Infliximab downregulates interferon-gamma production in activated gut T-lymphocytes from patients with Crohn's disease.

Agnholt J, Kaltoft K. Department of Medicine, Aarhus University Hospital, Aarhus C, Denmark. agnholt@dalnet.dk

Cytokine 2001 Aug 21;15(4):212-22

The tumour necrosis factor-alpha (TNF-alpha) neutralizing antibody, Infliximab (Ifx), reduces disease activity in patients with active steroid-dependent or fistulizing Crohn's disease. The mechanisms underlying the effects of Ifx are not fully understood. This study aims to investigate if and how Ifx regulates the interferon-gamma (IFN-gamma) production in human intestinal T-cells. Colonic T cells were expanded from 25 patients with Crohn's disease and ten healthy controls in an in vitro system, using medium supplemented with interleukin-2 and interleukin-4 but without exogenous antigen. The effect of Ifx was investigated in these in situ activated T cell cultures regarding the IFN-gamma production, proliferation, transmembrane TNF-alpha expression, cytolysis and apoptosis. T cell cultures from patients with Crohn's disease produced significantly higher levels of IFN-gamma (<0.001) and TNF-alpha (P=0.04) than T cell cultures from healthy controls. The production of IFN-gamma was downregulated by Ifx in early T cell cultures (P=0.002). Ifx bound to transmembrane TNF-alpha of activated T cells without inducing complement-mediated cytolysis, apoptosis and without affecting proliferation. Besides its known TNF-alpha neutralizing property, Ifx downregulates INF-gamma production in colonic T cell cultures. Colonic T cells express transmembrane TNF-alpha that binds Ifx. The data suggest that Ifx reduces the level of at least two pro-inflammatory cytokines leading to lower disease activity. Copyright 2001 Academic Press.

Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue.

Baulieu EE, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharriere O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J, Le Bouc Y, Raynaud A, Girerd X, Forette F. Institut National de la Sante et de la Recherche Medicale Unit 488 and College de France, 94276 Le Kremlin-Bicetre, France. baulieu@kb.inserm.fr

Proc Natl Acad Sci U S A 2000 Apr 11;97(8):4279-84

The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical-medical network in the United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly men and women. Two hundred and eighty healthy individuals (women and men 60-79 years old) were given DHEA, 50 mg, or placebo, orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active steroids was recorded. Besides the reestablishment of a "young" concentration of DHEAS, a small increase of testosterone and estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological-clinical manifestations here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry (DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging, but does not create "supermen/women" (doping).

[Sugar free diet: a new perspective in the treatment of Crohn disease? Randomized, control study] [Article in German]

Brandes JW, Lorenz-Meyer H.

Z Gastroenterol 1981 Jan;19(1):1-12

Since several studies have shown that patients with Crohn's disease have an increased consumption of refined carbohydrates, the influence of a diet excluding refined sugar on the course of the disease was examined. In a randomised control trial, 20 patients (10 patients in each group) with Crohn's disease were treated for an average of 18 months with two different diets. The patients used in the study had a low or middle activity of the disease. Drug treatment was omitted 14 days before commencement of the study. The first group was treated with a low carbohydrate diet (refined sugar excluded), the second group received a high carbohydrate diet (refined sugar-rich). In patients with higher activities of the disease (activity index 100-200 points), the diet which restricted refined sugar was superior to the sugar-rich diet; in 4 out of 5 patients the disease activity decreased and remained so throughout the study-period. In contrast to this 4 patients treated with the sugar-rich diet had to be taken off the treatment because of increasing activities of the disease. In patients with quiescent disease (activity index less than 100 points), neither of the diets showed detrimental effects. The statistical analysis of clinical and laboratory dates noted during the study period resulted in no significant differences between the two groups.

Effect of long-term oral glutamine supplements on small intestinal permeability in patients with Crohn's disease.

Den Hond E, Hiele M, Peeters M, Ghoos Y, Rutgeerts P. Department of Gastroenterology, University Hospital Leuven, Belgium.

JPEN J Parenter Enteral Nutr 1999 Jan-Feb;23(1):7-11

Background: Glutamine is a major fuel and an important nitrogen source for the small intestinal cell. It plays a key role in maintaining mucosal cell integrity and gut barrier function. Increased permeability may be a factor in the pathogenesis of Crohn's disease and may be an interesting parameter in the follow-up of the disease. Therefore, the aim of this study was to examine whether oral glutamine supplements are able to restore an increased intestinal permeability in patients with Crohn's disease.

