Decreased Tumor Necrosis Factor-α and Interleukin-1α Production from Intrahepatic Mononuclear Cells in Chronic Ethanol Consumption and Upregulation by Endotoxin

The relationship between the changes in liver pathology and the production of interleukin (IL)-1α, IL-6, and tumor necrosis factor-α (TNF-α) by intrahepatic mononuclear cells was studied in rats fed alcohol and subsequently exposed to lipopolysaccharide (LPS). Rats were fed 40% ethanol in drinking water, whereas control rats were provided with a chow diet with isocaloric or 2% sucrose drinking solutions for up to 20 weeks. Decreased IL-1α and TNF-α production in 24-hr culture supernatants of mononuclear cells isolated from liver perfusate was detected while IL-6 remained unchanged over 20 weeks. When animals were injected with LPS (1.0 μg/kg body weight), there was a 5-fold rise in ALT levels in the ethanol-fed group, but not in control groups. Increased IL-6 and TNF-α levels in the serum and supernatant of cultured intrahepatic mononuclear cells stimulated with or without LPS or concanavalin A was observed. There was a correlation between levels of ALT and TNF-α, but not IL-6. T cells and Kupffer cells were the major source of TNF-α in culture supernatants of hepatic perfusate mononuclear cells from ethanol-consuming rats injected LPS. In addition, pathological liver injury was evident, which suggests a pathogenic role for TNF-α in alcohol-induced liver disease.     

Lack of Plasma Complement Activation in Severe Acute Alcoholic Hepatitis

To investigate whether complement pathway activation contributes to the clinical and histological features of acute alcoholic hepatitis, we studied the activation of the classical and alternative pathways in patients with alcoholic hepatitis ( n = 20), inactive alcoholic cirrhosis ( n = 8), heavy drinkers without alcoholic liver disease ( n = 10), patients with liver disease of nonalcoholic etiology ( n = 11), and healthy control subjects ( n = 18). Complement activation was evaluated in the alcoholic hepatitis patients by its correlation with a number of clinical and laboratory features indicative of the severity of liver injury, as well as by comparison of the patient groups. There was no significant difference in circulating C3 [1.02 g/liter, confidence interval (CI) = 0.76–1.28] or C4 (0.25 g/liter, CI = 0.17–0.33) in patients with alcoholic hepatitis when compared with the four control groups. Factor B levels (0.24 g/liter, Cl = 0.21–0.27) were higher in the alcoholic hepatitis patients than the control groups ( p < 0.01). However, activation of complement (given by the ratios C3d/C3, C4d/C4, and Ba/factor B) was not different in alcoholic hepatitis patients when compared with the control groups. Univariate analysis of a wide range of clinical and laboratory features in the alcoholic hepatitis subjects showed a positive correlation between plasma C3 and serum alkaline phosphatase ( r = 0.68, p = 0.0014), AST ( r = 0.55, p = 0.015), and γ-glutamyltranspeptidase ( r = 0.47, p = 0.035), but no correlation with clinical or laboratory features associated with high morbidity or mortality. There is no relationship between clinical or laboratory indicators of disease severity and complement activation, and it is unlikely that complement activation contributes to the clinical and histological features of alcoholic liver disease.     

肿瘤坏死因子与乙型病毒性肝炎病情关系的探讨

目的：观察ＴＮＦ与肝炎类型,肝功能（ＡＬＴ）,ＨＢＶ复制之间的关系。方法：用放射免疫分析（ＲＩＡ）法检测３９０例各型乙型病毒性肝炎及３７例健康献血员肿瘤坏死因子（ＴＮＦ）水平。     

Human Hepatocyte Growth Factor in Alcoholic Liver Disease: A Comparison with Change in α-Fetoprotein

To evaluate the hepatic regenerative response in patients with alcoholic liver disease, sera from 263 patients with severe alcoholic hepatitis and/or cirrhosis were analyzed for hepatocyte growth factor (HGF) and α-fetoprotein (AFP). HGF concentration was elevated above healthy controls in 95% of the patients (median level = 2.4 ng/ml), whereas AFP tended to be depressed below controls (median level = 4.1 ng/ml). Correlations with parameters of liver injury (i.e., ascites, encephalopathy, AST bilirubin, and protime) all showed a more significant correlation with HGF concentrations than those of AFP. Patients with HGF levels below the mean (4 ng/ml) exhibited significantly better survival (median survival = 35 months vs. 8.5 months for those with HGF ≥4 ng/ml; p = 0.007). Serum HGF levels were associated with various specific histologic features of alcoholic hepatitis that included, but were not exclusively related to, necrosis.     

