J.-R. Malagelada

Patients with achalasia lack nitric oxide synthase in the gastro‐oesophageal junction

Abstract. The abnormal function of the lower oesophageal sphincter in achalasia is likely to be due to impaired nonadrenergic, noncholinergic (NANC) inhibitory input. Since recent studies in animals suggest that nitric oxide (NO) is implicated physiologically in the inhibitory responses of the lower oesophageal sphincter, we have investigated whether the synthesis of NO is altered in the gastro‐oesophageal junction of patients with achalasia. NO synthase activity was investigated in samples of tissue from the gastro‐oesophageal junction obtained during surgery in eight patients with typical achalasia and six non‐achalasic controls who underwent oesophagectomy for reasons other than sphincter dysfunction. The NO synthase activity was determined by the transformation of 14C‐L‐arginine into 14C‐L‐citrulline in tissue homogenates. In addition, immunohistochemical staining of the tissues was performed using a polyclonal antibody raised against a peptide sequence of rat brain NO synthase. Furthermore, the relaxant response to an exogenous NO donor (sodium nitroprusside, SNP) was measured in vitro in muscle strips obtained from two patients with achalasia and in two non‐achalasic controls. NO synthase activity was detected in each of the samples obtained from six control patients (0.59 ±0.21 pmol mg‐1 min‐1; mean æ). By contrast, none of the samples obtained from the eight patients with achalasia had any detectable NO synthase activity. Immunohistochemical studies confirmed the presence of NO synthase in the myenteric plexus of the gastro‐oesophageal junction of control patients and its absence in achalasia. SNP relaxed muscle strips precontracted with bethanechol in both control samples and those from patients with achalasia. We suggest that the absence of NO synthase in the myenteric plexus of the gastro‐oesophageal junction explains the impaired function of the lower oesophageal sphincter in achalasia.

Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis.

Eicosanoids are modulators of defensive and inflammatory processes in the gut mucosa, and may be involved in the pathogenesis of chronic inflammatory lesions of the bowel. As omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower (source of omega-6) or cod liver (source of omega-3) oil on the development of chronic granulomatous lesions in the rat colon. After four weeks on the supplemented diets, plasma omega-6 fatty acid content was significantly higher in the sunflower group, while omega-3 fatty acids predominated in the cod liver group. Inflammatory colitis was then induced by intracolonic administration of trinitrobenzene sulphonic acid. Luminal eicosanoid release, as measured by radioimmunoassay of intracolonic dialysis fluid, increased significantly after the challenge in both groups. Generation of prostaglandin E2 (PGE2) and leucotriene B4 (LTB4) peaked by day 3 and thereafter declined; thromboxane B2 (TXB2), instead, continued to increase from day 3 to 20 in sunflower fed rats, whereas this change was blunted in cod liver animals. The rats were killed 20, 30, or 50 days after the induction of colitis, and the colonic lesions were scored macroscopically (adhesions to surrounding tissues, strictures, ulcerations, and wall thickness) and histologically (ulceration, inflammation, depth of the lesions, and fibrosis). In cod liver animals, the damage score was markedly reduced by day 30, and inflammation and ulceration were almost absent by day 50. In conclusion, a fish oil diet prevents the increase in thromboxane in the chronic state of inflammation and shortens the course of the colonic disease by diminishing both the severity of the lesions and their progression to chronicity.

Factors affecting health related quality of life of patients with inflammatory bowel disease

Using a disease specific instrument to measure the health related quality of life (HRQOL) of patients with inflammatory bowel disease (IBD), it has been shown that their perceived HRQOL worsens during active disease. The precise factors involved in HRQOL changes reported by these patients are largely unknown. Our aim was to elucidate which socio-demographic and health status variables are related with HRQOL in IBD patients. To this end, 354 patients with IBD were interviewed. To quantify the impairment in the HRQOL, the 36-item version of the inflammatory bowel disease questionnaire (IBDQ) was administered to all patients. To explore the relation of each individual variable on the HRQOL an univariate analysis by using the Spearman correlation, the Mann–Whitney or the Kruskal–Wallis test was performed when necessary. Factors significant at the univariate analysis were assessed using multiple linear regression modeling with global IBDQ score as the dependent factor. Results: Disease type did not predict IBDQ score in the univariate nor in the multivariate analysis. Consequently, statistical analysis was performed in the global group of 354 patients independently of the type of disease. Lower recurrence/year index, longer disease duration, higher level of education, symptom activity, male gender and non-necessity of hospitalization all predict a better HRQOL (p < 0.05). Factors which remained significant (p < 0.05) in the multiple regression modeling were gender, need of hospitalization, symptomatic activity, recurrence/year index and education level. Conclusions: Symptomatic activity and socio-demographic variables such as gender and education are the most important factors involved in the impairment of HRQOL in patients with IBD.

