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Approach to the patient with obscure gastrointestinal bleeding
Approach to the Patient With Obscure Gastrointestinal Bleeding Don C. Rockey, MD
Obscure gastrointestinal bleeding occurs is an uncommon but important form of occult gastrointestinal bleeding. By definition, bleeding is recurrent and chronic. The patient population in which this occurs is most often elderly and has comorbid conditions. Therefore, these patients represent a considerable diagnostic and therapeutic challenge. The most common cause of bleeding is vascular ectasia, although a number of other lesions can be responsible for bleeding. Thus, familiarity with the various important lesions is required to make a specific diagnosis. The management includes early aggressive endoscopic evaluation (including small bowel investigation), often including capsule endoscopy. In certain clinical circumstances, other diagnostic studies such as angiography, computed tomographic examination, or Meckel’s scan is indicated. It is clear that management and care of this challenging group of patients requires a team approach. © 2003 Elsevier Inc. All rights reserved.
ccult bleeding is easily the most common form of gastrointestinal bleeding. However, the clinical presentation of patients with occult gastrointestinal bleeding is diverse. Symptoms and signs of occult bleeding generally reflect the site, etiology, and magnitude of bleeding. Occult bleeding may be bleeding that is either completely unknown to the patient (ie, fecal occult blood, covered by Dr Allison, or iron-deficiency anemia, covered by Drs Higgins and Rockey) or it may be clinically obvious (ie, manifest by hematemesis, melena, and/or hematochezia) but from an obscure source. This review will focus on “obscure” gastrointestinal bleeding. The source of bleeding remains unidentified in a significant proportion (on the order of 5%) of patients with gastrointestinal bleeding,1 despite appropriate and often aggressive evaluation. Obscure bleeding takes on 2 forms: those patients with gastrointestinal bleeding that is clinically apparent but of obscure origin and those patients with obscure bleeding that remains occult (usually refractory iron-deficiency anemia). Each of these entities represents substantial diagnostic and management challenges. By definition, readily identifiable causes of gastrointestinal bleeding (eg, an ulcer or a mass lesion) have been excluded, usually by upper and/or lower endoscopy. In patients with significant obscure bleeding, bleeding is most
O
From the Department of Internal Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC. Supported by the Burroughs Welcome Fund (DCR is the recipient of a BWF Translational Scientist Award). Address reprint requests to Don C. Rockey, MD, Room 336, Sands Building, Box 3083, Liver Center, Duke University Medical Center, Durham, NC 27710. © 2003 Elsevier Inc. All rights reserved. 1096-2883/03/0503-0002$30.00/0 doi:10.1053/j.tgie.2003.08.001
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often recurrent—a point that brings the patient to medical attention and more importantly forces evaluation. After recognition that bleeding is recurrent (and obscure), it becomes important to localize the site and etiology of bleeding so that appropriate therapy can be instituted.
Approach to Evaluation and Differential Diagnosis Localization of the site (ie, upper or lower gastrointestinal tract) of bleeding should begin with history and physical examination. Although melena and hematochezia are typically associated with upper and lower gastrointestinal tract bleeding, respectively, it should be emphasized that patients with slow oozing from the distal small bowel or cecum may have melena and occasional patients with aggressive bleeding from an upper gastrointestinal source may present with hematochezia. Additionally, history and physical examination should focus on elements likely to be active in patients with easily “overlooked” lesions (Table 1). Careful attention should be focused on the small bowel with reference to weight loss and obstructive symptoms. A general approach to patients with obscure bleeding is presented in Figure 1. In general, in patients with recurrent obscure bleeding, repeat endoscopy directed at the most likely site of bleeding is usually warranted—at least 1 additional time after the index endoscopy. This is important because if the endoscopy is performed during active bleeding, it may allow a specific diagnosis to be identified. It has been well documented in the literature that re-examination of the upper gastrointestinal tract within reach of a standard gastroscope (or an enteroscope) will identify lesions in a substantial proportion of patients.2-4 However, familiarity with uncommon and/or subtle bleeding lesions is required.5 If a lesion cannot be identified, further evaluation depends on the briskness of bleeding. In those with active bleeding, technetium-99 radionuclide scanning or angiography should be performed. This approach allows confirmation of the site of bleeding only. Angiography is less sensitive than technetium-99 radionuclide scanning but may identify the site of bleeding.6 In some patients, diagnostic tests such as computed tomography or Meckel’s scan may be helpful. In patients with subacute or intermittent bleeding in whom repeat endoscopy of the upper or lower gastrointestinal tract is negative, the focus of investigation should rapidly move to the small intestine. The lesions most commonly identified in the small bowel include tumors and vascular ectasias, which vary in frequency depending on age. In patients between the ages of 30 and 50, tumors are the most common abnormalities (in patients less than 25 years of age, Meckel’s diverticula are the most common source of small bowel bleeding), whereas vascular ectasias predominate in the elderly.7 Small bowel examination can be performed with several ra-
Techniques in Gastrointestinal Endoscopy, Vol 5, No 3 (July), 2003: pp 104-108
TABLE 1. Causes of Obscure Gastrointestinal Bleeding Common causes Vascular ectasia Mass lesion (tumor) *Less frequent causes Dieulafoy’s lesions Vascular ectasia Portal hypertensive gastropathy Gastric antral vascular ectasia (watermelon stomach) Gastric and small intestinal varices Crohn’s disease *Rare causes Aortoenteric fistula Hemobilia Pancreatic source *Lesions in these categories may be easily overlooked.
