Barbara M. Seide

Risk factors for fecal incontinence: A population-based study in women

BACKGROUND:In women with “idiopathic” fecal incontinence (FI), consensus guidelines recommend anal sphincter imaging and surgical repair, when feasible, of anal sphincter defects believed to cause FI. However, the relative contributions of obstetric trauma and bowel symptoms to FI in the community are unknown.METHODS:To assess risk factors for FI during the past year, a previously validated questionnaire was mailed to an age-stratified random sample of 5,300 women residing in Olmsted County, Minnesota.RESULTS:Altogether, 2,800 women (53%) responded. The risk of fecal incontinence increased with age (odds ratio [OR] per decade 1.3, 95% CI 1.2–1.4). The risk of fecal incontinence was higher among women with rectal urgency (OR 8.3, 95% CI 4.8–14.3) whether or not they also had other bowel disturbances (i.e., constipation, diarrhea, or abdominal pain) or had a vaginal delivery with forceps or stitches (OR 9.0, 95% CI 5.6–14.4). Among women with FI, rectal urgency and age were also risk factors for symptom severity. In contrast, obstetric risk factors for anorectal trauma did not increase the risk for FI. The risk for FI was not significantly different among women with cesarean section, vaginal delivery with or without forceps or stitches, or anorectal surgery, compared with nulliparous women without any of these risk factors.CONCLUSIONS:Rectal urgency rather than obstetric injury is the main risk factor for FI in women. These observations reinforce the importance of behavioral, dietary, and pharmacological measures to ameliorate bowel disturbances before anal imaging in women with “idiopathic” FI.

Day-to-day reproducibility of anorectal sensorimotor assessments in healthy subjects

Abstract  The reproducibility of tests widely utilized to assess anorectal sensorimotor functions is not well established. Our aims were to assess the intra‐individual day‐to‐day reproducibility of these parameters in healthy subjects. Anal sphincter pressures were assessed by perfusion manometry on two separate days in 19 healthy subjects. Rectal pressure–volume (p–v) curves and sensory thresholds were assessed in 12/19 subjects by inflating a highly compliant polyethylene balloon from 0 to 32 mmHg in 4 mmHg steps. Subjects also rated intensity of perception by visual analogue scale (VAS) during phasic distentions 8, 16 and 24 mmHg above operating pressure, in randomized sequence. Resting and squeeze anal pressures and rectal compliance were highly reproducible (rs ≥ 0.7) in the same subject on separate days. Pressure thresholds for urgency appeared less reproducible than thresholds for initial perception and the desire to defecate. VAS scores were highly reproducible only during the 24‐mmHg distention. Thus, anal pressures and rectal compliance are highly reproducible within healthy subjects on separate days, while sensory thresholds are reproducible to a variable degree, dependent on the intensity of stimulation and the perception being assessed.

Primary hyperoxaluria type III gene HOGA1 (Formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis

BACKGROUND AND OBJECTIVES Primary hyperoxaluria types I and II (PHI and PHII) are rare monogenic causes of hyperoxaluria and calcium oxalate urolithiasis. Recently, we described type III, due to mutations in HOGA1 (formerly DHDPSL), hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase activity, resulting in excess oxalate. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS To further explore the pathophysiology of HOGA1, we screened additional non-PHI-PHII patients and performed reverse transcription PCR analysis. Postulating that HOGA1 may influence urine oxalate, we also screened 100 idiopathic calcium oxalate stone formers. RESULTS Of 28 unrelated hyperoxaluric patients with marked hyperoxaluria not due to PHI, PHII, or any identifiable secondary cause, we identified 10 (36%) with two HOGA1 mutations (four novel, including a nonsense variant). Reverse transcription PCR of the stop codon and two common mutations showed stable expression. From the new and our previously described PHIII cohort, 25 patients were identified for study. Urine oxalate was lower and urine calcium and uric acid were higher when compared with PHI and PHII. After 7.2 years median follow-up, mean eGFR was 116 ml/min per 1.73 m(2). HOGA1 heterozygosity was found in two patients with mild hyperoxaluria and in three of 100 idiopathic calcium oxalate stone formers. No HOGA1 variants were detected in 166 controls. CONCLUSIONS These findings, in the context of autosomal recessive inheritance for PHIII, support a loss-of-function mechanism for HOGA1, with potential for a dominant-negative effect. Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition.

