Digestion

A century of Helicobacter pylori: paradigms lost-paradigms regained.

Kidd M. Modlin IM.
Gastric Surgical Pathobiology Research Group, Yale University School of Medicine, New Haven, Conn. 06520-8062, USA.
The investigation of gastric bacteria properly began in the latter half of the nineteenth century when microscope resolution had sufficiently advanced. Whilst a bacterial etiology was demonstrated for dysentery, tuberculosis and syphilitic ulcers, problems in the isolation and culture of pure strains circumvented a role for bacteria in gastric pathology. Furthermore, dogma and the intellectual chorus were in harmony advocating that gastric acid was critical in ulcer disease. The consideration of a role for a pathogen or pepsin was regarded as whimsical in the context of mucosal ulceration. Indeed, the effects of acid inhibitory agents were held as gospel truth whilst the use of antibiotics or metallic ions were deemed to be quackery or at least ill judged. Nonetheless, spiral-shaped bacteria had been identified in both mucosa and gastric contents of patients as early as 1889. Elegant studies had documented the infectivity of these organisms, and suggested but not proven a causative role in gastric disease. The prescient identification by Doenges of organisms associated with gastritis in both man and monkey, was buried by the observations of Palmer, and an opportunity for early progress lost. It required two decades and Antipodean pathological perspicacity to elucidate the warren of previous archaic gastric bacterial misinformation. The subsequent marshalling of clinical and pathological data established the fatal flaw in the mucosa to be bacteria and not only acid on the mucus shore. It is now widely apparent that Helicobacter is ubiquitous, pathological and, a century after its initial discovery, still remains a paradox of as yet incompletely determined biological consequence. It is of note that an organic helical configuration has twice in this century provided biological information of unique import.

Indomethacin interferes with EGF-induced activation of ornithine decarboxylase in gastric cancer cells.

Ishikawa T. Ichikawa Y. Tarnawski A. Fujiwara Y. Fukuda T. Arakawa T. Mitsuhashi M. Shimada H.
Yokohama City University, Yokohama, Japan.
BACKGROUND/AIMS: Epidermal growth factor (EGF) has a wide variety of biological activities in the protection of gastric mucosa against acute injury and the healing of gastric ulcer. However, the molecular basis of the EGF action remains unknown. EGF-induced activation of ornithine decarboxylase (ODC) was examined, because ODC is a key enzyme for the cell proliferation. METHODS: The effects of epidermal growth factor (EGF) and indomethacin on ornithine decarboxylase (ODC) mRNA and enzyme activity were examined in gastric cancer derived KATO-III cells. RESULTS: EGF induced both ODC mRNA expression and enzyme activation in a biphasic manner with the peaks at 0.5 and 3 h for mRNA and at 5 and 9 h for enzyme activity, respectively. Indomethacin pretreatment significantly reduced EGF-induced ODC activation and was completely abolished for the first 5 h. CONCLUSION: Since it has been reported that both EGF and ODC are involved in cell migration and proliferation, two actions of EGF for gastric mucosal healing may be through, at least in part, this biphasic activation of ODC. Indomethacin suppresses and changes the response of ODC induced by EGF.

Activation of epithelial cells in gastritis.

El Kaissouni J. Bene MC. Faure GC.
Laboratoire d'Immunologie, Faculte de Medecine, Vandoeuvre-les-Nancy, France. faure@grip.u-nancy.fr
BACKGROUND: Helicobacter pylori is now recognised to be the major cause of antral gastritis and a risk factor for further development of gastric cancer. This infection results in local inflammation and a modification of gastric mucosal epithelial cell characteristics. Systematic investigation for the expression of the secretory component by gastric epithelium in a personal historical series of biopsy specimens showed the expression of this activation marker in 38% of the cases, 19% also showing clear signs of H. pylori infection. AIMS: To further appreciate the activation of epithelial cells in the chronic gastric inflammation associated with H. pylori infection and other types of gastritis without consideration of the grade of gastritis. METHODS: Punch gastric biopsies from 36 patients (10 patients with confirmed H. pylori gastritis, 16 patients with non-H. pylori gastritis and 10 controls) were tested for the expression of ICAM-1/CD54, HLA-DP, -DQ, -DR, secretory component and bcl-2 by immunofluorescence. RESULTS: Up-regulation of most markers was observed both in H. pylori and non-H. pylori gastritis, although secretory component, CD54 and DP expression was more closely associated with H. pylori gastritis. CONCLUSION: H. pylori infection appears to activate gastric epithelial cells more strongly than other types of gastritis. This suggests an active relationship between this bacterium and epithelial cells. Investigation of the up-regulationship between this bacterium and epithelial cells. Investigation of the up-regulation of secretory component, ICAM-1/CD54 or DP in gastric biopsies may serve as extensive markers in search of H. pylori gastric infections.

