Impaired intestinal iron absorption in Crohn's disease correlates with disease activity and markers of inflammation

BACKGROUND: Anemia in patients with Crohn's disease (CD) is a common problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation. Anemia of inflammation is caused by the effects of inflammatory cytokines [predominantly interleukin-6 (IL-6)] on iron transport in enterocytes and macrophages. We sought to elucidate alterations in iron absorption in pediatric patients with active and inactive CD. METHODS: Nineteen subjects with CD (8 female, 11 male patients) were recruited between April 2003 and June 2004. After an overnight fast, serum iron and hemoglobin levels, serum markers of inflammation [IL-6, C-reactive protein (CRP), and erythrocyte sedimentation rate], and a urine sample for hepcidin assay were obtained at 8 am. Ferrous sulfate (1 mg/kg) was administered orally, followed by determination of serum iron concentrations hourly for 4 hours after the ingestion of iron. An area under the curve for iron absorption was calculated for each patient data set. RESULTS: There was a strong inverse correlation between the area under the curve and IL-6 (P = 0.002) and area under the curve and CRP levels (P = 0.04). Similarly, the difference between baseline and 2-hour serum iron level (Delta[Fe]2hr) correlated with IL-6 (P = 0.008) and CRP (P = 0.045). When cutoff values for IL-6 (>5 pg/mL) and CRP (>1.0 mg/dL) were used, urine hepcidin levels also positively correlated with IL-6 and CRP levels (P = 0.003 and 0.007, respectively). CONCLUSIONS: Subjects with active CD have impaired oral iron absorption and elevated IL-6 levels compared with subjects with inactive disease. These findings suggest that oral iron may be of limited benefit to these patients. Future study is needed to define the molecular basis for impaired iron absorption.     

Kallikrein-kinin system activation in streptococcal toxic shock syndrome.

A retrospective analysis of 7 patients with streptococcal toxic shock revealed isolated prolongation of the activated partial thromboplastin time, which returned to normal during recovery. Levels of factor XII were reduced in 2 patients who had single factor assays performed, consistent with activation of the kallikrein-kinin system. We speculate that bradykinin release following activation of the kallikrein-kinin system in streptococcal toxic shock may underlie the features of pain, capillary leaking, and severe hypotension characteristic of this syndrome.     

Acute inflammatory intestinal vascular lesions and in situ abnormalities of the plasminogen activation system in Crohn's disease.

OBJECTIVES: The distribution of the intestinal vascular lesions and their relation with the fibrinolysis process are poorly known in Crohn's disease (CD). The mediators of the plasminogen activator system, namely urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1), are a key complex involved in fibrinolysis. The aims of this study were: (1) to further define vascular lesions and their distribution in the intestine; and (2) to study concomitantly the qualitative in situ expression and the levels of u-PA, t-PA and PAI-1 in the ileum of patients with CD. PATIENTS AND METHODS: Histological, immunohistochemical and ultrastructural studies of vascular lesions in the resected ileum of 27 patients with CD were performed and compared with 36 control patients. Levels of u-PA, t-PA and PAI-1 measured by ELISA methods were compared in healthy and inflamed ileal tissues of 17 patients with CD. RESULTS: Acute vascular lesions involving mainly serosal venules and capillaries were present in 63% of patients with CD vs 3/36 controls and were associated with PAI-1 expression. They were prominent on the mesenteric border beneath macroscopically normal mucosa. In contrast, chronic vascular lesions were present in all layers beneath mucosal ulcerations, where a significant increase of PAI-1 levels was found. CONCLUSIONS: These results suggest that vascular involvement associated with abnormalities of PAI-1 expression is an early and widespread event in CD. Their prominence on the mesenteric border might explain the characteristic location of CD ulceration along the mesenteric margin.     

Crohn's disease and systemic lupus erythematosus

A 28-year-old man with inflammatory bowel disease with complex extraintestinal involvement was found to have diagnostic features of both systemic lupus erythematosus and Crohn's disease. Although some of the systemic complications of these diseases may overlap, both diseases may occur as primary disorders. Coexistence of systemic lupus erythematosus should be considered in patients with inflammatory bowel disease and complex extraintestinal manifestations.     