METHODS: The inclusion criteria for the study were Crohn's disease and a disturbed small intestinal permeability for 51Cr-EDTA. Of 38 patients screened, 18 had an increased permeability (6 hours urinary excretion >1.1% of label recovered in urine). Fourteen patients were included in the study and were randomized to receive either oral glutamine (7 g three times per day; n = 7) or placebo (7 g glycine three times per day; n = 7) in addition to their normal treatment during a 4-week period. The study was performed in a double-blind manner. RESULTS: Baseline permeability (mean SD) was 2.32%0.77% dose in the glutamine group and 2.29%0.67% dose in the placebo group. Permeability did not change significantly after glutamine (3.26%2.15% dose) or after placebo (2.27%1.32% dose). There was no significant effect on plasma glutamine, plasma glutamate, plasma ammonium, Crohn's disease activity index, C-reactive protein, or nutritional status.

CONCLUSIONS: Oral glutamine supplements, in the dose administered, do not seem to restore impaired permeability in patients with Crohn's disease.

Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor.

Dieckgraefe BK, Korzenik JR. Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8124, St Louis, MO 63110, USA. dieck@im.wustl.edu

Lancet. 2002 Nov 9;360(9344):1478-80.

Treatment for Crohn's disease is aimed at immunosuppression. Yet inherited disorders associated with defective innate immunity often lead to development of a Crohn's-like disease. We performed an open-label dose-escalation trial (4-8 microg/kg per day) to investigate the safety and possible benefit of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of 15 patients with moderate to severe Crohn's disease. No patients had worsening of their disease. Adverse events were negligible and included minor injection site reactions and bone pain. Patients had a significant decrease in mean Crohn's disease activity index (CDAI) score during treatment (p<0.0001). After 8 weeks of treatment, mean CDAI had fallen by 190 points. Overall, 12 patients had a decrease in CDAI of more than 100 points, and eight achieved clinical remission. Retreatment was effective, and treatment was associated with increased quality-of-life measures. GM-CSF may offer an alternative to traditional immunosuppression in treatment of Crohn's disease.

Mucosal metabolism in ulcerative colitis and Crohn's disease.

Duffy MM, Regan MC, Ravichandran P, O'Keane C, Harrington MG, Fitzpatrick JM, O'Connell PR. Department of Surgery, Mater Misericordiae Hospital and University College, Dublin, Ireland.

Dis Colon Rectum 1998 Nov;41(11):1399-405

PURPOSE: Colonic mucosal metabolism of butyrate may be impaired in ulcerative colitis. In this study we sought to confirm this observation, to determine if a similar change occurs in Crohn's colitis, and to establish whether a panenteric disorder of butyrate metabolism exists in either condition.

METHODS: With use of a microculture technique, mucosal metabolic fluxes of 14[C]-labeled butyrate and 14[C]-labeled glutamine were measured as 14[C] carbon dioxide production in mucosal biopsy specimens from the colon and ileum in patients with ulcerative colitis, Crohn's colitis, and healthy bowel. Results were expressed as pmol/microg biopsy DNA/hour.

RESULTS: In the colon the mucosal metabolic fluxes of both butyrate and glutamine are reduced in both ulcerative colitis and Crohn's colitis compared with healthy controls. These changes were most marked in the presence of moderate to severe mucosal inflammation, there being no significant difference in mucosal metabolic flux between mildly inflamed mucosa and healthy controls. In the ileum the mucosal metabolic fluxes of butyrate and glutamine did not differ between healthy controls and those with either ulcerative colitis or Crohn's colitis.

CONCLUSIONS: Changes in colonic mucosal metabolism of butyrate and glutamine in inflammatory bowel disease occur as a consequence of the inflammatory process and are not peculiar to ulcerative colitis. Ileal mucosal metabolism is unchanged in ulcerative colitis and Crohn's colitis, indicating the absence of a panenteric abnormality of mucosal metabolism in these two conditions.

Infliximab for the treatment of Crohn's disease: efficacy, safety and pharmacoeconomics.

