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Background & Aims: Myelosuppression in patients with Crohn's disease (CD) treated with azathioprine has been attributed to low activity of thiopurine S-methyltransferase (TPMT). Allelic variants of the TPMT gene responsible for changes in the enzyme activity have been characterized. We investigated the distribution of mutant alleles associated with TPMT deficiency in patients with CD and myelosuppression during azathioprine/6-mercaptopurine therapy. Methods: Forty-one patients with CD were included. They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment. Polymerase chain reaction-based methods were used to search for mutations associated with TPMT deficiency. Results: Four patients (10%) had 2 mutant alleles associated with TPMT deficiency, 7 (17%) had 1 mutant allele, and 30 (73%) had no known TPMT mutation. The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles, and ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype. Conclusions: Twenty-seven percent of patients with CD and myelosuppression during azathioprine therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine. GASTROENTEROLOGY 2000;118:1025-1030

Although abdominal complaints are frequent in both acute and chronic alcoholism, little is known of the effect of ingestion of ethanol with a meal on the function of the upper digestive tract. We have studied the effects of oral ethanol (1 g/kg body wt) taken with food on (1) the gastric emptying rate of a solid-liquid meal as measured by a dual radioisotope technique in six normal subjects; and (2) the gastric response (emptying and secretion), biliopancreatic secretions, and duodenal nutrient absorption after an homogenized meal, as evaluated by a gastroduodenal intubation-marker perfusion technique on seven healthy volunteers. In the latter experiments, radioimmunoassays of gastrin, secretin, cholecystokinin, pancreatic polypeptide, motilin, somatostatin, gastric inhibitory polypeptide, and vasoactive intestinal polypeptide were performed serially. As compared with the control experiment, alcohol induced the following effects: (1) marked delay of gastric emptying of solids, smaller slowing effect on gastric emptying of the liquid phase of the solid-liquid meal and of the homogenized meal; (2) no significant change in gastric acid secretion; (3) no change in the overall postprandial pancreatic enzyme outputs, but a delay of lipase secretion; (4) no change in the early bile salt postprandial output, but a reduced bile salt secretion from the second postprandial hour onwards; (5) no significant change in carbohydrate and lipid duodenal absorption; and (6) a significantly greater postcibal gastrin release. The mechanisms for these effects of alcohol on upper digestive tract function remain to be clarified.

Background & Aims: The etiology of refractory sprue is unclear. To gain insight into its pathogenesis, the phenotype and T-cell receptor (TCR) gene rearrangement status of intestinal lymphocytes were analyzed in a group of patients with clinical or biological features of celiac disease but either initially or subsequently refractory to a gluten-free diet. Methods: Intestinal biopsy specimens were obtained from 26 adults: 6 patients with refractory sprue, 7 patients with active celiac disease, and 13 normal controls. The phenotype of intestinal lymphocytes was studied by immunohistochemistry and, in 3 patients with refractory sprue, by cytometry of lymphocytes purified from intestinal biopsy specimens. TCR rearrangements were assessed by studying TCR@cV-J junctional regions from DNA extracted from intestinal biopsy specimens and purified intestinal lymphocytes. Results: In the 6 patients with refractory sprue, but not in normal controls or patients with active celiac disease, the intestinal epithelium was massively infiltrated by small lymphocytes that lacked CD8, CD4, and TCR, contained intracytoplasmic but not surface CD3@e chains, and exhibited restricted TCR@c gene rearrangements. Conclusions: Refractory sprue is associated with an abnormal subset of intraepithelial lymphocytes containing CD3@e and restricted rearrangements of the TCR@c chain but lacking surface expression of T-cell receptors. GASTROENTEROLOGY 1998;114:471-481

Patients with cœliac disease have a highly significant reduction in the release of secretin and gastric inhibitory polypeptide from the upper small intestine, but a greatly increased release of enteroglucagon, and also of neurotensin, from the lower part of the small intestine. The release of gastrin and pancreatic polypeptide, from the antrum and pancreas respectively, is, however, normal. Thus the pattern of hormone release reflects the location of the mucosal lesion. The gut-hormone profile may also help to characterise other gastrointestinal diseases.

