CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California

Transcription

1 GASTROENTEROLOGY 2004;126: CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California Rectal Bleeding and Diminutive Colon Polyps DAVID LIEBERMAN Division of Gastroenterology, Oregon Health and Science University, Portland VA Medical Center, Portland, Oregon Clinical Case Part 1 A 40-year-old man presents to his primary care provider with report of rectal bleeding when he strains during bowel movements. He is otherwise healthy, and does not have a family history of colorectal cancer or known adenomas. The primary care provider calls your office for expert advice about the appropriate diagnostic procedure to perform to evaluate this symptom. Background Visible rectal bleeding is a very common occurrence in the general population. Up to 15% of adults report seeing blood in the toilet bowl or on toilet paper in the previous 6 months. 1,2 This symptom is considered an important sign of colonic disease, including malignancy. Although relatively few people seek health care to evaluate rectal bleeding, 1 rectal bleeding is one of the most common indications for colonoscopy in the United States. In an evaluation of practice patterns among 100 diverse practice sites in the United States, visible rectal bleeding was listed as an indication in 22% of all colonoscopy procedures in adults (Clinical Outcomes Research Initiative: CORI; personal communication, January 2004). If bowel movements are otherwise normal, the differential diagnosis includes hemorrhoids, solitary rectal ulcer, diverticular bleeding, angiodysplasia, and proctitis. The most serious cause of rectal bleeding (with otherwise normal bowel movements) is malignancy. Several studies, which have determined the risk of malignancy in patients with rectal bleeding using colonoscopy, are summarized in Table These studies are plagued by inconsistent methods and reporting. There are no uniform definitions to describe the amount or frequency of bleeding. Some studies have included patients with serious lower GI bleeding, 4 while others define the patient population by passage of small amount of blood visible in toilet or tissue paper, or occult blood. Some studies do not stratify by age, and others exclude patients younger than 40 or 45 years old. Some, but not all, studies report the location of cancers. Most of the studies do not provide additional important clinical information such as family history of colorectal cancer (CRC), weight loss, or anemia. Therefore, it is difficult to apply these data to develop clinical guidelines. Potential Management Strategies The diagnostic approach to patients with rectal bleeding in clinical practice is quite variable, ranging from no evaluation to colonoscopy. No Evaluation Can a careful history represent a sufficient evaluation of rectal bleeding? The decision to evaluate rectal bleeding can be stratified based on age, symptoms, and other risk factors. In young patients ( 40 years old) with 1 or 2 episodes of minor bleeding, the pre-test probability of malignancy in the absence of a family history of CRC is extremely low. Under age 40 years of age, the risk of CRC in men and women is 0.06% (1 in ). There are fewer than 1000 deaths per year from CRC in patients younger than 40 years old. 12 Many of these cases occur in patients with familial cancer syndromes. There are limited data on colonoscopic evaluation of patients younger than 40 years old with rectal bleeding (Table 1). These studies suggest that the risk of malignancy is very low. Examination of the colon could Abbreviations used in this paper: AP, adenomatous; CRC, colorectal cancer; HP, hyperplastic polyps; MSI, microsatellite instability; NNE, number needed to endoscope by the American Gastroenterological Association /04/$30.00 doi: /j.gastro

2 1168 DAVID LIEBERMAN GASTROENTEROLOGY Vol. 126, No. 4 Table 1. Colonoscopic Evaluation of Rectal Bleeding Author Year No. of patients Cancers Cancer in patients 40 yrs Goulston (10.3%) a Guillem (16.4%) 0/35 Mant ( 40 yrs) 30 (21%) a Church (12.6%) a Outlet bleed (4%) Suspicious (22%) Hemorrhage 27 3 (11%) Occult (19%) Korkis ( 50yrs) 0/46 (age40 50) 0/56 Helfand (6.5%) 0/38 Segal ( 45 yrs) 4 (4%) a Fine (10.3%) 5/58 (8.6%) Mulcahy (4.0%) 2/165 (1.2%) a All patients 40 years old. detect other important pathology such as colitis, solitary ulcer, or trauma, although these patients may or may not have other symptoms in addition to bleeding which would require endoscopic evaluation. Therefore, a careful history may be sufficient for a patient younger than 40 years old, with minor outlet bleeding, no other symptoms, and no family history of CRC. Patients with significant bleeding or family history of CRC should have endoscopic evaluation. In the 40- to 59-year-old age group, the prevalence rate for CRC jumps to 0.88 (1 in 114) in men, and 0.69 (1 in 145) in women. 