Occult and Obscure Sources of Gastrointestinal Bleeding

Transcription

1 Occult and Obscure Sources of Gastrointestinal Bleeding W ccult gastrointestinal bleeding is defined by the American Gastroenterological Association as "the initial presentation of a positive fecal occult blood test (FOBT) result and/or irondeficiency anemia (IDA) without evidence, to the patient or physician, of visible fecal blood. ''1 Occult bleeding is detected during routine physical examination, by laboratory testing, or as the result of screening programs for colon cancer. In the past, patients with a positive FOBT result and those patients with IDA were viewed as different groups, but only because they were detected by different methods. Studies that separately investigated patients with positive FOBT results or IDA reported similar frequencies of various types of gastrointestinal diseases? -6 More recently it has been suggested that there is no need to separate these 2 groups. A positive FOBT result or the detection of IDA both indicate slow, chronic gastrointestinal bleeding from variable sources. 1 In contrast, the term obscure gastrointestinal bleeding denotes nothing about the chronicity of bleeding and implies only that the initial evaluation has failed to establish a specific diagnosis. As technology and the standard of care have changed, so have the criteria used to define obscure bleeding. For example, in the past bleeding could be called obscure if a barium enema result was negative, but now it cannot be termed obscure until (at least) a colonoscopy and esophagogastroduodenoscopy (EGD) are also negative. Obscure bleeding is now defined by the American Gastroenterological Association as "bleeding of unknown origin that persists or recurs (ie, recurrent or persistent IDA, FOBT positivity, or visible bleeding) after a negative initial or primary endoscopy (colonoscopy and/or EGD) result. ''1 Two subcategories have also been named: (1) obscure-occult (persistent IDA or positive FOBT results but without a cause discovered on initial endoscopies), and (2) obscure-overt (persistent visible bleeding lie, hematemesis, melena, or hematochezia] but without a cause discovered on initial endoscopies). 1 Potential causes of occult and obscure gastrointestinal bleeding are listed in Table 1. We review the initial evaluation of patients with occult or obscure forms of gastrointestinal bleeding. In addition, we discuss the differential diagnosis and outline algorithms for the localization of the sources of bleed- 872 Curr Probl Surg, December 2000

2 TABLE 1. Causes of occult and obscure bleeding Neoplasia Esophageal carcinoma Gastric carcinoma Colon carcinoma Tumors metastatic to the gastrointestinal tract Lymphoma Polyps Inflammatory Esophagitis Acid peptic disease Cameron's erosions Crohn's disease Ulcerative colitis Celiac sprue Meckel's diverticulum Radiation enteritis Previous gastdc surgery (ie, Billroth I or II) Vascular lesions Vascular malformations (ie, ar~iodysplasia) Watermelon stomach (gastric antral vascular ectasis [GAVE]) Blue rubber bleb nevus syndrome OslerWeber-Rendu syndrome (hereditary hemorrhagic telar~iectasia) Varices Dieulafoy's lesion Aortoenteric fistula Ischemia Infection Hookworm Whipworm Ascaris Ameba Stror~yloides Tuberculosis Other Long~listance running Medication induced (ie, aspirin or NSAIDs) Nasopharyr~eal bleeding Hemoptysis Hemosuccus pancreaticus Hemobilia NSAIDs, Non-steroidal anti-inflammatory drugs. ing. Finally, with reference to the location and natural history of the lesions that can cause such bleeding, we review the treatment options. The overall goal is to provide the practicing surgeon with a systematic approach to the diagnosis and treatment of these challenging problems. Curr Probl Surg, December

3 Occult Gastrointestinal Bleeding Fecal Occult Blood Test More than 100 years ago, it was proposed that the detection of blood in the stool might be clinically useful. In 1864 guaiac was first used to evaluate for fecal blood. 7 In 1901 the phrase "occult bleeding" was coined, and an FOBT was suggested for the detection of colonic neoplasms for the first time. 7 Screening asymptomatic patients for colon cancer with the use of home collection and guaiac-impregnated slides was popularized by Greegor in In 1993 a trial at the University of Minnesota with 13,000 patients was the first to show that annual FOBT may reduce the mortality rate from colorectal carcinoma? Currently, 3 techniques are available for the detection of fecal occult blood (FOB): guaiac-based, immunochemical, and heme-porphyrin tests. These 3 methods are compared in Table 2. Guaiac-based Tests. The original and most common form of FOBT uses the guaiac reagent. The test is based on a leuco dye that changes from a colorless form to a blue form in the presence of peroxidase activity or oxidants. ~~ A variety of compounds are capable of inducing this change in color, including the heme moiety of hemoglobin, hydrogen peroxidase, and a variety of other nonspecific peroxidases (including those present in certain foods). False-positive results caused by non-hemoglobin peroxidase activity can make clinical interpretation of the test results difficult.l~ False-negative test results can occur because of colonic bacteria that have the ability to degrade hemoglobin into porphyrins that lack the peroxidase-like activity of the original heme moiety? 2 Several different forms of the guaiac test are available, including Hemoccult II and Hemoccult II Sensa (SmithKline Diagnostics, Palo Alto, Calif). The Hemoccult II Sensa test has been shown to be more sensitive. 5,13,~4 To some extent, however, all guaiac-based tests are inconsistent in responses to similar levels of bleeding. 15 In addition, several factors can influence the specificity of the test for the detection of colonic bleeding. In the adult, normal gastrointestinal blood loss is 0.5 to 1.5 ml per day Even this small amount of blood loss can be detected in some individuals. 15 Stroehlein and colleagues 15 have reported that the Hemoccult II test was positive in 7% of apparently normal individuals. The sensitivity of the test increases with higher levels of bleeding; in individuals with daily fecal blood loss of 10 ml per day, the Hemoccult II test was positive in 50%. 15 Higher rates of detection were observed with higher rates of blood loss. The relationship between blood loss and the likeli- 874 Curr Probl Surg, December 2000

4 TABLE 2. Comparison of FOBT methods Guaiac-based Immunochemical Heme-porphydn Qualitative Qualitative Quantitative Office based Office based/laberatory processed Laboratory processed Inexpensive Moderate More expensive TABLE 3. Daily fecal blood loss* and rate of positive hemoccuh test Fecal blood loss (ml/d) No. of specimens Positive hemoccuit result (%) *Daily fecal blood loss measured by SlCr method. Data from Stroehlein JR, Fairbanks VF, Go VLW, Taylor WF, Thompson JH. Hemoccult stool tests: falsenegative results due to storage of specimens. Mayo Clin Proc 1976;51: hood of a positive test is shown in Table 3. These data emphasize that a single test may miss clinically significant levels of blood loss and provide a rationale for the seeking of multiple tests as means of reducing falsenegative examinations. Colonic bacteria degrade heme into various porphyrins that lack the peroxidase-like activity that is required for a positive guaiac test) 2 Although it is well recognized that lesions in the proximal gastrointestinal area can be associated with a guaiac positive test) 9 it is possible that blood loss from more distal lesions, which have limited exposure to colonic bacteria, would be more likely to result in a positive guaiac test. Interaction of Diet and Medications With FOBT Results. Certain dietary elements are known to increase the presence of nonspecific peroxidase activity that can, in turn, lead to false-positive tests. A list of factors that cause false-positive and false-negative test results is presented in Table 4. Peroxidases are found in a variety of raw fruits and vegetables, especially radishes, turnips, cantaloupes, bean sprouts, cauliflower, broccoli, and grapes) ~ The nonhuman heme found in red meat can also cause a false-positive reaction. 12 Certain medications or vitamin supplements should be avoided during the testing period for occult fecal blood. Aspirin and non-steroidal antiinflammatory medications (NSAIDs) can cause gastric mucosal inflam- Curr Probl Surg, December

5 TABLE 4. Factors that affect guaiac testing Causes of false positive tests Dietary peroxidases (raw radishes, turnips, cantaloupes, bean sprouts, cauliflower, broccoli, grapes) Hemoglobin from red meat Aspirin and NSAIDs Rehydration of test cards Causes of false-negative test results Bacterial degradation of heme in the colon Vitamin C Delayed development of testing cards (more than 4 days) NSAIDs, Non-steroidal anti-inflammatory drugs. mation and increased occult blood loss. 20'21 Most physicians recommend that these drugs be withheld during the testing period altogether. If a patient with a positive test result used aspirin during the testing period, the FOBT should probably be repeated after stopping aspirin for one week before an occult bleeding evaluation is begun. 22 Ascorbic acid (vitamin C) is an antioxidant that, when taken orally, can cause false-negative guaiac tests. Therefore, it is recommended that vitamin C supplements of more than 250 mg daily also be withheld during the testing period. 23 The following dietary restrictions are recommended for the 3-day period before and during testing: abstaining from red meat, high peroxidase fruits and vegetables (eg, radishes, turnips, cantaloupes, bean sprouts, cauliflower, broccoli, and grapes), vitamin C, aspirin, and other NSAIDs. Recommendations for FOBT testing conditions are presented in Table 5. In the past, concern was expressed that oral iron therapy can cause falsepositive guaiac results in guaiac testing. In fact, the green-black stool color typical during oral iron therapy can be confused with the blue color of a positive guaiac. 11 Oral iron supplements are in the ferrous form, and when passed into the stool at the physiologic ph of 7 will be in the nonreactive ferrous rather than the reactive ferric form and therefore unable to cause a positive guaiac test. 24 Other medications that cause dark stool, such as antacids and bismuth-containing antidiarrheal drugs, can make test interpretation difficult but do not actually cause a true change in color that is seen with a positive test. al Sample Collection Technique. The sample collection technique can also affect the test results. Cancers can bleed intermittently, and blood is not necessarily distributed uniformly in the stooly Patients are instructed to collect a total of 6 small samples from 2 different areas of 3 consecutive stools. A single positive sample is considered to be a positive test. Most patients collect their stool from toilet water. Toilet sanitizers can cause false-positive guaiac results and blood from the surface of the stool leaches quickly into 876 Curr Probl Surg, December 2000

