Does the simultaneous tumor necrosis factor receptor 2, tumor necrosis factor promoter gene polymorphism represent a higher risk for alcoholic liver disease?

BACKGROUND AND AIM: Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that seems to play a crucial role in the pathogenesis of alcoholic liver disease (ALD). TNF-alpha exerts its effects by binding to specific receptors (TNFR); the polymorphism of TNFRII T587G has been associated with increased TNF apoptotic response and its presence may increase the risk to develop liver disease. The aim of this study was to evaluate the prevalence of the TNF-alpha G238A promoter and TNFRII polymorphisms, individually or simultaneously, in ALD. METHODS: TNF-alpha G238A and TNFRII T587G polymorphisms were studied in 103 unrelated patients with ALD (biopsy confirmed or clinical evidence) and in 76 heavy drinkers without liver disease (NLD). Single nucleotide polymorphism gene was detected by a polymerase chain reaction-restriction fragment length polymorphisms method. All patients had, at least, a 5 year history of alcohol consumption greater than 80 g/day. RESULTS: TNF-alpha G238A allele frequency was similar in both groups. TNFRII T587G allele frequency was slightly higher in the ALD group than in the NLD group (21 vs. 18%, P=NS). TNF-alpha G238A and TNFRII T587G were simultaneously present in six ALD patients and in none of NLD patients (P=0.04). CONCLUSION: Although individually there was no association between TNFRII T587G or TNF-alpha G238A polymorphisms and ALD, this study suggests that the presence of both polymorphisms may enhance the susceptibility for ALD. TNF-alpha G238A may increase TNF-alpha production, which when associated with TNFRII T587G, can further exacerbate TNF-alpha response leading to a greater risk of ALD.

Bile acid levels are increased in the liver of patients with steatohepatitis.

BACKGROUND/AIMS: The pathogenesis of steatohepatitis remains largely unknown; however, bile acids may play a role as potential mediators of liver damage. The aim of this study was to characterize bile acid profiles in liver tissue of patients with steatohepatitis. METHODS: Bile acid composition was determined by gas-liquid chromatography in liver tissue from patients with nonalcoholic steatohepatitis (NASH; n=15), patients with alcoholic steatohepatitis (ASH; n=14), and controls (n=8). Liver biopsies were graded for steatosis, inflammation, and fibrosis. RESULTS: Bile acids were moderately increased in liver tissue of steatohepatitis patients compared with controls (P<0.05). Deoxycholic, chenodeoxycholic, and cholic acids were elevated by 92, 64, and 43%, respectively, in patients with steatohepatitis (P<0.05). Cholic acid was the prevailing bile acid in NASH patients and in controls. More hydrophobic bile acid species were elevated in ASH patients compared with controls (P<0.05). Significant correlations were found in NASH patients between hepatic chenodeoxycholic acid and fibrosis, and between cholic acid and trihydroxy/dihydroxy bile acids and inflammation (P<0.05). In patients with ASH, cholic acid and trihydroxy/dihydroxy bile acids were correlated with steatosis (P<0.01). CONCLUSION: This study shows a distinct pattern of bile acids in the liver of patients with steatohepatitis. Further, the association between bile acids and histological liver injury suggests an association of specific bile acids and disease progression, possibly through bile acid-induced liver injury.

Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis.

