 40 with alcoholic cirrhosis) were included. Their serum IL-12 levels were measured and followed-up at the 3(rd), 6(th) and 9(th) months. Data were further analyzed according to abstinence from alcohol or not. Mean serum IL-12 levels were higher in the alcoholic hepatitis group (163.1 +/- 57.8 pg/mL) than in the alcoholic liver cirrhosis group (110.5 +/- 41.6 pg/mL) and alcoholic steatosis group (74.4 +/- 26.2 pg/mL). All of these 3 alcoholic groups had higher serum IL-12 levels than the control group (39.3 +/- 8.3 pg/mL; p < 0.02). Among the patients who abstained from alcohol, there was no difference in serum IL-12 levels between control and steatosis patients at the 9(th) month, but the serum IL-12 levels of the hepatitis and cirrhosis groups were still higher than in the control group (p < 0.001 and p = 0.001, respectively). In addition, the patients who continued to drink alcohol had higher serum IL-12 levels than those who abstained from alcohol in the steatosis, hepatitis and cirrhosis groups. At the cut-off value of 54 pg/mL, IL-12 had good sensitivity and specificity in the diagnosis of alcoholic liver disease. Serum IL-12 levels reflected the different stages of alcoholic liver disease and can represent the status of continuous alcohol consumption. It has the potential to be a biomarker of alcoholic liver disease.

Prevalence of Septic Events, Type 1 Hepatorenal Syndrome, and Mortality in Severe Alcoholic Hepatitis and Utility of Discriminant Function and MELD Score in Predicting These Adverse Events

We sought to assess prevalence, and utility of discriminant function (DF) and MELD score in predicting septic events (SE), type 1 hepatorenal syndrome (HRS), and short-term mortality in severe alcoholic hepatitis (AH). Charts of patients with AH (group 1) and cirrhosis without AH (group 2) were retrospectively reviewed. Severe AH, discriminant function (DF) >or= 32 was treated with pentoxifylline. One hundred ninety-five patients were enrolled in the study and divided into 2 groups: group 1, n=99, and group 2, n=96. Of those with AH, 82% had a DF >or= 32 at presentation. Group 1 patients had a higher prevalence of SE (38% versus 25%, P=.04), type 1 HRS (30% versus 9%, P=.0003), and short-term mortality (28% versus 7%, P=.0001). In patients with AH, a MELD score >or=20 (but not a DF >or= 32) at presentation was an independent predictor of a SE (odds ratio [OR] 2.8 [1.0-7.9], P=.04), HRS (OR 4.0, 95% confidence interval [CI] 1.0-16.6, P=0.05), and short-term mortality (OR 6.4, 95% CI 1.1-37.6, P=.03). Kaplan-Meier survival curves confirmed that that a MELD >or= 20 but not a DF >or= 32 was associated with a poorer survival (P = .005 and .5, respectively). In conclusion, patients with severe AH have higher prevalence of SE, HRS, and short-term mortality compared to those with cirrhosis without AH. A MELD score >or=20 at presentation is an independent predictor of these adverse events in patients with AH who have been treated with pentoxifylline.

Late Increase of Peripheral CD34+ Cells Number during Acute Liver Failure Recovery.

