Showing papers in "Journal of Gastroenterology and Hepatology in 2003"

Intestinal barrier: an interface between health and disease.

Abstract: The intestine constitutes the largest interface between a person and his or her environment, and an intact intestinal barrier is thus essential in maintaining health and preventing tissue injury and several diseases. The intestinal barrier has various immunological and non-immunological components. The epithelial barrier is one of the most important non-immunological components. Hyperpermeability of this barrier is believed to contribute to the pathogenesis of several gastrointestinal disorders including inflammatory bowel disease, celiac disease and food allergy. Hence, assessing barrier integrity is of the utmost importance. One of the more quantitative gauges for this assessment is transepithelial permeability of various molecular probes, among which sugars are commonly used. Measures of intestinal permeability might also be useful as markers for assessment of prognosis and follow up in various gastrointestinal disorders. The present article is a review of the normal and abnormal functioning of the intestinal barrier, the diseases that can result from loss of barrier integrity, and some promising agents and strategies for restoring barrier normality and integrity.

Hepatic ischemia reperfusion injury: pathogenic mechanisms and basis for hepatoprotection.

Abstract: This review highlights recent advances in our understanding of mechanisms underlying reperfusion injury to the liver after warm hepatic ischemia. Sinusoidal endothelial cells and hepatocytes are targets of injury in the early 'cytotoxic' phase, although participation of apoptosis in the cell-death process remains contentious. Kupffer cells may play an important role as the initial cytotoxic cell type and are likely a source of reactive oxygen species and proinflammatory mediators, particularly tumor necrosis factor (TNF)-alpha. The latter are involved with subsequent neutrophil activation and recruitment. Microcirculatory disruption results from an imbalance between the actions of vasoconstrictors and vasodilators, such as nitric oxide, and also has a major impact on reperfusion injury. There is growing evidence that a brief prior ischemia-reperfusion period, termed 'ischemic preconditioning', is hepatoprotective. This can be mimicked by drugs that produce oxidative stress, and by interleukin-6 and TNF-alpha; both these cytokines are involved with priming hepatocytes to enter the cell cycle. Several mechanisms have been implicated including mobilization of adenosine and activation of adenosine type 2 receptors, nitric oxide, abrogation of TNF synthesis, preservation of energy metabolism, protection of the microcirculation and accelerated cell-cycle entry. A better understanding of preconditioning mechanisms will lead to novel approaches to improve outcomes of liver surgery.

Beneficial effects of terlipressin in hepatorenal syndrome: A prospective, randomized placebo-controlled clinical trial

Abstract: Background and Aim: Hepatorenal syndrome (HRS) occurs in about 18% of cirrhotic patients with ascites and is characterized by intense renal vasoconstriction, low glomerular filtration rate and preserved tubular function and normal renal histology. The aim of the present study was to examine the effects of terlipressin on renal function, systemic hemodynamics and clinical outcome in patients with HRS. Methods: The study was a randomized controlled single-blind trial. We randomly assigned 24 consecutive patients with HRS to treatment with terlipressin 1 mg i.v. at 12-h intervals (group A; n = 12) or placebo at 12-h intervals (group B; n = 12). The end-point of the study was improvement in renal functions defined as reversal of HRS and survival at 15 days. Results: The two groups were comparable at baseline. After treatment with terlipressin, urine output significantly (P < 0.05) increased progressively in group A (day 4, 960 ± 40 mL/24 h; day 8, 1068 ± 56 mL/24 h) compared with group B (day 4, 451 ± 40 mL/24 h; day 8, 291 ± 45 mL/24 h). Creatinine clearance improved (P < 0.05) in group A (day 4, 20.2 ± 2.1 mL/min; day 8, 35 ± 2.8 mL/min) compared with group B (day 4, 11.3 ± 1.3 mL/min; day 8, 9.3 ± 1.7 mL/min). Serum creatinine decreased in group A but not in group B (day 8, 1.6 ± 0.01 compared with 3.9 ± 0.26, P < 0.05). Mean arterial pressure increased significantly (P < 0.05) in group A. Terlipressin administration was associated with transient self-limiting side-effects including crampy abdominal pain in two patients and cardiac arrhythmias in three patients. Five of the 12 patients survived in group A compared with none in group B at day 15 (P < 0.05) and all survivors had reversal of HRS. Conclusion: In patients with HRS, terlipressin significantly improved renal functions and systemic hemodynamics, and showed a trend towards better clinical outcome. The drug merits further evaluation with different dosages and longer schedules.

Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region?

