Alterations in the function of circulating mononuclear cells derived from patients with Crohn’s disease treated with mastic

AIM: To assess the effects of mastic administration on cytokine production of circulating mononuclear cells of patients with active Crohn's disease (CD). METHODS: The study was conducted in patients with established mildly to moderately active CD, attending the outpatient clinics of the hospital, and in healthy controls. Recruited to a 4 wk treatment with mastic caps (6 caps/d, 0.37 g/cap) were 10 patients and 8 controls, all of who successfully completed the protocol. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), macrophage migration inhibitory factor (MIF) and intracellular antioxidant glutathione (GSH) were evaluated in peripheral blood mononuclear cells (PBMC) before and after treatment. RESULTS: Treating CD patients with mastic resulted in the reduction of TNF-α secretion (2.1 ± 0.9 ng/mL vs 0.5 ± 0.4 ng/mL, P = 0.028). MIF release was signif icantly increased (1.2 ± 0.4 ng/mL vs 2.5 ± 0.7 ng/mL, P = 0.026) meaning that random migration and chemotaxis of monocytes/macrophages was inhibited. No signifi cant changes were observed in IL-6, MCP-1 and GSH concentrations. CONCLUSION: This study shows that mastic acts as an immunomodulator on PBMC, acting as a TNF-α inhibitor and a MIF stimulator. Although further double-blind, placebo-controlled studies in a large number of patients is required to clarify the role of this natural product, this f inding provides strong evidence that mastic might be an important regulator of immunity in CD.     

Chios mastic treatment of patients with active Crohn＇s disease

AIM： To evaluate the effectiveness of mastic administration on the clinical course and plasma inflammatory mediators of patients with active Crohn＇s disease （CD）. METHODS： This pilot study was conducted in patients with established mild to moderately active CD, attending the outpatient clinics of the hospital, and in healthy controls. Ten patients and 8 controls were recruited for a 4-wk treatment with mastic caps （6 caps/d, 0.37 g/cap）. All patients successfully completed the protocol. CD Activity Index （CDAI）, Nutritional Risk Index （NRI）, C-reactive protein （CRP）, interleukin-6 （IL-6）, tumor necrosis factor-alpha （TNF-α）, monocyte chemotactic protein-1 （MCP-1）, and total antioxidant potential （TAP） were evaluated in the plasma at baseline and at the end of the treatment period. Results were expressed as mean values ± SE and P 〈 0.05 was considered to indicate statistical significance. RESULTS： Patients exhibited significant reduction of CDAI （222.9 ± 18.7 vs 136.3 ± 12.3, P = 0.05） as compared to pretreament values. Plasma IL-6 was significantly decreased （21.2 ± 9.3 pg/mL vs 7.2 ± 2.8 pg/ mL, P = 0.027）, and so did CRP （40.3 ± 13.1 mg/mL vs 19.7 ± 5.5, P = 0.028）. TAP was significantly increased （0.15 ± 0.09 vs 0.57 ± 0.15 mmol/L uric acid, P = 0.036）. No patient or control exhibited any kind of side effects. CONCLUSION： The results suggest that mastic significantly decreased the activity index and the plasma levels of IL-6 and CRP in patients with mildly to moderately active CD. Further double-blind, placebo-controlled studies in a larger number of patients are required to clarify the role of this natural PrOduct in the treatment of patients with CD.     

Plasma leptin and ghrelin concentrations in patients with Crohn＇s disease

AIM: To determine the concentrations of leptin and ghrelin, which have opposite effects on appetite, energy expenditure, and weight control, in the plasma of patients with Crohn's disease (CD), which is often associated with weight loss and malnutrition. METHODS: Plasma leptin and ghrelin concentrations were determined in 28 outpatients with CD by radioimmunoassay. Age- and sex-matched controls with and without Helicobacter pylori (H pylori) infection (28 for each) were enrolled in the study. Circulating levels of these hormones were assessed with respect to CD activity, disease localization and medical treatment. RESULTS: There were no significant differences in ghrelin levels between CD patients and H pylori -negative controls. However, circulating ghrelin levels were significantly lower in H pylori-infected subjects than in CD patients and uninfected controls. Plasma leptin levels were comparable among the groups. Localization and medication profile had no significant impact on circulating ghrelin and leptin levels. CONCLUSION: Apart from H pylori infection, CD itself has no significant influence on circulating ghrelin and leptin levels in the outpatients who were mostly in inactive state.     