Abstract Human Hematopoietic Stem Cells (HSC) of bone marrow origin are reported to transdifferentiate into various cell types, including cells of hepatic lineage, and to be involved in hepatic repopulation. As it has been previously reported in the course of myocardial infarction, we hypothesized that CD34+ cells would appear early in severe acute liver failure and could predict a favourable outcome. Methods: We quantified circulating CD34+ cells in peripheral blood of 146 patients without and with severe hepatic failure (HF) defined by factor V &lt;50%: 20 acute hepatitis with HF, 26 acute alcoholic hepatitis with HF, 22 major right hepatectomy (6/23 developped HF) and 78 controls (31 healthy subjects, 23 cirrhosis, 24 cirrhosis with chronic HF). CD34+ cells were quantified by flow cytometry, according to ISHAGE guidelines in both one and dual platform approaches. Phenotypic and functional analyses were performed in selected cases. In case of acute HF, quantification was done every day until correction of liver function. One patient underwent liver transplantation. The number of circulating CD34+ cells was correlated with factor V level. Results were presented using median and range. Results : At inclusion, the numbers of CD34+ cells /mm3 were similar in different groups (healthy controls = 1.0 [0.1– 4.0]; cirrhosis = 0.9 [0.1–5.1]; cirrhosis with chronic HF = 1.0 [0.1–3.7]; alcoholic hepatitis with HF = 1.2 [0.1–6.0]; liver resection 24H after surgery = 0.8 [0.2–3.2]; acute hepatitis with HF = 0.7 [0.2–3.1]. For patients with acute hepatitis with HF, the number of CD34+ increased over time, from 0.7 [0.2–3.1] to 1.8 [0.5–9.6] at the 4th day after admission and was significantly (p &lt;10–3) correlated with correction of factor V. There was no correlation between the number of CD34+ and the time between admission and onset of the disease. There was no significant increase over time in the hepatectomy group nor in the alcoholic hepatitis group. CD34+ cells detected during acute hepatitis regeneration presented an immature phenotype and coexpressed CD33, CD90, CD133, CD117, CD135 (FLT3-R), CD38, HLA-DR and not V-Cadherin. Clonogenic progenitor cell assays did not reveal specific features and correlation between number of CD34 and BFU-E colonies were in favour of their hematopoietic potentiality. Conclusion: By contrast with data reported in acute myocardial infarction in which early mobilisation of CD34+ cells was observed, we found that the increase of circulating CD34+ HSC is a late event occurring at the time of the recovery of liver function in acute severe hepatic failure. The hematopoietic potentiality of mobilized CD34+ cells suggests that they do not play a major role in liver repopulation in fulminant acute hepatitis.

Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis

The pathogenesis of alcoholic hepatitis (AH) remains poorly understood. Although apoptosis is now recognized as a mechanism of liver injury, the extent and mechanisms of apoptosis in human AH remain unknown. Thus, our aims were to quantify hepatocyte apoptosis in patients with AH, correlate it with disease severity, and identify the mechanisms of apoptosis induction. Hepatocyte apoptosis was assessed in 26 patients with AH and 27 controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspase 3. Liver specimens were also graded for disease severity. The expression of the death receptors, Fas and tumor necrosis factor-alpha receptor 1 (TNF-R1), was assessed by immunohistochemistry. In contrast to normal livers, TUNEL- and caspase 3-positive hepatocytes were readily observed in the livers of patients with AH. In the AH group, hepatocyte apoptosis was significantly higher in patients with a serum bilirubin of > 3 mg/dl. Apoptosis was also greater in grade 4 steatohepatitis. The Fas receptor was strongly expressed in hepatocytes in AH, but not in normal livers; the TNF-R1 expression was comparable in both groups. The present results demonstrate that hepatocyte apoptosis is significantly increased in human AH and justify therapeutic strategies aimed at inhibiting apoptosis in this disease.

Relationship between serum levels of anti-low-density lipoprotein-acetaldehyde-adduct antibody and aldehyde dehydrogenase 2 heterozygotes in patients with alcoholic liver injury.

We prepared low-density lipoprotein (LDL)-acetaldehyde-adduct (hereafter abbreviated as LDL-adduct) and anti-LDL-adduct antibody by using Watanabe hyperlipidemic rabbits, and determined values of serum anti-LDL-adduct antibody levels by the ELISA method in healthy adults and patients with alcoholic liver injury. In the nondrinking group in healthy adults, values of anti-LDL-adduct antibody levels were 25 +/- 13 microg/ml, and there was no significant difference between moderate drinkers without diseases and the nondrinking group in healthy adults. Values of anti-LDL-adduct antibody in alcoholic disease groups, 17 +/- 9 microg/ml for the patients with the fatty liver group, 21 +/- 14 microg/ml for the hepatic fibrosis group, 70 +/- 21 microg/ml for the alcoholic hepatitis group, 41 +/- 50 microg/ml for the alcoholic cirrhosis group, and 19 +/- 18 microg/ml for the alcoholic pancreatitis group. Examinations of aldehyde dehydrogenase 2 (ALDH2) genetic variations by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method in the healthy group and the liver injury group revealed a tendency for patients with ALDH2(1)/2(2) in the liver injury group to have relatively mild liver lesions. When comparing anti-LDL-adduct antibody levels between ALDH2 genetic variations, those for the patients with ALDH2(1)/2(2) (36 +/- 40 microg/ml) were significantly higher than those for patients with ALDH2(1)/2(2) (11 +/- 5 microg/ml). Results of the present study suggest that genetic variation may influence the progression of liver injury.