Spectrum of cytokine gene expression in intestinal mucosal lesions of Crohns disease and ulcerative colitis.

Funakoshi K. Sugimura K. Anezaki K. Bannai H. Ishizuka K. Asakura H.
Third Department of Internal Medicine, Niigata University School of Medicine, Japan.
BACKGROUND/AIMS: We investigated the mRNA expression of spectrum of cytokines in the colonic mucosa in inflammatory bowel disease (IBD). METHODS: The expression of cytokine gene was evaluated by using the reverse transcription-polymerase chain reaction and the radioactivity of amplified cDNA standardized by coamplified beta-actin cDNA. RESULTS: Crohn's disease and ulcerative colitis showed significantly increased expression of IL-1beta, IL-6, IL-8 and TNF-alpha mRNA as compared with controls (p < 0.05). CONCLUSION: Proinflammatory cytokines such as IL-1beta, IL-6, IL-8 and TNF-alpha are closely involved in the immune abnormalities of inflammatory mucosal lesions in IBD.

Sexual dysfunction in patients with irritable bowel syndrome and non-ulcer dyspepsia.

Fass R. Fullerton S. Naliboff B. Hirsh T. Mayer EA.
CURE Digestive Diseases Research Center, Department of Medicine UCLA, Los Angeles, Calif. 90073, USA.
The prevalence and type of sexual dysfunction in patients with functional gastrointestinal (GI) disorders involving the upper (functional dyspepsia) or lower GI tract (irritable bowel syndrome) were studied in 683 patients seen at a tertiary referral center and a comparison group of 247 community volunteers. Associations between sexual dysfunction and type and severity of GI symptoms, and psychological symptoms were examined. All subjects were evaluated with a validated bowel syndrome questionnaire, which included questions about sexual function. Psychological symptom severity was assessed by SCL-90R. The prevalence of self-reported sexual dysfunction in patients with functional GI disorders was 43.3% and did not differ by gender, age stratification or disease subtype: irritable bowel syndrome (IBS); non-ulcer dyspepsia (NUD), and IBS + NUD. In the comparison subjects without IBS symptoms and those with IBS symptoms but not seeking health care (IBS non-patients), the reported sexual dysfunction prevalence was significantly lower (16.1 and 24.4%, respectively, p < 0.005). Decreased sexual drive was the symptom most commonly reported by both male (36.2%) and female (28.4%) patients. Dyspareunia was reported by 16.4% of females and 4% of males with IBS, but was rarely observed in patients with NUD. Report of sexual dysfunction was positively associated with perceived GI symptom severity, but not with psychological symptom severity. Sexual dysfunction should be incorporated into the quality-of-life assessment of patients with functional GI disorders and addressed in future outcome studies.

Intestinal obstruction, progressive weight loss, and recurrent fever in two patients with mesenteric lesions.

Hoffmann JC. Lamberts R. Huppert P. Kaiserling E. Gregor M.
Department of Gastroenterology and Hepatology, Eberhard Karls University, Tubingen, Germany. 101504.3210@compuserve.com
We describe 2 patients who presented with fever and incomplete intestinal obstruction. Previously, both patients had had laparotomies showing unresectable lesions in the root of the mesentery which were histologically diagnosed as sclerosing mesenteritis in the first and mesenteric fibromatosis in the second patient. In spite of aggressive immunosuppressive therapy the first patient deteriorated with high-grade fever and progressive weight loss. Similar symptoms occurred in the second patient. Computed tomographic scanning revealed necrotic lesions in both patients which histologically were found to be an angiocentric T-cell lymphoma in the first and a superinfected necrotizing fibroma in the second patient. It is therefore clinically and radiologically impossible to distinguish between the different causes of mesenteric lesions. Reoperation for further biopsies needs to be considered if such patients do not respond to medical treatment.

Approach to the management of bleeding esophageal varices: role of somatostatin.

