Anne B. Ballinger

Symptom relief and quality of life after stenting for malignant bile duct obstruction.

Palliative treatment is appropriate for most patients with cancer of the head of pancreas. Insertion of a biliary stent relieves jaundice and pruritus but it is not known if stenting affects other symptoms or changes the quality of life. Nineteen patients have completed a standard questionnaire to assess symptom relief and quality of life after stent insertion. After stenting there was complete relief of jaundice and pruritus. Furthermore, there was also considerable improvement in anorexia and indigestion. All patients had anorexia before stent insertion, this was moderate/severe in 13 (68.4%). Anorexia was significantly better (p < 0.01) a week after stenting and this benefit was maintained at 12 weeks (p < 0.01). Sixteen (84.2%) patients complained of indigestion before stenting, moderate/severe in 11 (57.9%). This was significantly better (p < 0.01) a week after stenting with complete relief in six at eight weeks (p < 0.01). Fifteen (78.9%) felt that their mood was good/very good before stent insertion and this was unchanged even at the 12 week assessment. A similar result was obtained for physical health and level of activity. In conclusion stent insertion not only relieves jaundice and pruritus in these patients but also improves other symptoms and quality of life. The considerable improvement in appetite after stenting was of particular benefit.

Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis

BACKGROUND Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known. AIMS To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis. METHODS Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation). RESULTS Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44–60%. CONCLUSIONS It seems likely that approximately 30–40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.

Delayed puberty associated with inflammatory bowel disease

Delayed puberty frequently complicates the clinical course of young patients with inflammatory bowel disease, more often in Crohns disease than ulcerative colitis. Undernutrition has been thought to be the main reason for delayed puberty in these patients. However, puberty may be delayed despite a normal nutritional status. Observations in patients with inflammatory bowel disease and in rats with experimental colitis suggest that inflammatory mediators may have a direct adverse influence, independent of undernutrition, on the onset and progression of puberty. Serum androgens are consistently reported to be reduced in patients with delayed puberty and inflammatory bowel disease. This reduction is not necessarily secondary to a reduction in gonadotrophins as serum concentrations of gonadotrophins have been reported to be normal or even increased in some studies. Management of delayed puberty involves calorie supplements to correct undernutrition and treatment of inflammation. Observations in boys with delayed puberty and controlled studies in experimental models of intestinal inflammation suggest that testosterone therapy can accelerate puberty.

Adult height in patients with early onset of Crohn's disease

We read with great interest the recently published guidelines on the management of osteoporosis associated with chronic liver disease (Gut 2002;50(suppl I):i1–9). However, we would like to add a few words of comment. Associations between coeliac disease (CD) and primary biliary cirrhosis in particular and other autoimmune liver diseases in general have been reported. In addition, it has been suggested that these individuals should be considered as an at risk group for whom serological testing for CD is indicated. Patients with CD are at high risk of developing low bone mineral density and bone turnover impairment, and it has been shown that adherence to a gluten free diet has a significant positive impact on these parameters. Thus we suggest that physicians caring for patients with the above mentioned liver diseases should screen them for CD in the presence of signs and symptoms suggestive of malabsorption such as osteoporosis. This seems a reasonable strategy as detection of CD will allow for a more rational therapeutic approach to the risks determined by this association. Complications due to the presence of CD, such as malnutrition, anaemia, and osteoporosis, may have a considerable impact on liver disease management and the need/success of transplantation. 6

Fundamental Mechanisms of Growth Failure in Inflammatory Bowel Disease

Growth failure is common in children with inflammatory bowel disease (IBD) and has been attributed chiefly to undernutrition. Liquid enteral feeding can reverse the calorie deficit and increase growth velocity. The inflammatory process per se may also directly inhibit linear growth. After institution of enteral nutrition, significant changes in serum growth factors and inflammatory indices have been observed before any changes in nutritional parameters [Bannerjee et al., Gastroenterology 2000;118:A526]. In rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, about 60% of the final growth impairment can be attributed to undernutrition, inflammation accounting for the remaining growth deficit. Young patients with Crohn’s disease and growth failure have normal stimulated and spontaneous growth hormone (GH) secretion and reduced plasma concentrations of insulin-like growth factor-1 (IGF-I), suggesting a degree of GH resistance. Rats with TNBS colitis also have normal plasma GH and reduced IGF-I concentrations, mediated by a combination of undernutrition and active inflammation. Immunoneutralization of interleukin-6 (IL-6) increases hepatic IGF-I mRNA expression, plasma concentrations of IGF-I and linear growth. In contrast, administration of anti-tumour necrosis factor-α antibodies (TNF-ab) had no effect on IGF-I in this model. TNFab did, however, increase linear growth, suggesting inhibitory effects of TNF-α on the growth axis by mechanisms other than reduction in IGF-I. Preliminary data suggests that TNF-α inhibits maturation of growth plate chondrocytes. We have identified IL-6 receptors on growth plate chondrocytes but to date have not identified the effect, if any, of IL-6 directly at the growth plate.

Is intervention necessary after a first episode of acute idiopathic pancreatitis

Acute idiopathic pancreatitis is a term used when no underlying cause has been identified on routine investigation. However, more specialised investigations may identify aetiological factors, biliary sludge and sphincter of Oddi dysfunction for example, in 38-72% of patients with recurrent episodes. Treatment of these abnormalities may prevent further episodes of pancreatitis. The aim of this study was to follow up and determine the outcome in patients with a first episode of idiopathic pancreatitis, and thus determine the need for further investigation and treatment in this group of patients. Thirty one patients with a single episode of idiopathic pancreatitis were studied who had no specialised investigations or specific treatment. During a median follow up of 36 months only one patient has had recurrent pancreatitis. Two patients experienced a single episode of unexplained abdominal pain; serum amylase, liver biochemistry, and abdominal ultrasound were all normal and the pain resolved within 48 hours. In conclusion, in the medium term, the prognosis is good after a first episode of idiopathic pancreatitis and specialised investigation is unnecessary.

