hronic gastrointestinal bleeding leading toiron deficiency anemia continues to be a majorclinical problem in general as well as subspe-cialty practice. In adult men and women in the

western hemisphere, severe iron deficiency is almostalways caused by gastrointestinal bleeding. In approxi-mately 5% of all patients with gastrointestinal hemor-rhaging and anemia, standard evaluation with esopha-gogastroduodenoscopy (EGD) and colonoscopy willnot reveal a specific bleeding site.13 The source ofbleeding in these patients is most often the small intes-tine.

The cause of bleeding in the small intestine, unlessmassive, is often difficult to determine. Besides beingan unusual site of bleeding (and so not routinely con-sidered), the small intestine is relatively less accessiblethan are the stomach and colon.4 The diagnostic accu-racy of customary techniques (eg, barium enema stud-ies, endoscopic intubation, nuclear medicine scans,angiography) is limited by the small intestines length,its free intraperitoneal location, its vigorous contractili-ty, and its overlying loops. Moreover, bleeding in thesmall intestine is sometimes slow or intermittent, thusfurther limiting the usefulness of any diagnostic tool.

Because of the frequent inability to localize a bleed-ing site, patients with bleeding in the small intestinecan experience prolonged blood loss or recurrent epi-sodes of melena or maroon stool before receiving aspecific diagnosis. For example, cancer of the smallintestinean uncommon cause of acute and chronicgastrointestinal bleedingis notoriously difficult todiagnose and thus often advanced at the time of defini-tive treatment.48 This and other rare causes of gas-trointestinal blood loss can be overlooked by unsus-

pecting physicians if an adequate work-up (Figure 1) isnot performed.

This review will attempt to present useful informa-tion about the etiology, clinical evaluation, and treat-ment of patients with bleeding in the small intestine.As such, it should assist primary care physicians in pro-viding appropriate work-up, management, and refer-ral of these patients.

PREVALENCE

As mentioned previously, the small intestine, espe-cially beyond the duodenal bulb, is an uncommon siteof hemorrhage. According to published estimates, thesite of gastrointestinal bleeding is located between thesecond portion of the duodenum and the ileocecalvalve in only 3% to 5% of patients with gastrointestinalbleeding.13 Nevertheless, bleeding, whether occult ormassive, may be the only sign of a potentially fatalpathology in the small intestine. For this reason, anypatient with obscure gatrointestinal bleeding shouldundergo a thorough evaluation so that a diagnosis canbe reached without excessive delay. That such evalua-tions are not routinely performed is suggested by the

C

Dr. Nawaz is an Attending Physician, Division of Digestive Diseases,Bassett Health Care, Cooperstown, NY. Drs. Shehata and Mohamed areFellows in Gastrointestinal Medicine, Nassau County Medical Center,East Meadow, NY, and University of Pittsburgh, Pittsburgh, PA. Dr.Hadjiyane is an Assistant Professor of Medicine, Division of Gastro-enterology, State University of New York at Stony Brook, Stony Brook, NY.Dr. Karakurum is an Assistant Professor of Medicine, Nassau CountyMedical Center, East Meadow, NY. Dr. Pellecchia is an AssociateProfessor of Clinical Medicine, State University of New York at StonyBrook, Stony Brook, NY.

48 Hospital Physician June 2001 www.turner-white.com

C l i n i c a l R e v i e w A r t i c l e

Chronic Gastrointestinal Bleeding of Obscure Origin: Diagnosis and Management

Arif Nawaz, MDAhmed Shehata, MD

Imtiaz Mohamed, MD Carylann Hadjiyane, MD, FACG

Ali S. Karakurum, MD, FACP, FACG Crescens Pellecchia, MD, FACG

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Figure 1. Algorithm showing recommended work-up of obscure gastrointestinal bleeding. EGD = esophagogastroduodenoscopy;GI = gastrointestinal.

Perform appropriate endoscopy after resuscitation

GI bleeding

No bleeding source found Bleeding source found

Treat appropriatelyRepeat EGD or examinethe entire GI tract, if not

already examined

No bleeding source found Bleeding source found

Treat appropriatelySmall-bowel work-upPush/sonde enteroscopy

Small-bowel series with enteroclysis

Treat appropriately

No bleeding source found Bleeding source found

Active bleeding No active bleedingIntermittent bleeding

Angiography or radioisotope scan

Consider exploratorysurgery +/- intraoperative

endoscopy

Consider exploratorysurgery +/- intraoperative

endoscopy

Source found Source not found

Treat appropriately

fact that survival from primary cancers of the smallintestine has not improved during the last 4 decades,primarily because of delayed diagnoses.

