Analysis of the relationship between interleukin polymorphisms within miRNA-binding regions and alcoholic liver disease. / Análisis de la relación entre polimorfismos en regiones diana de micro-ARN y la enfermedad hepática alcohólica.

INTRODUCTION: Alcohol consumption promotes inflammation through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-?B pathway, leading to organic damage. Some micro-RNA (miRNA) molecules modulate this inflammatory response by downregulating TLR4/NF-?B pathway mediators, like interleukins (ILs). Thus, polymorphisms within IL genes located near miRNA binding sites could modify the risk of ethanol-induced damage. The present study analyzed potential relationships between alcoholism or alcoholic liver disease (ALD) and IL12B 2124 G>T (rs1368439), IL16 5000 C>T (rs1131445), IL1R1 3114 C>T (rs3917328), and NFKB1 3400 A>G (rs4648143) polymorphisms. PATIENTS AND METHODS: The study included 301 male alcoholic patients and 156 male healthy volunteers. Polymorphisms were genotyped using TaqMan® PCR assays for allelic discrimination. Allele and genotype frequencies were compared between groups. Logistic regression analysis was performed to analyze the inheritance model. RESULTS: Analysis of the IL1R1 (rs3917328) polymorphism showed that the proportion of alleleT carriers (CT and TT genotypes) was higher in healthy controls (9.7%) than in alcoholic patients (6.5%; P=.042). However, multivariable logistic regression analyses did not yield a significant result. No differences between groups were found for other analyzed polymorphisms. CONCLUSIONS: Our study describes, for the first time, the expected frequencies of certain polymorphisms within miRNA-binding sites in alcoholic patients with and without ALD. Further studies should be developed to clarify the potential relevance of these polymorphisms in alcoholism and ALD development.

Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis.

BACKGROUND: Several studies have reported an association between alcoholic liver cirrhosis (ALC) or other forms of alcoholic liver disease (ALD) and the genetic variant rs738409 (C>G) in adiponutrin/patatin-like phospholipase domain-containing 3 gene (PNPLA3). AIM: To evaluate the influence of this variant on ALC and other forms of ALD. METHODS: We performed a systematic review of previous studies on the relationship between rs738409 of PNPLA3 and ALD and meta-analysis was conducted in a random-effects model. Calculations of the odds ratios (ORs) and their confidence intervals (CIs), tests for heterogeneity and sensitivity analyses were performed. RESULTS: Database search identified 11 previous studies available for inclusion with a total of 3495 patients with ALD (2087 with ALC) and 5038 controls (4007 healthy subjects and 1031 alcoholics without ALD). Patients with ALC compared to controls had a significantly higher prevalence of the G allele when comparing GG vs. CC (OR 4.30, 95% CI 3.25-5.69; P < 0.00001) or GC vs. CC genotypes (GC vs. CC: OR 1.91, 95% CI 1.67-2.17) or under a recessive or dominant model. Similar results were found when comparing separately patients with ALC vs. alcoholics without ALD or healthy subjects. An association of the G allele with ALD emerged when comparing ALD patients vs. alcoholics without ALD and/or healthy subjects although moderate to large heterogeneity was observed. Our data suggested an additive genetic model for this variant in ALD. CONCLUSION: Our meta-analysis shows that the rs738409 variant of PNPLA3 is clearly associated with alcoholic liver cirrhosis.

A genetic variant in the microRNA-146a gene is associated with susceptibility to alcohol use disorders.

BACKGROUND: Polymorphisms in the microRNA (miRNA) regulatory pathways are novel functional genetic variants whose association with alcoholism susceptibility has not been previously studied. Given the potential relationship between certain miRNAs and alcohol use disorders (AUDs), this study was designed to explore the association between two polymorphisms within hsa-miR-146a and hsa-miR-196a2 genes and susceptibility to these diseases. METHODS: Three hundred and one male patients with AUDs and 156 sex-matched healthy volunteers were enrolled. Polymorphisms were genotyped using TaqMan(®) PCR assays. Allele and genotype frequencies were compared between groups and logistic regression analysis was also performed to analyze the model of inheritance. RESULTS: There was a significantly higher prevalence of allele C carriers (47.8%) of the miR-146a G>C polymorphism (rs2910164) among patients with AUDs when compared with controls (35.9%), and multivariable logistic regression analysis showed that the C allele was associated with these AUDs (OR=1.615, 95% CI 1.067-2.442; P=0.023). Neither the genotype nor the allele distribution of miR-196a2 polymorphism (rs11614913) was significantly different between groups. CONCLUSIONS: This is the first genetic association study to explore the relationship of miRNA polymorphisms with AUDs and to show an association of the miR-146a C>G rs2910164 allelic variant with this disease.

