BAD DIGESTION
| DYSPEPSIA: UNINVESTIGATED, NONULCER, AND MORE —Terrence J. Frick, MD, Associate Professor, Section
of Gastroenterology and Hepatology, University of Wisconsin Medical School, Madison
|
| Definition of dyspepsia: literally, “bad digestion”; consists predominantly of epigastric pain present ≥1 mo, with or
without heartburn (overlaps with classic reflux disease); experienced regularly by 25% to 34% of Americans; accounts
for ≥5% of visits to primary care providers
|
 | Causes of dyspeptic symptoms: top 3—ulcers, reflux disease, nonulcer dyspepsia (one of functional gastrointestinal
[GI] disorders); other causes—include carbohydrate malabsorption, gallstones, chronic pancreatitis, malignancies,
ischemic changes, and other systemic diseases; also consider celiac disease (affects 1 in 150
Americans), duodenogastric reflux, hypervigilance, and somatic manifestation of psychiatric disease; medication
intolerance—abdominal pain classic side effect of proton pump inhibitors (PPIs); many other medications may
cause dyspepsia; review all medications with patient, including nonprescription agents
|
| Pathophysiology of nonulcer dyspepsia: impaired gastric accommodation; visceral hypersensitivity; delayed gastric
emptying; Helicobacter pylori infection
|
| Uninvestigated dyspepsia: refer for upper endoscopy if alarm symptoms present; alarm symptoms—age >45 yr;
weight loss >10%; bleeding; increasing dysphagia; severe vomiting or early satiety; history of ulcers or esophagogastric
cancer; family history of GI cancer; abdominal mass or lymphadenopathy detected on physical examination
|
| Test and treat: first perform breath test for H pylori infection; if positive, treat with H pylori eradication for 2 mo,
then reevaluate; alternatively, try PPI at least twice daily for 4 to 8 wk; PPI trial should be first choice if community
H pylori prevalence <10%
|
| H pylori as cause of dyspepsia: results of 2 studies contradictory; American College of Gastroenterology recommends
H pylori testing for uninvestigated dyspepsia on case-by-case basis
|
| Testing for H pylori: rate of H pylori infection decreasing in western society; decreases effectiveness of tests, leading
to more false negatives and more false positives in low-prevalence areas such as United States; antibodies
persist, so serologic testing not recommended in low-prevalence areas (appropriate in places with higher prevalence);
urea breath test has high sensitivity and specificity, although high risk for false-negative results if patient
already on acid suppression, on antibiotics for past 2 mo, or taking PPIs or bismuth-based medication; stool antigen
test—sensitivity and specificity similar to those of urea breath test, but drawbacks also similar; rapid test
now available (results in 5 min)
|
| Obstacles to H pylori eradication: complexity of medication regimen (discourages compliance); resistance of some
H pylori strains to clarithromycin (cannot be overcome by prolonging regimen or increasing dosage)
|
| Managing dyspepsia: determine whether pain similar to ulcer pain or mainly bloating sensation
|
| Epigastric pain syndrome: ulcer-like pain; discontinue nonsteroidal anti-inflammatory drugs; try antisecretory
agents, eg, PPIs, instead; make sure dose adequate; tegaserod—used off-label for upper abdominal bloating;
withdrawn from market after retrospective analysis of old data showed unacceptably high risk for cardiovascular
events in patients with underlying preexisting cardiovascular disease or risk factors
|
| Drugs for managing epigastric pain: metoclopramide (high likelihood of side effects); cisapride essentially unavailable;
domperidone unavailable in United States; low-dose tricyclic antidepressants, selective serotonin reuptake
inhibitors, psychotherapy, and hypnosis all shown to help with functional GI disorders
|
| Dietary causes of bloating and dyspepsia: caffeine, fatty foods (in excess), fruit, sorbitol, fructose (in excess), lactose,
beans, raw cabbage, broccoli, cauliflower, carbonated beverages, and some spices; have patient keep dietary history
for 1 wk
|
| Complementary remedies: peppermint oil, caraway oil, artichoke leaf extract, capsaicin, celandine; STW
(Iberogast)—combination of 9 extracts; company-supported trials support use for functional dyspepsia