diologic and endoscopic modalities. Radiologic modalities include standard small bowel follow through and enteroclysis. Endoscopic techniques include push enteroscopy, sonde enteroscopy, intraoperative enteroscopy, and wireless capsule endoscopy. Small bowel follow through is rarely adequate to evaluate the small intestine and may miss significant mass lesions. Enteroclysis is more effective at detecting mass lesions8 but does not detect mucosal lesions such as vascular ectasias. Because vascular ectasias are often a major concern in this patient population, enteroclysis is probably best reserved for those in whom the clinical suspicion of a mass lesion or small bowel diverticula is high. A number of endoscopic approaches are capable of examining the small intestine. “Push” and “Sonde” enteroscopy have been prominent in the evaluation of many patients with obscure gastrointestinal bleeding.5 Push enteroscopy entails peroral insertion of a long endoscope during conscious sedation. This instrument can be passed up to 50 to 60 cm beyond the ligament of Trietz, providing a relatively thorough examination of the distal duodenum and proximal jejunum. Push enteroscopy commonly identifies a source of bleeding in patients with obscure bleeding.2,3,9-11 The reported likelihood of detecting lesions is 24% to 75%, although the clinical experience of many has been less. Although push enteroscopy can be uncomfortable for the patient, it is readily available, relatively safe, and allows biopsy and endoscopic therapy. Sonde enteroscopy involves placement of a long, small caliber endoscope into the proximal small bowel, with subsequent peristalsis carrying the endoscope to the more distal small intestine.12 This procedure permits visualization of the almost the entire small bowel and has led to diagnoses in a significant number of cases.13 Although Sonde enteroscopy is attractive diagnostically, it is associated with a number of problems. First, the technique requires a specialized endoscope and expertise with the procedure. Further, Sonde enteroscopy is extremely tedious and does not allow therapeutics. With the introduction of capsule endoscopy (see below and the review by Dr Lewis in this issue), Sonde enteroscopy will probably become phased out and limited to a very few centers. Intraoperative enteroscopy permits visualization of most or all of the small intestine with an enteroscope (or standard colonoscope), which is manually advanced through the small bowel by the surgeon during laparotomy. This combined technique has been reported to detect abnormalities in up to 70% to 100% of patients,14-16 although this has not been the practical experience of all clinicians. OBSCURE GASTROINTESTINAL BLEEDING
A new, conceptually simple approach to examine the small intestine includes wireless capsule endoscopy17-20 and is reviewed in detail by Dr Lewis (see article entitled “The Utility of Capsule Endoscopy in Obscure GI Bleeding”). In brief, this approach appears to be able to identify small bowel lesions with a greater frequency than the other forms of small bowel investigation. Furthermore, capsule endoscopy appears to be very safe and reasonably well tolerated. An important limitation associated with capsule endoscopy is the inability to administer therapy. Therefore, outcome data will be required before capsule endoscopy can be widely recommended. An alternative approach to the diagnosis of recurrent, obscure bleeding is to reactivate or augment bleeding with the use of vasodilators, anticoagulants, and/or thrombolytics in association with tagged red blood cell scintigraphy or visceral angiography. Available literature indicates that the diagnostic yield of this procedure is on the order of 20% to 40%.21,22 It should be emphasized that this is a highly specialized undertaking23 that requires local expertise and experience. Further study to clarify its role in the evaluation of patients with recurrent, obscure gastrointestinal bleeding is required.
Specific Causes of Obscure Gastrointestinal Bleeding Many different gastrointestinal lesions can cause obscure bleeding. Familiarity with the various lesions and their accompanying clinical presentations is critical to make a specific diagnosis. The most common cause of obscure bleeding is vascular ectasia and accounts for up to 60% of detectable bleeding lesions.24,25 Other important lesions include small bowel tumors, Dieulafoy’s ulcer, Meckel’s diverticulum, varices, and ulcers. With regard to the latter 2 disorders, a history of liver disease and nonsteroidal anti-inflammatory drug ingestion, respectively, should raise the level of suspicion for these processes. Rarely, patients present with factitious bleeding, having bled themselves, and ingested blood before presentation. A past history of
Fig 1. Suggested algorithm for management of obscure gastrointestinal bleeding. Given that vascular ectasias are the most common cause of obscure gastrointestinal bleeding, a high level must remain for other diseases. Repeat endoscopy, often during active bleeding, is emphasized. (Reprinted with permission from Rockey DC: Gastrointestinal bleeding, in Feldman, Friedman, Sleisenger (eds): Sleisenger & Fordtran’s Gastrointestinal & Liver Disease (ed 7). Philadelphia, PA, Saunders, 2002.)
