Showing papers in "Journal of Gastroenterology and Hepatology in 2006"

Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults.

Abstract: Background and Aim: Differences in the prevalence of non-alcoholic fatty liver disease (NAFLD) between Eastern and Western populations are primarily attributable to differences in definitions and biased population selection. Thus, the aim of the present study was to accurately determine the actual prevalence of NAFLD by sonography and to characterize the risk factors for NAFLD. Methods: The present cross-sectional study was performed with data obtained from 6648 subjects, all of whom were older than 20 years of age (3530 men and 3118 women). The term ‘non-drinker’ was applied to men who consumed less than 30 g alcohol/day and to women who consumed less than 20 g alcohol/day. Non-alcoholic fatty liver disease was defined as a sonographically detected fatty liver in the absence of viral hepatitis in a non-drinker. Results: Of the 1613 subjects who were diagnosed with sonographic fatty liver, 1240 were non-drinkers and had no viral hepatitis. Overall, the unadjusted and age-adjusted prevalences of NAFLD were 18.7% (23% in men, 13.7% in women) and 16.1% (21.6% in men, 11.2% in women), respectively. Multivariate analysis revealed that several risk factors were profoundly associated with the prevalence of NAFLD, including obesity, insulin resistance, hyperlipidemia and hyperglycemia in both genders, as well as age, menopausal status and estrogen medication in women only. Conclusions: These results demonstrate that the prevalence of NAFLD in Korean adults, according to sonographic surveys, is comparable to that seen in more developed countries. From the perspective of increasing obesity, the high prevalence rates noted in the study may herald an increased burden of chronic liver disease in the Korean population.

Hepatic stellate cells and the reversal of fibrosis.

Abstract: Hepatic fibrosis is an outcome of many chronic liver diseases, such as viral and autoimmune hepatitis, and of alcohol consumption and biliary obstruction. Prolonged liver injury results in hepatocyte damage, which triggers activation of hepatic stellate cells (HSC) and recruitment of inflammatory cells into the liver. The HSC play a critical role in fibrogenesis. They produce collagen type I and secrete pro-fibrogenic cytokines and inhibitors of matrix-degrading enzymes (tissue inhibitor of matrix metalloproteinase), causing the production of extracellular matrix deposition over degradation. However, many clinical and experimental studies suggest that this process can be reversed, including the apoptosis of activated HSC. Thus, HSC represent an appealing target for antifibrotic therapy. This review will focus on some aspects of etiology and molecular pathogenesis of liver fibrosis and the reversal of fibrosis.

Effect of exercise and dietary modification on serum aminotransferase levels in patients with nonalcoholic steatohepatitis

Abstract: Background: Nonalcoholic steatohepatitis (NASH) is commonly associated with overweight and insulin resistance. Aerobic exercise is known to reduce insulin resistance. We studied the effect of regular aerobic exercise on serum aminotransferase levels in patients with NASH. Methods: Sixty-five (mean age 38.7 ± 9.5 years; 46 [78%] males) out of 94 patients diagnosed with NASH participated in the study. Each patient was advised regular aerobic exercise for 30 min duration per day, and trained to achieve a heart rate of 60–70% of his/her maximal heart rate for at least 5 days a week. In addition, those with a high body mass index (BMI) were advised a moderately energy-restricted diet. Patients were followed up monthly for at least 3 months by BMI, waist-hip ratio (WHR), waist circumference (WC), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Results: Forty-three (72.8%) patients had a high BMI. Central obesity (WHR ≥0.90 cm in men and ≥0.85 cm in women) was present in 58 (98.3%) patients and metabolic syndrome in 12 (20.3%) patients. In the 44 patients who complied regularly with the exercise program, serum ALT normalized in 20 (45%; P < 0.05), and mean AST and ALT values declined from 70.5 and 104.0–41.5 (P < 0.001) and 63.2 (P < 0.001), respectively. Overweight patients lost a mean 3.1 kg (range 0–13 kg) weight and showed a decline in BMI (28.7 vs 27.5; P < 0.001) and WC (99.4 cm vs 96.1 cm; P = 0.001). Serum ALT did not normalize in any of the 15 patients who failed to comply with the exercise program; their pre- and post-AST (82.8 and 81.2, respectively) and ALT (98.0 and 96.1, respectively) levels, BMI (27.5 and 27.6, respectively) and WHR (0.99 cm and 0.99 cm, respectively) did not show any significant change at 3 months, and also for an extended mean follow-up period of 5.3 months. Conclusion: Moderate intensity aerobic exercise helps in normalizing ALT levels in patients with NASH.

Does butyrate protect from colorectal cancer

Abstract: Butyrate, the four-carbon fatty acid, is formed in the human colon by bacterial fermentation of carbohydrates (including dietary fiber), and putatively suppresses colorectal cancer (CRC). Butyrate has diverse and apparently paradoxical effects on cellular proliferation, apoptosis and differentiation that may be either pro-neoplastic or anti-neoplastic, depending upon factors such as the level of exposure, availability of other metabolic substrate and the intracellular milieu. In humans, the relationship between luminal butyrate exposure and CRC has been examined only indirectly in case-control studies, by measuring fecal butyrate concentrations, although this may not accurately reflect effective butyrate exposure during carcinogenesis. Perhaps not surprisingly, results of these investigations have been mutually contradictory. The direct effect of butyrate on tumorigenesis has been assessed in a number of in vivo animal models, which have also yielded conflicting results. In part, this may be explained by methodological differences in the amount and route of butyrate administration, which are likely to significantly influence delivery of butyrate to the distal colon. Nonetheless, there appears to be some evidence that delivery of an adequate amount of butyrate to the appropriate site protects against early tumorigenic events. Future study of the relationship between butyrate and CRC in humans needs to focus on risk stratification and the development of feasible strategies for butyrate delivery.

Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome.

