Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters.

Silencing of gene expression by aberrant cytosine methylation is a prominent feature of human tumors, including colorectal cancers. Epigenetic changes of this type play undisputed roles in cell transformation when they involve genes that safeguard genome stability, and they can also be detected in precancerous lesions and seemingly normal peritumoral tissues. We explored physiological conditions associated with aberrant promoter methylation involving two DNA-repair genes in normal colorectal mucosa. Samples of cecal, transverse colon, sigmoid and rectal mucosa collected from 100 healthy individuals undergoing screening colonoscopy were analysed for hMLH1 and MGMT promoter methylation with a quantitative PCR assay. Positivity in at least one colon segment was common in both sexes, with methylation involving 0.1-18.8% of the alleles (median=0.49%). Samples from males showed no consistent patterns for either promoter, but there were striking age- and colon segment-specific differences in the female subgroup. Here, the prevalence of hMLH1 and MGMT methylation increased significantly with age, particularly in the right colon, where there was also an age-related increase in the percentage of alleles showing hMLH1 methylation. Concomitant methylation of both promoters was also significantly more common in the right colon of women. These findings paralleled immunohistochemical patterns of hMLH1 and MGMT protein loss in an independent series of 231 colorectal cancers and were consistent with current epigenetic profiles of colorectal cancer subsets. They suggest the intriguing possibility that the epigenetic signatures of cancers may have early-stage, normal-tissue counterparts that reflect potentially important aspects of the initial carcinogenetic process.

Colonoscopy is the preferred colorectal cancer screening method in a population-based program.

BACKGROUND AND STUDY AIMS: Various screening methods for colorectal cancer (CRC) are promoted by professional societies; however, few data are available about the factors that determine patient participation in screening, which is crucial to the success of population-based programs. This study aimed (i) to identify factors that determine acceptance of screening and preference of screening method, and (ii) to evaluate procedure success, detection of colorectal neoplasia, and patient satisfaction with screening colonoscopy. PATIENTS AND METHODS: Following a public awareness campaign, the population aged 50 - 80 years was offered CRC screening in the form of annual fecal occult blood tests, flexible sigmoidoscopy, a combination of both, or colonoscopy. RESULTS: 2731 asymptomatic persons (12.0 % of the target population) registered with and were eligible to take part in the screening program. Access to information and a positive attitude to screening were major determinants of participation. Colonoscopy was the method preferred by 74.8 % of participants. Advanced colorectal neoplasia was present in 8.5 %; its prevalence was higher in males and increased with age. Significant complications occurred in 0.5 % of those undergoing colonoscopy and were associated with polypectomy or sedation. Most patients were satisfied with colonoscopy and over 90 % would choose it again for CRC screening. CONCLUSIONS: In this population-based study, only a small proportion of the target population underwent CRC screening despite an extensive information campaign. Colonoscopy was the preferred method and was safe. The determinants of participation in screening and preference of screening method, together with the distribution of colorectal neoplasia in different demographic categories, provide a rationale for improving screening procedures.

Severe life-threatening diarrhea caused by azathioprine but not by 6-mercaptopurine.

Azathioprine and its active metabolite 6-mercaptopurine are of increasing importance in the treatment of chronic inflammatory bowel disease. Most of the toxicity and the side effects of the medications are well known. However, it is relatively unknown that azathioprine toxicity itself can produce devastating diarrhea in patients with inflammatory bowel disease. This leads to great difficulties in differential diagnosis. We describe 2 patients with severe intestinal toxicity. This was life-threatening in 1 patient after reintroducing the drug. We therefore believe that any rechallenge with azathioprine should be only undertaken in a controlled hospital environment when a reaction to azathioprine is suspected. In addition, we found that this devastating intestinal toxicity did not reoccur after rechallenge with its active metabolite 6-mercaptopurine. Azathioprine and 6-mercaptopurine therefore cannot be used interchangeably.

[Autoimmune hepatitis in Switzerland]. / Zur Autoimmunhepatitis in der Schweiz.