|
| Impact of PPIs on endoscopy results: therapy for 2 wk can resolve abnormal findings; consider reasons for performing
endoscopy (simply to check for inflammation probably not justified; detection of possible cancer justified)
|
| Diagnosis: comprehensive evaluations reveal no identifiable causes of dyspepsia in 30% to 60% of cases; history
alone insufficient for distinguishing ulcer from nonulcer dyspepsia; animal studies suggest acid-induced gastric
damage makes normal distention painful, even after lesions heal; for humans, result is dyspepsia; some people genetically
more susceptible to unexplained functional dyspepsia
|
| GUT HORMONES AND INTESTINAL FUNCTION: THE NEXT GENERATION— Mark Pimentel, MD, Director,
GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, CA
|
| Gut-control hormones: endocrine-derived hormones produced in gut that affect gut motility; important for regulating
digestion; redundance built into system, ie, if one missing, others compensate; work centrally and peripherally;
control satiety, appetite, and nausea (in high doses); affect appetite centers, including hypothalamus,
nucleus tractus solitarius, and area postrema; direct control—provide feedback on electromechanical, inhibitory,
and prokinetic effects on bowel; also control small bowel, pancreas, and gallbladder; show greatest promise
in managing obesity and short-bowel syndrome (SBS)
|
| Management goals: SBS—to slow transit of food through bowel without inhibiting pancreatic function or increasing
satiety; obesity—goal to accelerate transit time through gut, or slow it down to point where patient does not
feel like eating more (inhibition of pancreatic and biliary function desirable because it promotes malabsorption);
increase satiety
|
| Agents of interest for future development: grehlin (produced in stomach); amylin and pancreatic polypeptide (both
produced in pancreas); cholecystokinin (CCK; produced in small bowel); glucagon-like peptide (GLP-1); oxyntomodulin;
peptide YY (PYY)
|
| Cholecystokinin: increases pancreatic secretions and gallbladder contractions; in animals, causes anorexia in superphysiologic
doses; works via CCK-A receptor; however, does not reduce food intake in animal studies, probably
because other molecules override its effects
|
| Grehlin: stimulates food intake and release of growth hormone; causes obesity when administered to rats, so grehlin
antagonists should promote weight loss; however, weight loss stimulates grehlin production; in one study of people
who lost weight, the more weight lost, the more grehlin levels increased, resulting in greater appetite; counteracts
effect of pharmacologic grehlin antagonist; however, grehlin levels decrease dramatically in patients who have undergone
gastric bypass surgery
|
| Pancreatic polypeptide: food triggers release from pancreas; inhibits pancreatic function, gallbladder contraction,
gastric secretion, and motility; little known about it; in early stages of development
|
| Peptide YY: produced in ileum; release triggered by food, especially fat; slows gastric emptying, inhibits pancreatic secretions,
gallbladder contractions, and gastric secretion; in animals, injection associated with satiety and weight loss;
now under development as possible weight-loss drug
|
| Glucagon-like peptide-1: produced in ileum by L-cells and released in response to carbohydrates; “one of the most
dramatic slowers of upper gastrointestinal tract emptying;” completely inhibits activity of stomach and small
bowel; enhances pancreatic function; increases insulin release, which could promote weight gain, however, satiety
also increased; has trophic effect on pancreas (stimulates islet cell proliferation); long-term effects unknown;
nesidioblastosis—trophic enlargement of islet cells seen with GLP-1; called dysplasia, although unknown whether
it progresses to cancer; can lead to hypoglycemia because of increased insulin production
|
| Short-bowel syndrome: usually occurs after distal small bowel resection; symptoms include severe postprandial diarrhea,
steatorrhea, weight loss, and malnutrition; patients often require parenteral nutrition (complications include
sepsis, death, cirrhosis, and gallstones); small-bowel transplantation associated with excessively high
