Showing papers in "Canadian Journal of Gastroenterology & Hepatology in 1990"

Overview of Newer Glucocorticosteroid Preparations for Inflammatory Bowel Disease

Abstract: Because the glucocorticosteroid receptor seems to be uniform in the human body, there is currently no support for a possibility of separating the therapeutic and adverse glucocorticosteroid actions at the receptor level. However, based on a new generation of glucocorticosteroids characterized by a high first pass metabolism in the liver, it seems possible today co reach a more selective topical therapy of inflammatory bowel disease. The properties of three new glucocorticosteroids are presented: the highly potent budesonide, fluticasone propionate and tixocortol pivalate - the latter with only low topical potency. Their properties can be exemplified by budesonide, which is currently the best documented compound. The topical potency of budesonide is 200 and 15 times higher than chose of hydrocortisone and prednisolone, respectively. This means that there is a high potential for anti-inflammatory and immunosuppressive actions on rectal and bowel mucosa. The compound is metabolically stable in the bowel compartment, which allows full retention of glucocorticosteroid activity in the target organ. However, when absorbed and distributed to the liver, there is a 90% first pass hepatic metabolism co metabolites of very low potency. This suggests that after topical application to rectal or bowel mucosa, glucocorticosteroid activity in the systemic circulation is low. This is in contrast to prednisolone, which has a hepatic first pass metabolism of just 20%.

Oral 5-ASA Versus Prednisone in Short Term Treatment of Crohn's Disease: A Multicentre Controlled Trial

Abstract: A multicencre randomized controlled trial was designed to compare the efficacy and safety of Eudragit-L coated oral 5-aminosalicylic acid (5-ASA) (Salofalk; lnterfalk) 3 g per day to a 'standard' oral prednisone therapeutic regimen in a 12 week treatment period of uncomplicated attacks of Crohn's ileitis and ileocolitis. Fifty patients with active Crohn's disease (Crohn's disease activity index [CDAI] 200 to 450) were randomized to receive either four 250 mg Eudragit-L-100 coated 5-ASA tablets three times a day for 12 weeks or oral prednisone ( 4 mg tablets) at a sustained 40 mg per day for two weeks followed by a 4 mg/day weekly dose reduction for the 10 subsequent weeks. Efficacy was determined by changes in the calculated CDAI and, as a novel assessment, the McMaster University quality of life index at two, four, six, eight, 10 and 12 weeks. Standard blood and urine values were obtained and physician's assessment completed at each two week visit. Clinical remission was obtained in 12 of 26 patients (46%) in the prednisone group and in nine of 19 (47%) in the 5-ASA group. Treatment failure was observed in three patients in each group. All other patients improved during the treatment period. Patients on prednisone reduced their CDAI scores significantly more rapidly during the first four weeks, but the reduction and maintenance of CDAI scores were similar in both groups for the remainder of the study period. In patients with ileocolitis, prednisone was significantly better than 5-ASA. Quality of life assessment parallelled the changes in CDAI, and appear a valid index. The two therapeutic regimens appear safe and did not disclose any unexpected adverse events or side effects. No significant biological abnormalities were detected in either treatment group. In conclusion, in this small trial, it was found that Salofalk at a dose of 3 g per day appears effective treatment for active Crohn's disease, and it is proposed chat higher doses may be beneficial in more extensive disease (ileocolitis) and during the first four weeks of treatment.

Role of Intestinal Microflora in Initiation and Perpetuation of Inflammatory Bowel Disease

Abstract: Ulcerative colitis and Crohn's disease occur in regions of the intestine colonized by the highest concentrations of normal flora bacteria and resemble certain chronic bacterial, viral or parasitic infections. However, the role of endogenous and pathogenic bacteria in the induction and perpetuation of chronic idiopathic intestinal inflammation remains controversial. No convincing evidence incriminates a single bacterial, mycobacterial or viral agent as the cause of a high percentage of cases of idiopathic inflammatory bowel disease (IBD). Subtle alterations of luminal microbial flora are nearly impossible to detect, but concentrations of certain anaerobic bacteria, including Bacteroides vulgatus, are increased in active Crohn's disease and correlate with disease activity. Recent investigations suggest mechanisms which bacteria may induce an autoimmune response through molecular mimicry or alterations in host antigens or immunoregulation. Intestinal bacteria contain formylated peptides and cell wall polymers ( endotoxin and peptidoglycan-polysaccharide complexes) which have potent and well characterized inflammatory and immunoregulatory properties and can produce acute and chronic intestinal and systemic inflammation in experimental animals. These proinflammatory molecules are probably absorbed more readily in IBO due ro increased mucosa! permeability during active and perhaps quiescent phases of disease. While the primary mechanisms of intestinal injury remain unknown, it is likely that commensal bacteria and their products amplify and perpetuate the inflammatory response of IBO and may be responsible for extraintestinal manifestations in addition to the frequent septic complications of these diseases.

