The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona.

BACKGROUND AND SCOPE: The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. METHODOLOGY: Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. RESULTS: Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. CONCLUSION: GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.

Predictors of disease-free survival in colorectal cancer with microsatellite instability: An AGEO multicentre study.

BACKGROUND: A microsatellite instability (MSI) phenotype is found in about 12% of colorectal cancers (CRCs) and is associated with a low recurrence rate after curative surgery. Several studies have identified clinical and pathological factors predictive of recurrence in resected CRC, but not in the MSI subgroup. PATIENTS AND METHODS: This multicentre retrospective study included patients with stage I, II or III MSI CRCs. Disease-free survival (DFS) was calculated with the Kaplan-Meier method. Factors associated with DFS were identified in univariate and multivariate Cox analyses. RESULTS: We studied 521 patients with MSI CRC. Respectively 11%, 51% and 38% of patients were at stage I, II and III. Mean age was 68.7years and 36% of the patients received adjuvant chemotherapy. Median follow-up was 32.8months. The disease recurrence rates were 6% and 21% in stage II and III patients, respectively. The 3-year DFS rate was 77%. In univariate analysis, age, bowel obstruction, lymph node invasion, stage T4, vascular emboli, lymphatic invasion and perinervous invasion were associated with poorer DFS (P<0.05). Three relevant independent predictors of poor DFS were identified in multivariate analysis, namely bowel obstruction (HR=2.46; 95%CI 1.31-4.62, P=0.005), vascular emboli (HR=2.79; 95%CI 1.74-4.47, P<0.001) and stage T4 (HR=2.16; 95%CI 1.31-3.56, P=0.002). CONCLUSIONS: Bowel obstruction, vascular emboli and stage T4 are independently associated with MSI CRC recurrence, suggesting that screening for vascular emboli in routine clinical practice may assist with adjuvant chemotherapy decision-making.

Review article: antitumoural immunity in colorectal cancer - current and potential future implications in clinical practice.

BACKGROUND: Most of the current research in gastrointestinal oncology is focused on biology of cancer itself, but there is growing interest in the patient's immune system response and its relation with cancer cells. AIM: To review the impact of the antitumoural immune response on epidemiology, prognosis and treatment of colorectal cancer. METHODS: Search of the literature published in English using the PubMed database. RESULTS: The role of the immune system in the antitumoural immunosurveillance is clearly supported by the increased incidence of colorectal cancer and adenomatous polyps in immunosuppressed patients. Moreover, the degree of infiltration of the tumours by the immune cells has been shown to be a strong prognostic factor of both disease recurrence and survival. The immune system plays an important role in the chemotherapy-induced cell death. New therapeutic strategies targeting the antitumoural immunity are being currently investigated with promising results. CONCLUSION: Better knowledge of antitumoural immune system can have a major impact on patients' management in daily clinical practice. Colorectal cancer screening is an important issue in immunosuppressed patients, and recommendations should be refined for selected high-risk patients. The use of an immune score to guide the therapeutic strategies in the adjuvant setting should be supported. Further and larger clinical trials are necessary to accelerate the development of innovative immune therapies.

Colonic mucosal biopsies obtained during confocal endomicroscopy are pre-stained with fluorescein in vivo and are suitable for histologic evaluation.

BACKGROUND AND STUDY AIMS: Confocal laser endomicroscopy (CLE) with intravenous infusion of fluorescein allows noninvasive, real-time in vivo visualization of gastrointestinal mucosa at ~ × 1000 magnification ("virtual biopsy"). Conventional biopsies obtained during these procedures serve as the reference and established diagnostic standard. The aim of the present study was to assess whether the standard histologic biopsies that are obtained during CLE retain fluorescein in the tissues and allow the visualization of mucosal structures without any additional staining. PATIENTS AND METHODS: CLE optical imaging of the mucosa was performed in 16 patients who were undergoing CLE colonoscopy. Standard conventional biopsies were also obtained from both normal colonic mucosa and colonic polyps. De-paraffinized mucosal sections were examined under a fluorescence microscope for the presence and distribution of fluorescein, and then underwent immunostaining for expression of vascular endothelial growth factor (VEGF). RESULTS: Standard mucosal biopsy sections from patients undergoing CLE displayed a strong fluorescence and showed well-delineated mucosal structures. In colonic adenomas, there was a 4.6-fold increased vascular permeability compared with normal mucosa (P<0.001), indicated by fluorescein leakage to the extravascular space. Immunostaining demonstrated an aberrantly increased expression of VEGF in the epithelium of colonic adenomas but not in the epithelium of normal mucosa or hyperplastic polyps. CONCLUSIONS: This study shows for the first time that standard colonic biopsies obtained during CLE retain fluorescein, show excellent delineation of mucosal structures without additional staining, allow the evaluation of mucosal microvasculature and vascular permeability, and are suitable for immunostaining.

Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy, the European Helicobacter Study Group, the European Society of Pathology, and the Sociedade Portuguesa de Endoscopia Digestiva have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach. A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia and the need for adequate staging in the case of high-grade dysplasia, and they focus on treatment and surveillance indications and methods.

Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.

In vivo real-time imaging of human duodenal mucosal structures in celiac disease using endocytoscopy.

BACKGROUND AND AIMS: Celiac disease is a gluten-induced enteropathy whose diagnosis is based on histological evidence of villous atrophy. The diagnosis may be difficult if the orientation of histological sections is other than optimal. During upper gastrointestinal endoscopy we studied in vivo duodenal mucosa in patients with celiac disease using endocytoscopy, a novel diagnostic technique allowing in vivo real-time visualization of mucosa under x 450 magnification. METHODS: Sixteen patients with documented celiac disease and seven controls without celiac disease were studied. Endocytoscopic images obtained from several fields were compared in a blinded fashion to standard histology. RESULTS: Endocytoscopy showed three different patterns of in vivo histology: (1) the presence of normal-appearing, long, thin villi, lined with clearly distinguishable surface epithelial cells, considered to be normal duodenal mucosa (n = 15, all controls and eight celiac disease patients); (2) the presence of thick, shortened villi, reflecting partial villous atrophy (n = 4); and (3) the total absence of villi and the presence of enlarged crypt orifices, reflecting total villous atrophy (n = 4). Good concordance between endocytoscopy and standard histology was found in all 16 patients with celiac disease. CONCLUSIONS: Endocytoscopy allows in vivo, real-time, noninvasive visualization and characterization of villous architecture and may be a promising method for in vivo evaluation of duodenal mucosa in celiac disease.

Adult celiac disease with severe or partial villous atrophy: a comparative study.

BACKGROUND AND AIMS: While severe villous atrophy (SVA) is the most typical histological feature in adult celiac disease (ACD), partial villous atrophy (PVA) is now also frequently found. So far, the impact of the severity of villous atrophy on the clinical presentation of ACD has been scarcely investigated. We aimed to compare the clinical, biological and immune features and outcomes in ACD patients presenting with PVA at diagnosis versus patients with SVA. PATIENTS AND METHODS: Medical files of 48 patients with ACD diagnosed between 1992 and 2003 were retrospectively studied. The diagnosis was based on the presence of intestinal villous atrophy, with increases in intraepithelial lymphocytes and circulating celiac specific antibodies. Villous atrophy was classified as severe (subtotal and total) or partial. Symptoms, biological signs of malabsorption, immune markers, bone mineral density at diagnosis and response to gluten-free diet were recorded. RESULTS: At diagnosis, ten patients (four M/six F) had PVA and 38 patients (five M/33 F) had SVA, with a median age of 54 and 33 years, respectively (p<0.05). Positivity for specific antibodies, HLA typing and frequency of autoimmune disease at diagnosis were similar in both PVA and SVA patients, as was their response to gluten-free diet. Diarrhea, malabsorption syndrome and osteopenia were independent of the degree of villous atrophy. CONCLUSION: PVA was observed in 21% of patients with ACD. Except for their older age at diagnosis, patients with PVA presented with similar clinical, biological and immune characteristics and outcomes as did patients with SVA.

Review article: rebamipide and the digestive epithelial barrier.