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previous psychological illness should raise the level of suspicion for this disorder. A number of important causes of obscure bleeding are highlighted later. Vascular ectasias. Vascular lesions are an important cause of obscure gastrointestinal tract bleeding. They are commonly associated with a variety of underlying conditions including scleroderma, the CREST syndrome, radiation injury, collagen diseases (such as pseudoxanthoma elasticum and Ehlers-Danlos syndrome), and von Willebrand’s disease. Vascular ectasias appear to be most often associated with chronic renal failure. For example, the prevalence of vascular ectasia as a cause of gastrointestinal bleeding was related to the duration of renal failure and need for hemodialysis.26 Bleeding caused by vascular ectasias is painless, and generally of moderate volume (except in the presence of underlying coagulopathy, in which case bleeding can be massive). There is little debate about the importance of vascular ectasias in obscure gastrointestinal tract bleeding; rather the challenge is in making the diagnosis and in identifying the culpable lesion. Patients with lesions that are readily identified or are actively bleeding are best treated with endoscopic methods. Endoscopic therapy (each laser, bipolar electrocoagulation, bicap, banding, injection therapy, and argon plasma coagulation) is generally successful and safe.24,27-29 Perforation of the gastrointestinal tract is possible, especially when using electrocoagulation or laser therapy. Those with massive bleeding may respond to angiographic therapy. Recurrent bleeding from an identified source (after endoscopic or angiographic therapy) is uncommon, but surgical therapy is curative so long as the source bleeding is clearly identified. The use of hormonal therapy is highly controversial (see the review by Dr Barkin in this issue). Diverticula. Diverticular disease of the small intestine is much less common than that of the colon, but it remains an important cause of obscure bleeding. The true pathogenesis of diverticular formation in the small bowel is unknown, as is the cause of bleeding, but is probably a result of penetration from an artery into the dome of a diverticulum. Evidence of concomitant diverticulitis is usually absent, and vessel rupture is thought to be the result of pressure erosion rather than infection. Diverticular bleeding is characterized by acute, painless bleeding. Bleeding is typically of large volume and often produces bright red or maroon stools. Bleeding is typically not hemodynamically significant, although it may be poorly tolerated by the very elderly, who often have comorbid conditions. The diagnosis of diverticular hemorrhage is usually one of exclusion and is most often made by identifying small bowel diverticula and excluding other diagnoses. Rarely, a definitive diagnosis can be made by directly visualizing active bleeding. Treatment of small bowel diverticular bleeding generally involves angiographic intervention and/or surgical resection. Endoscopic treatment requires identification of a bleeding lesion typically in the proximal small intestine and is uncommonly possible. The best approach in those with aggressive bleeding is to identify the location of bleeding and to perform resection. In patients with severe bleeding in whom a specific bleeding site cannot be identified, subtotal bowel resection has been advocated by some but is met with poor outcomes, especially in elderly patients. Meckel’s diverticulum. Meckel’s diverticulum is a remnant of the vitelline duct and is found within the final 100 cm of the
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ileum in up to 2% of the population. The diverticulum contains gastric mucosa, which secretes acid and results in ulceration of adjacent mucosa. Bleeding from Meckel’s diverticulum typically occurs in children but also occurs in young adults; it is the most common cause of gastrointestinal bleeding in patients younger than the age of 30. Bleeding is often brisk and painless. The diagnosis is typically made by radiolabeled technetium scanning. Surgery to remove the diverticulum is required in patients who have had hemorrhage. Dieulafoy’s lesions. Dieulafoy’s ulcer, also know as exulceratio simplex Dieulafoy, refers to an abnormally large artery that retains the large caliber of its feeding vessel as it approaches the mucosa. This large vessel is thought to compress the mucosa and causes a small erosion with rupture of the vessel into the lumen. Dieulafoy’s lesions are important in obscure bleeding because they may be present either in the proximal portion of the stomach (in which they are most commonly identified, usually within proximity to the gastroesophageal junction) but can also be found in more unusual locations such as in the small intestine. It is often difficult to identify the lesion, unless it is actively bleeding or is associated with stigmata of recent bleeding (which is uncommon). Therefore, a high index of suspicion is required to make this diagnosis. Bleeding is often massive and recurrent. Therapy with injection techniques, coagulative therapy, hemoclips, and banding can all control bleeding and prevent rebleeding in most cases.30-33 In 1 review of 24 endoscopically-treated patients in whom follow-up data were available, bleeding recurred in only 1 patient.30 Small intestinal mass lesions. Neoplasms of the small intestine are uncommon but constitute a significant cause of obscure gastrointestinal bleeding. It is noteworthy that gastrointestinal bleeding is the most common clinical manifestation of leiomyoma and leiomyosarcoma, important stromal tumors of the small intestine.34 A number of different benign and malignant tumors have been reported to cause bleeding (some reports suggest bleeding is more common with benign lesions35). The most common benign tumors of the small intestine are leiomyomas. The most common malignant tumors are (adenomas and) adenocarcinomas, carcinoids, lymphomas, and sarcomas. As emphasized earlier, a high index of suspicion is required to make this diagnosis. In the setting of bleeding, warning symptoms such as nausea, abdominal pain, or weight loss should lead to aggressive searches for malignancy. Evaluation of the small bowel should be as outlined (Fig 1); abdominal computed tomography may additionally be helpful for evaluation of possible small bowel mass lesions. Exploratory laparotomy is sometimes required to make a specific diagnosis.36 Management of small intestinal tumors depends on the primary diagnosis but is typically surgical. Aortoenteric fistula. Aortoenteric fistulas are rare but important lesions responsible for upper and/or obscure gastrointestinal bleeding. They are almost always secondary to previous reconstructive aortoiliac surgery37 and occur with a frequency of about 0.5% after aortoiliac surgery.38 Although aortoenteric fistulas are most commonly secondary (ie, after aortic grafting) and occur 3 to 5 years after graft surgery, primary aortoenteric fistulas have been reported.39 Aortoenteric fistulas typically involve the third portion of the duodenum but may involve other portions of the gastrointestinal tract. The typical presentation is of upper gastrointestinal bleeding, which often occurs as a “herald” bleed that stops, but is followed by further (often DON C. ROCKEY
fatal) bleeding. A high index of suspicion is required to make the diagnosis. Because the pathogenesis of this disease is subtle infection of the graft and perigraft area, symptoms and signs of infection (B-type symptoms such as weight loss, low-grade fever, and leukocytosis) raise the likelihood of aortoenteric fistula. All patients with previous aortic surgery and upper gastrointestinal bleeding should undergo esophagogastroduodenoscopy with particular attention to the distal duodenum. Given a negative examination, patients should undergo abdominal computed tomography. This examination will typically show periaortic inflammation and phlegmon, consistent with infection. Angiography is usually not helpful. The prognosis of patients with aortoenteric fistula has been historically poor (over 50% mortality rate) but appears to be improving.38 Definitive therapy typically involves extensive reconstructive surgery. Hemobilia. Hemobilia consists of hemorrhage into the biliary tract. Causes of communication between the vascular and biliary tree include trauma, liver biopsy, gallstones, hepatic artery or portal vein aneurysms, liver abscesses, and neoplasia.40 The most common causes of hemobilia appear to be blunt or iatrogenic trauma. A high index of suspicion is necessary to make the diagnosis; therefore, the clinical history is crucial. The diagnosis is made by visualizing blood coming from the ampulla of Vater and/or by angiography. Angiographic treatment with embolization may be effective,41 but surgical ligation of the hepatic feeding vessel may be required. Mortality from hemobilia is high. Hemosuccus pancreaticus. Hemosuccus pancreaticus is defined as bleeding from peripancreatic blood vessels into a pancreatic duct.42 Hemorrhage is most often a result of chronic pancreatitis with either erosion of a pseudocyst into the splenic or a peripancreatic artery or formation of an arterial aneurysm that subsequently develops a communication with the pancreatic duct. The diagnosis may be made by endoscopic visualization of blood coming from the papilla. Again, a high index of suspicion (typically a history of chronic pancreatitis) is required. Angiography is required to definitively identify the bleeding site and may be used to administer embolization. Surgery is often required to provide definitive control of bleeding.43
Treatment Treatment of lesions that bleed in an obscure fashion is aimed at the underlying abnormality. Treatment often involves a multifaceted approach involving the gastroenterologist, radiologist, and surgeon. For example, endoscopic therapy or embolization therapy for large focal vascular ectasias therapy may be effective. Therapy for mass lesions typically involves surgical resection. Vascular ectasias are particularly problematic because they are often multiple in number, and this feature significantly limits endoscopic and surgical intervention. For this reason, medical therapy has been advocated as a theoretically attractive approach for patients with obscure bleeding because of vascular ectasia.