Abstract: Background and Aim: Although increased mast cells in the gut and their role in visceral hypersensitivity in irritable bowel syndrome have been postulated, this relationship remains unclear. Our aim was to determine whether a relationship exists between the number of mucosal mast cells in the gut and visceral hypersensitivity. Method: Eighteen patients with diarrhea predominant irritable bowel syndrome (D-IBS) (eight females, 10 males aged 25–65 years; mean 42.6 years) with symptoms meeting the Rome-II criteria, and 15 healthy controls (five females, 10 males aged 31–57 years; mean 41.4 years) were recruited. Participants completed a questionnaire for bowel symptoms and psychological distress. Colonic mucosal mast cells were identified immunohistochemically and quantified by image analysis, and maximally tolerable pressures were evaluated using barostat test. Results: Numbers of mast cells were significantly greater in the terminal ileum, ascending colon and rectum of D-IBS patients compared with controls (P < 0.01). A multivariate analysis of the barostat test showed that maximally tolerable pressures of D-IBS patients were significantly lower than those of controls (P < 0.01). When patients were divided into the rectal hypersensitivity (+) and (–) groups by the distension level of 34 mmHg, mast cell counts were significantly higher in the rectal hypersensitivity (–) group than in the rectal hypersensitivity (+) group for the terminal ileum, ascending colon and rectum (P < 0.05, respectively). Conclusions: Rectal sensitivity was enhanced in D-IBS patients with moderately increased mucosal mast cells, but it was attenuated in patients with markedly increased ones. This study might provide evidence for an important role of mast cells in visceral hypersensitivity.

Exclusive enteral feeding as primary therapy for Crohn's disease in Australian children and adolescents: a feasible and effective approach.

Abstract: Background: Exclusive enteral feeding has been shown to be as efficacious as corticosteroids in inducing remission in children with Crohn’s disease (CD), with additional nutritional benefits. The use of polymeric formulae provides superior palatability and acceptance over elemental feeds, but polymeric formulae have not been universally adopted. The present retrospective analysis of enteral feeding in children with Crohn’s disease aims to demonstrate the short-term benefits of enteral feeding in children upon disease activity and nutrition parameters. Methods: The case records of children with CD managed with exclusive enteral nutrition (EEN) by a multidisciplinary team over a 2-year period were reviewed. Data relating to therapy, background disease details, and outcome were collated. Primary outcome measures established were weight change and disease activity (Pediatric Crohn’s Disease Activity Index: PCDAI). Results: Twenty-seven children received EEN with polymeric formulae. Fifteen children had newly diagnosed CD and 12 had known long-standing CD. Twenty-four children completed the prescribed period of EEN. Twelve of 15 (80%) newly diagnosed CD and seven of 12 (58%) with long-standing disease entered remission. Children with newly diagnosed CD responding to EEN took all feeds orally and gained an average of 4.7 ± 3.5 kg with mean PCDAI decreasing from 37.1 ± 10.8 to 6.7 ± 5.1 after 8 weeks. In addition, four children continued supplementary polymeric formula (without other medical therapies) and all have maintained remission during an average follow-up period of 15.2 months. Conclusion: Exclusive enteral feeds induced remission in 80% of children with newly diagnosed CD (on intention-to-treat basis) when used as sole initial therapy while also improving nutritional status. All newly diagnosed children treated with EEN, who were able to establish feeds, achieved remission. In addition, remission may be prolonged with oral supplementary formula as sole ongoing treatment. Further study of the role(s) of enteral feeds and of longer-term benefits of enteral feeding in children with CD is now required.

Gastric emptying time of fluids and solids in healthy subjects determined by 13C breath tests: influence of age, sex and body mass index

Abstract: Background and Aim: Disturbance of gastric emptying leads to a variety of symptoms. Furthermore, gastric motility disorders might play a role in the pathophysiology of functional dyspepsia. In previous studies 13C breath tests were validated as non-invasive tools in the measurement of gastric emptying time. So far, reliable reference values of healthy subjects are missing and the impact of constitutional traits (age, sex, body mass index [BMI]) needs to be clarified. Methods: A study was conducted in 90 healthy individuals (45 men, 45 women) that assessed the correlation of parameters of gastric emptying (half gastric emptying time [T1/2] and time of fastest gastric emptying [Tlag]) with age, sex and BMI for fluid and solid test meals by 13C breath tests. 100 mg of sodium acetate or sodium octanoate, respectively, were used as tracers. Breath probes were analyzed by non-dispersive infrared spectroscopy. Results: The mean ± SD of half gastric emptying time (T1/2) of a fluid test meal was determined to be 80.5 ± 22.1 min and for Tlag to be 40.3 ± 10.2 min. However, the T1/2 and Tlag of solid meals did not fit to normal distribution and thus median and percentiles were determined. The median time of T1/2 for solids was 127 min (25–75% percentiles: 112.0–168.3 min) and 81.5 min for Tlag (25–75% percentiles: 65.5–102.0 min). No significant correlation was found between gastric emptying and age, sex or BMI. Conclusion: This is the first study to examine gastric emptying in an adequate number of healthy subjects by 13C breath tests. No significant correlation was found with age, sex and BMI. Although there is considerable standard deviation in gastric emptying time, these results may nevertheless serve as reference values for further studies.

Non-alcoholic fatty liver disease: the unfolding monster?

