Harald Goebell

Effect of cigarette smoking on the course of Crohn's disease

OBJECTIVEnIt has been shown that smokers are more likely than non-smokers to develop Crohns disease. In order to examine the influence of smoking on the course of Crohns disease, as measured by the risk of surgery, the need for surgery was assessed in patients with Crohns disease.nnnDESIGNnThe course of Crohns disease was evaluated as to smoking status by life table analysis.nnnSETTINGnA tertiary hospital in Essen, Germany.nnnPATIENTSnThe study involved 346 patients with Crohns disease admitted to hospital between 1989 and 1992. Only patients residing in the City of Essen were included.nnnRESULTSnOf the 346 patients, 144 smokers and 143 non-smokers were included in the analysis. Overall, 73% of smokers and 39% of non-smokers required one or more operations. The corresponding relative risks (RR) and 95% confidence intervals were for one operation and more than one operation or no operation at all (RR 1.0) 3.9 (2.2-6.9) and 10.8 (5.3-22.1), respectively. There were significant differences as to recurrence rates (defined as further surgery after first surgery for control of disease) between smokers and non-smokers. For smokers the 5- and 10-year recurrence rates were 43% and 64%. For non-smokers corresponding recurrence rates were 26% and 33%. For 5- and 10-year recurrence rates the RR estimates for smokers versus non-smokers were 3.1 (1.7-5.8) and 6.7 (2.7-6.8). When stratified by gender, the increased risk for recurrence was obvious in both sexes. For the number of cigarettes smoked a dose-response effect was obvious in women.nnnCONCLUSIONnThese data suggest that the course of Crohns disease is less favourable in smokers than in non-smokers.

Dyspepsia in healthy blood donors : pattern of symptoms and association with Helicobacter pylori

WhetherHelicobacter pylori is causally linked to dyspepsia remains controversial. The aims of this study were to assess in healthy blood donors the prevalence of dyspepsia and dyspepsia subgroups, determine ifH. pylori is associated with different categories of dyspeptic symptoms, and evaluate the association between dyspepsia and nicotine, alcohol, and analgesic use. Consecutive blood donors (N=180) who had no clinical evidence of organic disease were included. Abdominal symptoms were measured by means of a standardized questionnaire that has been previously validated. Subjects with dyspepsia (defined as pain localized to the upper abdomen) were further subdivided into those with ulcer-like, dysmotility-like, reflux-like, or nonspecific dyspepsia. A total of 65 subjects reported abdominal pain or discomfort during the prior 12 months [36.1%, 95% confidence interval (CI) 29.1–43.1]; 44 subjects (24.4%, 95% CI 18.2–30.7) had dyspepsia. Dysmotility-like, reflux-like, and ulcer-like symptoms were reported by 19.4% (95% CI 13.7–25.2), 17.2% (95% CI 11.7–22.7), and 16.7% (95% CI 11.2–22.1) of subjects with dyspepsia, respectively. Fifty-seven subjects (31.7%, 95% CI 24.9–38.5) wereH. pylori positive; 26% of subjects withH. pylori and 24% withoutH. pylori had dyspepsia (P>0.50). The seroprevalence ofH. pylori was also similar among the different categories of dyspepsia. We conclude that infection withH. pylori is not associated with abdominal complaints in otherwise healthy subjects.

Selective 5-lipoxygenase inhibition by zileuton in the treatment of relapsing ulcerative colitis: a randomized double-blind placebo-controlled multicentre trial

Objective To test the efficacy and safety of zileuton 800 mg twice daily for up to 4 weeks against placebo. Design and setting A randomized double-blind, placebo-controlled multicentre trial including 76 outpatients with relapsing mild to moderately active ulcerative colitis from seven specialist gastroenterological departments in three countries. Main outcome measures Clinical responsé as defined by the dichotomous end points, CR25 and CR10, to combine improvement in both symptom and endoscopy scores [50% or more decrease in stool character and rectal bleeding scores, stable or improved scores of abdominal/rectal pain or urgency, and a 25% (CR25) or 10% (CR10) decrease in total sigmoidoscopy score] and leukotriene B4 concentrations in rectal dialysis fluid. Results Forty patients were randomized to zileuton and 36 to placebo; 45 patients received concurrent sulphasalazine, while 31 received no such medication. A clinical response occurred more often in the zileuton group and significantly so (P <0.05) in patients without concurrent sulphasalazine. No adverse events or toxicity indicating an unfavourable affect on risk ratio were observed. The leukotriene B4 concentrations in rectal dialysis fluid were significantly inhibited by zileuton with a median inhibition of 72%. Conclusion More potent 5-lipoxygenase inhibition may reduce leukotriene B4 production further and improve clinical outcome. Hence, further studies of zileuton at higher doses and over a longer period of time seem worthwhile.