12 Given the higher pretest probability of malignancy after age 40 years, some evaluation of the colon should be performed if there are lower gastrointestinal symptoms such as rectal bleeding. Anoscopy Limited anoscopy can detect perianal pathology such as hemorrhoids and anal fissures. Some would argue that if obvious bleeding or large hemorrhoids were found at anoscopy, this might represent a sufficient evaluation of patients with rectal bleeding. There are no data to inform this medical decision. However, since the anoscope does not typically provide a view of the rectum, it is insufficient to rule out the possibility of a rectal tumor or proctitis. Since hemorrhoids are so common, the very presence of hemorrhoids does not necessarily reduce the likelihood that there is some other pathology responsible for rectal bleeding. Barium or CT Imaging There are no data about the accuracy of using x-ray imaging studies to evaluate patients with rectal bleeding. If pathology were found, it would not be evidence for a source of bleeding (e.g., polyp, diverticulosis). The absence of radiographic abnormalities does not rule out the possibility of serious pathology. In the National Polyp Study, more than 50% of patients with polyps 1 cm were not identified with barium enema. 13 CT colography is still evolving as a diagnostic tool. In recent studies with CT colonography, the sensitivity for detection of polyps 1 cm was 75% in one study, 14 and 94% in another. 15 In some, but not all, recent studies there is considerable interobserver variability in interpretation. 15,16 Therefore, these methods may fail to identify patients with important colon pathology, and are unlikely to identify subtle mucosal lesions that might be a source of bleeding. Flexible Sigmoidoscopy Flexible sigmoidoscopy provides a highly accurate exam of the distal colon. In young patients, 40 years old, with rectal bleeding, most serious colon pathology can be found in the distal colon with sigmoidoscopy. 7 However, with increasing age, the prevalence of proximal colon malignancy increases, so that in older patients, sigmoidoscopy may be a somewhat less effective exam of the colon. 17 represents the most accurate, invasive, and costly evaluation of the colon. The risk of serious complications of colonoscopy is 0.3%. 18 Nevertheless, colonoscopy provides the most complete examination of the colon, and is currently recommended for screening of asymptomatic high-risk patients (positive family history of colon cancer) and for surveillance of patients with prior adenomas or cancer. 19 is

3 April 2004 RECTAL BLEEDING AND DIMINUTIVE COLON POLYPS 1169 Table 2. Recommendations for Evaluation of Rectal Bleeding ( ) Family history of CRC and small amounts of rectal bleeding ( ) Family history of CRC or large amounts of recurrent rectal bleeding 40 yrs Sigmoidoscopy yrs Sigmoidoscopy or colonoscopy 49 yrs also included among the current screening recommendations for average-risk individuals over 50 years of age. 19 Based on available evidence (Table 1), the risk of finding cancer in patients with rectal bleeding is higher than the expected risk in asymptomatic subjects, 17,20 which may justify the use of colonoscopy to evaluate such patients Recommended Management Strategy Lacking good clinical studies, the approach to the patient with visible rectal bleeding is uncertain. Since most studies do not define the frequency or severity of bleeding, we have little evidence to support any management algorithm. My recommendations are summarized in Table 2. The stratification of risk is based on 2 assumptions. First, patients with an increased risk of colorectal cancer require a complete evaluation of the colon. Second, patients with significant lower GI bleeding require a colon evaluation, irrespective of their cancer risk. In patients younger than 40 years old with symptoms of outlet bleeding who do not have family history of CRC, sigmoidoscopy should be adequate. In patients 50 years and older, the risk of colorectal neoplasia is increased due to age. The addition of rectal bleeding as a risk factor justifies the use of colonoscopy to evaluate such patients. In patients age 40 to 49 years, the recommendation should be individualized. Either colonoscopy or sigmoidoscopy can be justified based on the current evidence and the clinical features of the bleeding. Evolution of the Case While awaiting your reply, the primary care provider performed a flexible sigmoidoscopy in the office. Large internal hemorrhoids with erythematous areas were noted. In addition, a small polyp (5 mm) was seen in the rectum. No biopsy was obtained. The primary care provider calls you back with this information, and to obtain your advice about further management. Background Epidemiology of Small Polyps Small distal colonic polyps (defined as 10-mm in diameter) are common. In asymptomatic patients, age years undergoing screening colonoscopy, one or more small polyps less than 10 mm was the most significant finding in 20% 40% of patients. 