Abstract: Non-alcoholic steatohepatitis (NASH), is a critical link in the chain of metabolic fatty liver disorders that spans steatosis to cryptogenic cirrhosis. It is the hepatic manifestation of the insulin resistance (or metabolic) syndrome, and provides a clue to understanding fibrotic progression of other chronic liver diseases, particularly hepatitis C. Non-alcoholic steatohepatitis is often the first clinical indication of insulin resistance, with its complications of high blood pressure, coronary heart disease and type 2 diabetes. Among those with risk factors, NASH is common: present in at least 20% of obese adults or children with or without type 2 diabetes, and at least 5% of those overweight. With emerging urbanization, increasing affluence and behavioral changes of physical inactivity and high fat/energy-excessive diet, type 2 diabetes has become common in Asia and the western Pacific rim. The rates range from 7-40%, which in countries like Japan represents a 3-20-fold increase (depending on age) over the last 20 years. The increase is associated with central adiposity, insulin resistance, hepatic steatosis and NASH. After cancer, cirrhosis from NASH is now the second most common age-related cause of death in type 2 diabetes. Reversing these trends must become a public health priority; the first awakenings were evident in Taiwan at the time of this meeting. In order to stimulate clinicians to think more about the importance of metabolic liver disease for development of cirrhosis, this review will cover clinical and laboratory features, natural history and an approach to diagnosis and management of NASH. Some emerging concepts on pathogenesis will be mentioned briefly, but the emphasis will be on the potency of lifestyle adjustments (physical activity and diet) to prevent or reverse fatty liver disorders.

Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies.

Abstract: Background and Aim: The methionine choline-deficient (MCD) diet leads to steatohepatitis in rodents. The aim of the present study was to investigate species, strain and sex differences in this nutritional model of non-alcoholic steatohepatitis (NASH). Methods: Male and female Wistar, Long–Evans and Sprague–Dawley rats, and C57/BL6 mice (n = 6 per group) were fed a MCD diet for 4 weeks. Control groups received an identical diet supplemented with choline bitartrate (0.2% w/w) and methionine (0.3% w/w). Liver pathology (steatosis and inflammation) and ultrastructure, liver lipid profile (total lipids, triglycerides, lipid peroxidation products), liver : body mass ratios and serum alanine aminotransferase (ALT) levels were compared between these groups. Results: The MCD diet-fed male rats developed greater steatosis (P < 0.001), had higher liver lipid content (P < 0.05) and had higher serum ALT levels (P < 0.005) than did female rats. Wistar rats (both sexes) had higher liver lipid levels (P < 0.05), serum ALT levels (P < 0.05), and liver mass : body mass ratios (P < 0.025) than did Long–Evans and Sprague–Dawley rats. In female groups, Wistar rats showed greater fatty change than did the other two strains (P < 0.05). All rats fed the MCD diet developed hepatic steatosis, but necrosis and inflammation were minor features and fibrosis was absent. Compared with Wistar rats, male C57/BL6 mice showed a marked increase in inflammatory foci (P < 0.001), end products of lipid peroxidation (free thiobarbituric acid reactive substances) (P < 0.005), and mitochondrial injury, while showing less steatosis (P < 0.005), lower hepatic triglyceride levels, (P < 0.005) and lower early lipid peroxidation products (conjugated dienes and lipid hydroperoxides; P < 0.005 and P < 0.01, respectively). Conclusions: The Wistar strain and the male sex are associated with the greatest degree of steatosis in rats subjected to the MCD diet. Of the groups studied, male C57/BL6 mice develop the most inflammation and necrosis, lipid peroxidation, and ultrastructural injury, and best approximate the histological features of NASH.

Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer.

Abstract: Background and Aims: Irinotecan (CPT-11) is a chemotherapeutic drug for cancer that causes severe diarrhea by an uncertain mechanism. The aim of the present study was to investigate the time-course of apoptosis and whole intestinal damage after irinotecan to further elucidate the mechanism behind the diarrhea. Methods: Groups of breast cancer-bearing dark agouti (DA) rats were treated with 100, 150 or 200 mg/kg doses of irinotecan or vehicle control daily for two days, and killed at 6, 24, 72 or 96 h after treatment. Apoptosis and morphometry were examined in both the small and large intestines. Histopathology and goblet cell numbers were recorded. Data were analyzed using the Peritz′F-test. Results: Irinotecan increased apoptosis and caused villous atrophy and crypt hypoplasia in the small intestine, and increased apoptosis, crypt hypoplasia, crypt dilation and mucus secretion in the large intestine. Irinotecan at 100 and 150 mg/kg caused crypt hypoplasia at 6 and 24 h, with rebound hyperplasia at 72 and 96 h. At 200 mg/kg, irinotecan caused a more pronounced crypt hypoplasia earlier and all animals died by 96 h. Apoptosis peaked at 6 h and remained elevated over the remainder of the time-points. This was not dose-dependent. Irinotecan at all doses altered colonic, but not jejunal, goblet cells. Irinotecan increased colonic mucus secretion. Conclusions: We conclude that irinotecan causes diarrhea by inducing apoptosis and hypoproliferation in both the small and large intestines, and causes colonic damage with changes in goblet cells and mucin secretion.

