Unexplained Gastrointestinal Bleeding is part of a series discussing the use of gastrointestinal endoscopy in common clinical situations. Provided by the American Society for Gastrointestinal Endoscopy. In writing this guideline, a number of expert-recommended articles were consulted in addition to those retrieved from MEDLINE. The guidelines for the rational use of endoscopy are based on a number of important current reviews and expert consensus. A large number of controlled clinical studies are needed to determine and revise them as necessary. Appropriate adjustments should be made when clinical reality differs from the guidelines.
Introduction
Unexplained gastrointestinal bleeding (OGIB) is defined as persistent or recurrent bleeding of unknown origin that is negative on gastrointestinal endoscopy (including colonoscopy and/or upper gastrointestinal endoscopy). Information on OGIB (including its prognosis and clinical outcome) is scarce; therefore, there is no effective treatment for this group of patients.
It is estimated that approximately 5% of unexplained GI bleeding occurs between the Treitz ligament and the ileocecal valve. 30-40% occurs from small bowel vascular abnormalities. It occurs mainly in the elderly. in patients between 30 and 50 years of age, tumors are the main cause, such as smooth muscle tumors, carcinoid tumors, lymphomas and adenocarcinomas, and in younger patients mainly ulcers associated with Meckel’s diverticulum. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be associated with erosions, ulcers and strictures of the rectum and, therefore, may also be a potential factor in OGIB.Other rare causes of OGIB include pancreatic hemorrhagic disease, round nematode like infection, radiotherapy of the pelvis [10], elastic fibrous pseudoxanthoma, and Dieulafory injury.
OGIB is divided into two major categories, occult and overt, the former presenting with recurrent episodes of iron deficiency anemia and positive fecal occult blood. The latter presents with recurrent episodes of bleeding visible to the naked eye, such as black stools and bloody stools. Before evaluating small bowel bleeding, upper and lower GI endoscopy should be repeated, as the first endoscopy has a high rate of missed diagnoses. Upper GI endoscopy is prone to misses such as Cameron erosion, peptic ulcers, and vascular lesions. Colorectal microscopy should be performed to rule out easily missed colonic lesions and developing occult ileal lesions, including vasodilatation and abnormal neoplasia.
1. Diagnostic tests
1.1 Upper gastrointestinal endoscopy, namely esophagogastroduodenoscopy (EGD), is performed as a preliminary test for suspected upper gastrointestinal bleeding. If the initial EGD is negative, the test can be repeated to improve the positive rate. Studies have shown that 64% of the lesions detected by propulsive small bowel microscopy are detectable by conventional endoscopy [13]. repeat EGD before small bowel microscopy in patients with OGIB, which has been studied to increase the positive rate of EGD, including patients with intestinal hernias and those with a history of NSAID. If a patient with GI bleeding has developed iron deficiency anemia (IDA), a small bowel biopsy must be performed at the time of EGD, although there are conflicting reports on small bowel biopsy in such patients.
1.2 Propulsive enteroscopy (PE) PE is performed using a long endoscope inserted through the mouth into the jejunal cavity to examine large lesions in the small intestine, especially in patients with OGIB. the diagnostic rate of PE can reach 40-65% [13,16,20]. the advantage of PE is that it allows not only diagnostic examination but also interventional treatment. Biopsy of the lesion can be performed and electrocoagulation can be used to stop bleeding when bleeding spots are found. A prospective trial comparing the diagnostic value of PE with EGD after conventional colonoscopy for diagnosing IDA found that PE could increase the diagnostic rate from 41% to 67% with relatively little cost. A retrospective study suggested PE screening with positive results in 78% of patients and improved clinical outcomes in terms of hospital days and transfusions.
A study showed a higher diagnostic value of PE than barium whole small bowel angiography (SBFT) in patients with OGIB [23]. The study showed that PE improved treatment outcomes in 40-73% of patients. A retrospective survey of 83 patients with occult OGIB showed a PE diagnosis rate of 59% [24]. PE is a common lesion and is usually given with bipolar electrocoagulation and hormonal therapy, with long-term clinical follow-up (mean follow-up 12.2 mo) suggesting a better outcome of 50%. However, PE application reduces blood transfusion and improves quality of life.
The probing enteroscope (SE) is an endoscope approximately 270-400 cm long, inserted using the normal peristalsis of the small intestine. This examination technique is demanding and not commonly used because its operation takes too long to treat or biopsy the lesion even if it is found.