Differences between painless and painful constipation among community women

BACKGROUND:In the Rome II criteria, patients with both constipation and abdominal pain (AP) (i.e., “painful constipation” (PC)), who do not satisfy criteria for irritable bowel syndrome (IBS) are included in the same functional constipation (FC) category as patients with constipation without AP (i.e., “painless constipation” (PLC)). What differences, if any, exist between FC without (i.e., PLC) and with AP (i.e., PC) are unclear.METHODS:To compare clinical features among PLC, PC, constipation-predominant IBS (C-IBS), and non-C-IBS, a validated questionnaire was mailed (with telephone follow-up of nonresponders) to an age-stratified random sample of 5,200 adult women in Olmsted County, Minnesota.RESULTS:Altogether, 2,800 women (53%) responded. The age-adjusted prevalence of PLC (7.1 per 100; 95% confidence interval (95% CI), 6.2–8.0) was higher compared to PC (0.9 per 100; 95% CI, 0.6–1.2). Compared to PLC, patients with PC reported worse general health (i.e., excellent or very good = 37.5%vs 51.2%), more somatic symptoms (mean score = 1.3 vs 0.9), and urinary urgency (% often = 58%vs 32%), and had a higher prevalence of hysterectomy. Bowel symptoms significantly impacted ≥1 domain of quality of life (QOL) in 18% of PC versus 9% of PLC. In a logistic discriminant model, age, general health, impact of bowel symptoms on QOL, somatic symptoms, and urinary urgency independently discriminated between bowel subtypes.CONCLUSIONS:Patients with PC more closely resemble those with C-IBS than PLC. Consideration should be given to separating PC from PLC in the Rome criteria and in therapeutic trials.

Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.

Relation of bowel habits to fecal incontinence in women.

BACKGROUND:Though most women with fecal incontinence (FI) have anorectal dysfunctions, a majority have intermittent symptoms. Variations in bowel habits and daily routine may partly explain this.AIM:To compare bowel habits and daily routine between controls and FI, and between continent and incontinent stools among women with FI.METHOD: Using a mailed questionnaire, we identified 507 women with FI among 5,300 women in Olmsted County, MN. Bowel habits were compared among 127 randomly selected controls and 154 women with self-reported FI, who did (“active” FI, N = 106) or did not (“inactive” FI, N = 48) have an incontinent episode during a 2-wk bowel diary period.RESULTS:Independent risk factors for FI were: rectal urgency (odds ratio [OR] for inactive FI vs controls 5.6, 95% confidence interval [CI] 2.3–13.3; and OR for active FI vs inactive FI 2.0, 95% CI 0.9–4.3) and a sense of incomplete evacuation (OR for inactive FI vs controls 3.5, 95% CI 1.4–8.8; and OR for active FI vs inactive FI 2.2, 95% CI 1.1–4.9). Similar results were found for stool frequency and form. Among incontinent women, incontinent stools (versus continent stools) were less formed, more likely to occur at work, and to be preceded by rectal urgency.CONCLUSIONS:Bowel patterns, rectal urgency, and daily routine influence the occurrence of FI. Stool characteristics explained 46% of the likelihood for incontinence episodes, emphasizing that anorectal sensorimotor dysfunctions must also contribute to FI in women.

Insights into normal and disordered bowel habits from bowel diaries.

BACKGROUND:While symptom questionnaires provide a snapshot of bowel habits, they may not reflect day-to-day variations or the relationship between bowel symptoms and stool form.AIM:To assess bowel habits by daily diaries in women with and without functional bowel disorders.METHOD:From a community-based survey among Olmsted County, MN, women, 278 randomly selected subjects were interviewed by a gastroenterologist, who completed a bowel symptom questionnaire. Subjects also maintained bowel diaries for 2 wk.RESULTS:Among 278 subjects, questionnaires revealed diarrhea (26%), constipation (21%), or neither (53%). Asymptomatic subjects reported bowel symptoms (e.g., urgency) infrequently (i.e., <25% of the time) and generally for hard or loose stools. Urgency for soft, formed stools (i.e., Bristol form = 4) was more prevalent in subjects with diarrhea (31%) and constipation (27%) than in normals (16%). Stool form, straining to begin (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.7–10.2) and end (OR 4.7, 95% CI 1.6–15.2) defecation increased the odds for constipation. Straining to end defecation (OR 3.7, 95% CI 1.2–12.0), increased stool frequency (OR 1.9, 95% CI 1.02–3.7), incomplete evacuation (OR 2.2, 95% CI 1.04–4.6), and rectal urgency (OR 3.1, 95% CI 1.4–6.6) increased the odds for diarrhea. In contrast, variations in stool frequency and form were not useful for discriminating between health and disease.CONCLUSIONS:Bowel symptoms occur in association with, but are only partly explained by, stool form disturbances. These observations support a role for other pathophysiological mechanisms in functional bowel disorders.

