AGA technical review on the evaluation and management of occult and obscure gastrointestinal bleeding☆

Article Outline

• Abstract
• Bedside examination
• Evaluation of occult bleeding
  • Study design factors
  • Endoscopic evaluation
  • Bidirectional endoscopy
  • Radiographic evaluation
  • Other testing in occult bleeding
• Evaluation of obscure bleeding
  • Diagnostic techniques
    • Small bowel biopsy
    • Peroral and transnasal enteroscopy
    • Retrograde enteroscopy
    • Intraoperative enteroscopy
    • Small bowel x-ray series and enteroclysis
    • Nuclear scans
    • Angiography
    • Exploratory laparotomy
    • Other techniques
• Etiology
  • Occult bleeding sources
  • Obscure bleeding sources
  • Management
  • Endoscopic therapy
  • Angiotherapy
  • Pharmacotherapy
  • Surgery
  • Nonspecific measures
• Outcomes
• References
• Copyright

Abstract 

This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics committee. The paper was approved by the committee on May 16, 1999, and by the AGA governing board on July 18, 1999.

GASTROENTEROLOGY 2000;118:201-221

Occult and obscure gastrointestinal (GI) bleeding are common clinical scenarios, yet the meaning and diagnostic criteria for these terms are not well delineated. Many studies that have evaluated occult and obscure bleeding do not offer definitions or, in some cases, use these terms interchangeably. Stedman's Medical Dictionary¹ briefly defines occult GI bleeding as blood in the feces in amounts too small to be seen but detectable by chemical tests. No definition for obscure intestinal bleeding is offered.¹ Examining these disorders as separate clinical entities (Table 1) will be important for clarification of definitions and categorization of diagnostic, therapeutic, and outcome issues.*

Table 1. Bleeding definitions

Occult bleeding typically refers to the initial presentation of a positive fecal occult blood test (FOBT) result and/or iron-deficiency anemia (IDA) without evidence, to the patient or physician, of visible fecal blood (Table 1).², ³, ⁴, ⁵ Cases may be identified during routine laboratory testing, during screening of asymptomatic subjects for colon cancer, or as part of a physical examination. Published reports have routinely separated occult bleeding into IDA⁵, ⁶, ⁷ or FOBT³, ⁴ studies, with the implication that these categories represent separate clinical entities. Rather, these two presentations may represent a continuum of the same process—intermittent or chronic slow bleeding caused by various GI processes, benign or malignant. The FOBT may detect this bleeding at any point in a longitudinal course that may culminate in IDA.

Obscure bleeding has undergone a number of varied descriptions, the definitions changing with the evolution of investigative procedures that have progressed from radiological to endoscopic.⁸, ⁹, ¹⁰ When barium radiographs were used as the primary means of evaluation, GI hemorrhage was called obscure if its cause remained unknown after standard radiological investigations.¹¹ Other papers considered bleeding to be of obscure origin when all patients underwent “exhaustive” evaluations before study entry, with vague references to the definition of exhaustive.¹⁰, ¹² Others have defined obscure bleeding as bleeding for which no cause was uncovered after “standard investigations” of the upper and lower bowel, i.e., esophagogastroduodenoscopy and colonoscopy with or without other diagnostic studies.¹³ Thus, using these criteria, the definition of obscure was determined by the collective negative investigations.

Obscure bleeding is more appropriately defined as bleeding of unknown origin that persists or recurs (i.e., recurrent or persistent IDA, FOBT positivity, or visible bleeding) after a negative initial or primary endoscopy (colonoscopy and/or upper endoscopy) result (Table 1). This definition starts earlier in the patient evaluation and is important for clarifying the utility and predictive value of the various diagnostic tests.

No single study has followed the longitudinal course of obscure bleeding to determine the denominator for frequency or the diagnostic numerator of the various tests. Cases of obscure bleeding result from, or represent the residual of, two initial presentations: occult bleeding and acute visible bleeding.¹⁴ Obscure bleeding can thus have two clinical forms: (1) obscure-occult, as manifested by recurrent IDA and/or recurrent positive FOBT results; and (2) obscure-overt, with recurrent passage of visible blood (Table 1). Data are sparse on the frequency and natural history of these two forms of obscure bleeding. Although as many as 30%-50% of occult bleeding cases will not have a source identified at colonoscopy and upper endoscopy (Table 2),³, ⁴, ⁵, ⁶, ⁷ many of these patients do not evolve into obscure bleeding cases.⁵Undiagnosed occult bleeding would only be recategorized as obscure bleeding if there were recurrence or persistence of IDA or positive FOBT results. An investigation of IDA followed up a subgroup in which no bleeding source was found at colonoscopy or upper endoscopy and treated these patients with empiric oral iron; anemia resolved in 83% with no recurrence over a mean follow-up period of 20 months.⁵ Thus, the original work-up of most cases of occult bleeding should not require diagnostic testing other than colonoscopy and/or upper endoscopy, even when the results of these procedures are negative. Further diagnostic evaluation is necessary only when there are extenuating clinical circumstances or evidence of persistent or recurrent bleeding, which by definition becomes obscure bleeding (Table 1).

Table 2. Prospective studies of bidirectional endoscopy in patients with occult GI bleeding

	Zuckerman and Benitez3 1992 n (%)	Rockey et al.4 1998 n (%)	Rockey and Cello5 1993 n (%)	Bampton and Holloway6 1996 n (%)	Kepczyk and Kadakia7 1995 n (%)
Patient characteristics	Positive FOBT ± IDA	Positive FOBT alone	IDA ± positive FOBT	IDAa ± positive FOBTb	IDA ± positive FOBT
No. of patients	100	248	100	80	70
Mean age (yr [range])	65 (26-91)	61 (40-89)	60 (20-85)	70 (37-91)	64 (19-87)
With IDA alone	16 (16)	0 (0)	50 (50)	50 (63)	38 (54)
With positive FOBT alone	53 (53)	248 (100)	—c	—c	—c
Bleeding source found, total	53 (53)	119 (48)	62 (62)	49 (61)	50 (71)
Colorectal source	26 (26)	54 (22)	26 (26)	16 (20)	21 (30)d
Colon cancer	6 (6)	13 (5)	11 (11)	7 (9)	4 (6)
Polyps (adenomas)	14 (14)	29 (12)	5 (5)	5 (6)	7 (10)
Angiodysplasia	5 (5)	5 (2)	5 (5)	1 (1)	6 (9)
Colitis	—	5 (2)	—	1 (1)	—
Upper source	36 (36)	71 (29)	37 (37)	38 (48)	39 (56)
Duodenal ulcer	1 (1)	10 (4)	11 (11)	5 (6)	3 (4)
Gastric ulcer	6 (6)	14 (6)	5 (5)	3 (4)	3 (4)
Esophagitis	6 (6)	23 (9)	6 (6)	14 (18)	10 (14)
Gastritis	12 (12)	12 (5)	5 (5)	2 (3)	11 (16)
Angiodysplasia	8 (8)	3 (1)	3 (3)	0 (0)	4 (6)
Gastric cancer	1 (1)	4 (2)	1 (1)	1 (1)	3 (4)
Celiac disease	NB	NB	NB	0 (0)	4 (6)
Synchronous lesionse	9 (9)	6 (2)	1 (1)	7 (9)	12 (17)
No source found	47 (47)	129 (52)	38 (38)	31 (39)	20 (29)
aDefinite and probable IDA. bImmunochemical FOBT (89% of patients tested). cAll FOBT-positive patients also had IDA. dIncludes 4 cases of “severely bleeding hemorrhoids.” eLesions found in both upper GI tract and colon.

NB, not biopsied.

There is also little available information on the frequency and natural history of the obscure-overt form of bleeding. Hematemesis appears to represent an extremely rare presentation for obscure-overt bleeding; the vast majority of cases have passage of visible blood per rectum.¹⁵ One report found a 1% incidence of recurrent obscure-overt bleeding among 2751 patients with acute GI bleeding.¹⁶ Studies of lower intestinal bleeding have noted a 0.5%-1.2% incidence of recurrent bleeding after an initial nondiagnostic colonoscopy result.¹⁷, ¹⁸ These data suggest that although only a small percent of cases with visible bleeding will not have a diagnosis, an even smaller number from that group will have recurrent obscure bleeding.¹⁶, ¹⁷, ¹⁸