The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis

BACKGROUND & AIMS Experimental colitis is associated with anorexia that is attenuated by treatment with an interleukin (IL)-1 receptor antagonist. Serotonin (5-hydroxytryptamine [5-HT]) is a potent inhibitor of feeding, and its release from the hypothalamus is stimulated by IL-1. We have tested the hypotheses that anorexia associated with experimental colitis results from increased activity of hypothalamic 5-HT neurons and that the increase in activity occurs secondary to an increase in availability of tryptophan, the precursor of 5-HT. METHODS In vivo 5-HT release and regional hypothalamic 5-HT and tryptophan concentrations were measured in rats with 2,4,6,-trinitrobenzene sulfonic acid (TNBS)-induced colitis, healthy controls, and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after depletion of brain 5-HT by p-chlorophenylalanine (PCPA). RESULTS In the colitic group, release of 5-HT from the hypothalamic paraventricular nucleus (PVN) was 3-fold (P = 0.01) and 14-fold (P < 0.001) higher than in control and pair-fed groups, respectively. Concentrations of tryptophan were similar in each group in all hypothalamic regions. Food intake was significantly increased in the colitic group after PCPA treatment but was not restored to control values. CONCLUSIONS In animals with TNBS-induced colitis, 5-HT release from the PVN is increased. The increase in food intake after depletion of brain 5-HT suggests that hypothalamic 5-HT contributes to anorexia but is not the only mediator. Increased 5-HT release in the colitic group was not driven by increased precursor availability.

Anorexia in a rat model of colitis: interaction of interleukin-1 and hypothalamic serotonin

BACKGROUND AND AIMS Anorexia induced by experimental colitis in rats is mediated, in part, by increased release of serotonin (5-HT) from the hypothalamic paraventricular nucleus (PVN). In this model, anorexia is attenuated by treatment with an interleukin-1 (IL)-1 receptor antagonist (ra). However, a functional link between central IL-1 receptors and 5-HT release remains unproven. We have tested the hypothesis that anorexia associated with experimental colitis is mediated by IL-1 induced release of 5-HT. METHODS In vivo 5-HT release in the PVN was measured in rats with 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis, treated with intracerebroventricular infusion of IL-1ra or vehicle treated controls. The effect of inhibition of tumour necrosis factor-alpha on food intake and PVN 5-HT release in TNBS-colitis was also tested. RESULTS In rats with TNBS-induced colitis, intracerebroventricular infusion of IL-1ra resulted in a 18-fold reduction in PVN 5-HT release compared to vehicle-treated controls. This was associated with a significant increase in food intake in IL-1ra treated rats. In contrast intracerebroventricular administration of anti-tumour necrosis factor antibodies had no effect on either PVN 5-HT release or food intake in rats with TNBS-induced colitis. CONCLUSIONS In animals with TNBS-colitis, anorexia is mediated, in part, by the stimulatory effect of IL-1 on medial hypothalamic 5-HT.

Endothelin in human inflammatory bowel disease: comparison to rat trinitrobenzenesulphonic acid-induced colitis

There have been suggestions that endothelins (ET-1, ET-2, ET-3) are involved in the pathogenesis of human inflammatory bowel disease (IBD). Furthermore, the non-selective endothelin receptor antagonist, bosentan, ameliorates colonic inflammation in TNBS colitis in rats. However, no studies have measured the tissue expression and release of endothelins in human IBD in direct comparison to experimental TNBS colitis. Mucosal biopsies were obtained from 114 patients (42 Crohns colitis, 35 ulcerative colitis and 37 normal) and compared to whole colonic segments from rats with TNBS colitis. ET-1/2 levels were reduced in human IBD but greatly increased in experimental TNBS colitis. RT-PCR indicated ET-2 was the predominant endothelin isoform in human IBD whereas ET-1 prevailed in the TNBS model. No associations were found between human IBD and tissue expression, content or release of ET-1/2. Our study shows, therefore, that unlike TNBS colitis in rats, in which ET-1/2 levels are greatly elevated and ET receptor antagonists are efficacious, there is no significant link between endothelins and human IBD.

COX-2 inhibitors vs. NSAIDs in gastrointestinal damage and prevention

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit production of protective gastric mucosal prostaglandins and also have a direct topical irritant effect. In some patients this results in dyspepsia and development of gastroduodenal erosions and ulceration. The risk of ulcer complications, such as bleeding, perforation and death is increased approximately 4-fold in NSAID users. Patients at high risk of ulcer complications include the elderly, those taking anticoagulants, steroids and aspirin, those with a previous history of peptic ulceration and patients with concomitant serious medical problems. The interaction of NSAIDs with Helicobacter pylori (the major cause of peptic ulceration in non-NSAID users) is controversial and some studies suggest that H. pylori infection may even protect against NSAID-induced ulceration. Selective inhibitors of the inducible cyclooxygenase-2 (COX-2) enzyme spare COX-1 in the gastric mucosa and, hence, do not inhibit production of mucosal prostaglandins. COX-2-selective inhibitors are associated with a significant reduction in gastroduodenal damage compared with traditional NSAIDs. Proton pump inhibitors (PPI) are probably the best agents for healing and prevention of NSAID-induced ulcers. Preliminary studies suggest that COX-2 selective inhibitors, like traditional NSAIDs, may prevent lower gastrointestinal cancer. Further studies are needed but they may be useful in individuals at high risk of certain types of lower gastrointestinal malignancy with increased gastrointestinal tolerability and safety.