Antioxidant Properties of 5-ASA: Potential Mechanism for Its Anti-Inflammatory Activity

Abstract: There is a growing body of experimental data to suggest that the inflamed intestine and/or colon may be subjected to considerable oxidative stress. The most probable source of these oxidants are the phagocytic leukocytes, since these cells are present in large numbers in the inflamed mucosa and are known to produce significant amounts of potentially injurious reactive oxygen species in response to inflammatory stimuli. The authors' laboratory and others have demonstrated that 5-aminosalicylic acid (5-ASA) possesses potent antioxidant activity, including free radical scavenging properties and the ability to decompose neutrophilic oxidants (eg, hypochlorous acid) and detoxify hemoprotein-associated oxidizing agents. 5-ASA has the additional property of being able to chelate iron and render it poorly redox active. Therefore, it is proposed that much of the anti-inflammatory activity of 5-ASA may be due to its numerous antioxidant properties.

A Double-Blind, Placebo Controlled, Multicentre Study of the Efficacy And Safety of 5-Aminosalicylic Acid Tablets in the Treatment of Ulcerative Colitis

Abstract: This double-blind, placebo controlled, multicentre, parallel trial assessed the efficacy of two oral doses of a new formulation of 5-aminosalicylic acid (5-ASA) targeted to release in the cecum which was given for six weeks to 136 patients with active ulcerative colitis. Seven centres participated (two Canadian, five American). Patients were randomly assigned to one of three treatment groups (4 g 5-ASA, 2 g 5-ASA or placebo). Medication was dispensed as 250 mg identically appearing tablets containing either 5-ASA or placebo to be taken four times a day. Subjects were assessed at baseline and after three and six weeks of treatment. Assessments included a disease activity index, physician's global assessment and flexible sigmoidoscopy. Compliance was assessed through pill count. A total of 136 patients participated ( 4 7 on 4 g 5-ASA, 45 on 2 g 5-ASA, and 44 on placebo). The three groups were similar in terms of age, weight, distribution of disease, extent of disease, and previous use of steroids or sulphasalazine. Ninety patients completed the six week study. Of the 46 dropouts, 38 (82.6%) left because of insufficient efficacy ( most on either place ho or 2 g 5-ASA), four (8.7%) had adverse reactions (all on 5-ASA), the remaining four (8.7%) left for reasons not related to their ulcerative colitis. The disease activity index represents a composite score ( maximum of 12) with categories for number of daily stools, presence of bleeding, abdominal pain and physician's assessment of disease activity. Patients who received 4 g 5-ASA daily demonstrated significant declines in disease activity index within three weeks of therapy and maintained improvement until the end of the stuuy. Although disease activity index declined for patients receiving 2 g 5-ASA daily, these changes did not reach statistical significance when compared to placebo-treated patients. On a five point scale (much improved, somewhat improved, unchanged, somewhat worse, much worse) the physician's global assessment mirrored the changes in disease activity index. Patients randomized to receive 4 g 5-ASA tablets were consistently noted as being either much or somewhat improved compared to placebo-treated patients. Side effects were few and minor and 52% (4 g 5-ASA), 42% (2 g 5-ASA) and 37% (placebo) of patients had no complaints. Headache was the most commonly cited adverse reaction for 6.9% (4 g 5-ASA) and 9.4% (2 g 5-ASA) of treated patients but 3.5% of placebo-treated patients also complained of headache. In conclusion in this randomized double-blind, placebo controlled study, patients with active ulcerative colitis randomized to 4 g 5-ASA per day noted improvement in disease activity as measured by disease activity index and physician's global assessment when compared to placebo-treated patients. ln contrast, patients who received 2 g 5-ASA daily did not demonstrate significant differences compared to the placebo group.