Year 1998
Avgerinos A.
2nd Department of Gastroenterology, Evangelismos Hospital, Athens University, Greece.
Various treatment strategies have been used to control variceal bleeding, including drugs, esophageal tamponade, endoscopic sclerotherapy (ES), endoscopic variceal ligation, transjugular intrahepatic portosystemic shunt and emergency surgery. None of these procedures are ideal and treatment frequently requires a combination of techniques. Sclerotherapy is one of the most widely used methods to control variceal bleeding; however, success is largely dependent on an experienced endoscopist. Vasoactive drugs act by decreasing pressure and blood flow in the gastroesophageal collaterals and they offer the advantage of being administered by inexperienced personnel. Drugs currently used in the treatment of variceal hemorrhage include vasopressin, terlipressin, somatostatin and octreotide. In the clinical studies to date, somatostatin was more effective than vasopressin and as effective as terlipressin in the control of bleeding esophageal varices (BEV), with an improved safety profile. In contrast, octreotide has shown conflicting results and more data are required to support the drug in this indication. More recently the ABOVE (Acute Bleeding Esophageal Variceal Episodes) study has provided further evidence that early administration of vasoactive drugs such as somatostatin is significantly more effective than placebo in the overall control of acute BEV episodes in cirrhotic patients undergoing ES. Therefore, the administration of a vasoactive drug as early as possible before emergency sclerotherapy is recommended for the effective management of BEV.

Analysis of gastroduodenitis and oesophagitis in relation to dyspeptic/reflux symptoms.

Year 1998
Villani L. Trespi E. Fiocca R. Broglia F. Colla C. Luinetti O. Tinelli C. Solcia E.
Department of Pathology, IRCCS Policlinico San Matteo University Hospital, Pavia, Italy.
BACKGROUND/AIMS: The pathogenesis of dyspeptic/reflux symptoms and the clinico-pathologic profile of affected patients are still poorly understood. To improve our knowledge in this field we carried out a systematic, comparative analysis of symptom profiles and histopathologic patterns of oesophagogastroduodenal mucosa in a series of 221 subjects, 140 with and 81 without endoscopic evidence of hiatal hernia. Of these, 190 showed reflux and/or dyspeptic symptoms. METHODS: Before endoscopy, all the subjects were questioned about the presence and severity of 12 individual symptoms. Biopsies were taken from the distal oesophagus, cardia, corpus, angulus, antrum and duodenal bulb, and were scored in accordance with the Sydney system. RESULTS: Patient groups with a distinct clinico-pathologic profile were better identified when symptoms of adequate severity were compared with histopathologic parameters. A correlation between gastroesophageal reflux disease (GORD) symptoms and histologic signs of oesophagitis was mostly restricted to patients endoscopically positive for oesophagitis. Retroxiphoid pyrosis correlated with cardial gastritis but not with oesophagitis, either endoscopic or histologic, while ulcer-like epigastric pain correlated with active duodenitis and distal gastritis. No definite histopathologic background was detected in patients with putative dysmotility-like symptoms, endoscopy-negative GORD and low score or mixed symptoms. CONCLUSION: A contribution of Helicobacter pylori gastroduodenitis to the pathogenesis of some dyspeptic symptoms seems likely. However, the identification of specific histologic changes causing individual symptoms remains rather elusive, with the exception of active antroduodenitis in patients with ulcer-like pain and of active proximal gastritis in patients with severe retroxiphoid pyrosis.

K-ras mutations at codon 12 are rare events in chronic pancreatitis.

Year 1998
Orth M. Gansauge F. Gansauge S. Beger HG. Adler G. Schmid RM.
Department of Internal Medicine I, Ulm University, Germany.
BACKGROUND/AIMS: The activation of the K-ras gene at codon 12 is thought to be an early genetic event in the multistep pathogenesis of pancreatic cancer. Since the risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis, the aim of the present study was to determine the frequency of K-ras mutations in chronic pancreatitis. METHODS: Pancreatic DNA from intraoperatively resected tissues of 60 patients with chronic pancreatitis and 11 patients with histologically confirmed pancreatic carcinoma was evaluated by PCR amplification and restriction fragment length polymorphism analysis. RESULTS: In none of the 60 samples of chronic pancreatitis could K-ras mutations be identified using two independent PCR assays. In 5 of 11 patients with pancreatic carcinoma, K-ras mutations in codon 12 were detected. CONCLUSION: These data indicate that K-ras mutations are rare events in chronic pancreatitis. Alternatively, it is possible that the time span between the occurrence of K-ras mutations and malignant transformation is rather short.

Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants.

