Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease.

Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.

Production of insulin-like growth factor-binding proteins during the development of hepatic fibrosis due to chronic hepatitis C. / Producción de las proteínas de unión al factor de crecimiento insulinoide durante el desarrollo de la fibrosis hepática por hepatitis C crónica.

INTRODUCTION AND AIMS: Insulin-like growth factor 1 is modulated by the insulin-like growth factor-binding proteins (IGFBPs) that are synthesized in the liver. The aim of the present study was to evaluate the concentrations of IGFBPs 1-7 in patients with chronic hepatitis C and study their association with fibrosis stage. PATIENTS AND METHODS: A prospective, cross-sectional study was conducted that included patients with chronic hepatitis C. The stages of fibrosis were determined through FibroTest and FibroScan and the patients were compared with a control group. Serum levels of IGFBPs 1-7 were quantified through multiple suspension arrays. The Kruskal-Wallis test, Mann-Whitney U test, Spearman's correlation, and ROC curves were used for the statistical analysis. RESULTS: Upon comparing the patients and controls, the highest concentrations were found in IGFBPs 1, 2, 4, and 7 (p=0.02, p=0.002, p=0.008, and p<0.001, respectively). IGFBP-3 levels had a tendency to be lower in the patients (p=0.066), whereas values were similar between patients and controls for IGFBP-5 and 6 (p=0.786 and p=0.244, respectively). Of the seven IGFBPs, IGFBP-3 concentrations were the highest. There were significant differences between fibrosis stages for IGFBP-5 and IGFBP-7. CONCLUSION: IGFBPs play a relevant role in the fibrotic process in liver damage. IGFBP-7, in particular, differentiates fibrosis stages, making it a potential serum biomarker.

Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome.

BACKGROUND AND OBJECTIVES: There is evidence that patients with irritable bowel syndrome (IBS) have a low degree of inflammation in the intestinal mucosa. The aim of the study was to evaluate the profile of pro- and anti-inflammatory cytokines in plasma in Mexican pediatric patients with IBS. PATIENTS AND METHODS: Fifteen patients with IBS according to Rome III criteria for childhood and 15 healthy children, matched by age and sex, were included in the study. Plasma levels of tumoral necrosis factor alpha (TNF-α), interleukins 10 and 12 (IL-10, IL-12) and transforming growth factor beta (TGF-ß) were quantified and compared between groups. RESULTS: Plasma levels of IL-10 were lower in patients with IBS (86.07+21.3 pg/mL vs. 118.71+58.62 pg/mL: P=.045) and IL-12 levels were higher in patients with IBS compared to the control group of healthy children (1,204.2±585.9 pg/mL vs. 655.04±557.80 pg/mL; P=.011). The IL-10/IL-12 index was lower in patients with IBS (0.097±0.07 vs. 0.295±0.336; P=.025). Plasma concentration of TGF-ß was higher in patients with IBS (545.67±337.69 pg/mL vs. 208.48±142.21 pg/mL; P=.001). There was no difference in plasma levels of TNF-α between groups. CONCLUSIONS: This study suggests that children with IBS have a state of altered immune regulation. This is consistent with the theory of low-grade inflammatory state in these patients. Further studies are needed to elucidate the role played by these cytokines, specifically TGF-ß in the pathogenesis of IBS.

The role of oxidative stress in the development of alcoholic liver disease.

BACKGROUND: Alcohol is the most accepted addictive substance worldwide and its consumption is related to multiple health, economic, and social problems. The liver is the organ in charge of ethanol metabolism and it is susceptible to alcohol's toxic effects. OBJETIVOS: To provide a detailed review of the role of oxidative stress in alcoholic liver disease and the mechanisms of damage involved, along with current information on the hepatoprotective effectiveness of the molecules that have been studied. MATERIALS AND METHODS: A search of the PubMed database was conducted using the following keywords oxidative stress, alcoholic liver damage, alcoholic cirrhosis, and antioxidants. There was no time limit for gathering all available information on the subject at hand. RESULTS: According to the literature reviewed, oxidative stress plays an important role in the pathogenesis of alcoholic liver damage. Molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), formed during ethanol metabolism, structurally and functionally modify organic molecules. Consequently, biologic processes are altered and hepatocytes are sensitized to the action of cytokines like tumor necrosis factor-α, as well as to the action of endotoxins, activating signaling pathways such as those controlled by nuclear factor kappa B, extracellular signal regulated kinases, and mitogen activated protein kinase. CONCLUSIONS: Oxidative stress plays an important role in the development of liver damage resulting from alcohol consumption. The molecules that have currently displayed a hepatoprotective effect in preclinical and clinical trials must be studied further so that their effectiveness can be confirmed and they can possibly be used as adjuvant treatments for this disease.