Gallbladder bile composition in patients with Crohn＇s disease

AIM:To further elucidate the pathogenesis andmechanisms of the high risk of gallstone formation inCrohn's disease.METHODS:Gallbladder bile was obtained from patientswith Crohn's disease who were admitted for electivesurgery (17 with ileal/ileocolonic disease and 7 withCrohn's colitis).Fourteen gallstone patients servedas controls.Duodenal bile was obtained from tenhealthy subjects before and after the treatment withursodeoxycholic acid.Bile was analyzed for biliary lipids,bile acids,bilirubin,crystals,and crystal detection time(CDT).Cholesterol saturation index was calculated.RESULTS:The biliary concentration of bilirubin wasabout 50% higher in patients with Crohn's disease thanin patients with cholesterol gallstones.Ten of the patientswith Crohn's disease involving ileum and three of thosewith Crohn's colitis had cholesterol saturated bile.Fourpatients with ileal disease and one of those with colonicdisease displayed cholesterol crystals in their bile.About1/3 of the patients with Crohn's disease had a shortCDT.Treatment of healthy subjects with ursodeoxycholicacid did not increase the concentration of bilirubin induodenal bile.Several patients with Crohn's disease,with or without ileal resection/disease had gallbladderbile supersaturated with cholesterol and short CDT andcontained cholesterol crystals.The biliary concentrationof bilirubin was also increased in patients with Crohn'scolitis probably not due to bile acid malabsorption.CONCLUSION:Several factors may be of importance forthe high risk of developing gallstones of both cholesteroland pigment types in patients with Crohn's disease.     

Mutifactorial analysis of risk factors for reduced bone mineral density in patients with Crohn＇s disease

AIM: To determine the prevalence of osteoporosis in a cohort of patients with Crohn's disease (CD) and to identify the relative significance of risk factors for osteoporosis. METHODS: Two hundred and fifty-eight unselected patients (92 M, 166 F) with CD were studied. Bone mineral density (BMD) was measured at the lumbar spine and hip by dual X-ray absorptiometry. Bone formation was assessed by measuring bone specific alkaline phosphatase (BSAP) and bone resorption by measuring urinary excretion of deoxypyridinoline (DPD) and N-telopeptide (NTX). RESULTS: Between 11.6%-13.6% patients were osteoporotic (T score < -2.5) at the lumbar spine and/or hip. NTX levels were significantly higher in the patients with osteoporosis (P < 0.05) but BSAP and DPD levels were not significantly different. Independent risk factors for osteoporosis at either the lumbar spine or hip were a low body mass index (P < 0.001), increasing corticosteroid use (P < 0.005), and male sex (P < 0.01). These factors combined accounted for 23% and 37% of the reduction in BMD at the lumbar spine and hip respectively. CONCLUSION: Our results confirm that osteoporosis is common in patients with CD and suggest that increased bone resorption is the mechanism responsible for the bone loss. However, less than half of the reduction in BMD can be attributed to risk factors such as corticosteroid use and low BMI and therefore remains unexplained.     

Role of perioperative parenteral nutrition in severely malnourished patients with Crohn＇s disease

AIM: To evaluate the effect of perioperative parenteral nutrition on serum immunoglobulin, weight change, and post-operative outcome in severely malnourished patients with Crohn's disease. METHODS: Thirty-two severely malnourished patients with Crohn's disease who had undergone surgery in our hospital were reviewed. Sixteen patients who received perioperative parenteral nutrition were enrolled in the study group, and the other 16 patients who did not receive parenteral nutrition were enrolled in the control group. Serum immunoglobulin, body mass index (BMI), liver function, weight change, and postoperative complications were evaluated. RESULTS: Serum IgM levels elevated 1 wk before surgery in both groups, and decreased to normal value (from 139±41 to 105±29 mg/dL, P= 0.04) 4 wk after operation in the study group, while no significant changes was noted in the control group (from 133±16 to 129±13 mg/dL, P=0.34). There were no significant changes in concentrations of IgG and IgA. The BMI of the study group increased from 13.9±0.6 to 15.3±0.7 kg/m~2 (P=0.02) with no significant change in the control group (14.1±0.7 and 14.5±0.5, respectively, P= 0.81). The percentage of resuming work was higher in the study group than in the control group. CONCLUSION: Perioperative parenteral nutrition possibly ameliorates the humoral immunity, reverses malnutrition, and facilitates rehabilitation.     