1.3 Capsule endoscopy (CE) Wireless video-based capsule endoscopy is a new technique that allows the endoscopic detection of small bowel lesions. These capsules are 26.4 mm long and 11 mm in diameter and are taken after an 8 h fast, with small bowel peristalsis propelling the capsule forward. The capsule consists of a lens, a light source, a CMOS chip (complementary metal oxide semiconductor chip, required for imaging), a battery and a transmitting device. The information is sent at a rate of 2/s to a recording device strapped to the belt and then downloaded to a computer workstation where one can view it on a computer with the appropriate software [29]. This new technology could be useful in the diagnosis of OGIB and IDA [30,31]. Some earlier studies showed high diagnostic yield of OGIB for small bowel diseases, superior to PE and SBFT.
It has also been suggested that CE can be used as a complement to PE, as gastroesophageal lesions still have a greater rate of missed diagnoses. The disadvantage of CE is that it does not allow for treatment and precise localization of the lesion. The capsule may become lodged and require surgical removal, and caution should be exercised when using it in patients who may have obstructive lesions, strictures, dysphagia, or a history of abdominal surgery [38]. A controlled study of the small bowel prior to CE is recommended to rule out obstructive lesions, although it remains unclear whether this will reduce complications of CE examination. More in-depth studies are needed to clarify the role of CE on OGIB and its impact on clinical outcomes.
2.Radiology
2.1 Controlled radiographic studies of the small bowel SBFT has been used as a screening test for potential sources of bleeding sites in the small bowel. A comparative study of SBFT and PE concluded that the diagnostic rate of PE was high in the evaluation of OGIB. the diagnostic rate of SBFT for OGIB ranged from 0-5.6% [40,41]. Compared to SBFT, enucleation allows for better detailed visualization of the small bowel. Better results can be obtained by inserting a nasal intestinal tube in the proximal small intestine and instilling a contrast agent.
A retrospective study of 128 patients with OGIB found that this method had a 21% diagnostic yield in identifying obvious or highly suspected injuries, 13% of which were small bowel tumors. Another study showed a lower overall diagnostic rate although one group of patients had an improved diagnostic rate with definitive esophagogastroduodenoscopy and colonoscopy. Most studies have shown a higher diagnostic rate with the enema method than with SBFT. For detection of vasodilation, the diagnostic rate of the enema method was lower. In patients with negative PE, the enema method can identify bleeding sites in 8% of these patients. However, significant patient discomfort may limit the use of this method in clinical practice.
2.2 Nuclear scans Patients with overt OGIB may benefit from a radioisotope scan if the bleeding rate remains between 0.1 and 0.4 mL/min. Tc99m-labeled red blood cell scans are most commonly used. This method is most often used in patients with active bleeding when the bleeding site cannot be identified by routine esophagogastroduodenoscopy and colonoscopy. The scan allows localization of the bleeding site, which can then be verified by endoscopy or angiography and can also be used to guide surgical treatment.
Although a relatively sensitive test, nuclear medicine scans can only identify an approximate area of bleeding and have limitations in guiding treatment. In a study evaluating a Tc99m-labeled erythrocyte scintigraphy, bleeding could not be localized in 85% of cases and could not be adequately angiographed. After proper setup, Meckel’s scan is also a better test for OGIB. It uses Tc99m-pertechnetate and has a sensitivity of 75-100%. However, a positive scan only shows the presence of gastric mucosa and not a definite bleeding site.
2.3 Angiography In overt OGIB, angiography may also be helpful if the bleeding rate is greater than 0.5 mL/min. The bleeding appears as an active spill into the intestinal lumen. Unfortunately there are few useful data in OGIB. Although nuclear scanning should be technically more sensitive, angiography is likely to be more effective in localization [51]. In a study with 36 patients with visceral angiography, a 44% diagnostic rate was achieved. There were no false positives but three false negatives. There is evidence that if the initial angiography is negative, then a review is necessary [52]. Angiography is also used for embolization localization or pre-surgical examination. In patients who will undergo surgery, preoperative selective placement of an angiographic catheter through the combined use of methylene blue stain allows for more precise localization of the bleeding site so that the smallest amount of small bowel can be removed [53]. Angiography can be used to diagnose vasodilatation and tumor tissue without bleeding.
