Review article: from gastrin to gastro-oesophageal reflux disease--a century of acid suppression.

To commemorate Edkins' discovery of gastrin in 1905, we review a century of progress in the physiology and pathobiology of gastrin and acid secretion especially as it pertains to clinical aspects of gastro-oesophageal reflux disease. Although initially ignored, Edkins' observations eventually led to the enthusiastic investigation of gastrin and acid regulation in peptic ulcer disease, culminating in important therapeutic advances in the management of acid peptic disease. Following the improved understanding of gastric secretory physiology, and the development of acid suppressants with increasing efficacy, the use of surgical intervention for peptic ulcer disease was almost eliminated. Surgery became obsolete with the discovery of Helicobacter pylori. Three other advances are also influencing modern practice: the gastrotoxicity of aspirin and non-steroidal anti-inflammatory drugs is now increasingly appreciated, the role of endoscopy in the diagnosis and therapy of upper gastrointestinal bleeding, and the use of intravenous acid-suppressive agents. The major issue for the future resides within the epidemic of gastro-oesophageal reflux disease. How to diagnose, categorize and treat this condition and how to identify and prevent neoplasia, are the challenges of the new century.

Review article: acute severe ulcerative colitis - evidence-based consensus statements.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of ulcerative colitis. AIM: To develop consensus statements based on a systematic review of the literature of the management of ASUC to improve patient outcome. METHODS: Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre-determined by ≥80% votes in 'complete agreement' or 'agreement with minor reservation'. RESULTS: Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres. CONCLUSION: These evidenced-based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up-to-date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.

The C-caffeine breath test distinguishes significant fibrosis in chronic hepatitis B and reflects response to lamivudine therapy.

BACKGROUND: The 13C-caffeine breath test is a non-invasive, quantitative test of liver function. AIM: To determine the utility of the 13C-caffeine breath test in chronic hepatitis B virus and its ability to monitor response to lamivudine. METHODS: Forty-eight chronic hepatitis B virus patients and 24 controls underwent the 13C-caffeine breath test. In 28 patients commenced on lamivudine, 13C-caffeine breath tests were performed at 1 week (n = 12) and after 1 year of therapy. RESULTS: Patients with Metavir F0-1 fibrosis (2.30 +/- 1.02 Delta per thousand per 100 mg caffeine) had a 13C-caffeine breath test similar to controls (2.31 +/- 0.85, P = 0.96). However, patients with F2-3 fibrosis (1.59 +/- 0.78, P = 0.047) and cirrhotic patients (0.99 +/- 0.33, P = 0.001) had a decreased 13C-caffeine breath test. Fibrosis correlated best with the 13C-caffeine breath test (r(s) = -0.62, P < 0.001). The 13C-caffeine breath test independently predicted significant (F > or = 2) and advanced (F > or = 3) fibrosis and yielded the greatest area under the receiver operating characteristic curve (0.91 +/- 0.04) for predicting advanced fibrosis. The 13C-caffeine breath test was unaltered by 1 week of lamivudine but improved by 61% (P < 0.001) in responders to long-term lamivudine, whereas in those with viraemia and elevated alanine aminotransferase, values remained stable or deteriorated. CONCLUSION: The 13C-caffeine breath test distinguishes chronic hepatitis B virus-related fibrosis and detects improvement in liver function in response to long-term lamivudine.

A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO study.

AIM: To assess the efficacy of the 8-week therapy with esomeprazole 40 mg vs. pantoprazole 40 mg for healing erosive oesophagitis (EE) as part of a management study. METHODS: Patients had a history of gastro-oesophageal reflux disease symptoms (> or =6 months) and had suffered heartburn on at least 4 of the 7 days preceding enrollment. Endoscopies were performed to grade EE severity using the Los Angeles (LA) classification system at baseline, 4 and 8 weeks (if unhealed at 4 weeks). Heartburn severity was recorded by patients on diary cards. The primary end point was healing of EE by week 8 of treatment. RESULTS: Of 3170 patients randomized, the intent-to-treat population consisted of 3151 patients (63% male, mean age: 50.6 years, 27% Helicobacter pylori-positive). Esomeprazole 40 mg healed a significantly greater proportion of EE patients than pantoprazole 40 mg at both 4 weeks (life table estimates: esomeprazole 81%, pantoprazole 75%, P < 0.001) and 8 weeks (life table estimates: esomeprazole 96%, pantoprazole 92%, P < 0.001). The median time to reach sustained heartburn resolution was 6 days in patients receiving esomeprazole and 8 days with pantoprazole (P < 0.001). CONCLUSION: Esomeprazole 40 mg is more effective than pantoprazole 40 mg for healing EE and providing resolution of associated heartburn.