We have examined prospectively whether it was possible for a multicenter group (12 centers) to standardize data collection and to achieve a reasonable level of reproducibility of colonoscopic findings in Crohn's disease. Each colonoscopy was performed simultaneously by a pair of endoscopists who did not communicate with each other until they had completed a standardized form. A preliminary period was necessary to achieve an agreement on items to be recorded and on lesion definition. Thereafter 112 colonoscopies were carried out by 18 intracenter endoscopist pairs (both endoscopists from the same center) and 21 colonoscopies by 14 intercenter endoscopist pairs (endoscopists from different centers) in patients with Crohn's disease. The following data were recorded: (1) for each segment involved—rectum, sigmoid, and left colon, transverse colon, right colon, and ileum—the nature of elementary lesions (by ticking on a list of nine items) and an estimation of the surface of lesions and of ulcerations on two linear analog scales; and (2) a global assessment of lesion severity on a five-point scale and on a linear analog scale. Reproducibility of lesion detection was fair to excellent (kappa values greater than 0.54,P<0.05 or less) except, in the intercenter study, for erythema and swollen mucosa. Agreement on estimation of diseased and ulcerated segmental surfaces was good (intraclass correlation coefficient,r, >0.85;P<0.001) in both intra- and intercenter studies. Global assessment of lesion severity on a five-point scale (intra-and intercenter kappa=0.64 and 0.55, respectively;P<0.001) and on a linear analog scale [intra- and intercenterr=0.86 (P<0.001) and 0.58 (P<0.01), respectively was reproducible. In conclusion, reproducible endoscopic data can be collected by a cooperative multicentric group and thus be used in controlled therapeutic trial in Crohn's disease.

Twenty-eight patients with chronic idiopathic dyspepsia defined by the presence of chronic unexplained symptoms suggestive of gastric stasis and directly related to food ingestion were included in this prospective study. Gastric emptying of the liquid and solid phases of a meal was quantified by a dual-isotope method, and symptoms were evaluated by a diary and a visual analog scale. Delay in gastric emptying was evidenced in 59% of the dyspeptic patients; it occurred with liquids in more cases than solids. Quantitative and qualitative evaluation of symptoms was of no practical value in predicting the presence of objective stasis. The dyspeptic patients were included in a double- blind randomized controlled trial of cisapride, a new gastrokinetic drug devoid of central antiemetic effects. After six weeks of cisapride treatment, all patients with initially abnormal gastric emptying rates for liquids, and all but one for solids returned to normal ranges, and significant differences between cisapride and placebo groups were observed for half emptying times of both solids (136±16 min vs 227 ±32 min; P<0.02) and liquids (61±4 min vs 132±37 min; P<0.01). Cisapride also significantly improved dyspeptic symptom scores at weeks 3 and 6 of treatment as compared to those measured before treatment. Nevertheless, the decrease in global diary score was significantly higher than that seen with placebo at week 3 (-16±6 vs -1±9; P<0.05), but not at week 6 (-18±5 vs -10±8). The symptomatic effect of cisapride at week 3 was significantly more pronounced in patients with abnormal initial gastric emptying than in those with normal gastric emptying (-30±7vs -4±6; P<0.02).These results underline the importance of objective evaluation of gastric emptying in the detection of patients with gastric stasis who exhibited the best symptomatic response to cisapride.