Influencia de las unidades de corta estancia en la calidad de la atención hospitalaria en España. Revisión sistemática / Impact of short-stay units on the quality of medical care in Spain

Objetivo. Las unidades de corta estancia (UCE) se han desarrollado como alternativa a la hospitalización convencional. El objetivo de este estudio es analizar la influencia de las UCE creadas en España sobre la calidad asistencial. Material y métodos. Se realizó una revisión sistemática de la literatura en Medline e Índice Médico Español para identificar estudios que evaluaran los resultados de la implantación de las UCE de nuestro país, en términos de efectividad clínica, eficiencia y satisfacción de pacientes y se revisaron las referencias de los artículos hallados. Se extrajeron datos relativos a estancia media y tasas de mortalidad y de reingreso, entre otros. Resultados. Se encontraron 27 artículos con una importante heterogeneidad tanto en el tipo de UCE evaluada como en el propio diseño de los estudios. Tras comparar los resultados se observó que las UCE proporcionan cuidados asistenciales con efectividad. Además, se encontró evidencia de calidad baja que apoya que las UCE reducen la estancia media en el conjunto del hospital o del servicio considerado, sin encontrar evidencias que supongan otros beneficios al compararlas con otro tipo de unidades de hospitalización. Conclusiones. Las UCE pueden ayudar a mejorar la efectividad de la asistencia sanitaria en pacientes seleccionados, así como a reducir la estancia media hospitalaria, aunque es preciso realizar nuevas investigaciones para definir su papel y su modelo óptimo de funcionamiento(AU)

Objective. Short-stay units (SSUs) have been developed as an alternative to conventional hospitalisation. The aim of this study is to analyse the impact of short-stay units on the quality of medical care in Spain. Material and methods. A systematic review was performed by retrieving studies that analysed the results of SSUs in Spain, in terms of clinical effectiveness, efficiency and satisfaction among patients, using an electronic database search (Pubmed/Medline and Spanish Medical Index) and a review of selected references. The data collected included, mortality, length of stay and re-admission rates, as well as other variables. Results. Twenty-seven articles were found, with a great heterogeneity in both study design and type of SSU analysed. After analysing results, it was observed that SSUs in Spain provided effective clinical care. Low-quality evidence was also found supporting the hypothesis that SSUs are able to reduce overall length of stay in the whole hospital or department where they were created. There are not enough data to support any other advantages or benefits of SSUs, when compared with other hospitalisation units. Conclusions. SSUs may be able to effectively improve clinical care in selected patients, and may help to shorten overall length of stay. Further research is needed in order to define their exact role and to establish their optimal model(AU)

[Impact of short-stay units on the quality of medical care in Spain]. / Influencia de las unidades de corta estancia en la calidad de la atención hospitalaria en España. Revisión sistemática.

OBJECTIVE: Short-stay units (SSUs) have been developed as an alternative to conventional hospitalisation. The aim of this study is to analyse the impact of short-stay units on the quality of medical care in Spain. MATERIAL AND METHODS: A systematic review was performed by retrieving studies that analysed the results of SSUs in Spain, in terms of clinical effectiveness, efficiency and satisfaction among patients, using an electronic database search (Pubmed/Medline and Spanish Medical Index) and a review of selected references. The data collected included, mortality, length of stay and re-admission rates, as well as other variables. RESULTS: Twenty-seven articles were found, with a great heterogeneity in both study design and type of SSU analysed. After analysing results, it was observed that SSUs in Spain provided effective clinical care. Low-quality evidence was also found supporting the hypothesis that SSUs are able to reduce overall length of stay in the whole hospital or department where they were created. There are not enough data to support any other advantages or benefits of SSUs, when compared with other hospitalisation units. CONCLUSIONS: SSUs may be able to effectively improve clinical care in selected patients, and may help to shorten overall length of stay. Further research is needed in order to define their exact role and to establish their optimal model.

Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease.

BACKGROUND: Only a minority of alcoholics develop alcoholic liver disease (ALD) and allelic variants within genes encoding glutathione-S-transferases (GST) have been associated with ALD vulnerability with controversial results. AIM: To assess the effects of GST polymorphisms on ALD by means of a genetic association study and meta-analysis. METHODS: We retrieved published studies on the relationship between allelic variants within GST genes and ALD by means of electronic database search. A meta-analysis was conducted in a fixed or random effects model. Calculations of odds ratios (OR) and their confidence intervals (CI), tests for heterogeneity of the results and sensitivity analysis, have been performed. A genetic association study comparing GSTM1, GSTT1 and GSTP1 genotype distribution among 279 alcoholics with or without ALD and 144 controls was also performed. Results Fifteen previous studies were identified analysing the association of ALD with polymorphisms within GST genes. After meta-analysis, we found a significant association between the possession of the GSTM1 null allele and the presence of ALD (OR=1.43; 95% CI: 1.14, 1.78; P=0.002) among alcoholic patients. A significant association was also found for the possession of the GSTP1 Val/Val genotype and the presence of ALD (OR=2.04; 95% CI: 1.09, 3.80; P=0.03). CONCLUSIONS: Our results suggest that, among alcoholics, carriers of GSTM1 null genetic variant or Val/Val genotype of Ile/Val GSTP1 polymorphism have an increased risk to suffer from alcoholic liver disease. The role of glutathione-S-transferase as a potential therapeutic target in alcoholic liver disease is reinforced.

[Referral to internal medicine for alcoholism: influence on follow-up care]. / Influencia de la derivación a un Servicio de Medicina Interna en el seguimiento de pacientes alcohólicos.

BACKGROUND AND AIMS: The problem of high rates of patient drop-out in alcohol treatment programs is frequently reported in the literature. Our aim was to investigate if internal medicine referral could improve abstinence and retention rates in a cohort of alcoholic patients. PATIENTS AND METHODS: A retrospective observational study was conducted comparing 200 alcoholic patients attending a psychiatric unit (group 1) with 100 patients attending both this unit and an internal medicine unit (group 2). We collected sociodemographic and clinical variables and analysed differences regarding abstinence and retention rates by means of univariate and multivariate analysis. RESULTS: At 3 and 12 months follow-up, group 2 patients had higher retention and abstinence rates than group 1 patients. Multivariate analysis including potential confounding variables showed that independent predictors of one-year retention were internal medicine referral and being married. Independent predictors of one-year abstinence were being married, age > 44 years and receipt of drug treatment. CONCLUSIONS: The higher retention rate found among patients referred to Internal Medicine specialists, a result that has not been previously reported to the best of our knowledge, emphasizes the importance of a multidisciplinary team approach in the treatment of alcoholism.

Influencia de la derivación a un Servicio de Medicina Interna en el seguimiento de pacientes alcohólicos / Referral to Internal Medicine for alcoholism: influence on follow-up care

Fundamento y objetivo. El alto grado de abandonode los programas de tratamiento constituye uno delos principales problemas terapéuticos delalcoholismo. El objetivo de nuestro trabajo fueanalizar la eficacia de la inclusión de especialistasen Medicina Interna en la tasa de abstinencia y deretención de los pacientes alcohólicos tratados deforma ambulatoria.Pacientes y método. Estudio retrospectivolongitudinal que compara 200 pacientes atendidospor una unidad de psiquiatras y psicólogos con 100pacientes atendidos de forma conjunta por esaunidad y por especialistas en Medicina Interna. Seanalizaron las diferencias en la abstinencia y laretención de los pacientes según su derivación o noa Medicina Interna, incluyendo como factoresde confusión variables sociodemográficas y decomorbilidad.Resultados. A los 3 y 12 meses de seguimiento,los pacientes atendidos conjuntamente porpsiquiatras e internistas presentaron unas tasas deretención y abstinencia significativamente mayoresque los pacientes no derivados a Medicina Interna.Los factores que se asociaron de formaindependiente y significativa con la retención a los12 meses fueron la propia derivación a MedicinaInterna y estar casado. Los factores asociados conla abstinencia a los 12 meses fueron estar casado,una edad mayor de 44 años y recibir tratamientopara el alcoholismo.Conclusiones. La mayor retención en pacientesderivados a Medicina Interna, resultado nocomunicado previamente, refuerza la importancia deun abordaje multidisciplinar en el tratamiento delalcoholismo