A prospective analysis of the incidence and prevalence of Crohn's disease in an urban population in Germany

Objective: To study the incidence and prevalence of Crohns disease in the Ruhr area of Germany. Participants: The population at risk comprised 1.6 million inhabitants in the four industrial cities of Essen, Oberhausen, Mülheim and Duisburg. All 35 hospitals in the area, including 79 in- and outpatient departments of internal medicine, surgery and paediatrics participated in the study. Methods: A prospective epidemiological study of the incidence and prevalence of Crohns disease over 5 years from 1980 to the end of 1984. Results: Overall, 315 patients with Crohns disease (181 women and 134 men) were newly diagnosed during the study period. The mean incidence was 4.0 new cases per 100000 inhabitants (range, 3.10–4.9) with no significant difference between the 5 years. Incidence figures were somewhat higher for women than for men (4.3 versus 3.6 per 100000 inhabitants, respectively), but this difference was significant only for those aged 20–29 years. The age- and sex-adjusted incidence was highest among those aged 20–29 years for both sexes with no second peak later in life. The prevalence of Crohns disease on 31 December 1984 was calculated to be 36.0 per 100000 inhabitants (n = 556). Seventy-four per cent of cases living in the area were under 35 years of age and 44% were under 25 years; 30 were children under the age of 15 (5.4%). Conclusion: These figures for Crohns disease range in the upper level of those reported for western industrial areas.

Biochemische, histochemische, histologische und funktionelle Untersuchungen zur Phenforminwirkung auf die Dünndarmschleimhaut bei Ratte und Mensch

SummaryThe influence of Phenformin (25 mg/kg body weight) on the small intestinal absorption of glucose, glycine, water and electrolytes has been investigated in the rat using a continuous perfusion technique. Furtheron, its influence on adenin nucleotides, cytochemical reactivity and morphology of the mucosa of the small intestine was studied. The physiological relevance of the findings obtained in the rat was checked in man by studying glucose absorption after a 150 mg Phenformin load using a triple-lumen perfusion system.Results in the rat: 1. The transport of glucose, glycine and water as well as the unidirectional flux of22Na+ were significantly reduced. 2. ATP-levels were diminished by approximately 30%. 3. The enzymatic activity of the absorptive epithelium was slightly decreased as judged by cytochemical methods. 4. The morphological integrity of the mucosa of the small intestine was in general maintained, but extrusion of absorptive cells at the tips of the villi seemed to be increased.Results in man: 1. Glucose absorption was significantly reduced when a therapeutical load of 150 mg was given as a single dose. This effect was shown briefly after application of the drug but could not be demonstrated 12 hours thereafter. 2. Neither morphological nor cytochemical changes could be observed in the biopsies taken shortly after Phenformin application at the dosage given.ZusammenfassungIn der vorliegenden Studie wird erstmalig der Einfluß von Phenformin (25 mg/kg Ratte) auf die Wasser- und Elektrolytresorption an der Ratte untersucht. Im Hinbliek auf die an Leber- und Nierenmitochondrien nachgewiesene Hemmung der oxydativen Phosphorylierung durch Biguanide wird weiterhin der Einfluß des Phenformins auf die Adeninnucleotide des Rattendünndarms geprüft. Zur Frage nach der cellulären und mukösen Integrität der Dünndarmschleimhaut unter Phenformin werden cytochemische und morphometrische Untersuchungen angestellt. Darüber hinaus wird die Glucoseresorption mittels kontinuierlicher in vivo-Perfusion gemessen. Zur Frage der physiologischen Relevanz der an der Ratte durchgeführten Untersuchungen wird die Glucoseresorption am Menschen mittels der dreilumigen Sonde bei physiologischer Phenforminbelastung (150 mg/d) geprüft.Ergebnisse an der Ratte:1.Der Wassernettotransport sowie der unidirektionale22Na+-Fluß werden ebenso wie die Glucoseresorption signifikant durch Phenformin gehemmt.2.Der mittlere ATP-Gehalt der Dünndarmwand wird durch Phenformin um ca. 30% gesenkt.3.Die in den verschiedenen Kompartimenten des reifen Resorptionsepithels cytochemisch nachgewiesenen Markerenzyme sind insgesamt reduziert.4.Die morphologische Integrität der Dünndarmschleimhaut ist erhalten. Vermutlich als Ausdruck einer durch die Perfusion bedingten gesteigerten Zellexfoliation sind die Zottenhöhen geringgradig reduziert.nErgebnisse am Menschen:1.Die Glucoseresorption wird unter physiologischen Phenformingaben signifikant herabgesetzt. Dieser Effekt ist sehr flüchtig.2.Cytochemische und morphologische Veränderungen sind am Biopsiematerial nicht nachweisbar.