Abstract: Non-alcoholic fatty liver disease is now recognized as a common clinical condition that includes a spectrum of liver damage, ranging from simple, bland steatosis, which is usually associated with a benign prognosis, to NASH, which is believed to possess the potential to progress to cirrhosis and its inherent complications of liver failure and liver cancer. 4‐7 The scenario is quite similar to the Helicobacter pylori story. When the possibility that the organism H. pylori could produce peptic ulcer was first mooted in the 1980s, the idea was greeted with much skepticism: was it something of any import or was it a mere toy for researchers to fool around with and embellish their curriculum vitae? The attention that the ugly duckling, that is, NAFLD is now getting is obvious if one conducts a search of publications relating to NAFLD in PUBMED. While there was only one paper or two for the whole year a decade ago, the number of papers published on NAFLD in recent years is skyrocketing; last year, the figure almost reached 100. Every hepatologist worth their salt has jumped into the fray. What then is this entity? Is the hype justified? What are the facts? With the available information is it possible to separate the wheat from the chaff? Is there any basis to justify the claims that the disease is not the benign little thing that everyone thought it to be, that it could actually, over the years, progress to cirrhosis of the liver or even liver cancer? Is the evidence incriminating NAFLD foolproof? Let us take a look at the information available regarding the outcome or natural history of this disease. In 1990, Elizabeth Powell et al. from Australia published their experience on the natural history of 42 patients with NASH. 8 In their study, serial liver biopsy specimens revealed minimal or no apparent progression of the disorder in most of the patients, in keeping with their benign clinical course. Only one patient with minimal baseline fibrosis showed progression from fibrosis to cirrhosis during the 5-year observation period. However, in two patients who had extensive fibrosis at the outset, the liver disease evolved from one of active inflammation to one of inactive cirrhosis without fat or inflammation, and one of the patients with cirrhosis later died of hepatocellular carcinoma. This work has been widely acclaimed, and is considered a landmark paper in showing how two of their patients with fatty liver disease could progress to cirrhosis of the liver without any trace of fat, leading to the hypothesis that NASH could be a prime candidate for a significant proportion of cryptogenic cirrhosis. Notwithstanding, one needs to take this with a pinch of salt. That study involved a very small number of patients, and cirrhosis developed in only three patients, all of whom had fibrosis in the beginning itself; in fact two of these patients had extensive fibrosis at the outset. Also, this cohort had a disproportionate number of patients with significant fibrosis. When Harrison et al . at the Brooke Army Medical Center in Texas, USA decided to study the natural history of NASH, and reviewed liver biopsy slides from non-alcoholic fatty liver patients who underwent more than one liver biopsy during the period from 1985 to 2001, they could lay their hands on the slides of 22 patients only. 9 Of these, 10 patients (45%) had fibrosis stage 1 or 2, and two patients (9%) had bridging fibrosis or cirrhosis (stage 3 or 4) on first biopsy. Seven (32%) had increases in fibrosis score. Four patients (18%) had decreases in fibrosis score. The percentage of patients with stage 3 or 4 increased from 9% to 18%. In two patients the disease progressed rapidly, and three patients progressed from steatosis to steatohepatitis with fibrosis. The authors concluded that one-third of patients have fibrosis progression, and one-third of these have rapid progression to advanced fibrosis, and that steatosis alone may progress to NASH with fibrosis. A close look, however, reveals that these numbers were too small, only 22 during a 16-year period. These patients underwent repeated biopsies because they had qualified for same during therapeutic trial. It is obvious that these patients were the sicker ones, and that data pertaining to them should not be extrapolated to the average NAFLD patients. Another attempt by Fassio et al . in Argentina to elucidate the natural history also involved an identical figure of 22. 10

Review of genetic and epigenetic alterations in hepatocarcinogenesis.

Abstract: Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from pre-neoplastic lesions, usually in the background of cirrhosis. However, the genetic and epigenetic events of hepatocarcinogenesis are relatively poorly understood. HCC display gross genomic alterations, including chromosomal instability (CIN), CpG island methylation, DNA rearrangements associated with hepatitis B virus (HBV) DNA integration, DNA hypomethylation and, to a lesser degree, microsatellite instability. Various studies have reported CIN at chromosomal regions, 1p, 4q, 5q, 6q, 8p, 10q, 11p, 16p, 16q, 17p and 22q. Frequent promoter hypermethylation and subsequent loss of protein expression has also been demonstrated in HCC at tumor suppressor gene (TSG), p16, p14, p15, SOCS1, RIZ1, E-cadherin and 14-3-3 sigma. An interesting observation emerging from these studies is the presence of a methylator phenotype in hepatocarcinogenesis, although it does not seem advantageous to have high levels of microsatellite instability. Methylation also appears to be an early event, suggesting that this may precede cirrhosis. However, these genes have been studied in isolation and global studies of methylator phenotype are required to assess the significance of epigenetic silencing in hepatocarcinogenesis. Based on previous data there are obvious fundamental differences in the mechanisms of hepatic carcinogenesis, with at least two distinct mechanisms of malignant transformation in the liver, related to CIN and CpG island methylation. The reason for these differences and the relative importance of these mechanisms are not clear but likely relate to the etiopathogenesis of HCC. Defining these broad mechanisms is a necessary prelude to determine the timing of events in malignant transformation of the liver and to investigate the role of known risk factors for HCC.

Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis.

Abstract: Background and Aim: Inhibition of tumor necrosis factor (TNF)-α is a logical approach to manage patients with non-alcoholic steatohepatitis (NASH). Pentoxifylline reduces TNF-α and alanine aminotransferase (ALT) levels in patients with NASH. The aim of the present paper was to study if pentoxifylline can improve histological injury in patients with NASH. Methods: Nine patients (mean age 31.6 ± 7.2 years) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxyfylline at a dosage of 400 mg t.i.d. for 12 months. Besides biochemical assessment, a repeat liver biopsy was performed and the degree of inflammation and fibrosis was compared. Results: After 12 months of therapy a significant reduction in ALT (111 ± 53 IU/L vs 45 ± 19 IU/L, P = 0.003) and aspartate aminotransferase (AST) (61 ± 27 IU/L vs 33 ± 12 IU/L, P = 0.005) levels was observed. Steatosis and lobular inflammation each reduced in 55% and six (67%) patients down-staged on Brunt's staging (P = 0.009). Four out of six patients with baseline fibrosis had reduction in their fibrosis stage. Conclusions: Long-term pentoxyfylline therapy effectively achieves sustained biochemical improvement. This correlates well with histological resolution of the disease.

