Showing papers in "Journal of Gastroenterology and Hepatology in 2012"

Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.

Abstract: Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P < 0.05). UC-MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease scores. UC-MSC transfusion is clinically safe and could improve liver function and reduce ascites in patients with decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

Inflammatory bowel disease in Asia: A systematic review

Abstract: The incidence and prevalence of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are lower in Asia than in the West. However, across Asia the incidence and prevalence of IBD has increased rapidly over the last two to four decades. These changes may relate to increased contact with the West, westernization of diet, increasing antibiotics use, improved hygiene, vaccinations, or changes in the gut microbiota. Genetic factors also differ between Asians and the Caucasians. In Asia, UC is more prevalent than CD, although CD incidence is rapidly increasing in certain areas. There is a male predominance of CD in Asia, but a trend towards equal sex distribution for UC. IBD is diagnosed at a slightly older age than in the West, and there is rarely a second incidence peak as in the West. A positive family history is much less common than in the West, as are extra-intestinal disease manifestations. There are clear ethnic differences in incidence within countries in Asia, and an increased incidence in IBD in migrants from Asia to the West. Research in Asia, an area of rapidly changing IBD epidemiology, may lead to the discovery of critical etiologic factors that lead to the development of IBD.

Molecular pathways in colorectal cancer

Abstract: Colorectal cancer (CRC) is the second most common newly diagnosed cancer and accounts for the second highest number of cancer related deaths in Australia, the third worldwide and of increasing importance in Asia. It arises through cumulative effects of inherited genetic predispositions and environmental factors. Genomic instability is an integral part in the transformation of normal colonic or rectal mucosa into carcinoma. Three molecular pathways have been identified: these are the chromosomal instability (CIN), the microsatellite instability (MSI), and the CpG Island Methylator Phenotype (CIMP) pathways. These pathways are not mutually exclusive, with some tumors exhibiting features of multiple pathways. Germline mutations are responsible for hereditary CRC syndromes (accounting for less than 5% of all CRC) while a stepwise accumulation of genetic and epigenetic alterations results in sporadic CRC. This review aims to discuss the genetic basis of hereditary CRC and the different pathways involved in the process of colorectal carcinogenesis.

What's new in liver fibrosis? The origin of myofibroblasts in liver fibrosis

Abstract: Chronic liver injury of many etiologies produces liver fibrosis and may eventually lead to the formation of cirrhosis. Fibrosis is part of a dynamic process associated with the continuous deposition and resorption of extracellular matrix, mainly fibrillar collagen. Studies of fibrogenesis conducted in many organs including the liver demonstrate that the primary source of the extracellular matrix in fibrosis is the myofibroblast. Hepatic myofibroblasts are not present in the normal liver but transdifferentiate from heterogeneous cell populations in response to a variety of fibrogenic stimuli. Debate still exists regarding the origin of hepatic myofibroblasts. It is considered that hepatic stellate cells and portal fibroblasts have fibrogenic potential and are the major origin of hepatic myofibroblasts. Depending on the primary site of injury the fibrosis may be present in the hepatic parenchyma as seen in chronic hepatitis or may be restricted to the portal areas as in most biliary diseases. It is suggested that hepatic injury of different etiology triggers the transdifferentiation to myofibroblasts from distinct cell populations. Here we discuss the origin and fate of myofibroblast in liver fibrosis.

Clinical outcomes of endoscopic submucosal dissection and endoscopic mucosal resection for laterally spreading tumors larger than 20 mm.

Abstract: Background and Aims: Colorectal laterally spreading tumors (LST) > 20 mm are usually treated by endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR). Endoscopic piecemeal mucosal resection (EPMR) is sometimes required. The aim of our study was to compare the outcomes of ESD and EMR, including EPMR, for such LST. Methods: Atotal of 269 consecutive patients with a colorectal LST > 20 mm were treated endoscopically at our hospital from April 2006 to December 2009. We retrospectively evaluated the complications and local recurrence rates associated with ESD, hybrid ESD (ESD with EMR), EMR, and EPMR. Results: ESD and EMR were performed successfully for 89 and 178 LST, respectively: 61 by ESD; 28 by hybrid ESD; 70 by EMR; and 108 by EPMR. Between-group differ- ences in perforation rates were not significant. Local recurrence rates in cases with cura- tive resection were as follows: 0% (0/56) in ESD; 0% (0/27) in hybrid ESD; 1.4% (1/69) in EMR; and 12.1% (13/107) in EPMR; that is, significantly higher in EPMR. No metastasis was seen at follow up. The recurrence rate for EPMR yielding three pieces was significantly high (P < 0.001). All 14 local recurrent lesions were adenomas that were cured endoscopically. Conclusions: As for safety, ESD/hybrid ESD is equivalent to EMR/EPMR. ESD/hybrid ESD is a feasible technique for en bloc resection and showed no local recurrence.Although local recurrences associated with EMR/EPMR were seen, which were conducted based on our indication criteria, all local recurrences could obtain complete cure by additional endoscopic treatment.