Summary Obscure gastrointestinal bleeding occurs in a small fraction of all patients with gastrointestinal bleeding. However, these paOBSCURE GASTROINTESTINAL BLEEDING
tients represent a considerable diagnostic and therapeutic challenge. A high index of suspicion and familiarity with the various important lesions is required. These patients should undergo aggressive endoscopic evaluation (including small bowel investigation). Capsule endoscopy is rapidly emerging as an attractive approach for evaluation of the small intestine. In certain circumstances, other diagnostic studies are indicated (ie, angiography, computed tomographic examination). Management of this patient population is challenging given that many of these patients have co morbid conditions and harbor multiple small intestinal vascular ectasias. Therefore, care of this group of patients require a focused and experienced team approach.
References 1. Mujica VR, Barkin JS: Occult gastrointestinal bleeding. General overview and approach. Gastrointest Endosc Clin North Am 6:833-845, 1996 2. Chak A, Koehler MK, Sundaram SN, et al: Diagnostic and therapeutic impact of push enteroscopy: Analysis of factors associated with positive findings. Gastrointest Endosc 47:18-22, 1998 3. Zaman A, Katon RM: Puch enteroscopy for obscure gastrointestinal bleeding yields a high incidence of proximal lesions within reach of a standard endoscope. Gastrointest Endosc 47:372-376, 1998 4. O’Mahony S, Morris AJ, Straiton M, et al: Push enteroscopy in the investigation of small-intestinal disease. Q J Med 89:685-690, 1996 5. Waye JD: Enteroscopy. Gastrointest Endosc 46:247-256, 1997 6. Rollins ES, Picus D, Hicks ME, et al: Angiography is useful in detecting the source of chronic gastrointestinal bleeding of obscure origin. AJR Am J Roentgenol 156:385-388, 1991 7. Lewis BS, Kornbluth A, Waye JD: Small bowel tumours: Yield of enteroscopy. Gut 32:763-765, 1991 8. Rex DK, Lappas JC, Maglinte DD, et al: Enteroclysis in the evaluation of suspected small intestinal bleeding. Gastroenterology 97:58-60, 1989 9. Barkin JS, Lewis BS, Reiner DK, et al: Diagnostic and therapeutic jejunoscopy with a new, longer enteroscope. Gastrointest Endosc 38:55-58, 1992 10. Berner JS, Mauer K, Lewis BS: Push and sonde enteroscopy for the diagnosis of obscure gastrointestinal bleeding. Am J Gastroenterol 89:2139-2142, 1994 11. Landi B, Tkoub M, Gaudric M, et al: Diagnostic yield of push-type enteroscopy in relation to indication. Gut 42:421-425, 1998 12. Gostout CJ, Schroeder KW, Burton DD: Small bowel enteroscopy: An early experience in gastrointestinal bleeding of unknown origin. Gastrointest Endosc 37:5-8, 1991 13. Gostout CJ: Improving the withdrawal phase of Sonde enteroscopy with the “push- away” method. Gastrointest Endosc 39:69-72, 1993 14. Lau WY, Yuen WK, Chu KW, et al: Obscure bleeding in the gastrointestinal tract originating in the small intestine. Surg Gynecol Obstet 174:119-124, 1992 15. Ress AM, Benacci JC, Sarr MG: Efficacy of intraoperative enteroscopy in diagnosis and prevention of recurrent, occult gastrointestinal bleeding. Am J Surg 163:94-98, 1992 16. Szold A, Katz LB, Lewis BS: Surgical approach to occult gastrointestinal bleeding. Am J Surg 163:90-92, 1992 17. Appleyard M, Fireman Z, Glukhovsky A, et al: A randomized trial comparing wireless capsule endoscopy with push enteroscopy for the detection of small-bowel lesions. Gastroenterology 119:14311438, 2000 18. Iddan G, Meron G, Glukhovsky A, et al: Wireless capsule endoscopy. Nature 405:417, 2000 19. Lewis BS, Swain P: Capsule endoscopy in the evaluation of patients with suspected small intestinal bleeding: Results of a pilot study. Gastrointest Endosc 56:349-353, 2002 20. Lewis B, Goldfarb N: Review article: The advent of capsule endoscopy—A not-so-futuristic approach to obscure gastrointestinal bleeding. Aliment Pharmacol Ther 17:1085-1096, 2003 21. Malden ES, Hicks ME, Royal HD, et al: Recurrent gastrointestinal
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bleeding: Use of thrombolysis with anticoagulation in diagnosis. Radiology 207:147-151, 1998 Bloomfeld RS, Smith TP, Schneider AM, et al: Provocative angiography in patients with gastrointestinal hemorrhage of obscure origin. Am J Gastroenterol 95:2807-2812, 2000 Shetzline MA, Suhocki P, Dash R, et al: Provocative angiography in obscure gastrointestinal bleeding. South Med J 93:1205-1208, 2000 Foutch PGAngiodysplasia of the gastrointestinal tract [see comments]: Am J Gastroenterol 88:807-818, 1993 Descamps C, Schmit A, Van Gossum A: “Missed” upper gastrointestinal tract lesions may explain “occult” bleeding. Endoscopy 31: 452-455, 1999 Chalasani N, Cotsonis G, Wilcox CM: Upper gastrointestinal bleeding in patients with chronic renal failure: Role of vascular ectasia. Am J Gastroenterol 91:2329-2332, 1996 Cello JP, Grendell JH: Endoscopic laser treatment for gastrointestinal vascular ectasias. Ann Intern Med 104:352-354, 1986 Askin MP, Lewis BS: Push enteroscopic cauterizationLong-term follow-up of 83 patients with bleeding small intestinal angiodysplasia [see comments]: Gastrointest Endosc 43:580-583, 1996 Morris AJ, Mokhashi M, Straiton M, et al: Push enteroscopy and heater probe therapy for small bowel bleeding. Gastrointest Endosc 44:394-397, 1996 Schmulewitz N, Baillie J: Dieulafoy lesions: A review of 6 years of experience at a tertiary referral center. Am J Gastroenterol 96:16881694, 2001 Chung IK, Kim EJ, Lee MS, et al: Bleeding Dieulafoy’s lesions and the choice of endoscopic method: Comparing the hemostatic efficacy of mechanical and injection methods. Gastrointest Endosc 52:721-724, 2000