Feagan BG, Enns R, Fedorak RN, Panaccione R, Pare P, Steinhart AH, Wild G. London Clinical Trials Research Group, London, Canada. feagan@lctrg.com

Can J Clin Pharmacol 2001 Winter;8(4):188-98

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. From the perspective of the patient, symptoms of the disease significantly impair quality of life and interfere with activities of daily living. Conventional medical treatment of Crohn's disease includes the use of nonspecific anti-inflammatory drugs, immunosuppressives and antibiotics. These therapies are characterized by a delayed onset of action, incomplete response rates and a substantial risk of adverse effects. Although surgery is frequently used to treat complications, postoperative recurrence is an important problem. Infliximab, a chimeric monoclonal antibody directed toward tumour necrosis factor alpha, is highly effective for the treatment of active Crohn's disease. In randomized, placebo-controlled clinical trials, 82% of patients who received 5 mg/kg of Infliximab had a clinically significant response, compared with 17% of those given placebo (P<0.001). Moreover, Infliximab is the only medical therapy that has been shown to be effective for the treatment of fistulizing Crohn's disease. Infusion reactions are the most common adverse effect. Whether treatment with Infliximab is associated with an increased risk of neoplasia, infection or autoimmune disease is unknown. Therefore, further long term safety studies are required. Despite the relatively high cost of drug acquisition, preliminary pharmacoeconomic analysis indicates that Infliximab is cost effective compared with existing treatments. Infliximab is recommended for the treatment of active Crohn's disease refractory to conventional drugs, and is the treatment of choice for fistulizing Crohn's disease.

Nutritional supplementation with N-3 fatty acids and antioxidants in patients with Crohn's disease in remission: effects on antioxidant status and fatty acid profile.

Geerling BJ, Badart-Smook A, van Deursen C, van Houwelingen AC, Russel MG, Stockbrugger RW, Brummer RJ. Department of Gastroenterology, University of Maastricht, The Netherlands.

Inflamm Bowel Dis 2000 May;6(2):77-84

In patients with Crohn's disease (CD), malnutrition is frequently observed and is generally accepted to be an important issue. The aim of this study was to investigate the effects of 3 months of supplementation with a liquid formula containing either antioxidants (AO) or n-3 fatty acids plus AO on the antioxidant status and fatty acid profile of plasma phospholipids and adipose tissue, respectively, in patients with long-standing CD currently in remission. In a randomized, double-blind placebo-controlled study, CD patients received either placebo, AO, or n-3 fatty acids plus AO for 3 months in addition to their regular diet. In all, 25/37 CD patients completed the study. AO status was assessed by blood biochemical parameters. A statistical per-protocol analysis was performed. Serum concentrations of selenium, vitamin C, and vitamin E, the activity of superoxide dismutase and total antioxidant status were significantly (p < 0.05) increased after AO supplementation. Furthermore, compared with controls, serum concentrations of beta-carotene, selenium, and vitamin C and the activity of glutathione peroxidase (GPx) were significantly (p < 0.05) lower before supplementation; however, after AO supplementation these levels were not significantly different from controls (except for GPx). N-3 fatty acids plus AO supplementation significantly (p < 0.05) decreased the proportion of arachidonic acid, and increased the proportion of eicosapentanoic acid and docosahexanoic acid in both plasma phospholipids and adipose tissue. Supplementation with antioxidants improved antioxidant status in patients with CD in remission. In addition, supplementation with n-3 fatty acids plus antioxidants significantly changed the eicosanoid precursor profile, which may lead to the production of eicosanoids with attenuated proinflammatory activity. This study indicates that an immunomodulating formula containing n-3 fatty acids and/or AO may have the potential to play a role in the treatment of CD.

Controlled trial of polymeric versus elemental diet in treatment of active Crohn's disease.

Giaffer MH, North G, Holdsworth CD. Gastroenterology Unit, Royal Hallamshire Hospital, Sheffield.

Lancet 1990 Apr 7;335(8693):816-9

30 patients with active Crohn's disease, mean Crohn's Disease Activity Index 301 (SE 32), who would otherwise have been treated with steroids, were randomised to receive for 4 weeks either an elemental diet ('Vivonex') (n = 16) or a polymeric diet ('Fortison') (n = 14). Assessment on days 10 and 28 showed that clinical remission occurred in 5 (36%) of the 14 patients on fortison compared with 12 (75%) of the 16 patients assigned to vivonex. The difference in remission rate was significant (p less than 0.03). Dietary treatment resulted in little change in the nutritional state and various laboratory indices of activity over a 4 week period despite clinical improvement. Polymeric diets do not seem to offer an effective therapeutic alternative to elemental diets in patients with acute exacerbations of Crohn's disease.

