Showing papers in "Journal of Gastroenterology and Hepatology in 1999"

Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.

Abstract: Hepatic fibrosis is a wound-healing response to chronic liver injury, which if persistent leads to cirrhosis and liver failure. Exciting progress has been made in understanding the mechanisms of hepatic fibrosis. Major advances include: (i) characterization of the components of extracellular matrix (ECM) in normal and fibrotic liver; (ii) identification of hepatic stellate cells as the primary source of ECM in liver fibrosis; (iii) elucidation of key cytokines, their cellular sources, modes of regulation, and signalling pathways involved in liver fibrogenesis; (iv) characterization of key matrix proteases and their inhibitors; (v) identification of apoptotic mediators in stellate cells and exploration of their roles during the resolution of liver injury. These advances have helped delineate a more comprehensive picture of liver fibrosis in which the central event is the activation of stellate cells, a transformation from quiescent vitamin A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The progress in understanding fibrogenic mechanisms brings the development of effective therapies closer to reality. In the future, targeting of stellate cells and fibrogenic mediators will be a mainstay of antifibrotic therapy. Points of therapeutic intervention may include: (i) removing the injurious stimuli; (ii) suppressing hepatic inflammation; (iii) down-regulating stellate cell activation; and (iv) promoting matrix degradation. The future prospects for effective antifibrotic treatment are more promising than ever for the millions of patients with chronic liver disease worldwide.

Inflammation-induced cholestasis

Abstract: Inflammatory cytokines produced in response to various infectious and non-infectious stimuli are potent inducers of intrahepatic cholestasis (inflammation-induced cholestasis). The cholestatic effect of cytokines results mainly from inhibition of expression and function of hepatocellular transport systems which normally mediate hepatic uptake and biliary excretion of bile salts and various non-bile salt organic anions (e.g. bilirubin). These cytokine effects are reversible and bile secretory function is restored upon disappearance of the inflammatory injury. This review summarizes the clinical, pathophysiological and molecular aspects of inflammation-induced cholestasis.

Intravenous glycyrrhizin for the treatment of chronic hepatitis C: A double-blind, randomized, placebo-controlled phase I/II trial

Abstract: Background: In Japan, glycyrrhizin therapy is widely used for chronic hepatitis C and reportedly reduces the progression of liver disease to hepatocellular carcinoma. The aims of this study were to evaluate the effect of glycyrrhizin on serum alanine aminotransferase (ALT), hepatitis C virus (HCV)-RNA and its safety in European patients. Methods: Fifty-seven patients with chronic hepatitis C, non-responders or unlikely to respond (genotype 1/cirrhosis) to interferon therapy, were randomized to one of the four dose groups: 240, 160 or 80 mg glycyrrhizin or placebo (0 mg glycyrrhizin). Medication was administered intravenously thrice weekly for 4 weeks; follow up also lasted for 4 weeks. Results: Within 2 days of start of therapy, serum ALT had dropped 15% below baseline in the three dosage groups (P 0.1). No major side-effects were noted. None of the patients withdrew from the study because of intolerance. Conclusions: Glycyrrhizin up to 240 mg, thrice weekly, lowers serum ALT during treatment, but has no effect on HCV-RNA levels. The drug appears to be safe and is well tolerated. In view of the reported long-term effect of glycyrrhizin, further controlled investigation of the Japanese mode of administration (six times weekly) for induction appears of interest. © 1999 Blackwell Science Asia Pty Ltd

Molecular genetic basis of Gilbert's syndrome.

Abstract: Gilbert's syndrome, an hereditary, chronic, mild, unconjugated hyperbilirubinaemia resulting from impaired hepatic bilirubin clearance and otherwise normal liver function, is arguably the most common syndrome known in humans. Recent molecular genetic studies have determined that the clinical phenotype can be described by a dinucleotide polymorphism in the TATA box promoter of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT-1A1) gene, most frequently (TA)7TAA, affecting up to 36% of Africans, but only 3% of Asians. However, a second common heterozygous mutation in the coding exon 1 of the UGT-1A1 gene (G71R) can also cause the Gilbert's phenotype in Japanese and Asians. The clinical phenotype may not be apparent as frequently as the determined genotype, due to environmental factors such as alcohol-induced hepatic bilirubin glucuronidation, reducing serum bilirubin levels and causing a latent condition. Gilbert's disease is a contributory factor of prolonged neonatal jaundice in breast-fed infants and may precipitate jaundice when coinherited with other disorders of haem metabolism. The genetic variation described as Gilbert's syndrome may lead to pharmacological variation in drug glucuronidation and unexpected toxicity from therapeutic agents.

Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease.

