Transforming Growth Factor Beta 1 and Vascular Risk in Alcoholics.

INTRODUCTION: Transforming growth factor beta-1 (TGF-ß1) is a pleiotropic cytokine. Its relationship with atherosclerosis is debatable, protective or deleterious effects have been described. Alcoholics are at increased vascular risk. Although TGF-ß1 is increased in alcoholics, its role on vascular risk factors has not been analyzed. This is the objective of this study. PATIENTS AND METHODS: 79 heavy alcoholics and 34 controls were included. Calcium deposition in the aortic arch was assessed in the plain thorax X-ray film. Ankle-brachial index was recorded in 48 patients. All the patients underwent complete laboratory evaluation, including serum levels of TGF-ß1, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, and interferon-γ (IFN-γ).We analyzed the relationships between TGF-ß1 and vascular risk factors by both univariate (parametric or non parametric tests), or multivariate analysis to discern on which variables TGF-ß1 levels depend. RESULTS: Serum TGF-ß1 levels were higher among patients (t = 2.73; P = 0.008), but no differences exist among cirrhotics (17246 ± 11,021 pg/mL) and non-cirrhotics (21,340 ± 12,442 pg/mL). TGF-ß1 showed significant correlations with total cholesterol (r = 0.28; P = 0.017) and HDL- cholesterol (r = 0.25; P = 0.042), and inverse correlations with body mass index (BMI; ρ = -0.37; P = 0.004), IL-4 (ρ = -0.31; P = 0.009), INF-γ (ρ = -0.28; P = 0.001), and IL-6 (ρ = -0.38; P = 0.001). By multivariate analysis, only BMI, IL-6 and HDL-cholesterol showed independent relationships with TGF-ß1. No relationships were observed with ankle-brachial index or calcium in the aortic arch, hypertension, diabetes, left ventricular hypertrophy or atrial fibrillation. CONCLUSION: TGF-ß1 levels are increased in alcoholics, but are unrelated to vessel wall calcification or arterial stiffness.

Soluble α-Klotho in Liver Cirrhosis and Alcoholism.

AIMS AND BACKGROUND: Alpha Klotho is a transmembrane protein that serves as co-receptor for FGF23. Ectodomain of membrane bound α Klotho may be shed by membrane bound proteases (activated, among other factors, by tumor necrosis factor (TNF)-α) generating the soluble form of the protein (sKl) that functions as a hormone by itself. It modulates calcium influx into cells, blunts IGF-1/Insulin signaling, promotes synthesis of antioxidants, generally slows down tumor progression, delays cell senescence, is neuroprotective and promotes oligodendrocyte maturation and myelin synthesis, and muscle rejuvenation. It may be involved in inflammation and exerts antifibrogenic effects. Some of these pathways may become altered in alcoholism or liver cirrhosis, but data are scattered and scarce and an update is required. METHOD: Literature survey. RESULTS AND CONCLUSIONS: Alcohol consumption in non-alcoholics is inversely related to sKl, but alcoholic cirrhotics showed higher-than-normal sKl values in association with liver function derangement. In hepatoma cells, the intensity of Klotho staining was related to faster tumor progression and a shortened life span. Among severe alcoholic cirrhotics sKl is directly related to serum TNF-α levels, and, inversely, to brain atrophy. Given the antioxidant, anti-inflammatory, and antifibrogenic effects of Klotho, perhaps the increase in cirrhosis (and in other inflammatory conditions, such as sepsis or cancer) reflects an attempt to regulate increased inflammation, but clinical and experimental research is urgently needed in this field.

Clinicopathological differences between familial colorectal cancer type X and sporadic cancer in an isolated area of spain.

AIM: Very few studies have compared the epidemiological characteristics of patients with familial colorectal cancer Type X (FCCTX) with those of sporadic colorectal cancer (S-CRC). The aim of this study was to compare clinicopathological characteristics and survival between FCCTX and S-CRC in patients from a historically isolated geographical region. METHOD: A retrospective study was carried out of patients with S-CRC and FCCTX treated in the Canary Islands. Family and personal history of colorectal cancer (CRC) were recorded, together with genetic (microsatellite instability), immunohistochemical and clinical variables. RESULTS: Forty-eight (10.6%) of 451 patients were classified as FCCTX and the remaining 403 (89.4%) as S-CRC. Age at the diagnosis of tumour was significantly lower in FCCTX than in S-CRC (64.06 ± 12.65 years vs 69.13 ± 10.80 years; P = 0.01; Z = -2.48). Patients with FCCTX had a larger number of synchronous tumours (P = 0.09). Recurrence was significantly higher in FCCTX than in S-CRC (18.7% vs 8.6%; P = 0.01). Survival correlated significantly with the number of first-degree and second-degree relatives with CRC (P = 0.04; OR: 1.368, 95% CI: 1.01-1.84, and P = 0.04; OR: 1.363, 95% CI: 1.08-1.65) and with the total number of cases of CRC in the immediate family (P < 0.01; OR: 1.377, 95% CI: 1.17-1.61). Recurrence-free time was significantly lower in patients with FCCTX (log-rank = 0.01). CONCLUSION: Significant differences were found in several demographic and clinicopathological variables between patients with FCCTX and patients with S-CRC. These included increased tumour presentation under the age of 50 years and a higher recurrence rate in patients with FCCTX, suggesting an increased risk of CRC in this group.

