The most common indication for CE and deep enteroscopy is the evaluation of suspected small bowel bleeding. Obscure gastrointestinal bleeding (OGIB) is persistent bleeding from the gastrointestinal tract after negative esophagogastroduodenoscopy, colonoscopy, and small bowel radiologic test. It can be either overt (visible bleeding) or occult (iron-deficiency anemia without visible bleeding) [9]. The differential diagnosis is quite extensive and includes vascular, inflammatory, and neoplastic lesions, as well as hemobilia, hemosuccus pancreaticus, and vasculitis.

The diagnosis may be straightforward, as in the patient with multiple, bleeding, arteriovenous malformations or an ulcerated mass seen on capsule endoscopy. However, of all indications for evaluating the small bowel, obscure gastrointestinal bleeding can also be the most challenging because lesions can be located anywhere throughout the small bowel and, in the case of certain vascular lesions, may be difficult to identify when they are not bleeding. Lesions may be missed due to patient conditions (e.g., hypotension), the fleeting nature of the lesion (e.g., Dieulafoy), or human error. Lesions include, in order of decreasing prevalence, angiodysplasia, ulcer, varices, bleeding polyp, tumor, and other rare causes [10].

While many lesions are ultimately found in the distal small bowel, a significant amount can be located in regions accessible with standard endoscopes [11]. As such, this bleeding can be caused by lesions proximal to the ligament of Treitz or in the colon that were missed on initial endoscopic evaluation. Thus, second-look endoscopy is recommended prior to embarking on an extensive small bowel evaluation. It is also important to rule out other causes of anemia such as bone marrow diseases and malabsorption, before concluding that the cause is gastrointestinal bleeding. Once gastrointestinal bleeding has been documented or iron-deficiency anemia confirmed and malabsorption and hematologic causes have been excluded, and second-look endoscopy is negative, then one can proceed with a small bowel evaluation.

In most cases, Capsule endoscopy will be the next best test. Depending on results, deep enteroscopy may be indicated to follow up on suspicious lesions. Deep enteroscopy complements CE. One study showed that there is excellent concordance between deep enteroscopy and CE [12]. The results of CE can be used to identify a lesion and guide further management. Generally, if the lesion is present within the first 75 % of small bowel transit time, we use an antegrade approach, and otherwise use a retrograde approach. Cost-effectiveness models suggest that DBE is the most cost-effective approach for obscure overt gastrointestinal bleeding; however, CE-guided DBE may be associated with better long-term outcomes due to decreased risk for complications and appropriate resource utilization [13]. Cross-sectional imaging techniques including CT angiography and CT enterography can also be used to localize a source of bleeding with a diagnostic yield of 10–40 % [12, 13], which is lower than CE and deep enteroscopy. However, in difficult cases of OGIB, cross-sectional imaging, capsule endoscopy, and deep enteroscopy can be complementary. That is, complex cases will require all three modalities for diagnosis and treatment of the condition.

Tumors of the small bowel often present with OGIB. In the USA in 2014, cancers of the small intestine represented 0.5 % of total cancer cases and 0.2 % of cancer deaths [14]. Primary small bowel tumors comprise approximately 2–5 % of all primary gastrointestinal neoplasms [15, 16]. The most common malignant small intestine malignant neoplasms, in decreasing order of incidence, are carcinoid, adenocarcinoma, lymphoma, and stromal tumors [17].

Capsule endoscopy now plays an important role in the diagnosis and management of small bowel tumors. A meta-analysis found CE to be superior to push enteroscopy and small bowel follow through, in the setting of OGIB [4]. CE can provide initial diagnosis, estimated location, characteristics (size, shape, ulceration, etc.), and extent/number of mass lesions present. It can also be used for surveillance after polypectomy. However, CE can miss single-mass lesions in the small intestine at a rate approximating 19 % [18]. Factors that can affect the visualization in CE include rapid transit and poor/lack of preparation. In one study, most (74 %) missed lesions were located in the proximal small bowel [19]. Thus, CE and push enteroscopy may be complementary studies in this setting. CE is superior to MRE for evaluation of tumors in patients with Peutz-Jeghers syndrome (PJS) and familial adenomatous polyposis (FAP) [20, 21]. However, one study did suggest that MRE may be better at estimating the size of large polyps [22].

