Introduction  

The length and tortuous nature of the small intestine has constituted a considerable challenge for endoscopic practice. However, certain techniques are now well established. Three methods have dominated the field since the first enteroscopes were developed more than 30 years ago.

• Sonde enteroscopy (a thin floppy scope with a balloon tip)
  
• Push enteroscopy (a long standard endoscope)
  
• Intraoperative enteroscopy (endoscopy during surgery)
  

Recently, the field has been revolutionized by the development of wireless capsule endoscopy.

We here review technical developments, diagnostic results, and the outcomes of therapeutic interventions, particularly in patients with obscure gastrointestinal bleeding. Important new information on the clinical application and early results for capsule endoscopy are now available, and are certain to stimulate further research in this dynamic field.

 Techniques   

Sonde enteroscopy   

The Sonde endoscopy method is now mainly of historical interest, but it is worth reviewing, not least because there are important lessons for gastroenterologists now working with the capsule.

The sonde enteroscope is long (2.7 m), and thin (0.5 cm in diameter), with an inflatable balloon at the tip [1–4]. It is usually passed through the nose, and advances by the passive propulsive effects of small bowel peristalsis (Fig. 1). The jejunum and ileum are examined on withdrawal, but the method has significant problems. It takes several hours, and is often poorly tolerated. Visualization is limited due to lack of tip deflection, and the uncontrolled nature of withdrawal results in incomplete visualization. For these reasons, Sonde enteroscopy never established a place in routine clinical practice, other than in a few units with a particular interest in patients with obscure bleeding. Nevertheless, the technique did show that endoscopic examination of the small bowel was possible, and indeed clinically desirable. Reports of diagnostic yields superior to conventional radiological techniques emphasized the importance of diseases of the jejunum and ileum, and the need to develop more reliable methods for diagnosis and therapy [5,6].

Push enteroscopy   

Push enteroscopy is well established in clinical practice. Enteroscopes are essentially long floppy forward-viewing scopes, 2.2–2.5 m in length. Initial experience was reported using colonoscopes passed orally [7–13]. Preparation and sedation are the same as for standard upper endoscopy. Once the tip of the scope is in the descending duodenum, a stiffening overtube can be deployed to reduce gastric looping, which is a major factor limiting the duct through insertion. Even so, the tip of the endoscope rarely reaches beyond the first 50–70 cm beyond the pylorus. Usually, antispasmodic agents are avoided until the withdrawal/inspection phase of the examination.

Depth of insertion   

Using a longer enteroscope does not seem to increase the insertion depth predictably. A stiffening overtube can help, but the overall value of this technique is still in dispute, not least because its use has resulted in significant complications [14–19].

Newer methods to improve the intubation depth include utilizing a double balloon method to create a concertina effect. Total small bowel intubation can be achieved and the ability to biopsy or deliver therapy are likely to be of particular interest as an alternative to operation in patients with small bowel lesions found at capsule endoscopy [20,21]

Accurate measurement of the insertion depth is challenging. We simply pull the enteroscope back until the tip starts to withdraw. This gives a reasonably reliable measurement, which is used to guide subsequent therapy.

Routine biopsy?   

Routine biopsy is recommended when examining patients with suspected small bowel disease because there is a significant yield even with negative macroscopic views [22,23].

Intraoperative enteroscopy   

The small bowel can be examined during laparotomy, using either a sterilized colonoscope passed through an enterotomy, or a push enteroscope passed through the mouth [24–28]. The surgeon 'milks' the intestine over the endoscope. Encouraging diagnostic yields have been observed, but the procedure is not without risk. Complications have been reported in up to a quarter of these procedures, including serosal tears, prolonged ileus, even an enterovaginal fistula [29,30,31]. Intraoperative enteroscopy has usually been employed as an intervention of last resort in patients with significant ongoing GI bleeding after full investigations, including push enteroscopy. The recurrent nature of bleeding from arteriovenous malformations in particular was a major disincentive to intraoperative interventions, especially segmental resections.

