Translational approaches: From fatty liver to non-alcoholic steatohepatitis

Over the past few decades, non-alcoholic fatty liver disease(NAFLD) has become one, if not the most common,cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis(NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis.

Insulin sensitizers in treatment of nonalcoholic fatty liver disease:Systematic review

AIM: To summarize the evidence available for the clinical effectiveness of insulin sensitizers in the treatment of nonalcoholic fatty liver disease (NAFLD) systematically. METHODS: Relevant articles were located using computer-assisted searches of Medline (1966-March 2006), EMBASE (1988-March 2006), CINAHL (1982-March 2003), Educational Resource Information Center (1966-March 2006), Library, Information Science & Technology Abstracts (1967-March 2006), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (1994-2006), dissertations in ProQuest and FirstSearch databases. Manual searches were made in the abstracts from meetings of the American Gastroenterological Association (1999-2006), and the American Association for the Study of Liver Diseases (2003-2005). Studies were retrieved using the following selection criteria: (1) clinical trials using insulin sensitizers in subjects with NAFLD, (2) adult patients, (3) published as full manuscripts or abstracts, and (4) English, Spanish, German, and French languages only. Data were abstracted independently by two reviewers following standardized procedures. A face-to- face comparison of data was conducted to ensure the completeness and reliability of the abstraction process. RESULTS: Nine studies were included, six using metformin and three using thiazolidinediones. Only two studies were placebo-controlled trials. The mediansample size for all studies was 18 subjects. In the placebo-controlled trials, metformin improved insulin resistance markers and liver function tests, but not histological scores. In the single-arm trials, metformin and thiazolidinediones improved insulin resistance markers and liver function tests, and beneficial histological changes were reported. There is limited high-quality information available from which to draw categorical conclusions about the clinical use of insulin sensitizers in NAFLD.CONCLUSION: Current information indicates that the use of insulin sensitizers in NAFLD improves insulin resistance and liver function. Histological changes must be corroborated in randomized controlled trials.

PPIs are not associated with a lower incidence of portal-hypertension-related bleeding in cirrhosis

AIM:To determine if proton pump inhibitor use in cirrhotic patients with endoscopic findings of portal hypertension is associated with a lower frequency of gastrointestinal bleeding.METHODS:Patients with cirrhosis and endoscopic findings related to portal hypertension,receiving or not receiving proton pump inhibitor (PPI) therapy,were included retrospectively.We assigned patients to two groups:group 1 patients underwent PPI therapy and group 2 patients did not undergo PPI therapy.RESULTS:One hundred and five patients with a median age of 58 (26-87) years were included,57 (54.3%) of which were women.Esophageal varices were found in 82 (78%) patients,portal hypertensive gastropathy in 72 (68.6%) patients,and gastric varices in 15 (14.3%) patients.PPI therapy was used in 45.5% of patients (n=48).Seventeen (16.1%) patients presented with upper gastrointestinal bleeding;in 14/17 (82.3%) patients,bleeding was secondary to esophageal varices,and in 3/17 patients bleeding was attributed to portal hypertensive gastropathy.Bleeding related to portal hypertension according to PPI therapy occurred in 18.7% (n=9) of group 1 and in 14% (n=8) of group 2 (odds ratio:0.83,95% confidence interval:0.5-1.3,P=0.51).CONCLUSION:Portal hypertension bleeding is not associated with PPI use.These findings do not support the prescription of PPIs in patients with chronic liver disease with no currently accepted indication.

Serum leptin levels and insulin resistance are associated with gallstone disease in overweight subjects

AIM: To establish an association between the serum leptin levels and the development of gallstone disease (GD).METHODS: We carried out a non-matched case-controlled study in a university hospital in Mexico City. Two hundred and eighty-seven subjects were included: 97 cases with gallstones and 190 controls. Body mass index (BMI), fasting plasma leptin, insulin, serum lipid, and lipoprotein levels were measured. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Unconditional logistic regression analysis (univariate and multivariate)stratified by BMI was used to calculate the risk of GD.RESULTS: The multivariate conditional regression analysis revealed a model for those patients with BMI ＜30. The selected variables in the model were HOMA-IR index with OR = 1.31, P= 0.02 and leptin higher than median with OR = 2.11, P= 0.05. In the stratum of BMI ≥30, we did not find a useful model.CONCLUSION: We concluded that insulin resistance and the development of GD appears to be associated with serum leptin levels in subjects with overweight, but not in obese subjects with similar metabolic profiles.

Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis

AIM: To evaluate the prevalence of metabolic syndrome (MS), obesity and type 2 diabetes mellitus (T2DM) in a group of Mexican Mestizo patients with cryptogenic cirrhosis (CC) and to compare this group with patients with cirrhosis secondary to other causes (disease controls). METHODS: Patients with CC, diagnosed between January, 1990 and April, 2005, were included in a retrospective study. Patients with cirrhosis caused by chronic hepatitis C, alcohol abuse or autoimmune hepatitis (AIH) served as disease controls. RESULTS: A total of 134 patients with CC were analyzed. Disease controls consisted of 81 patients with chronic hepatitis C, 33 with alcohol abuse and 20 with AIH. The median age of patients with CC was 57 years (range, 16-87); 83 (61.9%) patients were female; 53 (39.6%) were Child A, 65 (48.5%) Child B, and 16 (11.9%) were Child C cirrhosis. The prevalence of MS (29.1% vs 6%; P < 0.001), obesity (16.4% vs 8.2%; P = 0.04) and T2DM (40% vs 22.4%; P = 0.013) was higher in CC patients than in disease controls. There were no differences in sex, age or liver function tests between the two groups. CONCLUSION: The prevalence of MS, obesityand T2DM were higher in patients with CC than in patients with cirrhosis secondary to others causes. Our findings support the hypothesis that non-alcoholic steatohepatitis (NASH) plays an under-recognized role in CC.

Smoking is not associated with nonalcoholic fatty liver disease

瞄准：分析在吸烟和不含酒精的脂肝疾病(NAFLD ) 之间的关系。方法：这是一张健康人口的代表性的研究，在墨西哥在一所大学医院的一个检查单位执行了城市。我们注册了 933 个题目， 368 个当前的吸烟者(盒子) 和从来没吸过的 565 个人(控制) 。人口统计、新陈代谢、生物化学的变量在二个组被测量。NAFLD 被超声和新陈代谢的症候群根据 ATPIII 决定。结果：548 个男人(205 个盒子和 343 控制) 和 337 个女人(114 个盒子和 223 控制) 的一个总数在分析被包括。盒子和控制之间的统计差别仅仅在高血压流行被观察(6.6% 对 11.3% ， P 【 0.05；盒子和控制分别地)，高密度的脂蛋白( 1.00 +/- 0.26 对 1.06 +/- 0.28 mmol/L ， P 【 0.005 )， triglycerides ( 2.18 +/- 1.49 对 1.84 +/- 1.1 mmol/L ， P 【 0.001 )，并且红细胞沉降率( 11.3 +/- 9.3 对 13.5 +/- 11.9 mm/h ， P 【 0.001 )。没有差别在 NAFLD 的流行被观察(22.27% 对 29.68% ， P = NS ) 并且新陈代谢的症候群(41.69% 对 36.74% ， P = NS ) 。Univariate 分析证明吸烟不是为 NAFLD 的一个风险因素(或 = 0.89， 95% CI 0.65-1.21 ) 。结论：在 NAFLD 流行的差别都没在当前的吸烟者和不抽烟的人之间被观察，并且而且，没有差别在重吸烟者(超过 20 包装 / 年) 被观察，显示在吸烟和 NAFLD 之间没有关系。

Clinical heterogeneity in autoimmune acute liver failure

AIM: To describe the outcome and prognosis in a cohort of patients with acute liver failure due to autoimmune hepatitis without liver transplantation. METHODS: A retrospective trial was conducted in 11 patients with acute liver failure due to autoimmune hepatitis who attended the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran. Demographic, biochemical and severity indexes, and treatment and outcome were assessed. RESULTS: Among the 11 patients, with a median age of 31 years, 72% had inflammatory response syndrome, and six patients received corticosteroids. The mortality rate within four weeks was 56%, and the one-year survival was 27%. In the survivors, severity indexes were lower and 83% received corticosteroids. CONCLUSION: We observed a relatively high survival rate in patients with acute liver failure due to autoimmune hepatitis. This survival rate could be influenced by severity of the disease and/or use of corticosteroids.