ETIOLOGY

Bleeding in the small intestine can result from sever-al causes, each of which has its own bleeding pattern.The most common causes will be discussed in the fol-lowing paragraphs.

Angiodysplasia

Angiodysplasia classically has been described asoccurring in the right colon.13 However, its character-istic vascular lesions also have been identified in thestomach and small intestine, although far less com-monly than in the colon. Angiodysplasia is the mostcommon cause of bleeding in the small intestine, ac-counting for 70% to 80% of cases. However, it is esti-mated that fewer than 10% of all patients with intesti-nal angiodysplasia eventually bleed. When bleedingdoes occur, it can be either brisk and evident or occult.According to a published report, melena was the pre-senting sign in 64% of 102 patients with bleedingcaused by angiodysplasia of the small intestine, whereasoccult blood in the stool was detected in only 36%.9

Little is known about the origin of angiodysplasia ofthe small intestine. The vascular lesions usually aredetected on either enteroscopy or intraoperative end-oscopy; angiography rarely leads to detection of vascu-lar lesions in the small intestine. The natural history ofangiodysplasia associated with bleeding also is not wellcharacterized. Spontaneous cessation of bleeding hasbeen reported in 44% of patients with angiodysplasiaof the small intestine during a mean follow-up of peri-od of 13.1 months.9,10 Moreover, once vascular lesionshave bled, their tendency to rebleed cannot be fullyknown. Although physicians are eager to treat theselesions, as many as 50% might not rebleed. Finally, pro-phylactic therapy is not recommended for angiodyspla-sia found incidentally.1,2

Tumors of the Small Intestine

Tumors are the second most common cause ofbleeding in the small intestine. As previously suggested,these tumors often are not diagnosed early in theircourse. A study found that the total number of testsper patient with a tumor of the small intestine aver-aged 2.3 and that the average time from onset of symp-toms to resection was 30.2 weeks.5 Tumors of the smallintestine account for only 6% of all gastrointestinaltumors and 5% to 10% of all cases of hemorrhage ofthe small intestine6; often, bleeding is the only symp-

tom. More than half of these tumors are benign. Be-nign tumors more commonly present with acute gas-trointestinal hemorrhage but are often asymptomatic,whereas malignant tumors more commonly presentwith abdominal pain and weight loss.

Leiomyomas and leiomyosarcomas are the mostcommon tumors of the small intestine that bleed.Adenocarcinomas, carcinoids, and lymphomas are asso-ciated with more gradual but also more chronic bloodloss. Adenocarcinomas (and adenomatous polyps)most frequently are found in the proximal small intes-tine, with 90% of lesions located in the duodenum andthe first 20 cm of the jejunum. Lymphomas, on theother hand, tend to be distally located.

Other Causes

Other causes of bleeding in the small intestine in-clude Crohns disease, Meckels diverticulum, Zollinger-Ellison syndrome, infections, use of certain drugs, vas-culitis, radiation enteritis,1 jejunal diverticulosis,11 andpancreatic pseudocysts.1

Crohns disease is the most common ulcerative dis-ease of the small intestine that can cause bleeding.Nevertheless, gross bleeding is unusual in Crohns dis-ease, occurring in only 4% to 10% of patients with thecondition.1 The diagnosis is virtually always made on aradiographic series of the small intestine.

Meckels diverticulum occurs in 2% of the popula-tion. Located approximately 100 cm from the ileocecalvalve,12 this anomaly occurs more frequently in menthan in women and is the cause of bleeding in twothirds of men younger than age 30 years who havebleeding in the small intestine. The bleeding is usuallybrisk. Although preoperative diagnosis is uncommon,technetium-99m pertechnetate scanning can diagnoseMeckels diverticulum.

Zollinger-Ellison syndrome can also cause bleedingulcerations of the small intestine in the second, third andfourth parts of the duodenum, as well as in the jejunum.Infections, including tuberculosis, syphilis, typhoid, andhistoplasmosis, similarly can result in bleeding in thesmall intestine. In addition, use of nonsteroidal anti-inflammatory drugs, potassium, 6-mercaptopurine, andother medications can cause ulcerations and bleeding inthe small intestine. Other etiologies include vasculitis(associated with, eg, polyarteritis nodosa, systemic lupuserythematosus, rheumatoid arthritis, hypersensitivity),radiation enteritis, jejunal diverticula,1,13 and pancreaticpseudocyst.14

CLINICAL EVALUATION

Patients with gastrointestinal hemorrhage usually

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undergo standard examinations such as EGD andcolonoscopy. If these tests do not identify a source ofthe bleeding, the small intestine is assumed to be thesource of blood loss. Several studies are available tohelp locate the precise source within the small intestine.

