Lipid peroxidation and serum cytokines in acute alcoholic hepatitis

AIMS: Increased exposure of Kupffer cells to intestinal-borne Gram-negative bacteria enhances the metabolism and leads to cytokine production by these cells. Activation of Kupffer cells increases free radical release, which may, in turn, enhance cytokine secretion, creating a positive feedback loop, which contributes to liver inflammation. Cytokines act on T cells, inducing their proliferation and secretion of additional interleukins. Lipid peroxidation products (malondialdehyde; MDA) form adducts with proteins and acetaldehyde, triggering a T cell immune response. Controversy exists about the predominance of either Th-1 or Th-2 cellular responses. We performed the present study in order to analyse the cytokine pattern in patients with acute alcoholic hepatitis, its relation to MDA and the relation between all these parameters and liver function and prognosis. SUBJECTS AND METHODS: The study included 53 male alcoholics, 47 followed up for a median time of 32 months, during which 17 of them died. We measured serum MDA, tumour necrosis factor-alpha, interferon gamma (IFNG) and interleukins (IL) 4, 6, 8, and 10. RESULTS: MDA levels were raised in cirrhotics and non-cirrhotics with alcoholic hepatitis, maintaining a relationship with bilirubin and Maddrey index, and with mortality in the univariate analysis. Both IFNG and IL-4 were raised in our patients compared with controls, as well as IL-8, and IL-6, but IL-10 were below the detection limit in the majority of cases, especially in cirrhotics. Using a Cox regression model, Maddrey index displaced MDA in the survival analysis. CONCLUSIONS: Our data lend support to the hypothesis that activation of both Th-1 and Th-2 cell subsets take place. MDA levels are raised in alcoholics with alcoholic hepatitis and are closely related to liver function derangement and to survival, although this is displaced by Maddrey index using Cox regression model.     

Neutrophilic infiltration in alcoholic hepatitis.

Leukocyte infiltration in the liver is one of the most important features of alcoholic liver disease. However, in alcoholic hepatitis, the role of polymorphonuclear neutrophils (PMNs) in liver injury still remains to be fully elucidated. Furthermore, the migration of PMNs and their presence in the liver during alcoholic hepatitis have not been fully investigated. Up-regulation of chemokine secretion and adhesion molecule expression on effector cells (i.e., PMNs) and target cells (i.e., hepatocytes) are important factors in neutrophilic infiltration of the liver. The CXC chemokines--that is, interleukin (IL)-8 (in human beings), cytokine-induced neutrophil chemoattractant (CINC) (in rats), and KC (in mice)--are proneutrophilic agents. They are up-regulated during chronic--that is, several years of--alcohol use in human beings and in up to 30 weeks in experimental models of ethanol intoxication in mice and rats. Up-regulation of these chemokines in the circulation and tissues is also associated with enhanced neutrophilic infiltration in the liver. In the rat, the up-regulation of CXC chemokine production is time dependent. For example, after 16 weeks of feeding, up-regulation of CXC chemokine is observed, whereas after 32 weeks, CC chemokines are enhanced. Concomitantly, selective migration of PMNs and mononuclear cells is observed. In another model, in which both CXC and CC chemokines were enhanced after chronic ethanol use for 12 weeks in mice, neutrophilic and mononuclear/lymphocytic infiltrations were also seen. This model correlates closely with alcoholic hepatitis in human beings, characterized by increased IL-8, RANTES (regulated upon activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1 (MIP-1) and profound increases in neutrophils and lymphocytes in the liver.     

Changes in cytokine levels during admission and mortality in acute alcoholic hepatitis

Cytokine levels are raised in acute alcoholic hepatitis. However, there are disparate results regarding the duration of altered plasma levels, and there are also discrepancies about the relation of changes during the first 15 days after admission with short-term (in-hospital) or long-term mortality. In 56 patients with acute alcoholic hepatitis we found that IL-8, IL-4, Interferon-γ (IFN-γ), malondialdehyde and C-reactive protein remained higher in patients than in 18 age- and sex-matched controls at admission, at the 7th day and at the 15th day after admission. Moreover, IL-4 levels (and to a lesser extent, IL-10 and IFN-γ ones) increased along the three determinations. However, comparing patients who died during the admission with those who did not, there were no statistically significant differences, but there was a nearly significant trend for MDA (Z = 1.89; p = 0.059), with higher levels among those who died. When changes between the first and the second determinations were compared with long-term survival, only IL-8 and IFN-γ showed a relation with mortality. IFN-γ values increased among those who survived and decreased among those who died (p = 0.048). IFN-γ values at the first determination also showed a relation with long-term mortality, especially when patients with IFN-γ values in the first quartile were compared with those of the 4th one (log rank = 5.64; p = 0.018; Breslow = 4.64; p = 0.031). Besides Interferon-γ, only C-reactive protein showed differences between the first and the 4th quartile regarding mortality (Log rank = 4.50; p = 0.034; Breslow 4.33; p = 0.038). In contrast with other studies, no relation was found between TNF-α or IL-6 and mortality.     