17,20 Prior studies in patients undergoing colonoscopy for various indications, find that small polyps are identified in more than 50% of examinations. 21 Histologically, more than 50% of small polyps were adenomas Small polyps located in the right colon are more likely to be neoplastic. Small lesions in the distal colon are equally likely to be adenomatous (AP) or hyperplastic polyps (HP). There is controversy about the importance of both small adenomas and hyperplastic polyps in the distal colon. Adenomas are common; 30% 50% of adults over age 50 years will have at least one adenoma. Recent studies using screening colonoscopy 17,20 concluded that patients with small distal adenomas have a 2 3 fold increased risk for proximal advanced neoplasia (defined as an adenoma 10 mm, adenoma with villous histology or high-grade dysplasia) compared with patients with no distal adenomas. In absolute terms, among patients with small distal adenomas, the number needed to endoscope (NNE) to identify one patient with proximal advanced neoplasia was 12. In patients with no distal adenomas, the NNE ranged from to These results suggest that patients with small distal adenomas should have a complete structural exam of the colon to rule-out proximal advanced neoplasia. There has also been considerable controversy about the significance of HP in the distal colon. Current evidence suggests that these lesions are nonmalignant, and are not harbingers of serious proximal pathology. 17,19,20 Therefore, a key clinical decision in patients with small distal polyps may depend on the determination of histology: if hyperplastic, no further evaluation is needed; if adenomatous, colonoscopy is recommended. If small polyps are ignored at sigmoidoscopy, some patients with proximal advanced neoplasia and cancer will not be detected. Malignant Risk of Small Polyps Another reason to consider biopsy and removal of diminutive polyps is because of the possibility that such lesions may actually be malignant. Most literature suggests, however, that the risk of high-grade dysplasia or cancer in small polyps is 0.5%, and probably lower in polyps 6 mm. 21,25 27

4 1170 DAVID LIEBERMAN GASTROENTEROLOGY Vol. 126, No. 4 In the mid-1980s, Japanese investigators raised concern about the existence of small, flat neoplasms which were distinct from the typical AP. 28 These lesions were only slightly raised, have central depressions, and were found to have relatively high rates of high-grade dysplasia and cancer compared with typical AP. The authors suggested that these lesions do not follow the typical adenoma-carcinoma sequence, and can progress to invasive malignancy without a typical polypoid phenotype. There has been considerable debate about the significance of these findings in the U.S. and Western Europe. Evidence from Great Britain 29 and the United States 30 suggests that the risk of cancer progression in patients with diminutive polyps is small. Each of these studies had an extensive long follow-up, so that if important flat adenomas were missed, they should have progressed to cancer during the follow-up period. Therefore, in the U.S. and Western Europe, the flat adenoma appears to be an unusual precursor of CRC. Potential Management Strategies No Further Evaluation There is a rationale for considering no further evaluation in patients with small rectal polyps of uncertain histology. If the polyp is hyperplastic (50% likelihood), no further evaluation would be needed. If the polyp is an adenoma, there is some evidence that patients with small rectosigmoid adenomas may not have an increased risk of developing CRC during an extended follow-up period. 