Showing papers in "Journal of Gastroenterology and Hepatology in 2013"

Role of the gut microbiota in human nutrition and metabolism

Abstract: The human gastrointestinal tract harbors trillions of bacteria, most of which are commensal and have adapted over time to the milieu of the human colon. Their many metabolic interactions with each other, and with the human host, influence human nutrition and metabolism in diverse ways. Our understanding of these influences has come through breakthroughs in the molecular profiling of the phylogeny and the metabolic capacities of the microbiota. The gut microbiota produce a variety of nutrients including short-chain fatty acids, B vitamins, and vitamin K. Because of their ability to interact with receptors on epithelial cells and subepithelial cells, the microbiota also release a number of cellular factors that influence human metabolism. Thus, they have potential roles in the pathogenesis of metabolic syndrome, diabetes, non-alcoholic fatty liver disease, and cognition, which extend well beyond their traditional contribution to nutrition. This review explores the roles of the gut microbiota in human nutrition and metabolism, and the putative mechanisms underlying these effects.

Update on epidemiology of hepatitis B and C in China.

Abstract: A high rate of chronic hepatitis B virus (HBV) infection in China is mainly caused by perinatal or early childhood transmission. Administration of universal HBV vaccination in infants has led to a dramatic decrease in HBV epidemiology, with hepatitis B surface antigen (HBsAg) prevalence declining from 9.75% in 1992 to 7.18% in 2006. The major HBV genotypes are B and C, with B being more prevalent in the southern part and C more prevalent in the northern part of China. A national survey carried out in 1992 showed that the hepatitis C virus (HCV) infection rate was 3.20% in general population in China. After implementation of mandatory HCV screening for blood transfusion and other precautions to prevent blood-borne disease since 1993, the new cases of HCV infection associated with blood or blood product has become very rare. Although the anti-HCV prevalence would be much higher in high-risk groups, a survey carried in 2006 showed that the anti-HCV prevalence rate was only 0.43% in general population. This sharp decline in HCV infection rate was mainly due to stringent administration and monitoring of blood donors and blood products, but may also be related to the remarkably improved specificity of anti-HCV test. The predominant HCV genotype in China is genotype 1b (60–70%), and the host interleukin-28b rs12979860 CC genotype is very frequent in Chinese population (over 80%).

Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn's disease.

Abstract: Background and Aims Dysbiosis is thought to be relevant to the etiology and pathogenesis of Crohn's disease (CD). In this study, we investigated the abundance of Faecalibacterium prausnitzii, as well as Bilophila wadsworthia, in the gut microbiota of Japanese CD patients. Methods Forty-seven CD patients and 20 healthy controls were enrolled. Abundance of F. prausnitzii in fecal samples was quantified by real-time polymerase chain reaction. The gut microbiota profile was evaluated by terminal restriction fragment length polymorphisms. Results The abundance of F. prausnitzii significantly decreased in CD patients compared with healthy subjects. B. wadsworthia was scarcely detected in the same samples. Among CD patients, the Crohn's Disease Activity Index, C-reactive protein levels, and erythrocyte sedimentation rate were significantly lower, and serum albumin levels were significantly higher in the high F. prausnitzii group compared with the low group. Terminal restriction fragment length polymorphisms analysis showed that fecal bacterial communities of CD patients differed from those of healthy individuals. The changes in simulated bacterial composition indicated that class Clostridia, including genus Faecalibacterium, was significantly less abundant in CD patients as compared with healthy individuals. The bacterial diversity measured by the Shannon Diversity Index was significantly reduced in CD patients compared with healthy individuals. Conclusion The decreased abundance of class Clostridia, including F. prausnitzii, may translate into a reduction of commensal bacteria-mediated, anti-inflammatory activities in the mucosa, which are relevant to the pathophysiology of CD. In contrast, the role of B. wadsworthia was suspected to be minimal.

Epidemiology of alcoholic and nonalcoholic fatty liver disease in China

Abstract: The prevalence of patients presenting with fatty liver disease (FLD) in China has approximately doubled over the past two decades. At present, FLD, which is typically diagnosed by imaging, is highly prevalent (≈ 27% urban population) in China and is mainly related to obesity and metabolic syndrome (MetS). However, the percentage of alcoholic liver disease (ALD) among patients with chronic liver diseases in clinic is increasing as well, and a synergetic effect exists between heavy alcohol drinking and obesity in ALD. Prevalence figures reveal regional variations, with a median prevalence of ALD and nonalcoholic FLD (NAFLD) of 4.5% and 15.0%, respectively. The prevalence of NAFLD in children is 2.1%, although the prevalence increases to 68.2% among obese children. With the increasing pandemic of obesity and MetS in the general population, China is likely to harbor an increasing reservoir of patients with FLD. The risk factors for FLD resemble to those of Caucasian counterparts, but the ethnic-specific definitions of obesity and MetS are more useful in assessment of Chinese people. Therefore, FLD/NAFLD has become a most common chronic liver disease in China. Public health interventions are needed to halt the worldwide trend of obesity and alcohol abuse to ameliorate liver injury and to improve metabolic health.

Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis

Abstract: Activation of innate immune systems including Toll-like receptor (TLR) signaling is a key in chronic liver disease. Recent studies suggest that gut microflora-derived bacterial products (i.e. lipopolysaccharide [LPS], bacterial DNA) and endogenous substances (i.e. high-mobility group protein B1 [HMGB1], free fatty acids) released from damaged cells activate hepatic TLRs that contribute to the development of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) and liver fibrosis. The crucial role of TLR4, a receptor for LPS, has been implicated in the development of ASH, NASH, liver fibrosis, and hepatocellular carcinoma. However, the role of other TLRs, such as TLR2 and TLR9 in chronic liver disease remains less clear. In this review, we will discuss the role of TLR2, 4, and 9 in Kupffer cells and hepatic stellate cells in the development of ASH, NASH, and hepatocarcinogenesis.

Non‐alcoholic steatohepatitis: Pathogenesis and novel therapeutic approaches

Abstract: Non-alcoholic fatty liver disease (NAFLD) refers to a disease spectrum, ranging from mere hepatic steatosis to hepatic necroinflammation (NASH, non-alcoholic steatohepatitis). NASH often leads to fibrosis, which can progress to cirrhosis with a high risk of liver failure and hepatocellular carcinoma. The course of NAFLD is highly variable, and only a minority of patients (2-3%) progress to end-stage liver disease. However, due to a dramatic increase of the risk factors for NAFLD, that is obesity and insulin resistance/type 2 diabetes, that affect 15-30% and 7-15% of subjects, in most industrialized countries, respectively, NAFLD has become the most frequent liver disease and is even considered a pace setter of the metabolic syndrome. Sedentary lifestyle, modern Western nutrition, and genetic predispositions have been identified as major causes of NAFLD. These lead to liver injury via insulin resistance and an excess of free fatty acids in hepatocytes, resulting in oxidant stress and lipotoxicity that promote the activation of intracellular stress kinases and apoptosis or necroapoptosis (NASH). The damaged hepatocytes directly trigger inflammation and fibrogenesis, but can also lead to the emergence of fibrogenic progenitor cells. Moreover, NASH is linked to inflammation in peripheral adipose tissues that involves mainly macrophages and humoral factors, such as adipokines and cytokines. The most efficient treatment is by weight loss and exercise, but (adjunctive) pharmacological strategies are urgently needed. Here, we highlight the aspects of NAFLD epidemiology and pathophysiology that are beginning to lead to novel pharmacological approaches to address this growing health-care challenge.

Diet and exercise in management of obesity and overweight

Abstract: According to World Health Organization, in 2010 there were over 1 billion overweight adults worldwide with 400 million adults who were obese. Obesity is a major risk factor for diabetes, cardiovascular disease, musculoskeletal disorders, obstructive sleep apnea, and cancers (prostate, colorectal, endometrial, and breast). Obese people may present to the gastroenterologists with gastroesophageal reflux, non-alcoholic fatty liver, and gallstones. It is important, therefore, to recognize and treat obesity. The main cause of obesity is an imbalance between calories consumed and calories expended, although in a small number of cases, genetics and diseases such as hypothyroidism, Cushing's disease, depression, and use of medications such as antidepressants and anticonvulsants are responsible for fat accumulation in the body. The main treatment for obesity is dieting, augmented by physical exercise and supported by cognitive behavioral therapy. Calorie-restriction strategies are one of the most common dietary plans. Low-calorie diet refers to a diet with a total dietary calorie intake of 800-1500, while very low-calorie diet has less than 800 calories daily. These dietary regimes need to be balanced in macronutrients, vitamins, and minerals. Fifty-five percent of the dietary calories should come from carbohydrates, 10% from proteins, and 30% from fats, of which 10% of total fat consist of saturated fats. After reaching the desired body weight, the amount of dietary calories consumed can be increased gradually to maintain a balance between calories consumed and calories expended. Regular physical exercise enhances the efficiency of diet through increase in the satiating efficiency of a fixed meal, and is useful for maintaining diet-induced weight loss. A meta-analysis by Franz found that by calorie restriction and exercise, weight loss of 5-8.5 kg was observed 6 months after intervention. After 48 months, a mean of 3-6 kg was maintained. In conclusion, there is evidence that obesity is preventable and treatable. Dieting and physical exercise can produce weight loss that can be maintained.

Alcoholic liver disease: Pathogenesis, management, and novel targets for therapy

Abstract: Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease (ALD). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD, which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL-22/STAT3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide (LPS), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD. We further discuss the findings of recent translational studies and potential therapeutic targets.