OBJECTIVES: Apoptosis may play a role in the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). In this study, we investigated the modulation of apoptosis-related liver proteins in steatohepatitis. METHODS: Hepatocyte apoptosis was evaluated by the TUNEL assay in liver tissue of 12 patients with NASH, 12 with ASH and in histologically normal controls. In addition, caspase-3 processing was evaluated by immunoblot analysis. Expression of death receptors, Bcl-2 family members, and NF-kappaB inhibitor (IkappaB) were determined by western blot. Liver biopsies were also graded for inflammation and fibrosis. RESULTS: Apoptotic hepatocytes were markedly increased in NASH (P<0.05) and ASH (P<0.001) as compared to controls. Active caspase-3 was also elevated in steatohepatitis (P<0.01), coinciding with upregulation of pro-apoptotic Bax (P<0.001). Further, production of tumour necrosis factor-receptor 1 was increased up to 4-fold (P<0.05). Degradation of IkappaB increased >70% in steatohepatitis (P<0.001). Notably, Bcl-2 was also strongly expressed (>100-fold; P<0.001). These data were significantly correlated with relative degrees of portal and lobular inflammation. CONCLUSION: The results show that liver injury in NASH and ASH is associated with apoptosis and NF-kappaB activation. Anti-apoptotic Bcl-2 is strongly expressed, probably reflecting an adaptive response to obesity or alcohol-related stress.

Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients.

OBJECTIVES: The increasing incidence of nonalcoholic (NASH) and alcoholic steatohepatitis (ASH), associated with lack of effective treatment, has prompted intensive studies on disease pathogenesis. Apoptosis is recognized as common in liver injury and may also contribute to tissue inflammation, fibrogenesis, and development of cirrhosis. In this study, we identified mechanisms of apoptosis induction in human steatohepatitis, and evaluated potential associations between apoptosis, liver pathology, and clinical presentation in NASH and ASH. METHODS: Hepatocyte apoptosis was evaluated by the TUNEL assay in 20 patients with NASH (all ambulatory), 40 with ASH (20 ambulatory, 20 hospitalized), and 20 controls. Liver biopsies were also graded for inflammation and fibrosis. Immunohistochemistry was performed for death receptors (Fas and TNF-R1), activated caspase-3, NF-kappaB p65, antiapoptotic Bcl-2 protein, and uncoupling protein 2 (UCP-2). RESULTS: TUNEL-positive hepatocytes were markedly increased in NASH (p < 0.05) and ASH (p < 0.01). Similar results were obtained for activated caspase-3, confirming the occurrence of apoptosis. The Fas receptor was upregulated in ASH, especially in hospitalized patients (p < 0.01), whereas TNF-R1 was expressed both in NASH and ASH (p < 0.01). In addition, patients with ASH showed a remarkable expression of active NF-kappaB, as compared to NASH and controls (p < 0.01). Degrees of inflammation and fibrosis correlated with NF-kappaB p65 expression, which in turn coincided with apoptosis albeit Bcl-2 and UCP-2 expression. CONCLUSIONS: Liver injury in NASH and ASH is associated with increased hepatocyte apoptosis mediated by death receptors. Further, apoptosis correlates with active NF-kappaB expression, and disease severity. This potential mechanistic link might provide multiple interesting targets for therapeutic intervention.

Cancer: disease and nutrition are key determinants of patients' quality of life.

GOALS OF WORK: The aims of this study were (1) to evaluate quality of life (QoL), nutritional status and dietary intake taking into account the stage of disease and therapeutic interventions, (2) to determine potential interrelationships, and (3) to quantify the relative contributions of the cancer, nutrition and treatments on QoL. PATIENTS AND METHODS: In this prospective cross-sectional study conducted in 271 head and neck, oesophagus, stomach and colorectal cancer patients, the following aspects were evaluated: QoL (EORTC-QLQ C30), nutritional status (percent weight loss over the previous 6 months), usual diet (comprehensive diet history), current diet (24-h recall) and a range of clinical variables. MAIN RESULTS: Usual and current intakes differed according to the site of the tumour ( P=0.02). Patients with stage III/IV disease showed a significant reduction from their usual energy/protein intake ( P=0.001), while their current intakes were lower than in patients with stage I/II disease ( P=0.0002). Weight loss was greater in patients with stage III/IV disease than in those with stage I/II disease ( P=0.001). Estimates of effect size revealed that QoL function scores were determined in 30% by cancer location, in 20% by nutritional intake, in 30% by weight loss, in 10% by chemotherapy, in 6% by surgery, in 3% by disease duration and in 1% by stage of disease. Likewise in the case of symptom scales, 41% were attributed to cancer location, 22% to stage, 7% to nutritional intake, 7% to disease duration, 4% to surgery, 1% to weight loss and 0.01% to chemotherapy. Finally for single items, 30% were determined by stage, 20% by cancer location, 9% by intake, 4% by surgery, 3% by weight loss, 3% by disease duration and 1% by chemotherapy. CONCLUSIONS: Although cancer stage was the major determinant of patients' QoL globally, there were some diagnoses for which the impact of nutritional deterioration combined with deficiencies in nutritional intake may be more important than the stage of the disease process.

