The Sydney System for classification of gastritis 20 years ago.

The roots of research into gastritis go back into the early decades of the 20th century. Modern aspects of its classification and knowledge of its biological course and consequences were relatively well known even at the time that Helicobcter pylori was discovered by Robin Warren and Barry Marshall in 1982. This discovery, however, significantly changed the field, establishing that the commonest form of gastritis is simply an infectious disease, a finding that raised enormous interest in the subject amongst gastroenterologists, microbiologists, pathologists and basic researchers. However, many of these "new" players in the field often had a limited knowledge of the morphological aspects of gastric inflammations and chronic gastritis. As a consequence in the late 1980's a Working Party was set up to review the biology and natural course of chronic gastritis, to propose a new classification for gastritis, and to provide simple guidelines for reporting the pathology of gastritis in endoscopic biopsies in an attempt to bring uniformity to the subject and facilitate comparative studies in what was to be an era of high research activity. These guidelines, The Sydney System: A New Classification of Gastritis was presented to the World Congress of Gastroenterology in Sydney in 1990, and was later published as six papers in the Journal of Gastroenterology and Hepatology. Now, twenty years on, this review looks back on the birth of Sydney System and why it is still important and successful.

Differential effect of Helicobacter pylori eradication on time-trends in brady/hypokinesia and rigidity in idiopathic parkinsonism.

BACKGROUND: We examine the effect of eradicating Helicobacter in idiopathic parkinsonism (IP). Marked deterioration, where eradication-therapy failed, prompted an interim report in the first 20 probands to reach de-blinding. The null-hypothesis, "eradication has no effect on principal outcome, mean stride length at free-walking speed," was rejected. We report on study completion in all 30 who had commenced post-treatment assessments. METHODS: This is a randomized, placebo-controlled, parallel-group efficacy study of eradicating biopsy-proven (culture and/or organism on histopathology) Helicobacter pylori infection on the time course of facets of IP, in probands taking no, or stable long-t(1/2), anti-parkinsonian medication. Persistent infection at de-blinding (scheduled 1-year post-treatment) led to open active eradication-treatment. RESULTS: Stride length improved (73 (95% CI 14-131) mm/year, p = .01) in favor of "successful" blinded active over placebo, irrespective of anti-parkinsonian medication, and despite worsening upper limb flexor rigidity (237 (57-416) Nm x 10(-3)/year, p = .01). This differential effect was echoed following open active, post-placebo. Gait did not deteriorate in year 2 and 3 post-eradication. Anti-nuclear antibody was present in all four proven (two by molecular microbiology only) eradication failures. In the remainder, it marked poorer response during the year after eradication therapy, possibly indicating residual "low-density" infection. We illustrate the importance of eradicating low-density infection, detected only by molecular microbiology, in a proband not receiving anti-parkinsonian medication. Stride length improved (424 (379-468) mm for 15 months post-eradication, p = .001), correction of deficit continuing to 3.4 years. Flexor rigidity increased before hydrogen-breath-test positivity for small intestinal bacterial overgrowth (208 (28-388) Nm x 10(-3), p = .02), increased further during (171 (67-274), p = .001) (15-31 months), and decreased (136 (6-267), p = .04) after restoration of negativity (32-41 months). CONCLUSION: Helicobacter is an arbiter of progression, independent of infection-load.

Helicobacter hypothesis for idiopathic parkinsonism: before and beyond.

We challenge the concept of idiopathic parkinsonism (IP) as inevitably progressive neurodegeneration, proposing a natural history of sequential microbial insults with predisposing host response. Proof-of-principle that infection can contribute to IP was provided by case studies and a placebo-controlled efficacy study of Helicobacter eradication. "Malignant" IP appears converted to "benign", but marked deterioration accompanies failure. Similar benefit on brady/hypokinesia from eradicating "low-density" infection favors autoimmunity. Although a minority of UK probands are urea breath test positive for Helicobacter, the predicted probability of having the parkinsonian label depends on the serum H. pylori antibody profile, with clinically relevant gradients between this "discriminant index" and disease burden and progression. In IP, H. pylori antibodies discriminate for persistently abnormal bowel function, and specific abnormal duodenal enterocyte mitochondrial morphology is described in relation to H. pylori infection. Slow intestinal transit manifests as constipation from the prodrome. Diarrhea may flag secondary small-intestinal bacterial overgrowth. This, coupled with genetically determined intense inflammatory response, might explain evolution from brady/hypokinetic to rigidity-predominant parkinsonism.