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Bedside examination 

The patient interview and physical examination may sometimes provide clues to the cause of occult or obscure GI bleeding. A directed history can reveal consumption of medications known to cause mucosal damage or exacerbate bleeding, e.g., aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), alendronate, potassium chloride, and anticoagulants.⁹, ¹⁹, ²⁰ A family history of GI blood loss will expand the differential diagnosis to include hereditary hemorrhagic telangiectasia and blue rubber bleb nevus syndrome.⁹, ²¹ Typical lesions can be found on the upper extremities, lips, and oral mucosa in patients with hereditary hemorrhagic telangiectasia.⁹ Patients with the blue rubber bleb nevus syndrome can have cutaneous hemangiomas in addition to those in the GI tract.⁹, ²¹ Other rare causes of occult or obscure GI bleeding that can have typical findings on physical examination include celiac sprue (dermatitis herpetiformis), acquired immunodeficiency syndrome (Kaposi sarcoma), Plummer–Vinson syndrome (brittle, spoon-shaped nails, atrophic tongue), pseudoxanthoma elasticum (chicken-skin appearance, angioid streaks in the retina), Ehlers–Danlos syndrome (hyperextensible joints, ocular and dental abnormalities), neurofibromatosis (caféau lait macules, axillary freckles, cutaneous neurofibromas), and malignant atrophic papulosis (discrete painless papules).²² Certain polyposis syndromes (e.g., Peutz–Jeghers syndrome, Gardner syndrome, Cronkhite–Canada syndrome, Cowden disease) can also have typical cutaneous manifestations, as can neoplastic disease (Sister Mary Joseph nodule of the umbilicus and left supraclavicular node enlargement in intra-abdominal malignancy, tylosis in esophageal cancer).²²

It has been proposed that information on either upper or lower intestinal symptoms can direct the initial endoscopic approach to patients with occult bleeding, although data on the ability of symptoms to predict the location of an intestinal lesion are variable.⁴, ⁵, ⁷ Symptoms have been categorized into upper and lower intestinal, but the definitions are not uniform among investigators.³, ⁴, ⁵, ⁷ When IDA is the predominant reason for endoscopy, both upper and lower intestinal symptoms are predictive of abnormalities in the corresponding portion of the bowel.⁵ Another report found that only upper intestinal symptoms had a site-specific association.⁷ A third study found no correlation between symptoms and location.⁶ In studies in which FOBT positivity is the predominant reason for endoscopy, the results are also inconsistent. One study found an association between symptoms and site of bleeding⁴; another found no relationship.³ These varied results may be related to study design. It should be noted that in some studies the majority of patients had no abdominal symptoms.³ Upper or lower intestinal site-specific symptoms may direct the initial endoscopic procedure, but these conflicting data do not support limiting the evaluation to the symptomatic region.

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Evaluation of occult bleeding 

Study design factors 

Results from investigations of occult bleeding are difficult to compare because of protocol limitations. Criteria used to determine the source of positive FOBT results or IDA are primarily circumstantial because GI mucosal lesions are rarely found to be bleeding or show stigmata of recent bleeding at the time of endoscopy.³ Predetermined diagnostic criteria addressing the likelihood that a specific lesion is responsible for occult bleeding have been used and lend some credibility to the endoscopic finding of a nonbleeding lesion.³, ⁴, ⁵, ⁶, ⁷ The relationship of polyp size and histology are characteristics that have been assessed to determine whether the polyp found at endoscopy has the potential for bleeding. These protocols show that adenomatous polyps ≥1-1.5 cm in size are more likely to bleed, and hyperplastic polyps are not.²³, ²⁴ Overall, only approximately 11% of adenomas have a propensity to bleed.²⁴ There is also evidence suggesting that only approximately 50%-60% of colon cancers have a propensity to bleed.²⁵ Furthermore, because screening studies do not investigate subjects that are FOBT negative, it is difficult to know if the colonoscopic findings in the FOBT-positive group represent true positives because of colon cancer or polyps or chance findings for a particular age group. In a study of 439 consecutive symptomatic patients who underwent FOBT before planned colonoscopy, colon cancer was found in 1% of FOBT-negative patients and 7% of FOBT-positive patients; the numbers for adenomatous polyps were 7% and 20%, respectively.²⁶ If colonoscopy had been performed only on the FOBT-positive patients, 31% of colon cancers and 47% of adenomatous polyps would have been missed. The predictive value of a positive FOBT result was 7.3% for colon cancer and 20% for adenomatous polyps.²⁶ Although this study targeted a symptomatic population that might have a higher prevalence of neoplasia, investigations addressing the value of colonoscopic screening in asymptomatic subjects aged >50 years with negative FOBT results have found a colon cancer prevalence of 0.5%-3% and an adenomatous polyp prevalence of 25%-35%.²⁷, ²⁸, ²⁹, ³⁰ These data suggest that some of the lesions found at colonoscopy in subjects with positive FOBT results are a chance finding, especially diminutive adenomatous polyps.³¹

Questions can also be raised with respect to the significance of findings on upper endoscopy in patients with occult bleeding. Asymptomatic gastroduodenal ulcers or erosions were found in 14% of patients undergoing screening upper endoscopy before unrelated major elective surgery.³² It is unknown how many of these patients may have been FOBT positive. In a small group of premenopausal females with IDA, 86% of those believed to have anemia related to excessive menstrual blood loss also had “significant” but nonbleeding upper GI disease found at upper and lower endoscopy.³³ The contribution of these nonbleeding lesions to anemia or FOBT positivity cannot be determined with any certainty.

Other protocol design variables include the method of stool collection and dietary admonitions. Specimens collected during mass colon cancer screening studies were obtained from spontaneously passed stool,³⁴, ³⁵, ³⁶, ³⁷ whereas other studies included specimens obtained during digital rectal examinations.³, ⁴ Although the digital collection method may not be ideal, it appears to represent a common clinical practice. A retrospective study found no statistically significant differences in the detection rate of neoplastic polyps or colon cancer in relation to the method of stool collection (i.e., digital rectal examination vs. spontaneously passed stool).³⁸ Another retrospective study suggests that the false-positive rate of FOBT for colonic neoplasia is not increased with digital stool collection.³⁹ A prospective evaluation of 248 patients with positive FOBT results, 38% of which were obtained by digital rectal examination, found a higher overall endoscopic detection rate in the group in which stool was obtained by digital rectal examination.⁴ Dietary modifications have also varied between protocols. Colon cancer screening trials attempted to control dietary variables by eliminating foods with a high peroxidase content (certain raw vegetables and fruits), red meat, poultry, fish, vitamin C, and aspirin immediately before and during the collection of stool samples in an effort to reduce false-positive and false-negative FOBT results.³⁴ More recent studies of occult bleeding that were not designed as colon cancer screening trials did not impose dietary restrictions.³, ⁴, ⁵ Other protocol design differences include the use of barium examinations⁴, ⁴⁰ and the inclusion of pediatric patients.⁴¹

Guaiac-based tests have been the primary technique used in FOBT studies,³, ⁴, ⁵, ⁴² yet there are differences between various guaiac tests in their ability to detect occult blood.⁴³ Immunochemical tests for hemoglobin have also been incorporated into some protocols.³⁶ Previous data obtained from patients with colonic neoplasia suggest that the likelihood of a positive guaiac-based FOBT result is proportional to the hemoglobin content of the stool.⁴⁴ Recent evidence suggests that guaiac-based techniques will detect small amounts of bleeding from the upper GI tract, whereas immunochemical tests are relatively insensitive to this type and location of bleeding.⁴³ These findings may have implications for future studies designed to improve FOBT testing.

Endoscopic evaluation 

Colonoscopy and upper endoscopy remain the cornerstones for investigation of occult blood loss. A partial model (colonoscopy only) for endoscopic evaluation of occult GI bleeding can be found in the large colon cancer screening trials that used stool FOBT results. These studies are also only partial models for colonic sources of bleeding because the location, size, and character of polyps and other lesions that could potentially be responsible for positive FOBT results are not consistently mentioned or detailed. If an upper GI source was considered, in some cases it was pursued with upper GI barium studies.⁴² The Minnesota Colon Cancer Control Study used colonoscopy to evaluate positive FOBT results and found a statistical advantage for screening.³⁴ Overall, colonoscopy was performed in approximately 81% of subjects that were FOBT positive. Of the 46,551 study participants randomly assigned to annual or biennial screening, colorectal cancer was found in 1.9% and 2.9% and polyps in 27.5% and 29.5%, respectively. The positive predictive value for colorectal cancer depended on whether the slides were rehydrated with a drop of water (2.2%) or not (5.6%).³⁴ The group screened with annual FOBT had reduced mortality from colorectal cancer.³⁴ Information was not detailed in this study about the colonoscopic yield for other lesions such as colonic polyps or angiodysplasia.³⁴ In other colon cancer screening trials, colonoscopy was performed on 78%-86% of patients who had positive FOBT results. The predictive value of a positive FOBT result ranged from 2.2% to 17% for colorectal cancer and from 16.7% to 40% for adenomatous polyps.³⁵, ³⁶, ³⁷ There is also evidence to show that increasing age is associated with a higher prevalence of colonic neoplasia.²⁷, ³⁰

Bidirectional endoscopy 

Some studies of occult bleeding have been retrospective or did not include endoscopy in all patients.⁴⁰, ⁴⁵, ⁴⁶ Investigations that prospectively evaluate both the colon and the upper GI tract may offer a more complete representation of potential bleeding sources. Bidirectional endoscopy refers to an investigative technique of colonoscopy and upper endoscopy performed in sequence and in temporal relationship to the finding of occult bleeding.³ These protocols were initially proposed in an era in which the colon was the primary target of occult bleeding investigations.³, ⁵ Prospective studies that used predetermined criteria for the diagnosis of a bleeding source and bidirectional endoscopy in all patients found a diagnostic spectrum of potential occult bleeding sources.³, ⁴, ⁵, ⁶, ⁷ However, despite examination of the GI tract from both directions, IDA and positive FOBT results are unaccounted for in up to 52% of cases (Table 2).