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32. Parra-Blanco A, Takahashi H, Mendez Jerez PV, et al: Endoscopic management of Dieulafoy lesions of the stomach: A case study of 26 patients. Endoscopy 29:834-839, 1997 33. Baettig B, Haecki W, Lammer F, et al: Dieulafoy’s disease: Endoscopic treatment and follow up. Gut 34:1418-1421, 1993 34. Blanchard DK, Budde JM, Hatch GF, et al: Tumors of the small intestine. World J Surg 24:421-429, 2000 35. Ciresi DL, Scholten DJ: The continuing clinical dilemma of primary tumors of the small intestine. Am Surg 61:698-702, 1995 36. Lewis MP, Khoo DE, Spencer J: Value of laparotomy in the diagnosis of obscure gastrointestinal haemorrhage. Gut 37:187-190, 1995 37. Bastounis E, Papalambros E, Mermingas V, et al: Secondary aortoduodenal fistulae. J Cardiovasc Surg (Torino) 38:457-464, 1997 38. Bergqvist D, Bjorkman H, Bolin T, et al: Secondary aortoenteric fistulae—Changes from 1973 to 1993. Eur J Vasc Endovasc Surg 11:425-428, 1996 39. Korkut AK, Arpinar E, Yasar T, et al: Primary aortoduodenal fistula complicated by abdominal aortic aneurysm. J Cardiovasc Surg (Torino) 41:113-115, 2000 40. Yoshida J, Donahue PE, Nyhus LM: Hemobilia: Review of recent experience with a worldwide problem. Am J Gastroenterol 82:448453, 1987 41. Merrell SW, Schneider PD: Hemobilia—Evolution of current diagnosis and treatment. West J Med 155:621-625, 1991 42. Risti B, Marincek B, Jost R, et al: Hemosuccus pancreaticus as a source of obscure upper gastrointestinal bleeding: Three cases and literature review. Am J Gastroenterol 90:1878-1880, 1995 43. Suter M, Doenz F, Chapuis G, et al: Haemorrhage into the pancreatic duct (Hemosuccus pancreaticus): Recognition and management. Eur J Surg 161:887-892, 1995
DON C. ROCKEY
Obscure gastrointestinal bleeding occurs is an uncommon but important form of occult gastrointestinal bleeding. By definition, bleeding is recurrent and chronic. The patient population in which this occurs is most often elderly and has comorbid conditions. Therefore, these patients represent a considerable diagnostic and therapeutic challenge. The most common cause of bleeding is vascular ectasia, although a number of other lesions can be responsible for bleeding. Thus, familiarity with the various important lesions is required to make a specific diagnosis. The management includes early aggressive endoscopic evaluation (including small bowel investigation), often including capsule endoscopy. In certain clinical circumstances, other diagnostic studies such as angiography, computed tomographic examination, or Meckel’s scan is indicated. It is clear that management and care of this challenging group of patients requires a team approach. © 2003 Elsevier Inc. All rights reserved.
ccult bleeding is easily the most common form of gastrointestinal bleeding. However, the clinical presentation of patients with occult gastrointestinal bleeding is diverse. Symptoms and signs of occult bleeding generally reflect the site, etiology, and magnitude of bleeding. Occult bleeding may be bleeding that is either completely unknown to the patient (ie, fecal occult blood, covered by Dr Allison, or iron-deficiency anemia, covered by Drs Higgins and Rockey) or it may be clinically obvious (ie, manifest by hematemesis, melena, and/or hematochezia) but from an obscure source. This review will focus on “obscure” gastrointestinal bleeding. The source of bleeding remains unidentified in a significant proportion (on the order of 5%) of patients with gastrointestinal bleeding,1 despite appropriate and often aggressive evaluation. Obscure bleeding takes on 2 forms: those patients with gastrointestinal bleeding that is clinically apparent but of obscure origin and those patients with obscure bleeding that remains occult (usually refractory iron-deficiency anemia). Each of these entities represents substantial diagnostic and management challenges. By definition, readily identifiable causes of gastrointestinal bleeding (eg, an ulcer or a mass lesion) have been excluded, usually by upper and/or lower endoscopy. In patients with significant obscure bleeding, bleeding is most
O
From the Department of Internal Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC. Supported by the Burroughs Welcome Fund (DCR is the recipient of a BWF Translational Scientist Award). Address reprint requests to Don C. Rockey, MD, Room 336, Sands Building, Box 3083, Liver Center, Duke University Medical Center, Durham, NC 27710. © 2003 Elsevier Inc. All rights reserved. 1096-2883/03/0503-0002$30.00/0 doi:10.1053/j.tgie.2003.08.001
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often recurrent—a point that brings the patient to medical attention and more importantly forces evaluation. After recognition that bleeding is recurrent (and obscure), it becomes important to localize the site and etiology of bleeding so that appropriate therapy can be instituted.