PPAR agonists treatment is effective in a nonalcoholic fatty liver disease animal model by modulating fatty-acid metabolic enzymes

Abstract: Background and Aims: In a previous study, the authors found that reduced expression of peroxisome proliferator-activated receptor (PPAR)-α might play an important role in developing nonalcoholic fatty liver disease (NAFLD). The aim of this study was to analyze the effects of PPAR-α and -γ agonists on NAFLD and verify the mechanisms underlying the PPAR-α and -γ agonist-induced improvements by evaluating the hepatic gene expression profile involved in fatty-acid metabolism, using the Otsuka–Long Evans–Tokushima fatty (OLETF) rat. Methods: Rats were assigned to a control group (group I), fatty liver group (group II), PPAR-α agonist treatment group (group III), or PPAR-γ agonist treatment group (group IV). Fasting blood glucose, total cholesterol, and triglycerides were measured. Liver tissues from each group were processed for histological and gene expression analysis. mRNAs of enzymes involved in fatty-acid metabolism and tumor necrosis factor (TNF)-α were measured. Results: After 28 weeks treatment with PPAR-α or -γ agonist, steatosis of the liver was improved in groups III and IV compared with group II. Fasting blood glucose levels were significantly lower in groups III and IV than in group II. In group III, mRNA expression of fatty-acid β-oxidation enzymes, such as fatty-acid transport protein (FATP), fatty-acid binding protein, carnitine palmitoyltransferase II, medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase, was significantly increased. However, the treatment-induced modulation of fatty-acid β-oxidation enzymes was confined to FATP and MCAD in group IV. TNF-α tended to be reduced in groups III and IV compared with group II. Conclusions: Treatment with PPAR agonists, especially a PPAR-α agonist, improved the histological and biochemical parameters in the OLETF rat model by inducing fatty-acid metabolic enzymes.

Prevalence of celiac disease among school children in Punjab, North India.

Abstract: Background: Celiac disease, as of today, is said to exist in almost all parts of the world, although it is rare among people of purely African–Caribbean, Japanese and Chinese background. The disease has also been considered uncommon in India until recently. Hospital records have revealed an increasing trend of the disease in predominantly wheat-eating areas of North India. The aim of the present study was to determine the prevalence of celiac disease among school children in Punjab, North India. Methods: The study was carried out in the Ludhiana district of Punjab, Northern India. A total of 4347 children aged 3–17 years attending different schools were enrolled. A structured questionnaire was used to collect sociodemographic data and symptoms and signs related to celiac disease and various sociodemographic factors. The screening for celiac disease for the suspected celiacs was done by testing for antitissue transglutaminase (anti-tTG) by indirect solid-phase immunometric assay (ELISA). All children with high anti-tTG whose parents consented underwent upper gastrointestinal endoscopy for small bowel biopsy from the second part of the duodenum. Histopathology was expressed according to the Marsh classification of 1992. Follow up was carried out among children who were put on a gluten-restricted diet, at monthly intervals for 3 months and every 3 months thereafter. The diagnosis of celiac disease was established on the basis of the revised European Society of Paediatric Gastroenterologists and Nutritionists (ESPGAN) criteria (confirmed cases). Results: A total of 4347 school children (1967 girls, 2380 boys, age range 3–17 years) were screened for celiac disease. Out of these, 198 suspected children were identified for further evaluation. Twenty-one children tested positive for anti-tTG assay (10.6%, 95% confidence interval: 16.91–34.79). Seventeen of these 21 children agreed to undergo biopsy; of these, 14 had histological changes consistent with celiac disease and all these 14 children had clinical response to gluten restriction. Three children with high anti-tTG had normal mucosa on duodenal biopsy and were not labelled as being in the celiac disease group. In the final analysis the disease prevalence was one in 310 children. Conclusions: This is the first study on celiac disease prevalence among school children from India. Although this disease frequency of one in 310 is thought to be an under-assessment, it clearly shows that celiac disease is not rare in wheat-eating areas of North India.

Matrix metalloproteinases, the pros and cons, in liver fibrosis.

Abstract: Residing in the space of Disse within loose extracellular matrix (ECM) resembling that in basement membranes, the hepatic stellate cells (HSC) remain in quiescence as vitamin A storage cells. In response to liver injury HSC undergo morphologic and functional trans-differentiation, converting from vitamin A-storing, star-like cells into contractile myofibroblastic cells, a process called activation. Accompanying cellular activation, the ECM components in the space of Disse switch from matrices rich in type-IV collagen and laminin, into condensed interstitial ECM, indicating that proteolytic degradation may occur to change the microenvironment in sinusoids as well as the fate of HSC. Indeed, matrix metalloproteinases (MMP), a family of ECM degradative enzymes, are promptly expressed by HSC in response to diverse hepatic toxins. In vitro experiments also demonstrated the role of MMP in activation of HSC cultured in 3-D ECM. Conversely, MMP may also contribute to regression of liver fibrosis through cleavage of the fibrillar ECM and promotion of apoptosis among the activated HSC. Thus, MMP play dual roles both bad and good in liver fibrosis, depending on the timing.

Prevalence and risk factors of gallstone disease in an adult population of Taiwan: an epidemiological survey