Flat colorectal neoplasms and the impact of the revised Vienna Classification on their reporting: a case-control study in UK and Japanese patients.

OBJECTIVE: The prevalence and interpretation of flat colorectal neoplasms in the East or West remain highly variable. Several factors may contribute to this variability including differences in reporting techniques between Japanese and Western histopathologists when lesions are classified. The aims of this study were (i) to determine the frequency and characteristics of flat colorectal neoplasms in British and Japanese patients, (ii) to examine whether histopathological discrepancies exist between Western and Japanese-trained pathologists applying conventional classification methods and (iii) to determine the impact of the revised Vienna Classification on any differences observed. MATERIAL AND METHODS: One hundred and forty-four patients in the United Kingdom with neoplastic lesions prospectively identified by a colonoscopist, fully-trained in Japan, were age and gender-matched with 144 Japanese patients with neoplastic lesions detected by the same colonoscopist. Two British and two Japanese pathologists were independently asked to assess all neoplasms using both conventional and revised Vienna Classification methods. RESULTS: No significant difference in the frequency of flat neoplasms was found between British and Japanese patients; however, flat neoplasia from Japanese patients tended to contain more advanced pathologies. Discrepancies in histological diagnoses were observed between pathologists but which were reduced with the revised Vienna Classification. Japanese pathologists tended to diagnose higher grades of dysplasia for the same lesion compared to their British counterparts. CONCLUSIONS: The frequency of flat neoplasms in British and Japanese patients is similar. However, Japanese lesions, especially flat (IIb) and slightly depressed (IIc) neoplasms tend to be more biologically aggressive. The revised Vienna Classification achieves greater consensus.

Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis.

BACKGROUND & AIMS: The value of colonoscopic surveillance for neoplasia in long-standing extensive ulcerative colitis remains controversial. This study reports on prospectively collected data from a surveillance program over a 30-year period. METHODS: Data were obtained from the prospective surveillance database, medical records, colonoscopy, and histology reports. The primary end point was defined as death, colectomy, withdrawal from surveillance, or census date (January 1, 2001). Follow-up information was obtained for patients who left the program. RESULTS: Six hundred patients underwent 2627 colonoscopies during 5932 patient-years of follow-up. The cecal intubation rate was 98.7%, with no significant complications. Seventy-four patients (12.3%) developed neoplasia, including 30 colorectal cancers (CRCs). There was no difference in median age at onset of colitis for those with or without CRC (P = .8, Mann-Whitney). The cumulative incidence of CRC by colitis duration was 2.5% at 20 years, 7.6% at 30 years, and 10.8% at 40 years. The 5-year survival rate was 73.3%. Sixteen of 30 cancers were interval cancers. CRC incidence decreased over time (r = -.40, P = .04; linear regression). CONCLUSIONS: Colonoscopic surveillance is safe and allows the vast majority of patients to retain their colon. Although two thirds of patients with potentially life-threatening neoplasia benefited from surveillance, the program was not wholly effective in cancer prevention. The cancer incidence, however, was considerably lower than in the majority of other studies, and was constant for up to 40 years of colitis duration, suggesting there is no need to intensify surveillance over time.

Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 1: eradication of Helicobacter in the cachexia of idiopathic parkinsonism.