The incidence and course of autoimmune hepatitis in Switzerland are unknown. In an attempt to obtain an overview of all patients at present under treatment in Switzerland for autoimmune hepatitis, we circulated a questionnaire to all Swiss gastroenterologists. Eighteen patients were identified and their symptoms, course and treatment were evaluated. The majority were females, usually without liver cirrhosis at the time of diagnosis. The course of the disease was largely favourable.

Audit of the change of outcome of peptic ulcer disease following treatment of Helicobacter pylori.

In this audit we tried to assess the effect of the detection of Helicobacter pylori on the change of outcome and symptoms of peptic ulcer disease outside well defined prospective studies, and its influence on treatment praxis by general practitioners. The study was carried out in the canton of Uri, a geographically closed area of Switzerland. The records of all patients with peptic ulcer disease diagnosed from 1991 to 1994 were evaluated retrospectively. In addition, the patients were followed by contact through their family doctors who were asked to fill out questionnaires on the immediate and long-term treatment of acute peptic ulcer, H. pylori therapy, recurrence of ulcers in light of symptoms or endoscopy, and on any surgery performed for ulcer disease. We found 453 patients with peptic ulcer disease proven by endoscopy, 134 patients presented with signs of ulcer bleeding, 45% of these had used nonsteroidal anti-inflammatory drugs previously. Only 9 of 453 patients required surgery. In 430 patients follow-up was possible (median of 18 months). H. pylori eradication was the primary treatment in 24% of the patients in 1991 and in 79% in 1994. Long-term prophylaxis with histamine H2 antagonists had been selected in 22%. Recurrence of the ulcer disease was seen in 157 patients during the follow-up period. The recurrence rate was 8% (3/39) in patients with documented H. pylori eradication, 43% (62/145) in patients with H. pylori eradication therapy without documentation of the result, 57% (31/54) in H. pylori positive and 50% (14/28) in H. pylori negative patients on long-term treatment with histamine H2 antagonists. 33% of the patients still had substantial abdominal pain despite using long-term histamine H2 antagonists as prophylaxis against recurrence, but this was the case in only 5% (2/39) after successful H. pylori eradication. The rate of successful antibiotic treatment improved substantially during this audit. This follow-up study demonstrates that patients with successfully eradicated H. pylori remain largely free of symptoms and of ulcer recurrence. Control of the eradication result seems to be necessary outside controlled studies. In contrast, symptoms and ulcer recurrence are frequent despite long-term treatment with histamine H2 antagonists. Few patients need surgery for ulcer disease today. Audits like this are a valuable method to improve acceptance and success of a new treatment modality.

[Portal hypertension]. / Die portale Hypertonie.

Portal hypertension is a frequent and dangerous consequence of chronic liver diseases. The most important complications are ascites and variceal bleeding. In this article new pathophysiological theories of portal hypertension are reviewed. In addition, the prophylactic and therapeutic management of variceal bleeding are discussed.

[Diagnosis and therapy of diarrhea]. / Abklärung und Therapie der Diarrhoe.

Diarrhea is still one of the most frequent causes of death and poses many diagnostic and therapeutic problems. Whereas the etiology of acute diarrhea is mainly infectious, the cause of chronic diarrhea is much more multifarious and thus more difficult to diagnose. The etiology of acute diarrhea as well as the sense and nonsense of diagnostic procedures and therapeutic possibilities are discussed. A rational and practical concept for evaluation of chronic diarrhea is presented.

[Is premedication in gastroscopy hazardous?]. / Ist die Prämedikation bei der Gastroskopie gefährlich?

Premedication for gastroscopies is still controversial. Most gastroenterologists use premedication routinely, often without control of vital signs. However, even if rarely, serious (mainly cardiorespiratory) complications still occur. In 101 patients in whom a gastroscopy had been performed, oxygen saturation before, during and after the endoscopy was investigated. A fall in saturation was seen in most of the patients but was usually minor. However, severe hypoxemia occurred in some patients, especially if premedication was used. Older patients and patients with severe anemia were particularly at risk. These results emphasize that premedication should not be used without precaution and special surveillance, especially in high risk patients. Prophylactic oxygen administration significantly diminishes the risk.