Predicting Short-Term Mortality and Long-Term Survival for Hospitalized US Patients with Alcoholic Hepatitis

Background

No study has evaluated current scoring systems for their accuracy in predicting short and long-term outcome of alcoholic hepatitis in a US population.

Methods

We reviewed electronic records for patients with alcoholic liver disease (ALD) admitted to Parkland Memorial Hospital between January 2002 and August 2005. Data and outcomes for 148 of 1,761 admissions meeting pre-defined criteria were collected. The discriminant function (DF) was revised (INRdf) to account for changes in prothrombin time reagents that could potentially affect identification of risk using the previous DF threshold of >32. Admission and theoretical peak scores were calculated by use of the Model for End-stage Liver Disease (MELD). Analysis models compared five different scoring systems.

Results

INRdf was closely correlated with the old DF (r ² = 0.95). Multivariate analysis of the data showed that survival for 28 days was significantly associated with a scoring system using a combination of age, bilirubin, coagulation status, and creatinine (p < 0.001), and an elevated ammonia result within two days of admission (p = 0.012). When peak values for MELD were included, they were the most significant predictor of short-term mortality (p < 0.001), followed by INRdf (p = 0.006).

Conclusion

On admission, two scoring systems that identify a subset of patients with severe alcoholic liver disease are able to predict >50 % mortality at four weeks and >80 % mortality at six months without specific treatment.     

Cutaneous Necrosis Associated With Interferon α-2b

Cutaneous necrosis may occur as a complication of treatment with interferon. Here we report the first case of cutaneous necrosis developing in a patient receiving interferon α-2b for the treatment of chronic hepatitis C viral infection. The patient developed two necrotic lesions while receiving high doses of interferon. We suggest that discontinuation of treatment may be necessary to permit healing of such lesions. Although the exact mechanism involved in cutaneous necrosis remains unknown, our observations support earlier findings suggesting that intraarterial injection may be a factor.     

右心室不同部位起搏早期对患者血浆肿瘤坏死因子-α的影响

目的比较右心室心尖部(RVA)和右心室间隔部(RVS)不同部位起搏早期对患者血浆肿瘤坏死因子(TNF-α)水平的影响。方法将25例植入DDD型起搏器患者随机分为3组,RVA起搏组、RVS起搏组、对照组,对比观察3组患者植入起搏器前及术后3个月血浆TNF-α的变化。结果术前3组患者血浆TNF-α水平比较差别无统计学意义(P0.05);术后一周3组患者血浆TNF-α水平两两比较差别无统计学意义(P0.05);术后3月RVA起搏组与术前、术后一周比较TNF-α水平,差别有统计学意义(P0.001),即RVA起搏组患者血浆TNF-α水平随时间增加而增加;RVS起搏组较术前、术后一周TNF-α水平比较,差别无统计学意义(P0.05);RVA起搏组较RVS起搏组TNF-α水平升高,差别有统计学意义(P0.001)。结论右心室间隔部起搏较右心室心尖部起搏更有利于双心室电激动的同步性,且对心功能的影响较小,右心室间隔部起搏是安全、有效的。     

酒精性肝硬化患者血清肿瘤坏死因子受体的检测及其临床意义

同特异性免疫测定ELISA法检测了32例酒精性肝硬化患者和10名健康人血清中肿瘤坏死因子受体的水平。酒精性肝硬化患者两种可溶性肿瘤坏死因子受体(P55、P75)均明显高于健康组(P<0.01),肝硬化代偿期与失代偿期患者比较有显著差异(P值分别<0.005,<0.01)。这些结果提示循环中可溶性肿瘤坏死因子受体(STNFR)的水平与肝硬化和疾病的进展程度呈正相关。     