Neutrophil-mediated tissue injury in alcoholic hepatitis.

The presence of polymorphonuclear leukocytes (neutrophils) in liver parenchyma is a prominent feature of alcoholic hepatitis. However, the pathophysiological importance of these phagocytes and potential injury mechanisms in alcoholic hepatitis remain unclear. This review summarizes the current knowledge on basic mechanisms of neutrophil-induced liver injury as it emerged from studying a number of different experimental models. This general concept of neutrophil-mediated liver cell injury agrees with many observations made by examining liver sections obtained from patients with alcoholic hepatitis. These include the presence of extravasated neutrophils in the liver, evidence for degranulation of neutrophils in the parenchyma, and excessive formation of neutrophil chemoattractants such as CXC chemokines in liver cells. Colocalization and a strong quantitative correlation between apoptotic hepatocytes and neutrophils could indicate apoptosis-induced transmigration of neutrophils during alcoholic hepatitis, similar to events previously demonstrated in experimental models. Furthermore, circulating neutrophils are primed for reactive oxygen species and inflammatory mediator formation. However, clear evidence for a neutrophil-induced injury in alcoholic hepatitis is missing. Unfortunately, most experimental models of alcoholic liver disease do not have a prominent neutrophilic infiltrate. Therefore, a high priority of future research has to be to develop an experimental model that realistically mimics the neutrophil component of alcoholic hepatitis in human beings. This would allow investigators to test the concept that neutrophils are important for cell injury during alcoholic hepatitis and to identify potential therapeutic intervention strategies.     

Role of Kupffer cells in alcoholic hepatitis.

Kupffer cells play a major role in alcoholic liver disease. Oxidative stress and endotoxin are major mediators of the inflammatory process in alcoholic hepatitis. Recent evidence supports the suggestion that endotoxin-induced signal transduction begins with CD14-mediated activation of Toll-receptor 4 and subsequent activation of nuclear factor-kappa B (NF-kappa B) binding activity. Free radicals from reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in Kupffer cells also activate NF-kappa B binding activity. Inflammatory cytokines and cyclooxygenase-2 are up-regulated in response to binding of NF-kappa B. A combined role for tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 is important in the pathogenesis of alcoholic hepatitis.     

急性胰腺炎严重度和坏死的预测因子

急性胰腺炎(AP)的临床经过个体间差异甚大, 多数病人是轻型的,自限性的,重型坏死型占10％ -15％,病死率为30％-50％。开始是胰内胰蛋白酶原激活,引起胰蛋白原激活多肽(TAP)的裂解变为胰蛋白酶,进而蛋白酶被激活,引起胰的自我消化和被免疫系统介导炎症反应,细胞因子在胰腺炎的发病机制上发挥关键性作用。酶原激活和自我消化引起局部炎症反应,炎症介导细胞因子释放进入循环,细胞因子引起细胞激活。AP的严重性取决于引起全身炎症反应的程度,最为严重的是引起远隔器官损害和多系统器官衰竭。     

Clinical and demographic factors and outcome of amyotrophic lateral sclerosis in relation to population ancestral origin

Background

To review how the phenotype and outcome of amyotrophic lateral sclerosis (ALS) change with variations in population ancestral origin (PAO). Knowledge of how PAO modifies ALS phenotype may provide important insight into the risk factors and pathogenic mechanisms of the disease.

Methods

We performed a systematic review and meta-analysis of the literature concerning differences in phenotype and outcome of ALS that relate to PAO.

Results

A review of 3111 records identified 78 population-based studies. The 40 that were included covered 40 geographical areas in 10 subcontinents. Around 12,700 ALS cases were considered. The results highlight the phenotypic heterogeneity of ALS at time of onset [age, sex ratio (SR), bulbar onset], age at diagnosis, occurrence of comorbidities in the first year after diagnosis, and outcome (survival). Subcontinent is a major explanatory factor for the variability of the ALS phenotype in population-based studies. Some markers of ALS phenotype were homogeneously distributed in western countries (SR, mean age at onset/diagnosis) but their distributions in other subcontinents were remarkably different. Other markers presented variations in European subcontinents (familial ALS, bulbar onset) and in other continents. As a consequence, ALS outcome strongly varied, with a median survival time from onset ranging from 24 months (Northern Europe) to 48 months (Central Asia).