Esomeprazole 20 mg vs. pantoprazole 20 mg for maintenance therapy of healed erosive oesophagitis: results from the EXPO study.

BACKGROUND: Following initial healing of erosive oesophagitis, most patients require maintenance therapy to prevent relapse. AIM: To compare endoscopic and symptomatic remission rates over 6 months' maintenance therapy with esomeprazole or pantoprazole (both 20 mg once daily) in patients with healed erosive oesophagitis. METHODS: Patients with symptoms of gastro-oesophageal reflux disease and endoscopically confirmed erosive oesophagitis at baseline were randomized to receive esomeprazole 40 mg or pantoprazole 40 mg for up to 8 weeks. Patients with healed erosive oesophagitis and free of moderate/severe heartburn and acid regurgitation at 4 weeks or, if necessary, 8 weeks entered the 6-month maintenance therapy phase of the study. RESULTS: A total of 2766 patients (63% men; mean age 50 years) received esomeprazole 20 mg (n = 1377) or pantoprazole 20 mg (n = 1389) and comprised the intention-to-treat population. Following 6 months of treatment, the proportion of patients in endoscopic and symptomatic remission was significantly greater for those receiving esomeprazole 20 mg (87.0%) than pantoprazole 20 mg (74.9%, log-rank test P < 0.0001). Esomeprazole 20 mg produced a higher proportion of patients free of moderate to severe gastro-oesophageal reflux disease symptoms and fewer discontinuations because of symptoms than pantoprazole 20 mg (92.2% vs. 88.5%, P < 0.001). CONCLUSIONS: Esomeprazole 20 mg is more effective than pantoprazole 20 mg for maintenance therapy following initial healing of erosive oesophagitis and relief of gastro-oesophageal reflux disease symptoms.

Smoking prevalence and its influence on disease course and surgery in Crohn's disease and ulcerative colitis.

BACKGROUND: Smoking demonstrates divergent effects in Crohn's disease (CD) and ulcerative colitis (UC). Smoking frequency is greater in CD and deleterious to its disease course. Conversely, UC is primarily a disease of nonsmokers and ex-smokers, with reports of disease amelioration in active smoking. AIM: To determine the prevalence of smoking and its effects on disease progression and surgery in a well-characterised cohort of inflammatory bowel diseases (IBD) patients. METHODS: Patients with smoking data of the Sydney IBD Cohort were included. Demographic, phenotypic, medical, surgical and hospitalisation data were analysed and reported on the basis of patient smoking status. RESULTS: 1203 IBD patients were identified comprising 626 CD and 557 UC with 6725 and 6672 patient-years of follow-up, respectively. CD patients were more likely to smoke than UC patients (19.2% vs. 10.2%, P < 0.001). A history of smoking in CD was associated with an increased proportional surgery rate (45.8% vs. 37.8%, P = 0.045), requirement for IBD-related hospitalisation (P = 0.009) and incidence of peripheral arthritis (29.8% vs. 22.0%, P = 0.027). Current smokers with UC demonstrated reduced corticosteroid utilisation (24.1% vs. 37.5%, P = 0.045), yet no reduction in the rates of colectomy (3.4% vs. 6.6%, P = 0.34) or hospital admission (P = 0.25) relative to nonsmokers. Ex-smokers with UC required proportionately greater immunosuppressive (36.2% vs. 26.3%, P = 0.041) and corticosteroid (43.7% vs. 34.5%, P = 0.078) therapies compared with current and never smokers. CONCLUSIONS: This study confirms the detrimental effects of smoking in CD, yet failed to demonstrate substantial benefit from smoking in UC. These data should encourage all patients with IBD to quit smoking.

Activity of metronidazole, azithromycin and three benzimidazoles on Giardia lamblia growth and attachment to a human intestinal cell line.

BACKGROUND: Attachment of Giardia lamblia trophozoites to enterocytes is essential for colonization of the small intestine and is considered a prerequisite for Giardia-induced enterocyte damage. Inhibition of attachment may therefore have therapeutic potential. METHODS: Enterocyte-like differentiated Caco-2 cells were used as a biologically appropriate attachment surface to determine the effect of three benzimidazole compounds (albendazole, mebendazole and thiabendazole), azithromycin and metronidazole on Giardia attachment. The results were compared with the ability for each drug to inhibit Giardia growth, measured using [3H]-thymidine uptake. RESULTS: The benzimidazoles inhibited Giardia attachment at much lower concentrations than did metronidazole. However, metronidazole was a much more potent inhibitor of growth than any of the benzimidazoles. Azithromycin did not significantly impair Giardia attachment or growth. The benzimidazoles decrease attachment but are less giardiacidal than metronidazole. CONCLUSION: This model appears useful for testing potential antigiardial compounds and investigating mechanisms of drug action.