A randomized clinical trial was conducted to determine whether colonoscopy is useful in deciding how long to maintain steroid treatment in attacks of Crohn's disease involving the colon. One hundred forty-seven patients with acute attacks of colonic or ileocolonic Crohn's disease were treated by oral prednisolone, 1 mg · kg−1· day−1; 136 achieved clinical remission, but 96 of them still had active endoscopic lesions and were randomized either to immediate start of steroid tapering (group A; n = 46) or to continued prednisolone treatment at the same dosage for 5 more weeks before steroid tapering was begun (group B; n = 50). In the remaining 40 patients (already in endoscopic remission, group C), steroid tapering was begun immediately. After prednisolone discontinuation, patients were followed up for 18 months or until clinical relapse. Prolongation of prednisolone therapy significantly improved the endoscopic scores in group B (30% of endoscopic remission). The frequency of successful steroid weaning was almost identical in groups A and B (82% and 80%, respectively), as was the actuarially calculated relapse clinical rate after steroid withdrawal (P= 0.22). No factor predictive of clinical relapse could be found. The clinical course of patients in group C was similar to that of those in groups A and B. Overall, only 22% of the 147 patients were still in clinical remission and off steroids 18 months after prednisolone discontinuation, outlining the need for maintenance therapy. In conclusion, for patients who have achieved clinical remission, adjustment of steroid treatment duration on the basis of endoscopy results is of no benefit, and the endoscopic aspect has no prognostic value; thus, it appears unnecessary to repeat colonoscopy in such patients before steroid tapering is begun.

BACKGROUND & AIMS: Familial aggregation argues for genetic susceptibility to Crohn's disease. The aim of this study was to compare the age of onset and the clinical features of Crohn's disease between patients with familial disease and those with sporadic disease and investigate the concordance for disease location and type among relatives with Crohn's disease. METHODS: Seventy-two families with 2 (n = 55), 3 (n = 8), 4 (n = 6), and 5 or more (n = 3) affected first- degree relatives were selected for the study. A population of 1377 patients with sporadic nonfamilial Crohn's disease was used for comparison. RESULTS: Clinical data were obtained from 176 patients with familial Crohn's disease (79 men and 97 women). Median age at onset was younger in familial Crohn's disease than in sporadic cases: 22 vs. 26.5 years (P < 0.01). In familial cases, fewer patients had exclusively colonic involvement and more patients had both small bowel and colonic involvement. Among relatives of families with 2 affected members, 56% were concordant for disease location and 49% for disease type. These percentages reached 83% and 76%, respectively, within families with more than 2 affected members. CONCLUSIONS: Patients with familial Crohn's disease are characterized by an early age at onset with more extensive disease and may represent a homogeneous clinical subgroup with a particularly strong genetic influence. (Gastroenterology 1996 Sep;111(3):604-7)

We have studied fasting levels and the response to a standard test breakfast of blood glucose and several gut hormones in 24 patients with ulcerative colitis, in 14 patients with Crohn's disease, and in 14 healthy control subjects. Patients with ulcerative colitis had significantly elevated fasting human pancreatic polypeptide (HPP) concentrations, and both basal and postprandial levels of gastrin, gastric inhibitory polypeptide (GIP), and motilin were greater than normal. In contrast, patients with Crohn's disease had normal gastrin levels but had increased fasting and postprandial levels of GIP and motilin and, in addition, of enteroglucagon, compared with controls. These patients also had greater than normal HPP concentrations 30 min after the breakfast. Normal levels of insulin, pancreatic glucagon, neurotensin, and vasoactive intestinal polypeptide were found in both groups of patients. Much remains to be known about the pathophysiology of these two debilitating diseases, and the abnormal release of gut hormones may be of importance.

Because of its simplicity, a tube with a proximal occlusive balloon is widely used to measure segmental intestinal absorption in man. Yet, the possibility that the presence of an inflated balloon might alter the absorptive capacity of the underlying segment of intestine has never been tested. In the present work the jejunal absorption of water and ions has been measured in 13 healthy subjects with the proximally occlusive tube and with the triple lumen nonocclusive method; precautions were taken to achieve similar flow rate and ionic composition of the fluid entering the test segment with both techniques in each subject. Under these conditions net water and ion movements measured by the two methods were identical. This finding validates the use of the proximal occlusive tube to measure intestinal absorption in man.

Omeprazole is a new, potent and long acting inhibitor of gastric acid secretion. This open, non-controlled trial has been carried out to assess the duodenal ulcer healing rate with omeprazole, 30 mg once daily.