Evaluación del estado nutricional de pacientes con cirrosis hepática alcohólica atendidos en la Clínica de Hígado del Hospital General de México / Nutritional assessment of alcoholic liver cirrhotic patients treated in the liver Clinic of the Mexico's General Hospital

La desnutrición en el paciente cirrótico se asocia a mayor morbi-mortalidad; sin embargo, su diagnóstico es complejo por lo que el objetivo del estudio fue evaluar el estado nutricional empleando distintos métodos. Se evaluaron pacientes adultos con cirrosis hepática de origen alcohólico que acudieron a la Clínica de Hígado del Hospital General de México. Se aplicó un recordatorio de 24 horas y antropometría, herramientas de tamizaje (Malnutrition Universal Screening Tool, Nutritional Risk Screening-2002) y de diagnóstico nutricional específica para pacientes con cirrosis hepática (Royal Free Hospital Global Assessment). Se incluyeron 62 pacientes y 51,6% fueron hombres. La desnutrición por área muscular de brazo fue de 31,3% en hombres y de 10% en mujeres, y por área grasa de brazo fue de 23,3% en mujeres y 3,1% en hombres (p < 0. 05). Con las herramientas de tamizaje se obtuvieron porcentajes de riesgo de desnutrición de 43,5% y 54,8% respectivamente, vs 1,6% identificado con peso bajo por Índice de Masa Corporal. Con la herramienta de diagnóstico nutricional Royal Free Hospital Global Assessment se identificó 45,2% de pacientes con desnutrición. Los pacientes con desnutrición tuvieron un aporte energético y proteico significativamente menor respecto a los bien nutridos: 19,7 kcal/kg y 0,89 g/kg vs 30 kcal/kg y 1,25 g/kg respectivamente (p < 0,005). La desnutrición es una complicación frecuente en los pacientes con cirrosis hepática. Los hombres presentan mayor afección en la reserva muscular y las mujeres en la reserva de tejido adiposo corporal. El Índice de Masa Corporal no es una buena herramienta para la detección de desnutrición. Es recomendable emplear herramientas con indicadores de composición corporal como el Royal Free Hospital Global Assessment (AU)

Malnutrition in the cirrhotic patient is associated to a higher morbidity and mortality rate; however, the diagnosis is complex, so the study objective was to assess the nutritional status using different methods. Adult patients with alcoholic liver cirrhosis treated in the Liver Clinic of the Mexico's General Hospital were evaluated. Anthropometric measurements and a 24 hours recall were made; screening tools (Malnutrition Universal Screening Tool, Nutritional Risk Screening-2002) and a method for assessing nutritional status specifically in cirrhotic patients (Royal Free Hospital Global Assessment) were used. We included 62 patients, 51.6% of them were men. Malnutrition by arm muscle area was 31.3% in men and 10% in women, and by arm fat area was 23.3% in women and 3.1% in men (p < 0.05). With the screening tools the percentages of malnutrition risk were 43.5% and 54.8% respectively, vs. 1.6% identified as "low weight" with the Body Mass Index. With the Royal Free Hospital Global Assessment tool the percentage of malnutrition was 45.2%. Patients with malnutrition had an energy and protein intake significantly lower than the well-nourished: 19.7 kcal/kg and 0.89 g/kg vs 30 kcal/kg and 1.25 g/kg (p < 0.005). Malnutrition is a common complication in patients with liver cirrhosis. Men have higher depletion of muscle mass and women a higher loss of body fat. The Body Mass Index is not a reliable tool for assessing malnutrition. It's advisable to use tools with indicators of body composition such as the Royal Free Hospital Global Assessment (AU)

[Nutritional assessment of alcoholic liver cirrhotic patients treated in the liver Clinic of the Mexico's General Hospital]. / Evaluación del estado nutricional de pacientes con cirrosis hepática alcohólica atendidos en la Clínica de Hígado del Hospital General de México.