Perception of gastric distension. Influence of mode of distension on perception thresholds and gastric compliance.

Gastric distension has been used to evaluate gastric sensory function in humans, but the methodology is poorly validated and studiesin vivo comparing different distension protocols are lacking. We aimed to compare the influence of the mode of gastric distension on sensation and gastric compliance utilizing a barostat device. In seven healthy volunteers, we positioned a barostat bag in the proximal stomach and tested in random order (in triplicate) four different distension protocols: (1) standard ramp distension with 4 mm Hg pressure step increments of 20 sec duration; (2) slow ramp distension with 2 mm Hg pressure increments of 40 sec duration; (3) random distension using a pressure ramp consisting of 2 mm Hg increments of 40 sec duration with randomly interposed pressure steps 50% below the preceding pressure step; and (4) rapid random distension with 4 mm Hg pressure increments of 10 sec duration with randomly interposed pressure steps 50% below the preceding pressure step. The distension procedures yielded mean airflow rates during the different distension protocols between 2.4 ml/sec for standard ramp and 18.4 ml/sec for rapid random distension. First perception and maximal tolerable pressure were 10.9±1.1 mm Hg and 19.6±1.5 mm Hg, respectively. First perception and maximal tolerable pressures were significantly correlated (r=0.93,P<0.005). The gastric pressure at occurrence of perception and the maximal tolerated pressure were not significantly different for the different distension protocols but gastric compliance was significantly reduced during rapid ramp distension (P<0.01 vs slow ramp andP<0.05 vs random distension) but not during standard ramp distension. We conclude that gastric sensory pressure thresholds as assessed by isobaric distension are not influenced by the mode of distension. The high correlation of pressure thresholds at first perception and maximal tolerated distension suggest a single population of gastric mechano-receptors that mediate first sensation at low intensity stimulation and pain at intense stimulation.

Healing and Relapse of Duodenal Ulcer During Ranitidine Therapy in the Elderly

A total of 2,109 outpatients with active duodenal ulcer (DU) entered an open, prospective study in order to investigate factors influencing healing and relapse during 2 years of ranitidine therapy (300 mg daily for healing, 150 mg as maintenance treatment). In a retrospective analysis, we evaluated the influence of age. Symptoms related to DU in 1,899 evaluable cases in patients over 65 years of age (n = 185) were identical to those of DU patients younger than 65 years old (n = 1,714). Rapid healing within 2 weeks of ranitidine therapy was less frequent in the elderly (32.5%) than in younger patients (40.7%) though identical healing rates (94.1%) in each group were achieved by continuation of ranitidine therapy for 8 weeks. Cumulative recurrence rates during the 2 years of long-term therapy were lower (17.3%) in old age than in patients under 65 years of age (23.3%). Adverse events were rare in both age groups. We conclude that DU healing during ranitidine is delayed in old age. Additional differences in relapse rates in favor of the elderly suggest that DU disease has a different course in the elderly.