Endoscopic Obturation of Esophageal and Gastric Varices with a Cyanoacrylic Tissue Adhesive

Abstract: An original method of obturation of esophageal and gastric varices with a cyanoacrylic glue has been used for nine years. This method allows treatment of gastric and very large esophageal varices, which is difficult with common endoscopic sclerotherapy, and makes hemostasis in case of acute bleeding easier. There are few complications, none lethal.

Oral 5-Aminosalicyclic Acid Versus 6-Methylprednisolone in Active Crohn's Disease

Abstract: The response to 5-aminosalicylic acid (5-ASA) in active Crohn's disease was studied in comparison to methylprednisolone in a 24 week randomized double-blind multicentre study. Sixty-two patients were included in the analysis. Thirty were treated with 500 mg 5-ASA qid and 32 with methylprednisolone (starting dose 48 mg for one week, then reduced weekly to 32, 24, 20, 16 and 12 mg with maintenance at 8 mg/day for the remaining 18 weeks). Mean age, earlier surgical intervention, localization of Crohn's disease and extraintestinal manifestations were not different in both groups. The Crohn's disease activity index (CDAI) and the van Hees index were not significantly different in both treatment groups at the entrance examination (median CDAI 232 in the 5-ASA group and 220 in the methylprednisolone group). According to the protocol, treatment was stopped due to insufficient efficacy in 73% of the patients receiving 5-ASA and in 34% of the patients receiving methylprednisolone (x2 test P=0.0019). The area under the curve for the CDAl was significantly greater in 5-ASA (median 170) than in methylprednisolone (P≤0.007) (68). Eleven per cent of patients taking 5-ASA and 26% of patients taking methylprednisolone presented relevant side effects to treatment (not significant). It is concluded from these data that 5-ASA at the dose used in this study is not efficient in the treatment of active Crohn's disease. Considering recent studies in ulcerative colitis, a trial using a higher dose is indicated.

Trends in inflammatory bowel disease therapy

Abstract: This volume is the proceedings of the symposium 'Trends in Inflammatory Bowel Disease Therapy 1999' held in Vancouver, Canada, August 27-29, 1999, and sponsored by the Canadian Association of Gastroenterology, The Crohn's and Colitis Foundation of Canada and Axcan Pharma. It is the seventh international IBD symposium to be held in Canada and focuses on all areas of IBD therapy.Topics include: genetics; pathogenesis with reference to the role of autoimmunity, bacterial factors and neutrophil -- epithelial interactions; special clinical problems such as difficult diagnoses and challenges presented by children and the elderly; bone disease in IBD; an overview of current therapy; and a discussion of alternative therapy.

Pouch Surgery — The Importance of the Transitional Zone

Abstract: Patients with preservation of the transitional zone of the anal canal have less leakage and less need to wear pads than patients who have had mucosectomy. There is a significant difference in mean maximum resting pressure between patients that have had anal transitional zone preservation and mucosectomy. With preservation of the anal transitional zone, a mean maximum resting pressure of 57.6±3.8 mmHg was obtained compared with 47.3±4 mmHg in the mucosectomy group. Preservation of the resting pressure is dependent on preservation of internal anal sphincter integrity. The integrity of the sphincter is injured during mucosectomy due to anal dilation. Other factors affecting continence and stool frequency, such as diet, antidiarrheal medications, stool consistency and compliance, when examined were found to be unrelated factors.

Endoscopic Drainage of Pancreatic Pseudocysts

Abstract: Endoscopic drainage of pancreatic pseudocysts was attempted in 17 patients over an eight year period. There were nine cysts located in the head of the pancreas, six in the body and two in the tail. Endoscopic retrograde cholangiopancreatography was performed in all cases and the pancreatic duct satisfactorily opacified in 16 of the 17 patients. This study identified a communication with the pancreatic duct in seven cases. There were two cases in which multiple cysts were present; in each, one cyst was drained endoscopically and the others surgically. Endoscopic drainage of the cyst was immediately possible in 16 of 17 cases (94%). Late follow-up (mean 26 months) documented cyst disappearance in 11 cases (69%). None of the five patients with persistent cysts has required secondary surgical intervention, and the cysts are asymptomatic and stable or decreasing in size by serial scanning. There was one case (6%) in which a pseudocyst recurred following initial resolution. There were two complications (12%) requiring surgical intervention: gastrointestinal perforation with peritonitis in one patient and hemorrhage at the cyst margin from an arterial bleeder in another. There were no deaths at 30 days, but in one case a recurrent acute necrotizing pancrearitis occurred 36 days following endoscopic drainage and the patient died. This death was felt to be unrelated to the endoscopic procedure. In conclusion, internal drainage of pancreatic pseudocysts by endoscopic means can be proposed as an alternative to surgical drainage when the cyst can be identified as bulging into the stomach or duodenum. Immediate drainage is usually effective with a minimal long term recurrence rate.

