Gastrointestinal Dilemmas

Educational Objectives

The goal of this program is to improve the management of dyspepsia and other functional gastrointestinal disorders, reduce the incidence of colorectal cancer (CRC) mortality with screening, and improve the understanding of clinical applications of pharmacogenomics. After hearing and assimilating this program, the clinician will be better able to:

1.   Diagnose and manage functional dyspepsia.

2.   Recognize the importance of the enteric nervous system in functional GI disorders.

3.   Follow recommended guidelines for CRC screening.

4.   Review the advantages and disadvantages of each of the screening tests for CRC.

5.   Discuss the relevance of thiopurine methyltransferase (TPMT) genotyping in the management of patients with Crohn’s disease.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee 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.

Acknowledgments

Dr. Frick was recorded at the 2008 Primary Care Conference, held November 13-14, 2008, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health, Office of Continuing Professional Development in Medicine and Public Health, Department of Family Medicine, Department of Medicine, and University of Wisconsin Con­tinuing Education in Nursing. Dr. Walsh was recorded at Primary Care Medicine: Principles and Practice, held October 29-31, 2008, in San Francisco, CA, and sponsored by the University of California, San Francisco, School of Medicine, Depart­ment of Medicine, Division of General and Internal Medicine. Dr. Achkar was recorded at the 44th Annual Gastroenterology Update, held September 11-12, 2008, in Cleveland, OH, and sponsored by the Cleveland Clinic Foundation. The Audio-Di­gest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Dyspepsia and Irritable Bowel Syndrome

Terrence J. Frick, MD, Associate Professor, Section of Gastroenterology and Hepatology, Department of Med­icine, University of Wisconsin School of Medicine and Public Health, Madison

Dyspepsia: “bad digestion”; definition  —  upper abdominal pain not related to colon function; may include early sati­ety, fullness, bloating, and nausea (component of many disorders, including chronic headaches); defined by Talley as predominant epigastric pain present for ³4 wk, with or without heartburn; heartburn defined as chest burning with gross regurgitation that can include dyspepsia; not 2 separate diseases, but consider more prominent symptom; affects 26% to 41% of citizens in United States; 5% of primary care visits

Uninvestigated dyspepsia: upper abdominal pain, as described, in which no investigation (invasive or noninvasive) previously performed; causes  —  irritable bowel syndrome (IBS), nonulcer dyspepsia (NUD), or functional dyspep­sia; ulcer disease; gastroesophageal reflux disease (GERD; often has dyspeptic component); carbohydrate malab­sorption; gallstones (foregut organ); chronic pancreatitis; malignancy (eg, pancreatic cancer); ischemia; systemic diseases (eg, amyloidosis, sarcoidosis)

Medications causing dyspepsia: top 2 aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs); both most com­mon cause of non-Helicobacter pylori, non-aspirin/non-NSAID ulcers (due to nonreporting of medication use by patients); others include angiotensin-converting enzyme (ACE) inhibitors, antibiotics, colchicine, estrogens, etha­nol (causes diarrhea), gemfibrozil, steroids, iron, and niacin

Gas-producing foods: everyone has carbohydrate intolerance (no human perfectly digests carbohydrates); fructose with glucose (eg, apples); fructans (eg, onions, leeks); breads and pasta; sorbitol (stone fruits); raffinose (eg, le­gumes, cabbage)

Lactose deficiency: clinically common; low threshold; lactose in meal easier to absorb; diagnosis  —  lactose toler­ance test or breath test; simpler test to have patient drink 3 glasses of milk without food; treatment  —  lactose avoid­ance or lactase supplement; yogurt well-tolerated; most people, regardless of lactase state, tolerate one glass of milk daily without problems; people who produce lactase enzyme “genetic mutants” (normally stop producing lac­tase at age of weaning); Northern Europeans have no lactase deficiency, whereas Asian-Americans lactase-defi­cient

Celiac disease: occurs in 1 in 125 people; >1 million Americans affected (>50% are women); only 90,000 exhibit classic signs and symptoms, including iron-deficiency anemia, diarrhea, and weight loss; screening  —  serum tissue transglutaminase antibody and IgA level; 20% of individuals with celiac disease do not produce IgA; diagnosis  —  minimum of 6 biopsies from duodenum (>90% accurate); unable to distinguish celiac disease from IBS by history