Background and aims. The problem of high ratesof patient drop-out in alcohol treatment programs isfrequently reported in the literature. Our aim was toinvestigate if internal medicine referral couldimprove abstinence and retention rates in a cohortof alcoholic patients.Patients and methods. A retrospectiveobservational study was conducted comparing 200alcoholic patients attending a psychiatric unit (group1) with 100 patients attending both this unit and aninternal medicine unit (group 2). We collectedsociodemographic and clinical variables andanalysed differences regarding abstinence andretention rates by means of univariate andmultivariate analysis.Results. At 3 and 12 months follow-up, group 2patients had higher retention and abstinence ratesthan group 1 patients. Multivariate analysisincluding potential confounding variables showedthat independent predictors of one-year retentionwere internal medicine referral and being married.Independent predictors of one-year abstinencewere being married, age > 44 years and receipt ofdrug treatment.Conclusions. The higher retention rate foundamong patients referred to Internal Medicinespecialists, a result that has not been previouslyreported to the best of our knowledge, emphasizesthe importance of a multidisciplinary team approachin the treatment of alcoholism

Comparative analysis of the morphological, cytochemical, immunophenotypical, and functional characteristics of normal human peripheral blood lineage(-)/CD16(+)/HLA-DR(+)/CD14(-/lo) cells, CD14(+) monocytes, and CD16(-) dendritic cells.

Human peripheral blood (PB) CD14(lo)/HLA-DR(+) cells were initially described as a subset of mature monocytes. Recently, it has been suggested that these represent a part of a new subset of dendritic cells (DC), characterized by the coexpression of MDC-8/HLA-DR/CD16. The aim of the present paper was to analyze the morphological, cytochemical, phenotypical, and functional characteristics of PB CD16(+)/HLA-DR(+) cells compared to both PB CD14(+) monocytes and CD16(-) DC. In contrast to CD14(+) monocytes, purified CD16(+)/HLA-DR(+) cells displayed cytoplasmic veils and lacked cytoplasmic myeloperoxidase and alpha-naphthyl acetate esterase. Normal human PB CD16(+)/HLA-DR(+) cells also displayed phenotypic characteristics different from those of CD14(+) monocytes: they lacked the CD64 Fcgamma receptor, showed lower levels of CD32, and expressed higher amounts of CD16 compared to CD14(+) monocytes. They also displayed a different pattern of expression of other antigens, including CD14, HLA-DR, CD45RA, CD45RO, complement receptors and complement regulatory surface proteins, adhesion and costimulatory molecules, and cytokine receptors, among others. When compared to CD16(-) DC, CD16(+)/HLA-DR(+) cells showed reactivity for CD16, dim positivity for CD14, higher expression of both Ig- and complement-receptors and lower reactivity for HLA-DR, adhesion, and costimulatory molecules (with the exception of CD86). The CD16(+)/HLA-DR(+) cell subset displayed a higher Ig/complement-mediated phagocytic/oxidative activity than CD16(-) DC, although this activity was significantly lower than that of mature monocytes. Regarding cytokine production at the single cell level, LPS plus IFN-gamma-stimulated PB CD16(+)/HLA-DR(+) cells produced significant amounts of IL1beta, IL6, IL12, TNFalpha, and IL8; however, the percentage of cytokine-producing cells and the amount of cytokine/cell were lower in CD16(+)/HLA-DR(+) cells than in CD14(+) monocytes. In addition, upon comparing CD16(+)/HLA-DR(+) cells with CD33(+++)/CD16(-) DC, we found that the percentage of cytokine-producing cells and the amount of cytokine/cell were significantly different in both cell subsets. In summary, our results show that CD16(+)/HLA-DR(+) cells clearly display different morphologic, cytochemical, immunophenotypical, and functional characteristics compared to both mature monocytes and CD16(-) DC. Interestingly, these cells are more frequent than other DC in normal human adult PB and cord blood samples, while they are less represented in normal bone marrow.