BACKGROUND: Neuronal damage in idiopathic parkinsonism may be in response to ubiquitous occult infection. Since peptic ulceration is prodromal, Helicobacter is a prime candidate. AIM: To consider the candidature of Helicobacter in parkinsonism with cachexia. METHODS: We explore the relationship between being underweight and inflammatory products in 124 subjects with idiopathic parkinsonism and 195 controls, and present the first case-series evidence of efficacy of Helicobacter eradication, in parkinsonism advanced to the stage of cachexia. RESULTS: Association of a low body mass index with circulating interleukin-6 was specific to parkinsonism (p = .002), unlike that with antibodies against Helicobacter vacuolating-toxin and cytotoxicity-associated gene product (p < .04). Marked reversibility in both cachexia and disability of idiopathic parkinsonism followed Helicobacter heilmannii eradication in one case, Helicobacter pylori eradication in another, follow-up being > or = 3.5 years. The latter presented with postprandial bloating, and persistent nausea: following eradication, radioisotope gastric-emptying returned towards normal, and upper abdominal symptoms regressed. Reversibility of their cachexia/disability contrasts with the outcome of anti-Helicobacter therapy where eradication repeatedly failed (one case), and in non-Helicobacter gastritis (three cases). Anti-parkinsonian medication remained constant. Intestinal absorption and barrier function were normal in all. CONCLUSION: Categorization, according to presence or absence of Helicobacter infection, was a useful therapeutic tool in late idiopathic parkinsonism.

Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 2: response of facets of clinical idiopathic parkinsonism to Helicobacter pylori eradication. A randomized, double-blind, placebo-controlled efficacy study.

BACKGROUND: Links between etiology/pathogenesis of neuropsychiatric disease and infection are increasingly recognized. AIM: Proof-of-principle that infection contributes to idiopathic parkinsonism. METHODS: Randomized, double-blind, placebo-controlled efficacy study of proven Helicobacter pylori eradication on the time course of facets of parkinsonism. Intervention was 1 week's triple eradication therapy/placebos. Routine deblinding at 1 year (those still infected received open-active), with follow-up to 5 years post-eradication. Primary outcome was mean stride length at free-walking speed, sample size 56 for a difference, active vs. placebo, of 3/4 (between-subject standard deviation). Recruitment of subjects with idiopathic parkinsonism and H. pylori infection was stopped at 31, because of marked deterioration with eradication failure. Interim analysis was made in the 20 who had reached deblinding, seven of whom were receiving antiparkinsonian medication (long-t(1/2), evenly spaced) which remained unchanged. RESULTS: Improvement in stride-length, on active (n = 9) vs. placebo (11), exceeded size of effect on which the sample size was calculated when analyzed on intention-to-treat basis (p = .02), and on protocol analysis of six weekly assessments, including (p = .02) and excluding (p = .05) those on antiparkinsonian medication. Active eradication (blind or open) failed in 4/20, in whom B-lymphocyte count was lower. Their mean time course was: for stride-length, -243 (95% CI -427, -60) vs. 45 (-10, 100) mm/year in the remainder (p = .001); for the ratio, torque to extend to flex relaxed arm, 349 (146, 718) vs. 58 (27, 96)%/ year (p < .001); and for independently rated, visual-analog scale of stance-walk videos (worst-best per individual identical with 0-100 mm), -64 vs. -3 mm from anterior and -50 vs. 11 lateral (p = .004 and .02). CONCLUSIONS: Interim analysis points to a direct or surrogate (not necessarily unique) role of a particular infection in the pathogenesis of parkinsonism. With eradication failure, bolus release of antigen from killed bacteria could aggravate an effect of ongoing infection.

A new prognostic staging system for rectal cancer.

OBJECTIVE: To clarify the appropriateness of tumor "budding," a quantifiable histologic variable, as 1 parameter in the construction of a new prognostic grading system for rectal cancer. SUMMARY BACKGROUND DATA: Patient division according to an accurate prognostic prediction could enhance the effectiveness of postoperative adjuvant therapy and follow-up. PATIENTS AND METHODS: Tumor budding was defined as an isolated cancer cell or a cluster composed of fewer than 5 cells in the invasive frontal region, and was divided into 2 grades based on its number within a microscopic field of x250. We analyzed 2 discrete cohorts comprising 638 and 476 patients undergoing potentially curative surgery. RESULTS: In the first cohort, high-grade budding (10 or more foci in a field) was observed in 30% of patients and was significantly associated with a lower 5-year survival rate (41%) than low-grade budding (84%). Similarly, in the second cohort, the 5-year survival rate was 43% in high-grade budding patients and 83% in low-grade budding patients. In both cohorts, multivariate analyses verified budding to be an independent prognosticator, together with nodal involvement and extramural spread. These 3 variables were given weighted scores, and the score range was divided to provide 5 prognostic groups (97%; 86%; 61%; 39%; 17% 5-year survival). The model was tested on the second cohort, and similar prognostic results were obtained. CONCLUSIONS: We propose that because of its relevance to prognosis and its reproducibility, budding is an excellent parameter for use in a grading system to provide a confident prediction of clinical outcome.