Alarm symptoms: age >45 yr; significant unanticipated weight loss; bleeding or anemia; difficulty swallowing; se­vere vomiting (cyclic vomiting syndrome common); severe early satiety; warrants investigation with endoscopy, imaging studies, or blood tests

Functional dyspepsia: symptoms present as described plus negative endoscopy; in investigating dyspepsia, decide whether to biopsy for celiac disease (necessary) or for H pylori; test for H pylori with active test (not antibody test); decision to test implies decision to treat; if treating for H pylori, must confirm eradication (new standard of care) with active test; 2 subtypes  —  ulcer-like and bloating-predominant NUD; dyspepsia and H pylori  —  for duodenal ulcer, number needed to treat (NNT) 2; for functional dyspepsia, NNT 20; testing for and treating H pylori  —  not cost-effective to screen everyone; should not use antibody testing (antibody persists); look for active infection with urea breath test or stool antigen; for stool antigen test, patient must discontinue proton pump inhibitors (PPIs), anti­biotics, and bismuth 2 wk before

Management of dyspepsia: discontinue NSAIDs and aspirin; determine whether ulcer-like or bloating-like by his­tory; if ulcer-like, use antisecretory agents (PPI, eg, esomeprazole bid); double dose of regular PPI bid for ³6 wk; PPIs require acid environment for efficacy (taken 15-30 min before meal at beginning and end of day); if bloating-like, use promotility agent (metoclopramide); base decision to test and treat H pylori on evidence, experience, and what patient asking for; however, must be realistic about chances of relief; other issues  —  if initial therapy failed, broaden investigation as appropriate with, eg, endoscopy, ultrasonography; if patient young, speaker takes time be­fore performing tests; treat any underlying anxiety and depression; hypnotherapy proven effective; integrative med­ical clinics also effective due to diversity of strategy

Functional gastrointestinal (GI) disorders: pathophysiology  —interaction between enteric nervous system (ENS) and immune system of gut; include IBS, bloating, constipation, diarrhea, and functional abdominal pain syndrome (never give narcotics to these patients); IBS  —  common; affects 20% of population of United States; most common diagnosis of gastroenterologists; one of top 10 reasons for physician visits; symptoms include dizziness, passage of mucus, and rectal dissatisfaction; meta-analysis  —  looked at all available data on IBS; found hyoscyamine, cime­tropium, and peppermint oil most effective; extensive testing unnecessary in absence of alarm symptoms (ie, unex­plained weight loss, bleeding, fever); family history of inflammatory bowel disease (IBD) or cancer of GI tract (does not include spastic colitis [old term for IBS]); ENS  —  50 million neurons; 95% of serotonin receptors in gut; communicates with brain; GI tract largest immune organ in body; visceral hypersensitivity more pronounced in IBS patients; role for inflammation  —  mast cells close to ENS; altered mucosal immune and inflammatory function changes ENS; large part of management long-term care; establish good rapport with patient; treatment guidelines  —identify concerns; explain basis for concerns; reassure; cost-effective evaluation; provide continuity; set realistic limits; International Foundation for Functional GI Disorders good resource

Screening for Colorectal Cancer 

Judith M.E. Walsh, MD, MPH, Professor of Clinical Medicine, Epidemiology, and Biostatistics, Department of Medicine, University of California, San Francisco, School of Medicine

Tests for colorectal cancer (CRC) screening: most commonly recommended include fecal occult blood testing (FOBT), sigmoidoscopy, colonoscopy, fecal immunochemical testing (FIT), or virtual colonoscopy; about two-thirds recommend colonoscopy; evidence for screening  —  CRC second most common cause of cancer mortality in United States; several studies show that screening with FOBT or sigmoidoscopy associated with reduction in CRC mortality