Asia–Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma

Abstract: Hilar cholangiocarcinoma (HCCA) is one of the most common types of hepatobiliary cancers reported in the world including Asia-Pacific region. Early HCCA may be completely asymptomatic. When significant hilar obstruction develops, the patient presents with jaundice, pale stools, dark urine, pruritus, abdominal pain, and sometimes fever. Because no single test can establish the definite diagnosis then, a combination of many investigations such as tumor markers, tissue acquisition, computed tomography scan, magnetic resonance imaging/magnetic resonance cholangiopancreatography, endoscopic ultrasonography/intraductal ultrasonography, and advanced cholangioscopy is required. Surgery is the only curative treatment. Unfortunately, the majority of HCCA has a poor prognosis due to their advanced stage on presentation. Although there is no survival advantage, inoperable HCCA managed by palliative drainage may benefit from symptomatic improvement. Currently, there are three techniques of biliary drainage which include endoscopic, percutaneous, and surgical approaches. For nonsurgical approaches, stent is the most preferred device and there are two types of stents i.e. plastic and metal. Type of stent and number of stent for HCCA biliary drainage are subjected to debate because the decision is made under many grounds i.e. volume of liver drainage, life expectancy, expertise of the facility, etc. Recently, radio-frequency ablation and photodynamic therapy are promising techniques that may extend drainage patency. Through a review in the literature and regional data, the Asia-Pacific Working Group for hepatobiliary cancers has developed statements to assist clinicians in diagnosing and managing of HCCA. After voting anonymously using modified Delphi method, all final statements were determined for the level of evidence quality and strength of recommendation.

Characteristics and diagnosis of NAFLD/NASH

Abstract: Non-alcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome. NAFLD has become an important public health issue because of its high prevalence. NAFLD consists of two clinicopathological entities: simple steatosis, which generally follows a benign non-progressive clinical course, and non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. The diagnosis of NAFLD is based on the following three criteria: non-alcoholic, detection of steatosis either by imaging or by histology, and appropriate exclusion of other liver diseases. Alcoholic liver disease can occur when daily alcohol consumption exceeds 20 g in women or 30 g in men. Thus, non-alcoholic indicates lower levels of these alcohol consumptions. However, there is still no clear consensus regarding the threshold alcohol consumption for defining non-alcoholic liver disease. Then, there is the strong recommendation for a change in the nomenclature, such as use of the term metabolic fatty liver and metabolic steatohepatitis. NASH has emerged as a clinicopathological entity, and even now, a liver biopsy remains the gold standard for making a definitive diagnosis. However, liver biopsy has several drawbacks. In general practice, NAFLD is a convenient-to-use term for the diagnosis and management of these patients, and serum biomarkers that indicate the severity of fibrosis serve as clinically useful tools for the identification of NAFLD in patients with bridging fibrosis or cirrhosis. In the future, improved understanding of the pathogenesis of NASH and new technologies may contribute to the diagnostic process and provide reliable, non-invasive alternatives to liver biopsy.

Long‐term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis

Abstract: Background and Aim Cirrhotic patients are predisposed to intestinal bacterial overgrowth with translocation of bacterial products which may deteriorate liver hemodynamics. Having shown that short-term administration of rifaximin improves liver hemodynamics in decompensated cirrhosis, we conducted this study to investigate the effect of intestinal decontamination with rifaximin on the long-term prognosis of patients with alcohol-related decompensated cirrhosis (Child-Pugh > 7) and ascites. Methods Patients who had received rifaximin and showed improved liver hemodynamics were enrolled in the current study and continued to receive rifaximin (1200 mg/day). Each patient was matched by age, sex, and Child-Pugh grade to two controls and followed up for up to 5 years, death or liver transplantation. Survival and risk of developing portal hypertension-related complications were compared between rifaximin group and controls. Results Twenty three patients fulfilled the inclusion criteria and matched with 46 controls. Patients who received rifaximin had a significant lower risk of developing variceal bleeding (35% vs 59.5%, P = 0.011), hepatic encephalopathy (31.5% vs 47%, P = 0.034), spontaneous bacterial peritonitis (4.5% vs 46%, P = 0.027), and hepatorenal syndrome (4.5% vs 51%, P = 0.037) than controls. Five-year cumulative probability of survival was significantly higher in patients receiving rifaximin than in controls (61% vs 13.5%, P = 0.012). In the multivariate analysis, rifaximin administration was independently associated with lower risk of developing variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and higher survival. Conclusions In patients with alcohol-related decompensated cirrhosis, long-term rifaximin administration is associated with reduced risk of developing complications of portal hypertension and improved survival.

Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis.