A review of the causes of bleeding finds similarities between trials that examined patients who were predominantly FOBT positive³, ⁴ and those who were predominantly anemic with iron deficiency.⁵, ⁶, ⁷ For both IDA and FOBT-positive cases, a lesion identified as responsible for the occult blood loss was as often, if not more often, located in the upper GI tract (29%-56% occurrence) than in the lower intestinal tract (20%-30%) (Table 2). The likelihood of finding a bleeding source was higher in patients with IDA than those with positive FOBT results (61%-71% and 48%-53%, respectively), but the lesions found and the frequency of such findings were similar between these two categories of occult bleeding (Table 2). These investigational protocols did not report on the sequential order in which the procedures were performed or on the frequency of a diagnosis after the first endoscopic procedure, but they do provide evidence that the upper GI tract is a contributor to sources of occult bleeding. Although one retrospective study suggests that upper endoscopy has a very low yield for significant lesions in the patient with occult bleeding and negative colonoscopy result,⁴⁷ gastric cancer was found in every prospective study that used bidirectional endoscopy for occult bleeding regardless of whether the indication for endoscopy was anemia (1%-4% gastric cancer occurrence) or positive FOBT results (1%-2% gastric cancer) (Table 2). A simultaneous source for occult bleeding was found in both the upper and lower GI tracts in approximately 6% (range, 1%-17%) of patients. These data lend support to the assumption that cases of IDA or FOBT positivity represent different signs of the same disease process–intestinal mucosal lesions that bleed slowly or intermittently.

Radiographic evaluation 

Barium studies have been used in some investigations of occult bleeding.⁸, ⁴⁰ Earlier colon cancer screening protocols used barium examinations as the primary means of evaluating the colon.⁴⁸, ⁴⁹ However, single-column barium enemas were discontinued in the early years of one screening trial because of a colon cancer miss rate of 20%.⁴² Double-contrast enemas have been used primarily when results of colonoscopy are suboptimal.⁴²

Clinical guidelines for colon cancer screening have recommended air-contrast barium enema (ACBE), preferably with flexible sigmoidoscopy, as an alternative to colonoscopy for the diagnostic work-up of a positive FOBT result.⁵⁰, ⁵¹ It has been suggested that although the ACBE performance rate is lower than that of colonoscopy, it is sufficient to identify the majority of clinically significant polyps and cancers.⁵⁰ These recommendations are based on the relatively high sensitivity and specificity of ACBE to examine the entire colon for large polyps (>1 cm) and cancer.⁵², ⁵³, ⁵⁴ Little information is available on the ACBE as the only diagnostic tool in cases of positive FOBT results. In a trial of screening with FOBT, ACBE alone missed approximately 25% of cancers and polyps in the rectosigmoid region.⁵⁵ The combination of flexible sigmoidoscopy and ACBE had a sensitivity of 98% for carcinomas and 99% for adenomas.⁵⁵ This combination has been said to have a performance comparable to that of colonoscopy and to offer an alternative method for evaluation of the entire colon,⁵⁰ although small mucosal lesions are not detected by ACBE. There are no randomized controlled trials comparing the diagnostic yield of colonoscopy with that of ACBE in patients with positive FOBT results or IDA. Approximately 5%–10% of ACBE results are suboptimal and result in repeat examination or colonoscopy.⁵⁶, ⁵⁷ An abnormal or positive examination result leads to subsequent colonoscopy in approximately 15% of cases.⁵⁸, ⁵⁹ There are also no data specific to occult bleeding comparing barium meal with upper endoscopy. Overall, the double-contrast upper GI series has a sensitivity and specificity of 54% and 91%, respectively, for detection of upper GI tract lesions, compared with 92% and 100% for upper endoscopy.⁶⁰ The decision to choose barium studies as an alternative to endoscopy will depend on various factors such as patient preferences, the risks of conscious sedation, discontinuation or continuation of anticoagulation, the patient's general condition, comorbid diseases, and local expertise.⁵¹

Other testing in occult bleeding 

Because the majority of occult bleeding cases do not recur,⁵ and unless indicated by extenuating clinical evidence, small bowel biopsy, small bowel follow-through radiographs, enteroclysis, and enteroscopy should be reserved for cases of persistent or recurrent IDA or positive FOBT results, which by definition fall into the category of obscure bleeding (Table 1).

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Evaluation of obscure bleeding 

When a source for blood loss is not apparent from examination of the colon and the upper GI tract, the small bowel is usually interrogated. Before examination of the small intestine, repeat upper endoscopy and colonoscopy can also be helpful to identify lesions potentially overlooked at initial endoscopy.⁶¹, ⁶², ⁶³ In one study of 17 patients with obscure blood loss, 35% had a bleeding source identified on repeat endoscopy (upper endoscopy, 29%; colonoscopy, 6%).⁶⁴ Even when the intent is to examine the small bowel with an enteroscope, a source that should have been discovered at the prior upper endoscopy was found in 28%-75% of patients in whom a diagnosis was made by enteroscopy.⁶², ⁶³, ⁶⁵, ⁶⁶, ⁶⁷ The most common lesions missed during upper endoscopy include erosions within large hiatal hernias (Cameron's erosions), peptic ulcer disease, and vascular ectasia. Lesions have also been found in the colon that had been missed on initial colonoscopy in up to 3% of patients⁶⁸; the major lesions overlooked included angiodysplasia and neoplasia.⁶⁸, ⁶⁹ However, one report of 39 patients with obscure bleeding found no additional diagnostic yield when upper endoscopy and colonoscopy were repeated.¹⁴ The skill and experience of the initial endoscopist may be factors that need to be taken into consideration when deciding to repeat upper endoscopy and/or colonoscopy, yet the diagnostic yield of repeat endoscopy may be enough to warrant a second look, if not a second opinion endoscopy. In this clinical setting, some investigators advocate enteroscopy in place of repeat upper endoscopy.⁶², ⁶³

Diagnostic techniques 

Small bowel biopsy performed during upper endoscopy or enteroscopy may be used to detect celiac sprue as a cause of IDA. Although as many as one half of anemic patients with untreated celiac disease have iron deficiency,⁷⁰ the prevalence in patients with IDA is much lower, 0%-11%.⁶, ⁴¹, ⁴⁶, ⁷¹ This finding may be related to various factors, including age, disease prevalence in the country of origin, and referral bias.⁴¹ Bidirectional endoscopy trials have yielded conflicting results. Small bowel biopsies performed during upper endoscopy as part of a protocol evaluating 79 patients with IDA did not find any cases of celiac sprue,⁶ whereas another protocol found histology-compatible sprue in 5.7% of 70 patients.⁷

The appearance of the small bowel during endoscopy may be a tip-off to the presence of sprue and the need for biopsy. Gross findings include loss or effacement of the circular folds or rings of Kerckring, scalloping of the circular folds, and smooth atrophic-appearing mucosa with pallor and pronounced vascular pattern.⁴¹, ⁷², ⁷³, ⁷⁴, ⁷⁵ Another simple screening technique relies on the increased magnification created by viewing the small bowel mucosa while the endoscope tip is submerged under water, and then observing for the presence or absence of villi.⁷⁶ Patients with celiac disease can have small intestinal folds that appear grossly normal, although this may be an infrequent finding.⁴¹

Demographic and clinical features may also help assess the need for a small bowel biopsy. Celiac disease is rare if not nonexistent among African Americans and Asians.⁷⁷, ⁷⁸ Patients with celiac sprue are also generally younger, with significantly more episodes of diarrhea and longer duration of anemia than those without celiac disease.⁴¹ Lack of response to oral iron therapy may also be a clue to the possibility of sprue.⁷⁰, ⁷¹ A confounding issue in the evaluation of occult and obscure bleeding is the recent evidence of positive FOBT results in approximately half of patients with celiac sprue.⁷⁹

Endoscopic examination of the small bowel has evolved around two main techniques: push enteroscopy, involving peroral insertion of a long endoscope directly into the jejunum, and Sonde enteroscopy, in which the enteroscope is usually inserted transnasally and the tip is propelled by peristalsis.