Guidelines for screening: 2 sets; new joint guidelines  — supported by American College of Radiology (ACR), American Cancer Society, and American GI Society; for early detection of CRC and polyps; screening tests grouped into 2 categories (those that detect cancer early [stool tests] and those that can also detect adenomatous polyps [structural exams]); choices include annual FOBT or FIT, flexible sigmoidoscopy every 5 yr, barium enema every 5 yr, computed tomographic colonography (CTC; virtual colonoscopy) every 5 yr, colonoscopy every 10 yr, or stool DNA testing (interval uncertain); must make patients aware of full range of screening options; offer pa­tients choice between screening test effective at early cancer detection or both early cancer detection and prevention by removal of adenomatous polyps; CRC prevention (ie, detection of polyps) should be primary goal of screening; patients and providers should understand limitations and requirements of noninvasive tests (less likely to prevent cancer because less likely to detect polyp, must be repeated at regular intervals for efficacy, and if test abnormal, subsequent invasive test necessary); United States Preventive Services Task Force guidelines  —recommend screen­ing with FOBT, sigmoidoscopy, or colonoscopy in adults 50 to 75 yr of age; no preferred screening test recom­mended; routine screening not recommended for individuals 76 to 85 yr of age, but life expectancy and comorbidities considered in making decision; advise against screening individuals ³85 yr of age; evidence insuffi­cient for CTC and fecal DNA

Test issues: FOBT  —  good evidence for reducing mortality, but trials repeated FOBT every 1 to 2 yr; positive test re­quires evaluation of entire colon; sigmoidoscopy  —  fair evidence for reducing mortality; can miss proximal neopla­sia, so positive test should be followed by colonoscopy; FOBT vs in-office single (digital) FOBT  —  sensitivity for neoplasia 24% for 6-sample FOBT vs 5% for single FOBT; specificity higher for digital FOBT; single FOBT poor screening method; screening colonoscopy  —  more sensitive than FOBT and sigmoidoscopy; more specific than FOBT; higher risk; more costly; not yet evaluated with clinical trials looking at mortality as outcome; presumed ef­fective because of use in FOBT trials; feasibility depends on insurance coverage and gastroenterologist availability; ACR Imaging Network (ACRIN) trial  —  looked at efficacy of CTC in detecting large polyps; the larger the polyp, the more likely its potential as precursor to cancer; sensitivity 90% for polyps ³10 mm (78% for smaller polyps); specificity 86% for polyps ³10 mm (88% for polyps ³6 mm); CTC vs standard colonoscopy  —  when diagnostic yield of each approach compared, and similar numbers of advanced neoplasms found, fewer complications in CTC group; issues around CTC  — requires bowel preparation and insufflation; not necessarily preferred by patients; test interpretation time-consuming; high rate of extracolonic findings; uncertain which action to take when small pol­yps found; fecal DNA testing  —  recommended in new joint guidelines, although test interval uncertain; DNA alter­ations in CRC detected in stool; potential advantages include noninvasiveness, absence of preparation, and ability to detect mutations along entire length of colon; when evaluated as screening test in multicenter study, found to de­tect more neoplasms than FOBT (eg, Hemoccult, Hemoccult Sensa), although had more false positives requiring unnecessary colonoscopies; higher sensitivity (20%) than FOBT (11%; Hemoccult) but lower specificity; remain­ing questions about fecal DNA —unknown health outcomes; unknown risk-benefit ratio; public expectations about accuracy of DNA testing; frequency of testing; acceptability and availability; cost; FIT  —  more sensitive than FOBT; detects human globin; globin does not survive passage through upper GI tract; no dietary restrictions; newer test uses brush sampling of toilet water rather than handling of stool; more sensitive in detecting CRC and large ad­enomas than FOBT (Hemoccult) but less specific (higher false-positive rate)

Rates of screening: 50% for CRC; slightly >50% had sigmoidoscopy or colonoscopy and 27% had FOBT in past 2 yr

Conclusions: any screening better than no screening for reducing CRC mortality; increase awareness of importance of CRC screening

Pharmacogenomic Testing for Inflammatory Bowel Disease

Jean-Paul Achkar, MD, Staff Gastroenterologist, Cleveland Clinic, Cleveland, OH

Pharmacogenomics: study of relation between variations in genes and individual differences in drug response and toxicity; potential genes of interest include drug receptors, metabolizing enzymes, transporters, and targets to which these drugs aimed, eg, tumor necrosis factor (TNF)-a; holds promise of tailoring drug therapy based on indi­vidual’s genetic makeup