Late evening snack: Exploiting a period of anabolic opportunity in cirrhosis

Abstract: Background and Aim: Cirrhosis is a state of accelerated starvation with impaired protein synthesis. Increased rate of gluconeogenesis and alterations in skeletal muscle signaling pathways result in anabolic resistance and consequent loss of muscle mass or sarcopenia in cirrhosis. Late evening snack (LES) is an intervention to reduce the postabsorptive (fasting) phase with the potential to improve substrate utilization and reverse sarcopenia. Published reports were evaluated to examine the effect of LES on regulation of substrate utilization (short-term studies) and nutritional outcomes (long-term studies). Methods: PubMed, EMBASE, Google scholar and OVID databases were searched. All studies published on LES in cirrhosis were included. Studies that included few (n < 3) subjects and patients with hepatocellular carcinoma were excluded. Results: Late evening snack decreased lipid oxidation and improved nitrogen balance, irrespective of the composition or type of formulation used. Daytime isocaloric isonitrogenous snacks did not have the metabolic or clinical benefit of LES. LES decreased skeletal muscle proteolysis. No studies have examined its effect on muscle protein synthesis. There was inconsistent translation into an increase in lean body or skeletal muscle mass. Improved quality of life occurs but decreased mortality or need for transplantation has not been reported. The optimal composition of LES has not been defined, but based on mechanistic considerations, a branched chain supplemented LES holds most promise. Conclusions: Late evening snack holds the most promise as an intervention to reverse anabolic resistance and sarcopenia of cirrhosis with improved quality of life in patients with cirrhosis. Long term benefit and improved survival need critical evaluation.

Prevalence and risk factors for non-alcoholic fatty liver disease in Asian people who are not obese

Abstract: Fatty liver (hepatic steatosis) is prevalent in industrialized countries. It is typically linked to obesity, central obesity and the presence of metabolic syndrome. With the introduction of a Westernized lifestyle and the increasing frequency of obesity in the Asia-Pacific region, the prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing over the past two decades. The risk factors are similar to those in other ethnic populations; but it is important to adopt the regional (ethnic-specific) anthropometric criteria to define overweight, obesity (including central obesity) and metabolic syndrome. To be noted, even using strict ethnic-specific criteria, a high percentage (15-21%) of Asia-Pacific NAFLD subjects in some series have been found to be non-obese, i.e. to have a normal body mass index (BMI) (17.5-22.4 kg/m(2)) or to be overweight (BMI 22.5-24.9 kg/m(2)). Differential distribution of visceral adipose tissue, recent increase in body weight, intake of high cholesterol diet and genetic background are factors likely associated with the development of NAFLD in these non-obese (but often overweight) Asia-Pacific subjects. Furthermore, insulin resistance may be the underlying key mechanism. In addition, since NAFLD may be the hepatic manifestation of metabolic syndrome, the presence of NAFLD is a predictor of future type 2 diabetes, metabolic syndrome and cardiovascular disease. Therefore, interventions at the public health level are indicated to halt the trend of overweight as well as obesity in Asia-Pacific region, particularly among those with relevant family history. Since the pathophysiology of NAFLD is closely related to metabolic derangement, lifestyle modification remains the cornerstone of management.

Oxidative stress in inflammation-based gastrointestinal tract diseases: challenges and opportunities.

Abstract: Oxygen free radicals in excessively high amounts are all very reactive chemically and can impose a detrimental influence on living organisms by provoking “oxidative stress” that can damage major cellular constituents. The latter includes the cell membrane, cytoplasmic proteins, and nuclear DNA. Conversely, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) when present in low amounts play an important role as regulatory mediators in signaling processes, through which, paradoxically, many ROS-mediated responses can protect the cells against oxidative stress by induction of “redox homeostasis.” Therefore, diseases associated with free radical overproduction are provoked by “blazed ROS productions” far beyond the host's capacity to quench. Free radicals have been implicated in the pathogenesis of diverse gastrointestinal (GI) diseases including gastroesophageal reflux disease (GERD), gastritis, enteritis, colitis and associated cancers as well as pancreatitis and liver cirrhosis. This article provides an overview of the role of oxidative stress in inflammation-based GI tract diseases, including reflux esophagitis, Helicobacter pylori-associated gastritis, non-steroidal anti-inflammatory drug-induced enteritis, ulcerative colitis, and associated colorectal cancer. The challenging issue that ROS can contribute to diverse gastrointestinal dysfunction, or manifest dual roles in cancer promotion or cancer suppression will also be discussed for the opportunity to enhance understanding of inflammation-based GI diseases.

Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease.