Abstract: Background: Interleukin-6 (IL-6) has multiple immunological effects on a wide variety of cells and tissues. The expression of IL-6 and IL-6 receptor (IL-6R) may be important to the pathogenesis of inflammatory bowel disease (IBD). Methods: In the present study, we examined whether mucosal IL-6 and soluble IL-6R were associated with the pathophysiology of IBD using the colonic mucosal specimens obtained from patients with IBD. Enzyme-linked immunosorbent assay was used to measure the levels of IL-6 and sIL-6R in organ cultures of mucosal tissues and in cell cultures of fractionated mucosal cells as well as in the serum. Expression of IL-6 and IL-6R was analysed by reverse transcription–polymerase chain reaction analysis using freshly isolated lamina propria mononuclear cells (LPMC). Results: The levels of IL-6 and sIL-6R in organ cultures were substantially elevated in patients with IBD, especially in those with histologically active inflammation. In contrast, considerably higher levels of sIL-6R were detected in patients with other types of colonic inflammation who were included as inflammatory controls, but elevation of IL-6 was less prominent in such patients. The positivity for expression of IL-6 and IL-6R mRNA in LPMC was in parallel with the results obtained in organ cultures. In cell cultures, mucosal macrophages were the main cell type producing both IL-6 and sIL-6R on a per cell basis and other cell fractions including colonic epithelial cells and lymphocytes produced substantially lower amounts of these molecules. The levels of IL-6 and sIL-6R in organ cultures, but not those in the serum, showed a significantly positive correlation with the degree of clinical disease activity in patients with IBD. Conclusions: Enhanced IL-6/sIL-6R-mediated immune and inflammatory responses may be implicated, at least partly, in the continuation of intestinal inflammation in patients with IBD. © 1999 Blackwell Science Asia Pty Ltd

Peripheral cholangiocarcinoma (cholangiocellular carcinoma): clinical features, diagnosis and treatment.

Abstract: Peripheral cholangiocarcinoma is a relatively rare cancer However, it is known to have an unfavourable prognosis compared with that of hepatocellular carcinoma Little is known about its aetiology, clinical or pathological features Recently, with the development of imaging modalities, early staged cholangiocarcinoma has been diagnosed with relative ease Surgery is the optimal therapy Total hepatectomy does not provide survival benefit Conventional surgery remains the only effective treatment, even for patients with advanced-stage tumours Factors influencing survival after hepatectomy were tumour-free margin, lymphnodes metastasis and histopathology of tumour Palliative intrahepatic tubing or percutaneous transhepatic biliary drainage and brachytherapy can alleviate jaundice and cholangitis, thereby prolonging survival in some cases

A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma.

Abstract: Background: The purpose of this study was to determine the potential role of three-dimensional (3-D) conformal radiotherapy (RT) in treatment of unresectable hepatocellular carcinoma (HCC). Methods: Thirteen patients were included in this study, which was conducted between 1993 and 1996. Nine patients (group A) were treated with 3-D conformal RT alone because of main portal vein thrombosis, inferior vena cava thrombosis, obstructive jaundice and failure of previous transcatheter arterial chemoembolization (TACE) to control the disease. The remaining four patients (group B) were treated with a combination of TACE and 3-D conformal RT. Results: The greatest dimension of the main tumour in the whole group of patients ranged from 6 to 25 cm (median 15 cm). The radiation dose ranged from 40 to 60 Gy. The tumour response was evaluated by computed tomography scans of the liver 6–8 weeks after completion of radiotherapy. Partial response was observed in 58% of the patients (seven of 12) and minimal response in another 25% of patients (three of 12). One patient could not be evaluated because of the development of hepatic failure 1 month after completion of RT. All patients in group B lived for more than 1 year (range 16–40 months). In group A, one patient who had a large tumour (11 × 10 × 21 cm) with portal vein thrombosis was converted to become resectable after 45 Gy of radiation. The resection specimen revealed no residual cancer cells. This patient is alive longer than 15 months after treatment without the evidence of disease. Conclusions: Our experience indicates that HCC is more radiosensitive than it was traditionally expected. Three-dimensional reconstruction of tumour and surrounding organs helps to avoid excessive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unresectable HCC. Our preliminary data show promise and are worthy of further study to explore the potential role of radiotherapy in the treatment strategy for HCC at various stages of involvement. © 1999 Blackwell Science Asia Pty Ltd

Comparing the treatment outcomes of endoscopic papillary dilation and endoscopic sphincterotomy for removal of bile duct stones.

Abstract: To compare the clinical usefulness of endoscopic papillary dilation (EPD) and endoscopic sphincterotomy (EST) for removal of bile duct stones, 110 patients with stones up to 15 mm in diameter and less than 10 in number were randomly treated with either EPD (55 patients) or EST (55 patients). The patients were followed up for a median period of 23 months and endoscopic manometry with the administration of morphine was carried out in 17 patients who were observed more than 12 months after the procedures to evaluate the post-procedure papillary function. Duct clearance was achieved in 51 EPD (92.7%) and 54 EST patients (98.1%, not significantly different). Forty EPD (78.4%) and 51 EST patients (94.4%) achieved duct clearance in the initial procedure (P=0.02). Early complications occurred in one EPD (2.0%) and in three EST patients (5.6%, P=0.62). Complications during the follow-up period occurred in two EPD and eight EST patients. Recurrence of bile duct stones was observed in two EPD and three EST patients (P=0.98). Acute cholecystitis was observed in one EPD and five EST patients (P=0.06) and among patients with gall-bladder stones in situ, the rate of acute cholecystitis after EPD was significantly lower than that after EST (P=0.03). Endoscopic manometry showed the existence of a choledochoduodenal pressure gradient only after EPD, while papillary contractile function was observed after both procedures. In conclusion, both EPD and EST are safe therapeutic modalities, although EPD is more clinically effective in decreasing the risk of acute cholecystitis in patients with gall-bladder stones in situ and in preserving post-procedure papillary function.