Approach to Evaluation and Differential Diagnosis Localization of the site (ie, upper or lower gastrointestinal tract) of bleeding should begin with history and physical examination. Although melena and hematochezia are typically associated with upper and lower gastrointestinal tract bleeding, respectively, it should be emphasized that patients with slow oozing from the distal small bowel or cecum may have melena and occasional patients with aggressive bleeding from an upper gastrointestinal source may present with hematochezia. Additionally, history and physical examination should focus on elements likely to be active in patients with easily “overlooked” lesions (Table 1). Careful attention should be focused on the small bowel with reference to weight loss and obstructive symptoms. A general approach to patients with obscure bleeding is presented in Figure 1. In general, in patients with recurrent obscure bleeding, repeat endoscopy directed at the most likely site of bleeding is usually warranted—at least 1 additional time after the index endoscopy. This is important because if the endoscopy is performed during active bleeding, it may allow a specific diagnosis to be identified. It has been well documented in the literature that re-examination of the upper gastrointestinal tract within reach of a standard gastroscope (or an enteroscope) will identify lesions in a substantial proportion of patients.2-4 However, familiarity with uncommon and/or subtle bleeding lesions is required.5 If a lesion cannot be identified, further evaluation depends on the briskness of bleeding. In those with active bleeding, technetium-99 radionuclide scanning or angiography should be performed. This approach allows confirmation of the site of bleeding only. Angiography is less sensitive than technetium-99 radionuclide scanning but may identify the site of bleeding.6 In some patients, diagnostic tests such as computed tomography or Meckel’s scan may be helpful. In patients with subacute or intermittent bleeding in whom repeat endoscopy of the upper or lower gastrointestinal tract is negative, the focus of investigation should rapidly move to the small intestine. The lesions most commonly identified in the small bowel include tumors and vascular ectasias, which vary in frequency depending on age. In patients between the ages of 30 and 50, tumors are the most common abnormalities (in patients less than 25 years of age, Meckel’s diverticula are the most common source of small bowel bleeding), whereas vascular ectasias predominate in the elderly.7 Small bowel examination can be performed with several ra-
Techniques in Gastrointestinal Endoscopy, Vol 5, No 3 (July), 2003: pp 104-108
TABLE 1. Causes of Obscure Gastrointestinal Bleeding Common causes Vascular ectasia Mass lesion (tumor) *Less frequent causes Dieulafoy’s lesions Vascular ectasia Portal hypertensive gastropathy Gastric antral vascular ectasia (watermelon stomach) Gastric and small intestinal varices Crohn’s disease *Rare causes Aortoenteric fistula Hemobilia Pancreatic source *Lesions in these categories may be easily overlooked.
diologic and endoscopic modalities. Radiologic modalities include standard small bowel follow through and enteroclysis. Endoscopic techniques include push enteroscopy, sonde enteroscopy, intraoperative enteroscopy, and wireless capsule endoscopy. Small bowel follow through is rarely adequate to evaluate the small intestine and may miss significant mass lesions. Enteroclysis is more effective at detecting mass lesions8 but does not detect mucosal lesions such as vascular ectasias. Because vascular ectasias are often a major concern in this patient population, enteroclysis is probably best reserved for those in whom the clinical suspicion of a mass lesion or small bowel diverticula is high. A number of endoscopic approaches are capable of examining the small intestine. “Push” and “Sonde” enteroscopy have been prominent in the evaluation of many patients with obscure gastrointestinal bleeding.5 Push enteroscopy entails peroral insertion of a long endoscope during conscious sedation. This instrument can be passed up to 50 to 60 cm beyond the ligament of Trietz, providing a relatively thorough examination of the distal duodenum and proximal jejunum. Push enteroscopy commonly identifies a source of bleeding in patients with obscure bleeding.2,3,9-11 The reported likelihood of detecting lesions is 24% to 75%, although the clinical experience of many has been less. Although push enteroscopy can be uncomfortable for the patient, it is readily available, relatively safe, and allows biopsy and endoscopic therapy. Sonde enteroscopy involves placement of a long, small caliber endoscope into the proximal small bowel, with subsequent peristalsis carrying the endoscope to the more distal small intestine.12 This procedure permits visualization of the almost the entire small bowel and has led to diagnoses in a significant number of cases.13 Although Sonde enteroscopy is attractive diagnostically, it is associated with a number of problems. First, the technique requires a specialized endoscope and expertise with the procedure. Further, Sonde enteroscopy is extremely tedious and does not allow therapeutics. With the introduction of capsule endoscopy (see below and the review by Dr Lewis in this issue), Sonde enteroscopy will probably become phased out and limited to a very few centers. Intraoperative enteroscopy permits visualization of most or all of the small intestine with an enteroscope (or standard colonoscope), which is manually advanced through the small bowel by the surgeon during laparotomy. This combined technique has been reported to detect abnormalities in up to 70% to 100% of patients,14-16 although this has not been the practical experience of all clinicians. OBSCURE GASTROINTESTINAL BLEEDING
A new, conceptually simple approach to examine the small intestine includes wireless capsule endoscopy17-20 and is reviewed in detail by Dr Lewis (see article entitled “The Utility of Capsule Endoscopy in Obscure GI Bleeding”). In brief, this approach appears to be able to identify small bowel lesions with a greater frequency than the other forms of small bowel investigation. Furthermore, capsule endoscopy appears to be very safe and reasonably well tolerated. An important limitation associated with capsule endoscopy is the inability to administer therapy. Therefore, outcome data will be required before capsule endoscopy can be widely recommended. An alternative approach to the diagnosis of recurrent, obscure bleeding is to reactivate or augment bleeding with the use of vasodilators, anticoagulants, and/or thrombolytics in association with tagged red blood cell scintigraphy or visceral angiography. Available literature indicates that the diagnostic yield of this procedure is on the order of 20% to 40%.21,22 It should be emphasized that this is a highly specialized undertaking23 that requires local expertise and experience. Further study to clarify its role in the evaluation of patients with recurrent, obscure gastrointestinal bleeding is required.