Abstract: Background and Aims: The aim of this study was to determine the prevalence and risk factors of gallstone disease (GSD) in an adult population of Taiwan through a population-based screening study. Methods: A cross-sectional community study in a rural village of Taiwan was conducted in 3333 Chinese adults (aged ≥18 years) undergoing ultrasonography. A questionnaire on personal history was completed to ascertain whether the removed gallbladder contained stones in all cholecystectomized subjects, the dietary habits (vegetarian/non-vegetarian diet), the history of GSD in the participant’s first-degree relatives, the history of gastrointestinal surgery (vagotomy, gastrectomy for peptic ulcer disease, or ileal resection), parity, and use of oral contraceptives. The demographic characteristics and biochemical parameters were recorded Results: The overall prevalence of GSD was 5.0% (4.6% in men, 5.4% in women) with no significant sex differences (men/women: odds ratio [OR] 0.71, 95% confidence interval [CI] 0.50–1.01, P = 0.058). Logistic regression analysis showed that increasing age (men: 40–64 years, OR 7.38, 95% CI 2.59–21.01, P < 0.001 and ≥65 years, OR 14.16, 95% CI 4.84–41.47, P < 0.001; women: 40–64 years, OR 4.08, 95% CI 1.90–8.75, P < 0.001 and ≥65 years, OR 6.78, 95% CI 2.97–15.46, P < 0.001) and the presence of fatty liver evidenced by ultrasonography (men: OR 2.24, 95% CI 1.32–3.80, P = 0.003; women: OR 2.13, 95% CI 1.33–3.42, P = 0.002) were risk factors for GSD. Additionally, fasting plasma glucose ≥126 mg/dL (OR 2.11, 95% CI 1.16–3.83, P = 0.014), history of GSD in the first-degree relatives (OR 7.47, 95% CI 2.22–25.12, P = 0.001), and use of oral contraceptives (OR 10.71, 95% CI 3.06–37.49, P < 0.001) were risk factors for GSD in women, but fasting plasma glucose ≥126 mg/dL was only correlated to GSD without controlling for other confounding factors in men. Other demographic characteristics and biochemical parameters, such as high body mass index (≥25 kg/m2), increased parity, hypercholesterolemia, hypertriglyceridemia, hyperuricemia, hepatitis C infection and cirrhosis, did not exhibit any correlation to GSD in logistic regression analysis, although they appeared to be related to GSD in women in univariate analysis. Conclusions: Age and fatty liver in both sexes were found to be risk factors for GSD in the study population. The finding of a correlation between fatty liver and GSD is an important addition to the literature concerning the risk factors of GSD. Diabetes mellitus, history of GSD in the first-degree relatives, and use of oral contraceptives were also risk factors for GSD in women.

Hepatitis B and C virus infections and anti-tumor necrosis factor-α therapy: Guidelines for clinical approach

Abstract: Anti-tumor necrosis factor-α (TNF) therapy has recently been recognized to be associated with activation of hepatitis B virus (HBV) infection, with a potentially fatal outcome, mirroring experience in the setting of immune suppression and subsequent reconstitution in cancer chemotherapy and transplantation. Although there is no current evidence that anti-TNF therapy influences the natural history of hepatitis C virus (HCV) infection, the involvement of TNF in the pathogenesis of hepatic injury and extrapolation from other clinical situations heighten awareness of a potential conflict. Preventive strategies should be mandatory. These include screening of all patients for HBV and HCV infection prior to commencement of anti-TNF therapy, and active monitoring of aminotransferases and, for HBV, viral load during and for 3 months after therapy has terminated. Prophylactic or early intervention strategies with nucleoside analogs are recommended for patients with evidence of HBV infection.

Constipation of anorectal outlet obstruction: pathophysiology, evaluation and management.

Abstract: Constipation is a subjective symptom of various pathological conditions. Incidence of constipation fluctuates from 2 to 30% in the general population. Approximately 50% of constipated patients referred to tertiary care centers have obstructed defecation constipation. Constipation of obstructed defecation may be due to mechanical causes or functional disorders of the anorectal region. Mechanical causes are related to morphological abnormalities of the anorectum (megarectum, rectal prolapse, rectocele, enterocele, neoplasms, stenosis). Functional disorders are associated with neurological disorders and dysfunction of the pelvic floor muscles or anorectal muscles (anismus, descending perineum syndrome, Hirschsprung's disease). However, this type of constipation should be differentiated by colonic slow transit constipation which, if coexists, should be managed to a second time. Assessment of patients with severe constipation includes a good history, physical examination and specialized investigations (colonic transit time, anorectal manometry, rectal balloon expulsion test, defecography, electromyography), which contribute to the diagnosis and the differential diagnosis of the cause of the obstructed defecation. Thereby, constipated patients can be given appropriate treatment for their problem, which may be conservative (bulk agents, high-fiber diet or laxatives), biofeedback training or surgery.

Curcumin ameliorates acute thioacetamide-induced hepatotoxicity.

Abstract: BACKGROUND AND AIM: Increased production of reactive oxygen species and nitric oxide and activation of nuclear factor kappa B are implicated in the pathogenesis of various liver diseases, including fulminant hepatic failure. Curcumin is a naturally occurring anti-oxidant that reduces oxidative stress and inhibits nuclear factor kappa B and nitric oxide formation. The aim of the present study is to assess curcumin's therapeutic potential in acute thioacetamide hepatotoxicity, a rat model of fulminant hepatic failure. METHODS: Fulminant hepatic failure was induced by two intraperitoneal (i.p.) injections of 300 mg/kg thioacetamide (TAA) at 24-h intervals. The experimental groups received a low-dose (200 mg/kg per day, i.p.) or a high-dose (400 mg/kg per day) of curcumin, initiated 48 h prior to the first TAA injection. A fourth group was administered neither TAA nor curcumin and served as a control. RESULTS: The survival rate was higher in both curcumin-treated groups compared to the TAA only treated group. Biochemical parameters of liver injury, blood ammonia and hepatic necroinflammation were lower in the low-dose curcumin group compared to TAA controls, and were further reduced in the high-dose group (P < 0.05 and P < 0.01, respectively). Curcumin treatment also reduced the TAA-induced elevated hepatic levels of thiobarbituric acid-reactive substances (TBARS), and inhibited the nuclear binding of nuclear factor kappa B (NFkappaB) and inducible nitric oxide (iNOS) protein expression. CONCLUSIONS: Curcumin improved survival and minimized oxidative stress, hepatocellular injury and hepatic necroinflammation, NFkappaB binding and iNOS expression in a rat model of FHF. These findings support the role of ROS, NFkappaB and iNOS in mediating liver insult due to TAA, and that of curcumin as a hepato-protectant.

Prevalence of irritable bowel syndrome in Korea: population-based survey using the Rome II criteria.