The initial studies describing push enteroscopy used orally passed adult or pediatric colonoscopes to examine the proximal small bowel.⁸⁰, ⁸¹, ⁸², ⁸³ Push enteroscopy has since evolved into the standard approach for further evaluation of obscure bleeding, facilitated by the availability of long videoscopes and relative ease of use.⁸⁴ Fluoroscopy has been used to assess depth of insertion of the enteroscope,⁶⁵, ⁸⁵ but it is not routinely used¹⁴, ⁸⁶, ⁸⁷; plain abdominal radiographs have also been used to document the point of deepest insertion.⁶⁷ An overtube is usually used to assist deep intubation,⁶⁵, ⁶⁷, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸ although some investigators report no clear advantage and complications with its use.⁶², ⁸⁹, ⁹⁰ The depth of insertion past the ligament of Treitz can range from 15 to 160 cm.¹⁴, ⁶⁵, ⁶⁷, ⁶⁸, ⁸⁵, ⁸⁷, ⁸⁹, ⁹¹ One study reported mean lengths of insertion past the ligament of Treitz of 108 cm with an overtube (range, 60-150 cm) and 11 cm without an overtube (range, 5-30 cm).⁹² Studies addressing the yield of push enteroscopy in the investigation of obscure GI bleeding report a diagnostic yield of 38%-75% (Table 3).¹⁴, ⁶², ⁶³, ⁶⁵, ⁶⁶, ⁶⁷, ⁸⁵, ⁸⁶, ⁸⁷, ⁸⁸, ⁸⁹, ⁹³, ⁹⁴, ⁹⁵ The diagnostic rates for obscure-overt and obscure-occult bleeding were similar in one study (72% and 69%, respectively)⁶³ but differed somewhat in another (37% and 55%, respectively).⁶²Push enteroscopy appears to be a relatively safe procedure, with a low incidence of complications, some of which are related to the overtube. Complications reported include postprocedure abdominal pain, acute pancreatitis, Mallory–Weiss tear with bleeding requiring cauterization, and a pharyngoesophageal tear⁶⁵, ⁸⁵ (Table 3).

Table 3. Push enteroscopy in obscure GI bleeding

Sonde enteroscopy was developed in the late 1970s and provides the potential for direct examination of the entire small bowel mucosa.⁹⁶ After transnasal or oral passage into the stomach, the tip is dragged into the proximal small bowel with the aid of an endoscope. Intrinsic gut peristalsis can propel the balloon at the tip of the endoscope to the terminal ileum.⁹⁷ Inspection is carried out on withdrawal of the enteroscope. Sonde-type enteroscopy is less popular than push-type enteroscopy. Patient discomfort is aggravated by the length of the procedure (average insertion time, 4 hours; average withdrawal/examination time, 45 minutes⁹⁷). Mucosal visualization is limited because of lack of four-way tip deflection and relatively uncontrolled instrument withdrawal.⁹⁷, ⁹⁸, ⁹⁹ Moreover, an alternate mode of intervention is necessary for therapy.⁹⁷ The advantage of Sonde enteroscopy is the potential for total small bowel examination, with ileal intubation rates reported at 60%-75%.¹⁰, ¹⁰⁰ Complications are said to be uncommon, although bowel perforation occurred in 3% of patients in one series.¹⁰¹ Fourteen percent of patients developed epistaxis in another series¹⁰²; epistaxis requiring nasal packing has also been reported.¹⁰³ The overall diagnostic rate ranges from 26% to 54%.¹⁰, ⁹⁸, ¹⁰⁰, ¹⁰¹, ¹⁰³, ¹⁰⁴, ¹⁰⁵ The yield was highest when closed biopsy forceps, passed through the instrument channel, were used to push away the bowel wall, thereby allowing better mucosal visualization.¹⁰⁵ In one study that combined push-type and Sonde-type enteroscopy in the same patients, 18% had lesions within push-type enteroscopy limits, whereas 26% had bleeding sources beyond the limits of push-type enteroscopy; 40% had lesions that were within the limits of upper endoscopes.¹⁰⁴ Newer Sonde-type enteroscopes have been developed with video-optics, a wider field of vision, and two-way tip deflection.⁹⁷ It remains to be seen whether these improvements increase the popularity of Sonde enteroscopy.

Retrograde enteroscopy involves examination of the distal ileum at colonoscopy using a standard colonoscope,¹⁰⁶ a small bowel enteroscope,⁶⁸ or a smaller endoscope passed through the instrument channel of a specially designed therapeutic colonoscope.¹⁰⁷ The ileocecal valve is intubated 72%-79% of the time at routine colonoscopy, the length of terminal ileum examined is variable, and the diagnostic yield has been reported up to 2.7%.¹⁰⁶, ¹⁰⁸, ¹⁰⁹, ¹¹⁰ In a study in which push enteroscopy from above was combined with retrograde ileoscopy (using a small bowel enteroscope) in the investigation of obscure GI bleeding and IDA, ileoscopy provided a diagnosis in only 1.3% of cases; the mean length of ileum examined was 60 cm (range, 20-120 cm).⁶⁸ In the only report on the use of a second 3.4-mm-diameter endoscope passed through the instrument channel of a colonoscope, the procedure was complicated by technical problems, and adequate visualization was achieved in only 70%; abnormalities were seen in 20%.¹⁰⁷ Examination of the terminal ileum during routine colonoscopy is simple and easily performed and should be included in the evaluation of obscure bleeding. However, dedicated retrograde enteroscopy appears to have a low diagnostic yield and should be reserved for instances in which other evidence indicates a potential source of blood loss in the terminal ileum.

Intraoperative enteroscopy (IOE) is usually applied in cases of transfusion-dependent bleeding that is not localized in spite of extensive diagnostic evaluation, with or without preceding nonoperative enteroscopy.¹¹¹ In these instances, the severity of the blood loss warrants further work-up, and the risks of continued bleeding outweigh the risks of laparotomy.¹¹¹ Laparotomy has been coupled with the passage of an endoscope orally,¹⁵, ¹¹² transnasally (using a Sonde endoscope),¹⁵, ¹¹³ per rectum,¹¹² or through enterotomies performed on the small bowel.¹⁵, ¹¹² The endoscope is advanced through the small bowel with the assistance of the surgeon, who pleats the small bowel over the endoscope. The lights in the operating room are lowered, and while the endoscopist examines the luminal aspect, the surgeon examines the transilluminated serosal aspect of the small bowel. Examination is performed while the endoscope is being advanced because surgical manipulation can create artifacts that can be mistaken for potential bleeding lesions.¹¹⁴ When performed for obscure GI bleeding, the ability of IOE to identify potential bleeding lesions has been impressive, ranging from 70% to 100% (Table 4).¹⁵, ¹¹², ¹¹³, ¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷ However, finding a lesion does not always equate to cessation of bleeding.¹², ¹⁵, ¹¹⁴

Table 4. Intraoperative enteroscopy in obscure GI bleeding

Technical difficulties with scope advancement have been attributed to dense adhesions or infiltrating neoplasia.¹¹⁵, ¹¹⁶, ¹¹⁷ Obscured visibility caused by luminal blood has been a problem¹¹⁷ that may be improved with oral purging.¹¹⁶ Complications range from 0% to 52% and include mucosal laceration, intramural hematomas, mesenteric hemorrhage, perforation, prolonged ileus, Ogilvie's syndrome, intestinal ischemia, intestinal obstruction, stress ulcer, wound infection, and postoperative pulmonary infection.⁹⁹, ¹¹², ¹¹³, ¹¹⁵ Mortality related to the procedure or to postoperative complications has been up to 11%⁹⁹, ¹¹⁵; however, most studies reviewed do not report mortality with IOE. One series reported small bowel ischemia from tight pleating of the bowel over a Sonde endoscope, resulting in death of the patient.⁹⁹ In another instance, ischemia from tight pleating of the bowel resulted in an enterovaginal fistula.¹¹⁸ Lesions can be missed even at IOE, possibly because of limited visibility and the evanescent nature of angiodysplasia.⁹⁹

IOE has also been performed through single or multiple intestinal incisions.¹¹⁴, ¹¹⁹ The advantages of IOE through an enterotomy include elimination of intestinal dead space (i.e., esophagus, stomach, and duodenum, or colon and rectum) that presumably was already extensively examined before IOE, and decreased trauma to the bowel. Less handling and pleating of the bowel is required to advance the endoscope, resulting in facilitation of antegrade bowel examination with less chance of mucosal artifacts.¹¹⁴ Comparative data for morbidity and mortality of nonenterotomy and enterotomy are not available, although it has been suggested that the addition of enterotomy to laparotomy does not increase morbidity or mortality.¹¹⁴ However, this method could miss lesions in the parts of the bowel that are bypassed, as suggested by reports that 22% of patients undergoing IOE without enterotomy had a bleeding source proximal to the duodenum,¹¹⁷ and 13% had a source distal to the ileocecal valve.¹¹³

The use of a Sonde enteroscope during laparotomy reportedly facilitates intestinal passage because of its small radius of curvature that reduces mucosal artifacts.¹¹¹, ¹¹³ However, the field of vision of a standard Sonde enteroscope is considerably less than that of a standard enteroscope or colonoscope (90° forward with no tip deflection vs. 120° forward and tip deflection capability).⁹¹ Newer video Sonde enteroscopes with a wider field of vision and tip deflection may eliminate some of the problems associated with the older enteroscopes.⁹⁷

The choice of instrument type and entry site will necessarily depend on instrument availability, familiarity with the diagnostic approaches, and the experience and technical expertise of both the surgeon and the endoscopist. Because of the initial capital expense of purchasing a dedicated enteroscope and the relative low prevalence of obscure bleeding cases, standard and pediatric colonoscopes probably will continue to be used as enteroscopes.

