Familial intestinal degenerative neuropathy associated with chronic intestinal pseudo‐obstruction

Background Few families with autosomal dominant forms of chronic idiopathic pseudo‐obstruction (CIP) have been identified and reported. Methods We compared two families by clinical, laboratory, histopathologic, and genealogical investigations. Ten patients (pts) (five women) from two families, A and B, both with a family history suggesting autosomal dominant CIP, were investigated. Key Results All pts had chronic diarrhea, nine of ten pts had chronic abdominal pain and seven of ten chronic vomiting. Median age for onset of symptoms was 23 (A) and 34 years (B). None had dysphagia, urogenital, neurologic, or ocular symptoms. Small bowel transit and jejunal culture were abnormal in eight of nine. Manometry showed severe jejunal hypomotility in the fasting and fed state and absence of normal phase III in all nine pts and neuropathy‐like duodenal alterations in eight of nine. Progress to overt CIP had occurred in six pts. Histopathologic re‐evaluation (three pts) showed that criteria of visceral degenerative neuropathy were fulfilled in both families including intranuclear inclusions in all three pts. Genealogic exploration using the unique Swedish Register for Catechetical Meetings disclosed that the two families with all likelihood shared a male ancestor in the 1890s. Conclusions & Inferences The compiled results with striking similarities between family A and B together with genealogy findings indicate that this is one, large kindred with a familial autosomal dominant form of intestinal degenerative neuropathy often progressing to CIP but without extra‐intestinal manifestations. This is the fourth and, so far, the largest family reported with these characteristics.     

Normal oxidative phosphorylation in intestinal smooth muscle of childhood chronic intestinal pseudo‐obstruction

Background Chronic intestinal pseudo‐obstruction (CIPO) is a severe disease of the digestive tract motility. In pediatric population, CIPO remains of unknown origin for most patients. Chronic intestinal pseudo‐obstruction is also a common feature in the course of mitochondrial oxidative phosphorylation disorders related for some patients to mutations in TYMP, POLG1, mtDNA tRNA^leu(UUR) or tRNA^lys genes. We hypothesized that CIPOs could be the presenting symptom of respiratory chain enzyme deficiency and thus we investigated oxidative phosphorylation in small bowel and/or colon smooth muscle of primary CIPO children. Methods We studied eight children with CIPO and 12 pediatric controls. We collected clinical, radiological and pathological data and measured respiratory chain enzymatic activity in isolated smooth muscle of the small bowel and/or the colon. We also sequenced TYMP, POLG, mtDNA tRNA^leu(UUR) and tRNA^lys genes. Key Results Neither pathological nor radiological data were in favor of a mitochondrial dysfunction. No respiratory chain enzyme deficiency was detected in CIPO children. In myogenic CIPO, respiratory enzymes and citrate synthase activities were increased in small bowel and/or colon whereas no abnormality was noted in neurogenic and unclassified CIPO. Levels of enzyme activities were higher in control small bowel than in control colon muscle. Sequencing of TYMP, POLG, mtDNA tRNA^leu(UUR) and tRNA^lys genes and POLG gene did not reveal mutation for any of the patients. Conclusions & Inferences The normal enzymatic activities as the lack of radiological and genetic abnormalities indicate that, at variance with adult patients, oxidative phosphorylation deficiency is not a common cause of childhood CIPO.     

Impaired intestinal gas propulsion in manometrically proven dysmotility and in irritable bowel syndrome

Background Intestinal manometry is the current gold standard for diagnosing small bowel dysmotility; however, the functional significance of abnormal manometry is unknown. Our aim was to determine whether, and to what extent, intestinal gas propulsion is impaired in patients with manometrically proven dysmotility compared with healthy controls and patients with IBS. Methods Clearance and tolerance of a jejunal gas load (12 mL min^?1 for 2 h) were measured in 15 patients with severe abdominal symptoms and intestinal dysmotility evidenced by manometry, 15 patients with IBS and 15 healthy subjects. Thereafter, the effect of neostigmine (0.5 mg i.v. bolus) vs placebo (i.v. saline) was tested in six dysmotility patients. Key Results After 2‐h gas infusion, patients with dysmotility developed significantly more gas retention (717 ± 91 mL) than IBS patients (372 ± 82 mL; P = 0.0037) and healthy subjects (17 ± 67 mL; P < 0.0001 vs dysmotility; P = 0.0060 vs IBS). Despite the greater retention in dysmotility patients, abdominal perception (2.5 ± 0.6 score) and distension (7 ± 2 mm girth increment) were similar to IBS (3.9 ± 0.6 score and 7 ± 2 mm, respectively). In dysmotility patients, neostigmine produced immediate clearance of gas, and by 30 min had reduced gas retention (by ?552 ± 182 vs 72 ± 58 mL after saline; P = 0.008), abdominal symptoms (by ?0.8 ± 0.3 score vs 0.3 ± 0.2 after saline; P = 0.019) and distension (girth change ?5 ± 1 mm; P = 0.003 vs?2 ± 2 mm after saline). Conclusion & Inferences Patients with manometric dysmotility have markedly impaired intestinal gas propulsion. In IBS patients, impaired gas propulsion is less pronounced but associated with concomitant sensory dysfunction and poor tolerance of gas retention.     