Síndrome de leche y alcalinos asociado a anorexia nerviosa / Milk alkali syndrome associated to anorexia

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Prognostic value of changes in lean and fat mass in alcoholics.

BACKGROUND & AIMS: The prognostic value of nutritional status and/or lean and fat mass assessed by dual-energy X-ray absorptiometry (DEXA) has been widely analyzed, in both alcoholics and non-alcoholics. However, the prognostic value of changes in fat and lean mass over time in alcoholics has scarcely been studied, nor has the effect of alcohol abstinence on these changes. METHODS: From an initial cohort of 113 alcoholic patients, 70 prospectively underwent two DEXA assessments six months apart. One hundred and five patients (including 66 of those who underwent two DEXA assessments) were followed up for 34.9 ± 36.4 months (median = 18 months, interquartile range = 7.25-53.75 months). During this follow-up period, 33 died (including 20 of those who had undergone a second DEXA assessment). RESULTS: Forty-two of the 70 patients undergoing a second DEXA assessment had abstained from alcohol. Of these, 69.04% (29) gained left arm lean mass, compared with only 35.71% (10 of 28) of those who had continued drinking (χ² = 7.46; p = 0.006). Similar results were observed regarding right arm lean mass (χ² = 4.68; p = 0.03) and right leg lean mass (χ² = 7.88; p = 0.005). However, no associations were found between alcohol abstinence and changes in fat parameters. Analysis by means of Kaplan-Meier curves showed that loss of total lean mass, right leg lean mass, left leg lean mass and total fat mass were all significantly associated with reduced survival. However, within 30 months of the second evaluation, significant associations were observed between changes of all parameters related to lean mass, and mortality, but no association between changes in fat parameters and mortality. CONCLUSIONS: Loss of lean mass over a period of six months after a first assessment is associated with worse prognosis in alcoholics, irrespective of whether they stop drinking during this period or not. Continued drinking is associated with greater loss of lean mass, but not with changes in fat mass.

Effects of protein deficiency on liver trace elements and antioxidant activity in carbon tetrachloride-induced liver cirrhosis.

In liver cirrhosis, liver tissue becomes progressively substituted by fibrosis, ultimately leading to architectural distortion, liver circulatory changes, and liver failure. Some data support the hypothesis that protein undernutrition may play a role in the development and progression of nonalcoholic liver cirrhosis and that this progression is at least partially mediated by changes in glutathione peroxidase (GPX), superoxide dismutase (SOD), and other antioxidative systems, leading to an increase in lipid peroxidation. We analyzed the effects of protein deficiency on liver Cu, Fe, Zn, Mn, and Se in carbon tetrachloride (CCl4)-induced liver cirrhosis, the relation of protein undernutrition and these trace elements with the activity of some hepatic antioxidative enzymatic mechanisms, and the relation of all of them with morphological and biochemical changes in 40 male adult Sprague-Dawley rats divided in four groups. Liver cirrhosis was induced by intraperitoneal injection of CCl4 to 10 rats fed a 2% protein diet and another 10 fed a 18% protein control diet; two further groups included rats without cirrhosis fed the 2% protein and the 18% protein diets. The study period lasted 6 wk. GPX, SOD, and lipid peroxidation products as well as Zn, Cu, Mn, Se, and Fe were determined in liver samples. We found that liver GPX and Se were reduced in the cirrhotic animals, especially in the low-protein-fed ones, protein deficiency, but not cirrhosis, exerting the main effects. A close correlation was found between liver GPX and serum albumin and weight loss and an inverse one among GPX and hepatocyte ballooning, liver fibrosis, and fat, histomorphometrically determined. These results suggest a pathogenetic role of decreased GPX in the progression of liver disease, which may become enhanced by concomitant protein undernutrition. In addition to iron, the levels of which were increased in the malnourished rats, no differences were found regarding the other trace elements, SOD activity, and lipid peroxidation products.

Combined effects of steroids, ethanol and protein deficiency on tissue content and urinary and faecal excretion of zinc, copper and iron.

