Emerging therapies in the management of Irritable Bowel Syndrome (IBS).

INTRODUCTION: Irritable bowel syndrome (IBS) is a symptom-based disorder of chronic abdominal pain and altered bowel habits. The pathogenesis of IBS is multifactorial, leading to the potential for the development of diverse treatment strategies. This mechanistic heterogeneity suggests that available therapies will only prove effective in a subset of IBS sufferers. Current US Food and Drug Administration (FDA) approved therapies for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) are reviewed. Limited symptom responses and side effect experiences lead to considerable patient dissatisfaction with currently available IBS treatments. Only a small percentage of IBS patients are on prescription therapies underscoring the potential market and need for additional therapeutic options. AREAS COVERED: Expanding on currently available therapies, the serotonergic and endogenous opioid receptor systems continue to be a focus of future IBS treatment development. Additional novel emerging therapies include the endogenous cannabinoid system, bile acid secretion and sequestration, and exploit our enhanced understanding of visceral sensory signaling and intestinal secretomotor function. EXPERT OPINION: While challenges remain for the future development of IBS therapies, the diverse etiologies underlying the disorder present an opportunity for novel therapies. Hence, great potential is anticipated for future IBS treatment options.

Gallbladder Dyskinesia.

Gallbladder dyskinesia is a functional disorder of the gastrointestinal tract, which can result in debilitating episodes of abdominal pain and associated symptoms. Key diagnostic criteria include a diminished gallbladder ejection fraction on scintigraphy and absence of other causes for the symptoms. Pathologic findings and follow-up suggest a distinct mechanistic basis for this condition. Unfortunately, the complexities of diagnosis and treatment combined with patient and provider preferences will likely continue to preclude randomized controlled studies to provide a clearer evidence-based management for this disorder. Patients meeting the clinical and diagnostic criteria for gallbladder dyskinesia should be referred for cholecystectomy, and most of these patients will have relief of their symptoms. A comprehensive preoperative discussion on expected outcomes needs to take place.

Prevalence of Colonic Polyps in Patients Undergoing Kidney Transplant Evaluation: A Meta-Analysis and Systematic Review.

OBJECTIVES: Colorectal canceris the third most common cancer worldwide, and kidney transplant patients have up to a 2.5-fold increased risk of colorectal cancer compared with the general population. Presently, colorectal cancer screening recommendations in kidney transplant candidates are the same as for the general population. We explored the literature on the prevalence of colonic polyps in patients with renal failure undergoing screening colonoscopy as part of kidney transplant evaluation. MATERIALS AND METHODS: We conducted a systematic review in PubMed, Embase, and Cochrane databases from inception through June 2023 to identify studies that explored the prevalence of colonic polyps in patients with chronic kidney disease undergoing a screening colonoscopy as part of their pretransplant evaluation. RESULTS: Of 937 patients, 371 had ≥1 polyp on their screening colonoscopy (39.6%; 95% CI, 29.3%-50.3%), 243 patients had ≥1 adenoma (25.9%; 95% CI, 14.3%- 39.6%), and 75 had ≥1 high-risk adenoma (8.7%; 95% CI, 6.9%-10.7%). Pooled analysis of the 2 studies comparing patients with end-stage renal disease versus matched control groups indicated higher pooled prevalence of adenomas in the end-stage renal disease group (33.4%) versus the control group (23.9%). CONCLUSIONS: Our results suggest an average or increased prevalence of polyps and adenomatous polyps in patients with chronic kidney disease undergoing colonoscopy during evaluation for kidney transplant. The pooled analysis of the studies comparing the end-stage renal disease population versus a matched control group indicates higher prevalence of adenomatous polyps in patients with end-stage renal disease. Multiple studies have shown that screening colonoscopy in this patient group is safe and does not delay kidney transplant evaluation or waitlistrates; hence, screening colonoscopy should be routinely considered.