Colonic tuberculosis: Clinical features, endoscopic appearance and management

Abstract: Background: Although rare in the West, colonic tuberculosis is not an uncommon disease in developing countries. However, the clinical manifestations and radiological appearance of the disease are non-specific. In recent years, colonoscopy has been found to be very useful in diagnosing patients with colonic tuberculosis. Methods: Clinical features, colonoscopic findings, histology and response to treatment were recorded in 50 patients with colonic tuberculosis. Results: Abdominal pain, fever, anorexia, weight loss and diarrhoea were the common symptoms. The colonoscopic features consisted of ulcers (92%), nodules (88%), deformed caecum and ileocecal valve (42%), strictures (25%), multiple fibrous bands (8%) and polypoid lesions (6%). Segmental tuberculosis and lesions simulating carcinoma were seen in 22 and 16% of patients, respectively. Histological examination of the colonic biopsy specimens showed well-formed, non-caseating granulomas in 18%, collection of loosely arranged epithelioid cells in 40% and chronic non-specific inflammatory changes in 42% of the patients. Six patients needed surgical intervention. The other 44 patients responded well to anti-tuberculous therapy and became asymptomatic. Conclusions: It is concluded that colonoscopy is a useful method for diagnosing colonic tuberculosis. It is suggested that if the clinical picture and colonoscopic appearance are suggestive of tuberculosis and target biopsies reveal non-caseating granulomas, a collection of loosely arranged epithelioid cells, or even non-specific changes, then a therapeutic trial of anti-tuberculous drugs should be given and continued if there is clinical improvement.

Role of alpha-fetoprotein in the diagnosis and management of hepatocellular carcinoma.

Abstract: Thirty-five years after its first description, alpha-fetoprotein (AFP) remains the gold standard by which other markers are judged. Serum levels above the reference range of 10 ng/mL occur in approximately 75% of cases of hepatocellular carcinoma (HCC). In individual patients, the serum AFP level behaves as if it reflects tumour mass. However, the specificity of AFP is relatively low because moderately raised levels are also found in some patients with uncomplicated chronic liver disease. Recently, tumour-specific AFP assays have been developed. These are based on the carbohydrate side-chains on the AFP molecule which exhibit characteristic differences in AFP of different origins. Monitoring response to treatment may often be more effectively carried out by serial estimation of AFP than by conventional imaging techniques. The relative specificity of AFP for HCC has also been employed to detect circulating HCC cells and to target gene therapy.

Prediction of oesophagogastric varices in patients with liver cirrhosis

Abstract: Background: All patients with liver cirrhosis are recommended for evaluation of oesophagogastric varices (EGV) regularly. This prospective study was designed to develop a predictive model for EGV in cirrhotic patients. Methods: Ninety-two patients were recruited. From all patients studied, the size of palpable spleen, liver chemistry value, platelet count, prothrombin time, diameter of main portal vein and splenic length as assessed by ultrasonography were determined. Upper endoscopy was performed. Oesophageal varices (EV) and gastric varices (GV) were graded (EV, grade 1-4; GV, grade 1-3). In the predictive model, the EGV was classified into two grades (low, grade 1-2 EV or grade 1 GV; high, grade 3-4 EV or grade 2-3 GV). Results: There were 53 patients with EGV and 39 patients without EGV as determined by endoscopy. Patients with EGV had a significantly higher degree of ascites and hepatic encephalopathy, lower platelet count and longer splenic length than those without EGV. Low platelet count and presence of ascites were the significant independent predictors for high-grade EGV (concordance rate 0.83). The optimal critical value for the platelet count was 150 x 10 9 /L. Of patients without thrombocytopenia and ascites, 37% had low-grade EGV but none had high-grade EGV, whereas 38 and 35% of patients with thrombocytopenia or ascites had low and high-grade EGV, respectively. Therefore, this predictive model for high-grade varices had a positive and negative predictive value of 35 and 100%, respectively. Conclusion: Endoscopic screening for EGV was not necessary until thrombocytopenia or ascites occurred.

Increased mucosal production of granulocyte colony-stimulating factor is related to a delay in neutrophil apoptosis in Inflammatory Bowel disease.

Abstract: Tissue accumulation of polymorphonuclear neutrophils (PMN) in Inflammatory Bowel disease (IBD) might be, in part, due to a delay in apoptotic processes associated with the effects of their specific growth factors and inflammatory cytokines. We addressed this hypothesis by examining the activity of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) in the organ culture supernatants of colonic mucosal specimens and their regulatory effects on PMN apoptosis in patients with IBD. The contents of G-CSF and GM-CSF in the supernatants were measured by the enzyme-linked immunosorbent assays and PMN apoptosis was evaluated by acridine orange/ethidium bromide staining, respectively. Mucosal specimens obtained from patients with active IBD exhibited higher levels of G-CSF and GM-CSF activity than controls. Notably, the levels of G-CSF activity were approximately 1000-fold higher than those of GM-CSF activity. Freshly isolated PMN showed a time-related increase in the proportion of cells with characteristic features of apoptosis when they were incubated with the culture medium alone and exposure of PMN to recombinant G-CSF and GM-CSF caused a concentration-dependent inhibition of apoptosis. Incubation of PMN with the supernatants from patients with active IBD induced an inhibitory effect on PMN apoptosis; this effect was abrogated to a significant degree by pre-incubation of the supernatants with anti-G-CSF serum. This study suggests that PMN apoptosis may be delayed under the influence of soluble mediators, especially G-CSF, in the microenvironment of IBD-affected mucosa, thus providing possible mechanisms for tissue accumulation of PMN in IBD.