Laparoscopic-assisted enteroscopy [32]   

This technique uses the peroral passage of a long push enteroscope or colonoscope, or even a Sonde enteroscope. The surgeon performs a standard diagnostic laparoscopy, and then uses laparoscopic instruments to help the endoscopist advance the enteroscope. Intubation of the terminal ileum has been described by this technique, but previous surgery and adhesions may interfere, and postoperative ileus has occurred [32].

Combined techniques   

Lack of predictable deep insertion has led to the combining of push enteroscopy with colonoscopy and ileoscopy and combining enteroscopy with enteroclysis [33,34].

Capsule enteroscopy   

This new technique involves the patient swallowing a wireless capsule camera which is 11 × 30 mm in length and consists of complimentary metal oxide silicon sensors (CMOS), an application specific integrated circuit (ASIC) device and white light emitting diode (LED) illumination(Fig. 2) No specific bowel preparation other than the overnight fast is needed. Some reports even suggest that capsule progression through the small intestine may be delayed by large bowel preparation (Fig. 3). The capsule images are transmitted at the rate of 2 per s to aerials positioned across the abdomen and stored in a recorder for subsequent analysis. The entire examination may obtain up to 50 000 images and battery life permits transmission for up to 6–8 h, during which patients are ambulant and independent [35]. Images are analyzed on a computer workstation. Problems with this technique include: the small risk of capsule impaction (in patients with unsuspected strictures); incomplete examination of the small bowel due to limited battery life in patients with prolonged small bowel transit (in up to 15% of patients); and the length of time it takes to review and analyze the recorded data (at least an hour in experienced hands).

 Clinical applications of enteroscopy and capsule endoscopy   

Enteroscopy and capsule techniques have been used for the investigation of patients with obscure gastrointestinal bleeding, suspected inflammatory bowel disease, malabsorption syndromes, and some rarities such as small bowel transplantation.

Obscure gastrointestinal bleeding   

Definitions and prevalence   

Gastrointestinal bleeding is defined as 'obscure' when patients continue to bleed despite normal upper and lower endoscopy examinations. This is not uncommon. Studies have shown that endoscopy and colonoscopy together reveal lesions in only just over one half of patients with documented iron deficiency anaemia [36,37]. The result was no higher in patients who also had positive fecal occult blood tests [38].

Multiple guidelines are available suggesting algorithms for the evaluation of this problem and defining the potential role of enteroscopy [39,40]. Patients with obscure gastrointestinal bleeding may be subdivided into those with overt (blood loss noticed by patient) and occult (unnoticed by patients) bleeding. Although such subdivision may seem arbitrary with inevitable overlaps, the appreciation that the rate of blood loss may influence diagnostic yield of enteroscopy will influence the enthusiasm for enteroscopy in such patients.

Historical estimates of the prevalence of small bowel lesions to account for blood loss have varied from 3% to 5% but these are undoubtedly underestimates resulting from lack of appropriate methods to evaluate the small bowel mucosa.

Alternative diagnostic procedures in obscure bleeding   

Small bowel radiology, isotope-labeled red cell studies, and angiography have all been used in this context, but the diagnostic yield is low [41–44]. Newer imaging modalities such as helical CT angiography might improve the yield, but availability is currently limited [45].

When to use enteroscopy in obscure bleeding   

Some clinicians question the need for further evaluation when endoscopy and colonoscopy are negative, since a number of series attest to the benign outcome of anaemia in this context [46–48]. This attitude fails to recognize the negative healthcare impact on the patient, and the significant resource implications of subsequent management [49]. It is our view that patients with more than a single unexplained episode of iron deficiency anaemia should undergo evaluation by enteroscopy or capsule endoscopy [50,51].