Rebamipide exerts a positive effect on the digestive epithelial barrier by reinforcing its integrity in normal and in inflammatory conditions, and by normalizing the macromolecular transport across this barrier, increased by Helicobacter infection. Moreover, in mice, rebamipide is capable of diminishing allergic sensitization and of counteracting the inhibitory effect of Helicobacter pylori on oral tolerance to dietary antigens. These properties of rebamipide could explain its anti-inflammatory activity with respect to the digestive mucosa and could provide protection against allergic sensitization to foreign antigens in susceptible individuals.

Alterations of epithelial permeability by Helicobacter and IL-1beta in vitro: protective effect of rebamipide.

Infection with Helicobacter increases the transcellular passage of macromolecules across the epithelium, and this effect can be prevented by a gastroprotective agent rebamipide. The aim was to gain insight into the mechanisms involved. The HT29-19A intestinal epithelial cells grown on microporous filters as monolayers were incubated in the presence or absence of rebamipide (1 or 2 mM) with: (1) suspension of a wild H. pylori strain, (2) IL-1beta (0.5 ng/ml) + IFN-gamma (2 units/ml). After incubation, the monolayers were submitted to evaluation of apoptosis by using the apoptotic cell death detection ELISA kit and to assessment of epithelial permeability in Ussing chamber where the ionic conductance (G), fluxes of mannitol (J(Man)) and of horseradish peroxidase in both intact (J(HRPi))- and degraded (J(D)) form, were measured. H. pylori increased the intact HRP fluxes across the barrier (J(HRPi) = 17 +/- 20 vs 97 +/- 70 ng/hr/cm2, P < 0.007), an effect prevented by rebamipide (J(HRPi) = 33 +/- 34 ng/hr/cm2, P < 0.006). IL-1beta increased the ionic conductance (G = 5.5 +/- 1.0 and 21.0 +/- 7.0 mS/cm2, P < 0.006), the intact HRP fluxes (J(HRPi) = 18 +/- 15 and 476 +/- 344 ng/hr/cm2, P < 0.006), and the apoptotic index of the cells (AI = 1 +/- 0 vs 3.7 +/- 0.8), all effects prevented by rebamipide (G = 12 +/- 4.9 mS/cm2, J(HRPi) = 79 +/- 38, AI = 1.6 +/- 0.6, P < 0.03 as compared to IL-beta-treated cells). In basal conditions, rebamipide increased the integrity of the barrier (G = 7.5 +/- 2.3 vs 6.0 +/- 1.8 mS/cm2 for controls, P < 0.007). In conclusion, H. pylori as well as IL-1beta, may alter epithelial permeability and rebamipide may exert its protective effect on gastric mucosa by reinforcing the epithelial barrier in normal conditions and by counteracting the deleterious effect of Helicobacter pylori and IL-1beta on macromolecular permeability.

Positive effect of rebamipide on gastric permeability in mice after eradication of Helicobacter felis.

BACKGROUND: Despite Helicobacter pylori eradication, gastric inflammation persists for months or years. Preliminary results have indicated that an increase in gastric permeability could be one reason. Our aim was to evaluate the effect of a mucosal protective drug, rebamipide, on gastric permeability in a model of H. felis-infected mice. METHODS: Thirty-three C57/BL6 mice were inoculated with H. felis, and seven controls were kept non-inoculated. After 2 months 20 infected mice were treated with omeprazole, amoxicillin, and clarithromycin for 1 week and then for 4 weeks with either rebamipide (n = 9) or placebo (n = 11). The 13 remaining mice were kept untreated. After cessation of treatment, a fragment of antrum obtained from each mouse was mounted in a small Ussing chamber to study the electric resistance of the tissue (R) and antral permeability. RESULTS: No modification of the paracellular permeability (R, JNa, JMan) was observed in either group. However, the transcellular permeability to horseradish peroxidase (HRP) was significantly increased in H. felis-infected non-treated mice (1131 +/- 463, 948 +/- 339, and 182 +/- 312 ng/h x cm2) as compared with non-infected controls (469 +/- 262, 458 +/- 261, and 10 +/- 6 ng/ h x cm2, for J3H-HRP, JD, and JHRPi, respectively) (P < 0.003). Eradication of the bacteria by antibiotics without subsequent treatment with rebamipide led to a non-significant decrease in the HRP fluxes. However, when rebamipide was used after the antibiotic treatment, a significant (P < 0.01) decrease in HRP fluxes as compared with non-treated mice was observed. CONCLUSIONS: These results confirm that gastric permeability to macromolecules remains increased despite H. felis eradication and show that rebamipide can facilitate the normalization of gastric permeability to macromolecules after bacterial eradication.