Radiographic Series of the Small Intestine

A radiographic series of the small intestine with ente-roclysis is usually the initial study performed in a patientwho is not actively bleeding. Standard radiographs bythemselves are likely to result in a relatively low yield ofpositive findings when patients have bleeding of ob-scure origin.15 Although Crohns disease and largeulcerations of the small intestine can readily be diag-nosed by standard radiographs, only 5% of such radio-graphic examinations will detect the bleeding site in thesmall intestine. 1618 Enteroclysis, however, can increasethe yield of such radiography to 10%.1618 In this proce-dure a tube is positioned in the duodenum and bariummixed with air, water, or methylcellulose is instilled. Theradiographs subsequently obtained are comparable tothe double-contrast radiographs obtained on bariumenema studies of the colon. This modality is unable todiagnose angiodysplasia but can help in the diagnosisof Meckels diverticulum, Crohns disease, adenocarci-noma, metastatic melanoma, leiomyoma, and leiomyo-sarcoma.16

Radioisotope Scans

Radioisotope scans can be diagnostic when bleedingis distal to the ligament of Treitz. Erythrocytes labeledwith technetium-99m are prepared in vivo (or pre-pared in vitro and then injected into the circulation).As little as 5 mL of intraluminal blood will yield positiveresults.1,2 These cells have a half-life of about 24 hoursand, therefore, sequential scans may be performed toincrease the probability of identifying the bleeding site.Technetium-99m pertechnetate can be used to detectMeckels diverticulum (reported sensitivity, approxi-mately 75 to 100%19) or leiomyomas (because of theirvascularity). Because of their ready availability, low cost,and absence of complications, such scans are universal-ly accepted and often are a prerequisite to angiography.

Angiography

Angiography can detect bleeding occurring at a rateof at least 0.5 mL/min and can localize a site of bleed-ing in 50% to 72% of patients with massive gastroin-testinal hemorrhage.19,20 The yield drops to 25% to50% in patients without active bleeding. A radiologistcan attempt embolization of the responsible lesions inorder to stop the bleeding. In addition to identifying

active bleeding sites, angiography can be used to diag-nose lesions (eg, angiodysplasia, tumors) of the smallintestine that are not bleeding. Angiography has beenreported to show a tumor blush in 86% of tumorouslesions in the small intestine.21

Exploratory Surgery

Exploratory surgery often is considered in patientswith recurrent gastrointestinal bleeding. However, thereis a low success rate for surgical exploration when unac-companied by other evaluations such as intraoperativeendoscopy. As an illustration of how uncommon it is toapproach patients with gastrointestinal bleeding ofobscure origin with surgical exploration only, the onlyestimates of the yield of the procedure come fromreports in the 1960s.22 If one excludes diagnoses readilymade by endoscopy (eg, peptic ulcer disease), the yieldof exploration alone falls to about 10%.

Endoscopy

Endoscopy of the small intestine can be accom-plished in several ways. The usual techniques of EGDand colonoscopy with intubation of the ileocecal valveprovide visualization of the most proximal and distalends of the intestines. Routine EGD generally reachesthe junction of the second and third portions of theduodenum.

Push enteroscopy. In the procedure referred to aspush enteroscopy, a long endoscope is passed beyond theligament of Treitz. The newer push enteroscopes allowintubation of the jejunum, to about 200 to 225 cm.Reported diagnostic yields of this procedure haveranged from 15% to 38%.1,2330 Angiodysplasia was themost common finding, accounting for 80% of diag-noses. Push enteroscopy not only is diagnostic but alsocan be therapeutic, allowing fulguration of bleedingsites and polypectomy.13 This technique also allowsdetection of a significant number of lesions which aremissed on EGD.31,32

Sonde enteroscopy. Sonde enteroscopy (ie, smallintestine enteroscopy), the only possible way to exam-ine the entire small intestine, entails the passage of along flexible fiberoptic instrument through the intes-tine by peristalsis. A balloon at the tip of the instrumentis carried forward by peristalsis, and the endoscopicexamination is performed during its withdrawal. Incontrast to push enteroscopy, this technique has notherapeutic capability and no tip deflection. Thus, visu-alization is not total, with only approximately 50% to70% of the mucosa of the small intestine observed dur-ing a standard examination.18 The ileum is reached in75% of examinations, and only 10% reach the ileocecal