The effect of dosing with omeprazole on the accuracy of the 13C-urea breath test in Helicobacter pylori-infected subjects.

BACKGROUND: The 13C-urea breath test (13C-UBT) is an accurate means of Helicobacter pylori diagnosis. However, proton pump inhibitors may suppress H. pylori and cause false negative results. AIM: To study the kinetics of H. pylori suppression by omeprazole during and after short-term use. METHODS: Volunteers underwent a baseline 13C-UBT (13C-urea 100 mg). H. pylori-positive subjects took omeprazole 20 mg daily for 14 days. Those who remained 13C-UBT positive (delta13CO2 >/= 5) continued omeprazole for a further 14 days. 13C-UBTs were performed weekly on omeprazole and then every second day after it was stopped. False negatives occurred when delta13CO2 fell to < 5. RESULTS: In 25 H. pylori-positive subjects (mean age 43.9 +/- 2.4 years; 21 females, 4 males) the mean baseline delta13CO2 was 28.1 +/- 3.4. False negative breath tests occurred in three subjects after 7 days of omeprazole and in a further four subjects after 14 days. A further six subjects developed negative tests between Days 14 and 28. Following cessation of omeprazole, the 13C-UBT became positive again in 12/13 subjects within 4 days and in all within 6 days, with a mean recovery to 99.9 +/- 18.6% of baseline delta13CO2. CONCLUSIONS: False negative 13C-UBTs are common during treatment with omeprazole and occur after as little as 7 days. Return to positive test results is rapid after cessation of omeprazole. These findings are relevant to the timing of testing in clinical practice.

Randomized trial of omeprazole and metronidazole with amoxycillin or clarithromycin for Helicobacter pylori eradication, in a region of high primary metronidazole resistance: the HERO study.

BACKGROUND: The efficacy of omeprazole-based eradication therapies has been determined mostly in populations with low to moderate prevalence of metronidazole resistant Helicobacter pylori, yet resistance is high in many regions. AIM AND METHODS: The H. pylori eradication and duodenal ulcer healing rates after 1 week of either omeprazole 40 mg mane, amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. (OAM) or omeprazole 20 mg b.d., metronidazole 400 mg b. d. and clarithromycin 250 mg b.d. (OMC) were compared in a randomized trial in Australia and New Zealand. Patients had a further 1 week of omeprazole 20 mg. Outcome was assessed at 6 weeks with stringent criteria (endoscopy, biopsies and 13C-urea breath test). RESULTS: Of 220 subjects randomized, the H. pylori eradication rates (all patients treated/per protocol) were 82%/85% for OMC and 58%/63% for OAM (P= 0.001). Pre-treatment metronidazole resistance was present in 56% and clarithromycin resistance in 6%. The eradication rate for primary metronidazole resistance isolates treated with OMC was 80% (CI: 65-90%) compared with 45% (CI: 29-62%) for OAM, whereas for sensitive organisms, the eradication rates were 94% (CI: 79-99%) and 79% (CI: 62-91%), respectively. Duodenal ulcer healing was 96% for OMC and 87% for OAM. Compliance was excellent and both treatments were well-tolerated. CONCLUSIONS: OMC is a well-tolerated, effective therapy for H. pylori eradication and duodenal ulcer healing in this region despite the high metronidazole resistance rate. OAM is less effective, largely due to the impact of metronidazole resistance.

A randomized prospective comparison of clarithromycin versus amoxycillin in combination with omeprazole for eradication of Helicobacter pylori.

