Intestinal Disaccharidase Deficiency in Adults: Evaluation and Treatment.

PURPOSE OF REVIEW: Disaccharidase deficiency in adults causes carbohydrate malabsorption, resulting in symptoms which significantly overlap with irritable bowel syndrome (IBS). This article discusses the diagnosis and treatment of disaccharidase deficiency within the context of recent literature. RECENT FINDINGS: Disaccharidase deficiency in adults is more common than previously thought, which includes lactase, sucrase, maltase and isomaltase enzymes. Deficiency in disaccharidases, which are produced by the intestinal brush border, will interfere with the breakdown and absorption of carbohydrates and may result in abdominal pain, gas, bloating and diarrhea. Patients deficient in all 4 disaccharidases are known as having "pan-disaccharidase" deficiency, which has a distinct phenotype with more reported weight loss than patients deficient in one enzyme. IBS patients who do not respond to low FODMAP dietary restriction may have undiagnosed disaccharidase deficiency and may benefit from testing. Diagnostic testing methods are limited to duodenal biopsies, which is the gold standard, and breath testing. Dietary restriction and enzyme replacement therapy have been shown to be effective treatments in these patients. Disaccharidase deficiency is an underdiagnosed condition in adults with chronic GI symptoms. Patients who do not respond to traditional treatment strategies for DBGI may benefit from testing for disaccharidase deficiency. Further studies delineating the distinctions between disaccharidase deficient patients and those with other motility disorders are needed.

Functional Anorectal Disorders.

This report defines criteria and reviews the epidemiology, pathophysiology, and management of common anorectal disorders: fecal incontinence (FI), functional anorectal pain and functional defecation disorders. FI is defined as the recurrent uncontrolled passage of fecal material for at least 3 months. The clinical features of FI are useful for guiding diagnostic testing and therapy. Anorectal manometry and imaging are useful for evaluating anal and pelvic floor structure and function. Education, antidiarrheals and biofeedback therapy are the mainstay of management; surgery may be useful in refractory cases. Functional anorectal pain syndromes are defined by clinical features and categorized into three subtypes. In proctalgia fugax, the pain is typically fleeting and lasts for seconds to minutes. In levator ani syndrome (LAS) and unspecified anorectal pain the pain lasts more than 30 minutes, but in LAS there is puborectalis tenderness. Functional defecation disorders are defined by >2 symptoms of chronic constipation or irritable bowel syndrome with constipation, and with >2 features of impaired evacuation i.e., abnormal evacuation pattern on manometry, abnormal balloon expulsion test or impaired rectal evacuation by imaging. It includes two subtypes; dyssynergic defecation and inadequate defecatory propulsion. Pelvic floor biofeedback therapy is effective for treating LAS and defecatory disorders.

Rome IV Diagnostic Questionnaires and Tables for Investigators and Clinicians.

The Rome IV Diagnostic Questionnaires were developed to screen for functional gastrointestinal disorders (FGIDs), serve as inclusion criteria in clinical trials, and support epidemiological surveys. Separate questionnaires were developed for adults, children/adolescents, and infants/toddlers. For the adult questionnaire, we first surveyed 1,162 adults without gastrointestinal disorders, and recommended the 90th percentile symptom frequency as the threshold for defining what is abnormal. Diagnostic questions were formulated and verified with clinical experts using a recursive process. The diagnostic sensitivity of the questionnaire was tested in 843 patients from 9 gastroenterology clinics, with a focus on clinical diagnoses of irritable bowel syndrome (IBS), functional constipation (FC), and functional dyspepsia (FD). Sensitivity was 62.7% for IBS, 54.7% for FD, and 32.2% for FC. Specificity, assessed in a population sample of 5,931 adults, was 97.1% for IBS, 93.3% for FD, and 93.6% for FC. Excess overlap among IBS, FC, and FD was a major contributor to reduced diagnostic sensitivity, and when overlap of IBS with FC was permitted, sensitivity for FC diagnosis increased to 73.2%. All questions were understandable to at least 90% of individuals, and Rome IV diagnoses were reproducible in ¾ of patients after one month. Validation of the pediatric questionnaires is ongoing.

Predicting Response to Neuromodulators or Prokinetics in Patients with Suspected Gastroparesis Using Machine Learning: the "BIDnD" Model.

INTRODUCTION: Pharmacologic therapies for symptoms of gastroparesis have limited efficacy and it is difficult to predict which patients will respond. In this study, we implemented a machine-learning model to predict the response to prokinetics and/or neuromodulators in patients with gastroparesis-like symptoms. METHODS: Subjects with suspected gastroparesis underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule (WMC) and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their Gastroparesis Cardinal Symptom Index (GCSI) at 6 months decreased by ≥1 from baseline. A machine-learning model was trained using lasso regression, ridge regression or random forest. Five-fold cross-validation was used to train the models and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set. RESULTS: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were non-responders. A ridge regression model with the variables: BMI, Infectious prodrome, delayed GES, no diabetes (BIDnD), had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with GET, duodenal MI, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75). DISCUSSION: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with gastroparesis-like symptoms.

Profile of plecanatide in the treatment of chronic idiopathic constipation: design, development, and place in therapy.

Constipation is a multifactorial disorder that can cause significant psychological distress to patients and economic burden on the health care system. Many patients are not satisfied with their current established treatment, highlighting the need for new and improved therapeutic options. Guanylate cyclase-C (GC-C)/cyclic guanosine monophosphate agonists have emerged as a safe and efficacious class of drugs for the treatment of chronic idiopathic constipation (CIC). Plecanatide, a second-in-class, US FDA-approved, synthetic GC-C agonist, has recently been approved in the US for the treatment of irritable bowel syndrome with constipation at doses of 3 and 6 mg and CIC at the 3 mg dosage. In this study, we summarize the design of this novel 16-amino acid uroguanylin analog, drug development through Phase I, II, and III clinical studies, and its role in the treatment of CIC.