Pathology of obscure bleeding   

Angiodysplasia and small bowel tumors are the commonest identified causes of obscure gastrointestinal bleeding (Fig. 4). Predominant tumor types are gastrointestinal stromal tumors (GIST), adenocarcinomas, and lymphomas (Figs 5 and 6). Secondary spread to the bowel from melanoma and lung cancer in particular can present as obscure gastrointestinal bleeding [52]. Whilst it is asserted that tumors frequently present in younger patients, our experience, particularly with a large population of patients with celiac disease, is that tumors are found equally in all age groups [53](Fig. 7). The superficial nature of angiodysplasia explains the disappointingly low diagnostic yield from non-endoscopic diagnostic methods. In approaching the management of a patient thought to be bleeding from angiodysplasia it is important to understand the likely geographic distributions, limited non-endoscopic treatment options and recurrent nature of these lesions, even if successfully treated initially by endoscopic methods or segmental resections. Angiodysplasias are most frequently found in the proximal jejunum and right colon and increase in frequency with age. The factors predisposing to this distribution are unknown, but suggestions include bowel wall surface tension. Recent data suggests that bleeding from angiodysplasia in some cases may be related to a deficiency of Von Willebrand factor, as these multimers promote hemostasis at very high shear conditions experienced in the gut wall related to vascular abnormalities [54]. Even if these lesions are treated, the persisting pathophysiological abnormalities mean that recurrence is almost inevitable. Clinicians should develop an expectation that further therapy may become necessary in the future. In attempting to allow objective assessment and comparison of treatment outcomes the European Club of Enteroscopy has proposed a classification of angiodysplasia which may be helpful in future studies [55].

Medical therapy for angiodysplasia   

Non-endoscopic therapy of a diffuse and recurring disease would seem to have some theoretical advantages. Early reports of successful hormone therapy (estrogen/progesterone) in inherited vascular disorders [56] seemed to encourage more widespread use and some non-randomised cohort studies supported the use of hormone therapy in acquired angiodysplasia [57–59]. However, a significant number of patients on hormone therapy have to discontinue the medication due to unacceptable side-effects. Other reports of the use of vasoactive drugs such as Octreotide seemed equally encouraging [60,61] but in clinical practice non-endoscopic therapy has remained disappointing. In a recent important study from Spain no benefit of the use of hormone therapy to prevent bleeding from angiodysplasia was observed in a controlled study. At present hormone therapy cannot be recommended for acquired vascular malformations of the gut [62].

Diagnostic yield and outcomes of enteroscopic techniques in bleeding   

In patients with obscure gastrointestinal bleeding/unexplained anaemia, three studies show remarkably similar diagnostic yield for sonde enteroscopy—26–30% [6,63,64]. New diseases have been identified, for example NSAID enteropathy, occurring in 47% of patients with unexplained anaemia receiving these drugs [65]. The rate of blood loss is a factor determining the diagnostic yield, which increases from 27% in patients with anaemia to 37% in those with acute bleeding [6]. Although the push examination is limited to the proximal jejunum, several series confirm the superior diagnostic yield of this procedure, compared with sonde enteroscopy, with diagnostic rates ranging from 30% to 64% depending on case selection [66–70]. This is probably a reflection of improved mucosal inspection as a result of a more controlled examination technique. Only one study has evaluated the combined diagnostic potential of push and sonde enteroscopy in the same patients giving a combined yield of 58% overall, with sonde enteroscopy adding an additional 26% of patients with a diagnosis achieved. This data confirms that depth of intubation is a key factor determining diagnostic yield of enteroscopy [71–73].

Comparing capsule and push enteroscopy   

Comparisons of the capsule technique with standard push enteroscopy have (not surprisingly) shown increased yields from the capsule, not least because push enteroscopy rarely examines more than half of the small intestine. One study involved sewing colored beads into the small intestine of dogs. Sensitivities for push enteroscopy and capsule endoscopy were 37% and 64%, respectively. There is now a plethora of clinical studies indicating significant diagnostic yields in patients with obscure bleeding. However, the effect on clinical outcomes awaits further evaluation [74,75].

Diagnostic yields of 55% and 68% for the capsule examination are impressive [76–79]. However, the low diagnostic yield of push enteroscopy in comparative studies to date might reflect selection bias, as some patients already had a negative push enteroscopy [76].

Repeat standard endoscopies before enteroscopy?   