Deep enteroscopy also plays a role in the evaluation of small bowel tumors, particularly because of the ability to attain a tissue diagnosis. DBE has a diagnostic yield between 94 and 100 % for all small bowel tumors. Thus, this test may be helpful in cases where CE is negative but suspicion for a tumor remains high. It also has the advantage of being able to obtain a histopathologic diagnosis and, potentially, treat with polypectomy. However, DBE is more invasive and has a risk of perforation (1.3 %) and pancreatitis (0.6 %) [19].

At this time, there are limited evidence-based guidelines for small bowel imaging for suspected tumors. We suggest capsule endoscopy, in most cases, as the initial test of choice. It is suggested to perform CE prior to deep enteroscopy due to increased patient tolerance, ability to visualize the entire small intestine, and less invasive nature of the test. If a tumor is identified on CE, it can help direct the approach to deep enteroscopy. Thus these two tests work well together in the diagnosis and management of small bowel tumors.

Two polyposis syndromes with increased risk of small intestinal malignancy are PJS and FAP. In patients with PJS the risk ratio of small intestinal tumors is 520 [23], and thus some have recommended capsule endoscopy every 3 years starting at age 8 [24]. Most patients with FAP will have duodenal adenomas and it is estimated that they occur in 54–74 %. By age 75, >95 % of patients with FAP will have duodenal adenomas [25].

Regarding polyposis syndromes, there are limited studies on the benefits of CE, either for diagnosis or surveillance. Research in this area is limited mostly by the rarity of each condition. It has been suggested to screen patients with Peutz-Jeghers syndrome and others [26, 27], and can be justified in patients presenting with gastrointestinal bleeding. The role of deep enteroscopy in these patients is to sample and/or remove polyps. Deep enteroscopy can also be combined with surgery when very large polyps are identified.

Small bowel imaging can play an important role in the evaluation of patients with IBD with also have small bowel involvement. The diagnosis of IBD, particularly Crohn’s disease, can be challenging because there is no single gold standard test. The disease involves the small bowel in approximately 70 % of patients and up to 30 % of patients have disease confined to the small bowel, usually the distal ileum [28]. Furthermore, even when the disease is not confined to the small intestine, involvement of this part of the GI tract can confer a worst prognosis and higher likelihood of recurrence [29]. In a subgroup of patients, identification of small bowel inflammation proximal to the terminal ileum can be difficult. Cross-sectional imaging has become popular for evaluation and monitoring of Crohn’s disease due to its noninvasive nature and relative ease of use (especially when compared to deep enteroscopy). The role of CE and deep enteroscopy in this area remains controversial and has yet to be determined. Notably, cross-sectional imaging is helpful in assessing transmural inflammation and fistulae; however, it probably does not assess mucosal disease as well as CE and deep enteroscopy.

Capsule endoscopy can be used to evaluate the small bowel, particularly when colonoscopy with ileoscopy is negative. The advent of capsule technology has facilitated the evaluation of suspected CD, allowing for a more thorough assessment of the mucosa. The technology appears to have additional diagnostic yield of up to 70 % for CD isolated to the small bowel following a negative ileocolonoscopy. CE has the potential to be used not only in the diagnosis of IBD, but also in assessing the severity and extent of disease, postsurgical recurrence, and, perhaps, response to therapy. Findings of aphthous ulcers, fissuring ulcers, granularity, loss of vascular patter, and mucosal edema are similar on CE as on traditional endoscopy.

Capsule endoscopy may also be of benefit in patients with established CD. It may be complementary to ileocolonoscopy and upper endoscopy and has been shown to affect medical and surgical decision making [30]. In particular, CE may be useful in assessing the extent and severity of small bowel inflammation, particularly in patients with unexplained symptoms. In addition, CE may be useful for assessing mucosal healing once therapy has been initiated. There are studies to suggest that it may play a role in the evaluation of postoperative recurrence when ileocolonoscopy is not successful or needs to be avoided [29]. Finally, CE may be of value in assessing indeterminate colitis and reclassifying a subgroup as CD.

There are definite concerns and unanswered issues with CE in CD. The risk of capsule retention, due to stricturing disease, is higher in patients with known Crohn’s disease, and in one study was reported to be 13 % [31]. Although CE has a high sensitivity (83–93 %), it has a low specificity (53–84 %) for diagnosing small bowel Crohn’s disease [32, 33]. Furthermore, it remains to be seen whether or not CE is cost effective in the diagnosis of Crohn’s disease [34].