Abstract: Background: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder in the West. But information on the prevalence of IBS in Asia is still lacking, especially in Korea. Therefore, the aims of the present study were to estimate the prevalence of IBS in the general population of Korea and also to investigate characteristics of IBS and health-care-seeking behavior of IBS patients. Methods: Telephone interview survey was conducted by Gallup, Korea using a validated questionnaire based on the Rome II criteria. The response rate of the telephone interview survey was 25.2% (n = 1066, 535 male and 531 female responders). A random sample of gender and age (between 18 and 60 years), based on a per capita ratio was obtained. Results: Among 1066 subjects, the prevalence of IBS was 6.6% (70 subjects; 7.1%, male; 6.0%, female). The difference in IBS prevalence by gender was not significant. The prevalence was higher among those in their 20s (P = 0.036). Among 70 subjects with IBS, 10/20 IBS subjects sought health care due to abdominal pain. Among the risk factors of IBS, marital status had a significant difference; the following risk factors are arranged in descending order: age (odds ratio [OR]: 1.38, 95% confidence interval [CI]: 0.85–2.25), alcohol intake (OR: 1.38, 95%CI: 0.81–2.35), gender (OR: 1.19, 95%CI: 0.73–1.94), demographics (OR: 1.09, 95%CI: 0.53–2.25), income (OR: 0.88, 95%CI: 0.54–1.45), education level (OR: 0.81, 95%CI: 0.46–1.40), smoking (OR: 0.64, 95%CI: 0.37–1.12), and marital status (OR: 0.59, 95%CI: 0.35–0.99). Conclusions: The prevalence of IBS in the Korean population is 6.6%, and the male : female ratio is similar. Also, IBS is more frequent in younger subjects. Irritable bowel syndrome subjects visited a physician mostly due to abdominal pain.

Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-alpha gene promoter polymorphisms.

Abstract: Background: The reasons for the viral persistence of hepatitis B virus infection (HBV) are unknown, but are probably related to host immune factors. Cytokines play a significant role in immune defense. The present study was undertaken to investigate the association between HBV infection and polymorphisms of tumor necrosis factor (TNF)-α and interleukin(IL)-10 gene promoter. Methods: A total of 412 Korean patients with HBV infection (72 inactive carriers, 261 witih chronic hepatitis, 79 with liver cirrhosis) and 204 healthy individuals who recovered from HBV infection, were studied. The polymorphisms in IL-10 gene promoter (−1082, −819, −592), and TNF-α gene promoter (−308, −238) were assessed by single base primer extension assay. Results: The frequency of C/C genotype at position −592 of IL-10 gene promoter was higher in the HBV clearance group than that in the persistence group in univariate analysis (12.7% vs 7.5%, P = 0.036). The IL-10 gene promoter −592 C/C genotype was related to clearance of HBV infection in logistic regression analysis after adjusting for age and sex (P = 0.003). Genotype frequencies of TNF-α gene promoter at position −308 and −238 were not different between the clearance and the persistence group in univariate analysis, but in multivariate analysis after adjusting for age and sex, −308G/−238G homozygotes were associated with HBV persistence (P = 0.005). Genotype distributions of both gene promoters in inactive carriers were similar to those in patients with chronic progressive liver disease. Conclusions: The carriers of the −592A allele in the IL-10 promoter and −308G/−238G haplotype homozygotes in the TNF-α promoter region have higher risk of persistent HBV infection.

Mitochondrial glutathione: hepatocellular survival-death switch.

Abstract: Steatohepatitis represents an advanced stage of fatty liver disease that encompasses alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). The progression from steatosis to steatohepatitis is poorly understood. One of the clues to this progression is the sensitization of hepatocytes to oxidative stress and cytokine-induced cell death. Mitochondrial glutathione (mGSH), which plays a central role in the control of mitochondrial reactive oxygen species (ROS) generation, modulates the sensitivity to cell death pathways. Mitochondrial GSH depletion due to alcohol-mediated alteration in mitochondrial membrane dynamics underlies the susceptibility of hepatocytes from alcohol-fed models to tumor necrosis factor (TNF), and in nutritional and genetic models of hepatic steatosis, mGSH depletion occurs due to the enrichment of mitochondria in free cholesterol, resulting in decreased mitochondrial membrane fluidity. The signaling of TNF through its membrane receptor TNFR1 from complex I to complex II is similar in hepatocytes depleted or not depleted in mGSH, yet hepatocellular susceptibility to TNF occurs if mGSH is depleted. Thus, mGSH is a critical factor in the development of steatohepatitis through sensitization of hepatocytes to inflammatory cytokines, and understanding the homeostasis of cholesterol and its trafficking to mitochondria may be of relevance in the pathophysiology of ASH and NASH.

Alcohol and lipid metabolism

Abstract: Hepatic lipid metabolism is controlled by several master transcription factors, in particular peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and sterol response element binding protein-1 (SREBP-1). Peroxisome proliferator-activated receptor-alpha is a receptor for free fatty acids (FFA), and can activate genes involved in transport, oxidation, and export of FFA. Sterol response element binding protein-1 is a sensor for the level of cholesterol in the liver, and is able to activate genes involved in synthesis of cholesterol and FFA. Chronic ethanol treatment of cells or animals inhibited PPAR-alpha function and activated SREBP. In addition, ethanol inhibited adenosine monophosphate-dependent protein kinase (AMPK). The AMPK controls fatty acid metabolism by inhibiting acetyl-coenzyme A carboxylase, reducing malonyl-coenzyme A, and thereby permitting fatty acid transport into and oxidation in the mitochondrion. Adenosine monophosphate-dependent protein kinase was inhibited in alcohol-treated animals and cells. The mechanisms by which ethanol affects AMPK and the transcription factors are as yet incompletely understood.

Alcohol-induced oxidative stress and cell responses.