Effect of the Type of Beverage and Meat Consumed by Alcoholics with Alcoholic Liver Disease

We analyzed meat products and alcoholic beverage preference in patients with the three stages of alcoholic liver disease (ALD) compared with controls using diet history data. Daily consumption of total alcohol, types of alcoholic beverages, and types of meat and meat products in grams was obtained by dietary history taken from patients with biopsy proven stage of ALD. A strong association was found between the ALD subjects and total alcohol and beer consumption. There was a significant increase in the consumption of total pig products, pork, and offal in the ALD groups compared with controls. There was a significant positive correlation between beer consumption and pork in alcoholic hepatitis, total pork products in alcoholic hepatitis, and cirrhosis and offal in alcoholic hepatitis and cirrhosis. There was no correlation with the fatty liver stage of ALD. The strongest correlation was between beer and total pig products in the alcoholic hepatitis group. Wine consumption was negatively correlated with the consumption of pig products and beer in the alcoholic cirrhosis group. In conclusion, the association of total pig product consumption with cirrhosis mortality in various countries was validated by personal diet history data obtained from ALD patients in a tested clinical microcosm. The results suggest that this association may be modified by the type of alcoholic beverage that is preferentially consumed.

Serum levels of interleukin-8 in alcoholic liver disease: relationship with disease stage, biochemical parameters and survival

Interleukin-8 (IL-8), a cytokine produced by a host of cells, including monocytes, macrophages, Kupffer cells and hepatocytes, can activate neutrophils. Peripheral neutrophilia and liver neutrophil infiltration are frequently noted in patients with alcoholic liver disease. However, the relationship between IL-8 and different stages of alcoholic liver disease is uncertain. The aim of this study is to determine if a correlation exists between circulating IL-8 levels and biochemical and histological parameters and survival in alcoholic liver disease. Serum levels of IL-8 were determined with an enzyme-linked immunosorbent assay in 166 subjects, consisting of 30 healthy controls, 26 patients with non-alcoholic fatty liver, 15 with alcoholic fatty liver, 32 with alcoholic hepatitis, 30 with alcoholic cirrhosis, 28 with chronic hepatitis B and 5 with chronic hepatitis C. Serum IL-8 levels were markedly elevated in patients with alcoholic hepatitis (437 +/- 51 pg/ml) when compared with all other groups (p < 0.05). Levels of IL-8 in patients with alcoholic fatty liver, alcoholic cirrhosis and viral hepatitis were higher than those in controls and in patients with non-alcoholic fatty liver. In addition, IL-8 levels were higher in patients who died (p = 0.007), and correlated with biochemical and histological parameters, and severity of liver injury: serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, prothrombin time, indocyanine green retention ratio, tumor necrosis factor-alpha and peripheral neutrophil count in patients with alcoholic hepatitis. After a 2-year follow up, patients with IL-8 above 479 pg/ml had a higher mortality rate in the alcoholic hepatitis group (p = 0.033). These findings suggest that IL-8 is activated in alcoholic liver disease, especially in alcoholic hepatitis, and is closely correlated with liver injury. IL-8 levels can reflect the stage and severity of alcoholic liver disease, and may serve as a predictor of survival in patients with alcoholic hepatitis.

Plasma Tumor Necrosis Factor α Predicts Decreased Long‐Term Survival in Severe Alcoholic Hepatitis

Plasma tumor necrosis factor alpha (TNF alpha), interleukin 1 alpha (IL-1 alpha), and interleukin 1 beta (IL-1 beta) were measured in plasma samples obtained from 23 patients with severe alcoholic hepatitis on admission and after 30 days of hospitalization. Over a 2-year follow-up period, 14 patients died at a mean time of 8 months following discharge. The presence of elevated plasma TNF alpha either at admission or discharge from the hospital was associated with death in 82% (14/17) of patients. By contrast absence of elevated plasma TNF alpha was associated with survival in 100% (6/6). The difference in survival with and without detectable plasma TNF alpha was significant at p = 0.0022. Plasma TNF alpha was not elevated in alcoholic patients without clinically apparent liver disease, with alcoholic cirrhosis, or in nonalcoholic healthy controls. Plasma IL-1 alpha was also significantly increased in alcoholic hepatitis whereas IL-1 beta was not. Neither IL-1 alpha nor beta was correlated with outcome in the alcoholic hepatitis group. It is concluded that the presence of elevated plasma TNF alpha is a significant predictor of decreased long-term survival in patients with severe alcoholic hepatitis.