Abstract: Background and Aim Ursodeoxycholic acid (UDCA) treatment is an effective medical therapy for patients with primary biliary cirrhosis (PBC); however, 40% of PBC patients show an incomplete response to the UDCA therapy. This study aimed to investigate the safety and efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusion in PBC patients with an incomplete response to UDCA. Methods We conducted a single-arm trial that included seven PBC patients with a suboptimal response to UDCA treatment. UC-MSCs were first cultured, and then 0.5 × 106 cells/kg body weights were infused through a peripheral vein. UC-MSCs were given three times at 4-week intervals, and patients were followed up for 48 weeks. Primary outcomes were to evaluate the safety and feasibility of UC-MSC treatment, and secondary outcomes were to evaluate liver functions and patient's quality of life. Results No obvious side-effects were found in the patients treated with UC-MSCs. Symptoms such as fatigue and pruritus were obviously alleviated in most patients after UC-MSC treatment. There was a significant decrease in serum alkaline phosphatase and γ-glutamyltransferase levels at the end of the follow-up period as compared with baseline. No significant changes were observed in serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, prothrombin time activity, international normalized ratio, or immunoglobulin M levels. The Mayo risk score, a prognostic index, was also stable during the treatment and follow-up period. Conclusions UC-MSC transfusion is feasible and well tolerated in patients with PBC who respond only partially to UDCA treatment, thus representing a novel therapeutic approach for patients in this subgroup. A larger, randomized controlled cohort study is warranted to confirm the clinical efficacy of UC-MSC transfusion.

Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis.

Abstract: Background and Aim Proton pump inhibitors (PPI) and H2-receptor antagonists (H2RA) are frequently prescribed in hospitalized patients with cirrhosis. There are conflicting reports regarding the role of acid-suppressive therapy in predisposing hospitalized patients with cirrhosis to spontaneous bacterial peritonitis (SBP). The aim of this meta-analysis was to evaluate the association between acid-suppressive therapy and the risk of SBP in hospitalized patients with cirrhosis. Methods We searched MEDLINE and four other databases for subject headings and text words related to SBP and acid-suppressive therapy. All observational studies that investigated the risk of SBP associated with PPI/H2RA therapy and utilized SBP as an endpoint were considered eligible. Data from the identified studies were combined by means of a random-effects model and odds ratios (ORs) were calculated. Results Eight studies (n = 3815 patients) met inclusion criteria. The risk of hospitalized cirrhotic patients developing SBP increased when using acid-suppressive therapy. The risk was greater with PPI therapy (n = 3815; OR 3.15, 95% confidence interval 2.09–4.74) as compared to those on H2RA therapy (n = 562; OR 1.71, 95% confidence interval 0.97–3.01). Conclusions Pharmacologic acid suppression was associated with a greater risk of SBP in hospitalized patients with cirrhosis. Cirrhotic patients receiving a PPI have approximately three times the risk of developing SBP compared with those not receiving this medication. Prospective studies may help clarify this relationship and shed light on the mechanism(s) by which acid-suppressive therapy increases the risk of SBP in hospitalized patients with cirrhosis.

Forkhead box class O transcription factors in liver function and disease

Abstract: The forkhead box transcription factor class O (FOXO) family represents a group of transcription factors that is required for a number of stress-related transcriptional programs including antioxidant response, gluconeogenesis, cell cycle control, apoptosis, and autophagy. The liver utilizes several FOXO-dependent pathways to adapt to its routine cycles of feeding and fasting and to respond to the stresses induced by disease. FOXO1 is a direct transcriptional regulator of gluconeogenesis, reciprocally regulated by insulin, and has profound effects on hepatic lipid metabolism. FOXO3 is required for antioxidant responses and autophagy and is altered in hepatitis C infection and fatty liver. Emerging evidence suggests dysregulation of FOXO3 in some hepatocellular carcinomas. FOXOs are notable for the extensive number of functionally significant posttranslational modifications that they undergo. Recent advances in our understanding how FOXOs are regulated are providing a more detailed picture of how specific combinations of posttranslational modifications alter both nuclear translocation as well as transcriptional specificity under different conditions. This review summarizes emerging knowledge of FOXO function in the liver, FOXO changes in liver disease, and the posttranslational modifications responsible for these effects.

Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong Province, China: a prospective population-based study.

Abstract: Background and Aims The incidence of inflammatory bowel disease (IBD) is increasing in China with urbanization and socioeconomic development. There is however a lack of prospective, population-based epidemiology study on IBD in China. The aim of the study is to define the incidence and clinical characteristics of IBD in a developed region of Guangdong Province in China. Methods A prospective, population-based incidence study was conducted from July 2011 to June 2012 in Zhongshan, Guangdong, China. All newly diagnosed IBD cases in Zhongshan were included. Results In total, 48 new cases of IBD (17 Crohn's disease [CD]; 31 ulcerative colitis [UC]) were identified over a 1-year period from July 2011. Age-standardized incidence rates for IBD, UC, and CD were 3.14, 2.05, and 1.09 per 100 000 persons, respectively. The median age of UC was 38, and that of CD was 25. Terminal ileum involvement only (L1), isolated colonic disease (L2), and ileocolonic disease (L3) were reported in 24%, 6%, and 71% of patients with CD, respectively. Twenty-four percent of patients had coexisting upper gastrointestinal disease (L4). Inflammatory (B1), stricturing (B2), and penetrating (B3) behavior were seen in 65%, 24%, and 12% of CD patients, respectively. Fifty-nine percent of CD and 26% of UC patients had extra-intestinal manifestations. Conclusions This is the first prospective, population-based IBD epidemiological study in a developed region of China. The incidence of IBD is similar to that in Japan and Hong Kong but lower than that in South Korea and Western countries.