Zur Pathogenese der durch Alkohol induzierten Fetteinlagerung in die Leber

Summary1. The aim of this study is to elucidate the origin of fatty acids accumulating as triglycerides in the liver following acute ethanol administration. In order to clarify this problem the effect of ethanol on the content of metabolites and coenzymes of the fatty acid and carbohydrate metabolism in liver and blood was assessed in man and in experimental animals.2. Metabolic changes induced by the oxidation of ethanol in the liver of rats fed a standard diet (marked increase in the reduction of the cytoplasmic NAD-system in the liver, measured by the lactate/pyruvate,α-glycerophosphate/dihydroxyacetonephosphate, and NADH/NAD ratios and increase of the acetyl-CoA content of the liver) can already be observed during the initial phase after a single oral load of ethanol.3. The pronounced accumulation of triglycerides in the liver following ethanol administration begins after a rather long lag period. This coincides with an increase in the concentration of free fatty acids in the plasma.4. In animals fed a protein-deficient diet (0.5% protein) the activity of liver alcohol dehydrogenase decreases to about 15% of the control values within 3 weeks. Under these conditions, ethanol oxidation is extremely slow when measured by blood elimination rate. This inhibition of ethanol oxidation caused by protein deficiency has been confirmed in man.5. Due to the reduced ethanol oxidation rate, metabolic changes induced by the oxidation of ethanol itself (increase of the reduction state of the cytoplasmic NAD-system and the hepatic content of acetyl-CoA) are not observed or at least much less pronounced in rats kept on a protein deficient diet than in normal control animals. Conversely the accumulation of triglycerides in the liver is even more marked in the former. Theβ-hydroxybutyrate/acetoacetate ratio and the concentration of these ketone bodies are also more elevated in liver and blood of protein deficient animals.6. Inhibition of lipolysis by adrenalectomy or application ofβ-receptor blocking agents diminishes the accumulation of triglycerides in the liver following acute ethanol administration. Under these conditions metabolic changes induced by the ethanol oxidation itself (increase in the lactate/pyruvate and NADH/NAD ratios) are similar to those observed in control animals.7. Acute ethanol administration to rats fed a standard diet increases the liver content of long-chain acyl-CoA esters. In protein deficient rats, ethanol application results in extremely high long-chain acyl-CoA levels. The marked increase in the long-chain acyl-CoA/free CoA ratio suggests a feed-back inhibition of fatty acid synthesis at the acetyl-CoA carboxylase reaction.8. Increased production ofα-glycerophosphate has been suggested to play a role in the preferential formation of triglycerides after acute ethanol administration. To elucidate this problem the effect of ethanol on hyperthyroid rats has been investigated. Hyperthyroidism inducesα-glycerophosphate oxidase a 20 to 30-fold and inhibits the elevation of hepaticα-glycerophosphate content caused by ethanol. Correspondingly, the ethanol-induced triglyceride accumulation in the liver was found to be distinctly lower than in euthyroid controls.9. In man, acute ethanol administration leads to analogous changes of the redox couples lactate/pyruvate andβ-hydroxy-butyrate/acetoacetate and other metabolic alterations as observed in animal experiments.10. It is concluded from these results that acute ethanol administration does not enhance hepatic fatty acid synthesis. Stimulated peripheral lipolysis is assumed to be the major source of the fatty acids which accumulate in the liver after acute ethanol intoxication. Both the marked elevation of hepaticα-glycerophosphate content and the increased fatty acid supply from adipose tissue are suggested to be of significance for the predominant triglyceride formation in the liver.Zusammenfassung1. In der vorliegenden Arbeit sollte geprüft werden, ob für die Fetteinlagerung in die Leber durch akute Alkoholzufuhr vorweigend eine Neusynthese von Fettsäuren in der Leber oder eine Mobilisierung von