Barium studies are often used for further work-up of the small bowel in obscure bleeding, either before enteroscopy or when push-enteroscopy has failed to reveal a source. Peroral ingestion of a barium suspension is used for the small bowel follow-through (SBFT) x-ray series, whereas enteroclysis involves instillation of contrast material through a small tube placed in the proximal intestine either directly or facilitated by endoscopy.¹²⁰ Diluted methylcellulose solution enhances the double-contrast effect, thereby improving the quality of the study.¹²⁰ Although radiation exposure and patient discomfort are higher with enteroclysis,¹²¹ studies have documented significantly higher overall diagnostic yield, higher sensitivity, and shorter procedure times than with SBFT.¹¹², ¹¹³, ¹¹⁴, ¹¹⁵, ¹¹⁶, ¹¹⁷, ¹¹⁸, ¹¹⁹, ¹²⁰, ¹²¹, ¹²², ¹²³, ¹²⁴, ¹²⁵, ¹²⁶ However, in studies specifically addressing occult bleeding, enteroclysis had a yield of 0%⁵, ⁷ when performed after negative colonoscopy and upper endoscopy, and SBFT had a yield of 0%-4%,⁵, ⁶ although the numbers of patients studied were small. When enteroclysis is used for the diagnosis of obscure GI bleeding, its yield can range from 10% to 21%,¹²⁷, ¹²⁸, ¹²⁹ which is higher than the yield of SBFT (0%-5.6%¹³⁰, ¹³¹). The sensitivity of enteroclysis in the diagnosis of small bowel neoplasia is much higher, approaching 95%.¹²³ Although enteroclysis has been suggested as the radiological study of choice for the investigation of suspected gross disorders of the small bowel,¹²⁶ there is a low yield in the diagnosis of angiodysplasia. In one report, of 128 enteroclysis studies performed for obscure GI bleeding, only 2% had subtle findings suggestive of angiodysplasia and substantiated on pathological examination of resected bowel.¹²⁷

Enteroclysis may be complementary to enteroscopy when performed after a negative examination result. Because nasal placement and pyloric intubation are the most uncomfortable aspects of enteroclysis tube placement,¹²⁴ recent diagnostic endeavors have used endoscopic placement of the enteroclysis tube after a negative push-type enteroscopic examination.⁶⁶, ¹³², ¹³³ The insufflation of air during enteroscopy and the administration of conscious sedation and glucagon do not seem to compromise the quality of the radiographs.¹²⁰, ¹³² Enteroclysis applied in this piggy-back technique was helpful in making a positive diagnosis in 8% of patients with negative enteroscopy results and improved the yield of enteroscopy from 54% to 58%.⁶⁶

Radioisotope bleeding scans may be helpful in localizing the site of obscure-overt bleeding, although there are few studies specifically addressing this approach. The in vitro technetium 99m–labeled red blood cell (TRBC) scan is the most used method of radioisotope scanning, its advantage being the long half-life of the label, which allows for repeat scanning if necessary over a 24-hour period.¹³⁴ The TRBC scan requires a bleeding rate of 0.1-0.4. mL/min for a positive result and is readily available and safe.¹³⁵, ¹³⁶, ¹³⁷ The overall rate of positivity of TRBC scanning in lower intestinal bleeding is 45% (range, 26%-78%).¹³⁸ When the results of TRBC scanning are verified by endoscopy, angiography, or surgery, its accuracy ranges from 41% to 97% (mean, 78%).¹³⁸ The yield of angiography for verification of scan localization is highest when the radionucleide “blush” (a function of rate of bleeding) is seen immediately upon initiation of scanning (angiography positive in 67%), compared with late scan positivity (angiography results positive in 7%).¹³⁹ Delayed scans obtained 12-24 hours after injection of labeled RBC can be misleading and can identify pooled blood at points different from the bleeding site.¹⁴⁰, ¹⁴¹

Specific data on the utility of TRBC scans in obscure GI bleeding are limited. In a preliminary report, 24% of all positive TRBC scans performed for presumed acute lower GI bleeding were localized to the small bowel.¹⁴² It is unknown if these data can be interpolated to obscure bleeding cases. In other reports, 37%-65% of TRBC scan results were positive; however, 15% were false positive, and 12%-23% of the negative scan results were false negative.¹⁴³, ¹⁴⁴ Because of the significant false localization and miss rates, verification with an alternate test such as angiography or endoscopy is usually necessary before an invasive therapeutic intervention is made.¹³⁸

Meckel's scanning using ^99mTc-pertechnate is also used for the evaluation of small bowel bleeding.⁶⁴, ¹⁴⁵ The sensitivity is reported to be 75%-100%.¹⁴⁶ Enhanced scans are performed using pentagastrin or cimetidine to increase the uptake of pertechnate, which can increase the sensitivity of the scan.¹⁴⁷, ¹⁴⁸ However, a positive scan result only indicates the presence of gastric mucosa in the small bowel, which may or may not represent the bleeding source.¹⁴⁶

Intraoperative scintigraphy has been advocated as a worthwhile method for intraoperative localization of the bleeding segment.¹⁴⁹, ¹⁵⁰, ¹⁵¹ The bowel is clamped every 30 cm, and a gamma camera assesses the presence of labeled blood within the clamped segment.¹², ¹⁴⁹ Other investigators have successfully used a handheld Geiger counter in similar circumstances, but the procedure is cumbersome and time-consuming.¹⁵⁰, ¹⁵¹

The role of angiography in obscure bleeding is difficult to assess because a limited number of angiographic protocols specifically address obscure bleeding. When active bleeding occurs at a rate of ≥0.5 mL/min, extravasation of contrast into the bowel lumen may be found on mesenteric angiography.¹⁵² The overall positivity on angiography in acute lower intestinal bleeding ranges from 27% to 77% (mean, 47%).¹³⁸ This increases to 61%-72% if patients are documented to be actively bleeding, as defined by number of transfusions, hemodynamic compromise, or TRBC scans showing an immediate blush.¹³⁹, ¹⁵³ However, these represent a mixture of bleeding presentations, and culling out the angiographic studies performed for obscure bleeding from cases of first-time acute bleeding is not always possible. Angiography can identify lesions that are not actively bleeding by demonstrating typical vascular patterns seen in angiodysplasia and neoplasia.¹⁵⁴, ¹⁵⁵, ¹⁵⁶, ¹⁵⁷ A slowly filling vein that persists after other mesenteric veins have emptied is the most common angiographic finding in angiodysplasia, seen in more than 90% of cases. Other findings include a vascular tuft seen during the arterial phase and an early filling vein. All three findings have been reported simultaneously in 44% of patients with angiodysplasia.¹⁵⁴ Using typical angiographic appearances for a positive diagnosis, the sensitivity of superior mesenteric angiography in identifying the cause of obscure bleeding was 40% in one retrospective series, with a specificity of 100%.¹⁵⁵ When bleeding is recurrent and results of primary angiography are negative, a repeat angiogram obtained during a subsequent bleeding episode may be helpful. In one protocol, the yield of initial angiography was 43% and increased to 54% for repeat angiography in patients with no initial diagnosis, either during the next bleeding episode or after an arbitrary period.¹⁵⁸

Administration of anticoagulants, vasodilators, or clot-lysing agents can potentially propagate or precipitate bleeding and improve the yield of angiography.¹⁵⁹, ¹⁶⁰ Data on the use of pharmacological techniques at angiography are scant. One retrospective review reported a diagnostic increase from 32% to 65% with the use of pharmacological techniques.¹⁵⁹ Complications were seen in 17% and included excessive GI blood loss related to the use of these pharmacological agents and a groin puncture site hematoma.¹⁵⁹ The potential risk of uncontrolled bleeding limits the use of this technique to selected cases that are without significant comorbid illnesses in whom other modes of diagnosis have been exhausted.

Angiography has also been performed intraoperatively to assist the surgeon in localizing a bleeding lesion.¹⁶¹, ¹⁶², ¹⁶³ Superselective catheter placement and methylene blue injection during laparotomy have helped localize small bowel angiodysplasia and bleeding mucosal erosions so that segmental resection of the stained bowel segment can be performed.¹⁶¹ Other investigators have also used superselective preoperative or intraoperative methylene blue, fluoroscein, or radiopaque coil injection into the bleeding artery to localize the lesions for resection.¹⁶⁴, ¹⁶⁵, ¹⁶⁶, ¹⁶⁷, ¹⁶⁸ The indications and utility of each of these angiographic techniques need further evaluation.