6 TABLE 5. Guaiac testing recommendations Dietary restriction for 3 days before and during testing: raw radishes, turnips, cantaloupes, bean sprouts, broccoli, grapes, red meat Medication restriction for 1 week before and during testing: aspidn, NSAIDs, and vitamin C Prompt development of cards (within 3 days of sample collection) Development of cards without rehydration NSAIDs, Non-steroidal anti-inflammatory drugs. the surrounding water. 26 To avoid these problems some patients are therefore provided with a disposable stool collection device. There is controversy regarding the collection of samples by patients in a spontaneously passed stool or by the physician during the digital rectal examination (DRE). Some physicians argue that the trauma of the DRE can cause false-positive results. 27 Patients who undergo a DRE during an office visit are also unlikely to have made the recommended dietary and medication modifications. The Findings and Impact of Nonrehydrated Guaiac Examination of the Rectum (FINGER) Study compared the diagnostic yield of colonoscopy in patients with occult blood detected either in spontaneously passed stools or during a DRE. 28 There was no difference in the positive predictive value of a positive FOBT result obtained by spontaneously passed stool (21.3%) or DRE (22.0%). Additionally, there was no difference in the number of adenomas and carcinomas found in the 2 groups. The authors concluded that a positive FOBT result obtained during a DRE cannot be ignored but should be evaluated further. 28 Spontaneously passed stools are typically collected by patients over the course of several days and then returned on cards to their physician, resulting in significant stool drying. The amount of liquid present in the sample can affect the test results. 9 This has prompted some physicians to rehydrate the specimen with deionized water before test development. Rehydration of the Hemoccult II test does improve the sensitivity significantly but also decreases the specificity and positive predictive value. 9 An additional factor that complicates home sample collection on cards is that some positive tests appear to become negative after 4 days at room temperature; even more become negative after 1 week. 29 In view of the inconsistencies created by sampling techniques in the home, the most important consideration in office-based guaiac screening is the physician's commitment to a uniform practice of instructing patients and collecting samples. When the guaiac cards are returned, the physician's office staff must ask the patient to describe any deviations from the instructions. Unfortunately, this means that the patient may have to take a fresh batch of cards home, if such deviations in protocol might alter the reliability of the test. Curr Probl Surg, December

7 Immunochemical Tests. Immunochemical tests are more specific for fecal occult blood because they detect only intact human hemoglobin and its epitopes with the use of antibodies. 19 They are able to detect small amounts of colonic bleeding but are less sensitive for upper gastrointestinal bleeding because of changes in hemoglobin's immunogenicity during transit. 3~ When first developed, these tests used either complex enzymelinked immunosorbent assays or double immunodiffusion techniques. A newer hemagglutination method (HemeSelect; Smith-Kline Diagnostics, Palo Alto, Calif) is available but still requires laboratory processing. An office test that uses a latex agglutination technique (FlexSure OBT; Smith-Kline Diagnostics) is also available. Although they are more specific for colonic occult blood than the guaiac-based tests, the immunochemical tests are more expensive and have a high false-positive rate. 31 Heme-porphyrin Tests. Heme-porphyrin tests use spectrofluorimetric techniques to give a quantitative measurement of fecal blood. 11 Both heme and its porphyrin breakdown products are assayed. The results can be affected by the amount of hemoglobin present in red meat but not by the peroxidases in fruit and vegetables. Hemoquant (Mayo Medical Laboratories, Rochester, Minn) is commercially available but not widely used, probably because of the cost and need to submit the sample to an outside laboratory. 3~ Unlike the qualitative guaiac-based and immunochemical tests, the heme-porphyrin tests are quantitative. However, physiologic and pathologic ranges have not been definitively established. 12 Goals of FOBT. The purpose of FOBT is to screen for colorectal cancer. A screening test for colorectal cancer is justified because it is a common disease that, when diagnosed in its late stages, usually cannot be treated successfully. Screening with FOBT has been shown to facilitate the diagnosis of colorectal cancer at earlier stages The use of annual FOBTs has also been shown to reduce the mortality rate from colorectal cancer. 9,32,34 The incidence of other gastrointestinal malignancies is not high enough, at least in Western countries, to justify the use of FOBT. 35 The biggest barrier to effective FOBT is low participation by patients. Table 6 lists the compliance rates in large screening trials. Most screening trials have approximately a 60% participation rate. 9,13,32,34,36,37 Screening campaigns advertised on television have a response rate of 13% to 63%. 13'36 In community-based screening programs, 10% to 50% of patients in the community who have tested positive for FOB do not complete the appropriate colonic investigations. 22,25,36,37 The large, prospective randomized trials that show that the FOBT leads to reduced colorectal mortality rates have used both nonrehydrated Hemoccult II 32,34 and rehydrated Hemoccult I19 tests. However, the tests 878 Curr Probl Surg, December 2000

8 TABLE 6. Participation in fecal occult blood screening Study Patients Patients who Patients who received received compliant appropriate FOBT with evaluation for matedal FOBT positive FOBT (n) (%) results (%) Kewenter et a137 13, McGardty at a136 73, Mandel et al 9 46,551 Hardcastle et a132 75,253 Kronborg et a134 30,967 At least i Annual group, test, 90; 83; all tests biannual (annual group, group), 46; 84 all tests (biannual group), 60 At least I test, 6O; all tests, 38 First test, Levin et al ~-3 85, FOBT, Fecal occult blood test. Study method Randomly chosen group; kit distributed by mail Kits distributed by pharmacy chain; television educational series Recruitment from community groups (ie, American Cancer Society, veterans groups, employers) Randomly chosen group; kit distributed by mail with letter from primary doctor Randomly chosen group; invitation distributed by mail Kits distributed by pharmacy chain and community groups, public service announcement on television, radio, and newspaper are not equivalent. When 3 different guaiac tests were compared in a large screening thai, the positive predictive value for carcinoma, when the nonrehydrated Hemoccult II test (13.9%) was used, was higher than when the Hemoccult II Sensa (11.1%) and the rehydrated Hemoccult 1I tests (6.6%) were used. 13 The positive predictive value for adenomas had an identical order. The test with the highest rate of positivity was rehydrated Hemoccult II, followed by Hemoccult II Sensa, then nonrehydrated Hemoccult II test. Differences in mortality rate reduction among the 3 methods have not been examined. A screening study that included the immunochemical HemeSelect method reported sensitivities of (in decreasing order) Hemoccult II Sensa Curr Probl Surg, December

9 TABLE 7. Comparison of FOBT methods for detecting carcinoma and polyps of more than 1 cm in size Hemoccult II Hemoccult II HemeSelect (not rehydrated; %) Sensa (%) (%) Sensitivity Carcinoma Polyp > I cm Combined Specificity Carcinoma Polyp > I cm Combined Positive predictive value Carcinoma Polyp > I cm Combined FOBT, Fecal occult blood test. Data from Allison JE, Tekawa IS, Ransom El, Adrain AL. A comparison of fecal occult-blood tests for co- Iorectal cancer screening. N Engl J Med 1996;334: (79%), HemeSelect (69%), and Hemoccult II (37%; Table 7).!4 The positive predictive values of the 3 methods were reversed: Hemoccult II (6.6%), HemeSelect (5.0%), and Hemoccult II Sensa (2.5%). Prospective, randomized screening trials that evaluated mortality rates with the newer immunochemical tests (HemeSelect or the heme-porphyrin tests) have not been performed. Their clinical usefulness is likely limited by the need for laboratory processing.l 1 Positive FOBT Results and Upper Gastrointestinal Lesions. FOBT is used to screen for colorectal cancer. If a patient with a positive FOBT result is found to have a negative colonoscopy, then an upper tract source of bleeding should be considered. In one study that used bidirectional endoscopy, upper tract lesions were actually more common than lower tract lesions in patients with a positive FOBT result that was not associated with IDA or active bleeding. 5 In that study, 28.6% of patients had upper tract lesions, 21.8% of patients had colonic lesions, and 2.4% of patients had both upper tract and colonic lesions. In decreasing order of frequency, the most commjn upper tract lesions were esophagitis, gastric ulcer, gastritis, duot_ ;na] ulcer, carcinoma, duodenitis, vascular malformation, and adenomatous polyp. The most common colonic lesions, also in order of decreasing frequency, were adenomas larger than 1 cm, carcinoma, colitis, vascular malformation, ulceration, and infection. 5 FOBT in Patients Receiving Anticoagulants. Not infrequently, a patient who is receiving aspirin or warfarin for anticoagulation will be found to have a positive FOBT result. Unfortunately, adequate prospec- 880 Curr Probl Surg, December 2000

10 tive trial has assessed the question of whether a positive FOBT result in a patient receiving anticoagulants has a different predictive value for colon cancer than in a patient not taking such medications. However, in young healthy volunteers, it has been shown that 325 mg per day of plain aspirin causes greater daily fecal blood loss than the same dose of enteric-coated aspirin. Blood loss in these volunteers receiving either form of aspirin is higher than in patients not receiving aspirin at all. 38 In a study by Blackshear and colleagues 39 of patients with atrial fibrillation who were being treated with aspirin, warfarin, or a combination of aspirin and warfarin, only the combination group had elevated fecal blood loss as measured by Hemoquant. Greenberg and colleagues 4~ also used Hemoquant to measure fecal blood loss in patients who were being treated with aspirin or warfarin. When patients were using either 81 or 325 mg of aspirin per day, their daily fecal blood loss was slightly higher than before treatment with aspirin but still within the normal range. Patients who were using warfarin had normal amounts of daily fecal blood loss. 4~ A study by Jaffin and colleagues 4] evaluated a group that consisted of both inpatients and outpatients who were being treated with heparin or warfarin. These patients who were receiving anticoagulants had a significant increase in positive hemoccult tests when compared with a control group (12% and 3%, respectively). Neither the degree of anticoagulation nor the duration of therapy was correlated with a positive test, although those patients who were undergoing anticoagulation therapy for therapeutic reasons were more likely to have a positive test than those undergoing anticoagulation for prophylactic reasons (25% and 7%, respectively). Although 29% of patients with a positive FOBT result refused endoscopic examination, most patients who underwent at least a partial evaluation had a gastrointestinal lesion identified. 41 Questions still remain about the significance of a positive FOBT result in patients who are using anticoagulants. It is recommended that patients avoid aspirin during the testing period if this is possible. 4~ However, a positive FOBT result in a patient who is receiving anticoagulation therapy should not be ignored or believed to result from the medication itself. Given the information currently available, the clinician should pursue an evaluation similar to that in patients not receiving anticoagulants. Iron-deficiency Anemia The typical Western diet includes 5 to 15 mg of elemental iron and 1 to 5 mg of heme per day. Under usual circumstances not more than 10% of dietary iron is absorbed. II The heme form of iron, present in myoglobin in meat, is more readily absorbed, and despite the smaller starting pool it Curr Probl Surg, December

