Stomach and Intestinal Issues

Educational Objectives

The goal of this program is to improve the management of gastroparesis and postinfectious gastrointestinal disease. After hearing and assimilating this program, the clinician will be better able to:

1.   Review the pathophysiology of gastroparesis.

2.   Describe how gastric electrical stimulation is used in the management of gastroparesis.

3.   Discuss the factors, including psychologic ones, that predict the development of postinfectious irritable bowel syndrome (PI-IBS).

4.   Explain the potential mechanisms of PI-IBS.

5.   Discuss studies related to the development of postinfectious functional dyspepsia.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committe to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Mellinger has re­ceived speaking honoraria from Gore and is a consultant for USGI Medical. Dr. Chang and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Mellinger was recorded at 14th Annual Medical and Surgical Approaches to GI Disorders Symposium, held July 20-24, 2009, in Kiawah Island, SC, and sponsored by the Medical College of Georgia. Dr. Chang was recorded at 10th Annual Educational Meeting in Gastroenterology, held October 9-11, 2009, in Santa Monica, CA, and spon­sored by the Cedars-Sinai Medical Center, Division of Gastroenterology. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Gastroparesis and Its Management

John D. Mellinger, MD, Professor of Surgery, Director, General Surgery Residency Program, and Chief, Gastrointestinal Surgery, Medical College of Georgia, Augusta

Physiology: receptive relaxation of fundus allows stomach to accommodate large volume of food; gastric pacemaker on greater curve stimulates rhythmic contractions necessary to mix food in body of stomach against pyloric resis­tance and allow chyme to develop into smaller particles with more fluid consistency; regulated cyclical peristaltic pattern in antrum controls emptying into duodenum; goal to deliver osmotic chyme to small intestine for digestion and absorption; emptying rate of stomach  —  determined by physical nature of food, fat, protein and carbohydrate content, and size of particles; solid homogenized meal emptied more readily than solid food just after chewing and swallowing; higher fat content slows gastric emptying; overall caloric content also factor; particles empty once down to 2 mm in size; process regulated by enteric hormones, specifically incretins (eg, amylin, glucagon-like pep­tide-1 [GLP-1], GLP-2); hormones regulate stomach, slow gastric emptying, suppress release of glucagon, and in­crease insulin secretion to control glycemic load presented to small intestine

Gastric dysrhythmia: correlates well with nausea (in motion sickness, pharmacologically induced after narcotics, first trimester of pregnancy); improvement seen with motility agents (eg, metoclopramide); nausea  —  most promi­nent symptom experienced in gastroparesis; other symptoms nonspecific; obstructive processes, especially neopla­sia, of utmost concern; alarm symptoms  —  prompt earlier endoscopic evaluation in patient with foregut complaints; include persistent nausea not relieved by standard therapy, with no diagnosed etiology; depressive or psychiatric overlay  —  seen in patients with complaints of chronic nausea from gastroparesis; studies show doubling of gastro­intestinal (GI) symptoms in diabetic patients with high levels of anxiety, depression, or other forms of neurosis (synergistic effect)

Gastroparesis: mechanisms  —  diabetic (most common), idiopathic, and postviral; significant number of diabetics show other stigmata of diabetes in end-organ effects; overall, only 5% to 12% of diabetics develop gastroparesis (higher in type 1 than type 2) but no association with mortality; economic and quality of life (QOL) impact  —  in pa­tients with severe gastroparesis before placement of gastric neurostimulators, average cost primarily related to re­peated emergency department (ED) visits and hospitalizations due to nausea, vomiting, and dehydration »$7000/mo; average time in hospital 2 days/mo; validated symptom severity scores and QOL indices worse in pa­tients with severe gastroparesis than in those with congestive heart failure, those on long-term dialysis, or with Crohn’s disease (CD); commonly offending medications  —  calcium-channel blockers; clonidine; antidepressants (due to anticholinergic side effects); medications for diabetes (through incretin mechanism; slows gastric empty­ing); narcotics; neuropathic mechanism of gastroparesis affected by poor diabetic control (blood glucose >180 mg/dL slows gastric emptying, primarily of solids)