Abstract: The activation of innate immunity by various factors (e.g. lipopolysaccharide and complements) plays an important role in initiating and promoting alcoholic liver injury via the stimulation of Kupffer cells to induce oxidative stress and to produce pro-inflammatory cytokines (e.g. tumor necrosis factor [TNF]-α) that cause hepatocellular damage. Accumulating evidence suggests that the activation of innate immunity also stimulates Kupffer cells to produce the hepatoprotective cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine IL-10 during alcoholic liver injury. IL-6 protects against alcoholic liver injury via the activation of signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via the activation of STAT3 in Kupffer cells/macrophages and the subsequent inhibition of liver inflammation. Recent studies have suggested that IL-10 may play a dual role in controlling ethanol-induced steatosis and liver injury via the inhibition of the pro-inflammatory cytokine TNF-α, thereby ameliorating alcoholic liver injury, or via the inhibition of the hepatoprotective cytokine IL-6, thereby potentiating alcoholic liver injury. IL-22 is another important hepatoprotective cytokine that protects against acute and chronic alcoholic liver injury by binding to a receptor complex composed of IL-10R2 and IL-22R chains on the surfaces of hepatocytes. Finally, IL-22 treatment is a potential therapeutic option for treating severe forms of alcoholic liver disease because of its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects, as well as the potential added benefit of few side effects.

Risk factors for perforation and delayed bleeding associated with endoscopic submucosal dissection for early gastric neoplasms: analysis of 1123 lesions.

Abstract: BACKGROUND AND AIM Endoscopic submucosal dissection (ESD) is a useful procedure for the treatment of early gastric neoplasms; however, this advanced technique has also resulted in an increase in serious complications such as perforation and delayed bleeding. This study aimed to elucidate the risk factors for these complications. METHODS A total of 1123 lesions diagnosed with early gastric neoplasms and treated by ESD at three institutions were investigated. Retrospectively, patients with or without these complications were compared on the basis of the patient characteristics and treatment results. RESULTS Perforation occurred in 27 lesions (2.4%) and delayed bleeding in 56 lesions (5.0%). Multivariate analysis indicated that lesions located in the upper area of the stomach (odds ratio [OR]: 4.88, 95% confidence interval [CI]: 2.21-10.75) was associated with a significantly higher risk of perforation, and that age ≥ 80 years (OR: 2.15, 95% CI: 1.18-3.90) and a long procedure time (OR: 1.01, 95% CI: 1.001-1.007) were associated with a significantly higher risk of delayed bleeding after ESD. The en bloc resection rate (74% vs 94%) and curative resection rate (48% vs 85%) of lesions with perforation were significantly lower than those without perforation. The rate of residual disease or recurrence after ESD was significantly higher in lesions with delayed bleeding than that without delayed bleeding (5.4% vs 0.84%). CONCLUSIONS This study demonstrated risk factors for perforation and delayed bleeding associated with ESD. Furthermore, it was clarified that perforation and delayed bleeding influenced post-procedure results and prognosis after ESD.

Mucins in inflammatory bowel diseases and colorectal cancer

Abstract: The gastrointestinal tract is protected by a mucus barrier with both secreted and cell-surface mucins contributing to the exclusion of luminal microbes and toxins. Alterations in the structure and/or quantity of mucins alter the barrier function of mucus and could play roles in initiating and maintaining mucosal inflammation in inflammatory bowel diseases (IBD), and in driving cancer development in the intestine. The aim of this review is to focus on the roles of the mucins in IBD. The polymorphisms of mucin genes that have been associated with susceptibility to IBD, and alterations in mucin expression as well as factors that regulate production of the mucins in IBD, are summarized. Data from animal models of intestinal inflammation, which support the importance of mucins in IBD and cancer development, are also discussed.

Management of T1 colorectal carcinoma with special reference to criteria for curative endoscopic resection

Abstract: Background and Aim: In guidelines 2010 for the treatment of colorectal cancer from the Japanese Society for Cancer of the Colon and Rectum (JSCCR), the criteria for identifying curable T1 colorectal carcinoma after endoscopic resection were well/moderately differentiated or papillary histologic grade, no vascular invasion, submucosal invasion depth less than 1000 µm and budding grade 1 (low grade). We aimed to expand these criteria. Methods: A total of 499 T1 colorectal carcinomas, resected endoscopically or surgically, were analyzed. Relationships between clinicopathologic findings and lymph node metastasis were evaluated. Results: Lymph node metastasis was found in 41 (8.22%) of the 499 cases. The incidence of lymph node metastasis was significantly higher in lesions featuring poorly differentiated/mucinous adenocarcinoma, submucosal invasion ≥ 1800 µm, vascular invasion, and high-grade tumor budding than in other lesions. Multivariate logistic regression analysis showed all of these variables to be independent risk factors for lymph node metastasis. When cases that met three of the JSCCR 2010 criteria (i.e. all but invasion < 1000 µm) were considered together, the incidence of lymph node metastasis was only 1.2% (3/249, 95% confidence interval: 0.25–3.48%), and there were no cases of lymph node metastasis without submucosal invasion to a depth of ≥ 1800 µm. Conclusions: Even in cases of colorectal carcinoma with deep submucosal invasion, the risk of lymph node metastasis is minimal under certain conditions. Thus, even for such cases, endoscopic incisional biopsy can be suitable if complete en bloc resection is achieved.