Discussion

This review sets the scene for a collaborative study involving a wide international consortium to investigate, using a standard methodology, the link between ancestry, environment, and ALS phenotype.

     

Response to hepatitis B vaccine in relation to the hepatitis B status of family members.

The influence of the hepatitis B status of family members on the response to hepatitis B vaccine of an infant has been examined in 395 families. The presence of one or more HBsAg-positive family members did not appear to have any effect on the vaccine response. This is an encouraging finding as children born into carrier families are at an increased risk of becoming carriers themselves. That the vaccine response of such children is as good as for those born into non-carrier families means that they are likely to be protected against the carrier state by the vaccine.     

Enteral nutritional support in acute alcoholic pancreatitis.

The experience to date with total enteral nutritional (TEN) support in acute alcoholic pancreatitis patients admitted to the University of Kentucky affiliated hospitals was reviewed.

Standard enteral formulas sufficient to meet patient's needs were administered into the small bowel via endoscopically placed nasoenteric feeding tubes in five patients. Feedings were administered for a mean of 28.4 days. Pancreatitis was mild to moderate in severity by Ranson's criteria in four patients, and severe in one.

Four patients developed complications of pancreatitis before initiation of TEN, representing the most common indication for nutritional support. Nutritional status was maintained by TEN with no significant complications from this nutritional support identified. Diarrhea that did not limit tube feeding developed in a single patient.

This experience further supports the safety of TEN in acute pancreatitis and suggests that adequate nutritional support can be delivered by this route.     

Plasma vitamin B12 titres as indicators of disease severity and mortality of patients with alcoholic hepatitis

Patients with alcoholic hepatitis with plasma B12 levels above 800 pg/ml have overt clinical manifestations of liver disease including severe hepatocellular damage. High plasma B12 levels significantly correlate (P less than 0.0001) with standard liver function tests, e.g. bilirubin, cholylglycine, alkaline phosphatase, AST and prothrombin time as an index of the severity of hepatic damage. Decrease in plasma B12 to normal titres implies a decrease in the severity of alcoholic liver disease, whereas increased plasma B12 levels relate to increased severity and mortality.     

肝移植术后患者急性肾损伤危险因素及严重程度分析

目的　分析肝移植术后患者急性肾损伤（acute kidney injury, AKI）的危险因素及AKI严重程度的影响因素。方法　收集2005年1月—2015年8月在我中心进行肝移植手术患者,排除术前AKI患者,共入组469例,对该组患者术前、术中、术后影响AKI的危险因素及术后4周时的转归进行分析、研究。结果　469例患者中,术后发生AKI者274例（AKI组）,无AKI者195例（非AKI组）,发病率为58.4%。受体身体质量指数（body mass index, BMI）、术前肌酐水平、冷缺血时间、手术时间、下腔静脉阻断时间、术后乳酸峰值、术后AST峰值等均是发生AKI的危险因素。术后4周AKI组20.4%患者肾功能仍然异常,病死率为3.6%,较非AKI组明显升高（P=0.027）。结论　肝移植术后发生AKI的影响因素较多,受体BMI、术前肌酐水平、阻断下腔静脉时间、手术时间、术后乳酸峰值、术后AST峰值均是发生AKI的独立危险因素。术后4周AKI组患者肾功能异常及病死率较非AKI组均明显升高。     

Risk factors for acute non-A, non-B hepatitis and their relationship to antibodies for hepatitis C virus: a case-control study.

A case-control study was carried out comparing 333 case subjects with non-A, non-B hepatitis and 1095 hospital control subjects. Of 333 case subjects, 197 (59%) were positive for hepatitis C antibody (anti-HCV). Excluding blood transfusion and intravenous drug use, surgical intervention and dental therapy were strongly associated with anti-HCV-positive cases: in particular, obstetric and gynecology surgical intervention was found to be strongly associated with HCV positivity (odds ratio [OR] = 32; 95% confidence interval [CI] = 7, 147). Raw shellfish consumption was a risk factor for anti-HCV-negative cases (OR = 2.2; 95% CI = 1.0, 5.1), thus suggesting an enterically transmitted virus in sporadic non-A, non-B hepatitis in Italy.     

IgM-antibody response to the hepatitis B core antigen in acute and chronic hepatitis B.

A solid phase M-antibody capture radioimmunoassay (MACRIA) and a serum fractionation method were used to quantitate the IgM response to the hepatitis B core antigen (IgM anti-HBc) in acute and chronic hepatitis B infections. Antibody to the core antigen was predominantly of the IgM class during the acute phase of hepatitis B. Resolving acute infections remained positive by MACRIA, but at decreasing levels, for as long as 6 months. IgM anti-HBc persisted in HBsAg carriers but at levels very much lower than seen in acute infections. There was no correlation of IgM anti-HBc with severity of chronic liver disease in carriers. Measurement of IgM anti-HBc by MACRIA enabled accurate identification of acute hepatitis B on single serum specimens.     