Currently, exploratory laparotomy for obscure bleeding is seldom reported without concomitant IOE. In one series from the 1980s, 64% of 14 patients who underwent exploratory laparotomy without IOE had a diagnosis made at surgery.¹⁶⁹ In another series, 24 (65%) of 37 patients undergoing surgery for obscure bleeding had a lesion identified by simple palpation and transillumination alone.¹⁶ Other surgical methods that do not use flexible enteroscopy include multiple enterotomies with eversion of the mucosa,¹⁶ examination of the small bowel using a rigid sigmoidoscope passed through an enterotomy,¹⁶ and exteriorization of a loop enterostomy to the abdominal wall to identify proximal vs. distal small bowel recurrent bleeding.¹⁷⁰ The use of laparoscopy-assisted enteroscopy (laparoendoscopy) with laparoscopic small bowel resection has been investigated successfully in dogs and could be useful in humans.¹⁷¹

The use of meperidine for conscious sedation during endoscopy may reduce mucosal blood flow and mask the detection of angiodysplasias.¹⁷² Consequently, the use of narcotic antagonists like naloxone or the avoidance of meperidine may enhance the appearance of GI angiodysplasias.¹⁷², ¹⁷³, ¹⁷⁴ Biphasic arterial- and venous-phase computerized tomographic (CT) scanning has been used for identification of angiodysplasia.¹⁷⁵ The bowel is distended by water, and intravenous contrast is rapidly injected using a power injector. Arterial- and venous-phase helical CT scans are obtained sequentially after an unenhanced scan. Angiodysplasias were noted during the arterial phase, and additional lesions became visible during the venous phase of the study. Intraoperative enteroscopy and pathological examination of the surgically resected bowel confirmed the presence of angiodysplasia.¹⁷⁵ Doppler ultrasonography has been reported to detect increased blood flow through angiodysplasia and has been used intraoperatively with a handheld probe to confirm lesions initially identified by transillumination.¹⁷⁶

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Etiology 

Occult bleeding sources 

Upon endoscopic evaluation of patients with predominantly positive FOBT results, a bleeding source was found in the colon in 22%-26% and in the upper GI tract in 29%-36% of cases³, ⁴ (Table 2). The most common lesions identified included colonic adenomas ≥1 cm (12%-14%), peptic ulcer disease (7%-10%), esophagitis (6%-9%), and colon carcinoma (5%-6%).³, ⁴ Angiodysplasia (upper GI tract and colonic) accounted for 3%-13% of diagnoses.³, ⁴ When patients with iron deficiency were evaluated using upper and lower GI endoscopy, 18%–30% had lesions in the colon, compared with 36%-56% in the upper GI tract.⁵, ⁶, ⁷, ⁴⁵ The etiologic lesions identified were similar to those seen in FOBT-positive cases, with peptic ulcer disease accounting for 9%-19%, esophagitis for 8%–18%, colorectal cancer for 6%-11%, and colon adenomas >1 cm for 5%-10% of the causes of iron deficiency. Angiodysplasia accounted for 2%-8%,⁵, ⁶, ⁷, ⁴⁵ and celiac disease was found in 0%-11% of patients with IDA.⁶, ⁴¹, ⁴⁶, ⁷¹ The varied diagnostic range for celiac disease may be related to many factors, including population- and age-related prevalence in the country of origin and referral bias. Celiac disease can also be associated with a positive FOBT result.⁴¹, ⁷⁹ Studies of patients with occult bleeding have noted NSAID or aspirin use in up to 60%, suggesting that these medications play a role in GI blood loss.³, ⁴, ⁵, ⁶, ⁷ The propensity of NSAIDs to induce mucosal damage to the gastroduodenum and small bowel is well recognized,¹⁷⁷, ¹⁷⁸ and there is increasing evidence implicating NSAID use in bleeding colonic mucosal lesions.¹⁷⁸, ¹⁷⁹, ¹⁸⁰ One study of occult bleeding reported a higher diagnostic yield for upper endoscopy than for colonoscopy (42% vs. 24%) in patients taking NSAIDs or aspirin³; another study did not find any association of NSAID or aspirin use with intestinal localization.⁴ The sources of occult blood loss are listed in Table 5.

Table 5. Causes of occult GI bleeding

IBD, inflammatory bowel disease; GAVE, gastric antral vascular ectasia.

Obscure bleeding sources 

The overall incidence and location of specific lesions responsible for obscure bleeding are unknown because there are no longitudinal studies addressing this issue. The investigation of obscure GI bleeding, when results are positive, frequently yields a bleeding source in the small bowel but can also show lesions within reach of an upper endoscope or, sometimes, within reach of a colonoscope. In protocols using enteroscopy in obscure bleeding, a source within reach of the standard upper endoscope was found at enteroscopy in 28%-75% of patients in whom a diagnosis was made,⁶², ⁶³, ⁶⁵, ⁶⁶, ⁶⁷ the most common lesions being peptic ulcer disease (0%-11%) and erosions within large hiatal hernias (i.e., Cameron's erosions, 0%-8%). Other lesions diagnosed within reach of the upper endoscope are esophagitis, esophageal varices, gastric polyps, gastroduodenal angiodysplasia, and gastric antral vascular ectasia (Table 6).

Table 6. Causes of obscure GI bleeding

Support for the colon as a source of obscure bleeding is not well addressed in the literature. Angiodysplasia and colonic neoplasia missed at initial colonoscopy have been found in patients undergoing investigation for obscure bleeding.⁶⁴, ⁶⁸, ⁶⁹, ¹¹³ Some of the less common causes of acute colonic bleeding can also be responsible for obscure bleeding.¹⁸⁰, ¹⁸¹ Up to 25% of lower intestinal bleeding cases can remain undiagnosed after initial and sometimes exhaustive investigation,¹⁸⁰ and it is conceivable that some of these cases may develop recurrent and therefore obscure bleeding.

Overall, angiodysplasias were the most common etiology for obscure bleeding identified during push enteroscopy (8%-45%), followed by small bowel tumors (0%-17%).¹⁴, ⁶⁵, ⁶⁷, ⁶⁸, ⁸⁵, ⁸⁶, ⁸⁷, ⁹², ⁹⁴, ⁹⁸ Similar numbers were found with Sonde enteroscopy, in which angiodysplasias were identified in 7%–27%, and tumors in 0%-6%.¹⁰, ¹⁰⁰, ¹⁰³, ¹⁰⁵ These various diagnostic procedures have also been used in combination. Using push and Sonde enteroscopy together, angiodysplasias were found to be responsible for 31% of cases of obscure blood loss, whereas tumors accounted for 6%.¹⁰⁴ When enteroscopy was combined with enteroclysis, angiodysplasias were found in 22% and small bowel tumors in 4%, with all tumors identified only by enteroclysis.⁶⁶ In the largest study involving IOE, angiodysplasias were identified in 34%, small bowel ulcers in 27%, neoplasms in 2%, and nonspecific mucosal findings of uncertain significance in 5%.¹⁵ Upon comprehensive investigation of obscure GI bleeding using preoperative enteroscopy, laparotomy with IOE, and intraoperative scintigraphy, angiodysplasia represented the largest diagnostic category, 40%, followed by small bowel neoplasia in 33%.¹² It is evident that angiodysplasia is the most common small bowel cause of obscure bleeding, followed by small bowel tumors, regardless of presentation (obscure-occult vs. obscure-overt)⁶³, ⁹⁸ or mode of investigation.¹⁰, ¹⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁸⁵, ⁸⁶, ⁸⁷, ⁹², ¹⁰⁰, ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁸ The use of NSAIDs is associated with a higher likelihood of nonspecific ulceration of small intestinal mucosa, which can manifest as obscure blood loss.¹⁷⁷, ¹⁷⁸, ¹⁸² Sonde enteroscopy in patients with obscure bleeding showed small bowel mucosal lesions in 56% of patients taking NSAIDs for rheumatoid arthritis.¹⁸² One autopsy study found an 8.4% incidence of small bowel ulcers in patients who had been taking NSAIDs.¹⁷⁷ Vasculitis involving the small and medium-sized arteries can also result in GI mucosal damage,¹⁸³ as can radiation injury¹⁸⁴; both can result in obscure bleeding. Other diagnoses made upon investigation of obscure bleeding are listed in Table 6. These various series also report finding no source for obscure bleeding in 29%-74% of patients.

The causes of obscure GI bleeding can also vary depending on the age of the patient. In a study involving 129 patients with obscure GI blood loss, 40% of patients older than 65 years had angiodysplasia diagnosed on enteroscopy, compared with 12% of patients <65 years old.⁶³ The incidence of small bowel tumors as a cause of obscure GI bleeding was noted to be higher in patients <50 years of age (14%, compared with 3% in patients >50 years old), whereas the incidence of angiodysplasia increased with increasing age into the ninth decade.⁹⁸

Rare causes of obscure bleeding are difficult to separate from unusual causes of acute bleeding.⁹, ¹⁸⁰, ¹⁸¹ However, it is important to remember that any common cause of GI bleeding can fall into the obscure category if it is missed initially and then found upon evaluation of recurrent blood loss. Swallowed blood from hemoptysis, oropharyngeal bleeding, or epistaxis may also represent infrequent causes for obscure bleeding.⁹

Management 

Although the management of the primary disorder leading to occult or obscure bleeding can vary depending on the nature of the disorder, management of blood loss generally falls into the following categories: endoscopic therapy, angiographic therapy, pharmacotherapy, surgery, and nonspecific measures.