Sterile inflammation in hepatic ischemia/reperfusion injury: Present concepts and potential therapeutics

Abstract: Ischemia and reperfusion (I/R) injury is an often unavoidable consequence of major liver surgery and is characterized by a sterile inflammatory response that jeopardizes the viability of the organ. The inflammatory response results from acute oxidative and nitrosative stress and consequent hepatocellular death during the early reperfusion phase, which causes the release of endogenous self-antigens known as damage-associated molecular patterns (DAMPs). DAMPs, in turn, are indirectly responsible for a second wave of reactive oxygen and nitrogen species (ROS and RNS) production by driving the chemoattraction of various leukocyte subsets that exacerbate oxidative liver damage during the later stages of reperfusion. In this review, the molecular mechanisms underlying hepatic I/R injury are outlined, with emphasis on the interplay between ROS/RNS, DAMPs, and the cell types that either produce ROS/RNS and DAMPs or respond to them. This theoretical background is subsequently used to explain why current interventions for hepatic I/R injury have not been very successful. Moreover, novel therapeutic modalities are addressed, including MitoSNO and nilotinib, and metalloporphyrins on the basis of the updated paradigm of hepatic I/R injury.

Role of diet and nutritional management in non-alcoholic fatty liver disease.

Abstract: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis, which causes an increased risk of cirrhosis, type 2 diabetes, and cardiovascular complications. With the worldwide growing incidence of obesity, sedentary lifestyle, and unhealthy dietary pattern, NAFLD has currently been recognized as a major health burden. Dietary patterns and nutrients are the important contributors to the development, progression, and treatment of NAFLD and associated metabolic comorbidities. Generally, hypercaloric diet, especially rich in trans/saturated fat and cholesterol, and fructose-sweetened beverages seem to increase visceral adiposity and stimulate hepatic lipid accumulation and progression into non-alcoholic steatohepatitis, whereas reducing caloric intake, increasing soy protein and whey consumption, and supplement of monounsaturated fatty acids, omega-3 fatty acids, and probiotics have preventive and therapeutic effects. In addition, choline, fiber, coffee, green tea, and light alcohol drinking might be protective factors for NAFLD. Based on available data, at least 3-5% of weight loss, achieved by hypocaloric diet alone or in conjunction with exercise and behavioral modification, generally reduces hepatic steatosis, and up to 10% weight loss may be needed to improve hepatic necroinflammation. A sustained adherence to diet rather than the actual diet type is a major predictor of successful weight loss. Moreover, a healthy diet has benefits beyond weight reduction on NAFLD patients whether obese or of normal weight. Therefore, nutrition serves as a major route of prevention and treatment of NAFLD, and patients with NAFLD should have an individualized diet recommendation.

Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma.

Abstract: Background and Aim Changes in microRNA (miRNA) expression have been detected in a broad range of biological processes including cancer. Here we determined the role of miRNA dysregulation in hepatocellular carcinoma (HCC). Methods We investigated the expression of nine cancer-related miRNAs in HCC. Among these, miR-224 was the most significantly uprgulated in HCC tissues (n = 18), compared with normal (n = 9) and HCC adjacent non-tumorous liver tissues (n = 18). After leading-in currently reported gene targets from Sanger miRBase, we characterized the expression profiles of target genes of miR-224 using cDNA microarray. The altered expression was subsequently validated by real-time polymerase chain reaction and Western blot. The phenotypic changes by miR-224 expression were identified by cell viability, apoptosis, and in vitro scratch assays. Results The microarray analysis and miRNA target prediction analysis allowed the identification of significant changes in 68 putative gene targets after overexpression of miR-224. The high-ranking genes CDC42, CDH1, PAK2, BCL-2, and MAPK1 were confirmed as important targets of miR-224 and involvement in hepatocarcinogenesis. Overexpression of miR-224 significantly in Hek293 and Huh7 cells altered the expression levels of CDC42, CDH1, PAK2, and BCL-2 at both mRNA and protein levels. Similar changes in the expression of the same genes were also observed in HCC tissues. Via functional analyses, cell proliferation, migration and anti-apoptosis were proved to be affected by miR-224 expression. Conclusion The results suggest that miR-224 plays a role in cell proliferation, migration, invasion, and anti-apoptosis in HCC by directly binding to its gene targets, implicating this RNA in HCC development and progression.

Non-alcoholic fatty liver disease as an independent manifestation of the metabolic syndrome: results of a US national survey in three ethnic groups.

