Correspondence *Division of Gastroenterology, Cardinal Carter Wing 16-050, St Michael's Hospital, Toronto, ON M5B 1W8, Canada

Email bakerj@smh.toronto.on.ca

The Case

A 65-year-old white Mediterranean male was referred by a hematologist for evaluation of a long-standing history of anemia, and presented at our hospital in March 2004. The patient was first diagnosed with anemia by his family physician 10 years previously, and from that point on the anemia had been intermittent. He had been treated with oral iron supplement pills; however, his anemia persisted. Tests of stool specimens for occult blood had occasionally been positive, although investigations, including numerous endoscopic and radiologic evaluations, were consistently negative. He was subsequently referred to our department for further gastrointestinal investigation.

Except for anemia, he was asymptomatic, and denied any gastrointestinal complaints. He denied diarrhea, rectal bleeding, weight loss or fever. The patient's medical history was significant for BETA THALASSEMIA. There was no family history of gastrointestinal pathology, and he had not undergone any previous abdominal surgery. He did not smoke tobacco or drink alcohol. The patient was taking several medications, including irbesartan 150 mg and hydrochlorothiazide 12.5 mg (Avalide^®, Sanofi-Aventis, Paris, France) orally once daily (for high blood pressure), alfuzosin 10 mg orally once daily (for an enlarged prostate), allopurinol 100 mg orally twice daily (for gout), enteric-coated aspirin 325 mg orally once daily (for primary prevention of coronary artery disease), zopiclone 5 mg orally once daily (for insomnia), and an iron supplement 300 mg orally three times daily (for anemia). The patient had been on the same dose of aspirin for the previous 3 years. On physical examination, the patient was obese, with a BMI of 36 kg/m². His vital signs were stable and his abdomen was soft and nontender, with no palpable masses. No oral or rectal lesions were present.

The patient's laboratory test results are listed in Table 1. His white blood cell count, platelet count, erythrocyte sedimentation rate, and albumin and C-reactive-protein levels were within the normal ranges. His ferritin and hemoglobin levels, and hematocrit and red blood cell counts, however, were all below the normal ranges. The patient's mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration indicated hypochromic microcytic anemia. A stool sample tested positive for occult blood. Stool cultures for bacteria and parasites were negative.

Table 1 Laboratory test results.

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Esophagogastroduodenoscopy and colonoscopy with retrograde ileoscopy were performed; no abnormalities were detected. Mesenteric angiography was reported as negative. A barium-contrast radiographic examination of the patient's small bowel revealed a short segment of the ileum to be irregular, with a 1 cm outpouching. A mild loop separation around this segment implied that it might be an extrinsic process (neoplastic mass). The remainder of the small bowel including the terminal ileum was normal. The radiologic picture was indicative of neoplasia or tuberculosis and further investigations were required to rule this suspicion out. A CT scan was performed, revealing a 3.4 cm, low-density, exophytic lesion, suggestive of MECKEL'S DIVERTICULUM (Figure 1). Nuclear scintigraphy for Meckel's diverticulum was negative.

Figure 1 CT scan of the abdomen of a 65-year-old white Mediterranean male with a long-standing history of anemia.

There is oral and intravenous contrast at the level of the abnormal barium collection (white arrow); the image is suggestive of Meckel's diverticulum.

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Capsule endoscopy showed a short segment of ulceration in the distal small bowel with minimal oozing (Figure 2). The small-bowel mucosa of this area of ulceration looked quite thickened with short, broadened villi, and the lumen of the affected bowel appeared to be narrowed. The observed lesion was in the distal ileum, significantly proximal to the ileo-cecal valve, and well beyond the reach of conventional endoscopes. The etiology of this ulceration and structure was unclear. The rest of the small bowel looked completely normal.

Figure 2 Capsule endoscopy of the small bowel of a 65-year-old white Mediterranean male with anemia.

The image shows a short segment of the small bowel that is ulcerated and narrowed (image acquired using the Pillcam^® SB capsule endoscopy, Given Imaging Ltd., Yocqneam, Israel).