Effect of liver disorders on ethanol elimination and alcohol and aldehyde dehydrogenase activities in liver and erythrocytes.

1. Liver biopsies were performed in healthy control subjects and in subjects with alcoholic and non-alcoholic liver disease in order to examine alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase [ALDH; aldehyde dehydrogenase (NAD+); EC 1.2.1.3] activities. Erythrocyte ALDH and ethanol metabolism were also investigated in the same subjects. 2. Fifteen per cent of the subjects studied (seven of 48 subjects tested) presented atypical ADH activity, characterized by elevated activity at pH 7.4 or 8.8 compared with that found in subjects with the usual ADH form. However, the ethanol elimination curves obtained in two subjects with atypical ADH were indistinguishable from the kinetics of the group with normal ADH. Subjects displaying atypical ADH activity showed normal liver and erythrocyte ALDH activities. 3. Considering only the subjects with the normal ADH form, hepatic ADH activity was unaltered in subjects with non-alcoholic liver disease (chronic hepatitis or cirrhosis) and in those with alcoholic steatosis. Subjects with alcoholic hepatitis or alcoholic cirrhosis showed a lower ADH activity compared with the healthy control group. 4. In spite of the changes detected in subjects with alcoholic liver disease, curves of blood ethanol concentration after oral administration of 0.4 g of ethanol/kg were indistinguishable between the alcoholic hepatitis group and the control group. 5. Hepatic ALDH activity, assayed at 300 mumol/l acetaldehyde, was found to be diminished in all liver pathologies investigated, regardless of their aetiology. Nevertheless, erythrocyte ALDH activity was not modified in subjects with non-alcoholic or alcoholic liver disease. As a result of these findings, no relationship was found between hepatic and erythrocyte ALDH.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic active hepatitis in alcoholic patients.

The histologic appearances characteristic of chronic active hepatitis (CAH) were observed in liver biopsies of seven patients among whom alcohol abuse was the only identifiable determinant of liver disease. Clinical, hematologic, biochemical and histologic features in these patients were contrasted with those of 20 patients with typical alcoholic hepatitis. For the CAH group, the liver was less enlarged below the costal margin, a palpable spleen was more frequent, the mean neutrophil count was lower, and there was a lower mean level of transaminase enzymes. In both groups there was minimal evidence of the serologic markers of autoimmune CAH or antecedent hepatitis B virus (HBV) infection. Histologically, all liver biopsies in the CAH group showed perilobular "piecemeal" necrosis, "rosette" formation and dense portal and septal lymphoid infiltrates, in contrast to the fatty change, Mallory bodies and intralobular neutrophil clusters of the alcoholic hepatitis group. In the CAH group, a second liver biopsy was assessed after a period during which alcohol consumption was known; histologic improvement or deterioration correlated with abstinence or continuation of drinking. Thus "alcoholic" CAH has some clinical and histologic features distinct from those of typical alcoholic hepatitis, but the two types were similar in other respects including dependence of the course of disease on continuing use of alcohol.

Depressed delayed cutaneous hypersensitivity in alcoholic hepatitis

Delayed cutaneous hypersensitivity was studied in 10 patients with severe alcoholic hepatitis, 9 patients with either inactive alcoholic cirrhosis or alcoholic fatty liver, and 10 agematched controls. The mean response of the alcoholic hepatitis group was significantly less compared to controls for SK-SD (P less than 0.001), mumps (P less than 0.001), trichophyton (P less than 0.025), and Candida albicans (P less than 0.025). Upon clinical recovery, the response of the 6 surviving patients with alcoholic hepatitis was similar to controls for 4 of the 5 antigens tested, and the improvements in response to SK-SD and Candida albicans were significant (P less than 0.02 and P less than 0.05). The mean percentage and absolute numbers of thymus-derived lymphocytes were significantly less in the alcoholic hepatitis group compared with controls. Both the alcoholic hepatitis patients and patients with less advanced alcoholic liver disease had a diminished response to concanavalin A and phytohemagglutinin. This study demonstrates a reversible depression of delayed cutaneous hypersensitivity in alcoholic hepatitis. Several mechanisms may help account for this finding. We recommend that skin tests in patients with alcoholic hepatitis be interpreted with this phenomenon in mind.