Fish Oil in the Treatment of Ulcerative Colitis

Abstract: Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa. Eicosapentaenoic acid (EPA) competitively inhibits the cyclo-oxgenase pathway and reduces the formation of cyclo-oxygenase pathway products. EPA is a good substrate for lipoxygenase enzymes and is efficiently converted to leukotriene 85, which is less biologically active. The conversion of EPA to leukotriene B5 is as efficient as that of arachidonic acid to teukotriene B4. Two pilot studies showed benefit of EPA in the treatment of ulcerative colitis. Two of three controlled studies suggest that EPA is more effective than placebo in the treatment of active chronic ulcerative colitis. The mechanism of action is probably reduction of leukotriene B4, but EPA could increase cell and lysosomal membrane stability, or it may exert its effect by reducing interleukin-l. More controlled studies and detailed investigation into the mode of action of EPA are required.

Clinical Efficacy of Oral Mesalazine in Crohn’s Disease

Abstract: A randomized controlled trial was performed to evaluate in Crohn's disease the clinical efficacy and safety of a higher dose of a new slow-release preparation of mesalazine (500 mg tablets). Twenty-four patients created with 3 g mesalazine/day were compared with 26 patients treated with sulfasalazine (3 g/day) and methylprednisolone (initially 40 mg). All patients had active Crohn's disease diagnosed by endoscopy, sonography and radiology. Patients were characterized before entry into the study and at two, four, eight and 12 weeks of treatment by activity indices according to Best and van Hees, as well as by erythrocyte sedimentation rate, thrombocyte count, Broca index and serum albumin. All clinical and laboratory parameters were well matched for the two groups of patients. During treatment with mesalazine and sulfasalazine/ methylprednisolone, clinical remission could be observed in 20 of 24 patients (83%) and 23 of 26 patients (88%), respectively. There was no difference between the two groups except for a slightly higher increase of the Broca index in the combined treatment group. Side effects were reported in three (12.5%) and six (23%) patients treated with mesalazine and sulfasalazine/methylprednisolone, respectively. In conclusion, oral mesalazine at a dose of 3 g/day was effective in active Crohn's disease and was well tolerated by the patients.

Primary Sclerosing Cholangitis and Sarcoidosis. Case Report and Review of the Literature

Abstract: A 43-year-old man with longstanding ulcerative colitis developed primary sclerosing cholangitis established by cholangiography and liver biopsy. Within one year of the diagnosis of primary sclerosing cholangitis, pulmonary sarcoidosis developed, proven by chest x-ray and transbronchial biopsy. The sarcoidosis initially presented with systemic systems rather than dyspnea. The relationship between primary sclerosing cholangitis, sarcoidosis and the symptomatology are discussed. Concomitant primary sclerosing cholangitis and sarcoidosis may be more common than previously anticipated and could be a further manifestation of disordered immune regulation.

Efficacy and Tolerance of 5-Aminosalicylic Acid Suppositories in the Treatment of Ulcerative Proctitis: A Review of Two Double-Blind, Placebo Controlled Trials

Abstract: The efficacy and tolerance of 500 mg 5-aminosalicylic acid (mesalamine) suppositories in the treatment of ulcerative proctitis were assessed in two double-blind, placebo controlled studies of six weeks' duration, involving a total of 173 patients. In trial 1, patients used one 500 mg suppository tid. In trial 2, patients used one 500 mg suppository bid. Physician's global assessment and a disease activity index based upon patient symptoms and sigmoidoscopic appearance were used to assess efficacy. At the endpoint of trial l (tid), there was an 80.4% mean reduction in the disease activity index seen in patients treated with mesalamine compared to a 36.8% mean reduction in the placebo group (P<0.05). Analysis of the physician's global assessment indicated that 84.2% of patients receiving mesalamine were considered to be 'much improved' compared to 41 % of patients on placebo (P<0.01). At the endpoint of trial 2 (tid), there was a 74.7% mean reduction in disease activity index compared to 34.2% in the placebo group (P<0.001). Analysis of the physician's global assessment indicated that 79.2% of the mesalamine group was considered to be 'much improved' compared to 26.2% on placebo (P<0.001). There was no significant difference in efficacy seen in patients treated with 500 mg mesalamine suppositories bid or tid. Mesalamine suppositories are effective and well tolerated in the treatment of ulcerative proctitis.