Most studies of enteroscopy indicate that lesions are often found within the reach of standard upper endoscopy, bringing into question the quality of the initial endoscopic procedures [80]. This has led to the suggested strategy of using push enteroscopy as the first (upper) examination in patients with unexplained anaemia [81]. Unfortunately, lack of access and experience with push enteroscopy will make application of this strategy unlikely for most patients.

Unusual causes of obscure bleeding   

The growing use of push enteroscopy in patients with bleeding has yielded many unusual diagnoses, including worm infestation, jejunal varices, ulceration related to Henoch Schonlein purpura, and bleeding from aortic graft fistula [82–85].

Enteroscopic therapy for bleeding   

The push enteroscope allows delivery of endoscopic therapy, primarily through cauterization of arteriovenous malformations. Whilst retrospective studies show encouraging results, only one prospective study has addressed the impact of heater probe ablation in this clinical setting [86–88]. We found complete resolution of bleeding in 83% of patients with a significant improvement in hemoglobin levels [88]. Due to the thin small bowel wall we recommend a maximum of three 10 J applications of the heater probe to each arteriovenous malformation. Following initial ablation bleeding is often seen (Figs 8–10). Whilst the reduction of blood loss was confirmed in subsequent studies, an interesting effect on improved quality of life has also been demonstrated, probably as a result of reduced transfusion and hospitalization [89]. Interest in the long-term outcome of patients having investigation and treatment by push enteroscopy has revealed important insights into the perceived benefit of the procedure. Although enteroscopy was perceived by clinicians to have positively influenced patient management in three studies, in one of these studies only one third of the patients felt it was beneficial [90–92]. This discrepancy probably reflects the lack of impact to an individual patient of not achieving a diagnosis after enteroscopy although once again these studies demonstrated reduced hospitalization in patients in whom a diagnosis was achieved. Rebleeding occurs in approximately one third of all patients with obscure bleeding. The risk is less on long-term follow-up patients who have undergone negative push enteroscopy [93]. Patients should be counselled about the risk of rebleeding, and the potential need for further investigation and treatment.

Intraoperative enteroscopy for obscure bleeding   

This procedure is normally reserved for those patients in whom bleeding persists despite negative push enteroscopy. In this highly selected group, studies using a colonoscope passed orally or via enterotomies reveal a diagnostic yield approaching 70–80% of patients [94–99]. The ability to examine the whole small bowel has led to the perception that intraoperative enteroscopy should be regarded as the gold standard for small bowel evaluation. The only study which has compared enteroscopy with intraoperative enteroscopy found that both procedures missed lesions, but that intraoperative enteroscopy had a higher sensitivity [100]. Most experts now use a push enteroscope through the mouth for intraoperative enteroscopy, not least because it obviates the need for opening the bowel.

Push enteroscopy or capsule endoscopy for bleeding?   

The problem for the clinician nowadays is to decide whether to use capsule endoscopy as the next step following negative upper endoscopy and colonoscopy, or whether to use push enteroscopy first. The latter would be advantageous only if lesions were found and treated at enteroscopy. Although data from diagnostic yield would seem to favor the capsule no studies are yet available to definitely answer this question. As stated in a recent ASGE technical review, patient factors and local availability will be major determinants in this process [101].

Small intestinal mucosal diseases   

Celiac disease   

Celiac disease is usually diagnosed (and excluded) by standard endoscopic biopsy from the distal duodenum. Enteroscopy is rarely required for diagnosis, although two studies did suggest an increased yield over standard duodenal biopsy [102,103]. Push enteroscopy should be restricted for diagnostic purposes when there is strong suspicion, or when the disease is refractory to treatment. Under these circumstances enteroscopy allows detection of macroscopic abnormalities such as ulceration and lymphoma, and the ability to obtain biopsies for immunopathological analysis [104,105]. Identifying patients at particular risk for developing lymphoma is an exciting prospect. Several studies have reported on an abnormal immunophenotype in which intraepithelial lymphocytes in patients with refractory celiac disease express on intracytoplasmic CD3 positive CD8 negative staining pattern. The majority also had clonal intestinal TCR gamma gene rearrangements [106–108]. These findings were found to be highly suggestive of subsequent development of enteropathy-associated lymphoma in the latter study whereas those without these patterns had good responses to steroid and gluten withdrawal.