Diagnosis: rule out other causes, especially neoplasms; scintigraphic evaluation gold standard (important to perform with standardized solid meal); liquid emptying less reliable; labeled food substances  —  metabolized in small intes­tine and absorbed; measured in exhaled breath; more specific but less sensitive than scintigraphy; significant differ­ence between normal emptying and diabetic emptying and between liquids and solids; liquid emptying fastest, then homogenized foods, then solids; electrogastrography (EGG)  —  often performed with water load (bedside test); pa­tient ingests water until full; normal individual ingests »600 mL in 5 min (»350 mL in patients with gastroparesis); arrhythmias often found on EGG, especially tachygastria

Treatment principles: tight glucose control in diabetes; correct fluid and electrolyte deficiencies; eliminate motility-suppressing medications; look for other causes besides gastropathy due to diabetic neuropathy; control symptoms and address nutritional needs; nutritional approach  —  avoid foods high in fat and in fruit and vegetable matter (po­tential for bezoar formation); intervene with invasive enteral-access or intravenous feeding if patient has  loses 10% of usual body weight over months or if repeated hospitalizations occur

Pharmacologic therapy: some prokinetic agents available only with specialized institutional review board approval or compassionate use protocols; antiemetics (some with anticholinergic side effects); switch to another class of agents if one class ineffective; multiple medications with multiple pathways possibly necessary to control symp­toms; prokinetic agents  —  few head-to-head comparisons; most studies show modest improvement in gastric emp­tying and symptom severity; erythromycin  —  motilin agonist; acts strongly with motilin receptors present throughout gut; used on short-term basis with some efficacy; causes tachyphylaxis; has other effects besdes gastric motility; significant side-effect profile, including nausea with oral administration; significant drug interaction is­sues; other macrolide-type antibiotics with longer half-life possibly useful; metoclopramide  —  30% discontinua­tion rate due to central nervous system side effects (eg, tardive dyskinesia); botulinum toxin  —  early data suggested benefit in pylorus relaxation and symptom control, although short in duration; reduces tachygastria; more recent studies show no substantial benefit over placebo; future options  —  study found that in diabetic neuron model, he­moxygenase-1 had effect on presence of c-kit protein as reflection of interstitial cells of Cajal (ICC; part of gastric pacemaker) and neuronal nitric oxide synthase (nNOS), that correlated with gastric emptying in diabetic mice

Gastric electrical stimulation: actual pacing of stomach for physiologic contraction not widely tested; not physio­logic; stimulation high frequency, compared to gastric pacemaker, with lower energy; affects tachygastria and gas­tric arrhythmia (correlates with nausea); approved by Food and Drug Administration for intractable, medication-refractory nausea and vomiting due to gastroparesis; approved under humanitarian device exemption; similar to cardiac pacemaker, leads placed in wall of stomach (not intraluminal); proper placement confirmed by endoscopy; open or laparoscopic procedure for placement; study data  —  show significant improvement in 50% of patients; sig­nificant placebo effect and almost statistically significant reduction in number of episodes of nausea and vomiting in diabetics; open-label phase of study showed reduction in number of episodes of nausea and vomiting from 7/day to 2-3/day at 12 mo; some efficacy also seen in postsurgical gastroparesis; results from Medical College of Georgia  —  showed significant improvement in symptom severity scores and significant reduction in medication re­quirements for symptom control; average cost savings $65,000 in first year after placement; benefit seen in »75% of patients; other surgical options  —(eg, subtotal gastrectomy) ineffective, although results slightly better in pa­tients with postsurgical gastroparesis

Acute Gastroenteritis and GI Disease  

 Christopher Chang, MD, PhD, Assistant Professor of Medicine, David Geffen School of Medicine at University of Califor­nia, Los Angeles, Associate Director of GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, CA