Some factors affecting nerve regeneration in relation to radiotherapy.

The effect of delay and irradiation, both separately and combined, on regeneration of rat sciatic nerve was evaluated in adult Wistar rats. Those animals which had received irradiation at some stage fared significantly worse than those which had immediate division and reanastomosis of the sciatic nerve without irradiation. The possible relevance of these findings to nerve regeneration in patients treated by surgery and radiotherapy for parotid cancer is discussed.     

急性胰腺炎腹膜后隙的CT炎性浸润程度与临床严重程度的相关性探讨

目的 探讨急性胰腺炎（acute pancreatitis,AP）患者腹膜后隙炎性浸润程度与临床严重程度之间的关系。方法 2016年6月-2017年6月67例AP患者（男32例,女35例,中位年龄48岁）,在其发病一周左右进行CT平扫及增强检查,观察腹膜后隙的炎性浸润情况,探讨其与急性胰腺炎临床严重程度的关系。采用spearman相关分析行统计学处理。结果 AP腹膜后间隙累及范围与其严重程度的相关性呈正相关（r=0.903,P<0.01）。结论 随着AP严重程度的增加,其腹膜后间隙受累程度也相应增加。     

Healthy dietary habits in relation to social determinants and lifestyle factors.

The aim of the present study was to evaluate the importance of social status and lifestyle for dietary habits, since these factors may influence life expectancy. We studied the association of four indicators for healthy dietary habits (fruits and vegetables, fibre, fat and Hegsted score) with sex, age, socio-economic status, education, physical leisure exercise, smoking and personal attention paid to keeping a healthy diet. Data were gathered with a self-administered quantitative food-frequency questionnaire distributed to a representative sample of Norwegian men and women aged 16-79 years in a national dietary survey, of whom 3144 subjects (63%) responded. Age and female sex were positively associated with indicators for healthy dietary habits. By separate evaluation length of education, regular physical leisure exercise and degree of attention paid to keeping a healthy diet were positively associated with all four indicators for healthy dietary habits in both sexes. Socio-economic status, location of residence and smoking habits were associated with from one to three indicators for healthy dietary habits. In a multiple regression model, age, education and location of residence together explained from 1 to 9% of the variation (R2) in the four dietary indicators. Length of education was significantly associated with three of four dietary indicators both among men and women. By including the variable 'attention paid to keeping a healthy diet' in the model, R2 increased to between 4 and 15% for the four dietary indicators. Length of education remained correlated to three dietary indicators among women, and one indicator among men, after adjusting for attention to healthy diet, age and location of residence. Residence in cities remained correlated to two indicators among men, but none among women, after adjusting for age, education and attention to healthy diet. In conclusion, education was associated with indicators of a healthy diet. Attention to healthy diet showed the strongest and most consistent association with all four indicators for healthy dietary habits in both sexes. This suggests that personal preferences may be just as important for having a healthy diet as social status determinants.     

Cerebral palsy: social class differences in prevalence in relation to birthweight and severity of disability.

STUDY OBJECTIVE--The aim of the study was to examine the possible influence of social class on the prevalence of cerebral palsy. DESIGN--The study was a retrospective population based survey of all cases of cerebral palsy. SETTING--The study involved all cases of cerebral palsy born to residents in the Eastern Health Board area of the Republic of Ireland between 1976 and 1981 inclusive. PATIENTS--There were 289 cases of cerebral palsy during the study period. Thirty one were excluded because they were attributable to postneonatal brain damage, leaving 258 children for analysis. Cases with uncertain diagnosis were excluded. MAIN RESULTS--There was a clear social class gradient in the overall prevalence of cerebral palsy, also evident in the individual syndromes of hemiplegia and diplegia. No such gradient was detected in the other syndromes, either singly or in combination. Among cases of low birthweight (less than or equal to 2500 g), the prevalence was the same across the social class range after allowing for the increased low birthweight rate in the lower social class categories. Among normal birthweight cases there was a strong positive association with decreasing social class. Intrauterine growth retardation seemed to be a factor in cerebral palsy in all social class groups. Prevalence of cerebral palsy severe enough to prevent walking by the fourth birthday, but not of cases ambulant by this age, increased with socioeconomic disadvantage. CONCLUSIONS--The clear social class gradients in hemiplegia and diplegia suggest that environmental factors play an important role in the aetiology of these syndromes, but there was no evidence of a contribution from this type of factor in the remaining types of cerebral palsy.