Non‐alcoholic fatty liver syndrome: A hepatic consequence of common metabolic diseases

Abstract: Background and Aims: The association of liver steatosis with a number of common metabolic conditions has been suggested. The aim of the present study was to evaluate the clinical features of subjects with different severities of steatosis. Methods: The present study was performed in 282 consecutive patients with ‘bright liver’ at ultrasonography and in 58 subjects without steatosis. They had no history of alcohol abuse and negative tests for the presence of hepatitis B and C virus. Patients underwent clinical examination, anthropometry, laboratory tests and routine liver ultrasonography. Steatosis was graded as absent, mild, moderate and severe. Results: A progressive increase in the prevalence of obesity (P < 0.001), type 2 diabetes (P < 0.001), alanine aminotransferase (ALT) elevation (P < 0.001) and hypertriglyceridemia (P < 0.001), and a decrease of hypercholesterolemia (P < 0.05) was observed from the control group to the groups with mild, moderate and severe steatosis. More than half the subjects with liver steatosis had insulin resistance metabolic syndrome. Obesity, diabetes and hypertriglyceridemia were more common by 5.3-fold, 4.0-fold, and 6.7-fold, respectively, in subjects with severe steatosis, as compared to controls. Prevalence of obesity, diabetes and hyperlipidemia was significantly higher in subjects with fatty liver and ALT elevation. Conclusion: Fatty liver can be considered as the hepatic consequence of common metabolic diseases. © 2003 Blackwell Publishing Asia Pty Ltd

Oval cell-mediated liver regeneration: Role of cytokines and growth factors.

Abstract: In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation.

Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy.

Abstract: Hepatitis flares or acute exacerbations, defined as an abrupt elevation of serum alanine aminotransferase (ALT) over fivefold the upper limit of normal (ULN), of chronic hepatitis B virus (HBV) infection are the results of HLA-I restricted, cytotoxic T lymphocyte (CTL)-mediated immune response against HBV and its downstream mechanisms. Higher ALT levels reflect a more vigorous immune response and a more extensive hepatolysis that, in the extreme situation, may lead to decompensation and failure. In contrast, higher ALT also reflects a more robust immune clearance of HBV and, therefore, a higher chance of HBV-DNA loss and hepatitis B e antigen (HBeAg) seroconversion, both in the setting of natural course and drug therapy. Alanine aminotransferase of fivefold the ULN appears to be a significant cut-off level to categorize the patients in terms of endogenous immune response against HBV. Patients with ALT levels less than fivefold the ULN or those with a less vigorous immune response require immunomodulation to induce robust immune response to enhance HBV clearance. In contrast, those with a more vigorous immune response or those with ALT flare over fivefold the ULN should be monitored closely for spontaneous HBV clearance/HBeAg seroconversion or to start direct antiviral therapy in time to prevent the occurrence or deterioration of hepatic decompensation. In conclusion, a better understanding of the pathogenetic mechanisms and natural course of hepatitis flares, wiser selection of patients and the timing of drug therapy are crucial to achieve better treatment results.

Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice

Abstract: Background and aims Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine thought to be involved in the pathogenesis of inflammatory bowel disease. To further define the role of TNF-alpha in intestinal inflammation, we studied the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of TNF-alpha gene. Methods Acute colitis was induced in female TNF-alpha-/- and TNF-alpha+/+ mice by administering 4.5% DSS orally in drinking water for seven days. The colonic mucosal injury and inflammation was evaluated based on body weight changes, total colon length, luminal hemoglobin, and histological findings. Colonic mRNA expression for inducible nitric oxide synthase (iNOS), TNF-alpha, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured by reverse transcription polymerase chain reaction (RT-PCR), and nuclear factor kappaB (NF-kappaB) activation was evaluated by electrophoretic mobility shift assay. Results In each assessment, colonic injury was significantly aggravated in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. The survival rate of TNF-alpha-/- mice on day seven was 40%; in contrast, all TNF-alpha+/+ mice were alive. Histological study also showed an enhanced infiltration of inflammatory cells, especially neutrophils, and mucosal cell disruption in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. On day seven, mRNA levels of IFN-gamma and IL-4 in the colons of TNF-alpha-/- mice were faint or not detected; in contrast, those of TNF-alpha+/+ mice were detected. Although the expression of iNOS mRNA and luminal nitrite levels were similarly increased in both mice on day seven, this induction was delayed in TNF-alpha-/- mice during the early phase. The degree of NF-kappaB binding activity seemed to be similar between the two types of mice on day seven. Conclusion DSS-induced inflammation is significantly enhanced in TNF-alpha-/- mice compared to TNF-alpha+/+ mice. These data suggest that persistent and marked blockage of TNF-alpha bioactivity may provide a detrimental effect on acute intestinal inflammation.

Differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in colorectal cancer.

Abstract: Background: The presence of hypoxic cells in solid tumors has been suggested to contribute to the malignant progression of various tumors. Recently, we reported an activation of heat shock transcription factor (HSF) and expression of heat shock proteins (Hsp) in murine tumor cells by hypoxia. Methods: To search for a possible role of Hsp in the malignant progression of human tumors, we analyzed the expression profiles of Hsp family proteins in weakly and highly metastatic human colorectal cancer (CRC) cell lines. We also analyzed the expression profiles of Bcl-2 family proteins because the altered expression of these proteins has been demonstrated in various solid tumors. Results: In the present paper we showed among various Hsp and Bcl-2 family proteins that the expression of Hsp70 and Hsp110 was elevated in highly metastatic CX-1 and HT-29 cells, while the expression of Bcl-2 was elevated in weakly metastatic MIP-101 and Clone A cells. Subsequent immunohistochemical analysis of 81 primary human CRC tissues demonstrated that the expression of Hsp70 and Hsp110 was highly correlated with the advanced clinical stages and positive lymph node involvement. The expression of Bcl-2, in contrast, was correlated to the early clinical stage and negative lymphovascular invasion. Conclusion: Taken together, our study demonstrated for the first time a differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in CRC. We suggest that the molecular mechanisms underlying the differential expression of Hsp and Bcl-2 family members deserves a more rigorous future study, the results of which might offer novel modes of rationale and strategy to predict and manipulate the malignant progression of colorectal cancers.