Postinfectious irritable bowel syndrome (PI-IBS): study  —2002 Salmonella outbreak in village in Spain; neighbor­ing village used as controls; 1200 patients; no contact between patients and researchers and no stool studies con­firming pathogen involved; questionnaires sent at 3-mo intervals for 1 yr; found prevalence of IBS similar before outbreak, and significant overlap between dyspepsia and IBS; relative risk (RR) at end of 1 yr, 7.8; no positive pre­dictor found; Walkerton study  —  livestock fecal contamination of water supply; acute gastroenteritis (AGE) in >2000 residents; no control group; questionnaire administered 2 yr after incident; Campylobacter and Escherichia coli O157:H7 most common pathogens; in patients who did not report episodes of AGE, prevalence of IBS 10% (baseline); if AGE self-reported, prevalence 27%, and if AGE based on clinical suspicion, prevalence 36%; inde­pendent risk factors included bloody stools, cramps, prolonged diarrhea, weight loss, female sex, and younger age; from literature, highest incidence 36%, with average of »10%; meta-analysis  —  found almost 10% of patients with previous infectious diarrhea developed PI-IBS (1.2% in controls); summary odds ratio (OR), 7.3; no evidence of publication bias; in patients with confirmed infection, OR almost 11; in self-reported infection, OR 5.3; more re­cent meta-analysis showed OR closer to 6 and pooled incidence of PI-IBS of »10%

Factors predicting PI-IBS: female sex; history of psychologic distress; younger age; greater duration and intensity of diarrhea and abdominal pain; psychologic factors   —adverse life events, especially in 6 mo before episode of AGE, and history of hypochondriasis independently predictive (with multivariate analysis); with univariate analy­sis, scores for somatization, neuroticism, and anxiety also significantly elevated; in study of IBS after Campylo­bacter infection, levels of perceived stress, somatization, anxiety, and negative illness beliefs correlated with development of PI-IBS

Potential mechanisms of PI-IBS: 1) immune activation or impaired anti-inflammatory mechanism in host; evidence includes increased lymphocytes in tissue and pro-inflammatory cytokine expression as well as polymorphisms affecting expression of anti-inflammatory cytokines (eg, interleukin [IL]-10, transforming growth factor [TGF]-) in patients prone to PI-IBS; 2) disruption of normal enteric microbiota dampens inflammation and other physio­logic processes; after AGE, £75% of normal flora in gut disappear temporarily, affecting normal production of short-chain fatty acids used by epithelium; 3) change in mucosal function, eg, permeability and absorptive changes; in infections with rotavirus, norovirus, or Giardia, disruption of epithelial layer of small bowel and hy­perplasia of neuroendocrine, Paneth, and mucus-producing cells seen; 4) persistent changes within enteric ner­vous system (ENS); 5) chronic changes in visceral hypersensitivity as seen in CD, eg, upregulation of receptors, motility changes; study  — found that 1 yr after patients infected with Campylobacter jejuni, high level of intraep­ithelial lymphocytes present, as seen in population with PI-IBS, suggesting that low-level chronic inflammation often characteristic of PI-IBS; high levels of immune cells also seen in lamina propria; study  — looked at diar­rhea-predominant IBS (D-IBS); mononuclear cells isolated from blood and stimulated in vitro with and without lipopolysaccharide (LPS) to determine response to proinflammatory cytokines; found elevation in IL-6 produc­tion only in D-IBS group before and after stimulation with LPS (in contrast to healthy controls and mixed and constipation forms of IBS); also seen with tumor necrosis factor (TNF)-a and IL-1b; serotonin (5-HT)  —increased 5-HT-positive enteroendocrine cells seen in rectal biopsies of patients with PI-IBS; predicted to in­crease formation of loose stools and may promote hyperalgesia and homing of inflammatory cells to site; ele­vated levels seen after test meal in patients with PI-IBS; study  —  found that flagellin (protein that makes up flagella) plays role in activating immune response by binding to toll-like receptor 5 (TLR5); dominant antigen in CD; frequency of finding antibodies to flagellin in patients with IBS elevated compared to controls and patients with ulcerative colitis (UC), but lower compared to CD patients; 24% of IBS patients classified as postinfectious; 52% of PI-IBS cohort positive for one antibody and 44% positive for other flagellin antibody

Persistent changes within ENS: start with inflammation mediated by inflammatory cytokines; in acute process, de­struction of tissue, including neurons, followed by remodelling of damaged nerves; leads to hypersensitivity, irri­tability, and altered muscle function (possibly affecting motility); in chronic process, persistence of inflammatory cytokines may impair release of neuro-transmitters, enhance muscular activity, and increase expression of nerve growth factor by mucosa