Pathology of drug-associated gastrointestinal disease.

A large number of drugs have gastrointestinal side-effects of which diarrhoea or constipation, nausea and vomiting are amongst the commonest. In relatively few are there diagnostic pathological changes and this review draws attention to the most common. Incriminating a drug as a cause of specific pathological changes requires the drug to be associated with the changes, for the latter to resolve when the drug is withdrawn and for them to re-appear when a patient is rechallenged with the drug. Individual histological features such as apoptosis, tissue infiltration by eosinophils and increased intra-epithelial lymphocytes within the gut mucosa can be clues to an iatrogenic aetiology but these are by no means specific. Amongst the few pathognomonic patterns of drug reactions is pseudomembranous colitis and diaphragm disease. These, along with others such as reactive gastritis and the collagenous and lymphocytic forms of microscopic colitis, in which drugs have also been implicated, are described here.

Microscopic colitis: the tip of the iceberg?

OBJECTIVES: The aims were to determine whether a wide variation exists between hospitals in the diagnosis of microscopic colitis and to assimilate clinical data. DESIGN: Retrospective study of 90 patients with microscopic colitis aged between 16 and 92 years from 11 hospitals in south-east England. METHODS: A questionnaire was designed to collect relevant data from all patients in whom a new diagnosis of microscopic colitis had been made at the source hospital between January 1990 and December 1996. The inclusion criteria were presentation with watery diarrhoea, a normal endoscopy and a histological report of microscopic colitis. Histology slides were then requested and reviewed. Clinical data were analysed with reference to the confirmed diagnosis. RESULTS: The number of patients diagnosed at each hospital ranged between zero and 30, with a median of six. Sixty-eight patients had histological slides reviewed. The numbers of patients with a final reviewed diagnosis of collagenous colitis, lymphocytic colitis and microscopic colitis, type undesignated, were 37, 18 and seven respectively. In thirty-one patients (34%) there was a recent history of the use of non-steroidal anti-inflammatory drugs. CONCLUSIONS: These data confirm that there is wide hospital variation in the diagnosis of microscopic colitis. Furthermore, the small group with the undesignated type may be associated with the use of non-steroidal anti-inflammatory drugs.

Female anal sphincter: age-related differences in asymptomatic volunteers with high-frequency endoanal US.

PURPOSE: To evaluate endoanal ultrasonographic (US) anatomy in a large group of nulliparous women by using a high-frequency 10-MHz transducer to define normal age-related differences in sphincter morphology. MATERIALS AND METHODS: One hundred fifty asymptomatic nulliparous women (mean age, 31 years; range, 19-80 years) underwent endoanal US with a high-frequency 10-MHz transducer. Anal canal structures were measured at high, middle, and low levels and were correlated with age by using the Pearson simple linear correlation coefficient. RESULTS: Internal sphincter thickness showed a highly significant positive correlation with age at both sites at which it was measured (high anal canal, r = 0.34, P <.001; middle anal canal, r = 0.33, P <.001). External sphincter thickness showed a highly significant negative correlation with age at all sites measured (high anal canal, r = -0.65, P <.001; middle anal canal, r = -0.49, P <.001; low anal canal, r = -0.21, P =.012). There was no significant correlation between age and thickness of subepithelial tissue, longitudinal muscle, or puborectalis muscle. Subjects whose internal sphincter showed mixed echogenicity were significantly older than those whose internal sphincter was uniformly hypoechoic (mean, 47.4 vs 34.6 years; P <.001). Subjects with mixed internal sphincter echogenicity also had a significantly thinner external sphincter at high (mean thickness, 3.8 vs 4.6 mm; P <.001) and middle (mean thickness, 3.7 vs 4.1 mm; P =.03) anal canal levels. CONCLUSION: At older ages there are increased internal anal sphincter thickness and decreased external anal sphincter thickness. Diagnosis of external sphincter atrophy on the basis of sphincter thinning requires that one distinguish between abnormal thinning and age-related differences.