Malnutrition in the cirrhotic patient is associated to a higher morbidity and mortality rate; however, the diagnosis is complex, so the study objective was to assess the nutritional status using different methods. Adult patients with alcoholic liver cirrhosis treated in the Liver Clinic of the Mexico's General Hospital were evaluated. Anthropometric measurements and a 24 hours recall were made; screening tools (Malnutrition Universal Screening Tool, Nutritional Risk Screening-2002) and a method for assessing nutritional status specifically in cirrhotic patients (Royal Free Hospital Global Assessment) were used. We included 62 patients, 51.6% of them were men. Malnutrition by arm muscle area was 31.3% in men and 10% in women, and by arm fat area was 23.3% in women and 3.1% in men (p < 0.05). With the screening tools the percentages of malnutrition risk were 43.5% and 54.8% respectively, vs. 1.6% identified as "low weight" with the Body Mass Index. With the Royal Free Hospital Global Assessment tool the percentage of malnutrition was 45.2%. Patients with malnutrition had an energy and protein intake significantly lower than the well-nourished: 19.7 kcal/kg and 0.89 g/kg vs 30 kcal/kg and 1.25 g/kg (p < 0.005). Malnutrition is a common complication in patients with liver cirrhosis. Men have higher depletion of muscle mass and women a higher loss of body fat. The Body Mass Index is not a reliable tool for assessing malnutrition. It's advisable to use tools with indicators of body composition such as the Royal Free Hospital Global Assessment.

Heartburn and other related symptoms are independent of body mass index in irritable bowel syndrome.

BACKGROUND: increasing body mass index (BMI) is a risk factor for GERD but little is known about this association in the irritable bowel syndrome (IBS). AIMS: to determine the presence of heartburn and other related symptoms in relation with BMI in IBS. METHODS: volunteers (n = 483) answered the Rome II-Modular Questionnaire, and were divided into IBS and non-IBS (controls) groups. The frequency of heartburn, chest pain, epigastric pain, nausea, vomiting and belching was compared between the groups in the study sample and within three BMI categories. RESULTS: the IBS (23.7%) and controls (76.3%) were similar in gender (females: 68.1%), age (32.2 +/- 12.7 years), and BMI (25.4 +/- 4.4). Raw associations analysis showed that heartburn: OR: 1.62 (95%CI: 1.04-2.53), chest pain: 1.77 (1.13-2.77), epigastric pain: 1.75 (1.03-2.98) and nausea: 2.45 (1.10-5.32) were more frequent in IBS vs. controls. Meanwhile, according to BMI, in those with obesity, heartburn was more frequent in IBS and among those with overweight, epigastric pain and nausea were also more frequent in IBS. However, in an adjusted log linear model, no significant interaction was found between BMI and any other studied symptom and heartburn was found to be independent of IBS: 1,4 (0.9, 4.7). Finally, a logistic regression model found no interaction between BMI and the presence of heartburn or IBS. CONCLUSIONS: while heartburn and other reflux-related symptoms are more frequent in IBS than in controls, these associations are independent of BMI.