Cytomegalovirus infection of the human gastrointestinal tract.

Abstract: Background: Current interest in cytomegalovirus (CMV) is largely due to an increase in the number of cases of acquired immunodeficiency syndrome and organ transplantation in recent years. The proper recognition of CMV-infected cells in gastrointestinal mucosal biopsies is critical for effective treatment of this condition. Methods: A total of 6580 endoscopic mucosal biopsies from 6323 patients in the 8-year period (1989–1996) were examined for CMV inclusion bodies. The endoscopic appearance and particularly the presence of ulcers were also analysed. Results and Conclusions: The prevalence of cytomegalovirus (CMV) inclusions was 9 per thousand in the gastrointestinal mucosal biopsies from an unselected group of patients. Of the 54 patients with CMV infection, 37 were immunocompromised and 17 apparently immunocompetent. Typical Cowdry inclusions and atypical inclusions were present, the latter more frequently in immunocompromised patients. The maximum prevalence of inclusions was in the oesophageal mucosa in immunocompromised individuals. © 1999 Blackwell Science Asia Pty Ltd

Projections of nitric oxide synthase and vasoactive intestinal polypeptide-reactive submucosal neurons in the human colon.

Abstract: Background: The submucosal plexus is important in the control of secretomotor and motor function of the intestine. Our aim was to describe the projections of submucosal neurons to the mucosa within the submucosal plexus and to the circular muscle of human colon and to determine whether submucosal neurons that projected to different layers were located at different levels of the submucosa. Methods: A retrogradely transported fluorescent dye was applied to the mucosa, submucosa or circular muscle layer of human colon which was then maintained in organotypic culture for 5 days. The submucosa was then dissected into two preparations, one containing the inner layer of the submucosal plexus and the other containing both the intermediate and outer layers. The dissected preparations were labelled with antibodies to nitric oxide synthase (NOS) or vasoactive intestinal peptide (VIP). Results: Submucosal neurons projected to the mucosa, submucosa and circular muscle layers for mean distances of 3.7, 3.0 and 4.3 mm, respectively. Ninety-seven per cent of submucosal neurons labelled from the circular muscle were located in the outer or the intermediate layers, while 51% of those projecting to the mucosa were in inner layer and 49% in the intermediate/outer layers of the submucosal plexus. Eleven per cent of submucosal neurons projecting to the circular muscle were immunoreactive for NOS and 12% were immunoreactive for VIP. Forty-five per cent of those projecting within the submucosa were immunoreactive for VIP and 38% of those projecting to the mucosa were immunoreactive for VIP. Conclusions: Submucosal neurons in the human colon innervate the mucosa, circular muscle and submucosa and different functional classes of neurons are located in different layers of the submucosal plexus. © 1999 Blackwell Science Asia Pty Ltd

Germinated barley foodstuffs attenuate colonic mucosal damage and mucosal nuclear factor kappa B activity in a spontaneous colitis model

Abstract: Background: Germinated barley foodstuffs (GBF), which are derived from brewer’s spent grain and are a highly safe food substance, increased butyrate production in the lower intestine and prevented mucosal damage and bloody diarrhoea in an acute experimental colitis model. As human histocompatibility leucocyte antigen (HLA)-B27 transgenic rats develop spontaneous and chronic intestinal inflammation resembling ulcerative colitis, we investigated the mechanisms underlying the preventive effects of GBF against a spontaneous and chronic colitis model. Specifically, the production of bacterial butyrate and the regulation of proinflammatory cytokine production were examined. Methods: A GBF diet and a cellulose (CE) diet were fed to HLA-B27 transgenic rats for 13 weeks. The presence of faecal occult blood, colonic mucosal protein, DNA and RNA content, colonic myeloperoxidase activity, nuclear factor kappa B (NFκB) DNA binding activity, the depth of the crypts and serum inflammatory parameters were then evaluated. Butyrate production in the caecal contents was also determined. Results: Feeding GBF significantly increased bacterial butyrate production and simultaneously attenuated the presence of faecal occult blood and colonic mucosal hyperplasia. Colonic mucosal NFκB-DNA binding activity and the production of interleukin-8 were also suppressed by the butyrate produced from GBF. Conclusions: Germinated barley foodstuffs feeding promotes bacterial butyrate production and attenuated inflammation in both spontaneous and chronic colitis in HLA-B27 transgenic rats. © 1999 Blackwell Science Asia Pty Ltd