Endoscopic therapy 

Angiodysplasias, gastric antral vascular ectasia, vascular malformations in blue rubber bleb nevus syndrome, and hereditary hemorrhagic telangiectasia have been treated successfully using thermal contact probes, injection sclerotherapy, argon plasma coagulation, and neodymium:yttrium-aluminium-garnet (Nd:YAG) laser.¹⁸⁵, ¹⁸⁶, ¹⁸⁷, ¹⁸⁸ However, most angiodysplasias are not bleeding at the time of diagnosis,¹⁸⁹ and up to 50% of patients with angiodysplasia found upon investigation of GI bleeding do not have bleeding again over several years of follow-up.¹⁹⁰, ¹⁹¹ Nonbleeding angiodysplasia is also found in conjunction with other potential sources of bleeding.¹⁸⁹ These data should be considered in analyzing reported success rates of endoscopic therapy of angiodysplasia. Endoscopic cauterization of bleeding angiodysplasia found on enteroscopy has been shown to decrease the requirement for blood transfusions significantly compared with no treatment.¹⁹² In another study, 11 transfusion-dependent patients with small bowel angiodysplasia were successfully treated with heater probe ablation and had significant increases in hemoglobin levels; only 2 patients remained transfusion-dependent after therapy.¹⁹³ To reduce treatment-induced bleeding, it is recommended that large angiodysplasia be initially treated around their circumference to obliterate feeder vessels.¹⁷² In a trial using the Nd:YAG laser, sustained reduction of transfusion requirements was found in 100% of patients with angiodysplasia, 75% with gastric antral vascular ectasia, and 66% with hereditary hemorrhagic telangiectasia.¹⁹⁴ Other studies have reported rebleeding rates of 13%-26% over 1 year of follow-up with the use of Nd:YAG laser for angiodysplasia ablation.¹⁸⁶, ¹⁹⁵ Slightly higher rebleeding rates (up to 34%) have been reported with the use of thermal contact devices.¹⁹⁶, ¹⁹⁷

Angiotherapy 

The number of patients successfully treated with vasopressin infusion or embolization for obscure-overt small bowel bleeding is limited and is reported as part of larger series involving transcatheter treatment of small bowel and colonic sources of acute bleeding. In one small series of patients with acute bleeding, transcatheter vasopressin infusion at angiography was effective for small bowel as well as colonic bleeding sources.¹⁹⁸ Other investigators have reported successful embolization of small bowel bleeding sources at angiography.¹⁹⁸, ¹⁹⁹, ²⁰⁰ Methylene blue dye injection into the bleeding artery at angiography stains the mucosa of the small bowel and can be helpful in directing the surgeon to the appropriate bleeding segment.¹⁶¹, ¹⁶⁷

Angiotherapy is not without complications that are sometimes serious and life threatening. Major cardiovascular complications have been noted in 9%-21% of patients receiving intra-arterial vasopressin, including myocardial infarction, arrhythmias, hypertension, and thrombosis of arteries remote from the bleeding site.²⁰⁰, ²⁰¹, ²⁰² Fatal myocardial infarction has been reported as a complication of intra-arterial vasopressin administration.²⁰³ Complications with embolization were noted in 17% of patients in one series, including ileus, intestinal infarction requiring surgical resection, fistulization between bowel segments, and arterial thrombosis.²⁰⁰ Ischemic complications have been reported less often when embolization is performed for small bowel or gastroduodenal bleeding than when it is performed for colonic bleeding.²⁰⁴, ²⁰⁵ This difference is thought to result from the relatively sparse collateral circulation in the colon.²⁰⁴, ²⁰⁵ Embolization may have utility in patients with coronary artery disease or other disorders wherein vasopressin infusion is relatively contraindicated or as an alternative to surgery in patients with significant comorbid conditions.²⁰⁴

Pharmacotherapy 

Medical therapy for vascular lesions causing obscure GI bleeding is usually reserved for diffuse disease, for lesions in areas inaccessible to endoscopic therapy, when there is continued bleeding despite endoscopic therapy or surgical resection, or when bleeding is recurrent, the diagnosis is unknown, and vascular lesions are suspected. In uncontrolled open-label studies, patients with chronic renal failure and GI bleeding caused by angiodysplasia are reported to benefit from estrogen-progesterone combination therapy.²⁰⁶ In a double-blind, randomized, cross-over trial, 6 of 8 patients with hereditary hemorrhagic telangiectasia and von Willibrandt's disease stopped bleeding during the hormonal therapy arm.²⁰⁷ However, in a cohort study of patients with small bowel angiodysplasia, treatment with combination hormonal therapy did not alter transfusion requirements or rebleeding rates compared with untreated controls.²⁰⁸, ²⁰⁹ More recently, in a group of patients with persistent or recurrent obscure bleeding despite comprehensive endoscopic investigation, treatment with combination hormonal therapy stopped rebleeding in all patients as long as therapy was continued, a benefit not demonstrated with estrogen therapy alone.²¹⁰ Only 58% of the patients had angiodysplasia identified on enteroscopy. Endoscopic cauterization of angiodysplasia had no influence on the rebleeding rate.²¹⁰ Although low-estrogen combination therapy (ethinyl estradiol, 0.035 mg, in combination with norethisterone, 1 mg) has been reported to be effective, a higher-estrogen combination (containing 0.05 mg ethinyl estradiol) may be required in subjects who do not respond to the lower-dose combination.²¹¹ Some investigators recommend 6-month courses of therapy with treatment pauses to reduce the incidence of adverse effects.²¹² Reported adverse effects include breast tenderness and vaginal bleeding in women and gynecomastia and loss of libido in men. In one series, up to 57% of patients reported adverse effects; these effects necessitated cessation of therapy in 40%.²⁰⁹ Few data are available on cardiovascular complications in patients with obscure bleeding who are receiving hormonal treatment. Although the potential risk of thromboembolic events exists, one study found no difference in mortality from cardiovascular diseases between treatment and control groups.²⁰⁹

Octreotide, in a dose of 0.05-0.1 mg subcutaneously two to three times a day, has been reported to reduce blood loss from intestinal angiodysplasia.²¹³, ²¹⁴ Response is reputedly fast, with disappearance of overt bleeding and improvement in transfusion requirements as early as 24 hours after initiation of therapy. In one instance, bleeding recurred when therapy was discontinued after 6 months.²¹⁴, ²¹⁵ No significant adverse effects other than mild hyperglycemia were noted. Although the exact mechanism of action is unknown, reduction in splanchnic blood flow is thought to play an important role.²¹³ Other hypotheses suggest an inhibiting role of somatostatin analogues on angiogenesis.²¹²

Other pharmacotherapeutic agents that have been used with partial success in epistaxis and GI bleeding from hereditary hemorrhagic telangiectasia include danazol (antigonadotrophin with weak androgenic activity)²¹⁶, ²¹⁷ and desmopressin.²¹⁸ Anecdotal reports suggest improvement in transfusion requirements with danazol but not with desmopressin in patients with diffuse angiodysplasia unresponsive to combination hormone therapy.²¹² Aminocaproic acid, an inhibitor of the fibrinolytic system, was reported to be effective in 2 patients with hereditary hemorrhagic telangiectasia and epistaxis, although it is not certain whether these patients had concomitant GI bleeding.²¹⁹

Surgery 

Most bleeding tumors will warrant surgical excision, and most other causes of obscure bleeding have the potential to require surgery if nonsurgical measures are ineffective for control of bleeding. Surgical exploration and subsequent bowel resection may also be necessary when bleeding is associated with high transfusion requirements. When patients present with exsanguinating GI bleeding, emergency surgery may be lifesaving. Simple bowel palpation and transillumination have traditionally enabled surgeons to identify culprit lesions requiring resection in up to 65% of patients undergoing exploratory surgery for obscure bleeding.¹⁶ Intraoperative enteroscopy has added a new dimension to the surgical localization of obscure GI blood loss, and small bowel resections are generally associated with preoperative or concomitant localization of the bleeding source.¹², ¹⁵, ¹¹⁴ In one series of 30 patients undergoing IOE, the findings directed surgical resection in all but 2 patients¹²; other studies have reported similar good results (Table 4). However, even surgical resection can be associated with rebleeding in up to 30% of patients.¹², ¹¹⁵ This probably reflects the multicentric nature of mucosal-based lesions such as angiodysplasia and again raises the question of whether the nonbleeding lesion found and resected was the source of bleeding. The lowest rebleeding rates after segmental bowel resection for bleeding angiodysplasia have been reported in instances in which angiographic localization of the bleeding source assisted resection.¹⁵³, ¹⁹⁶, ²²⁰

In reports addressing massive lower intestinal bleeding, blind total colectomy (i.e., without preoperative localization) has been associated with mortality rates up to 33%,²²¹, ²²² and blind limited resection has been associated with rates up to 57%.²²⁰, ²²³ Only 25% of patients subjected to blind total abdominal colectomy survived without complications in one series.²²² However, other surgical reports have noted lower mortality (5%-10%) and morbidity (<10%) rates for both total and limited colonic resection.¹²⁰, ¹²⁴, ¹⁵³ These differences may be related to the urgency of the clinical setting. An aggressive approach to preoperative localization of bleeding should be pursued in hopes of treating the lesion and avoiding the high morbidity and mortality rates of blind surgical resection performed in desperation.¹⁸⁰

Nonspecific measures 

Nonspecific measures used in the management of occult and obscure bleeding include iron supplementation, correction of coagulation and platelet abnormalities, and intermittent blood transfusions if the anemia cannot be controlled with iron supplementation alone. Little information is available on how often nonspecific measures are required or on their efficacy.⁵ When patients with bleeding GI angiodysplasia were treated with observation alone or intermittent transfusions, 54% had no rebleeding episodes during a 3-year follow-up period,¹⁹⁶ suggesting that nonspecific measures alone are sufficient in some instances. These measures are beneficial when the rate of blood loss is slow and in elderly patients in whom the risk of further diagnostic evaluation is greater than the risk of nonspecific management.