Inflammatory Mediators in Inflammatory Bowel Disease

Abstract: Tissue responses to an inflammatory stimulus (such as vasodilation, plasma exudation invasion and activation of inflammatory cells) are elicited by locally synthesized chemical mediators. Inhibition of biosynthesis and/or antagonism of action of these mediators is an important target of drug therapy, particularly when the cause of the disease is unknown. Recent investigations have revealed that the mucosa of inflammatory bowel disease (IBD) patients synthesizes a number of inflammatory mediators in increased amounts. These include the potent chemoattractant leukotricne B4, which seems to be responsible for the increase in chemotactic activity found in IBO mucosa, and the cysteinyl leukotrienes, which promote plasma leakage and induce edema formation. Synthesis of leukotrienes in normal and inflamed mucosa is dose-dependently inhibited by sulphasalazine, 5-aminosalicylic acid (5-ASA) and 4-aminosalicylic acid, while indomethacin, which is devoid of therapeutic efficacy in IBD patients, inhibits prostaglandin hut not leukotriene synthesis. These findings suggest that in IBD, mucosal leukotrienes may be more important inflammatory mediators than prostaglandins. ln addition to arachidonic acid-derived products, IBD mucosa generates platelet activating factor and various cytokines including interleukin-1 and tumour necrosis factor, all of which have potent proinflammatory actions. formation of most of these agents is inhibited by sulphasalazine and 5-ASA. The relative importance and the interactions of the various inflammatory mediators synthesized in IBD mucosa remain to be clarified.

Collagenous Inflammatory Mucosal Diseases of the Gastrointestinal Tract

Abstract: A new group of collagenous inflammatory disorders of the gastric and intestinal mucosa has been described in the past two decades. These entities appear to be characterized by a distinct histopathologic lesion in the subepithelial region of the lamina propria. Functional alterations may also occur, presumably related to collagen deposition and the associated inflammatory process. Collagenous sprue is characterized by progressive and unrelenting malabsorption; a lethal outcome has usually been described, possibly reflecting the site of collagen deposition and the critical role of the small bowel for maintenance of a normal nutritional state. In contrast, collagenous colitis is characterized by persisting or episodic watery diarrhea; clinical impairment appears to be less severe but the entity is not rare, possibly reflecting its colonic localization. Most recently, collagenous gastritis, possibly accompanied by a functional reduction in acid secretion and impaired gastric emptying, has been recognized. Further definition of these entities is still required, particularly in relation to etiology, pathogenesis and effective therapy.

Upper Gastrointestinal Tract Crohn's Disease

Abstract: Crohn's disease may involve any site within the gastrointestinal tract. Usually pathology is present in the ileum and/or colon, but atypical presentations may occur with apparently 'isolated' involvement of the oropharynx, esophagus or gastroduodenum. If changes typical of Crohn's disease are detected in the upper gastrointestinal tract, then a careful assessment is required involving radiographic, endoscopic and histologic studies to determine if pathology is present in more distal intestine. In addition , microbiologic studies may be important to exclude infectious causes, especially of granulomas. If these studies are negative, prolonged follow-up may be required to establish a diagnosis of Crohn's disease. Although upper gastrointestinal involvement is increasingly recognized as a significant cause of morbidity in Crohn's disease, the treatment options are limited , largely anecdotal and need to be the subject of detailed epidemiologic investigation and clinical trials.

Six-Pack Balancing Act: A Conceptual Model for the Intestinal Lining

Abstract: The cells chat form the lining of the intestine belong to a class of cells termed 'polarized' or 'asymmetric.' The membranes surrounding these cells show functional differences at the luminal and contraluminal surfaces. The cells line up to form sheets and it is across these sheers that movement of fluids and solutes occurs. Such movement occurs in both directions across the lining and the occurrence of diarrhea or constipation depends to a considerable extent upon the net result of the absorptive and secretory mechanisms and their modulation by a host of factors such as neurotransmitters, bacterial products, drugs, etc. This review provides a simple framework for understanding the dynamics of the gut lining. Diamond's six-pack model of epithelia is modified to include the dynamic tension between absorptive and secretory mechanisms.