Abstract: Epidemiological and animal studies have demonstrated that alcohol abuse is directly associated with the increase of multiple organ diseases, such as liver injury, cardiovascular diseases, and neurological disorders. While the mechanisms of alcohol-induced cell injury and disease remain to be investigated, recent studies indicate that reactive oxygen species (ROS) may play an important role. Reactive oxygen species are able to cause various cellular injuries, such as DNA damage, lipid peroxidation and protein modification. Cellular systems are protected from ROS-induced cell injuries by an array of defenses composed of various anti-oxidants with different functions. When the ROS present in the cellular system overpower the defense systems, they will cause oxidative stress or cell injury, leading to the development of diseases. This article reviews recent literature on alcohol-induced ROS production, oxidative stress, signal transduction, and cellular responses. The implication of these processes in alcohol-related diseases is also discussed.

Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models.

Abstract: Background/Aims: Oxidative stress has been implicated in liver cirrhosis. Carbon tetrachloride and thioacetamide are the most widely used models to develop cirrhosis in rats and the present study compares oxidative stress in the liver induced by these compounds at different stages of cirrhosis development. Methods: Twice-weekly intragastric or intraperitoneal administration of carbon tetrachloride or thioacetamide, respectively, produced liver cirrhosis after 3 months. Histology, serum markers and hepatic hydroxy proline content confirmed the cirrhosis. Results: An increase in oxidative stress parameters was seen in mitochondria, peroxisomes and microsomes from the liver after carbon tetrachloride or thioacetamide treatment. Oxidative stress was more severe in carbon tetrachloride treated animals than thioacetamide. Mild oxidative stress was evident at 1 and 2 months of treatment and a significant increase was seen by 3 months of treatment with either compound. By this time, frank liver cirrhosis was also observed. Conclusions: These results suggest that evidence of oxygen free radicals is also found early in the development of fibrosis and cirrhosis in both models.

Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum

Abstract: Intragastric ethanol feeding in mice induces expression of unfolded protein response/endoplasmic reticulum (UPR/ER) stress response genes. The proximate cause appears to be hyperhomocysteinemia, a well-known cause of ER stress in other contexts. Hyperhomocysteinemia appears to be due to downregulation of methionine synthase. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol-induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol-induced ER stress can activate sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which contribute to the accumulation of triglyceride and cholesterol. Hyperhomocysteinemia, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNF signaling. At present ER stress as an important factor in the pathogenesis of alcoholic liver disease is an exciting new hypothesis and ongoing research will need to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S-adenosylhomocysteine, or increased S-adenosylmethionine.

Management consensus of inflammatory bowel disease for the Asia–Pacific region

Abstract: At the present there are no large-scale epidemiologic data on inflammatory bowel disease (IBD) in the Asia-Pacific region, but several studies have shown an increased incidence and prevalence of IBD in this region. Compared to the West, there appears to exist a time lag phenomenon. With regard to the two main forms of IBD, ulcerative colitis (UC) is more prevalent than Crohn's disease (CD). In addition to geographic differences, ethnic differences have been observed in the multiracial Asian countries. Moreover, the genetic backgrounds are different in the Asian compared to Western patients. For instance, NOD2/CARD15 variants have not been found in Asian CD patients. In general, the clinical course of IBD seems to be less severe in the Asia-Pacific region than in Western countries. Diagnosis of IBD in this region poses special problems. The lack of a gold standard for the diagnosis of IBD, and the existence of a variety of infectious enterocolitis with similar manifestations to those of IBD make the differential diagnosis particularly difficult. So far, Western diagnostic criteria have been introduced for the diagnosis of IBD. A stepwise approach to exclude non-IBD enterocolitis also must be introduced, and a definite diagnosis must include typical histological features. In some patients, follow up and therapeutic trials might be necessary to obtain a definitive diagnosis. A better understanding of the pathogenesis of IBD will allow the development of better diagnostic markers. The management of IBD also poses some special problems in the Asia-Pacific Region. There is often a delay in using proper medications for IBD, and alternative local remedies are still widely used. With a combination of Western guidelines and regional experiences, similar principles can be used for induction and maintenance of remission. A stepwise selection of medications is advocated depending on the extent, activity and severity of the disease. Comprehensive and individualized approaches are suggested for different IBD patients. Deeper understanding of disease pathogenesis and the unique characteristics of IBD in the Asia-Pacific region, combined with reasonable and practical guidelines for drug management and the future use of biological agents would improve the therapeutic outlook of IBD in this region.

Hyaluronic acid levels can predict severe fibrosis and platelet counts can predict cirrhosis in patients with nonalcoholic fatty liver disease

Abstract: Background and Aim: Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease from simple steatosis to cirrhosis. Therefore, markers for predicting NAFLD with advanced fibrosis are needed. The aim of this study was to establish non-invasive predictive markers of liver fibrosis in NAFLD. Methods: One hundred and forty-eight patients were diagnosed as having biopsy-proven NAFLD. In order to separately identify severe fibrosis (bridging fibrosis plus cirrhosis) and cirrhosis, the patients were analyzed twice: first, as mild fibrosis versus severe fibrosis; and second, as non-cirrhosis versus cirrhosis. Univariate and multivariate analyses were conducted. The diagnostic ability to detect severe fibrosis and cirrhosis was assessed by the area under the receiver operating characteristic curve. The cut-off values of serum markers to detect severe fibrosis and cirrhosis were determined. Results: Hyaluronic acid was selected as a predictive marker for severe fibrosis. A cut-off value of 42 ng/mL of hyaluronic acid had a 100% predictive value for patients free of severe fibrosis and was associated with an optimal combination of sensitivity (100%, 95% confidence interval [CI] 90–100%) and specificity (89%, 95%CI 80–94%). The platelet count was found to be an independent predictor of cirrhosis. A cut-off value of 16 × 104/µL for the platelet count was associated with an optimal combination of sensitivity (100%, 95%CI 82–100%) and specificity (95%, 95%CI 90–98%). Conclusions: Hyaluronic acid levels can accurately identify NAFLD patients with severe fibrosis, and the platelet count can identify NAFLD patients with cirrhosis. Thus, these markers offer a good guideline for the assessment of hepatic fibrosis in the many patients with NAFLD.

Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells.