Crohn's disease and intestinal endometriosis: an intriguing co-existence

OBJECTIVES: We present a series of eight female patients who came to surgery for complicated Crohn's disease of the terminal ileum (n = 7) or colon (n = 1). Indications for surgery were medically intractable disease in three, steroid dependence in four and ileal perforation in one. RESULTS: Histological examination using routine haematoxylin-eosin stained sections revealed the presence of intestinal endometriosis of the ileum (n = 6), colon (n = 1) or ileum and rectum (n = 1) in addition to the typical features of Crohn's disease. In particular, chronic transmural inflammation was observed in locations other than the endometriotic deposits, which were confined to the serosa in three, the muscularis propria in two, both the serosa and the muscularis propria in one and the serosa, muscularis propria and submucosa in two. In none of these patients had the diagnosis of intestinal endometriosis been suspected pre-operatively based on clinical (gynaecological) or radiological tests. CONCLUSION: Intestinal endometriosis and Crohn's disease can occur simultaneously. The diagnosis is often only made after surgical resection of the diseased segment. In Crohn's disease, endometriosis of the terminal ileum seems more common.     

Phospholipase activation and arachidonic acid release in intestinal epithelial cells from patients with Crohn's disease

A method for studying the mobilization of free arachidonic acid (AA) in viable isolated human intestinal epithelial cells has been developed and applied to the study of patients with Crohn's disease. Cells were isolated from morphologically unaffected parts of the distal ileum and incubated with 14C-AA; most of the incorporated 14C-AA was then found in phospholipids (mainly phosphatidylcholine) and in a pool of neutral lipids (mainly triacylglycerols). Cells from patients with Crohn's disease incorporated more 14C-AA into their neutral lipids than did cells from control patients. When the labeled cells were stimulated with phospholipase C from Clostridium perfringens or with the calcium ionophore A23187, they released significant amounts of AA, mainly from phosphatidylcholine. There was no difference between cells from Crohn patients and controls in the 14C-AA amounts released, but unstimulated and phospholipase C-stimulated cells from prednisolone-treated Crohn patients released less AA than cells from control patients. The A23187-stimulated AA release was completely inhibited by the phospholipase A2 inhibitor 4-bromophenacyl bromide, whereas the phospholipase C-stimulated release was not. These findings suggest that AA release in human small-intestinal epithelial cells may be caused by calcium-mediated phospholipase A2 activation or by products of microbial phospholipase C activity and that prednisolone reduces the mobilization of free AA in intestinal epithelial cells. They also illustrate the potential use of isolated epithelial cells for revealing mechanisms underlying AA release in the intestinal mucosa in different disease states.     

Mechanisms of intestinal failure in Crohn's disease

PURPOSE: The purpose of this study was to determine the mechanisms by which patients with Crohn's disease develop intestinal failure and, in particular, to assess the relative importance of severe primary disease, repeated uncomplicated elective small intestine resection, and resection performed as a consequence of intra-abdominal septic surgical complications. METHODS: This was a retrospective analysis of 41 patients with Crohn's disease referred to a specialized intestinal failure unit between January 1987 and September 1998 for permanent home parenteral nutrition. To compare the surgical activity in patient groups, a resection index was calculated by dividing the number of intestinal resections by the interval in years between the first resection for Crohn's disease and referral for management of intestinal failure. RESULTS: Extensive primary Crohn's disease was responsible for intestinal failure in 7 cases (17 percent). The remainder (n=34, 83 percent) developed intestinal failure after intestinal resection. Nine of the surgical Crohn's patients developed intestinal failure after uncomplicated sequential resection, (median small-bowel length 65 (range, 60–120) cm) after a median of 3 (range, 2–8) operations over a median of 17 (range, 3–27) years. By contrast, the other 25 surgical Crohn's patients developed intestinal failure after multiple unplanned laparotomies for intra-abdominal sepsis (median small-bowel length 70 (range, 60–200) cm), with a median of 4 (range, 2–7) laparotomies performed over a median of 0.5 (range, 0.1 to 1.5) years (P<0.001). The resection index for the 25 Crohn's patients undergoing laparotomies for intra-abdominal sepsis was significantly greater than that of the 9 patients who had planned sequential resections (2.1 (0.27–25)vs. 0.23 (0.1–1.0);P < 0.002, Mann-WhitneyU test). CONCLUSION: Intestinal failure develops in Crohn's disease primarily as a result of complications of surgical treatment. The largest group of patients at risk consists of those who are undergoing multiple unplanned laparotomies to control intra-abdominal sepsis.     

Risks of intestinal cancer in Crohn's disease

This review described the principal features of the three studies that have established clearly that patients in the U.S.A. or the U.K. who have long-standing (>7 years) Crohn's colitis are at increased risk (up to 20-fold) of developing large bowel cancer. In addition, it emphasizes that there are no data on the extent of this risk in patients in other countries, and also that the magnitude of the risk of cancer of the small intestine in Crohn's disease is unknown. Despite the increased incidence of large bowel cancer in long-standing Crohn's colitis in the U.S.A. or the U.K., the total number of such patients is small, as is the number in which the colonic carcinoma will occur. However, careful supervision is advised for the small group at risk, despite the limitations of current methods for the early detection of cancer of the large intestine.     