Abstract: Background and Aim The metabolic syndrome (MetS) and each of its components are strongly associated with non-alcoholic fatty liver disease (NAFLD). This has led many investigators to suggest that NAFLD is an independent component of the MetS. We formally tested this hypothesis using confirmatory factor analysis, which allows comparison of different models, with or without including NAFLD as a component of the MetS. Methods We analyzed data from 3846 subjects of the Third National Health and Nutrition Examination Survey (1988–1994). NAFLD was defined by increased liver fat measured by ultrasonography. Results MetS by Adult Treatment Panel III criteria was present in 20.5%, and 30.2% had NAFLD, defined as mild, moderate, or severe ultrasonographic steatosis. Using confirmatory factor analysis, a basic model representing the MetS using its currently accepted components (glucose, waist, triglyceride/high-density lipoprotein ratio, and mean arterial pressure) showed excellent goodness-of-fit statistics. Addition of NAFLD to the model as a fifth independent variable decreased model fit, suggesting that NAFLD is not an additional independent component of the MetS. Analysis by ethnicity showed that addition of NAFLD decreased model fit in Whites but resulted in minor improvements in non-Hispanic Blacks and Mexican Americans. Conclusions The MetS is strongly associated with NAFLD. However, we found no evidence that NAFLD is an independent component or manifestation of the MetS. Interestingly, ethnic differences might be important in this relationship and require further study.

Non-alcoholic fatty liver disease contributes to hepatocarcinogenesis in non-cirrhotic liver: a clinical and pathological study.

Abstract: Background and Aim Hepatocellular carcinoma (HCC) is a major complication of cirrhosis and has been increasing in incidence in recent years. Fatty liver disease is an increasingly common cause of chronic liver disease, and there have been several case reports of HCC in patients with non-cirrhotic fatty liver disease. However, there is limited data from systematic studies with histological confirmation of the presence of both the HCC and the non-cirrhotic fatty liver disease. Methods We studied the occurrence of fatty liver disease and the associated demographic, clinical, and pathological characteristics of a large cohort of patients with HCC in non-cirrhotic livers. Patients with intrahepatic cholangiocarcinoma (CC) occurring in non-cirrhotic livers and diagnosed during the same time period were used as the comparison group. Results Significant steatosis in the nontumor liver had a statistically significant association with HCC, being present in 54% (85/157) of HCC compared with 27% (32/120) of CC (P < 0.0001). Steatohepatitis was present in 15% (24/157) of HCC and 1% (2/120) of CC (P = 0.0014). Furthermore, HCC was more prevalent in cases with higher grades of steatosis. In addition, the recently described intratumoral steatohepatitic morphology of HCC (SH-HCC) was also associated with significant steatosis in nontumor liver, with significant steatosis being present in 89% with SH-HCC compared with 50% without SH-HCC (P = 0.0162). Finally, SH-HCC was increasingly more prevalent in patients with higher grades of nontumor steatosis. Conclusions Taken together, these findings suggest a strong association between fatty liver disease and HCC in non-cirrhotic livers.

Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment.

Abstract: Hepatopulmonary syndrome (HPS) is an important cause of dyspnea and hypoxia in the setting of liver disease, occurring in 10–30% of patients with cirrhosis. It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation-perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin-1 and nitric oxide (NO). In experimental HPS, liver injury stimulates release of endothelin-1 and results in increased expression of ETB receptors on pulmonary endothelial cells, leading to upregulation of endothelial NO synthase (eNOS) and subsequent increased production of NO, which causes vasodilation. In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases NO production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. Despite these insights into the pathogenesis of experimental HPS, there is no established medical therapy, and liver transplantation remains the main treatment for symptomatic HPS, although selected patients may benefit from other surgical or radiological interventions. In this review, we focus on recent advances in our understanding of the pathophysiology of HPS, and discuss current approaches to the investigation and treatment of this condition.

Severity of non‐alcoholic steatohepatitis is associated with substitution of adipose tissue in skeletal muscle

Abstract: Background and Aims The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is now focusing on its organ cross-talk with not only adipose tissue but also systemic skeletal muscle. Cross-sectional and longitudinal studies were conducted to determine the role of intramuscular adipose tissue content (IMAC) measured by computed tomography on the severity of NAFLD/non-alcoholic steatohepatitis (NASH). Methods Two hundred eight Japanese patients with NAFLD/NASH diagnosed by liver biopsy were enrolled into a cross-sectional study. Twenty-one patients were enrolled in a longitudinal study and received a programmed diet and exercise intervention, in some cases the combination of pharmacotherapy. We measured IMAC in the multifidus muscle and biochemical parameters, and conducted liver histology to assess NAFLD/NASH status. Results Histopathological stage in terms of simple steatosis and Brunt's classification was significantly correlated with IMAC (P < 0.01). Multivariate logistic regression analysis indicated that risk factors associated with the severity of NASH were IMAC and aging (IMAC: odds ratio = 2.444, P < 0.05; Age: odds ratio = 2.355, P < 0.05). The interventions improved histopathological changes in 11 patients with NASH as well as IMAC. Conclusion These results suggest that skeletal muscle fat accumulation may have been linked to the pathogenesis and severity of NASH.

Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts.

Abstract: Background and Aim The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts.

Colorectal endoscopic submucosal dissection: Is it suitable in western countries?

Abstract: Endoscopic submucosal dissection (ESD) represents a significant advance in therapeutic endoscopy with the major advantage being the ability to achieve a higher en bloc resection rate for early stage lesions. Western endoscopists infrequently perform colorectal ESD (CR-ESD) because of the greater technical difficulty involved, longer procedure times, and increased risk of perforation. Specialized training and sufficient clinical experience are necessary to successfully perform ESDs, but a systematic education and training program has still not been established in Japan or elsewhere in the world. Experts generally acknowledge that the stomach is the first organ in which endoscopists should begin performing ESDs. The incidence and detection rates for early stage gastric cancer are significantly higher in Japan than in western countries, so Japanese endoscopists have a greater opportunity to perform gastric ESDs than their western counterparts. It is logical to ask, therefore, whether CR-ESD can be effectively applied in western countries. Based on a review of the relevant literature and our practical perspective, we have focused on the progress made in performing CR-ESD, its indications, training methods, and learning curve. Use of animal gastric and colon models is strongly recommended along with accumulating the necessary experience from the rectum to the colon on a step-by-step basis. It is reasonable to assume that an increasing number of CR-ESDs will be performed by western endoscopists in the foreseeable future given the continuing development of new techniques, and the refinement of instruments and other technologically advanced devices together with the creation of even more effective submucosal injection agents.

Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: A review

Abstract: The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)-associated lymphomas are typically B-cell LD, while T-cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four- to sixfold and the absolute risk varies between 1 in 4000-5000 for those aged 20-29 to 1 in 300-400 in those over 70. It is difficult to quantify the risk of anti- tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post-transplant-like LD in those with latent epstein-barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti-TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti-TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.

Risk stratification for hepatitis B virus related hepatocellular carcinoma

Abstract: Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, especially in the Asia-Pacific region. Several hepatitis B viral factors predictive of clinical outcomes in HBV carriers have been identified. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV (REVEAL-HBV) study from Taiwan illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time. In this community-based cohort study, male gender, older age, high serum alanine aminotransferase level, positive hepatitis B e antigen, higher HBV-DNA level, HBV genotype C infection, and core promoter mutation are independently associated with a higher risk of HCC. Another large hospital-based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers cohort of Taiwanese patients further validated the findings of REVEAL-HBV. The risk of HCC started to increase when HBV-DNA level was higher than 2000 IU/mL. Both HBV-DNA and HBsAg levels were shown to be associated with HCC development. While HBV-DNA level had better predictive accuracy than HBsAg level, when investigating the overall cohort in patients with HBV-DNA level < 2000 IU/mL, HBsAg level ≥ 1000 IU/mL was identified as a new independent risk factor for HCC. With the results from REVEAL-HBV, a risk calculation for predicting HCC in non-cirrhotic patients has been developed and validated by independent cohorts (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B).Taken together, ample evidence indicates that HBsAg level can complement HBV-DNA level in predicting HCC development, especially in HBV carriers with low viral load. In conclusion, HBV treatment guidelines should include the risk stratification of HCC to individualize the management of HBV carriers with different levels of HCC risk.

Coinfection with hepatitis B and D: Epidemiology, prevalence and disease in patients in Northern California

Abstract: Background and Aims: With no report on the overall prevalence and ramifications of hepatitis Delta virus (HDV) infection in the United States for more than two decades, the characteristics of chronic hepatitis B virus (CHB) patients coinfected with HDV, including clinical presentation, rate of hepatitis C virus tri-infection, and HDV viral load, were assessed. Methods: At California Pacific Medical Center, a retrospective chart review was con- ducted on all CHB patients. Results: Of 1191 CHB patients, 499 had been tested for HDV, with 42 (8%) determined to be coinfected; half of these were also hepatitis C virus-infected. Cirrhosis was present in 73% of the coinfected, 80% of the tri-infected, but only 22% of the monoinfected. Twenty-nine patients (69%) were Caucasian non-Hispanic; 10 (24%) were Asians and Pacific Islanders. Of 39 patients for whom HBV-DNA quantification at time of HDV presentation was available, 22 (56%) had undetectable levels; four (10%) had levels > 100 000 IU/mL. Conclusions: HDV affects individuals of all ages and various ethnic groups. Although HBV viral loads are lower, rates of cirrhosis are higher in coinfected patients and higher still in the tri-infected. Our data support revising screening guidelines to advocate for all patients with HBV to be screened for HDV in order to both give the individual patient important information related to the possible need for treatment and to support the public health goal of reducing transmission by educating HDV-negative patients about the need for protection against superinfection and HDV-infected patients about the need to protect against transmission to others.