Specific Causes of Obscure Gastrointestinal Bleeding Many different gastrointestinal lesions can cause obscure bleeding. Familiarity with the various lesions and their accompanying clinical presentations is critical to make a specific diagnosis. The most common cause of obscure bleeding is vascular ectasia and accounts for up to 60% of detectable bleeding lesions.24,25 Other important lesions include small bowel tumors, Dieulafoy’s ulcer, Meckel’s diverticulum, varices, and ulcers. With regard to the latter 2 disorders, a history of liver disease and nonsteroidal anti-inflammatory drug ingestion, respectively, should raise the level of suspicion for these processes. Rarely, patients present with factitious bleeding, having bled themselves, and ingested blood before presentation. A past history of
Fig 1. Suggested algorithm for management of obscure gastrointestinal bleeding. Given that vascular ectasias are the most common cause of obscure gastrointestinal bleeding, a high level must remain for other diseases. Repeat endoscopy, often during active bleeding, is emphasized. (Reprinted with permission from Rockey DC: Gastrointestinal bleeding, in Feldman, Friedman, Sleisenger (eds): Sleisenger & Fordtran’s Gastrointestinal & Liver Disease (ed 7). Philadelphia, PA, Saunders, 2002.)
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previous psychological illness should raise the level of suspicion for this disorder. A number of important causes of obscure bleeding are highlighted later. Vascular ectasias. Vascular lesions are an important cause of obscure gastrointestinal tract bleeding. They are commonly associated with a variety of underlying conditions including scleroderma, the CREST syndrome, radiation injury, collagen diseases (such as pseudoxanthoma elasticum and Ehlers-Danlos syndrome), and von Willebrand’s disease. Vascular ectasias appear to be most often associated with chronic renal failure. For example, the prevalence of vascular ectasia as a cause of gastrointestinal bleeding was related to the duration of renal failure and need for hemodialysis.26 Bleeding caused by vascular ectasias is painless, and generally of moderate volume (except in the presence of underlying coagulopathy, in which case bleeding can be massive). There is little debate about the importance of vascular ectasias in obscure gastrointestinal tract bleeding; rather the challenge is in making the diagnosis and in identifying the culpable lesion. Patients with lesions that are readily identified or are actively bleeding are best treated with endoscopic methods. Endoscopic therapy (each laser, bipolar electrocoagulation, bicap, banding, injection therapy, and argon plasma coagulation) is generally successful and safe.24,27-29 Perforation of the gastrointestinal tract is possible, especially when using electrocoagulation or laser therapy. Those with massive bleeding may respond to angiographic therapy. Recurrent bleeding from an identified source (after endoscopic or angiographic therapy) is uncommon, but surgical therapy is curative so long as the source bleeding is clearly identified. The use of hormonal therapy is highly controversial (see the review by Dr Barkin in this issue). Diverticula. Diverticular disease of the small intestine is much less common than that of the colon, but it remains an important cause of obscure bleeding. The true pathogenesis of diverticular formation in the small bowel is unknown, as is the cause of bleeding, but is probably a result of penetration from an artery into the dome of a diverticulum. Evidence of concomitant diverticulitis is usually absent, and vessel rupture is thought to be the result of pressure erosion rather than infection. Diverticular bleeding is characterized by acute, painless bleeding. Bleeding is typically of large volume and often produces bright red or maroon stools. Bleeding is typically not hemodynamically significant, although it may be poorly tolerated by the very elderly, who often have comorbid conditions. The diagnosis of diverticular hemorrhage is usually one of exclusion and is most often made by identifying small bowel diverticula and excluding other diagnoses. Rarely, a definitive diagnosis can be made by directly visualizing active bleeding. Treatment of small bowel diverticular bleeding generally involves angiographic intervention and/or surgical resection. Endoscopic treatment requires identification of a bleeding lesion typically in the proximal small intestine and is uncommonly possible. The best approach in those with aggressive bleeding is to identify the location of bleeding and to perform resection. In patients with severe bleeding in whom a specific bleeding site cannot be identified, subtotal bowel resection has been advocated by some but is met with poor outcomes, especially in elderly patients. Meckel’s diverticulum. Meckel’s diverticulum is a remnant of the vitelline duct and is found within the final 100 cm of the
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ileum in up to 2% of the population. The diverticulum contains gastric mucosa, which secretes acid and results in ulceration of adjacent mucosa. Bleeding from Meckel’s diverticulum typically occurs in children but also occurs in young adults; it is the most common cause of gastrointestinal bleeding in patients younger than the age of 30. Bleeding is often brisk and painless. The diagnosis is typically made by radiolabeled technetium scanning. Surgery to remove the diverticulum is required in patients who have had hemorrhage. Dieulafoy’s lesions. Dieulafoy’s ulcer, also know as exulceratio simplex Dieulafoy, refers to an abnormally large artery that retains the large caliber of its feeding vessel as it approaches the mucosa. This large vessel is thought to compress the mucosa and causes a small erosion with rupture of the vessel into the lumen. Dieulafoy’s lesions are important in obscure bleeding because they may be present either in the proximal portion of the stomach (in which they are most commonly identified, usually within proximity to the gastroesophageal junction) but can also be found in more unusual locations such as in the small intestine. It is often difficult to identify the lesion, unless it is actively bleeding or is associated with stigmata of recent bleeding (which is uncommon). Therefore, a high index of suspicion is required