Grade of deceased donor liver macrovesicular steatosis impacts graft and recipient outcomes more than the Donor Risk Index

Abstract: Background and Aim: Donor liver steatosis can impact on liver allograft outcomes. The aim of the present study was to comprehensively report on the impact of type and grade of donor steatosis, as well as donor and recipient factors, including the reported Donor Risk Index (DRI), on liver allograft outcomes. Methods: Areview of unit data for all adult liver transplant procedures from 2001 to 2007, as well as donor offers. Donor liver biopsies were regraded for steatosis by an experienced histopathologist. Results: Steatosis was detected in 184/255 (72%) of biopsies, of which 114 (62%) had microvesicular steatosis (MiS; 68 mild, 22 moderate, 24 severe) and 70 (38%) macrovesicular steatosis (MaS; 59 mild, 7 moderate, 4 severe). The majority (66/70, 94%) of biopsies with MaS also contained MiS. Allograft steatosis was associated with increasing donor body mass index (P = 0.000), plus donor male sex (P <0.05). Primary non function (P = 0.002), early renal failure (P = 0.040), and requirement for retransplantation (P = 0.012) were associated only with severe MaS. Early biliary complications were associated with moderate MaS (P = 0.039). Only severe MaS was significantly associated with inferior allograft survival at 3 months (relative risk = 12.09 [8.75-19.05], P = 0.000) and 1 year (P = 0.000). Conclusions: MiS is a common finding and frequently coexists with MaS on liver allograft biopsy, while isolated MaS is uncommon. Only the presence of moderate to severe MaS is associated with inferior early allograft outcomes. The impact of severe MaS on allograft survival appears greater than other donor factors, including the calculated DRI.

Dangerous liaisons: pancreatic stellate cells and pancreatic cancer cells.

Abstract: One of the characteristic features of the majority of pancreatic ductal adenocarcinomas is an abundant desmoplastic/stromal reaction. Until recently, this stroma had received little attention from researchers studying the pathogenesis of pancreatic cancer, with most of the research focus resting on the biology of tumor cells themselves. However, evidence is now accumulating that the stroma plays a critical role in pancreatic cancer progression. The cells responsible for producing the stromal reaction in pancreatic cancer are activated pancreatic stellate cells (PSCs, the key effector cells in pancreatic fibrogenesis). In vitro and in vivo studies have convincingly demonstrated a close bi-directional interaction between PSCs and pancreatic cancer cells, which facilitates local tumor growth as well as distant metastasis. PSCs also interact closely with endothelial cells to stimulate angiogenesis and are possibly involved in the known resistance of pancreatic cancer to chemotherapy and radiation. Most interestingly, it has recently been shown that PSCs from the primary tumor can travel to distant metastatic sites where they likely facilitate the seeding, survival, and proliferation of cancer cells. Thus, it is now recognized that the stroma is an important alternative therapeutic target in this disease and concerted pre-clinical research is underway to develop strategies to modulate/deplete the stromal reaction to inhibit cancer progression. The challenge is to translate these developments into clinically applicable treatments for patients.

Diabetes mellitus correlates with increased risk of pancreatic cancer: A population-based cohort study in Taiwan

Abstract: Background and Aim: This study investigated whether diabetes mellitus (DM) increased the risk of pancreatic cancer and whether anti-diabetic drugs reduced the risk in Taiwan. Methods: We designed a population-based cohort study using the Taiwan National Health Insurance Database, which consisted of 49 803 patients aged 20 years and older with newly diagnosed DM as the diabetic group and 199 212 people without DM as the non-diabetic group during 1998-2007. Results: The incidence of pancreatic cancer was higher in patients with diabetic duration less than 2 years, as compared to the non-diabetic group (27.81 vs 6.96 per 10 000 person-years, 95% confidence interval = 2.11-7.54). Age (aged 40-64, hazard ratio (HR) = 5.22, and aged 65 and older, HR = 7.59, respectively), chronic pancreatitis (HR = 19.40), gallstones (HR = 2.56), and hepatitis C infection (HR = 3.08) were also significant factors predicting pancreatic cancer. Patients with concurrent DM and chronic pancreatitis had an appreciably elevated risk of developing pancreatic cancer (HR = 33.52), as compared with subjects without these comorbidities. The association was not statisti- cally significant between use of anti-diabetic drugs and the risk of pancreatic cancer. Conclusions: Diabetes < 2 years' duration is associated with pancreatic cancer and could be an early manifestation of pancreatic cancer. Long-standing diabetes was not found to be a risk factor for pancreatic cancer in Taiwan's patients. Old age, chronic pancreatitis, gallstones and hepatitis C infection are other risk factors for pancreatic cancer. These high-risk patients should undergo close follow-up programs for pancreatic cancer.

Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation

Abstract: Background and Aim: Increasing evidence correlates the presence of systemic inflammation with poor survival in patients with hepatocellular carcinoma (HCC) We studied whether peripheral blood neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammatory response, would be a useful predictor for outcome in patients with early HCC undergoing radiofrequency ablation (RFA) Methods: A total of 158 patients with early HCC underwent RFA Potential prognostic factors such as age, gender, tumoral characteristics, Child-Turcotte-Pugh (CTP) class and NLR were analyzed The study endpoints were overall survival (OS) and new recurrence Results: We modeled NLR as a continuous explanatory variable in regression analyses Multivariate analysis revealed that tumor size (P = 0005) and high baseline NLR (P = 0001) were independent explanatory variables associated with unfavorable OS Regarding new recurrence, multivariate analysis showed that CTP class B (P = 0002), α-fetoprotein > 400 ng/mL (P = 0030), tumor size (P = 0002) and tumor multiplicity (P = 0013) were found to be worse prognosticators, but not baseline NLR In a subset analysis of 140 patients whose post-RFA NLR data at first follow-up visit were available, multivariate analysis revealed that high post-RFA NLR was identified as an independent covariate, not only for OS (P = 0006), but for new recurrence (P = 0010) as well Conclusions: High baseline NLR was associated with worse OS for patients with early HCC; post-RFA NLR predicted not only OS, but also tumor recurrence

Interleukin‐37 reduces liver inflammatory injury via effects on hepatocytes and non‐parenchymal cells

Abstract: Background and Aim The purpose of the present study was to determine the effects of IL-37 on liver cells and on liver inflammation induced by hepatic ischemia/reperfusion (I/R).

Epidemiology, risk factors, and the promotion of pancreatic cancer: Role of the stellate cell

Abstract: There are approximately 277,000 new cases of pancreatic cancer and 266,000 deaths from pancreatic cancer annually, indicating a mortality rate of 96% of the cases diagnosed. Because of the ineffectiveness of therapies, a major emphasis needs to be placed on prevention. This paper reviews the epidemiology and risk factors for pancreatic cancer, and uses this information to propose plausible research directions for determining the biological mechanisms mediating the effects of risk factors on the promotion of pancreatic cancer, with a focus on the pancreatic stellate cell.

Gallbladder cancer: can newer insights improve the outcome?

Abstract: Gallbladder cancer (GBC) is the leading cause of cancer related mortality in certain geographic areas. Most of the patients with GBC have advanced disease at presentation, precluding curative resection resulting in a dismal prognosis. However, recent advances in the understanding of its epidemiology and pathogenesis coupled with development of newer diagnostic tools and therapeutic options, has resulted in enhanced optimism towards the management of the disease. The leading risk factors are gallstones, advancing age, female gender, anomalous pancreaticobiliary ductal junction, certain ethnic groups and geographic populations. Advances in radiological imaging and the advent of endoscopic ultrasound have facilitated early detection and accurate staging of the tumor. A high index of suspicion in high risk groups is necessary to pick up incidental and early GBC, as surgical resection is curative. In patients with suspected GBC, an open surgical resection that is appropriate for that stage is advocated. Adjuvant combination chemotherapy and molecular targeted therapy are emerging as effective therapeutic options in those with advanced GBC. Endoscopic palliation of biliary and gastric outlet obstruction with metallic stents has improved their quality of life. Prevention remains the hitherto less explored option to reduce GBC related mortality. Prophylactic cholecystectomy in high risk groups is a cost-effective option. A multi-disciplinary systematic global approach to initiate collaborative ventures to understand epidemiology, standardize management strategies, conduct multi-centric trials with newer therapeutic agents and initiate preventive measures, would pave way for the future conquest of the disease.

Retinoic acids and hepatic stellate cells in liver disease.

Abstract: Quiescent hepatic stellate cells (HSCs) in healthy liver store 80% of total liver retinols and release them depending on the extracellular retinol status. However, HSCs activated by liver injury lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Emerging evidence suggests that retinols and their metabolites such as retinoic acids (RAs) contribute to liver regeneration, fibrosis and tumor. However, it is not clear yet why HSCs lose retinol, which enzymes are involved in the retinol metabolism of HSCs and what function of retinol metabolites on HSCs upon liver injury. Recently, our group and collaborators have demonstrated that during activation, HSCs not only lose retinols but also metabolize them into RAs by alcohol dehydrogenases and retinaldehyde dehydrogenases. As transcriptional factors, metabolized RAs induce retinoic acid early inducible-1 and suppressor of cytokine signaling 1 in HSCs, which plays an important role in the interaction between HSCs and natural killer cells. In addition, RAs released from HSCs may induce hepatic cannabinoid receptor 1 expression in alcoholic liver steatosis or regulate immune responses upon liver inflammation. The present review summarizes the role of endogenous metabolized RAs on HSCs themselves and on other liver cells including hepatocytes and immune cells. Moreover, the effects of exogenous retinol and RA treatments on HSCs and liver disease are discussed.

Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose.