Controlled attenuation parameter for non-invasive assessment of hepatic steatosis: does etiology affect performance?

Abstract: Background Hepatic steatosis is an important parameter to assess in chronic liver disease patients. The controlled attenuation parameter (CAP) assesses liver steatosis using transient elastography. Aim To determine the accuracy of CAP for evaluation of hepatic steatosis in chronic hepatitis B virus (CHBV)-infected, chronic hepatitis C virus (CHCV)-infected, and non-alcoholic fatty liver disease (NAFLD) patients and to determine the influence of etiology on the diagnostic accuracy of CAP. Methods One hundred forty-six CHBV patients, 108 CHCV-infected patients and 63 patients with NAFLD, who underwent both liver biopsy and successful CAP measurements within the study period, were assessed. Area under the receiver operating characteristics was used to evaluate performance of CAP for diagnosing steatosis compared with biopsy. Results Multivariate analysis found that CAP correlated with body mass index (odds ratio, 95% confidence interval = 4.09 [1.2–6.8] for CHBV; 4.7 [1.1–8.4] for CHCV, and 16.2 [9.1–24.5] for NAFLD patients respectively) and hepatic steatosis score on biopsy (odds ratio, 95% confidence interval = 30.7 [19.2–42.2] for CHBV; 24.2 [11.5–37.3] for CHCV, and 21.8 [10.1–45.0] for NAFLD patients respectively). Area under the receiver operating characteristics for CAP was 0.683 (0.601–0.757) for steatosis (S) ≥ 6%, 0.793 (0.718–0.856) for S > 33%, and 0.841 (0.771–0.896) for S > 66% respectively for CHBV-infected patients. There was no difference in accuracy of CAP for assessing liver fat among CHBV, CHCV, and NAFLD patients. Conclusions CAP is a novel, non-invasive tool that can detect and quantify steatosis accurately among CHBV, CHCV, and NAFLD patients, the accuracy being similar for all the three groups of patients.

Stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma

Abstract: AbstactBackground and Aims To compare the tumor control and safety of stereotactic body radiation therapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) for small, solitary, and hypervascular hepatocellular carcinoma (HCC) with TACE alone. Methods Three hundred and sixty-five HCC patients who had solitary, ≤ 3 cm, and hypervascular nodule were treated with TACE. Among them, 30 patients followed by SBRT (SBRT group) and 38 patients without additional therapy and previous HCC treatment (control group) were enrolled in this retrospective cohort study. Local tumor progression, complication, and disease-free survival were compared between these groups. Results There was no difference in clinical background between these groups. Complete response to therapy was noted in 29 (96.3%) patients of the SBRT group, and in only one (3.3%) patient of the TACE group (P < 0.001). None of the patients developed acute hematologic toxicity of more than Common Terminology Criteria for Adverse Events Grade 3 during and after the treatment. Furthermore, none of the SBRT group developed radiation-induced liver damage. Disease-free survival of the 12 patients without previous HCC treatments in SBRT group was significantly superior to that in control group (15.7 months vs 4.2 months; P = 0.029). Conclusion The results indicated that SBRT combined with TACE is a safe and effective modality for locoregional treatment of small solitary primary HCC, and could be potentially a suitable option.

Functional gastrointestinal disorders in adolescents and quality of school life

Abstract: Background and Aim The prevalence of functional gastrointestinal disorders (FGID) in adolescents and their relationship to quality of school life (QOSL) are not fully understood. This study investigated the relationship between FGID and QOSL. Methods Adolescents (10–17 years) were recruited from 40 schools. FGID diagnoses were based on the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III version (QPGS-RIII). QOSL was evaluated by a questionnaire and calculated as the QOSL score. Results Five hundred and fifty-two of the 3976 students (13.9%) met the FGID criteria for one or more diagnoses according to the QPGS-RIII: 12.3% met the criteria for one, 1.5% for two or more. Irritable bowel syndrome (IBS) was the most common diagnosis (5.9%) followed by functional abdominal pain (3.1%). The prevalence of FGID was significantly higher in the female students in comparison to male students (P < 0.01). The prevalence of FGID was 9.5% in elementary school, 15.4% in junior high school, 26.0% in high school students, respectively. The prevalence of FGID was significantly increased with age (P < 0.01). The QOSL score of the patients with FGID was 10.9 ± 4.5 and that without FGID was 8.2 ± 2.8, respectively. The QOSL score of the patients with FGID was significantly worse than those without FGID (P < 0.01). The QOSL scores with IBS, aerophagia, and cyclic vomiting syndrome were significantly worse among the FGID (P < 0.01). Conclusions The prevalence of FGID in adolescents was relatively high. The presences of FGID worsen the QOSL score. Medical intervention and/or counseling are needed for such students to improve the QOSL.