to make this diagnosis. Bleeding is often massive and recurrent. Therapy with injection techniques, coagulative therapy, hemoclips, and banding can all control bleeding and prevent rebleeding in most cases.30-33 In 1 review of 24 endoscopically-treated patients in whom follow-up data were available, bleeding recurred in only 1 patient.30 Small intestinal mass lesions. Neoplasms of the small intestine are uncommon but constitute a significant cause of obscure gastrointestinal bleeding. It is noteworthy that gastrointestinal bleeding is the most common clinical manifestation of leiomyoma and leiomyosarcoma, important stromal tumors of the small intestine.34 A number of different benign and malignant tumors have been reported to cause bleeding (some reports suggest bleeding is more common with benign lesions35). The most common benign tumors of the small intestine are leiomyomas. The most common malignant tumors are (adenomas and) adenocarcinomas, carcinoids, lymphomas, and sarcomas. As emphasized earlier, a high index of suspicion is required to make this diagnosis. In the setting of bleeding, warning symptoms such as nausea, abdominal pain, or weight loss should lead to aggressive searches for malignancy. Evaluation of the small bowel should be as outlined (Fig 1); abdominal computed tomography may additionally be helpful for evaluation of possible small bowel mass lesions. Exploratory laparotomy is sometimes required to make a specific diagnosis.36 Management of small intestinal tumors depends on the primary diagnosis but is typically surgical. Aortoenteric fistula. Aortoenteric fistulas are rare but important lesions responsible for upper and/or obscure gastrointestinal bleeding. They are almost always secondary to previous reconstructive aortoiliac surgery37 and occur with a frequency of about 0.5% after aortoiliac surgery.38 Although aortoenteric fistulas are most commonly secondary (ie, after aortic grafting) and occur 3 to 5 years after graft surgery, primary aortoenteric fistulas have been reported.39 Aortoenteric fistulas typically involve the third portion of the duodenum but may involve other portions of the gastrointestinal tract. The typical presentation is of upper gastrointestinal bleeding, which often occurs as a “herald” bleed that stops, but is followed by further (often DON C. ROCKEY
fatal) bleeding. A high index of suspicion is required to make the diagnosis. Because the pathogenesis of this disease is subtle infection of the graft and perigraft area, symptoms and signs of infection (B-type symptoms such as weight loss, low-grade fever, and leukocytosis) raise the likelihood of aortoenteric fistula. All patients with previous aortic surgery and upper gastrointestinal bleeding should undergo esophagogastroduodenoscopy with particular attention to the distal duodenum. Given a negative examination, patients should undergo abdominal computed tomography. This examination will typically show periaortic inflammation and phlegmon, consistent with infection. Angiography is usually not helpful. The prognosis of patients with aortoenteric fistula has been historically poor (over 50% mortality rate) but appears to be improving.38 Definitive therapy typically involves extensive reconstructive surgery. Hemobilia. Hemobilia consists of hemorrhage into the biliary tract. Causes of communication between the vascular and biliary tree include trauma, liver biopsy, gallstones, hepatic artery or portal vein aneurysms, liver abscesses, and neoplasia.40 The most common causes of hemobilia appear to be blunt or iatrogenic trauma. A high index of suspicion is necessary to make the diagnosis; therefore, the clinical history is crucial. The diagnosis is made by visualizing blood coming from the ampulla of Vater and/or by angiography. Angiographic treatment with embolization may be effective,41 but surgical ligation of the hepatic feeding vessel may be required. Mortality from hemobilia is high. Hemosuccus pancreaticus. Hemosuccus pancreaticus is defined as bleeding from peripancreatic blood vessels into a pancreatic duct.42 Hemorrhage is most often a result of chronic pancreatitis with either erosion of a pseudocyst into the splenic or a peripancreatic artery or formation of an arterial aneurysm that subsequently develops a communication with the pancreatic duct. The diagnosis may be made by endoscopic visualization of blood coming from the papilla. Again, a high index of suspicion (typically a history of chronic pancreatitis) is required. Angiography is required to definitively identify the bleeding site and may be used to administer embolization. Surgery is often required to provide definitive control of bleeding.43
Treatment Treatment of lesions that bleed in an obscure fashion is aimed at the underlying abnormality. Treatment often involves a multifaceted approach involving the gastroenterologist, radiologist, and surgeon. For example, endoscopic therapy or embolization therapy for large focal vascular ectasias therapy may be effective. Therapy for mass lesions typically involves surgical resection. Vascular ectasias are particularly problematic because they are often multiple in number, and this feature significantly limits endoscopic and surgical intervention. For this reason, medical therapy has been advocated as a theoretically attractive approach for patients with obscure bleeding because of vascular ectasia.
Summary Obscure gastrointestinal bleeding occurs in a small fraction of all patients with gastrointestinal bleeding. However, these paOBSCURE GASTROINTESTINAL BLEEDING
tients represent a considerable diagnostic and therapeutic challenge. A high index of suspicion and familiarity with the various important lesions is required. These patients should undergo aggressive endoscopic evaluation (including small bowel investigation). Capsule endoscopy is rapidly emerging as an attractive approach for evaluation of the small intestine. In certain circumstances, other diagnostic studies are indicated (ie, angiography, computed tomographic examination). Management of this patient population is challenging given that many of these patients have co morbid conditions and harbor multiple small intestinal vascular ectasias. Therefore, care of this group of patients require a focused and experienced team approach.
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