Overtubes and foreign bodies

Abstract: The most common article ingested in adults is food or food products such as nuts, shells, pits and bones. Poorly chewed steak causing bolus obstruction occurs especially in the elderly, while coins are most common in the pediatric group. New techniques of flexible endoscopy have altered and improved management, decreasing the need for surgery. A foreign body in the esophagus mandates prompt removal to avoid perforation. At least 80% of foreign, bodies reaching the stomach pass spontaneously. Once the foreign body is beyond the distal duodenum, it should be followed with serial x-rays. Techniques of removal of meat, bones, shells, bezoars, glass, bottle tops, sharps, pencils, pens, wires, thermometers, gastrostomy tubes, obesity balloons, safety pins, razor blades, button batteries and cocaine packets are described. Complications related to foreign body removal are rare.

Maintaining Remission in Distal Ulcerative Colitis and Ulcerative Proctitis

Abstract: Maintenance of remission is an important consideration in the medical care of patients with ulcerative colitis. The relapse rate is high when medications are discontinued. Many types of medications have been investigated for potential efficacy of maintaining remission. This paper reviews the literature on maintenance therapy for both distal and universal ulcerative colitis. Sulphasalazine is the drug of choice since il is effective and relatively low m cost. 5-aminosalicylic acid (5-ASA) derivatives, both oral and rectal forms, are also effective. Other medications such as metronidazole, cromolyn sodium and prednisone have nor been shown to be effective maintenance therapy. Strategies for maintenance are outlined and include possible regimens with 5-ASA enemas. While 1 g of 5-ASA is effective, the long term relapse rate is similar co that seen with sulphasalazine. Patients capered co 1 g 5-ASA enemas have a good chance of maintaining remission if the colitis does not flare within the first few months, because most colites will flare up early on. Other possible regimens include intermittent enemas, eg, every other night or every third night. Patients in remission can be safely maintained in remission with sulphasalazine or one of its 5-ASA derivatives.

Esophageal Carcinoma: Clinical TNM Staging with Endosonography and Computed Tomography

Abstract: The prognosis of esophageal carcinoma has remained poor despite improvement of diagnostic modalities. Endosonography and computed tomography were performed for preoperative TNM staging (clinical TNM) of esophageal carcinoma. Endosonography was superior to computed tomography for diagnosing early stages and nonresectability of carcinoma. Endosonography was also superior to computed tomography in diagnosing regional lymph node metastases. For diagnosing nonmetastatic lymph nodes, however, computed tomography was superior. Endosonography was superior for diagnosing celiac lymph node metastases but less accurate in detecting liver involvement. Endosonography was accurate for clinical TNM staging of esophageal carcinoma. The possibility of performing cytology and biopsy will further enhance the diagnostic value of endosonography.

Immune-Mediated Cytotoxicity in Inflammatory Bowel Disease

Abstract: Thirty years of research on the role of immune-mediated cytotoxic activity in the tissue injury of inflammatory bowel disease (IBD) has yielded only inconclusive data on the relevance of cytotoxic mechanisms. Two hypotheses have been advanced. One is that the destruction of target cells is mediated by direct recognition of target antigens by cytotoxic cells which in turn triggers lysis. Another hypothesis is that lysis occurs via an indirect bystander mechanism in which cells do not recognize a specific antigen on the target, but upon nonspecific activation release cytokines which are capable of lysing the target. The authors have investigated both hypotheses and studied the role of cytotoxic T cells and cytotoxic rectors released from activated T cells in the destruction of epithelial cells. Elevated levels of cytotoxic T cells were found in peripheral blood lymphocytes of patients with IBD, particularly Crohn's disease. The cytotoxic T cells were contained within the Leu 7

Natural Killer Cell and Large Granular Lymphocyte Deficiency in the Gut of Children with Inflammatory Bowel Disease