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An explorative laparoscopy showed that a short segment of the bowel was thickened and abnormal. Intra-operative enteroscopy demonstrated that the remainder of the small intestine was normal. Segmental small-bowel resection (20 cm of ileum with attached mesentery) with termino-terminal anastomosis was performed. Histologic examination of the resected small bowel revealed chronic active enteritis with increased submucosal fibrosis, characteristic of active Crohn's disease, including transmural inflammation with lymphoid aggregates, focal neuronal hyperplasia and abundant pyloric metaplasia (Figure 3). There was no evidence of dysplasia or malignancy. The patient recovered uneventfully, and was discharged and treated for Crohn's disease with Pentasa^® (Ferring A/S Corp., Wayne, PA) 4 g daily. The patient continues to be asymptomatic at present, without any gastrointestinal complaints or evidence of recurrent gastrointestinal bleeding.

Figure 3 Photomicrograph of the small-bowel mucosa and submucosa of a patient with Crohn's disease of the small bowel.

The mucosa contains moderate acute and chronic inflammation with reactive changes in the epithelial cells. A fissuring ulcer is evident centrally, extending into the muscularis mucosa. Pyloric metaplasia is noted focally (black arrow) (hemotoxylin and eosin, 50).

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Discussion of diagnosis

Crohn's disease is a chronic inflammatory disorder of unknown etiology. It most commonly affects the small bowel.^{1, 2, 3, 4} The estimated incidence of Crohn's disease is between 4.3 and 6.6 cases per 100,000 persons per year. Some ethnic groups (such as Ashkenazi Jews) have a significantly higher rate of prevalence than others. Males and females appear to be affected equally. Crohn's disease can affect persons of all ages, but the most common age of onset is between 15 and 35 years of age, with a second peak sometimes set between 55 and 65 years of age.

The true causes of Crohn's disease are unknown, although abnormal functioning of the immune system is clearly involved. Suggested causes include environmental factors, chronic infection, genetic abnormalities, autoimmunity, and other abnormalities of immunoregulatory mechanisms. Each of these factors might have a role as a causative trigger. It appears that the inflammation characteristic of Crohn's disease begins with interaction between the causative factor or factors in the gut lumen and the epithelial barrier, which in turn affects the vulnerable underlying tissues of the mucosa. Chemical compounds or bacteria enter the lamina propria and initiate a complex immunologic and inflammatory response. The inflammation becomes chronic and recurrent.

Crohn's disease is associated with fluctuating symptoms of diarrhea, 'crampy' abdominal pain, fever, fatigue, weight loss, arthritis, uveitis, aphthous stomatitis, and pyoderma gangrenosum. The clinical symptoms of Crohn's disease are protean, from clinically silent disease to severe, life-threatening disease. As in this case, isolated findings, without the more characteristic spectrum of disease, make diagnosis difficult, and the findings might be mistaken for those of other disorders. Diagnosis of Crohn's disease is founded on clinical, radiologic, endoscopic, and histopathologic features. The endoscopic appearance and histopathologic findings are generally distinctive and provide enough information to establish a diagnosis of Crohn's disease and to initiate therapy.^{5, 6} Up to 30% of patients, however, have limited small-bowel involvement, often beyond the reach of standard endoscopes.^{3, 4} This patient presented with long-standing iron-deficient anemia without any other symptoms; presentation of Crohn's disease with the single, nonspecific finding of anemia is unusual, and this initially obscured the correct diagnosis. The clinical picture was complicated by coexisting beta thalassemia, which masked the additional presence of iron deficiency and intestinal blood loss. Stool samples positive for occult blood, however, were indicative of intestinal blood loss. Barium contrast radiography, complemented by CT, is the primary modality for diagnosis of Crohn's disease of the small bowel; in this case it showed no terminal ileum involvement and led to a false diagnosis, as the small-bowel ulceration was initially interpreted as Meckel's diverticulum or a neoplastic process. Capsule endoscopy has demonstrated its usefulness in detecting small-bowel lesions and is currently used in the work-up of gastrointestinal bleeding.^{7, 8} In this patient, the findings on capsule endoscopy were indicative of an ulcerated segment of bowel; however, the diagnosis of Crohn's disease could not be conclusively made, because the capsule cannot take biopsies. Surgery with histologic findings indicative of Crohn's disease was necessary to determine the final diagnosis.