29 However, given the aforementioned data about likelihood of proximal advanced neoplasia and/or serious pathology in the polyp, I think that a no further evaluation approach carries a risk of missing important pathology, particularly in patients over age 60 years. However, patients aged 40 to 59 years have a very low pre-test probability for advanced neoplasia unless there is a family history of CRC. Imperiale et al. 31 have shown a 3.5% risk of advanced neoplasia in asymptomatic subjects age 40 to 49 years. The same group recently reported that only 6 of 137 patients age 50 to 59 with distal adenomas 1 cm had advanced proximal neoplasia, 32 with lower risk in women than men. This means that the number needed to colonoscope to identify 1 patient with proximal advanced neoplasia is 23. These data raise some doubt about the benefit of performing colonoscopy in young patients (age years) with only 1 or 2 small tubular adenomas in the distal colon. Young patients with adenomas raise another concern. Such patients may have a genetically inherited familial syndrome, which may place the patient at higher risk of developing malignancy in the future. Therefore, it is important to obtain a careful family history. Repeat Flexible Sigmoidoscopy With Biopsy Biopsy of small polyps is often not performed in the U.S. and U.K. However, the absence of pathology creates a conundrum. If the histology is critical to the clinical decision to proceed with colonoscopy, then it may be reasonable to repeat the sigmoidoscopy and obtain tissue. However, if I were the patient, I would not be thrilled with this approach, knowing that there would be a 50% likelihood that I would need to have a third colon exam if the polyp is an adenoma. This knowledge might discourage the patient from having any subsequent exams. To avoid this problem, and optimize the use of colonoscopy, the endoscopist should biopsy small polyps at the initial sigmoidoscopy to establish histology. Large polyps 1 cm probably do not require biopsy since they are very likely to be adenomas. Repeat Flexible Sigmoidoscopy in 1 5 Years Given the natural history of progression of colon malignancy over many years, it seems unlikely that a diminutive polyp, destined to grow up to be cancer would progress rapidly to malignancy. 33 Unfortunately, we have no clinical predictors or biologic markers to determine which polyps will progress to malignancy. Would it be safe and prudent to reexamine the polyp at some interval to see if it is growing? With regard to the specific rectal polyp, this approach would probably be safe if the interval was relatively short (1 5 years). However, patients with microsatellite instability (MSI) may have rapid progression to malignancy, and MSI is present in about 15% of sporadic CRC. This approach would also fail to identify those patients with distal adenomas who may harbor proximal advanced malignancy. Imaging With Barium or CT If noninvasive imaging could accurately identify those patients with serious colon pathology who would require colonoscopy, this might be an effective method for evaluating the patient with a diminutive rectal polyp. Unfortunately, barium enema detects less than 50% of polyps 1 cm. 13 As mentioned previously, CT colonography is a rapidly evolving technology. Recent studies with CT colonography 15 provide the most encouraging data about sensitivity, specificity, and interobserver variability. If these results can be reproduced in other centers, CT colonography may offer a very reasonable approach to evaluation of patients with distal polyps at sigmoidoscopy.

5 April 2004 RECTAL BLEEDING AND DIMINUTIVE COLON POLYPS 1171 Table 3. Recommendations for Evaluation of Patients With Polyps Found at Sigmoidoscopy Finding at Sigmoidoscopy Polyp 10mm Polyp (s) 10mm If hyperplastic If adenoma Histology unknown Recommendation ; biopsy optional at initial sigmoidoscopy Obtain biopsy No further evaluation In a patient with a distal polyp of uncertain histology, colonoscopy provides the most conservative approach to management. When performed by experienced endoscopists, the test is accurate (95%) for detection of serious colon pathology. Recommended Management Strategy Small Polyp (<10 mm) Seen at Sigmoidoscopy: Recommend Biopsy In patients who are 60 years, I recommend that biopsy of the polyp be performed during screening sigmoidoscopy by primary care providers to determine if it is a HP or AP (Table 3). The risk of malignancy in the small polyp is extremely small, but if it is an adenoma, the likelihood of proximal advanced neoplasia is 2- to 4-fold increased compared with patients with no polyps or those with distal HP. Therefore, colonoscopy would be warranted if an adenoma was found. Since up to one-half of small polyps will be hyperplastic, colonoscopy may not be needed in many cases. In patients who are 60 with no family history of CRC, the benefit of pursuing colonoscopy if the lesion is an adenoma is less certain. Although I favor obtaining a biopsy, and performing colonoscopy if the polyp is an adenoma, a case can be made for not obtaining a biopsy, and repeating sigmoidoscopy within 5 years. If a patient has a polyp 10 mm found at sigmoidoscopy, it is most likely an adenoma. I do not think it is necessary to biopsy the polyp, and recommend proceeding to colonoscopy without histology. Biopsy of the lesion may preclude complete histologic evaluation when polypectomy is ultimately performed at