Abstract: Background and Aim: Development of overt hepatic encephalopathy (HE) is associated with poor prognosis in patients with cirrhosis. Lactulose is used for the treatment of HE. There is no study on the prevention of overt HE using lactulose in patients who never had HE earlier. Methods: Consecutive cirrhotic patients who never had an episode of overt HE were randomized to receive lactulose (Gp-L) or no lactulose (Gp-NL). All patients were assessed by psychometry (number connection test [NCT-A and B], figure connection test if illiterate [FCT-A and B], digit symbol test [DST], serial dot test [SDT], line tracing test [LTT]) and critical flicker frequency test (CFF) at inclusion and after 3 months. These patients were followed every month for 12 months for development of overt HE. Results: Of 250 patients screened, 120 (48%) meeting the inclusion criteria were randomized to Gp-L (n = 60) and Gp-NL (n = 60). Twenty (19%) of 105 patients followed for 12 months developed an episode of overt HE. Six (11%) of 55 in the lactulose (Gp-L) group and 14 (28%) of 50 in the Gp-NL (P = 0.02) developed overt HE. Ten (20%) of 50 patients in Gp-NL and five (9%) of 55 patients in the Gp-L group died, P = 0.16. Number of patients with minimal hepatic encephalopathy (MHE) were comparable in two groups at baseline (Gp-L vs Gp-NL, 32:36, P = 0.29). Lactulose improved MHE in 66% of patients in Gp-L. Taking a cutoff < 38 Hz sensitivity and specificity of CFF in predicting HE were 52% and 77% at baseline and 52% and 82% at 3 months of treatment. On multivariate analysis, Child's score and presence of MHE at baseline were significantly associated with development of overt HE. Conclusions: Lactulose is effective for primary prevention of overt hepatic encephalopathy in patients with cirrhosis.

Matched case-control study comparing endoscopic submucosal dissection and endoscopic mucosal resection for colorectal tumors.

Abstract: Background and Aim: For large colorectal tumors, the en bloc resection rate achieved by endoscopic mucosal resection (EMR) is insufficient, and this leads to a high rate of local recurrence. As endoscopic submucosal dissection (ESD) has been reported to achieve a higher rate of en bloc resection and a lower rate of local recurrence in the short-term, it is expected to overcome the limitations of EMR. We conducted a matched case-control study between ESD and EMR to clarify the effectiveness of ESD for colorectal tumors. Methods: Between April 2005 and February 2009, a total of 28 colorectal tumors in 28 patients were resected by ESD and were followed up by colonoscopy at least once. As a control group, 56 EMR cases from our prospectively completed database were matched. En bloc resection, complication and recurrence rates were compared between the two groups. Results: The mean sizes of the lesions were 27.1 mm in the ESD group and 25.0 mm in the EMR group. The en bloc resection rate was significantly higher in the ESD group (92.9% vs 37.5% with ESD vs EMR), and the rate of perforation was also significantly higher (10.7% vs 0%). All cases of perforation were managed conservatively. No recur- rence was observed in the ESD group, whereas local recurrences were detected in 12 EMR cases (21.4%). Eleven of the 12 recurrences (91.7%) were managed endoscopically, and one required surgical resection. Conclusions: Endoscopic submucosal dissection is a promising technique for the treat- ment of colorectal tumors, giving an excellent outcome in comparison with EMR.

Clinical outcomes of radiofrequency ablation and surgical resection for small hepatocellular carcinoma: A meta-analysis

Abstract: Background and Aim: To evaluate the evidence comparing radiofrequency ablation (RFA) and surgical resection (RES) on the treatment of hepatocellular carcinoma (HCC) using meta-analytical techniques. Methods: Literature search was undertaken until March 2011 to identify comparative studies evaluating survival rates, recurrence rates, and complications. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated with either the fixed or random effect model. Results: These studies included a total of 877 patients: 441 treated with RFA and 436 treated with RES. The overall survival was significantly higher in patients treated with RES than RFA at 1, 3 and 5 years (respectively: OR: 0.50, 95% CI: 0.29–0.86; OR: 0.51, 95% CI: 0.28–0.94; OR: 0.62, 95% CI: 0.45–0.84). In the RES group the 1, 3, and 5 years recurrence-free survival rates were significantly higher than the RFA group (respectively: OR: 0.65, 95% CI: 0.44–0.97; OR: 0.65, 95% CI: 0.47–0.89; OR: 0.52, 95% CI: 0.35–0.77). RFA had a higher rate of local recurrence (OR: 4.08, 95% CI: 2.03–8.20). For tumors ≤ 3 cm RES was better than RFA in the 3-year overall survival rates (OR: 0.38, 95% CI: 0.16–0.89). Conclusions: Surgical resection was superior to RFA in the treatment of HCC. However, the findings have to be carefully interpreted due to the lower level of evidence.

Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: A cohort study

Abstract: Background and Aim: The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. Methods: We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. Results: We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1–22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3–67.4). Conclusions: Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.