Survival benefit associated with early detection of spontaneous bacterial peritonitis in veteran inpatients with cirrhotic ascites.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is common in hospitalized cirrhotic patients with ascites and carries high mortality. This study aimed to determine whether early diagnostic paracentesis (EDP) <12 h of hospitalization conveys an intermediate-term (6-month) survival benefit in cirrhotic patients diagnosed with SBP. METHODS: Consecutive US veterans with cirrhosis diagnosed with SBP over 13 years at a single VA medical center were reviewed retrospectively. Kaplan-Meyer analyses assessed the effects of EDP on survival. RESULTS: A total of 79 cirrhotic patients were diagnosed with SBP (61.8 ± 8.8 years, n = 77 male, n = 52 [66.8%] Caucasian, n = 23 [29.1%] African-American). Underlying liver diseases included hepatitis c viral infection (HCV) (17.5%), alcohol (28.6%), alcohol and HCV (30.1%), and cryptogenic/metabolic (15.9%). Median baseline model for end-stage liver disease (MELD) was 12 (range 6-34), and median MELD at presentation was 18. Seven subjects had a history of hepatocellular carcinoma (11.1%), and 26 (41.3%) presented with sepsis. Thirty-three (52.4%) subjects died within 6 months after the SBP admission. Of the subjects, 41 (65.1%) underwent EDP, of which 23 (56.0%) survived at least 6 months, compared to only 7 of the 22 patients (31.8%) undergoing paracentesis >12 h from presentation (P = 0.057). The maximal benefit of EDP on survival was observed beyond days 14 and 30; at these time points, no statistical difference in mortality was discernable (P = 0.55 and 0.71). In a multivariate model including age, MELD at admission, hepatocellular cancer, and sepsis criteria, EDP (p 0.034) positively impacted patient survival at 6 months. CONCLUSIONS: EDP is associated with improved 6-month mortality in cirrhotic patients with ascites. In this veteran cohort, EDP was as important as MELD as a predictor of intermediate-term survival.

High somatic symptom burdens and functional gastrointestinal disorders.

BACKGROUND & AIMS: Unexplained, multi-system somatic symptoms and syndromes, the hallmark features of somatization, are prevalent in patients with functional gastrointestinal disorders (FGIDs). We studied outpatients attending a gastroenterology clinic to see whether current somatic symptom burdens (a somatization state measure) or number of prior functional diagnoses (a somatization trait measure) could predict the presence of an FGID over structural gastrointestinal disease, and whether the predictive value was dependent on comorbid depression or anxiety disorders. METHODS: Clinical data from 327 consecutive new referrals to an outpatient gastroenterology practice were reviewed, 187 with an FGID and 140 with a structural illness. Somatization state and trait were measured by using self-reported current symptoms and functional diagnoses recorded in the medical history, respectively. Psychiatric comorbidity (depression or anxiety disorders) was extracted from chart review. RESULTS: FGID subjects endorsed more somatization state symptoms, had more somatization trait diagnoses, and had greater likelihood of psychiatric comorbidity (P < .001 for each). Logistic regression analysis adjusting for age and sex differences showed that each of these features independently predicted the likelihood of an FGID over structural disease (P < .05 for each). When high ratings on the somatization measures were present together with psychiatric comorbidity, the positive predictive value exceeded 0.95. CONCLUSIONS: Higher burdens of either current somatic symptoms or functional diagnoses in the medical history are strong predictors of an FGID in outpatients presenting with gastrointestinal complaints. The mechanism is not solely dependent on a relationship with affective disorders, which independently predicts FGID, at least in part, through another path.

Predictors of premature antidepressant discontinuation in functional gastrointestinal disorders.

OBJECTIVES: To identify factors responsible for premature antidepressant discontinuation that would assist in designing management strategies for patients with functional gastrointestinal disorders. Antidepressants are being used increasingly to manage patients with functional gastrointestinal disorders; poor patient adherence to treatment regimens, particularly in the period shortly after antidepressant initiation, is common and interferes with success. METHODS: Clinical records were reviewed from 172 outpatients who attended a university-based practice and who had been prescribed antidepressants to manage their functional gastrointestinal symptoms. Survival analysis methods were used to determine independent predictors of premature antidepressant discontinuation (within 6 months of initiation). Logistic regression analyses were used to see if the same predictors were responsible for side effects or poor treatment response. RESULTS: Premature antidepressant discontinuation occurred in 41 (23.8%) subjects. Somatization features (state or trait) and history of depression or an anxiety disorder were the most significant predictors of premature discontinuation (p < or = .01 for each). Advancing age and female sex also were independent predictors (p < .05 for each). Somatization features and psychiatric illness were each linked to poor treatment response, whereas somatization features most consistently were associated with antidepressant side effects. CONCLUSIONS: Failure to maintain treatment occurs in nearly a quarter of outpatients given antidepressants for functional gastrointestinal disorders. Somatization features and history of depression or anxiety most significantly interfered with treatment by predicting side effects, poor treatment response, and premature antidepressant discontinuation. Management algorithms should include specific strategies targeted at patients with these risk factors for poor treatment adherence.