Abstract: The occurrence of natural killer cells and large granular lymphocytes (LGL) within the epithelium of colonic mucosa in children with inflammatory bowel disease (IBD) was compared to normal controls. Their numbers and localization within the epithelium from various regions of the colon were analyzed with immunohistochemical techniques using fluorescent, light and electron microscopy. The average number of natural killer cells and LGL in normal controls was 3.0±1.l per mn2. In contrast, there were no natural killer cells in the gut epithelium of children with IBD, irrespective of disease activity, whether the biopsy specimens were obtained from involved or uninvolved inflammatory regions of the gut, or the treatment status of the patients. However, the number of natural killer cells was normal in patients in remission with left-sided colitis. The lack of natural killer cells and LGL in the gut epithelium in children with IBD may be indicative of a possible genetic predisposition. The authors also present a new therapeutic strategy consisting of low dose interferon-alpha-2a that is efficacious in ameliorating ulcerative col iris and Crohn's disease and concomitantly increasing the number of natural killer cells and LGL in the gut.

Overview of Inflammatory Bowel Disease Pathogenesis

Abstract: Inflammatory bowel disease (IBD) represents a difficult and challenging condition for patients, clinicians and basic investigators alike. Its etiology and pathogenesis are still unclear in spite of extensive investigations that have yielded a wealth of clinical. epidemiological, biochemical, bacteriological and immunological data on Crohn 's disease and ulcerative colitis. Although the precise mechanism(s) responsible for the intestinal inflammatory process remain to be defined, enough information has been assembled to hypothesize which components are likely to be important for this probably multifactorial disease. A consistent association between class I or II histocompatibility antigens and either Crohn's disease or ulcerative colitis has yet to be found. Nevertheless, ample epidemiological studies leave no doubt about the high frequency of familial clustering, and it must be determined whether this phenomenon translates a true genetic predisposition or a common environmental exposure, or both. Immune events occurring in the gastrointestinal tract are unquestionably linked to the pathogenesis of IBD, but it is unknown which are primary or secondary in nature. While most immune abnormalities detected in patients with established disease are likely to represent secondary events, these are no less important, as they probably contribute to the perpetuation of gut inflammation and tissue damage. This does not exclude that IBD is due to a primary defect of intestinal immunity, but this may no longer be detectable at the time of clinical manifestations. The answer to the question of wh1ch of the various intestinal immune abnormalities is central to pathogenesis must wait for additional research. Whether immune responses to the luminal flora, antigen processing mechanisms, antibody production, immunoregulation, cytotoxic activity, cytokine and mediator release are defective or disregulated is under intense investigation. It is likely that several of these events are involved, but they may interact in a complex and unpredictable fashion. lt is almost certain that there are various initiating and secondary events, and different immune mechanisms share relatively few common pathways for damaging the intestine, eg, cytokines, arachidonic acid metabolites, and oxidants. Perseverance in the study of these substances is finally yielding promising new approaches to the manipulation of immune and inflammatory responses chat cause bowel destruction. Future drugs may consist of combinations of highly specific inhibitors, antagonists or receptor blockers, that may selectively block one or several steps of the inflammatory cascade which is chronically active in the intestine of affected individuals. Therefore, we may soon face a situation not too dissimilar from what we have recently witnessed for peptic ulcer disease. The specific cause of IBD may still be beyond our comprehension, but a better understanding of its pathogenesis al lows us to put highly effective therapies within reach.

Safety Profile of the New 5-ASA Based Compounds

Abstract: 5-aminosalicylic acid (5-ASA) preparations were anticipated to be and generally are better tolerated than sulphasalazine. Minor side effects such as headache, dizziness, abdominal pain and nausea do occur but are not more frequent than in placebo-treated patients. Approximately 10% of patients thought to be allergic to sulphasalazine are also allergic to 5-ASA. An idiosyncratic reaction with worsening of symptoms can occur. Diarrhea is more common with olsalazine, and it is due to the effect of olsalazine itself on the small bowel. not the 5-ASA component. There are case reports of pancreatitis, pericarditis and bronchospasm, retrosternal chest pain, mild neutropenia, nephrotic syndrome and hair loss associated with 5-ASA treatment. Patients with oligospermia due to sulphasalazine have improved when switched to 5-ASA. 5-ASA enemas can cause local irritation or other effects resulting from enema tip insertion.