Treatment options for PI-IBS: treatment trials specific for PI-IBS lacking; gradual recovery over several years seen in pooled studies; consider  —  test for small intestinal bacterial overgrowth (SIBO) and treat accordingly, if positive; 5-aminosalicylic acid shows some efficacy; cholestyramine binds bile acids that reach colon (epithelial damage occur­ring in terminal ileum or right colon affects bile acid absorption, causing predominantly nocturnal diarrhea); probi­otics as adjunctive therapy; standard IBS treatment  —avoidance of general dietary laxatives (eg, dairy products, nonabsorbed sugars); loperamide for diarrhea; low-dose tricyclic antidepressants if pain predominant in symptoms; 5-HT antagonists; no improvement in IBS symptoms or number of enteroendocrine cells after 3-wk course of pred­nisolone 30 mg daily

Inflammatory bowel disease (IBD) after AGE: study   —used Danish registry; looked at all patients with Salmonella or Campylobacter infection documented by stool culture; followed for £15 yr (average 7.5 yr); among exposed population, 1.2% developed IBD (0.5% in unexposed controls); steep increase in rate occurred in first year after initial AGE; RR 2.9 for all patients with previous AGE; in patients hospitalized within 30 days before or after posi­tive stool culture, RR doubles

Postinfectious functional dyspepsia (PI-FD): study   —questionnaire given to 400 dyspeptic patients; infectious eti­ology presumed if suggestive signs present (eg, fever, malaise, nausea, vomiting); PI-FD presumed in »17% of pa­tients; diagnosis associated with complaints of early satiety, weight loss, and nausea and vomiting; no difference from noninfectious dyspeptics in gastric emptying or hypersensitivity; no increased prevalence of Helicobacter py­lori infection; impaired gastric accommodation only dif-ference found

Prevalence of dyspepsia after Salmonella outbreak: found frequent overlap between dyspepsia and IBS in these patients; RR for dyspepsia after AGE 5.2 (7.8 for IBS); positive predictors include prolonged abdominal pain and vomiting during AGE; study   —  survey of 12 presumed PI-FD patients and 12 unspecified FD patients based on pa­tient recall; duodenal biopsy taken 10 mo after symptom onset; found no difference in intraepithelial lymphocyte or enterochromaffin cell counts; focal aggregates of T cells only seen in almost 50% of PI-FD patients, with decreased CD4+ cells in villi and crypts; delayed gastric emptying of solids in PI-FD; gastric accommodation impaired but not statistically significant; potential recall bias

Postinfectious gastroparesis: rare; generally postviral, but usually not proven; improves spontaneously in most cases

Suggested Reading

Arts J et al: Influence of erythromycin on gastric emptying and meal related symptoms in functional dyspepsia with de­layed gastric emptying. Gut 54:455, 2005; Bortolotti M et al: Gastroparesis refractory to prokinetics: neuromuscolar unre­sponsiveness or faulty bioavailability of the drug? Dig Dis Sci 50:882, 2005; Brody F et al: Gastric electrical stimulation for gastroparesis. J Am Coll Surg 207:533, 2008; Dunlop SP et al: Relative importance of enterochromaffin cell hyperpla­sia, anxiety, and depression in postinfectious IBS. Gastroenterology 125:1651, 2003; García Rodríguez LA et al: Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease. Gastroenterology 130:1588, 2006; Hyett B et al: Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. Gas­troenterology 137:445, 2009; Lee HT et al: The mechanism and spread of pacemaker activity through myenteric interstitial cells of Cajal in human small intestine. Gastroenterology 132:1852, 2007 Lin Z et al: Chronic gastric electrical stimulation for gastroparesis reduces the use of prokinetic and/or antiemetic medications and the need for hospitalizations. Dig Dis Sci 50:1328, 2005; Marshall JK et al: Walkerton Health Study Investigators. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology 131:445, 2006; Mearin F et al: Dys­pepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroen­terology 129:98, 2005; Tack J et al: Clinical and pathophysiological characteristics of acute-onset functional dyspepsia. Gastroenterology 122:1738, 2002.