Emerging role of calprotectin in gastroenterology

Abstract: Calprotectin is a calcium and zinc binding protein of the S100 family derived predominantly from neutrophils and monocytes. It is detectable in body fluids and tissue samples and is emerging as a valuable marker in the diagnosis, and the monitoring and determining of the prognosis of commonly encountered gastroenterological conditions. Fecal calprotectin, in particular, has for a long time been regarded as a promising marker of gastrointestinal pathology and has now been established as a routine test in Norway and at several centers in the UK.

Balloon-occluded retrograde transvenous obliteration improves liver function in patients with cirrhosis and portal hypertension

Abstract: Background and Aim: Balloon-occluded retrograde transvenous obliteration (B-RTO) is a novel therapeutic method for the treatment of large gastric fundal varices with spontaneous splenorenal shunt (SRS) However, the effects of B-RTO on liver function remain unknown Methods: Fourteen patients with portal hypertension and gastric varices with SRS were studied, consisting of four patients with acute bleeding, five with high-risk varices, and five with refractory portosystemic encephalopathy Hepatic venous catheterization was performed to evaluate hepatic blood flow and liver function using the continuous indocyanine green (ICG) infusion method To assess the metabolic activity of the hepatocyte, the intrinsic clearance of ICG was calculated In all patients, endoscopic study was performed before and 1 week and 1 month after the B-RTO, and followed every 6 months thereafter After baseline measurements, B-RTO was performed Four weeks after the B-RTO, the same catheter measurements were repeated Results: The B-RTO was successful in all patients Contrast-enhanced computed tomography showed complete obliteration of the SRS prior to the follow-up measurements Endoscopic eradication of the fundal varices was obtained 6 months after B-RTO in all patients and encephalopathy was improved within 1 week after B-RTO Following the B-RTO, hepatic blood flow (441 ± 214 vs 668 ± 299 mL/min, P < 00001) and the intrinsic clearance of ICG (233 ± 123 vs 285 ± 148 mL/min, P < 005) were significantly increased Furthermore, intrahepatic resistance decreased after the B-RTO (P < 0005) Conclusion: From short-term assessment, B-RTO increases hepatic blood flow and improves the metabolic activity of the liver in patients with portal hypertension

Increasing incidence of Crohn's disease in Victorian children.

Abstract: Background: The incidence of Crohn's disease has been increasing in Western communities, but there are no published studies which have examined this change in children in Australia. The centralization of pediatric gastroenterology services in Victoria provides an opportunity to examine these changes within one state. Methods: We undertook a retrospective study over a 31-year period of all children aged 16 years or less initially diagnosed with Crohn's disease at either the Royal Children's Hospital, or Monash Medical Center, Melbourne, Victoria. Results: We identified 351 patients who met the diagnostic criteria between 1971 and 2001. The incidence of Crohn's disease in children aged 16 years or less rose from 0.128 to 2.0 per 100 000 per year over the three decades (r = 0.964, P < 0.01). There was a disproportionate over-representation of children from an urban background (incidence rate ratio 1.66, 95% CI 1.28–2.16). Children currently being diagnosed had on average a lower erythrocyte sedimentation rate (ESR) and higher albumin than in previous decades. The use of flexible endoscopy has increased markedly (1970s: 60%; 1990s: 96%, P < 0.05) and the proportion of children recognized at diagnosis with upper gastrointestinal and colonic involvement has increased significantly. Conclusion: There has been a significant increase in the incidence of Crohn's disease in Victorian children. The pattern of disease has also changed with colonic disease now more frequent, and inflammatory indices less abnormal. The increased use of endoscopy has established the frequent involvement of the upper gastrointestinal tract.

Wnt signaling in hepatocellular carcinoma: analysis of mutation and expression of beta-catenin, T-cell factor-4 and glycogen synthase kinase 3-beta genes.

Abstract: Background and aims Hepatocellular carcinoma (HCC) is a common killer cancer in the world. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of several human cancers including HCC. The goal of the present study was to investigate the mechanism of inappropriate activation of the Wnt pathway in hepatocarcinogenesis. Methods We analyzed the alterations of three key components of the Wnt pathway: beta-catenin, glycogen synthase kinase (GSK)-3beta and T-cell factor (Tcf)-4 in 34 HCC and paracancerous normal liver by immunohistochemistry, polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP), direct sequencing, and quantitative real-time reverse transcription (RT)-PCR. Results We found that 61.8% (21/34) of all HCC examined showed an abnormal beta-catenin protein accumulation in the cytoplasm or nuclei. The RT-PCR-SSCP and direct sequencing showed that beta-catenin exon 3 mutations existed in 44.1% (15/34) of the HCC. No mutations of GSK-3beta or Tcf-4 were detected in HCC. Moreover, messenger RNA of beta-catenin and Tcf-4, but not GSK-3beta, was found to be overexpressed in HCC. On analyzing the relationship between alterations of beta-catenin or Tcf-4 and C-myc or Cyclin D1 expression, we found that mutations of beta-catenin, as well as overexpression of beta-catenin or the Tcf-4 gene were independently correlated with C-myc gene overexpression in HCC. Conclusion Our present findings strongly suggest that mutations of beta-catenin, as well as overexpression of beta-catenin and the Tcf-4 gene, independently activate the Wnt pathway in HCC, with the target gene most likely to be C-myc.