Flow cytometric analysis of cytokine production by normal human peripheral blood dendritic cells and monocytes: comparative analysis of different stimuli, secretion-blocking agents and incubation periods.

In this paper, we comparatively analyze the effects of the following different stimuli on the production and intracellular accumulation of the interleukin (IL)-1 beta, IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), and IL-8 inflammatory cytokines in both normal human peripheral blood (PB) dendritic cell (DC) subsets and monocytes: lipopolysaccharide (LPS) versus Staphylococcus aureus cowan I (SAC) in the presence or absence of interferon-(IFN)-gamma-, cytokine secretion-blocking agents (brefeldin A alone versus brefeldin A plus monensin), and incubation periods (6, 12, and 24 h). For this purpose, a four-color multiple-staining direct immunofluorescence technique analyzed by flow cytometry was systematically used in all experiments (n = 19). Our results show that after stimulation, an important proportion of each of the two CD33(+) myeloid DC subsets as well as the monocytes produce significant amounts of all cytokines analyzed under each of the experimental conditions assayed. In contrast, CD33(-/+lo) lymphoplasmocytoid DC failed to produce detectable levels of any of the above-mentioned cytokines under the same stimulatory conditions. Upon comparing the different stimuli used, LPS was associated with higher percentages of cytokine-producing cells compared with SAC, especially within the CD33(hi) DC subset; interestingly, the addition of IFN-gamma enhanced the response of monocytes to both LPS and SAC. As regards the secretion-blocking agents, brefeldin A alone was superior to the combination of brefeldin A and monensin. This is because it was frequently associated with both a higher percentage of cytokine-positive cells and greater amounts of detectable cytokines per cell. Sequential analysis of cytokine production by PB DC and monocytes after 6, 12, and 24 h of cell culture showed that after 6 h, an increased cell death rate existed among DC, which became even undetectable at 24 h, in the absence of a significant increase in cytokine secretion. In summary, our results show that from the experimental conditions assayed in this paper, to induce cytokine production by normal human DC and monocytes, maximum response is obtained once PB samples are stimulated for 6 h with LPS (with or without IFN-gamma) in the presence of brefeldin A alone.

Alcoholic liver cirrhosis is associated with a decreased expression of the CD28 costimulatory molecule, a lower ability of T cells to bind exogenous IL-2, and increased soluble CD8 levels.

Despite the existence of high interleukin (IL)-12 serum levels in patients with chronic active alcoholism, previous studies from our group have shown that, during active ethanol intake, alcoholic patients with alcoholic liver cirrhosis (ALC) display an impaired T-helper-1 response together with abnormalities in the peripheral blood (PB) cytotoxic compartment. The aim of the present study was to gain further insights into the mechanisms underlying these abnormalities. For that purpose, we analyzed the expression on PB B- and T-cell subsets of both the CD28 and CD80 costimulatory molecules, the ability of T lymphocytes to bind to exogenous recombinant IL-2, and the serum levels of soluble CD8 (sCD8) that might interfere with CD8+ T-cell activation in a group of 10 ALC patients with active ethanol intake (ALCET group). As reference groups, we analyzed 10 healthy individuals, 10 chronic alcoholic patients without liver disease (AWLD group) but with active ethanol intake, and 10 ALC patients who had quit drinking for at least 1 year. Our results showed that ALCET patients display a significant decrease in the number of PB CD28+/CD8(hi) T cells (P < 0.05) and CD80+ B cells (P < 0.01) compared with both healthy controls and AWLD patients. In addition, in ALCET patients, PB T cells also showed a decreased ability to bind to exogenous IL-2 (P < 0.01). This was associated with the existence of increased serum levels of sCD8 in ALC patients, the highest levels being detected in the ALCET group (P < 0.01). Altogether, our results point to the existence of several abnormalities that would affect the cytotoxic response in ALCET patients.