Thiopurine methyltransferase (TPMT): azathioprine (AZA) and 6-mercaptopurine (MP) handled similarly after initial conversion of AZA into 6-MP; 3 competing enzymatic pathways, one of which leads to production of 6-thio­guanine nucleotide (TGN; thought to lead to beneficial effect in IBD); other 2 pathways lead to inactive metabo­lites; transfers methyl product onto 6-MP, making it 6-methylmercaptopurine (6-MMP); inherited differences in TPMT activity present; 2 wild type or normal alleles and £20 variant alleles associated with low TPMT activity; in white and black populations, most carry 2 wild-type alleles (normal TPMT); 3 alleles account for majority of TPMT deficiency inheritance; 89% have HH phenotype (associated with normal enzyme activity); 11% have 1 nor­mal allele and 1 abnormal allele, leading to intermediate enzyme activity; 0.3% have 2 copies of abnormal alleles, leading to low or absent TPMT activity, and, therefore, standard or high doses of 6-MP or AZA can lead to pro­found bone marrow suppression, infection, or even death; testing  —  prospective evaluation of 6-MP metabolites and TPMT genotyping in pediatric population (mostly Crohn’s disease [CD] patients) found that 6-TGN levels as­sociated with response to therapy, while 6-MMP (byproduct of TPMT) not associated with response; looked at TPMT genotype and found that those with intermediate activity made >2 times amount of 6-TGN than those with normal enzyme activity; 6-MMP not associated with response to therapy, but associated with hepatotoxicity; the higher the level of 6-MMP, the greater the risk of developing elevated liver enzymes; some in vitro data suggest that mesalamine products can inhibit TPMT activity, with clinical implications similar to being TPMT intermediate-ac­tivity genotype (by blocking TMPT enzyme, reducing production of 6-MMP and shunting production more to­wards 6-TGN); several studies looking at issue, and although several show shift towards producing 6-TGN, not clear whether difference clinically relevant; study  —  looked at patients with CD starting AZA therapy and deter­mined their TPMT genotype; using white blood cell (WBC) count as surrogate marker of response, those who re­ceived appropriate dose had appropriate decrease in WBC count, as did those with intermediate TPMT activity who were underdosed; those who should have received higher dose did not have substantial decrease in WBC count; no problems with leukopenia during therapy; one potential approach in using TPMT to guide therapy involves check­ing baseline TPMT genotype or phenotype before starting therapy; those with normal enzyme activity should re­ceive target dose immediately (1-1.5 mg/kg of 6-MP or 2-2.5 mg/kg of AZA); those with intermediate activity underdosed (£50% of usual dose); avoid therapy in those with absent activity; TPMT should not replace routine laboratory monitoring, as even those with normal TPMT activity can still develop leukopenia for other reasons

Anti-TNF therapy: up to one-third of individuals who receive anti-TNF therapy primary nonresponders; prospective infliximab studies looked at with subsequent genotyping for TNF-a and 2 of its receptors, no difference found (whether responder or not) based on individual genotype; reason other than polymorphisms in TNF-a or its recep­tors leads to nonresponse

Genetics: first genome-wide association study (GWAS) looked at 308,000 single nucleotide polymorphisms (SNPs), with 2 subsequent replication studies; first phase of results confirmed importance of NOD2 gene in CD; other de­scription of interleukin (IL)-23 receptor gene; 7 GWAS and meta-analysis show total of 32 genes or loci that meet strictest of statistical criteria for association with CD

Suggested Reading

Ahlquist DA et al: Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med 149:441, 2008; Graser A et al: Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population. Gut 58:241,2009; Lin OS et al: Risk stratification for colon neoplasia: screening strategies using colonoscopy and computerized tomographic colonography. Gastroenterology 131:1011, 2006; Longstreth GF: Functional dyspepsia--managing the conundrum. N Engl J Med 354:791, 2006; Seeff LC et al: Patterns and predictors of colorectal cancer test use in the adult U.S. population. Cancer 100:2093, 2004; Smith A et al: Comparison of a brush-sampling fecal immunochemical test for hemoglobin with a sensitive guaiac-based fecal occult blood test in detection of colorectal neoplasia. Cancer 107:2152, 2006; Hindorf U et al: Pharmacogenetics during stan­dardised initiation of thiopurine treatment in inflammatory bowel disease. Gut 55:1423, 2006; Thompson MR et al: Pre­dictive value of common symptom combinations in diagnosing colorectal cancer. Br J Surg 94:1260, 2007; Tremelling M et al: IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 132:1657, 2007; U.S. Preventive Services Task Force: Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 149:627, 2008;  Wu HC et al: Prevalence of peptic ulcer in dyspeptic patients and the influence of age, sex, and Helicobacter pylori infection. Dig Dis Sci. 53:2650, 2008; Zauber AG et al: Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force. Ann Intern Med 149:659, 2008.