morbidity and mortality
|
| Mechanism of short-bowel failure: possibilities include insufficient short-bowel length; inadequate villous absorptive
capacity; too-rapid transit time; bacterial overgrowth
|
| Study of exenatide in patients with SBS: studies suggest GLP-1 increases absorptive capacity; exenatide is GLP-1
agonist; synthetic form of hormone found in gila monster saliva; approved for treatment of diabetes; Cedars-Sinai
team tried in patients with SBS
|
| Study: after baseline evaluation and fasting small-bowel manometry, consecutive patients placed on exenatide;
manotmetry repeated for another 30 min, followed by meal; patients followed for 15 to 18 mo
|
| Dose of exenatide: 5 to 10 µg, administered subcutaneously
|
| Results: 5 patients participated; overall improvement recorded on questionnaires, 65% to 100%; before receiving
exenatide, patients would have bowel movement within 10 min of eating; 3 patients required total parenteral
nutrition before taking medication, compared to none 1 mo later, with no cases of malnutrition; increased urinary
frequency reflected improved GI absorption; baseline manometry showed gastric contractions even with
empty stomach, with cessation of activity after exenatide administration
|
| Amylin: produced by pancreas; slows stomach, but inhibits pancreatic function
|
| CELIAC DISEASE UPDATE— Christopher D. Lind, MD, Professor of Medicine, Digestive Disease Center,
Vanderbilt University Medical Center, Nashville, TN
|
| Definition of celiac disease (celiac sprue): abnormal proximal small-bowel mucosa that improves morphologically
on gluten-free diet; relapses upon reintroduction of gluten; also called gluten-sensitive enteropathy; patients have
genetic predisposition
|
| Dermatitis herpetiformis: pruritic blistering skin eruption strongly associated with celiac disease; characterized by
granular IgA deposits in dermal-epidermal junction
|
| Presentations: atypical—most common; may involve unexplained iron deficiency anemia, osteoporosis, short stature,
or other problems, eg, constipation; classic—malabsorption; asymptomatic (“silent”)—diagnosed only from serologic
testing; latent—symptoms can remit for many years; refractory
|
| Epidemiology: formerly thought to afflict only people of western European descent; now known to occur elsewhere;
US prevalence 1 in 100 to 1 in 300 people; overall prevalence in western countries ≈1%; 10% chance that first-degree
relative of patient will also have it (4% for second-degree relatives); prevalence ≈6% in asymptomatic people with idiopathic
iron deficiency; also suspect in patients with type 1 diabetes, and abnormal liver function tests (LFTs)
|
| Classic symptoms: altered bowel habits, bloating, dyspepsia, abdominal discomfort, irritable bowel syndrome (IBS;
patient may fulfill IBS criteria even with celiac disease under control)
|
| Atypical symptoms: currently most common presentation; atypical symptoms include unexpected iron deficiency
anemia, vitamin deficiencies, coagulopathy, dermatitis herpetiformis; almost all patients have abnormal intestinal
biopsy findings, even in absence of GI symptoms; treatment of skin lesions has no effect on gut, but gluten-
free diet may help both; obstetric and gynecologic manifestations also possible (eg, miscarriage), and may respond
to gluten-free diet; musculoskeletal manifestations (eg, osteoporosis, osteopenia); other autoimmune conditions
|
| Screening guidelines: screen patients with unexplained iron deficiency anemia, osteoporosis, Down syndrome, or
low-grade LFT abnormalities; consider for patients with other conditions, including IBS
|
| Pathogenesis: immune-mediated process in genetically predisposed individuals; patients intolerant to prolamins in
wheat and other cereals; tissue transglutaminase deaminates gliadin, triggering immune reaction by CD4 T-lymphocytes;
leads to inflammatory response; associated with specific HLA haplotypes (DQ2 and DQ8)
|
| Diagnosis: based on characteristic histologic findings; response to gluten-free diet (repeat biopsies unnecessary); can observe
clinical response to gluten challenge in rare patients who do not undergo other tests; serologic tests play key role
in screening; in recent study of patients with diarrhea-predominant IBS, presence of tissue transglutaminase antibodies