This study was performed in order to determine the relative and combined effects of ethanol, a low protein diet and steroid treatment on bone, muscle, liver, and urinary and faecal excretion of zinc, copper and iron in 64 rats divided into eight groups treated following the Lieber-DeCarli liquid diet technique, with and without dexamethasone, 1 mg/l. Steroids showed a lack of effect on liver zinc, but enhanced ethanol- and low protein-mediated liver iron overload when both factors were combined. Steroids also increased muscle copper, iron and zinc, and bone copper, especially in the low protein, ethanol-fed rats.

Actitudes diagnósticas en edema de pulmón no cardiogénico / No disponible

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High prevalence of hyperhomocysteinemia in chronic alcoholism: the importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR).

Alcoholism is related to malnutrition and low levels of several vitamins that take part in the metabolism of homocysteine. The objective of the study was to analyze the prevalence of hyperhomocysteinemia in patients with heavy alcohol intake and the factors on which it depends. Included in the study were 103 hospitalized heavy drinkers (i.e., patients with an intake of alcohol greater than 80 g per day). Serum homocysteine, folate, and vitamin B(12) levels, plasma vitamin B(6) levels, and CT677 polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were determined. We also recorded the intensity of alcoholism, the status of nutrition, and the existence of liver cirrhosis. Determination of biochemical data was repeated after 15 days of withdrawal. Serum homocysteine levels were found to be significantly elevated, whereas serum folate and plasma B(6) levels were significantly decreased. Serum homocysteine levels were significantly higher in those heavy drinkers who showed the TT polymorphism of MTHFR, with a prevalence of hyperhomocysteinemia of 84.2% in the homozygote TT, 54.3% in the heterozygote CT, and 31.6% in the normal CC genotype. Serum homocysteine inversely correlated with serum folate, serum B(12), and plasma B(6) levels. We did not find any relation between serum homocysteine and intensity of alcoholism, nutritional status, or liver cirrhosis. Serum folate levels were significantly decreased in heavy drinkers, mainly depending on irregular feeding and malnutrition. After 15 days of withdrawal, serum homocysteine levels significantly decreased, whereas folate, B(12), and B(6) levels significantly increased. The conclusion is that heavy drinkers show a high prevalence of hyperhomocysteinemia related to low levels of folate, B(6), and B(12) and to the TT polymorphism of MTHFR.

Prevalence and mortality of heavy drinkers in a general medical hospital unit.

This study was performed in order to analyse the prevalence, clinical characteristics and mortality of heavy drinkers among hospitalized patients during a 2-year period. Chronic excessive alcohol consumption (daily intake >80 g of ethanol for males and >40 g for females) was found in 278 of 2913 hospital admissions and was strongly associated with the male sex (90.69%). Heavy drinkers were significantly younger than other admissions (15 and 10 years for men and women, respectively), but showed similar mortality rates to other admissions, despite a much earlier age at death (19.5 years for men and 22 years for women). There was a trend towards higher mortality rates among severe alcoholic women than severe alcoholic men and non-alcoholic women. Liver cirrhosis was the entity most frequently observed in the heavy drinkers, and was significantly more prevalent in alcoholic women.

Neurotoxicidad por fenitoína / Phenitoin neurotoxicity

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Nutritional assessment in alcoholic patients. Its relationship with alcoholic intake, feeding habits, organic complications and social problems.

To establish their ability to predict malnutrition, irregular feeding, alcoholic intake, derangement of social and familial links and organic complications (liver cirrhosis) were assessed in 181 hospitalized male alcoholic. BMI was under 18.5 kg/m(2) in 8.9%, between 18.5-20 kg/m(2) in 8.9%, 20-25 kg/m(2) in 42%, 25-30 kg/m(2) in 32.2% and over 30 kg/m(2) in 8.2% of patients. Malnutrition was related to the intensity of ethanol intake, development of social or familial problems, irregularity of feeding habits and cirrhosis with ascites. Irregularity of feeding habits was also related to heavy drinking and to social or familial derangement. By logistic regression analysis, the only variables which independently predict malnutrition were irregular feeding habits and liver cirrhosis with ascites. In a second step, irregular feeding was dependent on social or familial troubles and daily intake of ethanol. So, malnutrition related to alcoholism seems multifactorial in its pathogenesis.

Relative and combined effects of ethanol and protein deficiency on bone histology and mineral metabolism.

