Showing papers in "Journal of Gastroenterology and Hepatology in 2008"

Antituberculosis drug-induced hepatotoxicity: concise up-to-date review.

Abstract: The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug-induced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

Animal models of NASH: getting both pathology and metabolic context right.

Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of referral to liver clinics, and its progressive form, non-alcoholic steatohepatitis (NASH), can lead to cirrhosis and end-stage liver disease. The main risk factors for NAFLD/NASH are the metabolic abnormalities commonly observed in metabolic syndrome: insulin resistance, visceral obesity, dyslipidemia and altered adipokine profile. At present, the causes of progression from NAFLD to NASH remain poorly defined, and research in this area has been limited by the availability of suitable animal models of this disease. In the past, the main models used to investigate the pathogenesis of steatohepatitis have either failed to reproduce the full spectrum of liver pathology that characterizes human NASH, or the liver pathology has developed in a metabolic context that is not representative of the human condition. In the last few years, a number of models have been described in which the full spectrum of liver pathology develops in an appropriate metabolic context. In general, the underlying cause of metabolic defects in these models is chronic caloric overconsumption, also known as overnutrition. Overnutrition has been achieved in a number of different ways, including forced feeding, administration of high-fat diets, the use of genetically hyperphagic animals, or a combination of these approaches. The purpose of the present review is to critique the liver pathology and metabolic abnormalities present in currently available animal models of NASH, with particular focus on models described in approximately the last 5 years.

Asia-Pacific consensus guidelines on gastric cancer prevention.

Abstract: Background and Aim: Gastric cancer is a major health burden in the Asia–Pacific region but consensus on prevention strategies has been lacking. We aimed to critically evaluate strategies for preventing gastric cancer. Methods: A multidisciplinary group developed consensus statements using a Delphi approach. Relevant data were presented, and the quality of evidence, strength of recommendation, and level of consensus were graded. Results: Helicobacter pylori infection is a necessary but not sufficient causal factor for non-cardia gastric adenocarcinoma. A high intake of salt is strongly associated with gastric cancer. Fresh fruits and vegetables are protective but the use of vitamins and other dietary supplements does not prevent gastric cancer. Host–bacterial interaction in H. pylori infection results in different patterns of gastritis and differences in gastric acid secretion which determine disease outcome. A positive family history of gastric cancer is an important risk factor. Low serum pepsinogens reflect gastric atrophy and may be useful as a marker to identify populations at high risk for gastric cancer. H. pylori screening and treatment is a recommended gastric cancer risk reduction strategy in high-risk populations. H. pylori screening and treatment is most effective before atrophic gastritis has developed. It does not exclude the existing practice of gastric cancer surveillance in high-risk populations. In populations at low risk for gastric cancer, H. pylori screening is not recommended. First-line treatment of H. pylori infection should be in accordance with national treatment guidelines. Conclusion: A strategy of H. pylori screening and eradication in high-risk populations will probably reduce gastric cancer incidence, and based on current evidence is recommended by consensus.

Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer.

Abstract: Background and Aim: Bacterial metabolites produced in the bowel are potentially related to the genesis of colorectal cancer. Butyrate is protective against cancer, whereas hydrogen sulfide and oxygen free radicals can be toxic to the epithelium. The present study was designed to quantitate Eubacterium rectale, Faecalibacterium prausnitzii (both butyrate-producing bacteria), Desulfovibrio (sulfate-reducing bacteria), and Enterococcus faecalis (that produces extracellular superoxide) in the feces of patients with colorectal cancer. Methods: DNA was extracted from feces of 20 patients with colorectal cancer, nine patients with upper gastrointestinal cancer and 17 healthy volunteers. Real-time polymerase chain reaction using primers aimed at 16S rDNA was used to quantitate the above bacterial species or genus, and this was expressed relative to amplification of universal sequences conserved among all bacteria. Results: Levels of E. rectale and F. prausnitzii were decreased approximately fourfold (P = 0.0088 and 0.0028, respectively) in colorectal cancer patients compared to healthy control volunteers. Levels of Desulfovibrio were not significantly different between the three groups. E. faecalis populations were significantly higher in colorectal cancer patients compared to healthy volunteers (P = 0.0294). Conclusions: Butyrate producers were decreased and E. faecalis increased in the feces of colon cancer patients. These shifts in the colonic bacterial population could potentially lead to epithelial cell damage and increased turnover and may be a factor leading to colon cancer.

Differences between right- and left-sided colon cancer in patient characteristics, cancer morphology and histology.

Abstract: Background and Aim: Recently, the clinical and biological differences between right- and left-sided colon cancers have been widely debated. However, close analyses of these clinical differences, based on large-scale studies, have been scarcely reported. Methods: A total of 3552 consecutive Japanese colorectal cancer cases were examined and the clinical differences between right- and left-sided colon cancer cases were investigated. Results: The proportion of right-sided colon cancer was relatively high in patients aged less than 40 years (33%) and more than 80 years (43%). The proportion of right-sided colon cancer in patients aged 40–59 years was relatively low (male 22% and female 29%). In male patients the proportion increased in the 70-79 years age group (30%), while in female patients the proportion increased in the 60-69 years age group (39%). Right-sided colon cancer was more likely to be detected at an advanced stage (T1 stage; left 22%, right 15%) (P < 0.01) with severe symptoms. Polypoid-type early cancer was dominant in the left colon (left 59%; right 40%) (P < 0.01), while the proportion of flat-type early cancer in the right colon was significantly higher than that in the left colon (left 25%; right 44%) (P < 0.01). Conclusions: Specific age distribution of right-sided colon cancer was observed and the difference between male and female patients was highlighted. Other clinical features also differed between right- and left-sided colon cancer, suggesting that different mechanisms may be at work during right and left colon carcinogenesis.

Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical features, viral interactions and treatment

Abstract: Because of the shared modes of transmission, hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection is not uncommon in highly endemic areas and among subjects with a high risk of parenteral infections. The worldwide prevalence of HBV/HCV coinfection is unknown and might be underestimated with the phenomenon of silent (occult) HBV infection. HCV superinfection in patients with chronic HBV infection was the most common clinical features of coinfection in Asia-Pacific countries. Further, most, but not all, clinical observations suggested that interference between the two viruses was more frequently characterized by an inhibition of HBV replication exerted by HCV. However, longitudinal follow-up studies have demonstrated that the virological patterns in coinfection cases are widely divergent and have dynamic profiles over time. As compared with monoinfected patients, HBV/HCV coinfected persons tend to have more severe liver injury, a higher probability of liver cirrhosis and hepatic decompensation, and a higher incidence of hepatocellular carcinoma. Detailed serological and virological evaluations are required for coinfected patients before initiation of antiviral therapy. Previous studies demonstrated that HBV/HCV coinfected patients responded poorly to interferon (IFN) monotherapy. Currently, for patients with dominant HCV infection and low level HBV viremia (<10(4) IU/mL), IFN or pegylated IFN plus ribavirin can achieve comparable sustained virus response as expected with HCV monoinfection. However, phenomenon of reciprocal viral interference can happen, and resultant "flare" of hepatitis activity may cause liver function deterioration. For coinfected patients with dually-active HBV/HCV, the optimal regimen for therapy remains unclear although adding oral nucleos(t)ide analogs to pegylated IFN and ribavirin seems a reasonable empiric option.

Changing trends in the proportion of adenocarcinoma of the esophagogastric junction in a large tertiary referral center in Japan

Abstract: Introduction: A dramatic increase in incidence of adenocarcinoma of the esophagogastric junction (EGJ) over the past two decades has been reported in the West. However, epidemiological data from Asian countries have not shown a similar trend. The aim of this study was to determine the incidence of adenocarcinoma of the EGJ in a cohort of consecutive patients operated on for gastric adenocarcinoma at a major cancer referral center in Japan. Method: We reviewed pathological reports of all patients who underwent surgery for advanced gastric adenocarcinoma between 1962 and 2005 at the National Cancer Centre Hospital in Tokyo. Adenocarcinoma of the EGJ was defined from images recorded for each patient, in accordance with the classification of Siewert and Stein. The proportion of adenocarcinoma at the EGJ among operated gastric adenocarcinoma patients was compiled at five-year intervals and serial comparison made. Results: A total of 6953 patients with advanced gastric adenocarcinoma were operated on; adenocarcinoma of EGJ was found in 520 patients. The overall proportion of adenocarcinoma of the EGJ increased from 2.3% (1962–1965) to 10.0% (2001–2005). The proportion of Siewert Type II rose from 28.5% (1962–1965) to 57.3% (2001–2005), while that of Type I remained at around 1%. Conclusion: An increasing trend of adenocarcinoma of EGJ is observed in this study of patients operated on for gastric adenocarcinoma from 1962 to 2005 in a large tertiary referral center in Japan.

S-Adenosylmethionine in cell growth, apoptosis and liver cancer

Abstract: S-Adenosylmethionine (SAMe), the principal biological methyl donor, is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferase (MAT). In mammals, two genes (MAT1A and MAT2A), encode for two homologous MAT catalytic subunits, while a third gene MAT2beta, encodes for the beta-subunit that regulates MAT2A-encoded isoenzyme. Normal liver expresses MAT1A, whereas extrahepatic tissues express MAT2A. MAT2A and MAT2 beta are induced in human hepatocellular carcinoma (HCC), which facilitate cancer cell growth. Patients with cirrhosis of various etiologies, including alcohol, have decreased hepatic MAT activity and SAMe biosynthesis. Consequences of hepatic SAMe deficiency as illustrated by the Mat1a knock-out mouse model include increased susceptibility to steatosis and oxidative liver injury, spontaneous development of steatohepatitis and HCC. Predisposition to HCC can be partly explained by the effect of SAMe on growth. Thus, SAMe inhibits the mitogenic effect of growth factors such as hepatocyte growth factor and, following partial hepatectomy, a fall in SAMe level is required for the liver to regenerate. During liver regeneration, the fall in hepatic SAMe is transient. If the fall were to persist, it would favor a proliferative phenotype and, ultimately, development of HCC. Not only does SAMe control liver growth, it also regulates apoptosis. Interestingly, SAMe is anti-apoptotic in normal hepatocytes but pro-apoptotic in liver cancer cells. In liver cancer cells but not in normal human hepatocytes, SAMe can selectively induce Bcl-x(S), an alternatively spliced isoform of Bcl-x(L) that promotes apoptosis. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.

Changes in the expression of claudins in active ulcerative colitis.