Influence of inflammatory bowel disease on different dimensions of quality of life.

Objective To establish the impairment of different dimensions of quality of life in inflammatory bowel disease (IBD). Design Prospective observational study. Participants 289 patients [160 with ulcerative colitis (UC) and 129 with Crohns disease (CD)]. Measures Health-related quality of life was assessed by means of the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Psychological General Well Being Index (PGWBI). Results In active IBD, all dimensions of the quality of life scored significantly lower than in inactive IBD, indicating a poor quality of life. Social impairment was the least impaired dimension of the IBDQ in active UC and CD, compared with digestive and systemic symptoms. In inactive IBD, the systemic symptoms domain received the lowest score (P < 0.01). In a subgroup of 22 patients studied before and after remission, emotional function was the most impaired dimension after achieving remission. The Psychological General Well Being Index was significantly impaired in active UC [78.5 (range 64–89)] and CD [76.5 (range 69–97)] relative inactive IBD [104 (range 93–111)] vs 106 (95–113), respectively;P < 0.05]. Conclusions Quality of life is impaired in IBD. During relapse, clinicians should pay attention to digestive symptoms and psychological distress. In remission, they should be sensitive to systemic symptoms.

Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin

Background Inulin and oligofructose promote selective growth of saccharolytic bacteria with low inflammatory potential.

Role of intestinal microflora in chronic inflammation and ulceration of the rat colon.

Bacteria and their products stimulate inflammatory responses. The effects of different antimicrobial regimens (amoxicillin/clavulanic acid, tobramycin, imipenem, vancomycin, metronidazole) were investigated on the course of experimental colitis induced by trinitrobenzenesulphonic acid (TNB) in the rat. On day 7 and 21 after the induction of colitis, matched groups of control and antibiotic treated rats were subjected to colonic dialysis to measure eicosanoid release, and killed for morphological assessment of the colonic lesions (macro and microscopic scores). Stool samples were cultured. Selective antibiotic treatment against Gram positive, Gram negative or anaerobic bacteria had no effect on colonic lesion scores. By contrast, certain broad spectrum antibiotics (amoxicillin/clavulanic acid or the association of imipenem plus vancomycin) significantly reduced macro and microscopic scores. Rats receiving these antibiotics did not develop chronic colitis as shown by the virtual absence of colonic strictures, adhesions, fibrosis, and granulomas. On day 21 after TNB, the intracolonic release of prostaglandin E2, thromboxane B2, and leukotriene B4 was significantly higher in control than in antibiotic treated rats. Control stool cultures showed abundant colony forming units of both aerobic and anaerobic bacteria. Amoxicillin/clavulanic acid and imipenem plus vancomycin induced appreciable reductions in luminal bacteria. In conclusion, certain broad spectrum antibiotics prevent chronic colitis. The normal colonic flora seems to play an important pathogenetic part in the progression of inflammatory colonic lesions to chronicity.

Outcome of patients with Ischemic colitis: Review of fifty-three cases

PURPOSE: Ischemic colitis is a disease of elderly patients and includes a wide clinical spectrum ranging from mild to severe forms. Some patients may develop complications. Management of this disorder depends on disease severity. Our aim was to review the clinical characteristics of patients diagnosed of ischemic colitis and analyze predictive factors of poor prognosis. METHODS: This study is a retrospective analysis of 53 cases of ischemic colitis (33 men, 20 women), 35 with moderate and 18 with severe forms, respectively. Clinical characteristics, diagnostic procedures, segment of colon involved and long-term evolution after discharge were analyzed. RESULTS: Hypertension (51 percent) was the main risk factor associated with ischemic colitis. Clinical presentation did not differ between groups, except for peritonitis which was present only in the severe group. Colonoscopy and histologic studies were the most used diagnostic procedures (90 percent). Peripheral vasculopathy (P < 0.01) and right colonic involvement (P < 0.001) were risk factors for severe outcome. Five patients died during admission. Among these, the right colon was affected in four (80 percent). No patient in either group developed chronic ischemic colitis during follow-up. CONCLUSION: Ischemic colitis usually runs a benign course after acute colonic insult. Peripheral vasculopathy and right colonic involvement are associated with severe forms of ischemic colitis.