AIM: To compare H. pylori eradication rates using omeprazole in conjunction with either amoxycillin or clarithromycin. BACKGROUND: Omeprazole with amoxycillin is the most widely used dual therapy regimen for eradication of H. pylori. A recent open study suggested a high eradication rate combining omeprazole with the newer macrolide, clarithromycin. METHODS: A randomized prospective trial in 54 patients was conducted to compare 2 weeks of treatment with omeprazole 40 mg once daily and either amoxycillin 500 mg three times daily or clarithromycin 500 mg three times daily. H. pylori eradication was assessed using the 13C urea breath test. RESULTS: Eradication was achieved in 18/26 (69.2%) of subjects treated with omeprazole and amoxycillin and 18/25 (72.0%) of those treated with omeprazole and clarithromycin (P = N.S.). Minor side effects, most commonly altered taste, were reported by 16% of patients and were more frequent in those randomized to clarithromycin (P = 0.01). CONCLUSIONS: These regimens are similarly effective. However, clarithromycin is more expensive, associated with a greater frequency of side effects and, unlike amoxycillin, resistance by H. pylori has been reported. This suggests that clarithromycin may be a useful alternative when there is penicillin allergy or previous treatment failure, but it should not replace amoxycillin as first choice in omeprazole-based dual therapy.

Review article: oesophageal complications and consequences of persistent gastro-oesophageal reflux disease.

The major oesophageal complications associated with persistent gastro-oesophageal reflux disease (GERD) include erosive oesophagitis, ulceration, strictures and gastrointestinal (GI) bleeding. Although the causes of these complications are uncertain, studies indicate that erosive oesophagitis may progress to the development of ulcers, strictures and GI bleeding. Pharmacological treatment with proton pump inhibitors is favoured over that with H(2)-receptor antagonists for the treatment of strictures. The treatment of strictures is accomplished with dilation and many favour the concomitant use of proton pump inhibitors. Most gastroenterologists are seeing far fewer oesophageal strictures these days since the introduction of proton pump inhibitors. In addition, research has shown that oesophageal complications have a greater impact on patients suffering from night-time GERD than on those suffering from daytime GERD. Barrett's oesophagus is a significant complication associated with persistent GERD and those at risk generally experience a longer duration of symptoms, especially those with a high degree of severity. In addition, there is a strong relationship between Barrett's oesophagus and oesophageal adenocarcinoma. This is in part due to the association of obesity and the development of hiatal hernias. Furthermore, endoscopic screening is being used to detect Barrett's oesophagus and oesophageal adenocarcinoma in persons suffering from chronic GERD, even though screening may not have an impact on outcomes (Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett's esophagus: The AGA Chicago Workshop. Gastroenterology 2004; 127: 310-30.).

Fulminant hepatic failure.

Most cases of fulminant hepatic failure (FHF) are related to viral hepatitis or to drugs and toxins. With improvement in supportive intensive care, the overall survival has increased, but specific forms of temporary hepatic support pending hepatic regeneration have been disappointing. With the widespread availability of orthotopic liver transplantation, this has become a viable option for those patients with FHF who are unlikely to survive with conservative treatment, although patient selection and timing of transplantation still presents a clinical dilemma.

An evaluation of factors affecting Helicobacter pylori prevalence in Tibetans exiled in India.

Helicobacter pylori infection is found world-wide although the epidemiology of infection has not been well defined in many geographical areas. The aims of this study were to determine the prevalence of H. pylori infection and chronic gastritis and the demographic correlates of infection in a single racial group in southern India. The sample population was selected randomly from the male population register of a Tibetan refugee settlement. Demographic data and results of endoscopy with antral mucosal biopsy were evaluated in 197 subjects (median age 28, range 21-81 years). H. pylori was present in 77.2% of subjects by histology and/or urease test. Chronic gastritis and H. pylori were closely related and there was an association between the number of bacteria present and the severity of the gastritis (P < 0.04). Infection with H. pylori was inversely associated with socio-economic factors, specifically educational level (P < 0.02) and occupation (P < 0.02). Unlike other studies, the prevalence of H. pylori was not found to rise with age, being lower in those older than 40 years (P < 0.005). This difference was still apparent when adjusted for socio-economic status. The major demographic difference between younger and older subjects of low socio-economic status was the greater proportion of early life spent outside India (and in Tibet) by older subjects. Among younger subjects, residence in India for 20 years or more was associated with a greater risk of H. pylori infection (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The impact of short-term ranitidine use on the precision of the 13C-urea breath test in subjects infected with Helicobacter pylori.