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valve.18 Other limitations of this procedure are itssparse availability and tedious nature. Recent studieshave shown a diagnostic yield of approximately 40% inpatients with obscure gastrointestinal bleeding whoundergo push enteroscopy and sonde enteroscopy.23

Intraoperative enteroscopy. In light of the many lim-itations of sonde enteroscopy, intraoperative enter-oscopy remains the most common form of endoscopicexamination of the entire small intestine, especially indifficult cases. Published investigations have reportedvariable success with this type of enteroscopy.31,33,34

Various specific techniques have been described thatare successful in determining the site of bleeding in 58 to 100% of patients.1,31 A study recently reported adiagnostic yield of 58% for patients with gastrointesti-nal bleeding of obscure origin who underwent intraop-erative enteroscopy, with a cecal intubation rate of93%.31 However, the authors also reported a high oper-ative morbidity (30%).

MANAGEMENT

Management of chronic gastrointestinal bleeding ofobscure origin continues to perplex clinicians. Treat-able conditions (eg, surgically resectable tumors, vasculitis, Crohns disease) should be managed defini-tively. Treatment of angiodysplasia continues to be con-troversial.1,35 Fulgration of the associated vascularlesions is most likely necessary only for actively bleed-ing lesions. Combination hormonal therapy has beentried, with variable success,35 and might be effective inselected cases. Although gastrointestinal bleeding canhave a negative effect on patients quality of life, giventhe need for repeated transfusions and hospitaliza-tions, it is seldom associated with high mortality or life-threatening bleeding.

SUMMARY POINTS

In approximately 5% of patients with chronic gas-trointestinal bleeding, the precise site of bleedingwill not be determined with EGD and colonoscopy.These patients should undergo aggressive evalua-tion, with intensive study of the small intestine.

The 2 most common etiologies of obscure gastroin-testinal bleeding include angiodysplasia and tumorsof the small intestine.

Radiographic techniques are not very sensitive inidentifying angiodysplasia, the most common causeof bleeding in the small intestine.

Push enteroscopy is becoming more widely avail-able as a diagnostic modality in patients with sus-pected bleeding in the small intestine. Becausesonde enteroscopy (or complete enteroscopy of the

small intestine) is not always feasible, surgical explo-ration with intraoperative enteroscopy is a possiblealternative.

Management of chronic gastrointestinal bleeding ofobscure origin continues to be controversial. Possibletreatment modalities include fulgration of vascularlesions as well as combination hormonal therapy. HP

REFERENCES1. Lewis, BS. Small intestinal bleeding. Gastroenterol Clin

North Am 1994;23:6791.2. Rockey DC. Occult gastrointestinal bleeding. N Engl J

Med 1999;341:3846.3. American Gastroenterology Association medical posi-

tion statement: evaluation and management of occultand obscure gastrointestinal bleeding. Gastroenterology2000;118:197201.

4. Maglinte DD, OConnor K, Bessette J, et al. The role ofthe physician in the late diagnosis of primary malignanttumors of the small intestine. Am J Gastroenterol 1991;86:3048.

5. Ciresi DL, Scholten DJ. The continuing clinical dilem-ma of primary tumors of the small intestine. Am Surg1995;61:698702.

6. Pastore C, DAnnibale A, Fregonese D, et al. [Malignanttumors of the small intestine. Review of the literature andreport of a clinical case]. [Article in Italian]. MinervaChir 1993;48:14715.

7. Martin RG. Malignant tumors of the small intestine.Surg Clin North Am 1986;66:77985.

8. Adrain AL, Krevsky B. Enteroscopy in patients with gas-trointestinal bleeding of obscure origin. Dig Dis 1996;14:34555.

9. Lewis BS, Kornbluth A, Waye JD. Small intestine tumours:yield of enteroscopy. Gut 1991;32:7635.

10. Lewis BS, Salomon P, Rivera-MacMurray S, et al. Doeshormonal therapy have any benefit for bleeding angio-dysplasia? J Clin Gastroenterol 1992;15:99103.

11. Mancuso G, Pujia A, Luzza F, et al. [Intestinal bleedingfrom an ulcerated diverticulum of the small intestine. Aclinical case]. [Article in Italian]. Ann Ital Med Int 1995;10:2468.