11 DIAGNOSIS OF IRON DEFICIENCY ANEMIA I Hemoglobin <12 g/dl (men) or 13 g/dl (women) J and/or MicrocytosJs t S umfa tim = I Diagnosis remains in doubt I Bone marrow biopsy I Iron defioency anemia l I Seek Another Etiology for M crocytic anemia Ria~ Fig 1. Algorithm for the diagnosis of IDA. GI, Gastrointestinal. accounts for 40% to 80% of the total iron absorption. 11 Normal total daily iron absorption is therefore approximately 1 mg per day, equal to daily iron losses. 43 Normal daily blood loss from the gastrointestinal tract is approximately 1 ml per day (corresponding to approximately 0.5 mg of iron), and it has been suggested that this normal blood loss is due to gastrointestinal microulcerations and microerosions. I1 Sloughed intestinal epithelial cells result in an additional 0.5 mg of daily iron loss. 11 The total daily loss from the 2 sources is approximately 1 mg. If increased iron losses should occur, the small intestine is able to increase its iron absorption to a maximum of 4 mg per day. 43 However, if daily blood loss is greater than 5 ml per day from any source, iron deficiency can result. 4 The National Health and Nutrition Examination Survey determined that, in the United States, women have a higher prevalence of iron deficiency and IDA. 44 This survey reported that the prevalence of iron deficiency in women is 5% to 11%, but only 1% to 4% in men. Likewise, IDA was found in 2% to 5% of women, but only 1% to 2% of men. Premenopausal women have the highest prevalence of iron deficiency and IDA, at I 1% and 2% to 5%, respectively. 44 Daily iron losses during menstruation increase to 2 mg per day; pregnant women lose 2 to 4.8 mg of iron per day. 45 Evaluation of IDA. In men and postmenopausal women without another obvious source of blood loss, IDA is usually presumed to have an 882 Curr Probl Surg, December 2000

12 occult gastrointestinal origin. However, before a gastrointestinal evaluation is embarked on, it is important to confirm the diagnosis of iron deficiency. The condition is suspected in patients with low hemoglobin level or hematocrit and/or microcytosis.ll Iron deficiency can be confirmed by a serum ferritin level less than 20 ~tg/l and strongly suspected with a ferritin level less than 50 ~tg/l. 46 IDA is the combination of a low ferritin level and a hemoglobin level less than 12 or 13 g/dl for women and men, respectively. 11 If the diagnosis of IDA remains in doubt, then bone marrow examination of iron stores may be performed as the gold standard test. 43 A suggested algorithm for the diagnosis of IDA is shown in Fig 1. Although no study has specifically examined patients who are iron deficient but not anemic, these patients have been suggested to have a high incidence of gastrointestinal disease that warrants further evaluation. 46,47 Historically, it has been suggested that IDA was commonly caused by carcinomas that were located in the proximal regions of the colon. Whether or not this is true, it is important to note that nearly all neoplasms and many benign lesions in the gastrointestinal tract can bleed in an occult fashion and cause IDA. Several studies have attempted to determine the prevalence of various lesions in the gastrointestinal tract in patients with IDA. 2-4,6 These studies evaluated somewhat different populations and do not use uniform methods of evaluating patients, so a comparison of results is difficult. The common theme is that lesions that result in IDA can be found throughout the gastrointestinal tract. Table 8 summarizes the prevalence of various upper and lower gastrointestinal lesions in 5 major studies. Lesions generally thought to be capable of causing IDA include esophagitis, esophageal cancer, previous gastric surgery (ie, Billroth I or II), gastritis, gastric ulcer, gastric cancer, duodenal ulcer, colon cancer, polyps (adenomas) greater than 1 cm, multiple vascular malformations, Crohn's disease, NSAID use, celiac sprue, and ulcerative colitis. Abnormalities generally thought not to be capable of causing IDA include hiatal hernia without associated gastric erosions, diverticula, hemorrhoids, polyps less than 1 cm, esophageal varices, and single vascular malformations. Some authors have suggested that certain lesions (such as hiatal hernia, hemorrhoids, esophageal varices, or previous gastric surgery) might be capable of causing iron deficiency. Despite these differences in opinion, it appears that approximately two thirds of patients (62%-71%) with IDA will be found to harbor a lesion that might be responsible for the blood loss. 3'4'48'49 IDA in Premenopausal Women. Historically, IDA in premenopausal women has been attributed solely to menstrual losses, which result in Curr Probl Surg, December

13 TABLE 8. Occult gastrointestinal bleeding, results of bidirectional endoscopy Zuckerman Rockey Kepczyk Bampton and and and and Rockey, Study Benitez s Cello 4 Kadakla 3 Holloway 2 et al s Occult bleeding type IDA or IDA + IDA + IDA + +FOBT +FOBT +FOBT +FOBT +FOBT No. of patients Mean patient age (y; range) (26-91) (20-85) (1987) (37-91) (4089) Total no. of lesions 53 (53) 62 (62) 50 (71) 54 (60) 119 (48) found (%) Upper (%) 36 (36) 37 (37) 39 (55) 38 (48) 71 (29) Esophagitis 6 (6) 6 (6) 10 (14) 14 (18) 23 (9) Esophageal cancer (1) - - Hiatal hernia (3) - Gastritis 12 (/2) 6 (6) 11 (16) 2 (3) 12 (5) 'Gastdc ulcer 6 (6) 5 (5) 3 (4) 3 (4) 14 (6) Gastdc cancer 1 (1) 1 (1) 3 (4) 1 (1) 4 (2)* Duodenal ulcer 1 (1) 11 (11) 5 (7) 10 (4) Vascular malformation 8 (8) 3 (3) 4 (6) 1 (1) 3 (1) Prior surgery - 3 (3) - 3 (4) - Celiac sprue (6) - - Other 5(5) 2(2) 4(6) 8(10) 5(2) Lower (%) 26 (26) 26 (26) 21 (30) 16 (20) 54 (22) Adenoma 14 (14) 5 (5) 7 (10) 5 (7) 29 (12) Colon cancer 6 (6) 11 (11) 4 (6) 7 (9) 13 (5) Colitis - 2 (2) - 1 (1) 5 (2) Vascular malformation 5 (5) 5 (5) 6 (9) 1 (1) 5 (2) Other 2 (2) 3 (3) 5 (7) r 0 2 (1) Upper and lower lesion (%) 9 (9) 1 (1) 12 (17) 5 (7) 6 (2) No lesion found (%) 47 (47) 38 (38) 20 (29) 26 (40) 129 (52) +FOBT, Positive fecal occult blood teat results; IDA, iron-deficiency anemia. *Carcinomas were not differentiated by location. qncludes 4 patients with hemorrhoids. infrequent referral for gastrointestinal evaluation. However, recent studies suggest gastrointestinal disease can play a bigger role than previously thought. 5~ A study by Bini and colleagues 5~ evaluated 186 premenopausal women with IDA who were referred for gastrointestinal evaluation. All patients underwent both colonoscopy and upper endoscopy. In this study, 12% of patients had a serious gastrointestinal lesion identified, including gastric cancer in 3% and colon cancer in 3%. One would assume that these patients represent a select group because they were referred to a gastroenterologist by their primary physicians; however, 884 Curr Probl Surg, December 2000

14 59% had neither gastrointestinal symptoms nor a positive FOBT result. Although the 12% prevalence of serious gastrointestinal disease is far lower than seen in other studies of IDA, it is high enough to justify the evaluation of the gastrointestinal tract in at least some premenopausal women. The subgroups with the highest prevalence of gastrointestinal disease (and those who probably benefit the most from gastrointestinal investigations) were those with abdominal symptoms, a positive FOBT result, or hemoglobin level less than 10 g/dl. Women who did not have any gastrointestinal disease identified were treated with oral iron therapy; in 92% of these women, the IDA resolved. 5~ In a separate smaller study, 19 premenopausal women with IDA had both a gynecologic and gastrointestinal evaluation. 51 Gastrointestinal symptoms (most commonly reflux) were present in 11 patients. A gynecologic cause for IDA was thought to be present in 7 patients; however, the subsequent gastrointestinal evaluation found significant lesions in 6 patients (86%). Of the 19 women evaluated, 18 women (95%) were found to have a gastrointestinal lesion. Although small, these 2 studies suggest that one cannot presume that premenopausal women with IDA do not have a gastrointestinal cause. Correlation Between Gastrointestinal Lesions and IDA. A recent study by Ferguson and colleagues 52 sought to better define the cause-and-effect relationship between various gastrointestinal lesions and IDA. In this study, whole gut lavage fluid (WGLF) was used to measure dally fecal blood loss. Patients underwent a bowel cleansing by drinking isotonic lavage fluid at a certain rate until clear fluid was passing per rectum. At this point, Hemoquant analysis was performed on a representative sample of the fluid. Forty-two patients with IDA were evaluated by WGLF/Hemoquant evaluation. Daily blood loss was calculated with the following formula: ([hemoglobin concentration in stool during bowel preparation] x WGLF perfusion rate)/(blood hemoglobin level). As in other studies of IDA, 66.7% of patients had gastrointestinal lesions that were generally thought to be capable of causing IDA. However, only 19% of patients were calculated to have gastrointestinal blood loss of more than 2 ml per day. It should be noted that intermittent bleeding might have contributed to the low rate of elevated hemoglobin levels in the lavage specimens. Despite this possible confounder, the authors concluded that one must be careful in attributing the cause of IDA to gastrointestinal lesions simply because they are present. The patients whose calculated daily blood loss was less than 2 ml per day were often suspected of having an iron-deficient diet or malabsorption because of previous gastric surgery or celiac disease. Curr Probl Surg, December