Prevalence of irritable bowel syndrome in young adult Malaysians: A survey among medical students

Abstract: Background and Aims: Irritable bowel syndrome (IBS) is a common functional bowel disease in the West. Information on the prevalence of IBS in the Asian population is relatively scanty. The aims of the present study were to determine the prevalence of IBS and to assess the symptom subgroups based on the predominant bowel habit in a young adult population of Asian origin. Methods: Basic demographic data and symptoms of IBS using the Rome I criteria were sought using a questionnaire administered to all apparently healthy students in a medical school. Other questions asked related to alcohol intake, smoking, chili consumption, dietary fiber intake, and to psychological and psychosomatic symptoms of anxiety, depression, insomnia, headache, and backache. The health-care seeking behavior of the subjects was also analyzed. Results: Of the 610 questionnaires administered, 533 complete responses were received (response rate of 87.4%). The responders comprised 229 men (43.0%) and 304 (57.0%) women with a mean age of 22 ± 1.8 years. The ethnic distribution was Malays 278 (52.2%), Chinese 179 (33.6%), Indians 46 (8.6%), and others 30 (5.6%). Eighty-four (15.8%) reported symptoms consistent with the diagnosis of IBS, predominantly women. Sixty-five (77.4%) and six (7.1%) were of the constipation-predominant and diarrhea-predominant IBS subgroups, respectively. Thirteen (15.5%) subjects fell into the non-specific IBS subgroup. The self-reported psychological and psychosomatic symptoms of anxiety (P = 0.02), depression (P = 0.002), insomnia (P = 0.006), headache (P = 0.04), and backache (P = 0.006) were encountered more frequently in the subjects with IBS. Only 13.1% of the IBS group had consulted their health-care practitioner, and 20.2% reported self-medication. Conclusions: Symptoms supportive of the diagnosis of IBS were common among young Malaysians, with a prevalence rate of 15.8%. There were significantly more women with IBS than men. Within the IBS population, the majority (77.4%) was of the constipation-predominant IBS subgroup. A significantly higher prevalence of psychological and psychosomatic symptoms was found in individuals with IBS. Only a minority sought medical advice for their symptoms.

Geographical difference in antimicrobial resistance pattern of Helicobacter pylori clinical isolates from Indian patients: Multicentric study.

Abstract: Aim: To assess the pattern of antimicrobial resistance of Helicobacter pylori isolates from peptic ulcer disease patients of Chandigarh, Delhi, Lucknow, Hyderabad and Chennai in India, and to recommend an updated anti-H. pylori treatment regimen to be used in these areas. Methods: Two hundred and fifty-nine H. pylori isolates from patients with peptic ulcer disease reporting for clinical management to the Post Graduate Institute of Medical Education and Research, Chandigarh; All India Institute of Medical Sciences, New Delhi; Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow; Deccan College of Medical Sciences and Allied Hospitals, Hyderabad; and hospitals in Chennai in collaboration with the Dr ALM Post Graduate Institute of Basic Medical Sciences were analyzed for their levels of antibiotic susceptibility to metronidazole, clarithromycin, amoxycillin, ciprofloxacin and tetracycline. The Epsilometer test (E-test), a quantitative disc diffusion antibiotic susceptibility testing method, was adopted in all the centers. The pattern of single and multiple resistance at the respective centers and at the national level were analyzed. Results: Overall H. pylori resistance rate was 77.9% to metronidazole, 44.7% to clarithromycin and 32.8% to amoxycillin. Multiple resistance was seen in 112/259 isolates (43.2%) and these were two/three and four drug resistance pattern to metronidazole, clarithromycin, amoxycillin observed (13.2, 32 and 2.56%, respectively). Metronidazole resistance was high in Lucknow, Chennai and Hyderabad (68, 88.2 and 100%, respectively) and moderate in Delhi (37.5%) and Chandigarh (38.2%). Ciprofloxacin and tetracycline resistance was the least, ranging from 1.0 to 4%. Conclusion: In the Indian population, the prevalence of resistance of H. pylori is very high to metronidazole, moderate to clarithromycin and amoxycillin and low to ciprofloxacin and tetracycline. The rate of resistance was higher in southern India than in northern India. The E-test emerges as a reliable quantitative antibiotic susceptibility test. A change in antibiotic policy to provide scope for rotation of antibiotics in the treatment of H. pylori in India is a public health emergency.

Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time

Abstract: Background: In tropical sprue (TS), response to antibiotics may suggest a role for bacterial contamination of the small bowel, which is known in diseases with prolonged orocecal transit time (OCTT). Methods: We studied 13 patients with TS (diagnosed by standard criteria) for frequency, nature and degree of bacterial contamination of the small bowel by quantitative culture of jejunal aspirate, glucose hydrogen breath test (GHBT), and OCTT by lactulose hydrogen breath test before and after treatment. Twelve patients with constipation-predominant irritable bowel syndrome (IBS) and 12 healthy subjects served as controls. Results: Ten of 13 patients with TS had bacterial contamination compared with 3/12 with IBS (all aerobic, P < 0.05). Median colony count in TS (36 000 CFU/mL, 400 to < 100 000) was higher than IBS (700 CFU/mL, 100-1000, P < 0.05). Gram-negative aerobic bacilli were commonly isolated in TS but not in IBS. Median OCTT was longer in TS (180 m, 40 - 240) than IBS (110 m, 70 -150, P = 0.008) and healthy subjects (65 m, 40 - 110, P = 0.0007, Wilcoxon rank sum test). Orocecal transit time in TS correlated with fecal fat (Spearman's rank correlation coefficient 0.69, P < 0.05). Orocecal transit time and fecal fat, repeated in 8/13 patients, decreased with treatment for TS (195 m, 130-240 vs 125 m, 90-200, P = 0.02; 8 g/24 h, 6.8-19.6 vs 7 g/24 h, 4.2-9, P = 0.04, respectively). Conclusion: Aerobic bacterial contamination of the small bowel is common in patients with TS. Prolonged OCTT in TS correlated with fecal fat and normalized in a subset of patients after treatment.

c‐kit Gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors

Abstract: Background and Aim: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the human gut. They frequently have gain-of-function mutations of the c-kit gene, which encodes a receptor, tyrosine kinase. The mutations were found at exon 11 in most cases, and either at exon 9 or at exon 13 in rare cases. Recently, we found a family with multiple GIST and a gain-of-function mutation at exon 17. The family was the first reported GIST case with c-kit gene mutation at exon 17 including sporadic GIST. Although we previously reported that the c-kit gene mutation at exon 17 was not detected in 124 sporadic GIST by single-strand conformation polymorphism (SSCP) analysis, the mutation at exon 17 observed in the familial GIST was detectable by the use of direct sequencing but not by our SSCP method. In the present study, we examined the mutations at exon 17 and exon 13 by using direct sequencing. Methods: Genomic DNA was extracted from formalin-fixed, paraffin-embedded GIST tissues. We could obtain 143 sporadic GIST cases appropriate for DNA analysis at exon 17 and 141 at exon 13. Exons 17 and 13 were amplified by using polymerase chain reaction and direct sequencing was conducted. Results: No mutation was found at exon 17, and only one case with the mutation at exon 13 was observed. The GIST with the mutation at exon 13 was large and showed frequent mitosis, and the patient died of the recurrent GIST 3 years after the first operation. Conclusion: The mutation at exons 17 or 13 was considered to be very rare in sporadic GIST.

Australian men's experiences of living with hepatitis C virus: results from a cross-sectional survey

Abstract: Background: Of the estimated 160 000 Australians currently infected with the hepatitis C virus (HCV), over one-third are women and very few have received clinical treatment, with most managing their illness in non-specialist settings. Little is known about the experiences of women living with HCV in the general community. The present study provides the results from the first comprehensive social survey of Australian women's experiences of living with HCV. Methods: In 2000, a questionnaire was administered to a largely non-clinical sample of women with HCV (n = 462) living in the state of Victoria and the Australian Capital Territory, Australia. The questionnaire was self-administered with a return rate of 75%. The mean age was 35 years and 83% were ‘current’ or ‘past’ injecting drug users. The mean time since diagnosis was 4.6 years (SD = 4.0) and the mean time since infection was 10.5 years (SD = 8.2). Results: Fifty-eight percent of women reported experiencing symptoms related to their HCV, the most common being tiredness (78%) and nausea (44%). Of the sample, 56% currently saw a doctor for their HCV, and while 52% had ever been referred to a specialist, only 17% of the total sample had ever begun interferon-based combination or monotherapy. Forty-eight percent of women reported experiencing less favorable treatment by a health professional because of their HCV. Age-related self-assessed health status was significantly lower than Australian norms, as were SF-12 physical and mental health scores. The SF-12 physical and mental health scores were highly correlated, indicating a significant physical and mental health burden associated with HCV. Conclusion: The social, physical and mental health needs of women living with HCV are considerable. Most women had not accessed specialist treatment and the response of the primary health care system to HCV-related women's health issues requires improvement. © 2003 Blackwell Publishing Asia Pty Ltd

Epidemiology of autoimmune liver disease.

Abstract: Primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are chronic liver diseases that likely have an autoimmune basis to their pathogenesis Although significant strides have been made in the clinical management of these conditions, their pathogenesis remains obscure Understanding of various epidemiological factors may shed light on predisposing or causative factors for these diseases Most is known about the epidemiology of PBC, with only minimal information on that of PSC and AIH In this review, the current data on the epidemiology of PBC, AIH and PSC are summarized and suggestions are made for future work in this important area

Asian-Pacific consensus statement on the management of chronic hepatitis B: an update.