Gallstone-associated acute pancreatitis: a field for endoscopic therapy?

The pathogenesis of acute pancreatitis even if associated with gallstone remains unclear. This explains that the best treatment for gallstone-associated pancreatitis remains a matter of debate. However, different theoretical and clinical evaluations support the strategy to perform an endoscopic papillotomy if a common bile duct stone is suspected and the course of the disease does not improve spontaneously during the first 48 h. The discrepancies of the current data and the difficulties to give rational suggestions have been reviewed.

[Antibiotic-associated colitis--the dark side of antibiotic therapy]. / Antibiotikaassoziierte Kolitis--Schattenseite der Antibiotikatherapie.

Intestinal side effects after antibiotic therapy are frequent. Mostly, harmless diarrhea disappears after cessation of therapy without inducing colitis; however, changing of the intestinal flora sometimes leads to colonization of the colon by toxin-producing strains of Clostridium difficile, inducing sometimes severe pseudomembranous colitis. A rapid correct diagnosis by anamnesis, clinical signs, endoscopical aspect and demonstration of toxin in the stool allows an efficient treatment. The therapeutic modalities, especially in recurrency, are delineated. In addition, the unusual and etiologically still unknown illness of penicillin-induced segmental hemorrhagic colitis will be discussed as well.

[Chronic viral hepatitis--hope of solving a worldwide problem]. / Die chronische Virushepatitis--Hoffnung auf Lösung eines weltweiten Problems.

Our knowledge on chronic hepatitis B and C infection has dramatically improved. For the first time it is possible, to eliminate these hepatitis-viruses at least in some patients. In addition an excellent immuno-prophylaxis is possible in hepatitis B today. However many problems are still unsolved: we still do not have a sensitive marker for hepatitis C infection and the possibility to transfer hepatitis C by blood transfusion will remain. The recurrence-rate of chronic hepatitis C after stopping treatment with Interferon is very high and many patients with hepatitis B do not respond to Interferon-treatment. These problems are especially great in third world countries. New hope comes from the possibility to successfully immunize babies immediately after birth and from the successful production of vaccine with gene technology.

[Diarrhea cause by parasites]. / Die parasitäre Diarrhöe.

Parasites, once an exclusively tropical problem, are rare causes of diarrhea in our countries. Increasing tourism and immune deficiencies due to treatment or to Aids lead to an increase of intestinal parasites in western countries. The most frequent pathogenic parasites are Giardia lamblia and Entamoeba histolytica but other organisms like Cryptosporidia seem to be of increasing importance and have to be considered in diarrhea of unknown origin.

[ERCP under ceftriaxone antibiotic cover in patients with obstructive jaundice]. / ERCP unter antibiotischem Schutz mit Ceftriaxon bei Patienten mit Verschlussikterus.

The risk of cholangitis after ERCP has been reported to occur in up to 50% of patients with obstructive jaundice. Prophylactic antibiotics have therefore been advocated to reduce the risk. Here we report on the results of 46 patients with obstructive jaundice who were given 1 g of Ceftriaxone i.v. 30 to 60 min. prior to the procedure. Only one patient developed cholangitis with septicemia, which was treated conservatively. No side effects were observed in this group of patients. It is suggested that Ceftriaxone is an adequate prophylactic method to prevent cholangitis and septicemia in patients with obstructive jaundice.

The influence of HLA antigens on progression of alcoholic liver disease.

The aim of our study was to elucidate further possible genetic influences on the incidence and progression of alcoholic liver disease. We determined HLA A, B and DR antigens in a well-controlled group of chronic alcoholics with and without liver disease, in repeated liver biopsies over period of 8.1 years (+/- 0.4 SEM). Patients with the antigen B 35 had an increased incidence of alcoholic liver cirrhosis, and especially a more rapid progression to cirrhosis (p less than 0.01). Increased susceptibility of these patients was shown by a more rapid progression of liver disease, despite the consumation of less alcohol over a shorter period. Results of this long-term study suggest that there is a sub-group of alcoholics genetically predisposed to higher susceptibility with more rapid deterioration of alcohol-induced liver disease.