Depression, anxiety, and nonalcoholic steatohepatitis.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a morbid liver disease with limited treatment. Depression and anxiety have been associated recently with insulin resistance and inflammatory states, factors that are relevant to the development of NASH. We hypothesized that depression and anxiety would be more prevalent in NASH patients and predict more severe histological findings on liver biopsy. METHODS: Histories of major depressive disorder (MDD) and generalized anxiety disorder (GAD) were determined using a structured interview and DSM-IV criteria in 36 NASH subjects and 36 matched controls without liver disease who had undergone cholecystectomy. Histological changes on liver biopsy in NASH subjects were age-adjusted and compared in subjects with and without psychiatric disorders. A multivariate model incorporating other potential risk factors for NASH (female sex, body mass index, waist-to-hip ratio, and presence of diabetes) was used to determine independent effects of MDD and GAD on severity of histological findings. RESULTS: NASH subjects had significantly increased lifetime rates of MDD (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.4-10.2; p = .018) and GAD (OR 5.0, 95% CI, 1.7-14.9; p = .005). The onset of psychiatric illness preceded diagnosis of liver disease by 18 to 20 years. Each psychiatric disorder was associated with more severe histological features (p < .05 for each), the effect of GAD on fibrosis stage persisting in the multivariate model. CONCLUSIONS: MDD and GAD are overrepresented in NASH subjects and are associated with more advanced liver histological abnormalities. Additional investigation will be required to determine if depression and anxiety affect the development or progression of NASH and serve as modifiable risk factors.

Diabetes mellitus increases risk for colorectal adenomas in younger patients.

AIM: To determine if diabetes mellitus (DM) is associated with increased risk of colorectal adenomas in younger subjects. METHODS: This was a retrospective cohort study of 375 patients undergoing index colonoscopy at a single tertiary care center in the United States. Three cohorts of patients matched for exam date and gender were compared: (1) ages 40-49 years with DM; (2) ages 40-49 years without DM; and (3) ages 50-59 years without DM. Data collected included demographics, co-morbidities, colonoscopy and pathology results. Adenoma detection rates (ADR) were calculated and compared. Conditional logistic regression analysis was performed to determine the association between each cohort and ADR. RESULTS: One hundred and twenty-five patients ages 40-49 with DM met study eligibility criteria. Patients in the other two cohorts were randomly selected, matching for date of exam and gender. ADR was 14.4% in those ages 40-49 years without DM, 30.4% in those ages 40-49 years with DM, and 32.0% in those ages 50-59 years without DM. Compared to those ages 40-49 years without DM, ADR was higher in those ages 40-49 years with DM (OR = 3.1; 95%CI: 1.5-6.4; P = 0.002) and those ages 50-59 years without DM (OR = 2.9; 95%CI: 1.5-5.6; P = 0.002). There was no difference between the ADR in those ages 40-49 years with DM and those ages 50-59 years without DM (P = 0.83). CONCLUSION: DM was associated with higher risk of colorectal adenomas in patients ages 40-49 years. These subjects harbored as many adenomas as those at the standard screening age of 50-59 years without DM.

Type 2 diabetes mellitus: the impact on colorectal adenoma risk in women.

OBJECTIVES: Increased risk for colorectal cancer (CRC) has been associated with type 2 diabetes. Despite several studies linking insulin resistance to increased CRC risk, there are limited data on colorectal adenoma risk in diabetic women. We hypothesized that diabetic women would have increased rates of colorectal adenomas relative to a group of nondiabetic women. METHODS: Colorectal adenoma rates were determined in 100 estrogen-negative women with type 2 diabetes mellitus and compared with 500 nondiabetic, estrogen-negative controls. Adenomas were defined as any adenoma or advanced adenoma (villous or tubulovillous features, size >1 cm or high-grade dysplasia). A multivariate model including age, race, diabetes, hypertension, hypercholesterolemia, body mass index, and nonsteroidal anti-inflammatory drug status was used to determine the independent effects of diabetes on colorectal adenoma incidence. RESULTS: Diabetics as compared with nondiabetics had greater rates of any adenoma (37%vs 24%, p= 0.009) and advanced adenomas (14%vs 6%, p= 0.009). Two hundred forty-five obese subjects compared with 355 nonobese subjects had a higher rate of any adenoma (32%vs 22%, p= 0.001). Obese diabetics compared with nonobese, nondiabetics had greater rates of any adenoma (42%vs 23%, p< or = 0.001) and advanced adenomas (19%vs 7%, p< or = 0.001). Multivariate analysis showed that adenomas and advanced adenomas were independently predicted by diabetes (p < 0.05) and adenomas by age. DISCUSSION: Women with type 2 diabetes mellitus had higher rates of colorectal adenomas as compared with lean and nondiabetic women. This finding adds to the evidence that type 2 diabetes is an important factor in the progression of the adenoma-carcinoma sequence.