Camilleri, Michael

AbstractPurposeThe objective was to review the genetics of human visceral pain with particular emphasis on pain associated with irritable bowel syndrome.BackgroundThe biomarkers most commonly employed in identifying visceral hypersensitivity are sensation ratings and thresholds or brain imaging during viscus (e.g., rectal) distension. Genetic studies suggest that variation in the control of candidate genes involved in ion channel function, neurotransmitter synthesis, reuptake or receptor functions, and inflammatory disease susceptibility loci may impact variations in prevalence of the symptom phenotype of abdominal pain or IBS, or quantitative traits (intermediate phenotypes) of rectal sensation. The candidate genes include SLC6A4, CNR1, and TNFSF15 reflecting serotonin reuptake, cannabinoid receptors, and inflammatory‐barrier functions. However, other than TNFSF15, the other candidate genes are only univariately associated with pain, IBS symptom complex, or quantitative traits of sensation. These data have generated hypotheses and present opportunities for study of mechanisms and treatment of visceral pain in humans, which remains an unmet clinical need in patients with IBS and functional abdominal pain.

Summary Background Daikenchuto, a Japanese herbal medicine used for post‐operative ileus and constipation, dose dependently stimulates gastrointestinal ( GI ) motility and decreases rectal compliance and sensation. Effects of TU ‐100 (commercial form of daikenchuto) in adults with constipation are unknown. Aim To compare the effects of oral TU ‐100, 2.5 g t.d.s. or 5 g t.d.s. and placebo t.d.s. on GI and colonic transit ( CT ), rectal compliance ( RC ) and sensation thresholds ( RST ), anal sphincter pressures ( ASP ) and bowel function in female patients with functional constipation ( FC ). Methods We conducted a single‐centre, randomised, parallel‐group, double‐blind, pharmacodynamic study; 45 female patients with FC without evidence of rectal evacuation disorder were assigned to 28 days' treatment with oral placebo or TU ‐100 (Tsumura USA, Princeton, NJ, USA). Demographic data and CT were measured at baseline and randomisation stratified by baseline CT (GC> or <1.9) and by BMI (<25 or ≥25 kg/m 2 ). At the end of treatment period, we measured GI and CT by scintigraphy, RST and RC by barostat, ASP by manometry, psychosensory sensations, bowel function by daily diary and quality of life ( QOL ). The study had power to detect effect sizes of 33% ( CT ), 40% ( RC ) and 46% ( RST ). Statistical analysis included BMI as covariate. Results TU ‐100 had no significant effects on GI or CT , RC , ASP , recto‐anal pressure difference, or RST . The 5 g t.d.s./day dose was associated with lower RST for first sensation and gas (unadjusted P : 0.045 and 0.024 respectively). There were no treatment effects on psychosensory symptoms, stool frequency, stool consistency or QOL . Conclusion Mechanisms underlying the observed clinical benefit of TU ‐100 remain unclear ( ClinicalTrials.gov NCT01139216).

BackgroundPrucalopride is a selective, high‐affinity, 5‐hydroxytryptamine (serotonin) type 4 (5‐HT4) receptor agonist with gastrointestinal prokinetic activities. This integrated analysis of data from three double‐blind phase III trials (ClinicalTrials.gov: NCT00488137, NCT00483886, NCT00485940) compared the efficacy and safety of prucalopride 2 mg once daily in women with chronic constipation [≤2 spontaneous complete bowel movements (SCBM) per week] in whom laxatives had failed to provide adequate relief with that in the all‐patient (AP) population of men and women with chronic constipation who had or had not obtained relief from laxatives.MethodsPatients received prucalopride 2 mg or placebo once‐daily for 12 weeks. Efficacy endpoints included an average of ≥3 SCBM/week and average increases of ≥1 SCBM/week and ≥1 SBM/week over this period. A response on any of these three endpoints was considered to be clinically relevant, and an overall response rate was derived for patients satisfying any of these endpoints.ResultsOf the AP population (n = 1318), 936 were women in whom laxatives had failed to provide adequate relief (WLF). More patients on prucalopride 2 mg than placebo had an average of ≥3 SCBM/week (AP 24.4 vs 11.0%; WLF 24.7 vs 9.2%), an average increase of ≥1 SCBM/week (AP 43.5 vs 24.8%; WLF 44.2 vs 22.6%), and an average increase of ≥1 SBM/week (AP 66.7 vs 38.4%; WLF 68.3 vs 37.0%) (all p < 0.001). Significant differences from placebo were evident in week 1 and sustained thereafter. Overall response rates in the AP and WLF populations, respectively, were 69.7 and 71.0% with prucalopride 2 mg and 44.5 and 41.6% with placebo (p < 0.001). Early (weeks 1–4) response predicted ultimate response over time. Common (>10%) adverse events were abdominal pain, nausea, diarrhoea, and headache.ConclusionsPrucalopride 2 mg once daily is effective in WLF. The efficacy and safety profile observed in WLF was similar to that in the total evaluated population of patients with chronic constipation who had or had not obtained adequate relief from laxatives.