Polymorphism in the interleukin-1 receptor antagonist gene is associated with alcoholism in Spanish men.

BACKGROUND: A polymorphism located in intron 2 of the interleukin-1 receptor antagonist (IL1RN) gene recently has been associated with the development of hepatic fibrosis in Japanese alcoholics. In the present study, we analyzed whether there is an association between this polymorphism, alcoholism, and alcoholic liver disease in a Spanish male population of alcoholics. METHODS: The IL1RN genotype was assessed by polymerase chain reaction by using oligonucleotides that flank a variable nucleotide tandem repeat polymorphism located in intron 2 of this gene in 90 male alcoholic patients from Spain: 30 alcohol-dependent men, 30 alcohol abusers, and 30 alcoholics with liver cirrhosis. We also studied 40 healthy subjects. RESULTS: The distribution of the IL1RN allelic frequencies in Spanish healthy subjects is similar to that previously reported in White subjects. However, the A1 allele is overrepresented in Spanish alcoholics when compared with healthy subjects. No significant differences in allelic frequencies were observed between alcoholics with liver cirrhosis and alcoholics without liver disease or between alcohol-dependent subjects and alcohol abusers. CONCLUSION: The presence of the A1 allele of the IL1RN gene is associated with a higher risk of alcoholism in Spanish men.

Diagnóstico del consumo de alcohol: lo primero, la atención primaria / Diagnosis of alcohol consumption: first of all, primary care

No disponible

Extensive characterization of the immunophenotype and pattern of cytokine production by distinct subpopulations of normal human peripheral blood MHC II+/lineage- cells.

Dendritic cells (DC) represent the most powerful professional antigen-presenting cells (APC) in the immune system. The aim of the present study was to analyse, on a single-cell basis by multiparametric flow cytometry with simultaneous four-colour staining and a two-step acquisition procedure, the immunophenotypic profile and cytokine production of DC from 67 normal whole peripheral blood (PB) samples. Two clearly different subsets of HLA-II+/lineage- were identified on the basis of their distinct phenotypic characteristics: one DC subset was CD33strong+ and CD123dim+ (0.16 +/- 0.06% of the PB nucleated cells and 55.9 +/- 11. 9% of all PB DC) and the other, CD33dim+ and CD123strong+ (0.12 +/- 0.04% of PB nucleated cells and 44.53 +/- 11.5% of all PB DC). Moreover, the former DC subpopulation clearly showed higher expression of the CD13 myeloid-associated antigen, the CD29 and CD58 adhesion molecules, the CD2, CD5 and CD86 costimulatory molecules, the CD32 IgG receptor and the CD11c complement receptor. In addition, these cells showed stronger HLA-DR and HLA-DQ expression and a higher reactivity for the IL-6 receptor alpha-chain (CD126) and for CD38. In contrast, the CD123strong+/CD33dim+ DC showed a stronger reactivity for the CD4 and CD45RA molecules, whereas they did not express the CD58, CD5, CD11c and CD13 antigens. Regarding cytokine production, our results show that while the CD33strong+/CD123dim+ DC are able to produce significant amounts of inflammatory cytokines, such as IL-1beta (97 +/- 5% of positive cells), IL-6 (96 +/- 1.1% of positive cells), IL-12 (81.5 +/- 15.5% of positive cells) and tumour necrosis factor-alpha (TNF-alpha) (84 +/- 22.1% of positive cells) as well as chemokines such as IL-8 (99 +/- 1% of positive cells), the functional ability of the CD123strong+/CD33dim+ DC subset to produce cytokines under the same conditions was almost null. Our results therefore clearly show the presence of two distinct subsets of DC in normal human PB, which differ not only in their immunophenotype but also in their functionality, as regards cytokine production.

Chronic alcoholism is associated with an imbalanced production of Th-1/Th-2 cytokines by peripheral blood T cells.