BACKGROUND: The 13C-urea breath test (13C-UBT) is a very accurate method of Helicobacter pylori diagnosis with a false-negative rate of 1-3%. However, the accuracy of the 13C-UBT is affected by potent acid inhibition with proton-pump inhibitors, which may suppress H. pylori and cause false-negative results. It is not known whether this occurs with less potent acid inhibition by H2-antagonists and any effect may be important clinically. OBJECTIVE: To determine the kinetics of 13CO2 excretion in H. pylori infected subjects during and after short-term ranitidine use. METHODS: Volunteers underwent a baseline 13C-UBT (positive: delta13CO2 > or = 5.0; negative: < or = 3.5; indeterminate: > 3.5 to < 5.0). Infected subjects took ranitidine 300 mg each evening for up to 28 days. 13C-UBTs were performed at weekly intervals and then every other day after ranitidine was ceased. If the 13C-UBT remained positive after 14 days, ranitidine was continued for a further 14 days. RESULTS: Thirty-one subjects were studied (mean age 40.4 +/- 2.1 years; 23 female/8 male; mean baseline delta13CO2 27.3 +/- 2.5). In 28 subjects the 13C-UBT remained positive during ranitidine use. The mean delta13CO2 rose to 124% (P< 0.06) and 121% (P < 0.05) of baseline at 14 and 28 days respectively. In two subjects, the delta13CO2 became indeterminate at day 7 (delta13CO2 4.3 and 3.8). In one of these, return to a positive value (delta13CO2 13.6; 103% of baseline) occurred while still on ranitidine. The other subject became positive again by day 3 off ranitidine (17.8; 119% of baseline). One subject had a transiently negative test after 21 days and this became positive again while still taking ranitidine. CONCLUSIONS: Ranitidine has a minimal effect on the 13C-UBT. The rate of indeterminate or false-negative tests is no greater than in patients on no anti-secretory medication.

Treatment of Helicobacter pylori infection.

Helicobacter pylori infects the human stomach and is associated with chronic gastritis, peptic ulcer disease and gastric cancer. Most patients with peptic ulcers are infected with H pylori. These patients suffer a high relapse rate following initial healing of the ulcer with anti-secretory agents. The rate of relapse can be greatly diminished following successful eradication of the organism. Although experience is still being accumulated, it is reasonable to use eradication therapy in any patient with H pylori positive active peptic ulcer disease. Combination triple and dual therapy regimens are effective but the search continues for better therapies. This review outlines the current evidence regarding which, when, how and with what H pylori infected patients should be treated.

Gastro-oesophageal reflux disease and Helicobacter pylori.

The interaction between gastro-oesophageal reflux disease (GERD) and Helicobacter pylori (H. pylori) infection has been the subject of intense scrutiny in recent years. Although the evidence base is incomplete it is now sufficient to clarify a number of key questions. H. pylori is not a risk factor for reflux disease. Similarly, H. pylori infection, in most patients, is not ''protective'' against the risk of developing reflux and oesophagitis. Furthermore, reflux and oesophagitis are not more likely to develop or to worsen after H. pylori eradication therapy and eradication does not make control of reflux symptoms with proton pump inhibitor (PPI) therapy more difficult. Long term PPI therapy in the presence of H. pylori infection does increase the rate at which gastric mucosal atrophy and intestinal metaplasia develop. Eradication therapy has been shown to reduce this risk. In the uninfected stomach, PPIs are associated with a low likelihood of these adverse histological changes. PPI therapy reduces the accuracy of diagnostic tests for H. pylori. The decision to test for and treat H. pylori infection in the context of reflux must be individualised based on patient factors including co-morbidity, age, gastric histology, family history and informed choice. Distinction must be made between treating symptoms and potentially reducing risks. A decision not to test for and treat H. pylori is now just as active a choice as is the decision to test and treat. Recent international consensus statements recommend eradication of H. pylori prior to long term PPI therapy in reflux disease, although there is not a universal agreement on this. Further research to clarify the risk and benefits of such an approach is required.

Chest pain. Differentiating GIT from cardiac causes.

BACKGROUND: Chest pain is a common presenting symptom in general practice. Although a cardiac cause is not the commonest origin, a high index of suspicion is needed. When the diagnosis is not clear, a cardiac cause should be considered until proven otherwise. A gastrointestinal origin of chest pain is not infrequent and may be due to oesophageal, gastric or biliary disease. Oesophageal causes are most common and include reflux, hypersensitivity or dysmotility. OBJECTIVE: This paper reviews the main gastrointestinal causes that may present with acute chest pain. DISCUSSION: Clinical history taking is the key to decision making and guides the choice of prompt or routine investigation or a therapeutic trial. When reflux is suspected as the cause, a therapeutic trial of high dose antisecretory therapy is appropriate. Investigations may be helpful when typical reflux symptoms are not present or there is a poor response to this approach. Investigations may include endoscopy, ambulatory pH monitoring, barium swallow or oesophageal manometry.