慢性酒精性胰腺炎患者体外肿瘤坏死因子和肿瘤坏死因子受体的诱导

肿瘤坏死因子(TNFa)是急性胰腺炎导致全身多器官损害的一种重要介质。本文研究的目的是了解慢性酒精性胰腺炎TNFa和可溶性肿瘤坏死因子受体p55、p75(sTNFRp55、sTNFRp75)是否升高,及其升高是否是内毒素或酒精的作用。我们对12例慢性酒精性胰腺炎患者和8例健康者用内毒素脂多糖(LPS)和乙醇(Ethanol)刺激后的周围血单核细胞上清液用ELISA方法进行了TNFa、sTNFRp55、p75的检测。LPS刺激后的单核细胞上清液中TNFa、sTNFp55、p75浓度不论是患者还是健康组均较自然表达明显增加,其中sTNFRp55、p75浓度在胰腺炎组较正常组明显增加,P值分别<0.05、<0.001。Ethanol刺激后 TNFa和sTNFRp55的表达在胰腺炎组与正常组之间无差异.但sTNFRp75较正常组增加。我们的结果提示慢性酒精性胰腺炎前炎性介质TNFa和sTNFRp55、p75的诱导与内毒素活化的单核细胞表达有关,而酒精对单核细胞活化不起直接作用。     

Plasma α-Amino-n-Butyric Acid/Leucine Ratio in Alcoholics

Fasting free amino acid concentrations in plasma of 20 control and 18 alcoholic subjects were compared in an attempt to validate previous reports that the molar ratio of α-amino- n -butyric acid/leucine (A/L ratio) is a marker for alcoholism. We were unable to confirm the observations of either altered α-amino- n -butyric acid or leucine concentrations or an increased A/L ratio in alcoholic subjects, and we conclude that the A/L ratio is not a biochemical marker for alcoholism.     

Recombinant α-Interferon May be Efficacious in Acute Hepatitis B

Whereas, in chronic type B hepatitis, the therapeutic effect of alpha-interferon has been studied extensively, data on the effect of interferon on the course and prognosis of acute hepatitis B are scarce in the literature. We report a case of acute type B hepatitis complicated by life-threatening extrahepatic manifestations where recombinant alpha-interferon facilitated clinical, biochemical, and serological recovery.     

The Correlation between Red-Cell Survival and Excess of α-Globin Synthesis in β-Thalassaemia

In 13 subjects affected by β-thalassaemia major, in three subjects affected by β-thalassaemia minor and in five normal healthy persons haemoglobin synthesis and the survival of red cells transfused into normal, group compatible, healthy recipients has been studied. The existence of an excess of newly synthesized α-chains and of a negative correlation between the excess α-chain and the red-cell survival has been demonstrated. The harmful role of the α-chain excess on the erythrocyte and the implications of this finding are discussed.     

Controversies in Early Liver Transplantation for Severe Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a condition of acute liver inflammation in the setting of heavy alcohol use that is often managed with corticosteroids in severe cases. Among non-responders to steroids, however, prognosis is poor with up to 75% mortality within 6 months after treatment failure. Early liver transplantation (LT) can achieve an acceptable short-term survival, and initial studies have demonstrated 3-year survival rates of up to 84%. However, the practice of early LT in severe AH remains controversial with concerns over the 6-month rule of sobriety and risk of alcohol relapse post-transplant. Proponents of LT advocate for better understanding of alcohol use as a disorder rather than self-inflicted cause of illness, aim to redefine the misguided application of the 6-month rule, and point out similar relapse rates among patients with early LT and those with greater than 6 months abstinence before transplant. Opponents of LT emphasize the correlation between alcohol relapse and graft failure and mortality, public resistance and potential for distrust among donors, and arguments that transplant centers need to establish improved models to predict relapse and standardize candidate selection criteria across centers. Here we review recent literature on this controversy and provide recommendations for moving forward to consensus.