Reduction in early recurrence of variceal bleeding by propranolol.

Survival after variceal bleeding depends greatly on the outcome of the immediate posthaemorrhagic period. This may in turn depend on the recurrence of bleeding. We therefore prospectively evaluated the influence of propranolol on the recurrence of variceal haemorrhage during the early period after the acute bleeding episode. Twenty consecutive patients with acute variceal haemorrhage and liver disease were randomly assigned to treatment either with propranolol or placebo orally for 14 days. Propranolol significantly decreased the rate of recurrence of variceal haemorrhage during this early period (p = 0.0028; 95% confidence interval in the placebo group, 90 +/- 20%; in the beta blocker group, 20 +/- 26%). Whereas a recurrence of variceal bleeding occurred in 9 of 10 patients in the placebo group, only 2 of 10 rebled during treatment with propranolol. These results suggest that propranolol may prevent rebleeding in the crucial early period after acute haemorrhage from oesophageal varices.

[Campylobacter pylori, gastritis and ulcer disease. Microbiological, histological and serological studies]. / Campylobacter pylori, Gastritis und Ulkuskrankheit. Mikrobiologische, histologische und serologische Untersuchungen.

In a prospective study of 70 patients with epigastric pain, gastroduodenoscopy revealed gastric and/or duodenal ulcers in a total of 41 and no ulceration in the remainder. Biopsies were taken to assess the severity of gastritis and the presence of Campylobacter pylori (CP) by histology and culture. Gastritis was found in 54 patients. CP was detected in 78% of the ulcer patients and 52% of the patients without ulcer (p less than 0.05). CP was demonstrated in 83% of the histologically diagnosed cases of gastritis (all grades) but no CP was detectable in patients with normal gastric mucosa. Among the ulcer patients, CP was more frequent in those with no history of medication with nonsteroidal antiinflammatory drugs (p less than 0.01). Sera from CP-positive ulcer and gastritis patients have significantly higher levels of IgG antibodies to CP than sera from those found to be free of ulcer or gastritis. In 200 blood donors an increasing percentage of elevated CP-antibody titres were found with advancing age (50% over 60 years of age). Quantification of circulating CP antibodies, would thus seem a valuable adjunct in the diagnosis of gastritis and probably also of peptic ulcer. The data presented furnish further evidence of the high rate of association of CP and the gastritis-peptic ulcer complex.

[Cellular immunoreactivity in chronic alcoholics with and without liver disease]. / Die zelluläre Immunreaktivität beim chronischen Alkoholiker mit und ohne Lebererkrankung.

To evaluate the influence of chronic alcohol consumption on the cellular immune system in man, we investigated the immune response to seven intradermally applied common antigens and in vitro stimulation of peripheral lymphocytes by Phytohemagglutinin A and concanavalin A in chronic alcoholics with (n = 15) and without (n = 15) liver disease. The results suggest that the diminished cellular immune response in chronic alcoholics is not primarily a direct sequel to alcohol consumption; it is more likely that the impaired immune response is linked to severity of the liver damage itself and to malnutrition.

Long-term histological evaluation of the natural history and prognostic factors of alcoholic liver disease.

In this long-term follow-up evaluation of chronic alcoholics without established cirrhosis we investigated the influence of alcohol on the progression of fibrosis and the prognostic significance of histological features. We were unable to confirm results of retrospective cross-sectional analysis suggesting a linear relationship between alcohol intake and the development of cirrhosis. Alcoholic hepatitis, advanced fibrosis, central hyaline necrosis and central vein sclerosis were unfavorable signs for the further course of the disease. All but one of the patients with central vein sclerosis who progressed to advanced fibrosis also had an alcoholic hepatitis in one of their biopsies. Two patients had an acute alcoholic hepatitis initially, and later showed the mixed histological pattern of an alcohol-induced chronic active hepatitis, a pattern which was also seen in four other patients, all progressing to cirrhosis. This may be taken as evidence that immunological factors contribute in some patients to progression of fibrosis.