Crohn's disease   

Enteroscopy is of value in selected patients with negative investigations when there is a high index of suspicion of Crohn's disease. Abnormalities and supporting histology have been reported in up to 50% of such patients [109]. Remarkably similar results are also observed in patients examined by capsule enteroscopy [110]. Therapeutic enteroscopy (e.g. balloon dilatation of strictures) has also been used successfully in patients with proximal Crohn's disease [111]. Enteroscopy has also been used during surgery for complications of Crohn's disease, and has often shown a high frequency of metachronous lesions [112–114]. However, these findings have not affected the outcome, but the situation might change with newer immunomodulating therapies.

Small bowel tumors   

Tumors of the small intestine are relatively uncommon. They account for less than 2% of tumors of the gastrointestinal tract and can be very difficult to identify [115]. Many present with obscure bleeding, and patients undergo repeated investigations prior to definitive diagnosis. Malignant tumors, particularly adenocarcinoma, present early with weight loss, pain, perforation, or obstruction [116]. Sonde enteroscopy revealed tumors in about 5% of 258 patients investigated for obscure bleeding [5]. This frequency reflects the over-representation of tumor patients in a series of patients with no diagnosis by other diagnostic modalities. However it emphasizes the fact that serious diseases occur in this patient group and that enteroscopy should be considered an important addition to non-endoscopic methods of evaluation [117, 118]. A further role of enteroscopy has recently been defined in patients with small bowel polyps in Peutz–Jeghers syndrome. Using push enteroscopy and intraoperative enteroscopy successful surveillance and polypectomy have been performed, avoiding the need for emergency surgery for intestinal obstruction. Although relatively small numbers of patients have been reported, these early results provide encouragement for future development of a screening and monitoring role for enteroscopy [119–122].

Novel indications   

Capsule endoscopy has not proven useful in evaluating unexplained abdominal pain [123]. Images from the transient passage through the esophagus were found in a recent study to be insufficient to evaluate for esophagitis or Barrett's esophagus [124]. It is clear that future enthusiasm for capsule endoscopy will lead to its evaluation in many novel diseases or anatomical areas.

 Conclusion   

Small bowel endoscopy has been developed and evaluated extensively over the past two decades. The techniques, diagnostic yield, and clinical outcomes have been defined. Initial scepticism over the need for endoscopic examination of the small intestine has been replaced by a recognition of the potential role that this technique fulfills in the management of patients with obscure bleeding, small intestinal mucosal diseases, and tumors. Newer techniques have improved diagnostic yield and patient tolerance and now it is important to acknowledge that complete endoscopic examination of the gastrointestinal tract is a clinical reality. As our methods become more reliable, enteroscopy research will move from defining the process of the techniques to evaluating their role in disease management. Capsule endoscopy has added substantial impetus to this process.

 Outstanding issues and future trends   

Capsule endoscopy heralds a new era for structural evaluation of the gastrointestinal tract.

Important questions that will need to be clarified are: refining techniques to maximize mucosal views; studies to define inter- and intraobserver variability; who should most appropriately read capsule studies; and outcomes for individual patient groups.

Although currently limited to examination of the small bowel, we should expect that modifications of capsule technology will lend themselves to total gastrointestinal visualization, perhaps by a steerable capsule.

Simple changes to capsule function including blood indicators which are in evolution will probably be supplemented by other abilities such as measuring physiological conditions including pH and motility.

These devices will revolutionize our approach to patients with mucosal disease and be used to monitor disease progress, outcomes of therapy (and possibly delivery of it) and be an ideal screening tool. It is likely that contrast radiology will become obsolete and diagnostic endoscopic procedures may be gradually replaced. Increased demand for therapy or biopsy of lesions detected by capsule will, for the present, maintain significant need for push enteroscopy.

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