Helicobacter pylori and extra-digestive diseases

Abstract: Helicobacter pylori is a recently rediscovered Gram-negative bacteria that causes peptic ulcer disease, gastric lymphoma and gastric carcinoma. Helicobacter pylori achieves its pathogenetic role by triggering an intense leucocyte infiltration of the gastric submucosa which is mediated by proinflammatory cytokines. This pathogenetic mechanism is common to many other diseases and, therefore, Helicobacter pylori seroprevalence has also been investigated in other diseases. It is now known that H. pylori seropositivity is associated with an increasing number of cardiovascular, respiratory, extra-gastroduodenal digestive, neurological, skin, autoimmune, growth and miscellaneous disorders. Although the precise role for H. pylori is unknown in these diseases, it is of tremendous interest to most clinicians and scientists as H. pylori is amenable to eradication therapy using simple and reliable drug regimens. The conditions associated with H. pylori seropositivity are highlighted in this concise article.

Prevalence of non-ulcer dyspepsia in the Japanese population.

Abstract: Background: Non-ulcer dyspepsia (NUD) is one of the most frequently encountered disorders in general practice in Western countries. The prevalence of this disorder in the Japanese, however, has not been fully investigated. This study is designed to clarify the characteristics and prevalence of dyspepsia in the Japanese. Methods: The subjects were 1139 people who visited our institutes for their annual medical check up for gastric cancers. After routine medical examination, all subjects were asked standardized questions in order to check for the presence of any symptoms suggesting dyspepsia. Results: The results of the study showed that dysmotility-like dyspepsia, characterized by the presence of nausea, fullness and early satiety, is the most frequently observed dyspepsia in Japanese and that this type of dyspepsia decreases with age. Ulcer-like dyspepsia, which is the major type of dyspepsia in Western countries, is the least frequently experienced dyspepsia in the Japanese. Conclusions: This study clarified that NUD is also one of the most prevalent disorders in the Japanese, although its characteristics may be somewhat different from those in Western countries. © 1999 Blackwell Science Asia Pty Ltd

Helicobacter pylori in Africa: Observations on an ‘enigma within an enigma’

Abstract: Background: We conducted a retrospective literature review of all the data published on Helicobacter pylori in Africa in order to test whether the prevalence of diseases associated with this organism differs from that in developed nations. Methods: Both sero-epidemiological (n = 8) as well as prospective endoscopic studies in subjects with either dyspepsia or epigastric pain (n = 23) and one retrospective study were available for analysis. Results: Sero-epidemiology confirmed both the early age of acquisition in children (50% by 10 years) as well as the high prevalence of the organism (61%) in adult asymptomatic individuals. Endoscopic studies in dyspeptic individuals revealed the presence of the organism in 72%. Duodenal ulceration was noted in 26% of 3473 cases and in these, H. pylori was present in 90%. An association of gastric metaplasia with duodenal ulceration was identified in the one study in which it was investigated. Gastric ulceration occurred approximately four-fold less frequently (7% of 2286 cases) than duodenal ulceration and the organism was evident in 75% of the gastric ulceration cases. Findings of intestinal metaplasia (14%) and gastric cancer (3.4%) were not infrequent, but the paucity of accurate epidemiological data made it difficult to establish a correlation between the two. Conclusion: It would appear that prospective endoscopic-based studies in African subjects may question the standard dogma of a low prevalence of H. pylori-associated diseases in Africa. Further research is clearly required. © 1999 Blackwell Science Asia Pty Ltd

Treatment strategies for chronic hepatitis C : Update since the 1997 National Institutes of Health Consensus Development Conference

Abstract: The National Institutes of Health Consensus Development Conference on the management of hepatitis C, which took place in March 1997 and was published in September 1997, established guidelines for the diagnosis and management of chronic hepatitis C. The recommended treatment of chronic hepatitis C virus (HCV) infection is interferon alpha (or equivalent) 3 MIU three times per week for 12 months, in patients showing response to therapy after 3 months. Patients with the greatest risk for progression to cirrhosis (i.e. persistently elevated alanine aminotransferase levels, detectable serum HCV-RNA and liver biopsy showing portal or bridging fibrosis and at least moderate inflammation and necrosis) are recommended as candidates for therapy. The indication for therapy is less obvious in patients with milder histological changes, compensated cirrhosis and age less than 18 years or older than 60 years. Treatment is not indicated for patients with persistently normal aminotransferases or decompensated cirrhosis. This review outlines the background studies that led to the recommendations of the National Institutes of Health for the treatment of chronic hepatitis C and reviews newer evolving treatment strategies over the past year. In particular, the results of studies exploring treatment options for relapsers and non-responders to prior interferon therapy and the reported results to date on the safety and efficacy of combination therapy with interferon plus ribavirin are highlighted. Although aggressive suppression of HCV-RNA with induction therapy (daily and/or higher doses) or long-acting pegylated interferon preparations may improve the current results of therapy, few data are yet available. Finally, the treatment of chronic hepatitis C with protease inhibitors holds promise but has yet to reach the stage of clinical trials.

Duplex Doppler sonography in patients with Budd-Chiari syndrome.