15 Gastrointestinal Symptoms in Patients With IDA. The relationship between gastrointestinal symptoms and serious gastrointestinal lesions that cause IDA is complex. Several studies have sought to determine whether the presence of gastrointestinal symptoms is associated with a greater likelihood of the discovery of gastrointestinal lesions in patients with IDA. These same studies also address the question of whether the type of gastrointestinal symptoms can be used to direct the gastrointestinal evaluation in a patient with IDA. 4'48'49'53 Symptoms specific to the gastrointestinal tract may be categorized by their association with lesions in the upper gastrointestinal tract or in the lower gastrointestinal tract. Upper gastrointestinal symptoms generally include dysphagia, heartburn, nausea, vomiting, anorexia, and upper abdominal pain relieved by antacids or food. Lower gastrointestinal symptoms generally include altered bowel habits, diarrhea, constipation, hematochezia, and colicky lower abdominal pain. 4'48'49'53 Some studies have reported a good correlation between the presence of gastrointestinal symptoms and gastrointestinal lesions. For example, Cook and colleagues 48 studied inpatients with IDA using EGD prospectively to evaluate the upper gastrointestinal tract and either colonoscopy or a combination of barium enema and flexible sigmoidoscopy to evaluate the colon. In this patient population, the positive predictive value of upper gastrointestinal symptoms for upper gastrointestinal lesions was 86%, and the positive predictive value of lower gastrointestinal symptoms for lower gastrointestinal lesions was 48%. McIntyre and Long 49 evaluated outpatients with IDA prospectively using a combination of EGD, barium enema, and flexible sigmoidoscopy. In this group with IDA, there was 50% sensitivity and 83% specificity for upper gastrointestinal symptoms, and 44% sensitivity and 80% specificity for lower gastrointestinal symptoms. Rockey and Cello 4 also found a good correlation between symptoms and disease. In their prospective evaluation of IDA patients with the use of bidirectional endoscopy, 77% of patients with upper gastrointestinal symptoms were found to have upper gastrointestinal lesions, and 81% of patients with lower gastrointestinal symptoms were found to have lower gastrointestinal disease. At the other end of the spectrum, Joosten and colleagues 53 found no correlation between gastrointestinal symptoms and the presence or absence of serious gastrointestinal lesions in patients with IDA. Zuckerman and Benitez 6 evaluated a mixed group of patients with IDA and/or positive FOBT results and also did not find any correlation between gastrointestinal symptoms and the presence or absence of gastrointestinal lesions. 886 Curr Probl Surg, December 2000

16 Most reports have included patients with IDA with and without gastrointestinal symptoms. Wilcox and colleagues 47 specifically examined asymptomatic patients using colonoscopy and upper endoscopy. A gastrointestinal cause for anemia was found in 44% of patients, with the most common diagnosis being colon cancer in 21%. In 56% of patients, a diagnosis was not established, and patients were then treated with oral iron therapy. At a median follow-up of 2 years, all but one patient responded appropriately to iron replacement. The one patient with recurrent IDA had an incomplete initial colonoscopy; she was eventually found to have colon cancer. The results of these studies suggest that, in some patients with occult bleeding, there is a correlation between the type of gastrointestinal symptom (eg, either upper or lower) and the location of gastrointestinal lesions. Therefore, if a patient with occult bleeding has specific upper or lower gastrointestinal symptoms then it is acceptable to begin with an endoscopic evaluation directed by the symptoms. However, if a malignancy is not found in the initial endoscopic investigation then the other endoscopy should be performed. Iron Deficiency l~tthout Associated Anemia. Iron deficiency without anemia has also been associated with gastrointestinal disease. Two recent studies 46'53 have enrolled patients with serum ferritin levels less than 50 ng/ml and included patients both with and without anemia. In both studies, the patients with and without anemia had essentially an equal prevalence of serious gastrointestinal disease that was diagnosed with the use of a combination of colonoscopy, barium enema, and upper endoscopy. Essentially an equal prevalence of serious gastrointestinal disease was found in patients with serum ferritin levels of 20 ng/ml or less and in patients with ferritin levels of 21 to 50 ng/ml. 46 Gastrointestinal evaluation is therefore indicated in patients with a ferritin level of 50 ng/ml or less. 54 NSAIDs. It has long been suspected that NSAID use might be associated with IDA. However, several studies have found no association between the prevalence of gastrointestinal lesions and the use of NSAIDs. 3'4'6'53 It should be noted that NSAIDs can lead to gastrointestinal blood loss by causing injury and bleeding from previously normal mucosa. 38 Surprisingly, Doran and Hardcastle 55 reported that, in patients with known colon cancer, daily aspirin does not increase the daily fecal blood loss, as measured by 51Cr, or the frequency of positive hemoccult tests. These considerations may account for the inconsistencies in previous reports. IDA and Celiac Sprue. Although patients with celiac sprue frequently have IDA, 56 in prospective studies of patients with IDA, it is found to be the cause in 0% to 11% of patients. 2~,49,57 Although IDA associated with Curr Probl Surg, December

17 celiac sprue is thought to be due to the malabsorption of dietary iron, one half of patients with known celiac sprue also have positive FOBT results. 56 Celiac sprue is a diagnosis that is confirmed by small-bowel biopsy results. Celiac sprue is most common among people of northern European heritage. 11 A study conducted in the United States, in which all patients with IDA underwent a small-bowel biopsy regardless of the appearance of the mucosa, did not find any cases of celiac sprue, 3 whereas similar studies from Australia 2 and Israel 57 found the prevalence to be 6% and 11%, respectively. Patients who are found to have celiac sprne typically are younger and have more frequent diarrhea than those patients without celiac sprne. 57 Evaluation of Occult Bleeding An algorithm for the diagnosis of occult gastrointestinal bleeding is given in Fig 2. As noted earlier, the correlation between the presence of upper or lower gastrointestinal symptoms and identifiable pathologic conditions is not consistent. Nevertheless, because some studies suggest that symptoms do correlate with the presence of a lesion, a symptomatic patient's initial evaluation should begin with either an EGD or colonoscopy, the choice being dictated by the type of symptom present. If the patient is asymptomatic then the evaluation should begin with colonoscopy. If a malignancy is found then the evaluation can be stopped. If a lesion other than malignancy is found, then endoscopy from the other direction is still indicated because the prevalence of combined upper and lower lesions ranges from 1% to 17%. 3,4,48,49 The asymptomatic patient should undergo colonoscopy first, followed by EGD if no malignancy is identified. If the evaluation after bidirectional endoscopy is negative and the occult bleeding persists, then small-bowel investigation should be considered. Potential lesions include vascular ectasias and celiac sprue, which can be associated with iron malabsorption and occult bleeding. Studies that use enteroscopy in patients with IDA and negative colonoscopy have identified lesions in as many as 6% to 26% of patients. 58,59 In contrast, when both colonoscopy and EGD were negative, enteroclysis was insufficiently sensitive to identify any abnormalities. 4 Small-bowel evaluation for iron deficient patients remains controversial. When evaluation of the small bowel is sought, enteroscopy is probably better than enteroclysis at identifying lesions and allowing biopsies to be performed. This technique is probably best reserved for patients who have had negative EGD and colonoscopy with persistent symptoms or refractory anemia. 888 Curr Probl Surg, December 2000

18 EVALUATION OF OCCULT GASTROINTESTINAL BLEEDING Symptoms? I~ I I No Upper ~_~n-'l ~nanc), to Endoeco~ Yes 9.I ~um E,.m, J ~I +I- UGI Sedes Lowe~'t "- k Colonoscopy I Malignancy t ~I /mnu=fobtw- I v I Oral Fe Supplement =J Stop Eva~ation J I "~ ; "I Fig 2. Algorithm for the evaluation of occult gastrointestinal bleeding. UGI, Upper gastrointestinal. Treatment Patients who undergo a negative initial evaluation for IDA should be treated with oral iron therapy. In most patients (72%-92%) the IDA will resolve without recurrence, and no further evaluation is needed. 4,5~176 Patients whose anemia is unresponsive to oral iron therapy have a tfigh prevalence of identifiable conditions (such as chronic renal failure or a metastatic carcinoma), and these are likely to be the cause of the anemia. 4'6~ Certainly, if the patient begins to require transfusions or the anemia remains persistent, then further evaluation is indicated. Additional tests would include repeat upper or lower endoscopy, enteroscopy, or small-bowel imaging studies. Obscure Sources of Gastrointestinal Definition Bleeding In a recent position statement by the American Gastroenterological Association, obscure gastrointestinal bleeding was defined as "bleeding of unknown origin that persists or recurs (ie, recurrent or persistent IDA, Curr Probl Surg, December

19 FOBT positivity, or visible bleeding) after a negative initial or primary endoscopy (colonoscopy and/or upper endoscopy) result. ''1 Two forms of gastrointestinal bleeding fulfill this definition: (1) obscure-occult (ie, obscure bleeding associated with recurrent IDA or a positive FOBT result), and (2) obscure-overt (ie, obscure bleeding that is visible [ie, hematemesis, melena, or hematochezia] and recurrent). 1 Ordinarily, bleeding is defined as obscure after a single colonoscopy and upper endoscopy have failed to identify the source. Up to 5% of patients with overt gastrointestinal bleeding will fail to have a source identified after initial endoscopic procedures 61 and can therefore be classified as obscureovert. Natural History Among all patients with occult bleeding, 29% to 52% will not have a lesion identified by initial endoscopic studies. 2-6,47 These patients with idiopathic occult bleeding have a good prognosis. Most patients (71%- 92%) will not have a recurrence or will have a resolution with oral iron therapy.n,50, 60 Unfortunately, the natural history of obscure bleeding is not so well defined. Patients with obscure bleeding are a diverse, difficult group to study, and there is little information to clarify the natural history of bleeding in this setting. 1 It has been reported that both overt upper and lower gastrointestinal bleeding in most patients will stop without any intervention. 62 Among patients hospitalized for gastrointestinal bleeding, 75% of patients are reported to have resolution of bleeding with bed rest, sedation, volume replacement, and blood transfusions. 63 Many patients with obscure bleeding have small-bowel vascular malformations. 64,65 In the untreated natural history of this disease, some patients will continue to have intermittent, transfusion-dependent bleeding episodes, whereas other patients will not experience rebleeding. 66 Richter and colleagues 67 evaluated patients with medically treated bleeding vascular malformations and found rebleeding rates of 26% and 46% at 1 and 3 years, respectively. The interpatient variability is one factor that makes determining the efficacy of treatment quite difficult. In the past, before the development of many of today's diagnostic tools, blind subtotal colectomy was used for patients with massive bleeding without a specific diagnosis. Natural history data from these patients are difficult to extrapolate to today's patients, who have the benefit of many more diagnostic modalities. Still, patients who undergo this procedure may continue to bleed after operation from noncolonic sources Curr Probl Surg, December 2000