12. Brown CK, Olshaker JS. Meckels diverticulum. Am JEmerg Med 1988;6:15764.

13. Askin MP, Lewis BS. Push enteroscopic cauterization:long-term follow-up of 83 patients with bleeding smallintestinal angiodysplasia. Gastrointest Endosc 1996;43:5803.

14. Zanen AL, van Vliet AC, Beukers R. Pancreatic pseudo-cyst as a cause of upper gastrointestinal bleeding. Neth JMed 1995;46:904.

15. Bowden TA Jr. Endoscopy of the small intestine. SurgClin North Am 1989;69:123747.

16. Rex DK, Lappas JC, Maglinte DD, et al. Enteroclysis inthe evaluation of suspected small intestinal bleeding.Gastroenterology 1989;97:5860.

52 Hospital Physician June 2001 www.turner-white.com

N a w a z e t a l : C h r o n i c G a s t r o i n t e s t i n a l B l e e d i n g : p p . 4 8 5 3

17. Antes G, Neher M, Hiemeyer V, Burger A. Gastroin-testinal bleeding of obscure origin: role of enteroclysis.Eur Radiol 1996;6:8514.

18. Willis JR, Chokshi HR, Zuckerman GR, Aliperti G. Enteroscopy-enteroclysis: experience with a combinedendoscopic-radiographic technique. Gastrointest Endosc1997;45:1637.

19. Browder W, Cerise EJ, Litwin MS. Impact of emergencyangiography in massive lower gastrointestinal bleeding.Ann Surg 1986;204:5306.

20. Ettorre GC, Francioso G, Garribba AP, et al. Helical CTangiography in gastrointestinal bleeding of obscure ori-gin. AJR Am J Roentol 1997;168:72731.

21. Ashley SW, Wells SA Jr. Tumors of the small intestine.Semin Oncol 1988;15:11628.

22. Retzlaff JA, Hagedorn AB, Bartholomew LG. Abdom-inal exploration for gastrointestinal bleeding of obscureorigin. JAMA 1961;177:1047.

23. Waye JD. Small-intestine endoscopy. Endoscopy 1999;31:569.

24. Lewis BS, Waye JD. Total small intestine enteroscopy.Gastrointest Endosc 1987;33:4358.

25. Shackel NA, Bowen DG, Selby WS. Video push enter-oscopy in the investigation of small intestine disease:defining clinical indications and outcomes. Aust N Z JMed 1998;28:198203.

26. Zaman A, Katon RM. Push enteroscopy for obscure gas-trointestinal bleeding yields a high incidence of proximallesions within reach of a standard endoscope. Gastrointest

Endosc 1998;47:3726.27. Vakil N, Huilgol V, Khan I. Effect of push enteroscopy

on transfusion requirements and quality of life in pa-tients with unexplained gastrointestinal bleeding. Am JGastroenterol 1997;92:4258.

28. Morris AJ. Small-intestine investigation in occult gastroin-testinal bleeding. Semin Gastrointest Dis 1999;10:6570.

29. Morris AJ, Mokhashi M, Straiton M, et al. Push enter-oscopy and heater probe therapy for small intestinebleeding. Gastrointest Endosc 1996;44:3947.

30. Aliperti G, Zuckerman GR, Willis JR, Brink J. Enter-oscopy with enteroclysis. Gastrointest Endosc Clin N Am1996;6:80310.

31. Zaman A, Sheppard B, Katon RM. Total peroral intraop-erative enteroscopy for obscure GI bleeding using a ded-icated push enteroscope: diagnostic yield and patientoutcome. Gastrointest Endosc 1999;50:50610.

32. Descamps C, Schmit A, Van Gossum A. Missed uppergastrointestinal tract lesions may explain occult bleed-ing. Endoscopy 1999;31:4525.

33. Bowden TA Jr, Hooks VH 3rd, Mansberger AR Jr. Intra-operative gastrointestinal endoscopy. Ann Surg 1980;191:6807.

34. Lewis MP, Khoo DE, Spencer J. Value of laparotomy inthe diagnosis of obscure gastrointestinal haemorrhage.Gut 1995;37:18790.

35. Barkin JS, Ross BS. Medical therapy for chronic gastroin-testinal bleeding of obscure origin. Am J Gastroenterol1998;93:12504.

N a w a z e t a l : C h r o n i c G a s t r o i n t e s t i n a l B l e e d i n g : p p . 4 8 5 3

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