This Month in Gastroenterology

Abstract

Low-dose tricyclic antidepressants are a well-established treatment modality for adult patients with functional gastrointestinal disorders (FGIDs), such as the irritable bowel syndrome, functional dyspepsia, or functional heartburn. FGIDs are among the most common causes for medical consultation in children as well. It is unclear whether, similar to adult patients with FGIDs, tricyclic antidepressants are effective in these children. In this issue of Gastroenterology, Saps et al report on a prospective, multicenter, randomized clinical trial that evaluated the efficacy of amitriptyline, a tricyclic agent, for pain relief in children with pain-predominant FGIDs. Children between the ages of 8 and 17 with a diagnosis of functional abdominal pain, functional dyspepsia, or the irritable bowel syndrome according to the Rome II criteria were recruited from the pediatric gastroenterology clinics of 6 tertiary care centers in the United States. After a 1-week baseline observation period, a 4-week treatment of amitriptyline (10 mg/kg per day in those weighing <35 kg; 20 mg/kg per day in those weighing >35 kg) or placebo was given in a randomized, double-blind fashion. Symptoms were recorded on a daily basis by age-appropriate validated questions and a pain scale. A number of psychologic questionnaires, including depression and anxiety scales, were completed at the start and the end of the study. The primary efficacy variable was the patient's overall assessment of satisfactory relief and satisfaction with treatment over the 4-week treatment period. A total of 90 children (mean age, 12.7 years; 73% girls) were recruited, of whom 46 were allocated to the amitriptyline group and 44 to the placebo group. Changes in pain scores did not differ between placebo and amitriptyline during the treatment period (Figure 1). No differences between the groups were found in overall assessment of satisfactory relief and satisfaction with treatment. In both groups, a significant improvement occurred in depression, coping, disability, and somatization scales during the study, regardless of the treatment arm. There was significant improvement in anxiety scores in the amitriptyline group, but not in the placebo group. This study did not show any benefit of amitriptyline over placebo in pediatric pain-predominant FGIDs. The results do not support routine use of tricyclic agents in these patients, although they could still be considered, especially when anxiety levels are high. The high placebo effect found in the study supports the importance of a positive and caring therapeutic alliance between physicians, patients, and families when managing children with FGIDs. Seepage 1261. Hereditary hemochromatosis (HH) is an autosomal-recessive disease characterized by excessive iron uptake and overload in multiple organs. HH is caused by mutations in the HFE gene, but only a subgroup of subjects who are homozygous for the mutation (genotypic HH) develop clinical signs (phenotypic HH). In subjects with phenotypic HH, increased morbidity and mortality from cirrhosis, liver cancer, diabetes mellitus, cardiomyopathy, and arthritis have been reported. Indeed, iron overload and increased iron-catalyzed free radicals may be involved in atherosclerosis, neurodegenerative disease, carcinogenesis, and anti-infectious host defense. There is also evidence of increased iron levels in individuals that are heterozygous for the HFE, and in first-degree relatives of subjects with HH. Whether this is associated with increased mortality has not been established. In this issue of Gastroenterology, Elmberg et al report on a Swedish population-based study cohort study of first-degree relatives of patients diagnosed with HH. Using a national health register, the authors identified a cohort of 3832 HH patients >15 years old and diagnosed between 1964 and 2005. For each patient identified in the registers, 10 controls matched for gender, date of birth, county of residence, and marital status (total n = 38,969) were selected from the population register. In addition, a total of 14,496 first-degree relatives of HH patients and 157,845 first-degree relatives of controls were identified. From the same register, spouses were identified and included in the study as nonbiological referents, sharing the same environment as the patients. Information on death, vital status, and emigration for these cohorts were obtained from the Swedish population register through 2007. Compared with controls, HH patients had a significantly higher mortality during the follow-period (relative risk [RR], 2.15; 95% confidence interval [CI], 2.00–2.31) (Figure 2). Mortality in HH patients was particularly elevated during the first year of follow-up after hospital discharge with a diagnosis of HH. Mortality was only marginally increased in first-degree relatives of patients with HH compared with first-degree relatives of controls (RR, 1.05; 95% CI, 1.01–1.10). There was no difference in mortality between spouses and biological relatives of patients. A total of 1059 first-degree relatives also occurred in the cohort of patients with HH. In these, mortality was not significantly increased (RR, 1.08; 95% CI, 0.85–1.36). Mortality tended to be lower in subsequent family cases compared with the index case. This cohort study confirms greater mortality in patients hospitalized with HH, but did not find a significant increase in mortality among first-degree relatives of HH patients. Furthermore, HH patients with a family history of HH do not necessarily have an increased risk of death, further supporting the hypothesis that genetic influences other than HFE, and possibly also exogenous factors, affect the clinical phenotype. It is common practice to screen first-degree relatives of HH patients for increased iron load and/or HH genotype. The present paper suggests that unselected intervention against iron overload in these individuals may not be beneficial from the perspective