Impaired autophagy and organellar dysfunction in pancreatitis.

Abstract: Recent findings from our group, obtained on experimental in vivo and ex vivo models of pancreatitis, reveal that this disease causes a profound dysfunction of key cellular organelles, lysosomes and mitochondria. We found that autophagy, the main cellular degradative, lysosome-driven process, is activated but also impaired in acute pancreatitis because of its' inefficient progression/resolution (flux) resulting from defective function of lysosomes. One mechanism underlying the lysosomal dysfunction in pancreatitis is abnormal processing (maturation) and activation of cathepsins, major lysosomal hydrolases; another is a decrease in pancreatic levels of key lysosomal membrane proteins LAMP-1 and LAMP-2. Our data indicate that lysosomal dysfunction plays an important initiating role in pancreatitis pathobiology. The impaired autophagy mediates vacuole accumulation in acinar cells; furthermore, the abnormal maturation and activation of cathepsins leads to increase in intra-acinar trypsin, the hallmark of pancreatitis; and LAMP-2 deficiency causes inflammation and acinar cell necrosis. Thus, the autophagic and lysosomal dysfunctions mediate key pathologic responses of pancreatitis. On the other hand, we showed that pancreatitis causes acinar cell mitochondria depolarization, mediated by the permeability transition pore (PTP). Genetic (via deletion of cyclophilin D) inactivation of PTP prevents mitochondrial depolarization and greatly ameliorates the pathologic responses of pancreatitis. Further, our data suggest that mitochondrial damage, by stimulating autophagy, increases the demand for efficient lysosomal degradation and therefore aggravates the pathologic consequences of lysosomal dysfunction. Thus, the combined autophagic, lysosomal and mitochondrial dysfunctions are key to the pathogenesis of pancreatitis.

Exercise and diet modification in non‐obese non‐alcoholic fatty liver disease: Analysis of biopsies of living liver donors

Abstract: Background and Aims: We evaluated efficacy of exercise and diet modification for steatosis improvement of non-obese non-alcoholic fatty liver disease (NAFLD) patients. Methods: We analyzed retrospectively the clinical and histological parameters of consecutive living liver donors, who experienced repeated liver biopsies due to steatosis and were treated using exercise and diet modification. Results: From 1995 to 2009, among a total of 1365 potential living liver donors with NAFLD seen on the initial liver biopsy, 120 consecutive donors with steatosis ≥ 30% or an estimated donor-recipient weight ratio < 0.8, underwent exercise and diet modification and received follow-up liver biopsy at our institution. Median age was 33 years, and median interval between the two consecutive biopsies was 10 weeks (range, 1–39). At the time of initial biopsy, the number of normal body mass index, overweight, and obese donors was 49 (40.8%), 65 (54.2%), and 6 (5.0%), respectively. After lifestyle modification, weight reduction and steatosis improvement were observed in 92 (76.7%) and 103 (85.8%) donors, respectively, at the time of follow-up biopsy. On multivariate analysis, initially higher steatosis (hazard ratio [HR] 1.03, P = 0.02), total cholesterol reduction ≥ 10% (HR 5.59, P = 0.02), and weight reduction ≥ 5% (HR 6.63, P = 0.03) were significantly associated with ≥ 20% steatosis improvement in 120 donors with NAFLD, after exercise and diet modification. Conclusions: Exercise and diet modification were effective in reducing steatosis in potential living liver donors with non-obese NAFLD. Total cholesterol reduction ≥ 10% could be used as a non-invasive predictor for steatosis improvement in liver donors with NAFLD, after exercise and diet modification.

Treatment of high-frequency gastric electrical stimulation for gastroparesis

Abstract: Background and Aims: The aim of this study was to assess the effects of gastric electrical stimulation (GES) on symptoms and gastric emptying in patients with gastroparesis, and the effects of GES on the three subgroups of gastroparesis. Methods: A literature search of clinical trials using high-frequency GES to treat patients with gastroparesis from January 1995 to January 2011 was performed. Data on the total symptom severity score (TSS), nausea severity score, vomiting severity score, and gastric emptying were extracted and analyzed. The statistic effect index was weighted mean differences. Results: Ten studies (n = 601) were included in this study. In the comparison to baseline, there was significant improvement of symptoms and gastric emptying (P < 0.00001). It was noted that GES significantly improved both TSS (P < 0.00001) and gastric retention at 2 h (P = 0.003) and 4 h (P < 0.0001) in patients with diabetic gastroparesis (DG), while gastric retention at 2 h (P = 0.18) in idiopathic gastroparesis (IG) patients, and gastric retention at 4 h (P = 0.23) in postsurgical gastroparesis (PSG) patients, did not reach significance. Conclusions: Based on this meta-analysis, the substantial and significant improvement of symptoms and gastric emptying, and the good safety we observed, indicate that high-frequency GES is an effective and safe method for treating refractory gastroparesis. DG patients seem the most responsive to GES, both subjectively and objectively, while the IG and PSG subgroups are less responsive and need further research.