A case of Crohn＇s disease involving the gallbladder

Crohn's disease is well known to affect any part of thegastrointestinal tract including the oral cavity and anus.Various extraintestinal complications have been reportedin Crohn's disease,but extraintestinal involvementcharacterized by granulomatous lesions is uncommon.Here,we have reported a case about the involvement ofthe gallbladder in Crohn's disease.A 33-year-old womanwas diagnosed having panperitonitis due to intestinalperforation and cholecystitis.The patient was moved tothe surgical service for an emergency operation.On theresected specimen,there was a broad longitudinal ulcerat the mesenteric side.The mucosa of the gallbladderwas nodular and granular,and the wall was thickened.The surface epithelium of the gallbladder was partiallyeroded and pyloric gland metaplasia was observedfocally.Rokitansky-Aschoff sinuses were also present.From the lamina propria to the subserosal layer,therewere several well-formed epithelioid cell granulomas,which were the non-caseating sarcoidal type differentfrom the foreign-body and xanthomatous granulomas.Periodic-acid Schiff and acid fast stains revealed noorganism within the granulomas.Lymphoid aggregateswere present throughout the gallbladder wall.Sectionsfrom the resected ileum showed typical features of theCrohn's disease.When cholecystectomy is performedin a patient with Crohn's disease,the possibility ofgallbladder involvement should be carefully examined byhistopathological tests.     

Transplantation of an eight-organ multivisceral graft in a patient with frozen abdomen after complicated Crohn＇s disease

To report an extended multivisceral transplantation (MVTx) including right kidney and ascending colon in a patient with complicated Crohn's disease (CD). A 36-year old female suffering from short bowel syndrome and frozen abdomen due to fistulizing CD after multiple abdominal operations underwent MVTx of eight organs including stomach, pancreatoduodenal complex, liver, intestine, ascending colon, right kidney, right adrenal gland, and greater omentum in November 2003. Immunosuppression consisted of alemtuzumab, tacrolimus and steroids. The patient was off parenteral nutrition by postoperative wk 3. She experienced one episode of pneumonia. The patient recovered completely and discharged 2.5 mo and was doing well 30 mo after MVTx. This is one of the very rare cases in which a complete mulitivisceral graft of eight abdominal organs was transplanted orthotopically.     

Conventional therapy for Crohn＇s disease

Crohn's disease (CD) is a multifactorial disorder of unknown cause. Outstanding progress regarding the patho-physiology of CD has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD over the last years. However, many drugs have not been approved by regulatory authorities due to lack of efficacy or severe side effects. Therefore, well-known drugs, including 5-ASA, systemic or topical corticosteroids, and immunosuppressants such as azathioprine, are still the mainstay of CD therapy. Importantly, biologicals such as infliximab have shown to be efficacious in problematic settings such as fistulizing or steroid-dependent CD. This review is intended to give practical guidelines to clinicians for the conventional treatment of CD. We concentrated on the results of randomized, placebo-controlled trials and meta-analyses, when available, that provide the highest degree of evidence. We provide evidence-based treatment algorithms whenever possible. However, many clinical situations have not been answered by controlled clinical trials and it is important to fill these gaps through expert opinions. We hope that this review offers a usefu] tool for clinicians in the challenging treatment of CD.     

Crohn＇s disease： Innate immunodeficiency？

In the past, Crohn's disease (CD) has been understood primarily as an immunologic disorder characterized by an abnormal T-cell response. Recent in vitro and in vivo data suggests that CD may instead be precipitated by innate immune dysfunction resulting from a combination of genetic and environmental factors. Some reports have demonstrated a defective immune response in a variety of other cellular components, including neutrophils, monocytes and dendritic cells. Recent studies of granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD, aiming to stimulate the innate immune system with the conception that an innate immune defect underlies the development of the disease, have been demonstrated a clinical benefit and reinforce this evolving understanding of the disease.     

Microinflammation in patients with Crohn's disease in clinical remission

Background and aimsIt is not clear whether Crohn's disease patients in clinical remission (Crohn's disease activity index < 150) display normal concentrations of inflammation sensitive biomarkers. Our goal in this work was to explore the intensity of the microinflammatory response in a group of Crohn's disease patients in clinical remission.MethodsHigh sensitivity C-reactive protein, quantitative fibrinogen, erythrocyte sedimentation rate as well as platelet and leukocyte counts were examined in a group of 76 patients with Crohn's disease in remission and in 228 matched controls.ResultsCrohn's disease patients in clinical remission displayed a statistically significant (p < 0.001) elevated concentration of hs-CRP (4.83 ± 3.8 mg/l) compared to controls (1.05 ± 2.9 mg/l). All other bio-markers were also significantly higher in Crohn's disease patients in remission compared to controls. Similar results were obtained in a subgroup of Crohn's disease patients with very low disease activity — CDAI < 75.ConclusionsClinical remission is not equivalent to biochemical remission raising a question concerning the true definition of remission in Crohn's disease.     

Immune status in healthy relatives of patients with familial Crohn's disease

Immune-mediated mechanisms and genetic factors are believed to be involved in the pathogenesis of Crohn's disease. We studied T- and B-cell subpopulation proportions and various functionnal assays, including proliferative responses to PHA and Con A, Con A-induced suppressive activity, and natural killer cell assay toward the K562 cell line, in the peripheral blood of 22 patients with inactive familial Crohn's disease and their 35 healthy relatives including nine families. HLA-A, -B, and -DR antigens were determined in all the subjects. With the exception of minor abnormalities of suppressor cell activity present in some relatives of two families, neither significant impairments of immunological parameters in patients or their relatives nor concordant segregation of HLA haplotypes and disease were observed. These data indicate that peripheral immune abnormalities previously described in patients with Crohn's disease do not constitute primary factors involved in the disease itself and that familial incidence in Crohn's disease cannot be linked to immunological markers presently studied.     

Intestinal permeability and its association with the patient and disease characteristics in Crohn＇s disease

AIM：To assess the intestinal permeability （IP） in patients with Crohn＇s disease （CD） and study the association of IP with the patient and disease characteristics.
METHODS： One hundred and twenty five consecutive patients of CD （Males： 66） were diagnosed on the basis of a combination of standard clinical, endoscopic, imaging and histological features. CD activity index （CDAI） was used to calculate the activity of the disease while the behavior of the disease was assessed by the modified Montreal classification. IP was measured by the ratio of the percentage excretion of ingested doses of lactulose and mannitol in urine （LMR）. The upper limit of normality of LMR （0.037） was derived from 22 healthy controls.
RESULTS： Thirty six percent of patients with CD had increased IP. There was no significant difference in mannitol excretion （patients vs controls = 12.5% vs 14.2%, P = 0.4652）, but lactulose excretion was significantly higher in patients compared to healthy controls （patients vs controls = 0.326% vs 0.293%, P = 0.0391）. The mean LMR was also significantly higher in the patients as compared to healthy controls [0.027 （0.0029-0.278） vs 0.0164 （0.0018-0.0548）, P = 0.0044]. Male patients had a higher LMR compared to females [0.036 （95% CI 0.029, 0.046） vs 0.022 （95% CI 0.0178, 0.028） （P = 0.0024）, though there was no difference in the number of patients with abnormal IP in boththe sexes. Patients with an ileo-colonic disease had a higher LMR than those with only colonic disease [0.045 （95% CI 0.033, 0.06） vs 0.021 （95% CI 0.017, 0.025） （P 〈 0.001）]. Of patients with ileo-colonic disease, 57.8% had an abnormal IP, compared to 26.7% with colonic and 15.6% with small intestinal disease. Patients with a stricturing disease had significantly higher LMR compared to non-fistulising non-stricturing disease [0.043 （95% CI 0.032, 0.058） vs 0.024 （95% CI 0.019, 0.029） （P = 0.0062）]. There was no correlation of IP with age, disease activ     

Preliminary report on isolation of mycobacteria from patients with Crohn's disease

Several investigators have recently described the isolation of slow growing mycobacteria from the tissues of patients with Crohn's disease (CD). The primary purpose of this study was to culture and identify mycobacteria from the intestines of patients with CD and other intestinal diseases (control tissues). The culture methods were designed to eliminate most rapidgrowing mycobacteria and to enhance the isolation of slow growing mycobacteria. Eighty-two surgically resected intestinal tissue samples were cultured over a four-year period: 27 tissues were from CD patients and 55 from patients with other intestinal diseases. After 4–12 months of culture, five mycobacteria were isolated, but only two have been identified thus far. Both of these organisms appeared to have initially grown as spheroplasts, but revertant bacteria were cultivated after transfer into fresh media. Four of the mycobacteria were from CD tissues, and one isolate was from a control tissue. Two of the isolates have been identified as M. cheloneisubsp. abscessus,strain 390, and M. paratuberculosisstrain 410. This M. paratuberculpsisis similar to the previously identified M. paratuberculosisstrains isolated from other human intestinal tissues from patients with CD. Both strains 390 and 410 were inoculated into neonatal goats, but they failed to reproduce a CD-like disease. The isolation of four mycobacteria from 27 CD tissues and only one from 55 control tissues strengthens the findings of previous investigators and supports the hypothesis that mycobacteria may be etiologically associated with some cases of Crohn's disease.     

Gut-liver axis plays a role in hepatocarcinogenesis of patients with Crohn's disease

The development of hepatocellular carcinoma(HCC) is attributed to several factors,including chronic viral infection,alcohol consumption,exposure to aflatoxin B1 and metabolic disorders.Several recent reports have shown that HCC can occur in patients with longstanding Crohn's disease(CD) in the absence of other underlying high-risk liver diseases.There may be an association between CD and hepatocarcinogenesis,however,the precise mechanism for this requires further investigations.     

Virtual colonoscopy-induced perforation in a patient with Crohn＇s disease

We report a case of sigmoid colon perforation in a patient with Crohn's disease undergoing computed-tomographic (CT) colonography. A 70-year-old patient with Crohn's disease with terminal ileitis and sigmoid stricture underwent CT colonography after incomplete conventional colonoscopy. During the procedure, the colon was inflated by air insufflation and the patient developed abdominal pain with radiological evidence of retroperitoneal and intraperitoneal free gas. Hartmann's operation was performed. This case highlights that CT colonography is not risk-free. The risk of perforation may be higher in patients with inflammatory bowel disease.     

Experience with perirectal fistulas in patients with Crohn's disease

The experience of the senior author has been reviewed in dealing with perianal fistulas in patients with Crohn's disease. Early surgical therapy was advocated, the theory being, that perianal fistulas start as intersphincteric fistulas. This fistula is easily controlled surgically by fistulotomy with partial internal anal sphincterotomy. Delay in surgical treatment, especially in Crohn's patients, results in more complicated fistulas that may require colostomy or proctectomy. The presence of Crohn's disease did not affect the healing of fistulotomy. In our series fistulotomy was the treatment of choice in patients with 26 fistulas; 18 of 19 went on to full healing. We conclude that early fistulotomy, before an intersphincteric fistula has time to blossom fistulotomy, before an intersphincteric fistula has time to blossom into a more difficult management problem, is the treatment of choice in patients with Crohn's disease who have perianal fistulas Read at the XIIth, Biennial Congress of the International Society of University Colon and Rectal Surgeons, Glasgow, Scotland, July 10 to 14, 1988. Work performed at the Orlando Regional Medical Center, Orlando, Florida.     

Development of acute myelocytic leukemia in patients with Crohn's disease

Summary In our hospital within one year two patients with Crohn's disease were seen who developed an acute myelocytic leukemia. A review of the literature reveals eight previously reported patients with both Crohn's disease and leukemia. Six of the reported 10 patients have had acute myelocytic leukemia and, interestingly, three of them, including our two patients, have shown monocytic differentiation (FAB type M4). It has been suggested that the relative risk of leukemia, especially acute myelocytic leukemia, is increased in patients suffering from ulcerative colitis. More data of patients with Crohn's disease and acute leukemia are needed to evaluate the possible association between these diseases.