Laparoscopic-assisted intestinal resection for Crohn's disease

PURPOSE: The inflammatory process associated with Crohn's disease often makes dissection difficult, even in open surgery. This study was undertaken to determine if dissection and resection could be performed laparoscopically and whether it would benefit this group of patients. METHODS: Between November 1992 and November 1994, laparoscopic-assisted intestinal resection was attempted in 18 patients with Crohn's disease and was successfully completed in 14. One patient had ileal disease, requiring ileal resection with ileoileal anastomosis. The remainder had disease requiring ileocolic resections. Muscle-splitting incisions averaging 5 cm in length were made to facilitate removal of specimens. RESULTS: Commencement of oral alimentation was possible at an average of 3.6 (range, 1–7) days postoperatively. Discharge occurred at an average of 6.6 (range, 4–9) postoperative days. In comparison, 14 patients operated on by the authors for the same disease in the open manner during the past six months stayed an average of 8.5 (range, 5–14) postoperative days. Postoperative complications were minimal. CONCLUSIONS: On the basis of this initial study, it appears that laparoscopic-assisted intestinal resection can be readily performed in patients with Crohn's disease. In our early experience, we have found that laparoscopic mobilization and resection may be difficult or impossible in patients with large fixed masses, multiple complex fistulas, or recurrent Crohn's disease. Extraction incisions are frequently so large in these patients that they do not derive the same benefits from laparoscopic surgery that are enjoyed by patients without these findings. Most patients having laparoscopic resections eat earlier, may require fewer narcotics, and are able to be discharged from the hospital an average of two days earlier than patients operated on in an open manner. In addition, it appears that laparoscopic-assisted intestinal resection results in a shorter, easier convalescence and an earlier return to full activity.     

Primary intestinal lymphoma complicating Crohn's disease

A 32-year-old man with a 12-year history of Crohn's disease of the colon was found to have a 5-cm cecal mass on colonoscopy. Histology examination of the lesion revealed high-grade B-cell lymphoma of Burkitt's type. He was treated with chemotherapy and has done well in the past 12 months. Review of the literature reveals 30 cases of lymphoma in patients with a history of Crohn's disease.     

Differentiating Crohn's disease from intestinal tuberculosis

Differentiating Crohn's disease(CD) and intestinal tuberculosis(ITB) has remained a dilemma for most of the clinicians in the developing world, which are endemic for ITB, and where the disease burden of inflammatory bowel disease is on the rise. Although, there are certain clinical(diarrhea/hematochezia/perianal disease common in CD; fever/night sweats common in ITB), endoscopic(longitudinal/aphthous ulcers common in CD; transverse ulcers/patulous ileocaecal valve common in ITB), histologic(caseating/confluent/large granuloma common in ITB; microgranuloma common in CD), microbiologic(positive stain/culture for acid fast-bacillus in ITB), radiologic(long segment involvement/comb sign/skip lesions common in CD; necrotic lymph node/contiguous ileocaecal involvement common in ITB), and serologic differences between CD and ITB, the only exclusive features are caseation necrosis on biopsy, positive smear for acid-fast bacillus(AFB) and/or AFB culture, and necrotic lymph node on cross-sectional imaging in ITB. However,these exclusive features are limited by poor sensitivity, and this has led to the development of multiple multi-parametric predictive models. These models are also limited by complex formulae, small sample size and lack of validation across other populations. Several new parameters have come up including the latest Bayesian meta-analysis, enumeration of peripheral blood T-regulatory cells, and updated computed tomography based predictive score. However, therapeutic anti-tubercular therapy(ATT) trial, and subsequent clinical and endoscopic response to ATT is still required in a significant proportion of patients to establish the diagnosis. Therapeutic ATT trial is associated with a delay in the diagnosis of CD, and there is a need for better modalities for improved differentiation and reduction in the need for ATT trial.     

Small intestinal adenocarcinoma in Crohn's disease: a case-control study

BACKGROUND: Small bowel adenocarcinoma is an uncommon complication of Crohn's disease. We sought to describe the clinical features, outcomes, and risk factors of small bowel adenocarcinoma in Crohn's disease. METHODS: A centralized diagnostic index identified all patients with Crohn's disease with small bowel adenocarcinoma evaluated at our institution between 1976 and 2000, and the medical records were abstracted. Two controls with Crohn's disease were selected for each case, matched by gender and age. RESULTS: Nine cases (four males) were identified. The patients presented with abdominal pain (89%), obstruction (89%), and weight loss (78%). Cancer was located in the ileum in 8 patients (89%) and the jejunum in 1 patient (11%). All cases but 1 had either lymph node involvement or metastasis. All cases had surgery, with 1 receiving adjuvant chemotherapy. No significant risk factors were found. The mortality rates at 1 and 2 years were 42% and 61%. CONCLUSIONS: Small bowel adenocarcinoma is a rare complication of Crohn's disease that typically involves the ileum. Affected patients have symptomatic, advanced malignancies upon diagnosis. No significant risk factors were identified.     