The role of deep enteroscopy in IBD is less clear due to limited randomized controlled trials assessing the utility of this modality for CD. Deep enteroscopy has the advantage of obtaining tissue samples and being able to perform therapeutic interventions such as stricture dilatation. Histological evaluation can be particularly helpful in confirming active IBD, both for initial diagnosis and monitoring of IBD. Regarding the diagnostic yield, a meta-analysis of 11 studies comparing CE and DBE showed that they were comparable for small bowel disease, including inflammatory lesions [12]. However, DBE is more invasive and should be reserved for cases where CE is contraindicated, to obtain a tissue diagnosis after a positive study, to perform endotherapy, or to retrieve a retained capsule.

In contrast to obscure gastrointestinal bleeding, radiologic imaging can be particularly useful in the assessment of patients with CD. On cross-sectional imaging, transmural inflammation manifests as bowel wall thickening and enhancement. Both magnetic resonance enterography (MRE) and computed tomography enterography (CTE) have a good accuracy (0.86–0.93) compared to endoscopic evaluation with a sensitivity (0.81–0.90) and specificity (0.88–1.0) for assessing disease activity by bowel wall thickening and enhancement [35]. However, both CTE and MRE lack the ability to visualize the mucosa and false-positive results can be seen if the bowel is under-distended.

In the majority of cases, ileocolonoscopy is the first test of choice in the assessment of patients with CD. However, it is reasonable to evaluate the small bowel, with either cross-sectional imaging or CE when suspicion of CD is high despite negative ileocolonoscopy. These new methods for evaluating the small bowel disease can assist clinicians in making a more timely and accurate diagnosis in patients with IBD, and can assist in determining prognosis and likelihood of recurrence. Armed with this information, the clinician can make better recommendations for treatment. Then, these methods can be used for monitoring response to treatment or disease recurrence.

The exact role of small bowel imaging in celiac disease is evolving. Celiac disease is an immune reaction to eating gluten manifesting as inflammation of the small intestine that affects 1 % of the white American population [36]. Other enteropathies include autoimmune, hypogammaglobulinemic sprue and drug-induced (e.g., olmesartan). Typically, patients present with chronic diarrhea, postprandial abdominal pain, bloating, and weight loss. For diagnosis of celiac disease, initial testing with serology (i.e., tissue transglutaminase antibodies) is followed by duodenal biopsies. Macroscopically, enteropathy appears as villous atrophy, nodularity, fissures, scalloping, layered or stacked folds, and a mosaic appearance of the mucosa [37, 38]. Duodenal biopsies show intraepithelial lymphocytes, crypt hyperplasia, and/or villous atrophy.

Although histology is the gold standard for diagnosing celiac disease, CE may play a role in evaluating those patients with positive serology and negative histology, for patients unwilling or unable to undergo upper endoscopy, and for complicated or refractory celiac disease. In patients who are symptomatic despite a gluten-free diet, especially if they have alarm symptoms such as weight loss, fever, and pain, up to 60 % may have evidence of ongoing villous atrophy, ulcers or erosions, or cancer [39–41]. Capsule endoscopy has a sensitivity of 89 % and specificity of 95 % for detecting enteropathy [42].

Deep enteroscopy techniques may also be useful in patients with refractory or complicated celiac disease. In one study of 21 patients who were symptomatic and had villous flattening on duodenal biopsies despite maintaining a strict gluten-free diet, referred for double-balloon enteroscopy, 5 patients were diagnosed with enteropathy-associated T cell lymphoma (EATL) and 2 with ulcerative jejunitis. CT scan of these patients only detected EATL in four patients and did not detect ulcerative jejunitis in any. The authors conclude that deep enteroscopy should be reserved for patients with refractory celiac disease or those with a history of EATL [43]. In another study of 12 patients with unexplained malabsorption, double-balloon enteroscopy with small bowel biopsies yielded a diagnosis in 8 patients (including amyloidosis and Crohn’s disease) even though duodenal biopsies were normal [44].

The role of radiologic evaluation is limited. Small bowel barium studies may show decreased jejunal folds, jejunal dilation, increased ileal fold thickness, and intussusceptions; however, this cannot reliably differentiate celiac disease or malabsorption from irritable bowel syndrome [45]. MRE, enteroclysis, and CTE, in contrast, can be useful in evaluating complicated celiac disease (malignancy, ulceration) [46].