Spiral CT imaging is a newer technique. It inserts a catheter into the abdominal aorta and then injects a contrast agent to develop the image. If the contrast extravasates to form a large high-density area in the intestinal lumen, the location of the hemorrhage can be localized. A study comparing spiral CT angiography with conventional angiography in 13 patients found that CT angiography was faster and easier in localizing OGIB and could guide subsequent selective conventional angiography.
2.4 Stimulation testing To avoid false-negative studies, the use of vasodilating drugs (e.g., tolazoline, nitroglycerin), anticoagulants (heparin), and fibrinolytic enzymes (urokinase, streptokinase) to induce bleeding during bleeding point scanning or angiography has been proposed. Some investigators have reported improved diagnostic rates [55], while others have found that the effect is not significant and can lead to cost-effectiveness and safety concerns as a result.
3. Surgery
Intraoperative endoscopy (IOE) via dissection is routinely used as a last resort in patients with OGIB requiring massive blood transfusions and/or repeated hospitalizations [58]. Intraoperative endoscopy can be performed through the mouth, rectum, or by performing an enterostomy. There is no controlled trial that can be used to compare this method with other OGIB detection methods, but it appears that this method is not only safe but also effective. An early study with 44 patients showed that IOE detected 70% of bleeding sites, although the treatment effect was only 41% [60]. One study showed an 82% success rate when combined with other localization tests [61]. A study evaluating 12 patients found that the terminal colon was reached in 93% of cases and had a roughly 58% diagnostic rate. A recent report with 25 cases found that IOE detected lesions in 16 of 20 of these patients with unexplained preoperative bleeding, with a 30% bleeding rate at a mean follow-up of 19 mo.
4. Diagnostic methods
In patients with occult OGIB, if no lesion is detected by repeated esophagogastroduodenoscopy and colonoscopy and there is recurrent anemia regardless of iron supplementation, further small bowel examination is necessary. Methods include CE, PE, or barium radiography (SBFT or enema method). How these tests are selected and how they are sequenced remains uncertain at this time. If these tests are negative, then further testing will need to be weighed against the merits. If repeated hospitalizations or transfusions are clinically indicated for further testing, angiography and/or intraoperative endoscopy must be considered.
In the case of overt OGIB, if the patient does not have active bleeding at the time of testing, the same steps should be taken as described above for occult OGIB. If the patient has active bleeding, then the EGD, PE, and/or colonoscopy should be repeated. If the results are negative, the next step should be to consider nuclear scan, angiography, and/or CE based on the rate and utility of bleeding. young patients should especially consider Meckel’s scan. If bleeding continues, a repeat angiogram or IOE should be considered.
5. Therapeutic measures
The treatment of OGIB relies on etiology. If the diagnosis is confirmed as a tumor, surgical resection is recommended. Vasodilation can be treated by endoscopic electrocautery or argon plasma coagulation, provided the lesion is within reach of the endoscope. There is evidence of a positive effect of reduced blood loss and transfusion on clinical outcome. If vasodilation is widespread in the gastrointestinal tract, medical therapy includes appropriate iron supplementation (oral or parenteral), blood transfusion, or hormonal therapy. Prospective longitudinal observational studies have shown estrogen/progesterone therapy to be effective. However, a recent multichannel randomized trial found no significant effect of hormone therapy. Octreotide showed some effect, but has not been extensively studied [69].
In conclusion, observational studies have shown that OGIB includes about 5% of gastrointestinal bleeding, with the majority of lesions located in the small intestine, which usually includes vasodilatation, tumors, NSAID intestinal lesions, and Meckel-associated ulcers. Experts believe that OGIB can be either occult bleeding, which presents as iron deficiency anemia, or overt bleeding, which presents as black stools or blood in the stool. A small bowel examination is necessary when it remains negative after careful repeat EGD and colonoscopy to the terminal ileum.
Diagnostic tests include PE, CE, barium examination (SBFT or enema), nuclear medicine testing, angiography, and intraoperative endoscopy. Although a large number of comparative studies are lacking, prospective controlled trials have demonstrated that PE examination is superior to EGD and SBFT, and CE is equally superior to SBFT and may be similar to PE. Experts believe that the choice of these examinations has not been established and needs to be made by clinical situation, feasibility and clinician. Intraoperative endoscopy is the last option for patients with recurrent episodes of severe bleeding requiring transfusion therapy or lesions that cannot be treated with PE or enteroscopy. Once the diagnosis is established, the choice of treatment is yet to be individualized.