predicted response to gluten-free diet
|
| Pathology: wide variance in degree of small-bowel damage; likelihood of classic malabsorption symptoms increases
with damage severity; blunted villi; loss of villi-crypt ratio (villous loss, crypt hyperplasia); epithelial
lymphocyte infiltration (first histologic change); endoscopy may reveal flattened mucosa; absent, notched, or
scalloped folds; mucosal fissures; however, findings not specific to celiac disease
|
| Serologic markers: main diagnostic test; tissue transglutaminase antibodies highly specific for celiac disease; antigliadin
antibodies less specific; both can be used to monitor patient adherence to gluten-free diet (titers should decrease);
most clinicians measure both, but tissue transglutaminase (antiendomysial) antibody study of choice,
although not 100% accurate (biopsies recommended); use serologic tests for initial diagnosis and to monitor compliance
with treatment; take biopsies from second portion of duodenum (take several samples)
|
| HLA-DQ tests: add nothing to tissue transglutaminase tests
|
Suggested Reading
Barnett A: Exenatide. Expert Opin Pharmacother 8: 2593, 2007; Esposito C et al: New therapeutic strategies for
coeliac disease: tissue transglutminase as a target. Curr Med Chem 14: 2572, 2007; Estall JL, Drucker DJ: Glucagon
and glucagon-like peptide receptors as drug targets. Curr Pharm Des 12: 1731, 2006; Lane JA et al: Impact of
helicobacter pylori eradication on dyspepsia, health resource use, and quality of life in the Bristol helicobacter
project: randomised controlled trial. BMJ 332: 199, 2006; Leeds JS et al: Is there an association between celiac disease
and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls. Scand
J Gastroenterol 42: 1214, 2007; Leffler DA et al: A prospective comparative study of five measures of gluten-free
diet adherence in adults with coeliac disease. Aliment Pharmacol Ther 26: 1227, 2007; Martin GR et al: Gut hormones
and short bowel syndrome: the enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation.
World J Gastroenterol 12: 4117, 2006; McGowan KE et al: Celiac disease: are endomysial antibody test results
being used appropriately? Clin Chem 53: 1775, 2007; McNally MA, Talley NJ: Current treatments in functional
dyspepsia. Curr Treat Options Gastroenterol 10: 157, 2007; Talley NJ, Vakil N, Practice Parameters Committee
of the American College of Gastroenterology: Guidelines for the management of dyspepsia. Am J Gastroenterol
100: 2324, 2005; Wildner-Christensen M et al: Rates of dyspepsia one year after Helicobacter pylori screening and
eradication in a Danish population. Gastroenterology 125: 372, 2003.
Educational Objectives
| The goal of this program is to improve the management of dyspepsia and celiac disease and to present current knowledge
on the role of digestive hormones in the management of short-bowel syndrome (SBS). After hearing and assimilating
this program, the clinician will be better able to:
|
| 1. List the 3 most common causes of dyspepsia.
|
| 2. Manage the various types of dyspepsia.
|
| 3. Name the gut hormones currently under investigation as agents for managing SBS and obesity.
|
| 4. Explain why exenatide might be effective for treatment of SOS.
|
| 5. Diagnose celiac disease in a patient with atypical symptoms.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
members 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 faculty and planning committee
reported nothing to disclose.
Acknowledgements
Dr. Frick spoke at the 5th Annual Update in Gastroenterology and Liver Disease, held April 21, 2007, in Madison,
WI, and sponsored by the University of Wisconsin School of Public Health, Section of Gastroenterology and Hepatology,
and the Office of Continuing Professional Development in Medicine and Public Health. Dr. Pimentel was recorded
at the 8th Annual Update in Gastroenterology, held October 26-28, 2007, in La Quinta, CA, and sponsored by
the Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles. Dr. Lind spoke at the Gastroenterology
Update, 2007, held September 28, 2007, in Nashville, TN, and sponsored by the Division of Gastroenterology, Hepatology,
and Nutrition, Vanderbilt University School of Medicine. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
|