Abstract: Background and Aim: Epithelial barrier function is impaired in ulcerative colitis (UC), but the pathophysiological mechanisms leading to this barrier defect are still far from clear. Because epithelial barrier function is primarily regulated by the most apical intercellular junction, referred to as the tight junction (TJ), we investigated the expression of TJ proteins on rectal epithelial mucosa in UC. Methods: Biopsies from the rectum of patients with active UC and of controls were studied. Tight-junction proteins were dual stained using specific antibodies (claudin-1, -2, -3, -4, and -7) as primary antibodies, and Cy-3 conjugated anti-rabbit IgG and Alexa488-conjugated anti-mouse IgG as secondary antibodies. Samples were analyzed by immunofluorescence microscopy. Immunoblotting and real-time polymerase chain reaction were performed to quantify TJ proteins and mRNA, respectively. Results: At TJ, claudin-4 and -7 staining was down-regulated in active UC, whereas claudin-2 staining was up-regulated. Claudin-4 and -7 proteins were down-regulated on immunoblotting, whereas claudin-2 protein was up-regulated in active UC. Claudin-1 and -3 expression levels were unchanged in controls and active UC. In active UC claudin-2 mRNA was increased, whereas claudin-4 and -7 mRNA were decreased. Conclusions: Down-regulation of claudin-4 and claudin-7, and up-regulation of claudin-2, might lead to altered TJ structure and be related to the impaired epithelial function in active UC.

Des‐γ‐carboxyprothrombin, α‐fetoprotein and AFP‐L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma

Abstract: Background and Aim: Hepatocellular carcinoma (HCC) is a common complication in patients with chronic viral hepatitis. Detection of HCC at an early stage is critical for a favorable clinical outcome. The study aim was to: (i) compare the levels of des-γ-carboxyprothrombin (DCP), α-fetoprotein (AFP) and AFP-L3 in HCC patients and in chronic viral hepatitis patients without HCC; (ii) define the level of each tumor marker with the best sensitivity and specificity for HCC diagnosis; and (iii) to correlate the levels of these markers with respect to size and tumor burden. Methods: Two hundred and forty patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection were studied. These included 144 with HCC, 47 with chronic hepatitis (fibrosis stage I–III on liver biopsy) and 49 with cirrhosis. Results: Levels of DCP, AFP and AFP L-3 were significantly higher in patients with HCC than in those without HCC (P ≤ 0.0001). Receiver–operating curves (ROC) indicated that the cut-off value with the best sensitivity and specificity for each test was ≥84 mAU/mL for DCP, ≥25 ng/mL for AFP and ≥10% for AFP-L3. The sensitivity, specificity and positive predictive value (PPV) for DCP was 87%, 85% and 86.8%, for AFP 69%, 87% and 69.8%, and for AFP-L3 56%, 90% and 56.1%, respectively. DCP levels were below the ROC cut-off in all patients without HCC. In patients with single lesions, there was a direct correlation of DCP to tumor size. High levels of AFP correlated with diffuse type of HCC. All three markers were significantly elevated in the presence of metastatic HCC. No advantage was observed by combining two or three markers for HCC diagnosis. Conclusion: DCP had the highest sensitivity and PPV for HCC diagnosis, had a direct correlation with tumor size, and was not elevated in any patients without HCC. DCP should be used as the main serum test for HCC detection.

The alteration of enterochromaffin cell, mast cell, and lamina propria T lymphocyte numbers in irritable bowel syndrome and its relationship with psychological factors

Abstract: Background/Aims: Psychological factors and subtle histopathological changes have been implicated in irritable bowel syndrome (IBS). The aims of the present study were to investigate whether the numbers of enterochromaffin (EC) cells, mast cells, and lamina propria T lymphocytes are altered in IBS, and evaluate the relationship of such alterations with psychological factors. Methods: Forty-two consecutive IBS patients (M : F = 17:25, mean age 48 years) fulfilling the Rome III criteria and twelve asymptomatic healthy controls underwent rectal biopsy. Immunostaining was performed for EC cells, mast cells, and lamina propria T lymphocytes. Results: The IBS group included five post-infectious (PI) IBS and 37 non-PI IBS patients. Significantly more EC cells, mast cells and lamina propria T lymphocytes were observed in PI IBS patients. Mast cells significantly increased in non-PI IBS-D (diarrhea) patients, but not in non-PI IBS-C (constipation) and non-PI IBS-M (mixed) patients. Enterochromaffin cell numbers were not significantly altered in non-PI IBS patients. Anxiety and depression scores did not differ between IBS patients with and without abnormal increase in EC cell or mast cell counts, defined as more than the mean of controls + 2 standard deviations. Enterochromaffin cell, mast cell, or lamina propria T lymphocyte numbers were poorly correlated with anxiety and depression scores in the IBS group. Conclusions: Enterochromaffin cells, mast cells, and lamina propria T lymphocytes significantly increase in PI IBS, whereas only mast cells significantly increase in non-PI IBS-D. Such histopathological changes do not seem to be directly associated with psychological factors.