of mortality at population level. Seepage 1301. Helicobacter pylori infection is associated with gastric tumorigenesis, but only a minority of persons colonized with the bacterium develop cancer, suggesting that other items like genetic and environmental factors modify or exacerbate H pylori-induced gastric cancer development. Dietary carcinogens such as nitrosamines are 1 environmental factor associated with increased risk for gastric cancer, and it is possible that this association could be due to synergism with H pylori infection, but this has not been studied directly. In the study by Liu et al, 23 Rhesus monkeys were examined at 3-month intervals over 5 years after chronic infection with H pylori (strain USU101 from a patient with gastric adenocarcinoma), treatment with the nitrosating compound ethyl-nitro-nitrosoguanidine (ENNG), or the combination of H pylori infection and ENNG treatment, and examined by endoscopy and mucosal biopsy. Control animals had normal endoscopy throughout the entire 5-year observation, but starting at 1 year after infection, some biopsies from H pylori-infected monkeys and combined H pylori/ENNG monkeys showed evidence for gastropathy. More significantly, starting at 2 years postinfection, only combined H pylori/ENNG monkeys demonstrated intestinal-type gastric metaplasia, followed by visible telangiectasias after 3 years and by 5 years, 3 monkeys developed polypoid lesions with high-grade intraglandular neoplasia (Figure 3). Gene expression profiles, including those of interleukin (IL)-1β and IL-8, remained persistently elevated in monkeys that were H pylori-infected only; global gene expression profiles of 18,000 Rhesus monkey genes demonstrate a unique signature within combined H pylori/ENNG monkey biopsies with more affected cancer-associated genes than any other group, suggesting synergism between the bacterium and the nitrosating compound, and this neoplastic profile was present in non-neoplastic mucosa indicating the changes precede histologic cancer. The study indicates that synergism is present and necessary between chronic H pylori infection and the intake of nitrosating compounds (typically found in East Asian foods) to form precancerous lesions and carcinoma of the stomach. Neither H pylori or nitrosating compounds alone were sufficient for gastric neoplasia, suggesting that screening for this combination and preventing synergism could be one strategy to reduce gastric cancer formation. Seepage 1367. Irritable bowel syndrome (IBS) is a common gastrointestinal condition causing abdominal pain and/or bloating and altered bowel habits without any clear etiology, and may have local as well as central nervous system cause and effect. There is evidence that released local mucosal mediators can alter signaling within epithelial cells in patients with IBS, but there has been no prior study regarding these mediators on enteric neurons in the submucosal plexus, which are in very close proximity to mucosa cells. In the study by Buhner et al, supernatants made from mucosal biopsies from 11 IBS patients with active symptoms (7 diarrhea-predominant and 4 constipation-predominant) as well as 5 non-IBS controls were applied to enteric neurons from the submucosal plexus taken from macroscopically normal regions of fresh colectomy specimens from 76 patients (and comprising 137 ganglia containing 1207 neurons), and subsequent action potentials (AP) recorded. IBS supernatants, but not normal controls, evoked a fast-onset discharge of AP in enteric neurons, without regard to the type of IBS based on Rome criteria (Figure 4), and did not quench with repeated supernatant applications over time. Utilizing pharmacologic inhibitors to serotonin (72% reduction in spike discharge), histamine (77% reduction), and serine proteases (100% reduction) indicated all 3 of these mediators are involved in inducing AP, with the proteases predominating. Mucosal biopsies from IBS patients revealed higher levels of mast cells, and supernatants contained higher amounts of proteases and histamine (but not serotonin) compared with controls that correlated with the frequency of AP, and proteases correlating with the percentage of responding enteric neurons. This study indicates that mucosal mediators from IBS patients, particularly proteases, can excite submucosal plexus neurons, which may play a role in the pathobiology of IBS. Seepage 1425. Multicenter, Randomized, Placebo-Controlled Trial of Amitriptyline in Children With Functional Gastrointestinal DisordersGastroenterologyVol. 137Issue 4PreviewThere are no prospective, multicenter, double-blind, placebo-controlled, randomized pharmacologic trials for the treatment of pain-predominant functional gastrointestinal disorders in children. The aim of this study was to evaluate the efficacy of amitriptyline in children with pain-predominant functional gastrointestinal disorders. Full-Text PDF Increased Mortality Risk in Patients With Phenotypic Hereditary Hemochromatosis But Not in Their First-Degree RelativesGastroenterologyVol. 137Issue 4PreviewHereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. Full-Text PDF Diet Synergistically Affects Helicobacter pylori–Induced Gastric Carcinogenesis in Nonhuman PrimatesGastroenterologyVol. 137Issue 4PreviewGastric cancer results from a combination of Helicobacter pylori (H pylori) infection, exposure to dietary carcinogens, and predisposing genetic make-up. Because the role of these factors in gastric carcinogenesis cannot be determined readily in human beings, the present study examined the role of an oral carcinogen and H pylori infection in rhesus monkeys. Full-Text PDF Activation of Human Enteric Neurons by Supernatants of Colonic Biopsy Specimens From Patients With Irritable Bowel SyndromeGastroenterologyVol. 137Issue 4PreviewPathological features in irritable bowel syndrome (IBS) include alterations in mucosal cell content and mediator release that might alter signaling to nearby submucosal neurons. Full-Text PDF