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Outcomes 

In assessing the outcomes of acute GI bleeding, the usual parameters analyzed include hospital mortality, length of hospital and intensive care unit stay, cost-effectiveness and utility of diagnostic and therapeutic procedures, success of therapy in prevention of recurrence of bleeding, transfusion requirements, and need for repeat hospitalization.

Many of these outcome measures do not apply to occult bleeding. The overall prognosis in occult bleeding is generally good, with no early mortality noted in multiple prospective studies.³, ⁴, ⁵, ⁶, ⁷ The long-term outcome will depend on diagnostic findings such as colon cancer. In addition, these patients are most often evaluated on a nonemergent basis in an outpatient setting. Other outcome measures need to be considered for occult bleeding. Can the physician optimally predict which endoscopic procedure (upper endoscopy or colonoscopy) will be necessary to make a diagnosis? If the first procedure is negative, is it necessary to perform endoscopy in the other direction? The protocols for bidirectional endoscopy were developed as investigational tools and are not meant to imply that both colonoscopy and upper endoscopy are necessary in all cases of occult bleeding. Although these studies showed that the upper GI tract can be a source of occult bleeding, they did not randomize the procedure sequence.³, ⁴, ⁵, ⁶, ⁷ Findings on upper endoscopy have resulted in a change in treatment in 29%–49% of patients with occult bleeding.³, ⁴ These management changes include endoscopic ablation of potential bleeding lesions, institution of antisecretory or combination hormone therapy, discontinuation of NSAID therapy, and surgery for neoplastic disease.³, ⁴

Obscure bleeding also has outcome measures that are unique from those for acute and occult bleeding. The time from disease onset to diagnosis may be much longer, adding to the costs incurred in making the diagnosis. In one study, the median time to diagnosis of obscure-overt bleeding was 2 years, with a range of 1 month to 8 years.¹⁸ More than 50% of patients with obscure bleeding have had at least two bleeding episodes before presentation for enteroscopy.⁶⁸ When enteroscopy is performed after a previous negative upper endoscopy result, 28%–75% of patients have lesions within reach of an upper endoscope diagnosed.⁶², ⁶³, ⁶⁵, ⁶⁶, ⁶⁷ Using Medicare reimbursement figures from 1997, an estimated cost savings of $187 per patient is anticipated if repeat upper endoscopy is replaced by enteroscopy.²²⁵ Although some patients with obscure-occult bleeding may undergo outpatient evaluation, obscure bleeding may necessitate hospital admission and transfusions. One study of patients with obscure bleeding that required IOE noted a mean of 5 hospital admissions (range, 2-20) and a mean of 46 units of blood transfused (range, 6-200) before surgical intervention.¹¹⁴ No longitudinal studies have addressed the relative costs of diagnostic evaluation of obscure bleeding compared with occult or acute bleeding.

Enteroscopy with endoscopic ablation of angiodysplasia has been reported to significantly improve the hemoglobin levels over long-term follow-up of patients with obscure bleeding.¹⁹³ Significant decreases in transfusion requirements (13 ± 6 units before lesion ablation vs. 6. ± 3 units in the year after ablation; P= 0.02) have also been reported by other investigators.⁶⁷ This has been associated with improvement in quality of life, as measured by a standardized questionnaire.⁶⁷ Pharmacotherapy with combination hormone therapy has also improved outcomes in selected patients with severe undiagnosed obscure bleeding, regardless of whether or not angiodysplasia has been found or endoscopically ablated.²¹⁰ Other studies suggest that rebleeding rates are not much different whether endoscopic ablation, pharmacological treatment, or no therapeutic intervention is pursued.⁸⁶, ²⁰⁸

The outcomes of surgery for obscure bleeding are variable and probably depend on whether a bleeding source is discovered and resected at exploratory laparotomy. Intraoperative enteroscopy is reported to influence the type of surgery performed in >70% of cases, but over a 2-year follow-up, 20%–52% of patients can develop rebleeding that necessitates transfusions.¹², ¹⁵, ¹¹⁴ The long-term success rate of IOE-directed therapy in eliminating recurrent GI blood loss has ranged from 41% to 71%.¹⁵, ⁹⁹, ¹¹⁴, ¹¹⁵

There appears to be no single efficient diagnostic approach or therapeutic panacea in the management of obscure bleeding. Most patients will benefit from a meticulous investigation routine that attempts to visualize as much of the bowel as necessary.²²⁶ For some, this will entail multiple diagnostic procedures and eventually exploratory laparotomy. In other cases, the risks of further diagnostic procedures may be higher than the risks of nonspecific therapy with iron supplementation and intermittent blood transfusions. Further outcome studies are needed to determine the most expedient diagnostic approach and optimal management strategies.

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210. Barkin JS, Ross BS. Medical therapy for chronic gastrointestinal bleeding of obscure origin. Am J Gastroenterol. 1998;93:1250–1254
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211. van Cutsem E, Rutgeerts P, Coremans G, Vantrappen G. Dose-response study of hormonal therapy in bleeding gastrointestinal malformations. (abstr) Gastroenterology. 1993;104:A286
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212. van Cutsem E, Pissevaux H. Pharmacologic therapy of arteriovenous malformations. Gastrointest Endosc Clin North Am. 1996;6:819–832
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213. Rossini FP, Arrigoni A, Pennazio O. Octreotide in the treatment of bleeding due to angiodysplasia of the small intestine. Am J Gastroenterol. 1993;88:1424–1427
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214. Torsoli A, Annibale B, Viscardi A, Dellafave G. Treatment of bleeding due to diffuse angiodysplasia of the small intestine with somatostatine analogue. Eur J Gastroenterol Hepatol. 1991;3:785–787
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215. Piesseroux M, Conemans G, Rutgeerts P, van Cutsem E. Octreotide in the treatment of bleeding gastrointestinal vascular malformations. (abstr) Gastroenterology. 1996;110:A353
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216. Haq AU, Glass J, Netchvolodoff CV, et al.  Hereditary hemorrhagic telantiectasia and danazol. (letter) Ann Intern Med. 1988;109:171
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217. Korzenik J, Topazian M, Burdge C, White RI. Danazol in the treatment of GI hemorrhage secondary to hereditary hemorrhagic telangiectasia. (abstr) Gastroenterology. 1995;108:A297
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218. Quit M, Froom P, Veisler A, et al.  The effect of desmopressin on massive gastrointestinal bleeding in hereditary hemorrhagic telangiectasia unresponsive to treatment with cryoprecipitate. Arch Intern Med. 1990;150:1744–1746
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220. Parkes BM, Obeid FN, Sorenson VJ, Horst HM, Fath JJ. The management of massive lower gastrointestinal bleeding. Am Surg. 1993;59:676–678
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221. Bender JS, Weincek RG, Bouman DL. Morbidity and mortality following total abdominal colectomy for massive lower gastrointestinal bleeding. Am Surg. 1991;57:536–541
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222. Setya V, Singer JA, Minken SL. Subtotal colectomy as a last resort for unrelenting, unlocalized, lower gastrointestinal hemorrhage: experience with 12. cases. Am Surg. 1992;58:295–299
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223. Drapanas T, Pennington G, Kappelman M, Lindsey E. Emergency subtotal colectomy: preferred approach to management of massively bleeding diverticular disease. Ann Surg. 1973;177:519–526
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224. Baker R, Senagore a. Abdominal colectomy offers safe management for massive lower GI bleed. Am Surg. 1994;60:578–582
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225. Chak A, Cooper GS, Canto MI, Pollack BJ, Sivak MV. Enteroscopy for the initial evaluation of iron deficiency. Gastrointest Endosc. 1998;47:144–148
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226. American Gastroenterological Association medical position statement: evaluation and management of occult and obscure gastrointestinal bleeding. Gastroenterology. 2000;118:197–200
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• * *Although this report is not meant to be an exhaustive listing of all the articles that deal with these issues, it uses appropriate studies to analyze occult and obscure bleeding. The studies referenced were identified by literature searches of articles published in English-language peer-reviewed journals, using relevant search terminology reflecting occult and obscure gastrointestinal bleeding and the various procedures performed to evaluate these conditions.