20 Differential Diagnosis Upper Lesions. Upper gastrointestinal lesions are often found in patients with obscure gastrointestinal bleeding. A small study that investigated the use of repeat EGD in patients with obscure-overt bleeding reported a diagnostic yield of 29%. 69 When obscure bleeding is investigated with enteroscopy, 20% to 64% of patients in whom a diagnosis is made (10%-38% of all patients with obscure bleeding) are found to have a lesion that was within reach of standard EGD. 58'7~ Upper gastrointestinal lesions (Table 9) found in patients with obscure bleeding include peptic ulcer disease in 0% to 8%, Cameron's erosions (erosions in a large hiatal hernia) in 0% to 8%, and gastric or duodenal vascular malformations in 0% to 8%.58'72-75 Less connilon upper tract sources of obscure bleeding are esophagitis, 74 esophageal ulcer, 73 esophageal varices, 58 gastric or duodenal polyps, 74,75 Dieulafoy's lesion, 73 gastric antral vascular ectasia (GAVE; also known as watermelon stomach), 75 blue rubber bleb nevus syndrome, ~ Osler-Weber-Rendu syndrome, l and celiac sprue. 1 Undoubtedly some of these lesions might have been identified by the first endoscopist but were not recognized as the source of bleeding because of their unusual nature. GAVE. GAVE is an increasingly recognized cause of occult bleeding. This condition is most common in elderly women. Patients generally experience occult bleeding and have IDA that fails to respond to oral iron therapy. The cause is unknown. Patients frequently have autoimmune or connective tissue disorders and atrophic gastritis, hypergastrinemia, cirrhosis, or portal hypertension. The typical endoscopic appearance resembles stripes on a watermelon: rugal folds containing a column of vessels that converge at the pylorus. The optimal treatment is not yet established. Supportive treatment with blood transfusions, steroid use, endoscopic ablation, or surgical resection have all been reported. 76 Dieulafoy Lesion. A Dieulafoy lesion is a large artery very close to the mucosal surface, possibly as a congenital lesion. Traditionally, the name refers to a lesion in the proximal stomach, but up to one third of Dieulafoy lesions can be found elsewhere in the gastrointestinal tract (most frequently duodenum, but also esophagus, jejunum, and colon). The mechanisms that lead to bleeding have not been well characterized. It is thought that bleeding is caused by focal vessel wall necrosis, with gastritis and disruption of the overlying mucosa. Bleeding is frequently life-threatening. The usual presentation is with hematemesis, but hematochezia occurs in up to one third of patients. Dieulafoy lesions reportedly account for approximately 2% of cases of acute gastrointestinal bleeding. In 37% of patients, more than 1 endoscopic procedure will be required to establish Curr Probl Surg, December

21 TABLE 9. Causes of occult and obscure bleeding by location Location Upper tract lesions Small-bowel lesions Colonic lesions Cause Esuphagitis Esophageal cancer Acid peptic disease Gastritis Previous gastric surgery Duodenitis Varices Polyps Gastric cancer Vascular malformations. Gastral antral vascular ectasia (GAVE) Dieulafoy's lesion Blue rubber bleb nevus syndrome Osler-Weber-Rendu syndrome Celiac sprue Vascular malformations Celiac sprue Small-bowel tumors (ie, lymphoma, metastatic tumors, carcinoid, primary adenocarcinoma, leiomyoma, leiomyosarcoma, melanoma, lipoma) Crohn's disease Polyps Small-bowel varices Meckel's diverticulum Radiation enteritis Aortoenteric fistula Osler-Weber-Rendu syndrome Blue rubber bleb nevus syndrome Von Willebrand's disease Diverticula Hemosuccus pancreaticus Hemobilia Colon cancer Polyps Vascular malformations Colonic ulcers Colitis (any cause) Parasitic infection?hemorrhoids?diverticulosis the diagnosis. Endoscopic treatment with various ablative methods is successful in more than 95% of patients. If bleeding cannot be controlled endoscopically, then operation is indicated. 77 Blue Rubber Bleb Nevus Syndrome. Blue rubber bleb nevus syndrome is characterized by blue-colored vascular nevi of the skin (but not mucous membranes). Gastrointestinal bleeding is also characteristic and is due to 892 Curr Probl Surg, December 2000

22 the presence of cavernous hemangiomas, which can be located throughout the gastrointestinal tract but are most common in the small bowel. Most cases are sporadic. Less commonly, autosomal dominant transmission has been reported. The gastrointestinal lesions can be seen endoscopically and are best treated by endoscopic ablative methods. Surgical resection is indicated for recurrent hemorrhage. 78 Osler-Weber-Rendu Syndrome. Osler-Weber-Rendu syndrome is also known as hereditary hemorrhagic telangiectasia. It is inherited in an autosomal dominant manner and is characterized by telangiectasias of the skin and mucous membranes and recurrent gastrointestinal bleeding. The gastrointestinal lesions are most common in the stomach and small bowel, although they can be encountered in the colon as well. Bleeding usually is encountered as melena. The lesions can be seen on endoscopy. Although the optimal treatment method has not been determined, lesions can be treated with endoscopic ablation. If endoscopic treatment fails, then surgical resection can be performed. 78 Combination estrogen/progesterone hormonal therapy can reduce the transfusion requirements. 79 Hormonal therapy is probably best used in patients with diffuse lesions or lesions that are inaccessible to endoscopic or surgical treatment. Lesions in the Small Intestine. The small bowel is the least frequent site of obscure gastrointestinal bleeding, being the source in only 3% to 5% of patients. 8~ The most common sources of obscure bleeding from the small bowel that are identified during push enteroscopy are vascular malformations, reported in 8% to 40% of patients. 58,64'7~ Small-bowel tumors are the second most frequent cause of small-bowel bleeding. Among patients with occult bleeding who are evaluated by push enteroscopy, vascular malformations are present in 0% to 6% of patients. 58'64'72-75'81'82 The findings with sonde enteroscopy are similar. Vascular malformations are found in 20% to 40% of patients, and tumors are identified in 0% to 8%. 65,83-85 Less conlltlon sources of small-bowel bleeding are Crohn's disease, 65,75 small-bowel varices, 65'75 diverticula, 64'75'84 ulcers, 75'85 Meckel's diverticulum, 65,75 ischemia, 75 celiac sprne, 72'84 aortoenteric fistula, 65'65 radiation enteritis, 58 blue rubber bleb nevus syndrome, 81 Osler-Weber-Rendu syndrome, 81 Dieulafoy lesion, 73 polyposis syndromes, Gardner's syndrome, amyloidosis, hemosuccus pancreaticus, and hemobilia. 1 Vascular Malformations. Vascular malformations are also termed angiodysplasias and vascular ectasias. Regardless of their name, vascular malformations are responsible for 70% to 80% of small-bowel bleeding. 1~ A vascular malformation is a dilated complex of preexisting submucosal arterioles, capillaries, and venules that can usually be seen by Curr Probl Surg, December

23 endoscopy or angiography. 1~ True arteriovenous malformations are a different disease, being composed of thick-walled arteries and veins that are not connected by capillaries. 1~ Historically, vascular malformations that caused bleeding were thought to be located predominately in the right colon. However, it is now clear that vascular malformations can cause bleeding in any location: left colon, stomach, or small bowel. Multiple lesions are present in 30% to 75% of patients. 66 Vascular malformations are probably best considered as a degenerative disease of aging, because they are most common in patients over the age of 60 years. The exact prevalence in the general population is unknown because many patients are asymptomatic, with lesions discovered only incidentally during bowel resection for another indication or during autopsy. Based on these data, their prevalence in the general population is estimated to be approximately 3%. 66 Aortic stenosis and chronic renal failure have been reported to be associated with vascular mafformations. However, a recent critical review looked specifically at the methods used to document the presence of aortic stenosis in these patients. In this careful and systematic review, there was no clear association between aortic stenosis and vascular malformations. 86 The natural history of vascular malformations is variable. Vascular malformations that are identified incidentally rarely bleed. 67 Approximately 50% of patients with untreated or medically treated vascular malformations who have experienced a bleeding episode will have an additional bleeding episode that requires transfusion. 67'87 Lower Gastrointestinal Lesions. Any lesion that is missed during the initial evaluation can become the source of obscure bleeding. Although colonoscopy is considered to be the gold standard for detecting large bowel lesions, it is not infallible. Lesions that have been missed by initial colonoscopy include neoplasias, 88 vascular malformations, 58 and ulcerated diverticulitis. 58 In studies to evaluate the "miss rate" for adenomas, back-to-back colonoscopies were performed on a single day. The miss rate for adenomas smaller than 1 cm is 15% to 25%, but for those larger than 1 cm, only 0% to 6%. 88,89 This suggests that colonoscopy reliably finds the polyps that are capable of bleeding or harboring malignancy. The smaller, more frequently missed lesions are less likely to be the sources of overt or occult bleeding. Special Tools of Evaluation Once a patient is determined to have obscure bleeding, either of the overt or occult variety, the next question is how to proceed with the diagnostic evaluation. Available special tools of evaluation include retrograde 894 Curr Probl Surg, December 2000

24 enteroscopy, push enteroscopy, sonde enteroscopy, small-bowel followthrough, enteroclysis, nuclear scan, angiography, and helical computed tomography (CT) scan. In the following section, we discuss the technical aspects and usefulness of each method in the evaluation of the condition of the patient with obscure gastrointestinal bleeding. With rare exception, one or more of these techniques should be used in every patient with obscure gastrointestinal bleeding before surgical intervention is contemplated. Retrograde Enteroscopy. Retrograde enteroscopy is an endoscopic evaluation of the terminal ileum during routine colonoscopy. Successful intubation of the ileocecal valve can be achieved in 72% to 95% of patients with a standard colonoscope. 9~ Despite the relatively low diag- nostic yield of retrograde ileoscopy, this technique should be attempted during routine colonoscopy. When retrograde enteroscopy is performed during routine colonoscopy, the diagnostic yield is 0.5% to 5% In a single series of 82 patients with occult and obscure bleeding reported by Borsch and colleagues, 9~ no patients had a diagnosis established with retrograde ileoscopy. Retrograde enteroscopy has also been performed with a push-type enteroscope, with a diagnostic yield of 1.6%. 58 Jakobs and colleagues 93 have reported retrograde enteroscopy with the use of a specialized enteroscope piggy-backed onto a specialized colonoscope. This procedure is technically difficult and requires 2 endoscopists but is reported to allow deeper intubation than a standard colonoscope. In this single study, it was possible to identify an obscure source of chronic bleeding in 2 of 10 patients. In one patient, the lesion was located just past the ileocecal valve; in the other patient, a vascular malformation was encountered 25 cm past the ileocecal valve. 93 Push Enteroscopy. Several studies have examined the value of push enteroscopy in patients with obscure-overt and obscure-occult bleeding. 58'7~ Push enteroscopy is the endoscopic method used most often to visualize the small intestine. The push enteroscope is of similar caliber to a gastroscope but longer, measuring 200 to 300 cm. The push enteroscope is passed orally to the stomach and duodenum. Once the instrument is in the duodenum a series of push-pull maneuvers is used to pleat the small bowel over the instrument. Some endoscopists use a semirigid gastric overtube to facilitate deeper intubation of the small intestine by preventing intragastric looping. Plain films or fluoroscopy have been used to determine the maximum depth of insertion but are not considered helpful in most circumstances. The small-bowel mucosa is examined both during intubation and extubation. There is an instrument channel through which biopsy forceps, Curr Probl Surg, December