colonoscopy. Small Polyp, No Histology Obtained: Recommend When confronted with a patient who has a small polyp of unknown histology in the distal colon, there is a 50% likelihood that the polyp is neoplastic. In patients who are 60, I recommend colonoscopy because of the increased risk of advanced proximal neoplasia if the lesions should be an adenoma. In patients who are 60, the benefit of pursuing colonoscopy even if the lesion is an adenoma is less certain. Although I generally recommend colonoscopy in such cases, the expected rate of finding advanced neoplasia will be low. Evolution of the Case The patient has one tubular adenoma, 5-mm in diameter, removed at colonoscopy. The primary care provider wants to know what follow-up should be recommended for the patient and for members of the patient s family. Background Current recommendations for surveillance after removal of adenomas are based on evidence from the National Polyp Study that 32% 42% of patients who have colonoscopy with removal of all visible adenomas will be found to have adenomas within 3 years. 34 Some of these lesions may be missed lesions from the first exam, 35,36 and some may be new lesions. Since we believe that patients with adenomas have an increased risk of developing CRC, surveillance colonoscopy is routinely recommended. Most patients with adenomas will never develop cancer. We have few predictors of risk. The National Polyp Study data suggest that patients with multiple ( 3) adenomas at the baseline exam may be more likely to found to have advanced neoplasia at a 3-year follow-up examination. 34 The data regarding 1 or 2 small ( 10 mm) tubular adenomas is uncertain. Most evidence suggests that such patients represent a low-risk group, and that the surveillance interval can be safely extended in these patients to at least 5 years, assuming the baseline exam was complete to the cecum, and that the bowel preparation permitted an adequate exam. 19 Potential Management Strategies No Surveillance Patients with only 1 or 2 small tubular adenomas may not represent a higher-than-average-risk group. 29 Can they be managed like patients with either no polyps or hyperplastic polyps, and be re-enrolled in regular colon screening? Currently, there is insufficient evidence to support this approach.

6 1172 DAVID LIEBERMAN GASTROENTEROLOGY Vol. 126, No. 4 Surveillance With Imaging There is no evidence that imaging with either barium or CT would be an effective form of surveillance. The aforementioned data on the sensitivity for detection of advanced neoplasia raise concerns about the use of these tests in a higher risk population of patients with known adenomas. Surveillance With Colonoscopic surveillance is the current recommended approach to patients with prior adenomas. 19 However, the appropriate interval is uncertain, and not evidence-based. Although there is good evidence that patients with cancer or multiple adenomas may have an increased risk of advanced pathology within 3 years, the evidence in patients with only 1 2 small tubular adenomas is uncertain. Current recommendations call for a 5-year interval for such patients, but future studies may provide a basis for extending this interval. There is indirect evidence from a case-controlled study of sigmoidoscopy, that a protective effect of polypectomy was maintained for 10 years. 37 Strategies for Relatives There is some evidence that relatives of patients with adenomas may have an increased risk of CRC Ahsan et al. 38 found the risk to be highest if the index relative with adenoma was younger than 50 years old. Such families may have an inherited genetic mutation. The National Polyp Study 39 found the risk of CRC to be increased in the siblings of patients diagnosed with adenoma before age 60 years. The VA Cooperative Study 40 also found that family members of adenoma patients had an increased risk of CRC, but the effect was limited to patients with an advanced adenoma (defined as 10 mm, adenoma with villous histology or high-grade dysplasia). From these studies we can conclude that family members of patients with adenomas do have an increased risk of CRC. The risk may be higher if the index family member with adenoma is young ( years), and has an advanced adenoma. However, we should keep in mind that the risk of adenomas in the general population is high (30% 50%). It is likely that many, if not most, individuals have a first-degree relative with an adenoma. What is a prudent recommendation for screening of family members of patients with adenomas? should be the preferred screening method in this higherthan-average risk group, since it permits the most complete and accurate examination of the colon. This is consistent with other recommendations for higher risk Table 4. Recommendation