Visceral adipose tissue area is an independent risk factor for hepatic steatosis

Abstract: Background and Aim: Recent data indicate that hepatic steatosis is associated with insulin resistance, dyslipidemia and obesity (especially central body fat distribution). There have been few studies on the correlation between biopsy-proven hepatic steatosis and the above factors in a disease-free population. The aim of the present study was to evaluate the relation between hepatic steatosis assessed by biopsy and clinical characteristics including regional fat distribution measured by computed tomography (CT) in living liver donors. Methods: Laboratory data, liver/spleen Hounsfield ratio (L/S ratio), regional fat distribution by CT and liver status by biopsy were evaluated retrospectively in a total of 177 living liver donors without a history of alcohol intake. Results: The unpaired t-test showed that age, triglycerides (TG), high density lipoprotein, total cholesterol, alanine aminotransferase, body mass index, L/S ratio, visceral adipose tissue area (VAT) and subcutaneous adipose tissue area (SAT) were associated with hepatic steatosis. In the multiple logistic regression analysis, VAT (odds ratio 1.031, 95% CI 1.013–1.048, P < 0.01) and TG (odds ratio 1.012, 95% CI 1.004–1.020, P < 0.01) were independent risk factors of hepatic steatosis. Subgroup analysis also showed that VAT was an independent risk factor in men (odds ratio 1.022, 95% CI 1.003–1.041, P < 0.05) and women (odds ratio 1.086, 95% CI 1.010–1.168, P < 0.05). Conclusion: Our results suggest that visceral abdominal adiposity is correlated with hepatic steatosis in healthy living liver donors.

Malnutrition in end stage liver disease: recommendations and nutritional support.

Abstract: Malnutrition has increasingly been acknowledged as an important prognostic factor which can influence the clinical outcome of patients suffering from end-stage liver disease (ESLD). Despite the fact that malnutrition is not included in the Child-Pugh classification, its presence should alert clinicians to the same extent as do other complications, such as ascites and hepatic encephalopathy. The pathophysiological mechanisms and the clinical conditions that drive cirrhotic patients to an ill-balanced metabolic state are multiple and they intertwine. Inadequate offer of nutrients, the hypermetabolic state in cirrhosis, the diminished synthetic capacity of the liver and the impaired absorption of nutrients are the main reasons that disrupt the metabolic balance in ESLD. Identifying patients that are approaching the state of malnutrition by simple and easily applied methods is necessary in order to provide nutritional support to those that need it most. According to the European Society for Clinical Nutrition and Metabolism, simple bedside methods such as Subjective Global Assessment and anthropometric parameters are reliable in assessing the nutritional state of cirrhotic patients. Correcting the nutrient deficit of the affected patients is mandatory. Avoidance of alcohol and excess fat and ingestion of 4-6 meals/day containing carbohydrates and protein are the most common recommendations. In severe malnutrition, initiation of enteral feeding and/or use of special formulae such as branched-chain amino acid-enriched nutrient mixtures are often recommended. Enteral nutrition improves nutritional status and liver function, reduces complications, prolongs survival and is therefore indicated.

Long-term results of balloon-occluded retrograde transvenous obliteration for gastric variceal bleeding and risky gastric varices: a 10-year experience.

Abstract: Background and Aim: Balloon-occluded retrograde transvenous obliteration (B-RTO) is a new alternative treatment for gastric varices (GVx), but the long-term efficacy is not known. We investigated the long-term effects of B-RTO on rebleeding, prevention of first bleeding, mortality and occurrence of risky esophageal varices (EVx). Methods: B-RTO was performed in 68 cirrhotic patients with GVx. Twenty patients had recent bleeding, transiently treated by endoscopic Histoacryl injection or balloon tamponade. Forty-eight patients had varices likely to bleed, but no bleeding. After B-RTO, the recurrent bleeding, occurrence of EVx and mortality over the long-term were evaluated. Results: B-RTO was successfully performed in 63 of 68 patients (92.6%). Varices eradication was confirmed by endoscopy in 61 of 63 patients (96.6%). During follow up, GVx bleeding occurred in two patients (3.2%). The 8-year cumulative rebleeding rates of patients with bleeding and risky GVx were 14% and 0%, respectively. Risky EVx occurred in 10 patients (17%) and the cumulative occurrence rate was 22% in 8 years. The cumulative occurrence rate of risky EVx was higher in GVx with EVx (GOV2-GVx) compared to GVx without EVx (IGV1, P < 0.05). No ectopic variceal bleeding occurred. No patients died from variceal bleeding. Hepatocellular carcinoma was the only significant prognostic factor (P < 0.05). Conclusion: B-RTO is beneficial over the long-term, despite worsening EVx in some patients, because of excellent treatment efficacy and improved mortality. We believe that B-RTO can become a first-choice radical treatment following hemostasis for gastric variceal bleeding and prophylactic treatment for risky GVx.

Oxidative stress in alcoholic liver disease: Role of NADPH oxidase complex

Abstract: Alcohol is a well-known risk factor for liver damage and is one of the major causes of liver disease worldwide. Chronic intake of alcohol, over a certain limit, inevitably leads to hepatic steatosis. If the injury persists, steatosis with concomitant tumor necrosis factor-alpha and other cytokines, progresses to steatohepatitis, fibrosis and finally cirrhosis. Among the multiple factors involved in the process of alcohol-induced liver injury, a crucial role is played by oxidative stress. Several mechanisms during ethanol metabolism result in reactive oxygen species (ROS) production. Although the main site of ethanol metabolism is hepatocytes, other mechanisms are involved in alcohol-induced liver injury. Specifically, in the ROS production activity, an important role is played by the NADPH oxidase complex. NADPH oxidase is expressed in hepatocytes, hepatic stellate cells and Kupffer cells in the liver. Studying NADPH oxidase gives new insights into alcohol-induced liver damage and provides new direction for future therapeutic strategies.

Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection.

Abstract: The discovery of "ground glass" hepatocytes (GGH) that contain hepatitis B virus (HBV) surface antigens by Hadziyannis and Popper in 1973 represents a historical landmark in the pathology of chronic HBV infection. Different types of GGH have been correlated to the expression patterns of surface/core antigens and the stages of virus replication. The original two types (designated types I & II) of GGH were found to contain specific pre-S mutants with deletions over either pre-S1 or pre-S2 regions, respectively. Type II GGH consistently harbor pre-S2 deletion mutants, which can escape from immune attack and grow prefer- entially to form clusters. Both types of pre-S mutants can induce endoplasmic reticulum (ER) stress and oxidative DNA damage. The pre-S2 mutants, albeit inducing a weaker level of ER stress signals, could additionally initiate ER stress-independent retinoblastoma/ adenovirus E2 promoter binding factor/cyclin A signaling through their interaction with c-Jun activation domain binding protein 1 to degrade p27, illustrating the growth advantage of type II GGH. The combined effects of genomic instability and the proliferation of hepatocytes harboring pre-S mutants could potentially lead to hepatocarcinogenesis over the decades of chronic HBV infection. The presence of pre-S mutants in sera was reported to carry a high risk of developing hepatocellular carcinoma (HCC). Furthermore, trans- genic mice harboring pre-S2 mutant plasmids have been shown to develop a dysplastic change of hepatocytes and HCC. Therefore, in addition to being a histological marker of chronic HBV infection, GGH, particularly type II GGH, may represent the preneoplastic lesions of HBV-related HCC.

Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreatography pancreatitis.

Abstract: Background and Aims: Acute pancreatitis following endoscopic retrograde cholangiog- raphy presents a unique opportunity for prophylaxis and early modification of the disease process because the initial triggering event is temporally well defined and takes place in the hospital. We report a prospective, single-center, randomized, double-blind controlled trial to determine if rectal diclofenac reduces the incidence of pancreatitis following cholangiopancreatography. Methods: Entry to the trial was restricted to patients who underwent endoscopic retro- grade pancreatography. Immediately after endoscopy, patients were given a suppository containing either 100 mg diclofenac or placebo. Estimation of serum amylase level and clinical evaluation were performed in all patients. Results: One hundred patients entered the trial, and 50 received rectal diclofenac. Fifteen patients developed pancreatitis (15%), of whom two received rectal diclofenac and 13 received placebo (P < 0.01). Conclusions: This trial shows that rectal diclofenac given immediately after endoscopic retrograde cholangiopancreatography can reduce the incidence of acute pancreatitis.

Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study.

Abstract: Background & Aims Fatty liver is the hepatic manifestation of obesity, but community-based assessment of fatty liver among unselected subjects is limited. We sought to determine the feasibility of and optimal protocol for quantifying fat content in liver in the Framingham Heart Study using multi-detector computed tomography (MDCT) scanning.

Survival analysis of 904 patients with hepatocellular carcinoma in a hepatitis B virus-endemic area.

Abstract: Background and Aim: To investigate the clinical characteristics and survival outcomes of a large cohort of hepatocellular carcinoma (HCC) patients treated at a single institute in a hepatitis B virus (HBV)–endemic area. Methods: Between 2000 and 2003, 904 patients with HCC treated at our institute were enrolled, and followed until 2005. Results: The mean age of the patients was 56 years and 76.3% were HBV-positive. The 1-, 2-, 3-, and 4-year survival rates were 53.8%, 40.0%, 31.4%, and 25.7%, respectively. The 4-year survival rates for Child–Pugh class A patients treated by resection or transarterial chemoembolization (TACE) were 77.3% and 63.2% for those with modified International Union Against Cancer (UICC) stage I or II disease (P = 0.043), and 58.6% and 19.2% for those with modified UICC stage III disease (P < 0.001). In patients with Child–Pugh class A and stage IVa, the median survival times differed between TACE and chemotherapy treatments (6.9 vs 4.0 months, P = 0.003), whereas in patients with stage IVb there was no difference between treatments (8.5 vs 6.1 months, P = 0.173) Serum α-fetoprotein level, presence of portal vein tumor thrombosis, Child–Pugh class, tumor, node, and metastasis stage, and the number and type of HCC were all related to prognosis. Significant differences in survival curves were observed among the Japanese Integrated Staging scores. Conclusions: The results of this study will be helpful in determining the survival outcomes and treatment strategies for HCC patients in HBV-endemic areas.

Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury

Abstract: Accumulation of unfolded or malfolded proteins induces endoplasmic reticulum (ER) stress which elicits a complex network of interacting and parallel responses that dampen the stress. The ER stress response in the liver is controlled by intrinsic feedback effectors and is initially protective. However, delayed or insufficient responses or interplay with mitochondrial dysfunction may turn physiological mechanisms into pathological consequences including apoptosis, fat accumulation and inflammation all of which have an important role in the pathogenesis of liver disorders such as genetic mutations, viral hepatitis, insulin resistance, ischemia/reperfusion injury, and alcoholic and non-alcoholic steatosis. In both alcohol and non-alcohol-induced ER stress, a common candidate is hyperhomocysteinemia. Betaine supplementation and/or expression of betaine-homocysteine methyltransferase (BHMT) promote removal of homocysteine and alleviate ER stress, fatty accumulation and apoptosis in cultured hepatocytes and mouse models. The rapidity and magnitude of homocysteine-induced activation of each of the main ER resident transmembrane sensors including inositol requiring enzyme 1 (IRE-l alpha), activating transcription factor 6 (ATF-6) and RNA-activated protein kinase (PKR)-like ER kinase (PERK) appear different in different experimental models. Dissection and differentiation of ER stress signaling may reveal clues on the specific importance of the ER stress response in contributing to liver injury and thus provide better strategies on prevention and treatment of liver disease.

Endoscopic submucosal resection with a ligation device is an effective and safe treatment for carcinoid tumors in the lower rectum.

Abstract: Background and Aims: Various methods for complete endoscopic resection of rectal carcinoid tumors have been reported; however, the number of cases investigated in each study has been limited. The aim of the present study was to clarify the clinical usefulness of a novel technique named endoscopic submucosal resection with a ligation device (ESMR-L) in a large number of rectal carcinoid tumors. Patients and methods: Between January 1999 and March 2005, a total of 61 patients with 63 rectal carcinoid tumors estimated at 10 mm or less in diameter, without atypical features and resected by ESMR-L were recruited for this analysis. The complete resection rate, complications associated with the procedure, local recurrence, and distant metastases were evaluated. Results: Sixty-one patients were 36 males and 25 females with a mean age of 59 ± 11 years (24–76 years). Tumor size ranged from 2 to 12 mm in diameter, with an average size of 6.4 ± 2.4 mm. Fifty-nine lesions (93.6%) were located in the lower rectum (Rb), three in the upper rectum (Ra) and one in the recto-sigmoid colon (Rs). In total, 60 out of 63 lesions (95.2%) were histologically determined to be completely resected. The complete resection rate for lesions located in the Rb was 98.3%, which was significantly higher than that for lesions in Ra and Rs (50%). Minor bleeding associated with the procedure occurred in five lesions (7.9%), but all cases were successfully managed with hemoclips. Histopathologically, all tumors were located in the submucosal layer, and all were classified as classical-type carcinoids without lymphovascular invasion. Neither local recurrence nor distant metastasis was detected during a median follow-up period of 24 months. Conclusion: In a large number of cases, ESMR-L proved to be a useful and safe procedure to resect rectal carcinoid tumors 10 mm or less in diameter, especially for those located in the Rb.

Liver disease and the renin-angiotensin system: recent discoveries and clinical implications.

Abstract: The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type-1 receptor (AT1) and, together with ACE, these components represent the ‘classical’ axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang-(1–7). Conceptually, ACE2, Ang-(1–7), and its putative receptor, the mas receptor represent an ‘alternative’ axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang-(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang-(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.

Endoscopic diagnosis of early squamous neoplasia of the esophagus with iodine staining: High-grade intra-epithelial neoplasia turns pink within a few minutes

Abstract: Background and Aim: The ability to detect early squamous neoplasia of the esophagus can be enhanced considerably by iodine staining during endoscopic examination; however, there has been no study on distinguishing high-grade intra-epithelial squamous neoplasia from low-grade dysplasia by endoscopic examination. We assumed that high-grade intra-epithelial neoplasia could be identified as iodine-unstained areas more distinct and reddish than low-grade dysplasia after the brown color of iodine solution has faded, because there is almost no remaining glycogen-containing epithelium in high-grade intra-epithelial neoplasia. Methods: Seventy-nine patients who were found to have demarcated iodine-unstained areas (0.5 cm to 1.5 cm at widest part, 121 lesions in total) were studied. After a target lesion was found, the lesion was observed for about 3 min and its discoloration was evaluated. If a light-pink part appeared in the iodine-unstained area, the lesion was regarded as being positive for pink color. If no light-pink part was observed in the lesion within 3 min, the lesion was regarded as being negative for pink color. Results: Thirty-four (87.2%) of the 39 lesions diagnosed as pink-color positive were histologically confirmed to be high-grade intra-epithelial squamous neoplasia or squamous cell carcinoma, whereas only three (3.7%) of the 82 lesions diagnosed as negative for pink color were histologically confirmed to be high-grade intra-epithelial squamous neoplasia (P < 0.0001). Using the pink-color sign as a diagnostic index for high-grade intra-epithelial squamous neoplasia and squamous cell carcinoma, sensitivity was 91.9% and specificity was 94.0%. Conclusion: By using the pink-color sign for endoscopic diagnosis, accurate diagnosis without endoscopic biopsy for iodine-unstained areas was possible.

Low levels of awareness, vaccine coverage, and the need for boosters among health care workers in tertiary care hospitals in India.