Reproducibility of esophageal high‐resolution manometry

Background Esophageal high‐resolution manometry (HRM) is a novel method for esophageal function testing that has prompted the development of new parameters for quantitative analysis of esophageal function. Until now, the reproducibility of these parameters has not been investigated. Methods Twenty healthy volunteers underwent HRM on two separate days. Standard HRM parameters were measured. In addition, in conventional (virtual) line tracings, lower esophageal sphincter (LES) resting pressure, relaxation pressure, and relative relaxation pressure were measured. Firstly, for each variable, the mean percentage of covariation (100 × SD/mean: %COV) was derived as a measure of inter‐ and intra‐individual variation. Secondly, Kendall’s coefficients of concordance (W values) were calculated. Thirdly, Bland–Altman plots were used to express concordance graphically. Key Results Statistically significant concordance values were found for upper esophageal sphincter (UES) pressure (W = 0.90, P = 0.02), transition zone length (W = 0.92, P = 0.01), LES length (W = 0.81, P = 0.04), LES pressure (W = 0.75, P = 0.05), LES relaxation pressure (W = 0.75, P = 0.03), relative LES relaxation pressure (W = 0.78, P = 0.05), gastric pressure (W = 0.81, P = 0.04), and contraction amplitude 5 cm above the LES (W = 0.86, P = 0.03). In conventional setting, only LES resting pressure (W = 0.835, P = 0.03) proved significant. In HRM tracings, concordance values for contraction wave parameters, and in conventional line tracings, LES relaxation pressure and relative relaxation pressure did not reach levels of statistical significance. Conclusions & Inferences Esophageal HRM yields reproducible results. Parameters that represent anatomic structures show better reproducibility than contraction wave parameters. The reproducibility of LES resting and relaxation pressure assessed with HRM is better than with conventional manometry and further supports the clinical use of HRM.     

High‐resolution manometric characteristics help differentiate types of distal esophageal obstruction in patients with peristalsis

Background High‐resolution manometry (HRM) can identify obstructive motor features at the esophagogastric junction and abnormalities in esophageal bolus transit. We sought to determine if HRM patterns can differentiate functional from organic mechanical lower esophageal sphincter (LES) obstruction. Methods Segmental characteristics of peristalsis were examined using HRM in symptomatic subjects with elevated postdeglutitive residual pressure gradients across the LES (≥5 mmHg). Sixteen consecutive patients with non‐achalasic mechanical fixed obstruction were compared with 13 patients with elevated pressure gradients yet no mechanical obstruction and 14 asymptomatic controls. Pressure volumes were determined in mmHg cm s for peristaltic segments defined on HRM Clouse plots using an on‐screen pressure volume measurement tool. Key Results Residual pressure gradients were similarly elevated in both patient groups. A visually conspicuous and distinctive shift in the proportionate pressure strengths of the second and third peristaltic segments was apparent across groups. Whereas the ratios of peak pressures and pressure volumes between second and third segments approached 1 in controls (0.92, 0.98), pressures shifted to the second segment in mechanical obstruction (peak pressure ratio: 1.2 ± 0.4; pressure volume ratio: 1.8 ± 0.9) and to the third segment in functional obstruction (peak ratio: 0.7 ± 0.2; volume ratio: 0.5 ± 0.2; P < 0.02 for any comparison of either group with controls). A threshold volume ratio of 1.0 correctly segregated 93% of obstruction (P < 0.0001); visual pattern inspection was equally effective. Conclusions & Inferences When elevated residual pressure gradients are present in non‐achalasic patients, topographic characteristics of peristalsis can differentiate fixed mechanical obstruction from functional obstruction.