for Surveillance in Patients With Neoplasia Recommended Most serious baseline exam findings a surveillance interval 1 2 small tubular adenomas 10 mm 5 years or more 3 or more small tubular adenomas 3 years Advanced adenoma b Possible incomplete removal 3 6 months, then 3 years Complete removal certain 3 years Cancer, postresection 1 year, then every 3 to 5 years a Assumes that baseline exam was complete to cecum with adequate bowel preparation. b Advanced adenoma defined as adenoma 10 mm, or with villous histology or high-grade dysplasia. cohorts. Screening should be considered for patients under age 50 years if the index relative with adenoma was younger than 50 years old at the time of diagnosis. Recommendations for Surveillance My recommendations for surveillance of patients with neoplasia are summarized on Table 4. The surveillance interval can be safely extended to at least 5 years if the worst finding at colonoscopy is 1 or 2 small tubular adenomas. Future study is needed to determine if these patients benefit from surveillance, and whether any surveillance is needed. I want to highlight the recommendation for patients with prior CRC. These patients have either genetic, environmental, and/or lifestyle factors which contributed to the progression of malignancy. I worry about 2 possibilities in these high-risk patients. First, could they harbor a synchronous malignancy that was missed on the baseline examination? We know that colonoscopy is not perfect, and that the rate of synchronous malignancy is as high as 5%. Secondly, I am concerned that this might be a patient with microsatellite instability (present in 15% of sporadic CRCs), who might develop new polyps and cancer more quickly than the typical pattern of growth. Therefore, my approach to these patients is very conservative. I recommend that the first surveillance exam be performed at 1 year to rule out the possibilities of missed lesions or new fast-growing lesions. After this exam is negative, follow-up can be safely extended to 3 to 5 years. Conclusions Minor rectal bleeding and small distal colon polyps are very common. In young patients without a family history of CRC, the risk of malignancy is very low.

7 April 2004 RECTAL BLEEDING AND DIMINUTIVE COLON POLYPS 1173 Nevertheless, an examination of at least the distal colon is warranted in all patients with recurrent rectal bleeding. The finding of a small polyp on this exam should lead to colonoscopy if the histology is confirmed to be adenomatous. Patients with distal hyperplastic polyps do not have an increased risk of proximal advanced neoplasia, and colonoscopy is generally not recommended. Colonoscopic surveillance of patients with 1 or 2 small ( 10 mm) adenomas can be safely extended to at least 5 years. References 1. Talley NJ, Jones M. Self-reported rectal bleeding in a United States community: prevalence, risk factors and health care seeking. Am J Gastroenterol 1998;93: Crosland A, Jones R. Rectal bleeding: prevalence and consultation behaviour. Br Med J 1995;311: Goulston KJ, Cook I, Dent OF. How important is rectal bleeding in the diagnosis of bowel cancer and polyps? 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8 1174 DAVID LIEBERMAN GASTROENTEROLOGY Vol. 126, No. 4 F, Kurtz RC, Shike M and the National Polyp Study Workgroup. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993;328: Hixson LJ, Fennerty MB, Sampliner RE, Garewal HS. Prospective blinded trial of the colonoscopic miss-rate of large colorectal polyps. Gastrointest Endosc 1991;37: Rex DK, Cultler CS, Lemmel GT, Rahmani EY, Clark DW, Helper DJ, Lehman GA, Mark DG. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112: Selby JV, Friedman GD, Quesenberry CP Jr, Weiss NS. A casecontrol study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326: Ahsan H, Neugut AI, Garbowski GC, Jacobson JS, Forde KA, Treat MR, Waye JD. Family history of colorectal adenomtous polyps and increased risk for colorectal cancer. Ann Intern Med 1988;128: Winawer SJ, Zauber AG, Gerdes H, O Brien MJ, Gottlieb LS, Stermnberg SS, Bond JH, Waye JD, Schapiro M, Panish JF, Kurtz RC, Shike M, Ackroyd FW, Stewart ET, Skolnick M, Bishop DT. Risk of colorectal cancer in the families of patients with adenomatous polyps. N Engl J Med 1996;334: VA Cooperative Study Group # 380 Lynch KL, Ahnen DJ, Byers T, Weiss DG, Lieberman DA. First degree relatives of patients with advanced colorectal adenomas have an increased prevalence of colorectal cancer. Clin Gastroenterol Hepatol 2003;1: Address requests for reprints to: David Lieberman, M.D., Chief, Division of Gastroenterology, Oregon Health and Science University, Portland VA Medical Center P3-GI, 1037 SW Veterans Hospital Road, Portland, Oregon lieberma@ohsu.edu; fax: (503)