Antral gastric permeability to antigens in mice is altered by infection with Helicobacter felis.

OBJECTIVE: Gastric inflammation is observed not only during Helicobacter pylori infection but also after eradication of the bacterium. The hypothesis that an altered gastric permeability could be involved was tested using a model of mice infected with Helicobacter felis. DESIGN: The antral and corpus gastric permeability during infection and after eradication of bacteria was studied. METHODS: Gastric fragments from the antrum and corpus of healthy mice, mice infected with H. felis, or mice after bacterial eradication, were mounted in Ussing chambers, and fluxes of sodium (JNa), mannitol (JMan) and horseradish peroxidase (HRP) under intact (JHRPi) and degraded (JD) form were measured. RESULTS: In healthy mice, JNa, JMan, JHRPi and JD, respectively, were greater in the antrum (6.5 +/- 0.5 microEq/h.cm2; 0.137 +/- 0.016 micromol/h.cm2; 30.4 +/- 7.4 ng/h.cm2 and 852 +/- 173 ng/h.cm2) than in the corpus (5.0 +/- 0.3 microEq/h.cm2; 0.085 micro 0.013 micromol/h.cm2; 9.5 +/- 2.8 ng/h.cm2 and 434 +/- 139 ng/h.cm2). In H. felis-infected mice, HRP fluxes in the antrum were increased (JHRPi = 182 +/- 86, JD = 948 +/- 94 ng/h.cm2) as compared to controls (JHRPi = 10.3 +/- 2.6, JD = 458 +/- 98 ng/h.cm2). Bacterial eradication led to the reduction of intact (JHRPi = 53 +/- 26 ng/h.cm) but not of degraded (JD = 844 +/- 213 ng/h.cm) HRP fluxes. After eradication, degraded HRP fluxes returned to normal in mice without inflammation (JD = 558 +/- 36 ng/h.cm2) but not in those with persistent inflammation (JD = 987 +/- 310 ng/h.cm2). CONCLUSIONS: The results suggest that during H. felis infection, bacterial colonization and inflammation lead to an increased gastric permeability along the direct and degradative pathways, respectively. Such an increased antigenic load could contribute to the perpetuation of gastric inflammation after bacterial eradication, and possibly to food protein sensitization.

Helicobacter pylori alters exogenous antigen absorption and processing in a digestive tract epithelial cell line model.

To study the influence of Helicobacter pylori on epithelial barrier function, bacteria, bacterial sonicates, or broth culture supernatants were incubated for 24 h with HT29-19A intestinal cells grown as monolayers. Subsequently, the monolayers were mounted in Ussing chambers, and electrical resistance (R), fluxes of 22Na (JNa) and 14C-mannitol (JMan) (markers of the paracellular pathway), and fluxes of horseradish peroxidase (HRP) in total (J3H-HRP), intact (JHRPi), and degraded forms were measured. H. pylori did not induce any modification of the paracellular pathway (R = 148 +/- 10 versus 174 +/- 16 Omega. cm2; JNa = 4.16 +/- 0.44 versus 3.51 +/- 0.41 microEq/h. cm2; JMan = 0.081 +/- 0.01 versus 0.058 +/- 0.009 micromol/h. cm2), nor did it modify J3H-HRP (2,201 +/- 255 versus 2, 110 +/- 210 ng/h. cm2 for H. pylori-infected and control cells, respectively). However, in the presence of H. pylori, we observed a significant increase in JHRPi (520 +/- 146 versus 171 +/- 88 ng/h. cm2). This effect was not dependent of the cag status of the strain and was not reproduced by the sonicates or the culture supernatants. It was related to the presence of urease, since a urease-negative mutant of H. pylori did not induce this effect. Ammonia and bafilomycin A1, two agents known to increase the endolysosomal pH, reproduced the increase in JHRPi. In conclusion, H. pylori does not affect directly the integrity of intercellular junctions of epithelial cells in vitro, but it increases the passage of intact HRP, probably by inhibition of the intralysosomal degradation due to the release of ammonia. The increased transport of intact macromolecules may contribute to the induction and maintenance of gastric inflammation by H. pylori.