25 multipolar probes, heater probes, lasers, or snares may be passed. Total procedure time is reported to range from 10 to 80 rninutes. 95 Push enteroscopy is diagnostic in 26% to 54% of patients with obscure gastrointestinal bleeding. 58,7~ Interestingly, all studies of push enteroscopy used for the evaluation of obscure gastrointestinal bleeding have found that a substantial number of newly identified lesions were in locations that should have been easily reached by standard EGD. In patients in whom a lesion was identified, 20% to 64% had proximal lesions that should have been detected by EGD alone (10%-26% of all patients with obscure bleeding undergo push enteroscopy). 58,71-73'94 These considerations should not be interpreted to diminish the value of enteroscopy. However, they emphasize the importance of careful EGD before recommendation of enteroscopy. The lesions most commonly identified during repeat EGD or the proximal portion of push enteroscopy are gastroduodenal ulcers, Cameron ulcers, and vascular malformations. 94 All authorities agree that the skill of the endoscopist is a major factor in recognizing these rare lesions during the initial endoscopy. There is some controversy concerning which is more appropriate as the first step in evaluating obscure bleeding: push enteroscopy or repeat upper endoscopy. Some authors feel that push enteroscopy is well tolerated and should be the procedure of choice, but with special attention paid to the proximal gastrointestinal tract. 72'94 However, 2 studies in which most newly identified lesions were within reach of standard EGD prompted the authors to recommend EGD rather than push enteroscopy as the initial procedure of choice. 58'73 Yet another suggestion for patients with occult bleeding and a negative colonoscopy is that proceeding directly to push enteroscopy as the next diagnostic tool is more cost-effective than EGD. 59'96 Although considered to be a safe procedure, push enteroscopy is not without risk. Bowel perforation has been reported. 58 Complications believed to be associated with the use of the gastric overtube include Mallory-Weiss tear, 97 acute pancreatitis, 97 pharyngeal tear, 7~ and gastric mucosa stripping. 98 There are conflicting data regarding the patient groups that would benefit most from push enteroscopy. Some studies have reported a higher rate of lesions detected in patients with obscure-overt bleeding than in patients with obscure-occult bleeding. 58,7z Another study has reported the reverse. 73 Sonde Enteroscopy. When the distal small bowel is very strongly suspected to be the source of occult bleeding, sonde enteroscopy may be indicated. In this procedure a long (2.7 m), thin (5 ram), highly flexible 896 Curr Probl Surg, December 2000

26 enteroscope is passed transnasally and guided into the duodenum then allowed to migrate passively by peristalsis into the distal ileum. As the instrument is withdrawn, the endoscopist under direct vision inspects the small-bowel mucosa. The procedure has several drawbacks. The most commonly used instrument (SIF-SW; Olympus America Inc, Melville, NY) has an angle of view of 120 degrees but no tip deflection, allowing only 50% to 70% of the mucosa to be visualized. In addition, if loops of small bowel uncoil rapidly and fall off the tip, there is no possibility of reinsertion to examine that region. Biopsies and other interventions are not possible because there is not an instrument channel. The total time needed for the procedure ranges from 4 to 8 hours. Despite the length of the procedure, the distal ileum is reached in less than 75% of patients. 95 Reported complications of sonde enteroscopy include bowel perforation in 0% to 3% 85,99 and epistaxis in 0% to 14%. 85'99'1~176 Sonde endoscopy has been reported to identify a bleeding source in 26% to 54% of patients with obscure bleeding. 65'75'83-85'99 The highest diagnostic yield was reported in a study that used a prototype enteroscope that was equipped with an instrument channel through which closed biopsy forceps were used to push the bowel wall away, permitting a better view. 84 When stratified by indication, a diagnosis was established in 41% of patients who were using NSAIDs, 27% of patients with IDA, and 37% of patients with obscure-overt bleeding. 99 Vascular malformations account for most identified lesions and are present in 3% to 40% of all patients. 65'75'83'99 Tumors are the second most frequently identified lesions, encountered in 0% to 6% of patients who undergo sonde enteroscopy. 65'75'85 Patients with small-bowel tumors that are diagnosed by sonde enteroscopy tend to be younger than those patients with vascular malformations, with mean ages of 51.4 years and 69 years, respectively. 65 Currently, sonde enteroscopy is rarely used, usually being reserved for patients with a contraindication to surgical exploration. 1~ Recently, prototype enteroscopes with tip deflection, an instrument channel, and video capability have become available. 83,84,1~ With these newer instruments, perhaps the indications for sonde enteroscopy will expand. Small Bowel Follow-through (SBFT) and Enteroclysis. SBFT is a radiographic study in which a patient drinks a barium suspension followed by radiographic evaluation at different angles and during maneuvers of compression or change in the body position. In enteroclysis, a small tube that has been guided into the proximal small bowel either with the assistance of fluoroscopy or endoscopy is used to instill barium and methylcellulose, and a series of double contrast radiographs are taken. 1~ Advantages of enteroclysis are the ability to study the entire small bowel, Curr Probl Surg, December

27 injection of contrast under pressure that allows increased bowel distention, and the ability to control the rate of contrast injection. 1~ When used in the prospective evaluation of patients with occult bleeding, both SBFT and enteroclysis have low diagnostic yields. In prospective studies of patients with IDA who had normal upper endoscopy and colonoscopy results, SBFT and enteroclysis both were reported to have diagnostic yields of 0%. 2-4 A retrospective review of enteroclysis that included patients with both obscure and occult bleeding reported an overall diagnostic yield of 10%. 1~ The subgroup of patients with negative upper and lower endoscopies had the highest diagnostic yield, at 20%. 1~ Similarly, another retrospective review of enteroclysis performed in patients with rectal bleeding, melena, or a positive FOBT result reported that 21% had lesions that were responsible for bleeding that was diagnosed during enteroclysis. 1~ In this study, the most frequent diagnosis established by enteroclysis was tumor in 13%; vascular malformations were suspected in only 2%. A combination of push enteroscopy and enteroclysis was used to study patients with obscure bleeding. 71 Push enteroscopy was performed first and, if nondiagnostic, was immediately followed by enteroclysis. Push enteroscopy had a diagnostic yield of 54%. Vascular malformations were the most common diagnosis, followed by ulcers. Eight percent of patients had a diagnosis established during enteroclysis; masses were the only findings. The combined diagnostic yield was 57%. Advantages of combining the 2 procedures are that the time to intubate the small bowel during enteroclysis is shortened, the patient is exposed to less radiation, and a single conscious sedation session is needed (although not all enteroclysis is performed with conscious sedation). Overall, SBFT or enteroclysis, as the sole approach to obscure bleeding, has few indications in the initial evaluation of occult bleeding. However, it may be reasonable to perform enteroclysis in the evaluation of obscure bleeding if used as a follow-up to push enteroscopy. One must remember that enteroclysis is best used to identify small-bowel tumors or relatively prominent abnormalities in the mucosa. Vascular malformations are rarely, if ever, identified. 1~ Nuclear Scan. Radioactive red-cell-labeled bleeding studies are used to localize the source of obscure-overt bleeding. The technetium-99m-labeled red blood cell (TRBC) scan is the most commonly used method, having a higher diagnostic yield than the technetium Tc-99m sulfur colloid scan. 107 Additionally, a longer haft-life allows TRBC scans to be performed repeatedly over a 24-hour period. 1~ By calculating the transfusion requirements of patients with positive scans, it has been determined that a bleeding rate 898 Curr Probl Surg, December 2000

28 as low as 0.1 ml/min can be detected by TRBC scan. 108 TRBC scans and angiograms are both considered to be initial diagnostic maneuvers for acute lower gastrointestinal bleeding. Therefore, bleeding believed to be from a lower gastrointestinal source is not considered to be "obscure" until a colonoscopy, TRBC scan, and angiogram are all negative. Although TRBC scans are usually performed to identify gastrointestinal bleeding sources distal to the ligament of Treitz, upper sources can also be identified. In one study, among patients with positive TRBC scans, the source was identified as the stomach or duodenum in 8% of patients, the small bowel in 21% of patients, and the colon in 61% of patients) ~ In 11% of patients, the scan confirmed a bleeding site but could not localize it precisely. In a review of TRBC studies, an average of 45% of TRBC scans were positive in patients with lower gastrointestinal bleeding. 62 Positive TRBC scans are confirmed with other tests (eg, endoscopy, angiography, or surgery) in an average of 78% of patients (range, 41%-97%). 62 Therefore, a positive TRBC scan alone is probably not enough to guide a surgical resection. ~ 10 The time course of a positive scan is likely important. Sixty percent of patients with a TRBC scan that is immediately positive will also have a positive angiogram; angiograms are only positive in 7% of patients who have a TRBC scan that is positive by delayed "blush. ''111 Scans that are positive only after 6 hours or more often cannot be confirmed by other methods and may represent the accumulation of blood that originated elsewhere in the gastrointestinal tract.ll2 A negative TRBC scan may still provide useful clinical information. Various studies have reported that 5% to 13% of patients with a negative TRBC scan may require surgical intervention, whereas operation is required in 35% of patients with a positive TRBC scan. 110'113 One group of authors therefore believes that a negative scan identifies a group of patients with lower morbidity and mortality rates. ~3 However, another group of authors points out that, in absolute numbers, they performed more operations in patients who had negative TRBC scans than positive TRBC scans. H~ Meckel's Scan. Nuclear scans that use sodium pertechnetate Tc 99m can be used to diagnose the presence of a Meckel's diverticulum. The radionuclide is taken up by ectopic gastric tissue that is present within the diverticulum and mucus-secreting cells in the normal gastric mucosa. In a primarily pediatric population, the sensitivity is reported to be 85%, and the specificity is 95%. In a purely adult population, the sensitivity decreases to 63% because ectopic gastric mucosa is not present as fre- Curt Probl Surg, December