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

BACKGROUND AND OBJECTIVES Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models. RESULTS Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m(2) and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/1.73 m(2) per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8). CONCLUSIONS Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.

Effect of tolterodine on gastrointestinal transit and bowel habits in healthy subjects

Abstract  Clinical trials and observations suggest that constipation is an uncommon side effect of treating overactive bladder with the muscarinic receptor antagonist tolterodine. Because muscarinic antagonism inhibits gastrointestinal motor activity, we evaluated the effects of tolterodine on bowel habits, gastrointestinal and colonic transit in healthy subjects. In this double‐blind study, 36 healthy subjects were randomized to tolterodine extended release (ER, 4 mg daily) or placebo for 6 days. Gastric emptying (GE), small bowel and colonic transit were assessed on days 4–6 by scintigraphy. Bowel habits were recorded by diaries. Tolterodine did not significantly affect half‐time for GE (GE thalf) [116 ± 6 min (mean ± SEM) for placebo vs 126 ± 7 min for tolterodine], small bowel transit measured by colonic filling at 6 h (45 ± 6% for placebo vs 36 ± 6% for tolterodine) or the geometric center of colonic transit at 24 h (2.9 ± 0.2 for placebo vs 2.6 ± 0.3 for tolterodine). Subjects who received tolterodine had slightly fewer bowel movements (i.e. 1.34 ± 0.1 stools per day for placebo vs 1.0 ± 0.1 for tolterodine; P = 0.02 for treatment effect). Tolterodine did not significantly affect stool consistency or ease of defecation. At the therapeutic dose used to treat overactive bladder, tolterodine did not significantly affect gastrointestinal or colonic transit and had minor effects on bowel habits in healthy subjects. Further studies are necessary to elucidate whether these observations are explained by tolterodine effects at muscarinic receptors which stimulate and inhibit gastrointestinal motility.

Effects of glucagon-like peptide-1 and sympathetic stimulation on gastric accommodation in humans.

Abstract   In humans, glucagon‐like peptide‐1 (GLP‐1) delays gastric emptying by inhibiting vagal activity and also increases gastric volumes, by unclear mechanisms. Because GLP‐1 inhibits intestinal motility by stimulating the sympathetic nervous system in rats, we assessed the effects of a GLP‐1 agonist and yohimbine, an α2‐adrenergic antagonist, on gastric volumes in humans. In this double‐blind study, 32 healthy volunteers were randomized to placebo, a GLP‐1 agonist, yohimbine or GLP‐1 and yohimbine. Gastric volumes (fasting predrug and postdrug, and postprandial postdrug) were measured by 99mTc single photon emission computed tomography imaging. Plasma catecholamines and haemodynamic parameters were assessed. Compared with placebo, GLP‐1 increased (P = 0.03) but yohimbine did not affect fasting gastric volume. However, GLP‐1 plus yohimbine increased (P < 0.001) postprandial gastric accommodation vs placebo and vs GLP‐1 alone [postprandial volume change = 542 ± 29 mL (mean ± SEM, placebo), 605 ± 31 mL (GLP‐1), 652 ± 54 mL (yohimbine) and 810 ± 37 mL (GLP‐1 and yohimbine)]. Plasma noradrenaline and dihydroxyphenylglycol concentrations were higher for yohimbine vs placebo and for GLP‐1 and yohimbine vs GLP‐1. Yohimbine stimulates central sympathetic activity and in combination with GLP‐1, augments postprandial accommodation in humans.