Year 1998
Hofstad B. Almendingen K. Vatn M. Andersen SN. Owen RW. Larsen S. Osnes M.
Medical Department, Ullevaal University Hospital, Oslo, Norway.
BACKGROUND: Dietary calcium and antioxidants have been suggested as protective agents against colorectal cancer. This has been supported by animal experimental studies, case control and cohort studies. MATERIALS AND METHODS: In a prospective intervention study of colorectal adenomas, and intermediary stage in colorectal carcinogenesis, 116 polyp-bearing patients received a placebo-controlled daily mixture of beta-carotene 15 mg, vitamin C 150 mg, vitamin E 75 mg, selenium 101 microg, and calcium (1.6 g daily) as carbonate for a period of 3 years with annual colonoscopic follow-up to test if the mixture was able to reduce polyp growth or recurrence. All polyps of < 10 mm at enrollment or follow-up were left unresected until the end of the study. RESULTS: 87-91% of the patients attended the annual endoscopic follow-up investigations, and 19% of the patients dropped out of the medical intervention. The rest consumed 85% of the total amount of tablets over the 3 years. The fecal calcium concentration was 2.3-2.7 times higher in patients taking active medication compared to the placebo group. Diet registration showed that, when adding the intake of antioxidants and calcium from diet and intervention, there was a significant difference between the intake of these substances in the active and the placebo group. No difference was detected in the growth of adenomas between the active and the placebo group from year to year and for the total study period. Moreover, there was no effect on polyps of < 5 or 5-9 mm, or on polyps in the different colonic segments analyzed separately. A reduced growth of adenomas was found in patients

Chlamydia trachomatis infection: is it relevant in irritable bowel syndrome?

Year 1998
Francis C. Prior A. Whorwell PJ. Morris J.
Department of Medicine, University Hospital of South Manchester, UK.
BACKGROUND: Irritable bowel syndrome can present with gynaecological symptoms similar to those of chronic pelvic inflammatory disease, which is commonly caused by Chlamydia trachomatis. Infection with this organism might therefore lead to diagnostic and management difficulties in patients, not only as a result of symptom overlap between the two disorders but also because chlamydial infection might exacerbate the symptoms of irritable bowel syndrome. This study was designed to investigate any possible link between chlamydial infection and irritable bowel syndrome. PATIENTS/METHODS: The prevalence of antibodies to C. trachomatis and abdominal symptomatology was assessed in a group of 100 female patients with irritable bowel syndrome and 100 matched female controls. RESULTS: 25% of patients and 17% of controls were found to have evidence of previous chlamydial infection. This difference was not statistically significant. Within the patient group, no association was found between chlamydial infection and any particular pattern of symptomatology. CONCLUSIONS: The results of this study indicate that occult chlamydial infection is not a major problem in irritable bowel syndrome and that routine investigation for this organism is unnecessary. They also provide some reassurance that pelvic inflammatory disease and all its potentially serious consequences is not being significantly overlooked in gastroenterological practice.

Gastric carcinoid with histamine production, histamine transporter and expression of somatostatin receptors.

Year 1998
Kolby L. Wangberg B. Ahlman H. Jansson S. Forssell-Aronsson E. Erickson JD. Nilsson O.
Department of Surgery, Sahlgrenska University Hospital, Goteborg, Sweden.
A case of sporadic, histamine-producing gastric carcinoid with liver metastases is reported. The patient was treated with somatostatin analogue (octreotide) combined with cortisone and blockade of histamine receptors prior to surgery, which included subtotal gastrectomy, excision of lymph node metastases and superficial liver metastases. Residual liver metastases were injected with ethanol. These interventions markedly reduced the urinary excretion of the main histamine metabolite (MelmAA). Eighteen months later combined immuno- and chemotherapy was initiated due to tumour progression and recurrent hormonal symptoms with good clinical results over 12 months. Scintigraphy, using 111In-DTPA-D-Phe1-octreotide, visualized somatostatin receptors (sstr) in primary tumour, lymph node metastases and liver metastases. The tissue/blood 111In concentration ratios of tumour biopsies were very high. Northern analyses confirmed expression of all subtypes of sstr1-5. Immunocytochemically, tumour cells were strongly positive for chromogranin A, histamine and vesicular monoamine transporter (VMAT) 2 (histamine transporter), but negative for VMAT 1, suggesting an origin from gastric enterochromaffin-like cells. In primary tumour cell cultures, histamine, 5-HTP and 5-HIAA, but not 5-HT, could be detected in conditioned culture medium, indicating a defective decarboxylation of the tryptamine precursor. This rare case of histamine-producing gastric carcinoid demonstrates that excellent symptom relief can be achieved despite disseminated disease, if active, multimodal treatment strategy is instituted. The presence of high numbers of sstr in tumour tissue also raises the possibility of receptor-guided radiotherapy.