29 quently. TM Cimetidine can be used to increase the sensitivity by decreasing the secretion of the radionuclide into the bowel lumen. 115 Pentagastrin increases the metabolism of mucus-secreting cells and has been reported to increase the sensitivity of the scan. 116 However, this agent is not commonly used because of the possibility of the induction of bleeding ulcers in the diverticulum. 114 Angiography. Selective mesenteric angiography can demonstrate bleeding at a rate as low as 0.5 me/rain. 117 Venous bleeding is usually not demonstrable by angiography, u8 Active arterial bleeding of at least 0.5 ml/min is necessary at the time of contrast injection to demonstrate extravasation into the bowel lumen, which indicates a positive test. 119 Angiography should therefore be performed during an active bleeding episode, rather than between episodes. 118 TRBC scans are capable of demonstrating bleeding at a rate of 0.1 ml/min. Therefore, some authors suggest that patients with obscure-overt bleeding have a screening TRBC scan before proceeding to angiography to select patients who are more likely to have a positive arteriogram. 1~ Among patients with a positive TRBC scan, those who had an immediately positive test are the most likely to have a positive arteriogram.lll In a review of previous studies, the mean positivity rate of angiography in patients with acute lower gastrointestinal bleeding was 47% (range, 27%-77%). 62 The sensitivity of angiography for patients with chronic occult, recurrent acute, and acute bleeding is 40%, 30%, and 47%, respectively. The specificity for all groups is 100%. 12~ Pharmacotherapy can be used to increase the diagnostic yield of angiography. In a study by Koval and colleagues, 119 the diagnostic yield increased from 32% to 65% when patients who had initially had a negative study received heparin, tolazoline, or streptokinase to increase the rate of bleeding. This technique was recommended for patients whose overall medical condition would tolerate the provocation of bleeding. Patients with significant comorbidities, who could not tolerate such pharmacologic intervention, had a femoral catheter left in place instead so that angiography could be performed immediately if bleeding recurred. In a group of patients with an initial diagnostic yield of 60%, repeat angiography was reported to increase the total diagnostic yield to 80%. 121 Most of the patients with a positive repeat arteriogram had continuous or recurrent bleeding. Surprisingly, patients whose bleeding had stopped but whose angiography was repeated 4 weeks after the initial bleeding episode also had positive tests. These patients had vascular malformations, the vessels of which were believed to be in spasm during the initial arteriogram. 900 Curr Probl Surg, December 2000

30 Although contrast extravasation into the bowel lumen indicates a positive test, angiography may occasionally identify candidate lesions when bleeding is not active. Nonbleeding, structural lesions (such as vascular malformations, tumors, and inflammatory lesions) can also be detected. In one study of patients with chronic bleeding, 30% of patients (68% of all positive tests) had only structural, nonactively bleeding lesions. 122 If a lesion is identified during angiography and surgical resection is required, methylene blue injection, fluorescein, and radiopaque microcoils have all been reported as adjuncts to precise anatomic localization in the operating room Helical CT Scan. Helical CT scanning can be used to provide virtual colonoscopy. This is a relatively new technique that has been used in both colorectal cancer screening and the evaluation of obscure gastrointestinal bleeding. 126,127 The helical CT scan is performed after a bowel preparation and insufflation of the colon with a rectal tube. When compared with standard colonoscopy in patients at high risk for colorectal cancer, helical CT scan is nearly as sensitive at detecting neoplasia. Among polyps diagnosed during colonoscopy, 71% are also detected by helical CT scan. 126 However, the sensitivity of helical CT scanning varies with polyp size; the respective sensitivities for polyps larger than l0 mm, 6 to 9 mm, and 1 to 5 mm are 91%, 82%, and 55%, respectively. In the same study, all cancers detected by colonoscopy were also detected by helical CT scan. Helical CT angiography has been reported to be useful in the evaluation of patients with obscure bleeding when other diagnostic modalities have failed to reveal the bleeding source. This technique requires the helical CT scan to be performed 30 seconds after contrast dye is injected through a catheter in the abdominal aorta (contrast becomes too dilute when injected peripherally). 127 In a series of 18 patients with obscure-overt bleeding who underwent helical CT angiography followed by standard angiography, helical CT angiography identified a bleeding source in 13 patients (72%). The bleeding site was also identified by standard angiography in 1 1 of these 13 patients; 2 patients with negative helical CT angiograms had bleeding sites identified by standard angiography. 127 Thus, some patients who fail to have a bleeding site identified by standard angiography may benefit from helical CT angiography. However, standard angiography allows the possibility of therapeutic intervention, whereas the new technique does not. Helical CT, however, has much promise for replacing SBFT or enteroclysis in assisting in the detection of structural lesions located beyond the normal range of standard endoscopes. Curr Probl Surg, December

31 Treatment The treatment of patients with obscure bleeding will depend on the diagnosis. Fortunately, some patients can be both diagnosed and treated during the same endoscopic or angiographic intervention. Other patients may require pharmacologic or surgical treatment. Endoscopic Treatment. EGD, push enteroscopy, and colonoscopy all allow therapeutic interventions; sonde enteroscopy does not. Endoscopic treatment includes polypectomy and ablation of lesions (such as vascular malformations) by various techniques. TM The available endoscopic ablation methods include monopolar and bipolar electrocoagulation, neodymium- YAG laser, argon laser, injection sclerotherapy, and heater probe. 67,128-13~ Vascular malformations in the stomach, proximal small bowel, and colon are all amenable to ablative therapy. 67,128,129 Vascular malformations, watermelon stomach, Osler-Weber-Rendu syndrome, and blue rubber bleb nevus syndrome have all been treated endoscopically. 129,131 Patients with small-bowel vascular malformations often require more than 1 cauterization session because of the diffuse nature of the disease and rebleeding, m After cauterization treatment of small-bowel vascular malformations, patients require significantly fewer blood transfusions than before treatment. 132 There is evidence that patients in whom all vascular malformations are believed to have been treated have a lower rebleeding rate than those in whom some lesions are left untreated. 128 Vascular malformations treated with the neodymium-yag laser are less likely to rebleed than the lesions of watermelon stomach or Osler-Weber- Rendu syndrome treated in the same manner. 129 Significant rebleeding has been reported in 13% of patients with vascular malformations that were treated with neodymium-yag laser, compared with 34% of patients who were treated with electrocauterization. 67,~3~ Patients with colonic vascular malformations who were treated endoscopically had a higher rate of rebleeding than those treated surgically, although the difference did not reach statistical significance. 67 Angiographic Treatment. Angiographic treatment performed by interventional radiologists include the transcatheter delivery of the vasoconstrictor vasopressin and selective transcatheter embolization. Materials used for embolization include Gelfoam pledgets (Upjohn, Kalamazoo, Mich), stainless steel coils, platinum microcoils, and polyvinyl alcohol particles. TM Gastric, small-bowel, and colonic lesions can all be treated with these methods. 135 Treatment with intra-arterial vasopressin infusions requires that a catheter be left in place for several hours, whereas embolization, if effec- 902 Curr Probl Surg, December 2000

32 tive, will control bleeding very rapidly. TM In a single series of 47 patients reported by Gomes and colleagues, 135 the primary success rates of both treatments were comparable, at 70% each. However, rebleeding after vasopressin reduced its overall success rate to 52%, although a second attempt at embolization increased its success rate to 880~. 135 Vasopressin is associated with cardiac side effects (such as coronary vasoconstriction, hypertension, bradycardia, arrhythmias, and bowel ischemia), with such complications occurring in 35% of patients. 135 In this same report, embolization had an associated 17% complication rate. Such complications included enteroenteric fistula, ischemic bowel injury, ileus, and occlusion of the arterial puncture site. The segmental blood supply to the colon increases the chance of ischemic injury by treatment with embolization. 136 Intra-arterial vasopressin infusion administered after embolization has failed to control bleeding is reported to have a higher risk of bowel ischemia than either procedure performed alone. 137 If bleeding cannot be controlled with angiographic techniques, angiographers may still be able to assist with surgical management. The injection of methylene blue dye into an identified lesion has been reported to assist the surgeon with precise localization when resection is required, lea Medical Treatment. Medical treatment can be used for patients with lesions not amenable to endoscopic or angiographic treatment because of a diffuse disease pattern, an inaccessible location, or a continuation of bleeding despite previous interventions. Hormonal therapy has been used for patients with vascular malformations, Osler-Weber-Rendu syndrome, von Willebrand's disease, and obscure bleeding of unknown origin. 54 In a study of 40 patients with transfusion-dependent obscure bleeding, no patients had bleeding episodes while being treated with a combination estrogen/progesterone oral contraceptive, whereas treatment with conjugated estrogen alone did not prevent bleeding. 54 In contrast, a group of patients with known small-bowel vascular malformations who were treated with hormonal therapy (either conjugated estrogen alone or a combination oral contraceptive) had a rebleeding rate of 50%, the same as a historic control group of patients who received no treatment. 87 Hormonal therapy appears to be more effective in patients with Osler-Weber-Rendu syndrome and with vascular malformations associated with renal disease than in those patients with isolated vascular malformations only. 79'138 The mechanism by which hormonal therapy reduces bleeding in any of these types of patients is unknown. 79,87,139 Side effects of hormonal treatment have been reported to occur in 57% of patients. These include vaginal bleeding, congestive heart failure, Curr Probl Surg, December