AbstractBackgroundNon‐invasive single photon emission computed tomography (SPECT) has been validated as a test for postprandial gastric volume accommodation, with volumes measured twice over 30 min and averaged. The purpose of this study is to simplify the SPECT measurement of gastric accommodation.MethodsThe primary aim of this study was to compare two postprandial gastric volume measurements with data collected retrospectively from 443 patients and healthy volunteers who had undergone SPECT in the last decade. The differences in the two gastric volumes were compared in the entire group and each subgroup, and the correlation between the two measurements and their differences across a wide range of gastric volumes were plotted.Key ResultsThere was a median difference of <2% (P = 0.041) between postprandial scan 1 (757 mL) and scan 2 (743 mL), with significant correlation (rs = 0.859, P < 0.01) and excellent agreement (SD 60 mL) between the two scans across the entire range of observed postprandial gastric volumes.Conclusions & InferencesA single postprandial scan can detect gastric accommodation with the same accuracy as averaging two postprandial scans. These data support simplifying SPECT measurement of postprandial gastric volume with a scan in the first 15 min after a meal.

Abstract Background There is little information regarding gender‐specific measurements of colonic transit and anorectal function in patients with defecation disorders ( DD ). To compare overall colonic transit by gender in DD . Methods In 407 patients with constipation due to DD diagnosed by a single gastroenterologist (1994–2012), DD was characterized by anorectal manometry, balloon expulsion test, and colonic transit by scintigraphy. The primary endpoint was overall colonic transit (geometric center, GC ) at 24 h ( GC 24). Effects of gender in DD on colonic transit, and comparison with transit in 208 healthy controls were assessed by Mann–Whitney rank sum test. Secondary endpoints were maximum anal resting ( ARP ) and squeeze ( ASP ) pressures. We also tested association of the physiological endpoints among DD females by pregnancy history and among DD patients by colectomy history. Key Results The DD patients were 67 males (M) and 340 females (F). Significant differences by gender in DD patients were observed in GC 24 (median: M: 2.2; F: 1.8; P = 0.01), ARP (median: M: 87.8 mmHg; F: 82.4 mmHg; P = 0.04), and ASP (median: M: 182.4 mmHg; F: 128.7 mmHg; P < 0.001). GC 24 was slower in DD compared with same‐gender healthy controls. GC 24 did not differ among DD females by pregnancy history. Anorectal functions and upper GI transit did not differ among DD patients by colectomy history. Conclusions & Inferences Patients with DD have slower colonic transit compared with gender‐matched controls. Among DD patients, males have higher ARP and ASP , and females have slower colonic transit. Although the clinical significance of these differences may be unclear, findings suggest that interpretation of these tests in suspected DD should be based on same‐gender control data.

Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small bowel and colonic transit were measured by scintigraphy, rectal sensation by isobaric distensions. Associations with genotype were assessed by χ2test (symptom phenotype) and ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ2P = 0.028). There was significant association of CNR1 rs806378 ( P = 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas ( P = 0.025), but not pain; the strongest associations for gas ratings were in IBS-D ( P = 0.002) and IBS-alternating ( P = 0.025) subgroups. For CNR1 (AAT)n, gene-by-phenotype interactions were observed for colonic transit at 24 ( P = 0.06) and 48 h ( P = 0.002) and gas ( P = 0.046, highest for IBS-D, P = 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.

Background Inherent to some immunobullous disorders is potential for intraepidermal or dermal–epidermal junction fragility, a phenomenon that may compromise biopsy specimen integrity and direct immunofluorescence (DIF) interpretation. In these situations, cutaneous adnexal structures (e.g. hair follicles, sweat apparatus) usually remain intact. Whether periadnexal DIF findings are reliable in diagnosing immunobullous conditions is unknown. Methods We evaluated 56 cutaneous specimens with diagnostic immunoglobulin (Ig) deposition patterns that contained adnexal structures. In a corollary study, we examined 145 hematoxylin‐eosin‐stained frozen specimens to determine biopsy factors associated with the presence of adnexal structures. Results Periadnexal DIF findings offered diagnostic sensitivity in conditions with linear or cell‐surface Ig deposition or lupus band. Periadnexal DIF findings were unreliable in dermatitis herpetiformis. Biopsy specimens from scalp and genitalia were most likely to contain folliculosebaceous units and sweat duct apparatus, respectively. Relative depth of biopsy correlated directly with the likelihood of identifying sweat duct apparatus but not folliculosebaceous units. Conclusions Periadnexal DIF findings may add diagnostic sensitivity in DIF evaluation of pemphigoid, pemphigus and lupus erythematosus. Pathologists can guide clinicians to biopsy certain anatomic sites and to obtain sufficient biopsy depth to increase the probability of capturing adnexal structures and, therefore, diagnostic yield from DIF specimens.

Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability ( P < 0.001), a borderline increase in colonic permeability ( P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.