Abstract: Induction of cytochrome P450 2E1 (CYP2E1) is a central pathway by which ethanol generates oxidative stress. Cytochrome P450 2E1 metabolizes many other toxicologic compounds. Toxicity of these agents is enhanced by ethanol, due to induction of CYP2E1. Cytochrome P450 2E1 is induced under a variety of physiological and pathophysiological conditions. The laboratory at Mount Sinai School of Medicine established HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells that express CYP2E1 (E47 cells) but not control HepG2 cells. The E47 cells had higher glutathione levels than control HepG2 cells due to activation of the genes encoding the heavy and light subunits of gamma glutamyl cysteine synthetase (GCLC and GCLM). There was also a twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 (HO-1) in the E47 cells due to activation of their respective genes. These activations were prevented by anti-oxidants, suggesting that the upregulation of these anti-oxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) protein and mRNA were observed in livers of hepatocytes of chronic alcohol-fed and of pyrazole-treated rats or mice, conditions known to elevate CYP2E1. E47 cells showed increased Nrf2 mRNA and protein expression. Upregulation of GCLC and HO-1 in E47 cells is dependent on Nrf2. These results suggest that Nrf2 is activated and its levels are increased when CYP2E1 is elevated. It is suggested that Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1.

Expression of nerve growth factor receptors is correlated with progression and prognosis of human pancreatic cancer.

Abstract: Background and Aim: The aim of the present study was to investigate the prognostic value of the two types of nerve growth factor receptors (NGFR), namely high-affinity receptor TrkA and low-affinity receptor p75NGFR, in pancreatic cancer. Methods: The mRNA expression of NGFR for TrkA and p75NGFR was examined in 56 human primary pancreatic cancers using real-time quantitative reverse transcription–polymerase chain reaction. Results: Nerve growth factor (NGF) receptors were found in all tumor specimens. It appears that the growth of pancreatic cancer cells stimulated by NGF depended on the expression levels and the ratio of TrkA to p75NGFR. TrkA and p75NGFR were negatively correlated and both were associated with abdominal or back pain and perineural invasion. Regarding this, patients with high TrkA expression levels exhibited more frequent perineural invasion and a higher degree of pain, whereas the results of p75NGFR were opposite. For Cox univariate analyses in the overall survival study, high expression of p75NGFR was associated with longer overall survival, but TrkA exhibited opposite effects and included an effect on perineural invasion and pain. Histoprognostic grading, tumor size and node involvement were not prognostic factors. In Cox multivariate analyses, TrkA and p75NGFR were both prognostic parameters. Conclusions: The present study found that the expression of TrkA in pancreatic cancer is a marker of tumor aggressiveness. Conversely, we also found that elevated p75NGFR expression is associated with a favorable prognosis. We demonstrated that NGF exerts both stimulatory and inhibitory effects on pancreatic cancers, with the overall effect determined by the expression levels and the ratio of TrkA to p75NGFR.

Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well‐being in patients with chronic hepatitis C

Abstract: Background/Aims: Silybum marianum is a herbal preparation commonly used by subjects with chronic hepatitis C (CHC). The aims of this pilot study were to assess the efficacy and safety of S. marianum on serum hepatitis C virus (HCV) RNA, alanine aminotransferase levels and well-being in patients with CHC. Methods: Twenty-four subjects with CHC were enrolled into a randomized, double-blind, placebo-controlled, crossover study. Subjects received 12 weeks of S. marianum (either 600 mg or 1200 mg/day) and placebo separated by a 4-week washout interval. Baseline biochemical, virological, psychological and quality-of-life tests were performed, with biochemical tests repeated monthly, and HCV RNA titer and quality-of-life and psychological assessments repeated at the end of both treatment periods. Results: Seventeen patients completed the trial. Mean changes in HCV RNA titers, serum ALT levels and Short Form-36 scores were not significantly different for subjects on S. marianum compared to those on placebo. There was no significant change in mean State-Trait Anxiety Inventory State-Anxiety scores on S. marianum from baseline. Adverse events were similar with S. marianum and placebo. Conclusions: S. marianum is well tolerated in subjects with CHC, but does significantly affect serum HCV RNA, alanine aminotransferase levels, quality of life or psychological well-being in subjects with this condition.

Terlipressin versus albumin in paracentesis‐induced circulatory dysfunction in cirrhosis: A randomized study

Abstract: Background: Therapeutic paracentesis in patients with cirrhosis induces arterial vasodilatation, causes a decrease in effective arterial blood volume and leads to circulatory dysfunction, which can be prevented by intravenous albumin. However, the use of albumin, being a blood product, is controversial. Recently, terlipressin, a vasoconstrictor, has been successfully used to combat this adverse effect of therapeutic paracentesis. Therefore, the aim of the present study was to investigate the preventive effect of terlipressin on paracentesis-induced circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis and compared with that of intravenous albumin. Methods: Forty patients with cirrhosis and tense ascites underwent therapeutic paracentesis with albumin or terlipressin in a randomized pilot study at a tertiary center. Effective arterial blood volume was assessed by measuring plasma renin activity at baseline and at 4–6 days after treatment. Results: Effective arterial blood volumes as indicated by plasma renin activity before and 4–6 days after paracentesis did not differ in the two groups (19.15 ± 12.1 to 20.33 ± 12.8 ng/mL per h, P = 0.46 in the albumin group; and 20.11 ± 10.6 to 21.08 ± 10.52 ng/mL per h, P = 0.44 in the terlipressin group). Plasma aldosterone concentrations before and 4–6 days after paracentesis were also similar in both groups (1334.75 ± 1058 to 1440.0 ± 1161 pg/mL, P = 0.06 in the albumin group; and 1473.0 ± 1168 to 1572.29 ± 1182 pg/mL, P = 0.24 in the terlipressin group). Both terlipressin and albumin prevented paracentesis-induced renal impairment in these patients. Conclusions: Terlipressin may be as effective as intravenous albumin in preventing paracentesis-induced circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis.