Zinc supplementation tightens "leaky gut" in Crohn's disease

OBJECTIVES: Small intestinal permeability is often increased in patients with Crohn's disease and may be pathogenic for clinical relapses. No effective prophylactic treatment is available for these patients. The aim of this study was to ascertain whether zinc supplementation may improve intestinal permeability. METHODS: We studied 12 patients with quiescent Crohn's disease who had been in remission for at least 3 months and had increased intestinal permeability on two separate occasions within the last 2 months. Patients received oral zinc sulfate supplements (110 mg three times a day) for 8 weeks and were followed-up for 12 months thereafter to monitor relapses. RESULTS: We found that the lactulose/mannitol ratio was significantly higher before supplementation than after (0.041 +/- 0.003 versus 0.026 +/- 0.005). During follow-up, 10 patients had normal intestinal permeability and did not relapse; of the remaining two who had increased intestinal permeability, one relapsed. CONCLUSIONS: Our findings show that zinc supplementation can resolve permeability alterations in patients with Crohn's disease in remission. Improving intestinal barrier function may contribute to reduce the risk of relapse in Crohn's disease.     

Clinical Response Does Not Correlate with Intestinal or Blood Cyclosporine Concentrations in Patients with Crohn's Disease Treated with High-Dose Oral Cyclosporine

Objective : High-dose (>5 mg/kg/d) oral cyclosporine may be effective treatment for Crohn's disease, whereas low-dose oral cyclosporine (≤5 mg/kg/d) is not. This study determined the correlation between blood and intestinal tissue cyclosporine concentrations and clinical response in patients with Crohn's disease treated with cyclosporine 8 mg/kg/day. Methods : Twelve patients with inflammatory Crohn's disease were treated for 6 wk with oral cyclosporine 8 mg/kg/day, adjusted to a whole blood cyclosporine concentration (chromatography) of 200-300 ng/ml. Response was determined by the Crohn's disease activity index. Cyclosporine was measured in intestinal tissue biopsies obtained by colonoscopy at week 6 (chromatography). Results : Eight patients responded and four did not respond. There were no significant differences between the responders and non-responders in the mean whole blood or intestinal tissue cyclosporine concentrations. Similarly, there were no significant correlations between change in the Crohn's disease activity index score (baseline to week 6) and whole blood or intestinal tissue cyclosporine concentrations. Cyclosporine side effects, including nephrotoxicity and peroneal nerve palsy, were common. Conclusions: Clinical response did not correlate with whole blood or intestinal tissue cyclosporine concentrations in patients treated with high-dose cyclosporine for Crohn's disease. Cyclosporine side effects, including a significant decrease in renal function, were common.     

Appendiceal carcinoids in Crohn's disease.

Earlier investigations demonstrate an increased risk for colon cancer in Crohn's disease. For other intestinal neoplasms, such as carcinoids, studies are limited. In Crohn's disease, repeated endoscopic and imaging studies along with intestinal resections may facilitate clinical recognition of neoplastic diseases, including appendiceal neoplasms. To date, however, only sporadic cases of appendiceal carcinoids have been described in Crohn's disease. In the present study, in a single clinician database of 1000 Crohn's disease patients, three of the 441 patients who had undergone intestinal resection had appendiceal carcinoids, all of which were pathologically confirmed. All were observed in female patients and were not suspected before surgical treatment. In one case, even though management was not altered, the tumour had already invaded serosal fat indicating a potential for more advanced disease. In this series, a carcinoid tumour was found in a resection specimen during a later clinical case review and another was a microcarcinoid, implying that these tumours may be overlooked in Crohn's disease. The percentage detected in the entire database (0.3%) exceeds the reported rates of detection of appendiceal carcinoids after removal of the appendix for appendicitis, as well as the rate of detection of appendiceal carcinoids in autopsy studies. This percentage would be higher if only those having an intestinal resection were considered (0.68%). Additional studies are needed to further define this risk of appendiceal carcinoids in Crohn's disease.     

Tabulation of myeloid, lymphoid and intestinal malignancies in Crohn's disease.

A variety of malignant complications occur in Crohn's disease, and previous studies have recorded an increased intestinal cancer risk. The present investigation tabulated myeloid and lymphoid malignancies compared with intestinal cancers in 1000 consecutively evaluated patients with Crohn's disease who were followed over an extended period by a single clinician. Myeloid and lymphoid neoplasms were present in 0.5% of patients, while cancer in the intestinal tract was detected in 1%. Most of these patients with a malignancy had Crohn's disease for a prolonged period of more than 20 years and had negative outcomes, including death or presentations with advanced disease. In this cohort, lymphoma was not detected in a single patient after definition of Crohn's disease, possibly reflecting the limited use of immunosuppressives or infused biological agents in this clinical practice. Bypassed rectal 'stumps' were associated with subsequent colorectal cancer in half of all males with colon cancer in this series, suggesting an important risk factor following colectomy in Crohn's disease. Epithelial dysplasia was detected in only a single male patient before colorectal cancer, implying that this histopathological marker may be a poor predictor of subsequent colon cancer development in Crohn's disease, an inflammatory bowel disease process that is typically patchy or focal in distribution in the intestinal tract.     

Indications for surgery in Crohn's disease: analysis of 500 cases.

Data for 500 patients with Crohn's disease who underwent operations were analyzed (316 patients, 1966 to 1969; 184 patients, 1972 to 1973) by comparison of various anatomic disease locations (clinical pattern): (1) ileocolic, 225 patients; (2) small intestinal, 130 patients; (3) colonic, 127 patients; (4) anorectal, 18 patients. Indications for surgery were tabulated and compared using statistical analysis for the three large patterns. For patients with ileocolic Crohn's disease, the primary surgical indications were internal fistula and abscess, 44%, intestinal obstruction, 35%, and perianal disease, 12%. For patients with Crohn's disease of the small intestine, the primary surgical indications were intestinal obstruction, 55%, and intestinal fistula and abscess, 32%. Patients with colonic Crohn's disease had a significantly more diverse surgical indication, with poor response to medical therapy, 26%, internal fistula and abscess, 23%, toxic megacolon, 20%, and perianal disease, 19%. These values were highly statistically significant (P less than 0.0001) in all instances but one. This study demonstrates that statistically significant differences occur in the surgical indication depending on the location of Crohn's disease. Patients with ileocolic, small intestinal, and colonic involvement have striking differences in clinical course. It is concluded that Crohn's disease is not a homogeneous entity, but should be recognized as having a varying course depending on clinical pattern.     

Fecal alpha 1-antitrypsin measurement: an indicator of Crohn's disease activity

Random fecal alpha 1-antitrypsin levels were determined in 34 patients, 24 with Crohn's disease, and 10 "controls" having diarrheal illnesses not associated with intestinal protein loss, in an effort to evaluate its usefulness as a measure of Crohn's disease intestinal activity. In the control group, all alpha 1-antitrypsin levels were less than 2 mg/g dry wt of stool. The mean fecal level among those with Crohn's disease was 52.9 mg/g (range less than 2 to greater than or equal to 200). There was a strong correlation between disease activity, as measured by a clinical score, and the alpha 1-antitrypsin levels (Spearman r = 0.65, p = 0.001). This correlation was similarly strong among those with colitis or ileitis. A fecal value greater than 20 mg/g may provide a rough guideline to separate patients with clinically active disease from those with inactive Crohn's disease, despite a considerable range of fecal levels among patients with a particular clinical score. Fecal alpha 1-antitrypsin levels correlated with several other laboratory measures that have been proposed as indicators of Crohn's disease activity. The serum orosomucoid, C-reactive protein, and albumin correlated with the clinical activity score among some of our patient groups. Both clinical scores and laboratory parameters, however, may have limited usefulness in a variety of circumstances. Random fecal alpha 1-antitrypsin determinations seem to provide a reliable, although not directly quantitative, measure of the intestinal activity among patients with Crohn's disease, especially when other methods may be inconclusive.     

Absorption of 51chromium-labeled ethylenediaminetetraacetate in inflammatory bowel disease

Intestinal permeability was assessed in patients with inflammatory bowel disease by measuring the urine excretion of 51chromium-labeled ethylenediaminetetraacetate over periods up to 24 h after oral administration. Twenty-eight control subjects and 10 patients with ulcerative colitis excreted less than 2.6% of the test dose in 24 h. Ten patients with small bowel Crohn's disease excreted 3.3%-14.0%, and 10 of 11 patients with ileocolonic involvement had increased excretion. At the same time, 5 of 11 patients with Crohn's colitis were clearly outside the normal range, suggesting small bowel involvement. The 24-h urine excretion of 51chromium-labeled ethyl-enediaminetetraacetate after oral administration appears to be a sensitive, noninvasive test for assessing small intestinal integrity, and may be a valuable adjuvant in the differential diagnosis of inflammatory bowel disease.     

Proctitis after fecal diversion in Crohn's disease and its elimination with reanastomosis: implications for surgical management. Report of four cases

Diverting the fecal stream has been considered to affect the course of Crohn's disease favorably. Adverse effects on the distal segment have not previously been distinguished from clinical signs and symptoms. The course of four patients with Crohn's disease who underwent fecal diversion with an in situ rectum were observed in whom sigmoidoscopy was initially normal at the time of the diversion, became distinctly abnormal during the year after the diversion, and then returned to normal within 3 mo following reestablishment of intestinal continuity. The entity of nonspecific diversion proctitis might account for this phenomenon independently or by accelerating the Crohn's disease process. The inflammation present was nonspecific and did not show the stigmata of Crohn's disease. Continuity of the intestinal tract should be maintained in the course of Crohn's disease surgery if feasible. If a diversion is clinically warranted, reanastomosis should be considered as early as possible despite evidence of inflammation in the rectal mucosa.     

Clinicopathologic features of Crohn's disease with free intestinal perforation

BACKGROUND/AIMS: Free perforation is the most serious intestinal complication of Crohn's disease, and early diagnosis is an important determinant of survival. The aim of this study was to evaluate the clinical and histopathologic characteristics of free perforation associated with Crohn's disease. METHODOLOGY: Twelve free perforations in 10 patients with Crohn's disease were studied. We mainly examined the clinical characteristics, methods for definitive diagnosis and histopathologic features of free intestinal perforation with Crohn's disease. RESULTS: Nine patients had 1 perforation, and 1 had 3 perforations occurring within a short period. Computed tomography was significantly more sensitive than plain radiography for detecting free air in the abdomen at the time of perforation. Histopathologic examination showed that free perforation occurred most frequently in the ileum, on the side attached to the mesentery. Intestinal strictures and dilatations were presented distal to 10 perforations (83%). CONCLUSIONS: Our results suggest that computed tomography of the abdomen was useful for the definitive diagnosis of free intestinal perforation in Crohn's disease. Histopathologic findings indicated that increased intraluminal pressure due to stricture and local circulatory disturbance of the mucosa caused by intestinal dilatation were involved in the development of free perforation in patients with Crohn's disease.     

Current status and influence of operation on perianal Crohn's disease

Two hundred and two patients with Crohn's disease have been examined during the year 1984 to assess the frequency of perianal disease. One hundred and ten have had evidence of perianal complications (54%). In 30% of patients with perianal disease, the anal manifestations preceded any evidence of intestinal disease. Perianal disease was associated with pain in only 39%. Operations for perianal disease rarely achieved healing and were frequently associated with complications. Attempts to lay open a fistula-in-ano caused healing in only one of 12 cases and 6 developed incontinence. A high proportion of patients with Crohn's ulcers and strictures required proctectomy (87%). Proctectomy was performed in 27 patients with perianal disease of whom only 8 (30%) had primary healing of the proctectomy wound compared with complete healing in all 9 patients having a proctectomy without perianal disease (p less than 0.01). These results imply that patients with perianal Crohn's disease should be treated conservatively and that proctectomy, particularly in patients with rectal strictures, is associated with very high incidence of persistent perineal sinus.     

Increased production of tumour necrosis factor-alpha interleukin-1 beta, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease.

BACKGROUND: Increasing evidence points to a important role for inflammatory cytokines for the pathogenesis of Crohn's disease. AIM: To compare the secretion rate of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) by morphologically normal and inflamed intestinal mucosa from patients with Crohn's disease. RESULTS: Organ cultures of intestinal biopsy specimens taken from areas of affected mucosa from patients with Crohn's disease spontaneously produced increased amounts of TNF-alpha, IL-1 beta, and IL-6 compared with controls but also biopsy specimens taken in macroscopically and microscopically unaffected areas in the same patients. Concentrations of IL-1 beta and IL-6 measured in the supernatant fluid of biopsy cultures were positively correlated with the degree of tissue involvement measured by both endoscopic and histological grading. By contrast, TNF-alpha concentrations were not correlated to endoscopic and histological grading. CONCLUSIONS: These consistently raised TNF-alpha, IL-1 beta and IL-6 secretions by normal appearing mucosa from patients with Crohn's disease provide evidence for a sustained immune stimulation in Crohn's disease even in the absence of patent inflammation. The results shed a new light on the role of inflammatory cytokines in the onset of intestinal tissue damage in Crohn's disease and suggest that the range of intestinal lesions in Crohn's disease may be wider than suspected on the basis of regular endoscopic and histological examinations.     

Meckel's diverticulum in Crohn's disease.

Meckel's diverticulum is a congenital abnormality of the distal ileum associated with failed vitelline duct closure. Detailed pathological studies have estimated its frequency to be about 2% of the general population, and it has been anecdotally recorded in patients with Crohn's disease. Most patients with Crohn's disease have imaging studies of the small intestine during the course of their disease, and often, an intestinal resection. Thus, it seems possible to estimate the prevalence of Meckel's diverticula in Crohn's disease. In addition, patient characteristics may be important, especially if management of Crohn's disease is altered. Of 877 patients with Crohn's disease, 10 (about 1%) had a Meckel's diverticulum diagnosed, including six men and four women. All were diagnosed with Crohn's disease before age 50 years and seven were diagnosed before age 30 years. There were five with ileocolonic disease, two with colon-only disease and three with ileum-only disease. The clinical behaviour of five patients could be classified as penetrating and two as stricturing. A total of 311 patients had an ileocolonic resection, including eight (about 2%) with a Meckel's diverticulum. In contrast to some case reports, no heterotopic mucosa was detected and the Meckel's diverticulum was incidental and, apparently, an unexpected finding. In each case, the diverticulum was not involved with Crohn's disease but was included in the ileal resection. These results suggest that the overall prevalence of a Meckel's diverticulum is not increased in Crohn's disease but may result in resection of additional small intestine.     

Jejunal dilatation in Crohn's disease. Intestinal obstruction or intestinal edema?

Although dilatation of the jejunum is a well-recognized feature of Crohn's disease there has been no systematic inquiry as to whether this is related simply to distal intestinal obstruction or to other factors such as hypoalbuminemia and mucosal disease. Barium follow-up examinations of 21 patients with Crohn's disease who had serum albumin concentrations of 2.1-4.4 g/dl were reviewed. Fourteen of these patients (67%) had increased mean jejunal width. All patients with direct radiologic evidence of a stricture (six patients) had increased jejunal caliber, but this only accounted for 43% of patients with this abnormality. Of the remaining eight patients, six had hypoalbuminemia, three of whom had serum albumin concentrations less than or around 2.7 g/dl, the previously determined "albumin threshold" for jejunal dilatation. We conclude that increased jejunal caliber in Crohn's disease not only occurs in association with distal intestinal stenosis but also with severe hypoalbuminemia in the absence of obstruction. We were unable to define a cause of jejunal dilatation in 36% of these patients, but propose that functional obstruction due to distal nonstenosing inflammatory disease may be a factor.     

Open label trial of clarithromycin therapy in Japanese patients with Crohn's disease

BACKGROUND AND AIM: The pathogenesis of Crohn's disease is unclear, but many studies suggest that luminal bacteria play an important role in chronic intestinal inflammation in patients with this condition. Clarithromycin is a macrolide antibiotic with immunomodulatory activity. The aim of this study was to evaluate the effect of clarithromycin therapy in Japanese patients with Crohn's disease. METHODS: Fourteen patients with active Crohn's disease (12 with ileocolonic, one with colonic, one with small bowel type) were treated with oral clarithromycin 200 mg twice daily for 4 weeks. Patients who showed a clinical response within 4 weeks continued the therapy for up to 24 weeks. Four patients also received azathioprine. Clinical activity was assessed with the Crohn's Disease Activity Index (CDAI) at entry and at 4, 12, and 24 weeks after starting clarithromycin. RESULTS: The mean CDAI score at entry was 343.5. Within 4 weeks, eight (57.1%) of the 14 patients showed clinical improvement, and five (35.7%) of the eight patients achieved remission. All of those eight patients continued clarithromycin therapy after 4 weeks, and six (42.9%) were in clinical remission at 12 weeks. Of the 14 total patients, four (28.6%) continued clarithromycin for more than 24 weeks, and have remained in remission. Patients who received azathioprine concomitantly had a better response to clarithromycin therapy. No severe side-effects were observed during the study period. CONCLUSIONS: This open label study showed encouraging results of clarithromycin therapy in Japanese patients with active Crohn's disease.     

Increased pulmonary and intestinal permeability in Crohn''s disease.

We tested the hypothesis that an increased epithelial permeability may affect sites other than the intestine in patients with Crohn's disease by simultaneously evaluating their pulmonary and intestinal permeability. Pulmonary and intestinal permeability were measured by clearance of inhaled technetium-99m diethylene triamine pentacetate (99mTc-DTPA) and by urinary recovery of chromium-51 ethylene diamine tetracetate respectively in 22 patients with Crohn's disease. The half time clearance of 99mTc-DTPA from lung to blood (t1/2LB) was decreased--that is pulmonary permeability increased--in the whole group of patients with Crohn's disease as compared with 13 controls (median 45.5 minutes (8-160) v 85 minutes (34-130) (p less than 0.003)). When analysed separately only patients with active Crohn's disease (n = 15) had a decreased t1/2 lung to blood v controls (42 minutes (8-160) v 85 minutes (34-130) (p less than 0.0025)). Among patients with active Crohn's disease, six were studied again when their disease was quiescent and their t1/2 lung to blood did not differ significantly. The intestinal permeability was increased in the whole group of Crohn's disease patients as compared with 15 controls (5.25% (1.2-24) v 1.7% (0.65-5.75) (p less than 0.0002)). When analysed separately both patients with active and inactive Crohn's disease had increased intestinal permeability v controls (8.1% (1.6-24) and 3.5% (1.2.9.2) v 1.7% (0.65-5.75)) (p less than 0.0001, p = 0.05 respectively). Six patients with active Crohn's disease were studied again when their disease was quiescent and their intestinal permeability decreased significantly p less than 0.04). Pulmonary permeability was increased in patients with Crohn's disease but was not greatly influenced by Crohn's disease activity as opposed to intestinal permeability. The mechanism of this increase is unknown, but may be related in some patients to the presence of an alveolitis.     

Long-term clinical behavior of jejunoileal involvement in Crohn's disease.

Diffuse and extensive jejunoileal Crohn's disease is an uncommon entity. In 39 patients, including 21 males and 18 females, followed for a mean duration of over 16 years between 1979 and 2004, the extent of disease was defined and disease behaviour characterized. Over 80% of patients had concomitant colonic and/or gastroduodenal involvement with Crohn's disease, suggesting that this entity may represent a specific clinical phenotype of extensive disease localization. Classification of Crohn's disease behaviour using the Vienna classification schema revealed that virtually all patients in this study suffered from intestinal stricture formation or penetrating disease complications. Moreover, pharmacological therapies with corticosteroids and immunosuppressant drugs were rarely successful, with virtually all patients requiring at least one, and usually multiple, intestinal resections. Finally, most patients required long-term nutritional support, often with home parenteral nutrition. New treatments are required, possibly defined on the basis of their effectiveness in reducing the severity and extent of intestinal disease, rather than more conventional statistically driven reductions in disease activity indexes.     