33 gynecomastia, vaginal cramping, confusion, and stroke. 87 Forty percent of patients in this series stopped treatment because of side effects. Overall, the experiences with hormonal treatment have been confusing. Nevertheless, there may be small subgroups of patients who would benefit from estrogen and progesterone therapy. It should probably be viewed as treatment of last resort for diffuse disease. Another pharmacologic agent used to treat vascular malformations is octreotide. In a very small number of patients with small-bowel vascular malformations, this agent decreased transfusion requirements in a dosedependent manner. 133 Octreotide is not intended to be a treatment for an acute bleeding episode but rather as a long-term treatment for patients with frequent and chronic bleeding episodes. The mechanism was believed to be reduction of the splanchnic blood flow. Octreotide is administered subcutaneously and is quite expensive, which limits its usefulness. Medical treatment also includes supportive treatment (ie, blood transfusions and iron supplementation alone). Medical treatment has specific indications for (1) supportive treatment of acute bleeding episodes although investigations are being performed, (2) patients with significant other comorbidities who are not candidates for other treatment modalities, (3) patients whose bleeding source remains obscure despite exhaustive investigations, and (4) patients with diffuse disease or disease located in an anatomic location that makes other treatment modalities impossible. Surgical Treatment. Surgical treatment is the definitive treatment for tumors that are located throughout the gastrointestinal tract. Operation is also indicated for other known lesions if endoscopic and angiographic methods have failed to control the bleeding. 1 Patients with continued transfusion-dependent bleeding of obscure cause despite exhaustive evaluation are candidates for surgical exploration. During exploratory laparotomy, simple operative techniques (such as visual inspection, manual palpation, and transillumination) have been reported to identify the bleeding source in up to 64% of patients. 14~ When these methods fail, intraoperative enteroscopy is indicated.140,141 Intraoperative Enteroscopy. Intraoperative enteroscopy is primarily designed to better examine the small bowel in patients with transfusiondependent chronic obscure bleeding. This is usually a procedure of last resort, when several other methods have failed to locate the source of blood loss. In various reports, tests performed before a decision is made to undertake intraoperative enteroscopy include EGD, colonoscopy, push 904 Curr Probl Surg, December 2000

34 enteroscopy, sonde enteroscopy, angiography, SBFr, enteroclysis, barium enema, Meckel's scan, or TRBC scan. 61, The procedure requires a team that consists of both a surgeon and a gastroenterologist. During exploratory laparotomy, the entire bowel is first visually inspected and palpated. If a definitive bleeding source is not found, then intraoperative enteroscopy is performed. Multiple insertion locations and types of endoscopes have been used, including adult or pediatric colonoscopes passed orally, 6~ by the rectum, or by enterotomy. 141 Other groups prefer an enteroscope passed orally or nasally or by enterotomy or ileostomy. 142,143 The surgeon helps to maneuver the endoscope through difficult areas such as the duodenum, ileocecal valve, sigmoid colon, or areas of adhesions. Both teams examine the bowel simultaneously, with the endoscopist viewing the lumen with the aid of video equipment and the surgeon examining the transilluminated serosal surface. The obvious advantage that intraoperative enteroscopy holds over sonde enteroscopy is the possibility of therapeutic intervention. Intraoperative enteroscopy is much more effective at the localization of a source of bleeding than exploratory laparotomy alone. As early as 1961, Retzlaff and colleagues 144 reported that exploratory laparotomy for occult bleeding resulted in a definitive diagnosis in only 30% of patients and a possible diagnosis in an additional 17% of patients. In that era, of course, most patients had not undergone an upper endoscopy or colonoscopy, and the most common diagnosis was peptic ulcer disease. 144 More recent studies have reported that a cause for occult bleeding could be found during the initial exploratory laparotomy in 31% to 65% of patients. When intraoperative enteroscopy was used, the diagnostic yield increased to 70% to 93 %.61, In these studies the most common diagnosis made during the intraoperative enteroscopy portion was vascular malformation in 31% to 83% of patients. Other common findings were tumors and small-bowel ulcerations. Rarer diagnoses are Meckel's diverticulum, small-bowel varices, aortoenteric fistula, Peutz-Jeghers syndrome, blue rubber bleb nevus syndrome, Crohn's disease, and small-bowel diverticulitis. 61'140'141'143 Patients can be treated with segmental bowel resection for a variety of lesions; for diffuse vascular malformations, transmural oversewing or laser photocoagulation can be used. 142 Reported complication rates have ranged from 0% to 12% and include ileus, small-bowel obstruction, and wound infections. Mortality rates in the immediate postoperative period are 0% to 8%. 61'140'142'143 It should be noted that previous reports of operative intervention for obscure bleeding include patients who have undergone exploratory laparotomy alone and those patients who also underwent intraoperative enteroscopy. Curr Probl Surg, December

35 Unfortunately, these reports did not fully evaluate the impact of enteroscopy on morbidity and mortality rates. With rare exceptions, enteroscopy is not, by itself, a cause of death. 61 Trauma to the bowel may occur as it is pleated by the surgeon over the endoscope. It has been suggested that mucosal trauma can be minimized by inserting the endoscope through an enterotomy. This minimizes the "dead space" (ie, esophagus, stomach, duodenum, or colon and rectum) through which the instrument must be passed, thereby allowing advancement with the use of less force. Also, insertion through an enterotomy results in less pleating of the small bowel, which reduces trauma. It has also been suggested that the use of an enterotomy allows the inspection as the scope is advanced rather than withdrawn, which eliminates the need to distinguish a traumatic lesion from a preexisting one. 142 The use of a sonde enteroscope has been reported to be less traumatic than a standard colonoscope, because its smaller radius of curvature results in less stretching of the bowel and its mesentery. 143 As stated previously, the drawbacks of the commonly used sonde enteroscopes are the restricted angle of vision and the lack of tip deflection. Additionally, the expense and limited indications of a sonde enteroscope means that many clinicians will, by default, use a colonoscope for intraoperative enteroscopy. In a series by Lewis and colleagues 14~ that involved 53 patients with obscure gastrointestinal bleeding (66% with obscure-overt and 33% with obscure-occult) that required exploratory laparotomy with or without intraoperative enteroscopy, no lesion was identified in 9 patients. Of these undiagnosed patients, 3 patients (33%) experienced rebleeding. 14~ The diagnoses included vascular malformation in 34% of the patients, small-bowel tumor in 26% of the patients, bleeding Meckel's diverticulum in 7.5% of the patients, and other diagnoses in 15% of the patients. In this series the rebleeding rate among patients who did have a diagnosis established during laparotomy was still 22%. 14~ Nevertheless, exploratory laparotomy, coupled with intraoperative enteroscopy if a diagnosis is not made, clearly is beneficial in patients with persistent obscure bleeding. Despite the high diagnostic yield of intraoperative enteroscopy and the capability of immediate therapeutic intervention, other series have also reported the problem of postoperative rebleeding. When followed for several years after exploratory laparotomy, 12% to 52% of patients will have an additional bleeding episode. 61,140,142,143 Most patients who experience rebleeding have vascular malformations, which highlights the difficulty in caring for patients with this frequently diffuse process. Blind Colectomy. In the past, blind subtotal colectomy was advocated for obscure massive lower gastrointestinal bleeding.145 This procedure usually is 906 Curr Probl Surg, December 2000

36 performed with primary anastomosis of the terminal ileum to distal sigmoid colon. 145 In the era before colonoscopy, the most common cause of exsanguinating lower gastrointestinal hemorrhage was diverticular bleeding. In 1973 Drapanas and colleagues 145 reported a series of 35 patients who were treated with blind subtotal colectomy. Their operative mortality rate was 11%, and although the follow-up period is unclear, no patients were reported to experience rebleeding. ~45 A review of the blind colectomy procedure reported an average mortality rate of 23%, with recent series still having rates as high as 43%. ~46 Although rebleeding from small-bowel and anorectal sources has occurred, 6s overall rebleeding rates after blind subtotal colectomy have not been reported. The high mortality rate and the possibility of not resecting the area that contains the bleeding lesion has led some authorities to state that blind colectomy is never indicated, m7 In a 1991 series reported by Bender and colleagues, patients underwent emergent blind subtotal colectomy for obscure-overt lower gastrointestinal bleeding. The mortality rate of 13 patients whose preoperative transfusion requirement was 9 units of blood or less was 8%. In contrast, among the 22 patients whose preoperative transfusion requirement was 10 units of blood or more, the mortality rate was 50%. In the same group of patients, the method of anastomosis did not affect the leak rate. Hand-sewn anastomosis was associated with a 13% leak rate, whereas a stapled anastomosis was associated with a 22% leak rate.~46 On the basis of these considerations, we suggest that blind subtotal colectomy is acceptable in certain patients with acute, life-threatening hemorrhage. The patients whose bleeding is most likely to be controlled by this procedure are those whose bleeding is definitely colonic in nature, ffthe ileocecal valve is competent and visible blood is only located in the colon, then subtotal colectomy is not unreasonable. On the other hand, if blood is located throughout the gastrointestinal tract then subtotal colectomy is unlikely to resect the source of bleeding. Conclusions Surgeons are often involved in the diagnosis and treatment of patients with occult and obscure gastrointestinal bleeding. These difficult conditions can require a multidisciplinary approach that involves a primary physician, a gastroenterologist, a radiologist, and a surgeon. The diagnostic approach to occult bleeding is relatively straightforward; an algorithm is provided in Fig 2. In relatively few patients with occult but persistent bleeding, the clinician will not be able to localize the source. However, it can be quite difficult to diagnose and treat the bleeding in these selected patients. A separate diagnostic algorithm is shown in Fig 3. Curr Probl Surg, December

37 EVALUATION OF OBSCURE GASTROINTESTINAL BLEEDING Repeat Bi-clirectional 41 Endoscopy + NO I,[ oj:c, eu~o~,rt I $ Active Blee~g? I Ar~rat~ ar~l Nuclear Scan + Fig 3. Algorithm for the evaluation of obscure gastrointestinal (GI) bleeding. Rx, Medication. Surgeons may become involved in the care of such patients at any time. When a lesion is identified, initial attempts at treatment may be with endoscopic or angiographic methods. If these fail, perhaps because of recurrent bleeding or difficult to reach anatomic location, then surgical resection may be required. A separate group of patients with whom surgeons become involved has recurrent, transfusion-dependent bleeding, the source of which remains obscure despite multiple diagnostic investigations. This group may benefit from exploratory laparotomy with or without intraoperative enteroscopy. Unfortunately, in these patients, even when a bleeding lesion is diagnosed and treated, rebleeding is not uncommon. One suggestion is that surgeons should become involved in the care of such patients sooner rather than later. Early involvement of the surgeon will result in a more detailed discussion of diagnostic and treatment options and will certainly lead to more effective communication among health care providers. Better communication alone may lead to earlier diagnosis, definitive management, and better outcomes. 908 Curr Probl Surg, December 2000

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