Abstract: Background and Aim: The risk of acquiring hepatitis B virus (HBV) infection through exposure to blood or its products is highest amongst health care workers (HCWs). Despite potential risks, a proportion of HCWs never get vaccinated. India is second to China in the numbers of people with chronic HBV. This study aimed to investigate the vaccination practices and the prevalence of HBV infection in HCWs in India. Methods: A total of 2162 HCWs were screened for the presence of serological markers of HBV and hepatitis C virus (HCV). Occult HBV infection was tested by detection of HBV-DNA for surface and core regions by nested polymerase chain reaction in HBsAg-negative and IgG anti-hepatitis core antigen-positive subjects. Results: Only 1198 (55.4%) of the 2162 HCWs screened had been vaccinated; and 964 (44.6%) were not vaccination-status conscious; of these HCWs, 600 (27.7%) had never been vaccinated and 364 (16.4%) were unaware of their vaccination status. Protective (> 10 IU/mL) anti-hepatitis B surface (anti-HBs) antigen titers were seen in only 61.7%. The anti-HBs titers were found to be lower with the passage of time; the median anti-HBs titers in subjects who were vaccinated > 10 years ago were significantly lower than those who had been vaccinated 10 IU/mL. Conclusions: Even today, 28% HCWs in India are unvaccinated and 17% are unaware of their vaccination status. This data suggests that use of hepatitis B immune globulin be mandatory in needle-pricked HCWs in India, and that implementation of awareness strategies is urgent. Since the anti-HBs titers decline in a fair proportion, there is justification for giving a booster dose of vaccine 10 years after primary vaccination to HCWs in India.

What prognostic factors are important for resected intrahepatic cholangiocarcinoma

Abstract: Background and Aim: Our aim was to evaluate the predictive factors for survival and disease-free survival of patients with resected intrahepatic cholangiocarcinoma (ICC) Methods: Between October 1994 and 2005, 97 patients with ICC underwent curative hepatic resection The tumors in 97 patients were reviewed retrospectively to examine the prognosis of ICC Results: The 1-, 3- and 5-year survival rates were 749%, 518% and 311%, respectively The 1-, 3- and 5-year disease-free survival rates were 213%, 64% and 21%, respectively Univariate analysis showed that tumor size, tumor number, the gross type, resection margin status, T-stage and lymph node involvement were significant prognostic factors Multiple tumors and cancer cells in the resection margin were found in multivariate analysis to be significantly related to the prognosis In the multivariate analysis disease free survival was poor for the patients with a large tumor, multiple lesions, a high CA 19-9 level, cancer in the resection margin, advanced T-stage and lymph node involvement Conclusions: The overall 5-year survival rate of ICC was 311% Multiple intrahepatic lesions were a sign of a poor prognosis for ICC Better survival could be achieved by curative resection with a tumor-free margin

Transforming growth factor‐β and hepatocyte transdifferentiation in liver fibrogenesis

Abstract: Currently, hepatic stellate cells (HSC) are thought to be the major fibrotic precursor cells that transdifferentiate to fibrogenic, extracellular matrix producing myofibroblasts in inflammatory liver tissue upon transforming growth factor-beta (TGF-beta) signaling, whereas hepatocytes are thought to respond with apoptosis to this cytokine. Starting out from in vitro experiments with primary hepatocyte cultures and immortalized AML-12 cells, TGF-beta signaling in this cell type was assessed and apoptosis was found to be only a minor effect. Instead, hepatocytes undergo epithelial mesenchymal transition (EMT), a physiological process in embryogenesis and of relevance for cancerous cell transformation. In injured liver, however, this process contributes to the promotion of fibrosis. Already after a few days of culture, hepatocytes lose their epithelial honeycomb-like shape towards a fibroblast-like phenotype. We could demonstrate by microarray analysis that stimulation of hepatocytes with TGF-beta regulates the expression of genes involved in EMT and fibrosis. Among these were, for example, Snail, a known mediator of EMT, and connective tissue growth factor (CTGF), a strong inducer of fibrosis. In a mouse model, hepatocyte-specific overexpression of Smad7 was able to blunt a fibrogenic response after CCl(4) intoxication. These results emphasize the dynamic nature of liver fibrosis, challenge the paradigm of HSC as a crucial source of liver myofibroblasts and hint towards a prominent role for hepatocytes in liver fibrogenesis.

Etiological spectrum of esophageal varices due to portal hypertension in Indian children: is it different from the West?

Abstract: Background and Aim: Information about portal hypertension (PHT) in children is meagre. We therefore studied the spectrum and outcome of PHT in children (≤14 years of age) over a period of 9 years. Methods: PHT was diagnosed on endoscopy (presence of varices) in 517 cases during the study period. The diagnosis of extrahepatic portal venous obstruction (EHPVO) and Budd–Chiari Syndrome (BCS) were made on the basis of ultrasound examination. Cirrhosis was diagnosed on the basis of clinical, biochemical, ultrasound, and liver biopsy (whenever feasible). Noncirrhotic portal fibrosis (NCPF) and congenital hepatic fibrosis (CHF) were diagnosed on liver biopsy. Endoscopic sclerotherapy (EST) was done in all the patients who presented with variceal bleeding and surgery was performed whenever indicated. Results: Causes of PHT included EHPVO in 54%, cirrhosis in 39%, CHF in 3%, NCPF in 2%, and BCS in 2%. Of these, 279 (54%) patients presented with upper gastrointestinal bleeding and this group comprised of EHPVO in 85%, cirrhosis in 10%, CHF in 2.5%, NCPF in 2%, and BCS in 1%. Bleeding was the presenting feature in 85% of EHPVO cases and in 13% of cirrhosis cases. In EHPVO cases, variceal eradication was achieved in 95% of cases with a mean 5 ± 2.4 EST sessions. Surgery was required in 24 cases of EHPVO. Mortality due to bleeding was 1.7% in EHPVO and 30% in cirrhosis. Conclusions: EHPVO and cirrhosis are the two major causes of PHT in children. However, predominant cause of variceal bleeding is EHPVO. EST is an effective method of treatment in EHPVO.

Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors.

Abstract: Background and Aims: Hepatic steatosis is commonly seen in chronic hepatitis C (CHC) patients. It has been reported to be associated with both metabolic factors and viral factors, and affects the severity of fibrosis in CHC. However, the relationship between hepatic steatosis and chronic hepatitis B (CHB) is unclear. The aims of this study were to investigate the frequency of hepatic steatosis in CHB patients, to identify the factors associated with its presence, and assess the relationship between the stage of steatosis and the severity of fibrosis. Methods: Medical records of 153 adult patients with CHB who had undergone a liver biopsy within the past 4 years were included in the study. Results: Body mass index (BMI) and age of CHB patients with steatosis was significantly higher than the patients without steatosis (P < 0.05), as determined by the univariate analysis. Steatosis was found to correlate with the BMI values and alanine aminotransferase (ALT) levels, and ALT levels were associated with hepatitis B virus (HBV)–DNA levels and histology activity index (HAI) scores, stages of fibrosis were associated with the HAI score and HBV–DNA, as determined by the multivariate analysis. In contrast, there was no significant association between advanced stages of fibrosis and steatosis. Conclusion: Our data indicate that hepatic steatosis is more frequently present in CHB patients than in the general population. We hypothesize that steatosis in CHB patients may be due to metabolic factors and the ability of HBV to indirectly facilitate the development of steatosis. In the present study, steatosis in CHB patients was not found to be associated with the severity of fibrosis.

Probiotic administration alters the gut flora and attenuates colitis in mice administered dextran sodium sulfate

Abstract: Background: Probiotics are used in the therapy of inflammatory bowel disease. This study aimed to determine whether prior administration of probiotic lactobacilli and bifidobacteria would prevent disease and change gut flora in an animal model of colitis. Methods: Swiss albino mice received a probiotic mixture (four Lactobacillus and four Bifidobacterium species) or medium (control) for a week prior to induction of colitis by oral 4% dextran sodium sulfate (DSS) for seven days. Appropriate non-colitis controls were used. Histological damage was assessed (n = 5 per group), as was expression of mRNA for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β1 and SOCS-1 in the colonic mucosa (n = 6 per group). Secretion of TNF-α was measured in distal colon organ culture (n = 5–6 per group). Levels of Bacteroides, Bifidobacterium, and Lactobacillus acidophilus in feces were quantified by real time polymerase chain reaction (PCR) targeting 16S rDNA. Results: Compared to untreated DSS colitis, probiotic treatment significantly reduced weight loss (P < 0.05), shifted histological damage to lesser grades of severity (P < 0.001), reduced mRNA expression of TNF-α and TGF-β1 (P < 0.05), and down-regulated production of TNF-α from distal colon explants (P < 0.05). Colitis induced a significant reduction in the relative proportions of Bifidobacterium, Bacteroides and Lactobacillus acidophilus group bacteria in feces, and these levels were significantly increased in probiotic-treated mice compared to DSS mice (P < 0.001). Conclusion: Prior administration of probiotic bacteria reduced mucosal inflammation and damage in DSS-induced colitis. DSS colitis was associated with significant changes in the fecal anaerobic bacterial flora and these changes were modulated by administration of probiotic bacteria.

Quantifying the risk for alcohol-use and alcohol-attributable health disorders: present findings and future research needs.

Abstract: The aim of the present review was to: (i) highlight epidemiological and other studies that have generated important data on the harmful patterns of drinking that increase the risk for chronic diseases, including alcohol dependence, and on the mechanisms by which alcohol produces and, in some instances, may protect against damage; and (ii) discuss a conceptual basis for quantifying risk criteria for alcohol-induced chronic disease based on the quantity, frequency, and pattern of drinking. The relationship between heavy drinking and risk for adverse health conditions such as alcoholic liver disease (ALD), dementia, and alcohol dependence is well known. However, not everyone who drinks chronically develops ALD or dementia, and the major risk factors for disease development and the mechanisms by which this occurs have remained unclear. Large-scale, general population-based studies have provided the evidence by which quantifying the frequency of a pattern of high-risk drinking can be related directly to risk and the severity of alcohol dependence. Cellular and molecular biology studies have identified the major pathways of alcohol metabolism and how genetics and the environment can interact in some individuals to further increase the risk of organ damage. Extant databases should allow scientists and clinicians jointly to develop the framework for quantifying the drinking patterns that increase the risk of alcohol-induced organ pathologies, to develop clinical practice guidelines, such as those used to diagnose other common complex diseases (e.g. diabetes and hypertension), and to propose future studies for refining such guidelines. Attention must be paid to comorbid conditions such as hepatitis B and C infections, HIV, obesity, and environmental exposures other than alcohol. Developing trait and state biomarkers is critical to the process of discovery and to fulfilling the promise of personalized medicine.