BACKGROUND: In the present study, we analyzed, at the intracellular level, the pattern of cytokine secretion by the major CD4+ and CD8strong+ peripheral blood (PB) T-cell subsets in patients with chronic alcoholism, and we correlated it both with the ethanol (EtOH) intake status and with the presence or not of alcoholic liver disease. METHODS: For that purpose, a total of 30 chronic alcoholic patients, 10 without liver disease (AWLD group) and 20 diagnosed with alcoholic liver cirrhosis (ALC) were studied. In all cases, flow cytometric measurement of intracellular expression of interferon-gamma (IFN-gamma), interleukin (IL)-2, and IL-4 was performed on PB CD4+ and CD8strong+ T lymphocytes. RESULTS: After studying AWLD patients, we found increased numbers of both CD4+ and CD8strong+ PB T cells with detectable cytoplasmic levels of the IL-2 and IFN-gamma T helper (Th)-1-associated cytokines, the greater increase being observed for this latter cytokine (p<0.001 for CD4+ and p<0.01 for CD8strong+ T cells). Regarding ALC patients, the pattern of expression of intracellular cytokines by PB T cells was different depending on the status of EtOH intake at the moment of entering this study. Accordingly, as in AWLD patients, ALC individuals who were actively drinking also displayed increased numbers of both CD4+ and CD8strong+ T cells expressing Th-1-associated cytokines. However, in these patients, expression of IFN-gamma, although being significantly greater than that observed in control individuals (p<0.05), was significantly lower than that in AWLD patients (p<0.01 and p<0.05, for CD4+ and CD8strong+ T cells, respectively). After a withdrawal period of > or =1 yr, ALC patients did not show significant changes in the cytoplasmic expression of Th-1-associated cytokines compared with the control group; in contrast, these patients showed a marked increase on the proportion of CD4+ and CD8strong+ T cells expressing IL-4, a Th-2-associated cytokine (p<0.01). After considering the ratio between the number of T cells expressing Th- (IFN-gamma)- and Th-2 (IL-4)-associated cytokines in each individual, we found that there was a significant imbalance in this ratio, with a predominance of IFN-gamma-producing T cells over IL-4+ T lymphocytes during EtOH intake. CONCLUSIONS: Our results showed that in patients with chronic alcoholism, active EtOH intake is associated with a Th-1 pattern of cytokine production by PB T cells.

Increased interleukin-12 serum levels in chronic alcoholism.

BACKGROUND/AIMS: In the present study the serum levels of interleukin-12 were analyzed in alcoholic patients in order to explore the possible relationship between them and both the ethanol intake status and the existence of alcoholic liver disease. METHODS: For that purpose interleukin-12 levels were analyzed in a total of 26 alcoholic patients. Additionally, both interferon-gamma and interleukin-4 serum levels were measured in the same patients as a means of exploring the balance between the T-helper-1 and T-helper-2 immune responses. All patients had consumed at least 90 g of ethanol per day for more than 5 years. Fourteen were alcoholics without liver disease (AWLD group) and the other 12 patients were diagnosed as having alcoholic liver cirrhosis. In parallel to the patients, 10 age- and sex-matched healthy volunteers were included in the study. RESULTS: Our results show that interleukin-12 serum levels are significantly increased in AWLD patients as compared to normal controls (p<0.05). In patients with cirrhosis, interleukin-12 serum levels varied, depending on the ethanol intake status at the time of evaluation. Accordingly, as compared to normal controls, significantly increased concentrations of serum interleukin-12 were found in the alcoholic liver cirrhosis patients with active ethanol intake (ALCET group) (p<0.01), while in the cirrhotic individuals with at least 1 year of alcohol withdrawal interleukin-12 serum levels remained within the normal range. Only the cirrhotic patients had increased interferon-gamma serum levels. Among them, the highest levels were found for individuals from the ALCET group, the differences with respect to the healthy subjects being close to statistical significance (p=0.05). No significant differences were detected regarding interleukin-4 serum levels for any of the groups of patients analyzed compared to the control individuals. CONCLUSIONS: Our results show the existence of a relationship between ethanol intake and increased interleukin-12 serum levels, suggesting that this cytokine may play an important role in the induction of the immunological abnormalities found in chronic alcoholism, independently of whether or not alcoholic liver disease is present.