Differential diagnosis

Ulcers of the distal small bowel are uncommon, and almost always related to other gastroduodenal diseases such as infections, inflammatory bowel disease, malignancies, celiac disease, systemic diseases, or drugs (particularly NSAIDs).

Infection

The most common infectious causes, including tuberculosis, cytomegalovirus, typhoid, Yersinia, Campylobacter, parasites, HIV and systemic diseases, were excluded from this patient based on negative laboratory tests and the absence of clinical presentation. There was no evidence of villous atrophy or increased numbers of intraepithelial lymphocytes, and, thus, celiac disease was also ruled out.

Drugs

The main differential diagnosis for the cause of the ulceration was the use of NSAIDs. Patients who regularly take NSAIDs are at an increased risk for small-bowel mucosal ulceration and bleeding, which might present as anemia of undetermined gastrointestinal origin.⁹ The risk of ulceration due to therapeutic doses of NSAIDs is estimated at fivefold to tenfold.¹⁰ Ulcers induced by NSAIDs, however, are usually widespread and multiple, from tiny punched-out ulcers to deep ulceration. By contrast, this patient presented with a sole segmental ulceration. It is also dubious that such a low dose of NSAIDs, as taken by the patient, could be responsible for the observed findings. Crohn's disease has rarely been reported to present with isolated iron-deficient anemia.¹¹ With such a clinical presentation, with no family history of Crohn's disease, radiologic findings inconsistent with a diagnosis of the disease, and video images of a single, short, ulcerated segment of bowel, the findings, while consistent with Crohn's disease, would not be diagnostic.

Cancer

Neoplasia is another cause of ulceration and bleeding, but the patient's 10-year history of anemia was not consistent with the diagnosis of a malignant tumor.

Treatment and management

Conventional treatment options for patients with Crohn's disease generally include sulfasalazine-derivatives (e.g. 5-aminosalicylic acid, or 5-ASA), oral steroids (e.g. prednisolone and budesonide), immunosuppressants (e.g. azathioprine, 6-mercaptopurine, methotrexate, FK506 tacrolimus, and ciclosporin), antitumor-necrosis factor- therapy (e.g. infliximab), and surgery. Medical therapy is usually implemented in an ascending order starting from medications that are believed to be safer but might be less effective (5-ASA) to more potent agents that have more side effects (steroids and immunosuppressive drugs). Pentasa^® is a form of 5-ASA that contains the active ingredient in coated microgranules. The special plastic coating delays release of the active 5-ASA substance until the tablets reach the end of the ileum. This allows delivery of most of the medicine to the ileum, and it is preferably used in patients with mild Crohn's disease of the small bowel. Pentasa^® was therefore the drug of choice for this patient.

Surgery is not curative for Crohn's disease, and is reserved for specific indications, most notably complications of the disease. Patients with ileal Crohn's disease are at greater risk of complications, such as stenosis, and have a greater need for surgical, rather than immunosuppressive, treatment.¹² A segmental resection of the ulcerated or stenotic lesion with primary, end-to-end anastomosis was the procedure of choice in this case. The probability of surgery in patients with ileal Crohn's disease has been reported to be 69%, 78% and 90% after 5, 20 and 30 years of symptoms, respectively.¹³ This patient had suffered from Crohn's disease for an indefinite period, and had never received medical therapy, owing to the difficulties in diagnosing isolated small-bowel Crohn's disease.

Reports suggest that 23% of patients with ileal Crohn's disease are first diagnosed at the time of surgery.^{14, 15} We speculate whether timely diagnosis of Crohn's disease, with early initiation of conservative medical treatment, might have reduced, or even prevented, the need for surgical resection in this case. If diagnosis could have been established without a resection, this patient might have responded to drug therapy.

Conclusion

Crohn's disease of the small bowel might mimic other gastrointestinal conditions, such as Meckel's diverticulum, and can be a challenging diagnosis. The clinical presentation can be confusing, and conventional test results might be misleading. This article pinpoints these difficulties and underlines the importance of a thorough diagnostic approach to small-bowel investigation in patients with complex clinical pictures, when small-bowel bleeding is suspected.

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Subject areas under which this article appears: Inflammatory bowel disease