Abstract: Background/Aims: A large amount of new data on the treatment of chronic hepatitis B has become available such that the 2003 consensus statement requires revision and update. Methods: New data were presented, discussed and debated in an expert pre-meeting to draft a revision. The revised contents were finalized after discussion in a general meeting of APASL. Results: Conceptual background, including the efficacy and safety profile of currently available and emerging drugs, was reviewed. Nineteen recommendations were formed and unresolved issues and areas for further study were suggested. Conclusion: The current therapy of chronic hepatitis B is modestly effective but not satisfactory. The development of new drugs and new strategies is required to further improve the outcomes of treatment.

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection.

Abstract: Background and Aim: Evidence showing a higher prevalence of diabetes mellitus (DM) in patients with chronic hepatitis C virus (HCV) infection has been accumulating. However, the reason why chronic HCV infection promotes DM remains unknown. In the present study, the authors focused on non-cirrhotic and non-diabetic patients with chronic HCV infection and evaluated the factors responsible for increases in insulin resistance. Methods: Fifty-six patients diagnosed with HCV-related chronic liver disease were included. Biochemical information including body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase, cholinesterase, triglyceride, total cholesterol, hemoglobin, platelet count, glycosylated hemoglobin, immunoreactive insulin (IRI), and serum levels of tumor necrosis factor (TNF)-α and HCV-RNA were determined using venous blood samples obtained from each patient after overnight fasting. Homeostasis model assessment of insulin resistance (HOMA-IR), a simple and convenient measure of insulin resistance, was also calculated. The relationship between the stage of liver fibrosis and HOMA-IR, and the clinical factors responsible for the increase in HOMA-IR in non-diabetic patients was investigated. Results: Homeostasis model assessment of insulin resistance and IRI levels increased parallel with the progression of fibrosis. Among the non-diabetic patients with mild to moderate liver fibrosis, BMI, serum levels of AST and TNF-α were related with HOMA-IR (BMI: r = 0.395, P = 0.041; AST: r = 0.465, P = 0.014; TNF-α: r = 0.396, P = 0.040). In contrast, HOMA-IR related to TNF-α (r = 0.526, P = 0.013) in non-diabetic patients with advanced liver fibrosis. Conclusion: Collectively, hepatic fibrosis and inflammation appear to play key roles in the increase in insulin resistance in patients with chronic HCV infection.

Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C

Abstract: Background and Aim: Hyaluronic acid (HA) is a glycosaminoglycan synthesized by hepatic stellate cells that has been shown to correlate with liver fibrosis in chronic hepatitis C (HCV) patients. However, its use in monitoring fibrosis over time has not been established. The aim of the present study was to assess the serial relationships between HA and liver fibrosis before and after treatment. Methods: Seventy-six previously untreated chronic HCV patients received interferon-based therapy over 48 weeks. Serum HA levels were measured and liver biopsies were obtained at baseline, and 24 weeks post-treatment. Histological fibrosis was assessed by using the Knodell and METAVIR scoring systems. Results: Knodell fibrosis was evaluated in 76 patients; METAVIR fibrosis in 72 patients. Following treatment, patients were grouped into those with increased fibrosis (Knodell = 17; METAVIR = 16), no change (Knodell = 50; METAVIR = 45), or decreased fibrosis (Knodell = 9; METAVIR = 11), relative to baseline. Moderate correlations between HA and fibrosis scores were found before treatment (Knodell R = 0.45; METAVIR R = 0.40) and post-treatment (Knodell R = 0.45; METAVIR R = 0.61). However, changes in HA correlated poorly with changes in fibrosis scores over the study period (Knodell R = 0.11; METAVIR R = 0.06). There was poor qualitative agreement between the direction of HA change and the direction of change in fibrosis scores (Knodell kappa = 0.04; METAVIR kappa = 0.08). The sus-tained virological response group (n = 18) had a significantly decreased mean HA compared with non-responders (−27.9 vs 21.7 µg/L; P = 0.009), but pretreatment HA did not predict a response. Conclusions: Serum HA showed a modest association with hepatic fibrosis, and remains a useful non-invasive marker. However, serum HA alone has limited value in predicting histological changes over a treatment period.

Lactobacillus gasseri OLL2716 as a probiotic in clarithromycin-resistant Helicobacter pylori infection.

Abstract: Backgrounds and Aim: Clarithromycin (CAM)-resistant Helicobacter pylori sometimes offers serious problems with eradication by antibiotics. The aim of this study was to determine whether a probiotic can be an alternative therapy in CAM-resistant Hp infection. Methods: The effects of Lactobacillus gasseri (strain OLL2716) on the growth of CAM-susceptible and CAM-resistant H. pylori and interleukin (IL)-8 production provoked by these strains were examined by in vitro experiments. Moreover, mice were infected with these CAM-susceptible or CAM-resistant H. pylori, and were treated with CAM or L. gasseri. Results: In vitro experiments demonstrated that L. gasseri inhibited the growth of H. pylori and suppressed H. pylori-associated IL-8 production. Such effects were noted in CAM-resistant and CAM-susceptible H. pylori. Similarly, in an in vivo model of H. pylori infection, H. pylori colonization was significantly decreased by L. gasseri. Conclusion: Therefore, L. gasseri was found to act as a probiotic in CAM-resistant H. pylori infection.

Steatosis in chronic hepatitis C: association with increased messenger RNA expression of collagen I, tumor necrosis factor-alpha and cytochrome P450 2E1.

Abstract: Background: Increased levels of tumor necrosis factor (TNF)-alpha and oxidative stress have been implicated as factors contributing to hepatic injury in fatty liver diseases. As steatosis is associated with an accelerated progression of fibrosis in chronic hepatitis C (HCV), we hypothesized that the messenger (m)RNA expression of genes involved with the production of reactive oxygen species, inflammation and cellular injury would be increased in liver tissue from subjects with steatosis and chronic HCV. Methods: Real-time polymerase chain reaction was performed to determine relative mRNA expression levels of collagen I, TNF-alpha, cytochrome P450 2E1 (CYP 2E1), transforming growth factor-beta1 and CD14 in liver biopsies from 38 patients with chronic HCV. The mRNA expression levels were compared between subjects with and without steatosis, fibrosis, and inflammation. Results: Multivariate analysis demonstrated that collagen I mRNA expression was increased by 199% in steatosis (P = 0.02), 85% in moderate to severe fibrosis (P = 0.02) and 157% in inflammation (P = 0.03). Livers of patients with steatosis also had an increase in TNF-alpha mRNA expression by 50% (P = 0.03) and CYP 2E1 expression by 37% (P = 0.04) compared with non-steatotic livers. Tumor necrosis factor-alpha protein was localized to Kupffer cells, bile ducts and portal inflammatory cells by immunohistochemistry. Conclusion: Increased expression of TNF-alpha may be involved in the pathogenesis of liver injury and progression of fibrosis in individuals who have steatosis in association with chronic HCV. (C) 2003 Blackwell Publishing Asia Pty Ltd.

Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice.

Abstract: Background and Aim: The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. Methods: Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. Results: The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg. Conclusions: These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice.

Seroepidemiology of hepatitis A virus infection among school children in Delhi and north Indian patients with chronic liver disease: implications for HAV vaccination.

Abstract: Background: Universal vaccination against hepatitis A virus (HAV) has been recommended for children because of the changing epidemiological pattern of HAV. Vaccination has also been advised for patients with chronic liver disease as HAV superinfection in these patients can result in severe or even fatal disease. In India, the indications for HAV vaccination are not clear due to contradictory seroepidemiological data in children and lack of data on HAV seroprevalence in patients with chronic liver disease. Methods: Sera were collected from children studying in two government-run schools and from patients with chronic liver disease attending the Liver Clinic at the All India Institute of Medical Sciences (AIIMS). The sera were tested for anti-HAV antibodies. The incidence of HAV-induced acute hepatitis and acute liver failure at AIIMS over the last 10 years was also assessed. Results: A total of 93.2% (1328/1424) of the school children between 4-18 years of age who were included in the study had anti-HAV antibody in their sera. Eighty percent of the children had antibodies against HAV in their sera by the age of 5 years, whereas all the children above 16 years were positive for anti-HAV antibody. A total of 256 patients with chronic liver disease (94 with cirrhosis of the liver, 160 with chronic hepatitis) were tested for the presence of anti-HAV antibody. Of them, 97.6% (248/254) had anti-HAV antibody in their sera. The annual frequency of HAV-induced acute viral hepatitis and acute liver failure at AIIMS during the last 10 years did not show any change. Conclusion: Mass vaccination against HAV is not required in north India because of the presence of protective antibodies against HAV in the majority of the population.

Validation of Rome II criteria for functional gastrointestinal disorders by factor analysis of symptoms in Asian patient sample.

Abstract: Background: It has been unclear as to whether the Rome II criteria could be applied to patients in the Asia region with functional gastrointestinal (GI) diseases. The aim of the present study was to determine if symptoms of Asian patients with functional gastrointestinal disorders formed groups which corresponded to the Rome II diagnostic criteria. Methods: A modified English version of Talley's bowel disease questionnaire was developed in collaboration with various research teams in accordance with the Rome II criteria. This instrument was translated into the local languages of the following nine Asian regions: China, Hong Kong, Indonesia, Korea, Malaysia, Singapore, Taiwan, Thailand and Vietnam. From September to December 2001, newly enrolled outpatients attending 14 GI or medical clinics in these regions were invited to complete the questionnaire. From these respondents, patients with functional gastrointestinal disorders fulfilling the ‘12 weeks out of 12 months’ criteria were separated for further analysis. Principal component factor analysis with varimax rotation was used to identify symptom clusters or factors. These factors were compared with the existing classification of functional GI diseases derived from the Rome II criteria. Results: Factor analysis of symptoms from 1012 functional GI patients supported the Rome II classification of the following groups of functional GI disorders: diarrhea-predominant irritable bowel syndrome, functional constipation, functional dyspepsia, functional abdominal pain syndrome, functional heartburn, and functional vomiting. Functional diarrhea was combined with functional anorectal disorders, and globus merged with functional dysphagia into one factor. Some of the functional dyspepsia, abdominal bloating and belching symptoms were loaded into one factor. Conclusions: Factor analysis of symptoms from a sample of Asian patients with functional GI disorders partially supported the use of the Rome II classification. © 2003 Blackwell Publishing Asia Pty Ltd