Validation of the Spanish Version of the Inflammatory Bowel Disease Questionnaire on Ulcerative Colitis and Crohn’s Disease

The objective of this study is to validate the Spanish translation of the Inflammatory Bowel Disease Questionnaire (SIBDQ) on ulcerative colitis and Crohn’s disease by assessing its convergence validity, discriminatory power, reliability and sensitivity to change. For that purpose, 211 patients with inflammatory bowel disease (116 with ulcerative colitis and 95 with Crohn’s disease) completed the SIBDQ, the Psychological General Well-Being Index and the EuroQol. SIBDQ was repeated in those patients who remained in stable remission and in those with changes in clinical activity. Clinical activity was assessed by the Rachmilewitz and Harvey-Bradshaw indices. Correlations among scores of SIBDQ, EuroQol, Psychological General Well-Being Index and clinical indices of activity were all positive and comparable for both diseases (r = –0.50 to r = –0.70, p < 0.01). Analysis of variance showed that SIBDQ discriminates between different clinical degrees of activity. Cronbach’s α was 0.96 in ulcerative colitis and Crohn’s disease. SIBDQ was also highly reliable when it was repeated in clinically stable patients with ulcerative colitis (intraclass correlation coefficient = 0.82) and Crohn’s disease (intraclass correlation coefficient = 0.86). SIBDQ was sensitive to clinical changes in ulcerative colitis and in Crohn’s disease, whether patients entered remission (effect size –1.88 and –1.81, respectively) or relapsed (effect size 1.70 and 8.04, respectively). In conclusion, the Spanish version of the IBDQ has proven to be a valid, reliable and sensitive instrument to detect clinical changes in patients with ulcerative colitis and Crohn’s disease.

Impact of surgery for Crohn's Disease on health-related quality of life

OBJECTIVE:When patients with Crohns disease (CD) express concerns about their disease, they emphasize worries about surgery. However, most studies about the impact of surgery in CD on health-related quality of life (HRQOL) have compared postsurgical changes on HRQOL relative to HRQOL before surgery, not taking into account the influence of CD activity on HRQOL. Our aim was to assess whether surgical treatment of CD modifies HRQOL, compared with inactive CD, active CD, or healthy controls.METHODS:Outcomes of 29 CD patients in remission with a previous bowel resection were compared with those from 42 clinically active CD patients and 48 patients with medically induced remission. A reference control group of 63 healthy individuals was also studied. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ), the Psychological General Well Being Index (PGWBI), and the EuroQol.RESULTS:Active CD patients scored the lowest on the IBDQ. Both operated and nonoperated inactive CD patients had lower HRQOL scores than controls in overall IBDQ and in all five domains. However, neither global score, digestive, systemic, emotional, social, or functional dimensions differed significantly between operated and nonoperated inactive CD patients. PGWBI and the visual analog scale of the EuroQol were also similar in both groups of inactive CD patients (103 [range, 94–107] vs 103 [97–106] and 90 [73–87] vs 82 [76–84]), but significantly higher than in active CD.CONCLUSIONS:HRQOL is impaired in active CD, and improves during remission irrespective of whether it had been achieved medically or surgically. Our results suggest that to improve HRQOL it is more important to achieve remission than the approach, drugs or surgery, chosen.

Effects of smoking on the presentation and clinical course of inflammatory bowel disease

Objective: To evaluate the influence of regular smoking on the presentation and clinical course of inflammatory bowel disease. Methods: We performed a case‐control study interviewing 160 inflammatory bowel disease patients (63 with Crohns disease (CD) and 97 with ulcerative colitis (UC)) and 140 first‐degree relatives as controls. The risk of developing the disease relative to a smoking habit was calculated as the odds ratio. Furthermore, to evaluate the influence of smoking on the subsequent course of inflammatory bowel disease, we performed a multivariate analysis that included pertinent variables such as the need for surgery, number of hospitalizations and relapses. Results: The pattern of smoking in UC patients was different from that in CD patients. In UC there was a significant predominance of non‐smokers and ex‐smokers (P = 0.02), whereas smoking habits in CD were not different from those in controls. Giving up smoking was a risk factor to develop UC (odds ratio: 3.2, P=0.02). In UC, non‐smokers and specially ex‐smokers need surgery more frequently than smokers (P <0.01). Otherwise the relapse/year index was not influenced by smoking. In CD there was a non‐significant association between smoking habits and the various clinical parameters analysed. UC patients who begin smoking after diagnosis of the disease present a significant reduction in the number of recurrences. Conclusion: Smoking habit significantly affects the presentation and clinical course of UC, whereas in CD, a smoking habit does not have any apparent influence on the disease.