This study was performed to analyze the relative and combined effects of ethanol and protein deficiency on bone histology and mineral metabolism in 4 groups of 7 animals each which were pair-fed during 8 weeks with 1) a nutritionally adequate diet; 2) a 36% (as energy) ethanol containing isocaloric diet; 3) a 2% protein, isocaloric diet; and 4) a 36% ethanol 2% protein isocaloric diet, respectively, following the Lieber-DeCarli model. Another group of five rats were fed ad libitum the control diet. The first and second lumbar vertebrae were removed after sacrifice, and processed for histomorphometrical analysis of undecalcified bone samples. Blood and 24-h urine were also collected. Protein malnutrition, but not ethanol, leads to osteoporosis and reduced osteoid synthesis, whereas ethanol and protein malnutrition both lead to impaired bone mineral apposition and increased urinary hydroxyproline excretion. These changes are accompanied by an increase in serum parathormone and serum 1,25 dihydroxy vitamin D3, a slight hypomagnesemia, hypercalciuria and hyperphosphaturia; protein deficiency plays an independent role in these alterations, whereas both ethanol and protein deficiency exert independent effects on decreasing serum testosterone levels; this last alteration may contribute to the bone changes mentioned before.

Osteopenia assessed by body composition analysis is related to malnutrition in alcoholic patients.

Osteopenia is frequent among alcoholics. Its pathogenesis seems to be multifactorial, including ethanol intake, hormonal changes, liver cirrhosis, and malnutrition. Our objective is to determine the relative role of malnutrition on bone loss. One hundred and eighty-one male alcoholic patients, drinkers of more than 80 g ethanol/day, were included, recording data on the intensity of alcoholism, liver cirrhosis, nutritional assessment based on feeding habits, body mass index (BMI), midarm anthropometrics, subjective nutritional assessment, lean and fat mass by dual energy X-ray absorptiometry (DEXA), serum proteins and insulin growth factor Type I (IGF-I), calcitropic hormones, parathyroid hormone (PTH), osteocalcin 25OHD3, and bone mass assessed by DEXA, which was also performed in 43 healthy controls. Alcoholics showed decreased serum osteocalcin, PTH, 25OHD3, IGF-I, and bone mass. Alcoholics were frequently malnourished with decreased BMI, lean, and fat mass. The loss of bone mass was not related to the alteration of calcitropic hormones, to the intensity of alcoholism, or to the existence of liver cirrhosis, but to malnutrition. For a similar BMI, bone loss was more intense in alcoholics than in controls, especially in those with irregular feeding habits. Although cross-sectional ones, our data suggest that alcoholic osteopenia may be interpreted as a form of nutritional osteoporosis, notwithstanding the influence of other factors.

Valor pronóstico del estado de nutrición y de las citoquinas proinflamatorias (IL-1, FNTa e IL-6) en pacientes graves / Prognostic value in nutritional assessment and cytokine (IL-1, FNTa e IL-6) in critically ill patients

Objetivo: En el pronóstico del paciente hospitalizado influyen, entre otros factores, el estado de nutrición, la intensidad de la reacción de fase aguda (RFA) y la gravedad de la enfermedad. Estos tres factores están estrechamente interrelacionados: la enfermedad, a través de la RFA mediada por citoquinas, produce desnutrición, más intensa cuanto más grave es la enfermedad. Nuestro objetivo es analizar en que medida los mencionados factores están relacionados con la mortalidad y cuáles de ellos tienen valor predictivo independiente. Método: Se ha estudiado a 119 pacientes ingresados consecutivamente en una unidad de cuidados intermedios, en los que se realizó una valoración nutricional objetiva y subjetiva, determinaciones bioquímicas nutricionales, reactantes de fase aguda y citoquinas IL-1, FNTa e IL-6. La gravedad de la enfermedad se valoró a través de la existencia de insuficiencia de órganos. Se consideró como único punto final el fallecimiento o el alta hospitalaria del paciente. Resultados: Se relacionaron con mayor mortalidad un peor estado de nutrición, tanto los antecedentes de alimentación deficiente, como una peor valoración nutricional subjetiva, la elevación de la IL-6, el aumento del porcentaje de neutrófilos, el descenso de los linfocitos, de la hemoglobina, de la transferrina y la anergia al PPD; también la existencia de alguna de las siguientes complicaciones o insuficiencia de órganos: sepsis, ventilación mecánica, shock, insuficiencia renal aguda y alteraciones de la coagulación. En el análisis multivariante (regresión logística) sólo las variables nutricionales, la existencia de sepsis y los datos de insuficiencia de órganos mostraron valor pronóstico independiente, mientras que la IL-6 era desplazada por los datos de fallo de órganos. Conclusión. De cara al pronóstico, la gravedad de la enfermedad y el estado de nutrición aportan información independiente, mientras que la IL-6 queda desplazada, probablemente debido a su estrecha relación con la respuesta inflamatoria y la existencia de fallo de órganos (AU)