Abstract: Background: Angiography has been the mainstay for diagnosis of Budd–Chiari syndrome even though other modalities are increasingly being used. We have evaluated our findings of duplex Doppler sonography (DDS) in patients with Budd–Chiari syndrome. Methods: Duplex Doppler sonography was performed in 37 consecutive angiographically proven patients with Budd–Chiari syndrome. Results: Real time ultrasonography showed abnormalities of right, middle and left hepatic veins (HV) in 21, 15 and 18 patients, respectively. Duplex Doppler sonography showed abnormal flow patterns in 37, 22 and 31 patients in the right, middle and left HV, respectively, thereby increasing the diagnostic yield by 40%. An abnormal waveform in one or more HV was present in all 37 patients. Uniphasic flow was the commonest abnormality and was seen in 22, nine and 14 patients, respectively, in the right, middle and left HV, while there was no flow in five, four and seven patients in the right, middle and left HV, respectively. Intrahepatic collaterals were seen in 35 of 37 patients (94.6%). Hepatopetal flow was found in the portal vein of 21 of 23 patients (91.3%), while flow was hepatofugal in one and portal vein thrombosis was found in another. Conclusion: Duplex Doppler sonography is a useful procedure which helps in the diagnosis of patients with Budd–Chiari syndrome.

Natural history of chronic hepatitis B and C.

Abstract: Hepatitis B virus (HBV) affects more than 300 million individuals worldwide and in the United States approximately 1.25 million individuals are chronic carriers of HBV. The risk of becoming a chronic hepatitis B virus surface antigen carrier is dependent upon the mode of acquisition of infection as well as the age of the individual at the time of infection. For those individuals with high levels of viral replication, chronic active hepatitis with progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC) is common and liver transplantation is an excellent treatment option for patients with end-stage liver disease from HBV. Patients with chronic HBV infection should be screened periodically for hepatoma, although screening strategies have not been proven to prolong survival. Newer antiviral agents for the treatment of HBV are potent inhibitors of HBV-DNA and their long-term effect on the natural history of HBV is yet to be proven. The natural history of hepatitis C virus (HCV) infection is less well defined than that of chronic HBV. Certain patients who are chronic carriers of HCV may never develop extensive fibrosis, whereas others will progress to chronic active hepatitis with cirrhosis, HCC and end-stage liver disease. Factors that influence the progression of HCV are those related to the host, including the age at acquisition of infection, gender and immune status, and the disease process is accelerated in patients who consume regular amounts of alcohol. Hepatocellular carcinoma develops frequently in patients with HCV infection and its overall incidence is increasing due to this chronic viral disease. Patients with HCV cirrhosis should be screened regularly for hepatoma and liver transplantation is an effective treatment option for those with end-stage disease. The impact of antiviral therapy on the natural history of HCV is still to be determined and should be the focus of large clinical trials.

Molecular biology of gastric carcinoma: From laboratory to bedside

Abstract: Although the advancement of molecular oncology in gastric cancer lags behind that of colorectal cancer, the rapid developments witnessed in recent years have improved our understanding of the carcinogenesis, aetiology, progression and metastasis of gastric cancer. The different molecular genetic alterations in intestinal and diffuse types of gastric cancer have further supported the concept that these two pathological types are different disease entities. The association of telomerase and cadherin changes with Helicobacter pylori infection reinforces its aetiological role. The mutated cadherin gene identified in familial gastric cancer has shone light onto the pathogenesis. Adhesion molecules have already been applied to daily clinical practice as prognostic markers. Future molecular studies will contribute to the screening, classification, disease monitoring and therapeutics of gastric cancer.

Extracorporeal support and hepatocyte transplantation in acute liver failure and cirrhosis.

Abstract: The relative shortage of donor organs and lack of immediate availability mean that many patients with acute liver failure die before orthotopic liver transplantation can be performed. An effective temporary liver support system could improve the chance of survival with or without a transplant being ultimately carried out. Recent technological advances resulting in improved maintenance of hepatocyte viability and function in culture and bioreactor designs which facilitate adequate perfusion of the cellular component and removal of products of cellular metabolism have led to the development of a number of bioartificial devices for liver support. Three such devices have undergone preliminary clinical evaluation in the setting of acute liver failure, with a statistically significant reduction in raised intracerebral pressure along with improvements in consciousness level and some biochemical parameters associated with treatment with one of these. Several other devices with different characteristics have shown promise in vitro and/or in animal models but await clinical evaluation. Several new totally artificial systems have also been described, along with the emergence of isolated hepatocyte transplantation, with reports of successful 'bridging' to liver transplantation. Controlled trials on a multicentre basis in well-defined patient groups and with standardized outcome measures will be required to properly evaluate the clinical value of each of these approaches to providing liver support in acute liver failure and cirrhosis. A better understanding of mechanisms underlying multiorgan failure and of factors inhibiting liver regeneration, thereby allowing a more targeted approach, will be essential to the further development of effective liver support strategies in these settings.