Fettsäuren aus dem peripheren Fettgewebe verantwortlich ist. Hierzu wurde der Einfluß von Alkohol auf den Gehalt von Metaboliten und Coenzymen des Fett- und Kohlehydratstoffwechsels unter verschiedenen Ausgangsbedingungen in der Rattenleber und auf Metabolitspiegel im Blut bei der Ratte und beim Menschen gemessen.2. Die durch die Alkoholoxydation selbst bedingten Stoffwechseländerungen in der Leber (deutliche Zunahme der Reduktion des cytoplasmatischen NAD-Systems der Leber, gemessen an den Quotienten Lactat/Pyruvat,α-Glycerophosphat/Dihydroxyacetonphosphat, NADH/NAD und Anstieg des Acetyl-CoA-Gehaltes) sind bereits sehr früh nach einmaliger Alkoholgabe zu beobachten.3. Die Triglycerideinlagerung in die Leber erfolgt im Vergleich hierzu erst relativ spät und geht parallel dem Anstieg der freien Fettsäuren im Plasma, die in den ersten Stunden nach der Gabe von Alkohol zunächst abfällt.4. Unter proteinarmer Kost (0,5% Protein) nimmt die Aktivität der Alkohol-Dehydrogenase in der Leber stark ab. Nach 3 Wochen beträgt sie nur noch 15% des Wertes der Kontrolltiere. Unter diesen Bedingungen ist die Alkoholoxydation, gemessen an der Abnahme des Blutalkoholspiegels nach einmaliger Alkoholabgabe, stark verlangsamt. Hierdurch ist bei gleicher Alkoholdosis die Alkoholkonzentration im Blut eiweißarm ernährter Ratten stärker und über längere Zeit erhöht als bei normal ernährten Tieren. Auch beim Menschen ist der Alkoholabbau, gemessen an der Alkoholelimination im Blut, unter eiweißarmer Kost deutlich verringert.5. Bei proteinarm ernährten Ratten bleiben, wie bei der verminderten Oxydationskapazität für Alkohol zu erwarten, die Stoffwechseländerungen in der Leber durch die Äthanoloxydation (Zunahme der Reduktion des cytoplasmatischen NAD-Systems, Anstieg des Acetyl-CoA-Gehaltes und derα-GP-Konzentration) aus oder sind stark reduziert. Die Triglycerideinlagerung in die Leber ist dagegen noch ausgeprägter als bei den normal ernährten Kontrollen. Auch die Ketokörperkonzentration und der Quotientβ-HOB/AcAc nehmen in der Leber und im Blut stärker zu als bei Normaltieren.6. Die Hemmung der Ausschüttung der lipolytisch wirksamen Catecholamine durch Adrenalektomie oder Gabe vonβ-Receptorenblockern vermindert die alkoholinduzierte Triglycerideinlagerung in die Leber. Stoffwechseländerungen durch die Alkoholoxydation selbst, wie der Anstieg der Quotienten Lactat/Pyruvat und NADH/NAD in der Leber entsprechen dabei den Befunden der Kontrolltiere.7. Über 12 Std dauernde Alkoholeinwirkung führt bei Ratten, die Standardkost erhielten zu einer deutlichen Zunahme langkettiger Acyl-Co-Ester in der Leber. Bei proteinarm ernährten Ratten ist die Akkumulation langkettiger Acyl-CoA-Ester in der Leber unter Äthanol noch erheblich ausgeprägter. In den beiden Fällen erfolgt die Zunahme auf Kosten von freiem CoA. Die starke Zunahme des Gehaltes an Acetyl-CoA-Ester läßt eine „feed-back“-Hemmung der Fettsäuresynthese am Ort der Acetyl-CoA-Carboxylase vermuten.8. Bei hyperthyreoten Ratten ist die Oxydationskapazität fürα-Glycerophosphat (α-GP) um eine Größenordnung gegenüber Normaltieren erhöht. Diese Stoffwechseländerung bietet eine Möglichkeit, den Einfluß vonα-GP auf die Triglycerideinlagerung zu untersuchen, daα-GP rascher oxydiert wird und für die Triglyceridsynthese weniger zur Verfügung steht. Wie zu vermuten, wird der Anstieg desα-GP-Gehaltes in der Leber nach Alkoholgabe durch Hyperthyreose vermindert. Gleichzeitig ist die Triglycerideinlagerung durch Äthanol deutlich geringer als bei euthyreoten Tieren.9. Beim Menschen verhalten sich die Redoxquotienten Lactat/Pyruvat,β-HOB-AcAc, sowie weitere Stoffwechseleffekte, im Blut nach oraler Alkoholgabe analog den bei den Tierversuchen beobachteten Veränderungen.10. Aus den Ergebnissen wird geschlossen, daß akute Alkoholzufuhr nicht zu einer gesteigerten Fettsäuresynthese in der Leber führt. Die Fettsäuren für die akute alkoholinduzierte Triglycerideinlagerung stammen wahrscheinlich vorwiegend aus dem peripheren Fettgewebe, wo sie durch indirekte Alkoholeinwirkung vermehrt freigesetzt werden. Der starke Anstieg desα-GP-Gehaltes ist zusammen mit dem vermehrten Fettsäureangebot entscheidend für die bevorzugte Triglyceridsynthese.