The European view of hospital undernutrition.

Disease-related undernutrition is significant in European hospitals but is seldom treated or prevented. In 1999, the Council of Europe decided to collect information regarding nutrition programs in hospitals, and for this purpose, a network consisting of national experts from 12 of the Partial Agreement member states was established. The aim was to review the current practices in Europe regarding hospital food provision, to highlight deficiencies, and to issue recommendations to improve the nutritional care and support of hospitalized patients. Five major common problems were identified: 1) lack of clearly defined responsibilities, 2) lack of sufficient education, 3) lack of influence and knowledge of the patients, 4) lack of cooperation between different staff groups, and 5) lack of involvement from the hospital management. To solve the problems highlighted, a combined timely and concerted effort is required from national authorities and hospital staff, including managers, to ensure appropriate nutritional care and support.

Artificial nutrition: dilemmas in decision-making.

Artificial nutrition is a supportive medical therapy to attain pre-defined objectives, which should be adjusted to changing clinical situations. Optimal decision-making is based on the available scientific evidence blended with the science of probability and a spice of the art of uncertainty. Complex dilemmas in decision-making often occur given the paucity of solid scientific data to endorse precise indications and timing of prescription, whilst goals to be achieved may vary from clinical benefits to compassionate use. Hence, healthcare professionals must be aware and abide by the current norms of medical ethics, whereby eliciting and respecting patients' preferences is paramount. Patient-focused care implies: to respect patients' rights, to clearly inform and involve the patient in the decision-making process, to implement a therapeutic plan based on the best available care to suit patients' needs and informed options.

Lack of effect of colchicine in alcoholic cirrhosis: final results of a double blind randomized trial.

BACKGROUND: Colchicine, an inhibitor of collagen synthesis, has been suggested as potentially beneficial in cirrhosis. OBJECTIVE: This long-term, randomized, double blind, placebo controlled trial was conducted in order to evaluate the efficacy of colchicine in alcoholic cirrhosis. METHODS: Ambulatory patients with biopsy proven alcoholic cirrhosis, presenting from 1989 to 1997, with no exclusion criteria (e.g. Child-Pugh C, bilirubin > 10 mg/dl and gastrointestinal bleeding in the previous 15 days), were randomized to receive orally, 5 days/week, 1 mg/day of colchicine or placebo. MAIN OUTCOME MEASURES: Results were analysed on an intention to treat basis, for survival, incidence of complications, biochemical liver tests and safety. RESULTS: Twenty-nine patients received colchicine and 26 placebo; characteristics of both groups were similar. The median follow-up was 40.6 (1.4-126.3) months in the colchicine versus 42.4 (5.7-118.2) months in the placebo group (NS). No significant side effects were reported. During follow-up, there were no significant differences in compliance and alcohol abstinence (86% vs 85%). Overall survival was not statistically different (P = 0.38). Cumulative 3-year survival rates were 74.9% in the colchicine versus 91.4% in placebo group (NS). The annual incidence rate of complications was similar with colchicine or placebo: gastrointestinal bleeding, 1.5% vs 1.2%; ascites, 3.7% vs 3.7%; and encephalopathy, 1.0% vs 0.9%. The comparison of changes in biochemical parameters between groups did not show any significant difference. CONCLUSIONS: Although well tolerated, colchicine does not appear to overcome the progression and natural history of long-established alcoholic cirrhosis.