Heartburn and other related symptoms are independent of body mass index in irritable bowel syndrome

Background: increasing body mass index (BMI) is a risk factor for GERD but little is known about this association in the irritable bowel syndrome (IBS). Aims: to determine the presence of heartburn and other related symptoms in relation with BMI in IBS. Methods: volunteers (n = 483) answered the Rome II-Modular Questionnaire, and were divided into IBS and non-IBS (controls) groups. The frequency of heartburn, chest pain, epigastric pain, nausea, vomiting and belching was compared between the groups in the study sample and within three BMI categories. Results: the IBS (23.7%) and controls (76.3%) were similar in gender (females: 68.1%), age (32.2 ± 12.7 years), and BMI (25.4 ± 4.4). Raw associations analysis showed that heartburn: OR: 1.62 (95%CI: 1.04-2.53), chest pain: 1.77 (1.13-2.77), epigastric pain: 1.75 (1.03-2.98) and nausea: 2.45 (1.10-5.32) were more frequent in IBS vs. controls. Meanwhile, according to BMI, in those with obesity, heartburn was more frequent in IBS and among those with overweight, epigastric pain and nausea were also more frequent in IBS. However, in an adjusted log linear model, no significant interaction was found between BMI and any other studied symptom and heartburn was found to be independent of IBS: 1,4 (0.9, 4.7). Finally, a logistic regression model found no interaction between BMI and the presence of heartburn or IBS. Conclusions: while heartburn and other reflux-related symptoms are more frequent in IBS than in controls, these associations are independent of BMI(AU)

Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C.

The cellular and humoral natural immune response induced by hepatitis C virus (HCV) is commonly unable to eradicate the virus. HCV is a highly mutable, hepatotropic RNA virus that causes acute and chronic hepatitis, an infection that involves the production of various cytokines. The aim of the study is to analyse the expression of pro-inflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma and the chemokine CXCL8 (IL-8) in liver tissue and their expression and secretion in PBMC of patients with chronic hepatitis C (CHC), in response to pentoxyfilline (PTX). We studied six CHC patients, naive to treatment. Patients received PTX 400 mg twice a day/8 weeks. Pentoxyfilline resulted in decreased expression of mRNA of liver IL-1beta, TNF-alpha and IFN-gamma: 144.2 versus 83.5 molecules of IL-1beta (P < 0.05), TNF-alpha 194.3 versus 17.6 molecules (P = 0.03) and IFN-gamma 26.1 versus 0.5 molecules (P = 0.04). Following PTX, PBMC exhibited a decrease in IFN-gamma mRNA 12.2 versus 1.5 molecules (P = 0.028) and CXCL8 4.2 versus 2.5 molecules (P = 0.027). In PBMC, only the secretion of TNF-alpha was decreased 1109 versus 933.5 pg/ml, P = 0.046. Production of cytokines both locally (within the liver) and systemically (PBMC) may serve as biomarkers of the infection with hepatitis C. PTX inhibits the expression of several pro-inflammatory cytokines in the liver. These results indicate that it is worth exploring PTX in hepatitis in future clinical trials in nonresponders to antiviral treatment.

Early hepatitis C virus changes and sustained response in patients with chronic hepatitis C treated with peginterferon alpha-2b and ribavirin.

BACKGROUND: Interferon-based therapy induces changes in viral dynamics in chronic hepatitis C (CHC) patients. AIMS: The aim of this study was to assess early hepatitis C virus (HCV)-RNA changes and evaluate its predictive value to achieve sustained viral response (SVR) in patients with CHC treated with peginterferon alpha-2b weekly plus ribavirin daily for 48 weeks. METHODS: HCV-RNA was measured at baseline, 48 h, 4, 12, 24 and 48 weeks of treatment and 24 weeks after treatment. RESULTS: Eighteen HCV genotype 1 patients were included (13 male, five female) with a mean age of 44.4+/-11.9 years. Nine patients achieved SVR (50%). Viral decline occurred as early as 48 h; the magnitude of decline was statistically different between both groups (P<0.01). Responders had a > or =1 log(10) drop in HCV-RNA at 48 h (positive predictive value (PPV) of 89% to achieve SVR) that persisted at week 4. By week 12, serum HCV-RNA was undetectable (PPV 100%). CONCLUSIONS: Our data indicate that peginterferon alpha-2b plus ribavirin treatment produces significant changes in HCV dynamics that can be detected as early as 48 h after the first dose of peginterferon alpha-2b and that these changes are useful in predicting response to therapy in CHC patients.