Modelling the hepatitis C virus epidemic in Australia

Abstract: Introduction: In Australia, to the end of 1997, more than 110 000 people have been diagnosed with hepatitis C virus (HCV) antibodies and reported to State/Territory surveillance systems. The available data indicate that the overwhelming majority (around 80%) of people with HCV antibodies were infected through injecting drug use. Methods: Models of the HCV epidemic in Australia were developed based on estimates of the pattern of injecting drug use in Australia. Estimates of HCV infections due to injecting drug use thus obtained were then adjusted to allow for HCV infections resulting from other transmission routes. Projections of cirrhosis and hepatocellular carcinoma (HCC) resulting from HCV were obtained by combining modelled HCV incidence with estimates of the progression rates to these outcomes. Results: Based on the models, it was estimated that there were 196 000 (lower and upper limits of 149 000 and 234 000) people in Australia living with HCV antibodies at the end of 1997, with HCV incidence in 1997 estimated to be 11 000 (8500–13 500). It was estimated that 8500 (4000–13 000) people were living with HCV-related cirrhosis in 1997 and that there were 80 (40–125) incident cases of HCV-related HCC. Discussion: Model-based estimates were broadly consistent with other sources of information on the HCV epidemic in Australia. These models suggest that the prevalence of HCV-related cirrhosis and the incidence of HCV-related HCC will more than double in Australia by 2010. © 1999 Blackwell Science Asia Pty Ltd

Effect of butyrate on paracellular permeability in rat distal colonic mucosa ex vivo.

Abstract: Background and Aims: The effects of butyrate on colonic epithelial barrier function are poorly understood. The aim of this study was to examine the short-term effects of butyrate on paracellular permeability of rat distal colonic epithelium. Methods: Mucosa mounted in Ussing chambers was treated with butyrate (1–10 mmol/L) for 4 h. Transepithelial conductance, [51Cr]-EDTA flux, mucosal brush border hydrolase activity and epithelial kinetics, using proliferating cell nuclear antigen (PCNA) staining, were measured. Results: On exposure to butyrate (10 mmol/L, but not 1 or 5 mmol/L), transepithelial conductance was 65 ± 2% higher (mean ± SEM; n = 8, P < 0.05, paired t-test) and the rate coefficient for [51Cr]-EDTA flux was 65 ± 25% higher (P = 0.03) than those of control tissue. Histologically, the epithelium exhibited no signs of injury, but butyrate-treated tissue exhibited interstitial oedema consistent with water uptake in association with butyrate absorption. Butyrate caused a reduction in crypt column height to 30.6 ± 1.6 cells from 33.4 ± 1.8 cells in controls (n = 10, P < 0.03), but the number of cells per crypt column staining with PCNA was unchanged. Butyrate significantly reduced the mucosal activities of alkaline phosphatase by 40 ± 16%, maltase by 54 ± 12% and dipeptidyl peptidase IV by 41 ± 14%. Conclusions: Acute exposure to butyrate increased paracellular permeability in rat distal colon. The mechanism involved may relate to the loss of differentiated surface epithelial cells, or as a physiological response to Na+-coupled butyrate uptake.

Endoscopic management of gastric varices using a detachable snare and simultaneous endoscopic sclerotherapy and O-ring ligation.

Abstract: Background: Cyanoacrylate injection is highly effective and is regarded as the treatment of choice in bleeding gastric varices in Europe, but intravenous injection of cyanoacrylate is not allowed in the USA and Japan because it may cause embolisms in other organs. Accordingly, we developed a new endoscopic combined treatment of endoscopic management of gastric varices using a detachable snare (EVLs) and simultaneous endoscopic sclerotherapy and O-ring ligation (EISL) (i.e. EVLs + EISL), and we prospectively evaluated its efficacy and safety. Methods: Gastric varices were ligated with the loop of a detachable snare that opened to a diameter of 4 cm (EVLs). Then the residual varices around the ligated portion were sclerosed by ethanolamine oleate and the injected vessel was ligated using a pneumo-activated EVL device (EISL). The EVLs + EISL was performed in 35 patients: on an emergency basis in eight patients, on an elective basis in six patients and as primary prophylaxis in 21 patients. Liver function was classified as Child–Pugh class A in 12 patients, class B in 12 patients and class C in 11 patients. Results: Endoscopic disappearance of gastric varices was obtained in 97.1% of the patients and they regressed in all patients. Haemostasis was achieved in all eight emergency cases. The 2-year cumulative non-recurrence rate was 85%, the 2-year cumulative non-bleeding rate was 92% and the 2-year cumulative survival was 80%. No patients died of bleeding from gastric varices. There were no serious short-term complications, such as haemorrhage, gastro-oesophageal perforation, ileus, or renal impairment. Conclusion: Combined EVLs + EISL appears to be a useful treatment for gastric varices due to its safety and good clinical outcome.