Clinical Relapse of Crohn's Disease under Standardized Conservative Treatment and after Excisional Surgery

The course of 205 patients with Crohns disease at one gastroenterological center was studied in patients with conservative drug treatment or with operative management of their disease. The decision for one or the other treatment regimen was made by an interdisciplinary team of gastroenterologists and surgeons. Using life-table analysis the 205 patients showed a clinical relapse rate of 27% after two years and 38% after four years. Clinical relapse was defined by a Crohns disease activity index (CDAI) over 150. We used a standardized drug regimen of salazosulfapyridin and prednisone; the indication for excisional surgery was limited strictly to life-threatening situations, absolute nonresponse to drug treatment, and severe intervisceralfistulae. The operated patients (N=93) had a lower relapse rate than the patients treated conservatively (N=112), 20% and 51%, respectively, after four years. There were considerably fewer relapses in Crohns colitis patients who were operated upon than in conservatively treated patients (18% versus 67% after four years); the same was found for ileocolitis (20% vs 49% after four years), but there was no difference between the treatment groups in ileitis (25–30% relapses for both after four years). In addition the patients with Crohns disease of the colon had a more favorable course after resection with respect to symptoms, clinical and laboratory findings, and CDAI in remission. This paper gives data only for surgery in severe clinical situations and does not give a rationale for earlier surgery. This problem should now be studied in a randomized trial.

Histochemische und biochemische Untersuchungen an einem Pankreastumor eines Patienten mit Zollinger-Ellison-Syndrom

ZusammenfassungEs wird über das Krankheitsbild eines 60jährigen Patienten mit Zollinger-Ellison-Syndrom berichtet. Im exstirpierten Tumor ließ sich eine gastrinähnliche Aktivität nachweisen. Histologisch und histochemisch kam neben dem reichlichen Bindegewebe und dem Tumorepithel eine dritte Struktur in Form von Granula, die intralacunär in der Gefäßwand oder intraluminal gelegen waren, zur Darstellung. Neben Mucopolysacchariden und Protein enthielten diese Granula lysosomale Enzyme. Auf Grund dieser Eigenschaften dürfte es sich um Sekret- bzw. Inkretgranula handeln. Ihre Beziehung zur nachgewiesenen gastrinähnlichen Aktivität wird diskutiert. Die ergänzend durchgeführten biochemischen Untersuchungen im Tumorgewebe ergaben mit den histochemischen Befunden übereinstimmende Ergebnisse und zeigten darüber hinaus eine gegenüber dem normalen Pankreas um das fünffache gesteigerte Aktivität der glykolytischen Enzyme. Abweichend von anderen Tumoren fand sich eine ungewöhnlich hohe Aktivität der Glycerophosphatdehydrogenase (E.C.1.1.1.8) im Tumorgewebe.SummaryA non-β-cell islet tumor of the pancreas, removed on operation from a sixty year old man with the Zollinger-Ellison-Syndrom has been investigated by pharmacological, histochemical and biochemical methods. The gastrin-like activity of this tumor could be demonstrated by pharmacological assay in the cat. On histochemical and histological investigation large extracellularly situated globules containing mucopolysaccharides, reactive protein-groups and lysosomal enzymes were found among cords of tumorcells separated by connective tissue. On histochemical grounds it is concluded that these granules contain secretory material with some endocrine qualities. The biochemical assay of the tumor tissue corresponded to the histochemical pattern of the tumor; in addition, it revealed a very high activity of the glycolytic enzymes compared with normal pancreas. In contrast to the finding in other tumors a very high activity of the enzyme glycerophosphatedehydrogenase (E.C. 1.1.1.8) in the tumor was found.