[Frequency of Helicobacter pylori infection depending on morphological changes in gastric mucosa in patients over 65 years of age]. / Czestosc zakazenia Helicobacter pylori w zaleznosci od zmian morfologicznych blony sluzowej zoladka u ludzi po 65 roku zycia.

In older patients involution processes are observed. Frequency of H. pylori infection has been related of histopathological changes of gastric mucosa in patients over 65 yrs old. In 73% of analyzed patients gastritis atrophica has been documented.

Epidemiology of Helicobacter pylori infection with special reference to professional risk.

Helicobacter pylori infection is one of the most common chronic bacterial infection worldwide. Two different epidemiological patterns can be distinguished: one concerning the industrialized countries where an increased prevalence of infection with age is noted and the other found in the developing countries where the majority of young people are already infected when they reach adulthood, the prevalence ranging from 60 to 90% in all age groups. Poland, like most of the Eastern European countries, represents an overall infection rate of 73% and the infection rate for the subjects over 25 years of age of 85-95%. The infection rate observed in the developed countries reflects a so called cohort effect, i.e., a change in the incidence of infection according to generation or age cohort due to changes in socioeconomic conditions. The infection rate observed in the developing countries is mainly determined by a high rate of incidence of this infection in childhood. The risk factors of H. pylori infection are linked to living conditions during childhood, especially to a low socio-economic level of the family including promiscuity. The available data strongly suggest person-to-person transmission of the infection but no agreement has been reached so far whether the oral-oral or faecal-oral route predominates. The incidence of new infections in adults is low, no exceeding 0.5-1.0 per year in the developed countries. One of the greatest risk of infection in adulthood seems to be professional exposure. Studies in industrialized countries show an increase risk of infection among endoscopists with the probability of infection correlating positively with the number of endoscopies performed. In Poland, the medical staff presents a lower seroprevalence (70%) than the general population, however, this prevalence is higher in endoscopists (75%) than in non-endoscopists (59%).

Helicobacter pylori infection in Eastern Europe: seroprevalence in the Polish population of Lower Silesia.

The Helicobacter pylori status of the population of Eastern European countries has not been explored despite the high incidence of peptic ulcer disease and gastric cancer observed in these countries. A seroprevalence study has been performed in Wroclaw, a city of Lower Silesia, Poland, to provide insight into this question. Sera were collected to obtain 50 subjects per 5 yr increment of age. A second generation ELISA kit with a high sensitivity and specificity was used. The results plotted by year of birth show a very high prevalence of H. pylori infection in all adults groups born before 1970 (80-100% positive). In the younger age groups, a dramatic decrease was observed. Because it is now known that most H. pylori infections are acquired in childhood (cohort effect), it can be predicted that the infection rate in the adult population will be much lower in the future compared with that presently observed, and it can be expected that evolution in H. pylori prevalence will have an impact on the rate of gastroduodenal diseases in Poland. Because of the high prevalence, it was not possible to identify risk factors for infection in this population.

High intracolonic acetaldehyde values produced by a bacteriocolonic pathway for ethanol oxidation in piglets.

BACKGROUND: Human colonic contents and many colonic microbes produce considerable amounts of acetaldehyde from ethanol in vitro. AIMS: To examine in piglets if acetaldehyde is produced in the colon also in vivo, and if so, what is the fate of intracolonically formed acetaldehyde. ANIMALS: Seventeen native, non-fasted female piglets (20-25 kg) were used. METHODS: Six piglets received either 1.5 g/kg bw or 2.5 g/kg bw of ethanol intravenously. In seven piglets, 0.7 g or 1.75 g of ethanol/kg bw was administered intravenously, followed by a subsequent intragastric ethanol infusion of 1.8 g/kg bw and 4.5 g/kg bw, respectively. The samples of colonic contents for the assessment of ethanol and acetaldehyde concentrations were obtained up to seven hours. In four additional piglets, the intracolonic values of ethanol, acetaldehyde, and acetate were observed for 60 minutes after an intracolonic infusion of acetaldehyde solution. RESULTS: A raised intracolonic, endogenous acetaldehyde concentration (mean (SEM); 36 (9) microM) was found in all piglets before ethanol infusion. After the infusion of ethanol, intracolonic ethanol and acetaldehyde values increased in parallel, reaching the peak values 57 (4) mM of ethanol and 271 (20) microM of acetaldehyde in the group that received the highest dose of ethanol. A positive correlation (r = 0.45; p < 0.001) was found between intracolonic ethanol and acetaldehyde values. Acetaldehyde administered intracolonically was mainly metabolised to acetate but also to ethanol in the colon. CONCLUSIONS: Significant endogenous intracolonic acetaldehyde values can be found in the normal porcine colon. Furthermore, our results suggest the existence of a bacteriocolonic pathway for ethanol oxidation. Increased amounts of acetaldehyde are formed intracolonically from ingested ethanol by this pathway.