Butyrate from bacterial fermentation of germinated barley foodstuff preserves intestinal barrier function in experimental colitis in the rat model

Abstract: Background and Aims: The consumption of germinated barley foodstuff (GBF) prevents inflammation and diarrhoea in a colitis model. In this study we investigated the mechanism of the preventative effect of GBF on experimental colitis in rats, in view of production of bacterial butyrate and preservation of intestinal barrier function. Methods: Sprague–Dawley rats administered with diets supplemented with 3.5% dextran sodium sulphate were used as an experimental colitis model. Butyrate was given to rats orally or intracaecally. Intestinal barrier function was estimated by light microscopic observation of the mucosa, intestinal permeability and bacterial translocation. Results: Mucosal damage was reduced by intracaecal administration of butyrate, but not by oral administration. Bacterial butyrate production and reduction of mucosal damage depended on the dose of GBF in diets. The action of endogenous bacterial butyrate, including the reduction of intestinal permeability and bacterial translocation, was inhibited by administration of an inhibitor of β-oxidation of short-chain fatty acids. Conclusions: The feeding of GBF promotes bacterial butyrate production and improves intestinal barrier function in rats, resulting in mitigation of experimental colitis.

Dextran sodium sulphate-induced colitis activity varies with mouse strain but develops in lipopolysaccharide-unresponsive mice.

Abstract: Bacteria and their products have been implicated in the pathogenesis of chronic Inflammatory Bowel disease. The aim of this study was to investigate the potential role of lipopolysaccharides (LPS) in the development of intestinal injury by comparing the effects of the dextran sodium sulphate (DSS)-induced model of colitis in LPS-sensitive and -insensitive mice. Experimental colitis was induced in LPS-sensitive mice (C3H/He) and their LPS-insensitive congenic strain (C3H/HeJ). Colitis was assessed clinically using a disease activity index (derived from the three main clinical signs; diarrhoea, rectal bleeding and weight loss) and by histological scoring of the diseased colon. The clinical signs and disease activity index did not differ between the LPS-sensitive and -insensitive costrains. Similarly, histological scores did not differ significantly for either C3H strain at any time point during exposure to DSS. However, there were differences in the inflammatory response when different strains were compared (C3H vs CBA): the effects of DSS in C3H mice were immediate, more severe and mainly involved the caecum and ascending colon. These findings suggest that LPS from colonic bacteria do not play a primary role in the initiation of DSS-induced colitis and demonstrate clear differences in the responsiveness of different mouse strains to DSS.

A prospective study of the clinical features, manometric findings, incidence and prevalence of achalasia in Singapore.

Abstract: Background: This study aimed to describe the clinical features, manometric findings, prevalence and incidence of achalasia in Singapore. Methods: A total of 615 new patients referred for oesophageal manometry between 1989 and 1996 were examined prospectively. Twenty-four men and 25 women fulfilled the manometric and clinical criteria for achalasia. Results: Their median age of onset of symptoms was 37 years (range 15-71) and 37% first developed symptoms after the age of 50 years. The presenting symptoms were dysphagia (100%), regurgitation (80%), weight loss (67%) and chest discomfort (33%). Five patients (10%) had a history of benign (mostly autoimmune) thyroid disorders. Endoscopy was reported as normal in 10/43 patients (23%) and achalasia was suggested in only 31 (72%) of 43 barium examinations. Lower oesophageal sphincter (LOS) dysfunction was present in 82% of cases. Using data from medical records and from a survey of gastroenterologists and surgeons in Singapore, the prevalence (in 1996) and incidence of achalasia in Singapore were estimated to be 1.8 per 100 000, and 0.3 per 100 000 per year, respectively. The incidence was significantly lower in Malays than Chinese or Indians. The age-specific incidence of achalasia for both genders followed a bimodal distribution with the larger peak in the sixth decade. No cases of oesophageal carcinoma were identified among these patients. Conclusion: Achalasia is an uncommon condition in Singapore. The clinical and manometric features were similar to those described in Western countries.

Case report: oral antioxidant therapy for the treatment of primary biliary cirrhosis: a pilot study.

Abstract: Background: The symptoms of the chronic cholestatic liver disease primary biliary cirrhosis (PBC), in particular fatigue and chronic pruritus, adversely affect quality of life and respond only poorly to treatment. Recent studies have suggested that oxidative stress may play a role in tissue damage in cholestatic liver disease and may contribute to symptoms, such as fatigue. We have, therefore, examined, in an open-label pilot study, the therapeutic effects of antioxidant medication on the biochemistry and symptomatology of PBC. Methods: Patients were randomized to 3 months treatment with a compound antioxidant vitamin preparation (Bio-Antox), four tablets daily (n = 11, group 1), or the combination of Bio-Quinone Q10 (100 mg) with Bio-Antox (n = 13, group 2). Biochemical and symptomatic responses were assessed at 3 months. Results: Significant improvement in both pruritus and fatigue was seen in the patients in group 2. Mean itch visual analogue score improved from 2.4 ± 3.0 to 0.4 ± 0.7 post therapy (P < 0.05) while mean night itch severity score improved from 2.6 ± 1.9 to 1.3 ± 0.7 (P < 0.05). Nine of 13 of these patients reported less fatigue, while 10/13 showed an improvement in at least one domain of their Fisk Fatigue Severity Score. No significant improvement in itch and only limited improvement in fatigue were seen in the patients in group 1. No change in biochemical parameters was seen in either group. Conclusions: Antioxidant therapy, as a combination of Bio-Antox and Bio-Quinone Q10, may improve the pruritus and fatigue of PBC. This combination of therapy should be investigated further in a double-blind, placebo-controlled trial. © 1999 Blackwell Science Asia Pty Ltd