Oral Manifestations in Crohn''s Disease: Report of a Case

Oral lesions are an important clinical finding in Crohn's disease. We describe a patient who had extensive involvement of the oral mucosa and esophagus and histologically confirmed Crohn's ileocolitis. The patient had exquisitely tender, edematous, ulcerating lesions involving the lips, tongue, buccal mucosa, and posterior pharynx. Rapid and dramatic improvement of both the oral and the intestinal manifestations occurred after systemic corticosteroid therapy.     

The relationship and epidemiology of acute terminal ileitis and Crohn's disease

The frequency of admission for acute terminal ileitis, Crohn's disease, and acute mesenteric lymphadenitis has been compared from the years 1951 to 1970, and the long-term results of operation for acute terminal ileitis in 1951-1965 have been examined.Whereas the admission rates for both acute terminal ileitis and Crohn's disease rose during the review period, that for acute lymphadenitis tended to fall slightly. Sixty-eight of 72 patients operated upon by appendicectomy who had acute terminal ileitis were followed up. One of these, with small intestinal stenosis at the initial operation, proved to have histological evidence of Crohn's disease, and a further nine have since developed unequivocal evidence of the disease. A cutaneous fistula developed in only one patient after appendicectomy. It is concluded that appendicectomy can safely be performed in acute terminal ileitis provided that the caecum is not inflamed and that Crohn's disease seldom develops as a sequel.     

Crohn's disease small bowel strictureplasties: early and late results

BACKGROUND: Strictureplasty is an alternative surgical procedure for Crohn's disease, particulary in patients with previous resections or many intestinal stenosis. AIM: To analyze surgical complications and clinical follow-up in patients submitted to strictureplasty secondary to Crohn's disease. METHODS: Twenty-eight patients (57.1% male, mean age 33.3 years, range 16-54 years) with Crohn's disease and intestinal stenosis (small bowel, ileocecal region and ileocolic anastomosis) were submitted to strictureplasty, at one institution, between September 1991 and May 2004. Thirteen patients had previous intestinal resections. The mean follow-up was 58.1 months. A total of 116 strictureplasties were done (94 Heineke-Mikulicz--81%, 15 Finney--13%, seven side-to-side ileocolic strictureplasty--6%). Three patients were submitted to strictureplasty at two different surgical procedures and two in three procedures. RESULTS: Regarding to strictureplasty, postoperative complication rate was 25% and mortality was 3.6%. Early local complication rate was 57.1%, with three suture leaks (10.7%) and late complication was present in two patients, both with incisional hernial and enterocutaneous fistulas (28.6%). Patients remained hospitalized during a medium time of 12.4 days. Clinical and surgical recurrence rates were 63% and 41%, respectively. Among the patients submitted to another surgery, two patients had two more operations and one had three. Recurrence rate at strictureplasty site was observed in 3.5%, being Finney technique the commonest one. Presently, 19 patients had been asymptomatic with the majority of them under medical therapy. CONCLUSION: Strictureplasties have low complication rates, in spite of having been done at compromised site, with long term pain relief. Considering the clinical course of Crohn's disease, with many patients being submitted to intestinal resections, strictureplasties should be considered as an effective surgical treatment to spare long intestinal resections.     

Elemental diet in the management of Crohn''s disease during pregnancy.

Four patients with Crohn's disease were treated with an elemental diet during pregnancy. Two had active disease and two also had symptoms of small intestinal obstruction. All went into a clinical remission within a few days of starting treatment. Treatment periods varied from two to four weeks, and were followed by elemental diet as a supplement to normal food in two patients. At term, all delivered a healthy infant. These patients indicate that elemental diet is a safe form of treatment for Crohn's disease during pregnancy and may be considered as an alternative to conventional drug treatments which carry a theoretical risk of teratogenesis.