Hepatotoxicity and absorption of extrahepatic acetaldehyde in rats.

Acetaldehyde, the first metabolite of ethanol oxidation, has been proposed as a major initiating factor in ethanol-induced liver injury. The aims of this study were to examine whether acetaldehyde is absorbable from the digestive tract and whether, when delivered chronically in drinking water, it is capable of inducing liver injury in rats. Acetaldehyde concentrations in the rat portal and peripheral blood were measured by head space gas chromatography after intragastric (5 ml) and intracolonic (3 ml) administration of 20 mM acetaldehyde solution. In the hepatotoxicity study, rats were exposed to acetaldehyde (20 and 120 mM) delivered in drinking water for 11 weeks and histopathological changes in the liver were morphometrically assessed. Peak blood acetaldehyde levels were found at 5 min after acetaldehyde infusion and were 235 +/- 11 microM (mean +/- SE) after intragastric and 344 +/- 83 microM after intracolonic infusion of 20 mM acetaldehyde solution. The exposure of rats to 120 mM acetaldehyde solution for 11 weeks resulted in the development of fatty liver and inflammatory changes. Morphometric analysis showed significantly more fat accumulation in rats receiving 120 mM acetaldehyde solution (85 +/- 2 per cent of hepatocytes occupied by fat) than in rats receiving 20 mM acetaldehyde solution (38 +/- 11 per cent) or in controls (36 +/- 10 per cent). The dose of extrahepatic acetaldehyde (500 mg/kg per day) producing liver injury corresponds to only around 3 per cent of that derived from hepatic ethanol oxidation in animals receiving an ethanol-containing totally liquid diet (15 g/kg per day). These results indicate that acetaldehyde delivered via the digestive tract can reach the liver by the portal circulation and that acetaldehyde of extrahepatic origin appears to be more hepatotoxic than acetaldehyde formed during ethanol oxidation within the liver.

Inhibition of gastric cell proliferation by acetaldehyde.

Helicobacter pylori possesses alcohol dehydrogenase activity and is capable of producing acetaldehyde from ethanol in vitro. Acetaldehyde is a toxic and reactive compound and has been shown to inhibit the proliferation of many different cell lines in vitro. To study the effects of acetaldehyde on the proliferation of gastric epithelial cells in vivo, we employed an immunohistochemical method after labelling proliferating cells with 5'-bromo-2'-deoxyuridine in rats receiving acetaldehyde intragastrically. Chronic (16 weeks) exposure of gastric mucosa to acetaldehyde given to rats in their drinking water in concentrations of 10 or 20 mM resulted in significant (P < 0.05) inhibition of gastric epithelial cell proliferation, expressed as 332 +/- 36, 348 +/- 8, and 695 +/- 15 proliferating cells per ten high-power (x 400) fields in the groups drinking 10 mM acetaldehyde, 20 mM acetaldehyde, and in controls respectively. In an acute study, significant inhibition of proliferation was observed after as few as 4 days of exposure to acetaldehyde, but only when a higher dose (50 mM) of acetaldehyde was given (438 +/- 44 versus 615 +/- 19 in controls, P < 0.05). The inhibition of gastric cell renewal by acetaldehyde may play a role in the pathogenesis of ethanol- and/or H. pylori-associated gastric diseases by inhibiting normal gastric mucosal protection and repair.