Colorectal neoplasms in relation to non-alcoholic fatty liver disease in Korean women: a retrospective cohort study

Abstract: Background and Aim: Metabolic syndrome has been associated with an increased risk for colorectal cancer. Non-alcoholic fatty liver disease (NAFLD) is regarded as a hepatic manifestation of metabolic syndrome. We investigated whether NAFLD is associated with colorectal neoplasms in Korean women. Methods: This retrospective cohort study included data from 5517 women, aged 35–80 years, who underwent life insurance company health examinations between July 2002 and June 2006. Fatty liver disease was assessed by abdominal ultrasound, with NAFLD defined as fatty liver disease in the absence of alcohol use of > 40 g/week or other secondary causes. The incidence of colorectal neoplasms through December 2008 was obtained through medical certificate codes for insurance claims. The association between NAFLD and the risk of colorectal neoplasms was estimated using standard Cox proportional hazards models. Results: Of the study population, 15.1% were diagnosed with NAFLD. During follow-up, 65 women were verified as having adenomatous polyps and 15 as having colorectal cancer. Adjusted relative risks (95% confidence interval [CI]) for adenomatous polyps by age, low high-density lipoprotein-cholesterol, and NAFLD were 1.12 (95% CI 1.09–1.15), 2.56 (95% CI 1.53–4.28) and 1.94 (95% CI 1.11–3.40). Adjusted relative risks (95% CI) for colorectal cancer by age and NAFLD were 1.23 (95% CI 1.17–1.29) and 3.08 (95% CI 1.02–9.34). Conclusions: Our findings demonstrate a significant relationship between NAFLD and colorectal neoplasms. Among the various manifestations of metabolic syndrome, NAFLD may predict the development of colorectal neoplasms in Korean women.

Management of ascites in cirrhosis.

Abstract: Ascites is a common complication of liver cirrhosis associated with a poor prognosis. The treatment of ascites requires dietary sodium restriction and the judicious use of distal and loop diuretics, sequential at an earlier stage of ascites, and a combination at a later stage of ascites. The diagnosis of refractory ascites requires the demonstration of diuretic non-responsiveness, despite dietary sodium restriction, or the presence of diuretic-related complications. Patients with refractory ascites require second-line treatments of repeat large-volume paracentesis (LVP) or the insertion of a transjugular intrahepatic portosystemic shunt (TIPS), and assessment for liver transplantation. Careful patient selection is paramount for TIPS to be successful as a treatment for ascites. Patients not suitable for TIPS insertion should receive LVP. The use of albumin as a volume expander is recommended for LVP of >5-6 L to prevent the development of circulatory dysfunction, although the clinical significance of post-paracentesis circulatory dysfunction is still debated. Significant mortality is still being observed in cirrhotic patients with ascites and relatively preserved liver and renal function, as indicated by a lower Model for End-Stage Liver Disease (MELD) score. It is proposed that patients with lower MELD scores and ascites should receive additional points in calculating their priority for liver transplantation. Potential new treatment options for ascites include the use of various vasoconstrictors, vasopressin V(2) receptor antagonists, or the insertion of a peritoneo-vesical shunt, all of which could possibly improve the management of ascites.

Prevalence of the JAK2V617F mutation in Chinese patients with Budd‐Chiari syndrome and portal vein thrombosis: A prospective study

Abstract: Background and Aim: Whether routine screening for the JAK2V617F mutation should be performed in Chinese patients with Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) is unclear. Therefore, we aimed to evaluate the prevalence of the JAK2V617F mutation in such patients and to explore the risk factors associated with the mutation. Methods: All consecutive patients with BCS and PVT diagnosed between September 2009 and May 2011 were prospectively enrolled in the observational study and underwent the JAK2V617F mutation detection. Results: Prevalence of the JAK2V617F mutation was 4.3% (4/92) in patients with primary BCS, 26.6% (17/64) in non-malignant and non-cirrhotic patients with PVT, and 1.4% (1/71) in cirrhotic patients with PVT. All BCS patients with the JAK2V617F mutation had both platelet count (PLT) of above 100 × 109/L (range, 107–188 × 109/L) and splenomegaly. In non-malignant and non-cirrhotic patients with PVT, higher PLT and older ages were the independent predictors of the JAK2V617F mutation. Further, the difference in PLT between the patients with and without the mutation displayed greater significance in the subgroup of patients with splenomegaly (P < 0.0001), but the statistical significance disappeared in the subgroup of patients with splenectomy (P = 0.1312). Conclusions: The low prevalence of the JAK2V617F mutation in patients with BCS suggests that myeloproliferative neoplasm should be an uncommon etiological factor of BCS in China. Routine screening for the JAK2V617F mutation might be recommended in non-malignant and non-cirrhotic patients with PVT, but not in cirrhotic patients with PVT. The coexistence of higher PLT and splenomegaly might be closely associated with the JAK2V617F mutation.