Modulation of intestinal immune system by dietary fat intake: Relevance to Crohn's disease

Gut-associated lymphoid tissue is the major inductive site of the mucosal immune system, which is functionally independent of the systemic immune system. Both the amount and type of dietary fat modulate intestinal immune function. Absorption of long-chain fatty acids stimulates lymphocyte flux and lymphocyte blastogenesis in intestinal lymphatics. Long-chain fatty acid absorption also significantly enhances migration of T lymphocytes to Peyer's patches, possibly due to up-regulation of adhesion molecules, such as α4-integrin and L-selectin. Lipoproteins are involved in stimulation of lymphocyte function by both receptor-dependent and independent mechanisms. However, unsaturated fatty acids at higher concentrations have a suppressive effect on cell-mediated immunity via eicosanoid release, receptor affinity changes or interactions with intracellular signal transduction. Fat absorption also influences various other cells in the intestinal mucosa: increased cytokine release from intestinal epithelial cells follows long-chain fatty acid absorption. In Crohn's disease, elemental diets and total parenteral nutrition often induce remission, possibly by reducing antigenic load on activated immune cells in the intestine and, thus, down-regulating hyperreactive CD4 cells. Dietary oleic acid supplements caused an immunological reversal effect in the intestinal immune system of animals fed an elemental diet. An excess of long-chain fatty acids in an elemental diet, therefore, may negate its beneficial effect on gut-associated lymphoid tissues in Crohn's disease. In contrast, supplemental dietary fish oil apparently tends to prevent relapse of Crohn's disease. Because dietary fat intake is closely associated with immunological function of the intestinal mucosa, careful manipulation of dietary fat can be important in management of this disease.     

克罗恩病肠道纤维化的发生机制和临床治疗

肠道纤维化是克罗恩病的特征表现,其反复发作导致的肠道狭窄是克罗恩病最严重的并发症之一,目前治疗手段有限.本文对克罗恩病肠道纤维化发生机制及目前治疗手段进行综述.     

Selectivity of small intestinal exudate in celiac disease and Crohn's disease

The small intestinal exudates of patients with protein-losing enteropathies produced by celiac disease or proximal jejunal Crohn's disease were compared with controls. The exudates in control subjects were highly selective, whereas those of the celiac and Crohn's disease subjects were relatively nonselective. It is believed that this loss of selectivity is secondary to basement membrane damage. An analogy is drawn with the renal lesion in nephrotic syndrome where basement membrane damage is associated with nonselective proteinuria.     

Racial differences in disease phenotypes in patients with Crohn's disease

BACKGROUND: Our objectives were to assess the differences in perforating disease behavior, disease severity, and extraintestinal manifestations (EIM) in patients with Crohn's disease (CD) by race. MATERIALS AND METHODS: We identified outpatients with CD evaluated at the University of Maryland Gastroenterology Faculty Practice office or the Baltimore Veterans Affairs Maryland Health Care System, from 1997 to 2005. We assessed age at diagnosis, disease behavior, disease location, need for surgery and EIM. RESULTS: Race was not associated with perforating disease behavior (relative risk [RR] 0.79, 95% confidence interval [CI] 0.46-1.35), need for surgery (RR 0.89, 95% CI 0.56-1.12), and EIM of CD (RR 0.77, 95% CI 0.46-1.27). White patients were significantly more likely to have ileal disease, whereas African American patients were significantly more likely to have ileocolonic and colonic disease. Age at diagnosis younger than 40 years (odds ratio [OR] 4.41, 95% CI 1.84-10.56) and ileocolonic disease (OR 2.39, 95% CI 1.24-4.63) were independent risk factors for perforating disease behavior. Similarly, age at diagnosis younger than 40 (OR 2.79, 95% CI 1.45-5.33), ileal disease (OR 3.76, 95% CI 1.66-8.48), and ileocolonic disease (OR 2.57, 95% CI1.21-5.46) were associated with the need for surgery. Female gender (OR 4.23, 95% CI 1.87-9.58) and a positive family history of CD (OR 3.45, 95% CI 1.49-8.0) were associated with joint manifestations of CD. DISCUSSION: We did not detect differences in disease behavior, severity, or joint EIM by race. Although African American patients were more likely to have ileocolonic or colonic disease, these factors did not affect disease behavior or severity.