Quality of Life after Liver Transplantation

Abstract: The results of liver transplantation are now well established in terms of graft and patient survival, but there is surprisingly little data on the quality of life attained. The authors mailed questionnaires to 32 consecutive adult liver recipients to assess their quality of life. Thirty-one patients (14 males, 17 females) with a mean age of 37 years (range 16 to 55), responded (97%). The mean time since transplantation was 19 months (range three to 50). Eighty percent of the respondents functioned at normal or near normal levels as measured by the Karnofsky Performance Index. Sixty-five per cent (20 patients) indicated they were currently able to live and function as they did before they became ill with liver disease. The respondents' scores were similar to normative scores on all of the following measures: life satisfaction, well being, and general affect (Campbell); and material well being, personal growth, marital relations, family relations and friendships (Evans). It is concluded that liver transplantation restores physical, mental and social well being in most patients with endstage liver disease.

Dysplasia in Ulcerative Colitis

Abstract: Patients at highest risk for developing cancer in ulcerative colitis are those with ‘extensive’ or total involvement of the large bowel who have had the disease for at least seven years. Dysplasia is used as a marker bur has many problems including those of sampling, reproducibility and management. The risk in patients with colitis is unclear particularly in those with left-sided or distal ulcerative colitis. In countries at high risk from colorectal cancer about 4 to 6% of the population can be expected to develop this disease. It is assumed that surveillance will reduce the mortality from colorectal cancer, although the evidence that this is happening is very limited. Cancers which are resected but from which the patient survives are an acceptable outcome, although less so in theory, as survival is to a certain extent fortuitous. Many surveillance studies include patients who have both developed and died from carcinoma. Surveillance also assumes that cancers can be detected before they have become lethal, or that a marker such as the presence of dysplasia precedes all carcinomas for a long enough period of time to be detectable. Considerable question has been raised as to whether dysplasia is both endoscopically detectable and morphologically identifiable. Surveillance is based on the principle that carcinoma arises from a cancerous lesion, and that the identification of dysplasia and excision of the large bowel in these patients prevents subsequent death from disseminated carcinoma. Conversely, patients with quiescent disease and no dysplasia could be followed and not subjected to unnecessary colectomy. There is currently no ‘best’ way of managing patients with colitis who are at risk for developing carcinoma. Routine follow-up of patients relies heavily on colonoscopy with multiple biopsies. Controversy continues regarding the management of dysplastic biopsies because there are relatively few data regarding the likelihood of an underlying invasive carcinoma on which to base a rational decision. The notion that all patients must be managed on an individual basis, guarantees that data remain difficult to obtain. The presence of a dysplasia-associated lesion or mass are high risk factors for carcinoma. Dysplasia is frequently confined to small areas of the mucosa causing major sampling problems for the endoscopist both in detection and if confirmation by re-endoscopy is proposed. The finding of aneuploidy as a marker for both dysplasia and carcinoma may prove useful in the detection of patients at greatest risk.

Immunogenetic Susceptibilities in Inflammatory Bowel Disease

Abstract: It is now clear that the major identified risk factor for the inflammatory bowel diseases (IBDs) is a positive family history. Furthermore, the available data in spouses and twins indicate that the genetic susceptibility is due in large measure to shared familial predisposition. This emphasizes the importance of identifying the actual familial susceptibilities. Given the data for immunopathogenetic etiologies in the genesis of IBD, the logical candidate genes are those that involve the immune system. Data for several of these gene marker systems have been considered confusing or inconclusive. When approached with the concept that IBD is a genetically heterogeneous group of disorders, patterns are beginning to emerge for the human lymphocyte antigen class II region genes on chromosome 6, and the complement C3 gene on chromosome 19. Available data do not yet implicate the immunoglobulin or T cell receptor genes, but further studies are needed, especially for the latter. Firm identification of genetic susceptibilities will require the study of an adequate number of families, which is being facilitated by the establishment of an IBD family-based cell line bank. Identification of the genes that predispose to IBD will allow the study of natural history from susceptibility to clinical disease and, when understood, will provide new approaches to disease therapy and even prevention.

Helicobacter (Campylobacter) pylori and Acid Peptic Diseases

Abstract: Helicobacter pylori is a spiral-shaped Gram-negative bacteria implicated as a cause of histological gastritis, contributing to peptic ulcer disease and perhaps playing a role in gastric cancer in humans. The organism is found worldwide; the prevalence of infection increases with age; and colonization probably persists for life. Diagnostic approaches chat have been used include tissue stains, culture of stomach biopsy specimens, labelled-urea breath tests and serology. It is too early to advocate treatment for all infected individuals; the benefits and risks have yet to be carefully studied and assessed.