DHEA and the skeleton (through the ages).

Gordon CM, Glowacki J, LeBoff MS. Division of Adolescent/Young Adult Medicine, Children's Hospital, Boston, MA 02115, USA. Gordon_c@al.tch.harvard.edu

Endocrine 1999 Aug;11(1):1-11

Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the most abundant steroids 0in the human circulation, although their exact biological significance is not completely understood. DHEA(S) levels are high in fetal life, decrease after birth, and show a marked pubertal increase to a maximal level during young adulthood. In healthy adults, DHEAS levels decline to 10-20% of peak levels by age 70 yr. This review summarizes information concerning the role of DHEA in skeletal physiology, including modulation of the skeletal insulin-like growth factor regulatory system, and its effects on secretion of proresorptive cytokines. The pattern of secretion of DHEA throughout the life cycle is discussed, as well as its potential usefulness in specific disease states as an agent with anabolic and antiosteolyic effects on bone.

Refined carbohydrate, smooth-muscle spasm and disease of the colon.

Grimes DS.

Lancet 1976 Feb 21;1(7956):395-7

A diet high in refined carbohydrate is implicated in the aetiology of some diseases of the colon-i.e., diverticular disease, irritable bowel syndrome, ulcerative colitis, non-occlusive ischaemic colitis, and pseudomembranous colitis. It is suggested that spasm of the smooth muscle is the common pathogenetic mechanism in these colonic diseases. The strength of the spasm producing increased pressure in the colonic lumen or wall and the length of time for which the colon has been affected are believed to determine the type of disease resulting. A diet high in refined carbohydrate allows the intense muscle spasm to occur because the physical buffering effect of faecal bulk is considerably reduced.

Management of Crohn's Disease in Adults.

Hanauer SB and Sandborn W.

Am J Gastroenterol March 2001;96:635-643.

No abstract available.

Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: the possible role of nitric oxide.

Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, Sumi D, Jayachandran M, Iguchi A. Department of Geriatrics, Nagoya University School of Medicine, Nagoya, Japan. hayashi@med.nagoya-u.ac.jp

Arterioscler Thromb Vasc Biol 2000 Mar;20(3):782-92

Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg x kg(-1) x d(-1)), a specific aromatase inhibitor; group 4, an HCD plus 17beta-estradiol (20 microg x kg(-1) x d(-1)); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by approximately 60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that approximately 50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17beta-estradiol.

[Chemically prepared fats and Crohn disease. A pilot study of the occurrence of trans-fatty acids in the subcutaneous tissue of Crohn patients in comparison with healthy controls as a parameter of long-term fat intake] [Article in German]

Heckers H, Melcher FW, Kamenisch W, Henneking K. Zentrum fur Innere Medizin, Justus-Liebig-Universitat Giessen.

Z Gastroenterol 1988 May;26(5):259-64

In a pilot study the fatty acid pattern of subcutaneous adipose tissue from 22 patients with Crohn's disease and 22 subjects of a healthy control group was analyzed using glass capillary gas-liquid chromatography. Among all fatty acids amounting to at least 1% peak area of the chromatograms, only trans-octadecenoate differed significantly (p less than 0.05) between both study groups, the mean value being 2.39 0.83% in patients with Crohn's disease and 1.96 0.46% in healthy controls. Also the mean value of trans-hexadecenoate was significantly (p less than 0.05) higher in the Crohn group (0.25 0.07%) than in the control group (0.21 0.06%). There was a strongly positive linear correlation (p less than 0.001) between the trans-hexadecenoate and trans-octadecenoate values for the Crohn patients but not for the controls. Our results demonstrate that patients with Crohn's disease as a group consume more trans-monoene fatty acids than healthy controls, thus providing evidence for a higher intake of chemically processed fats like margarine, shortenings, frying and cooking fats. In further studies which are necessary to examine Guthy's hypothesis the fatty acid composition of adipose tissue should be followed up as an ideal marker of long-term dietary compliance.

Treatment of Crohn's disease.

Hoffmann JC, Zeitz M. Innere Medizin II, Universitatskliniken des Saarlandes, Homburg, Germany. joerg.hoffmann@medrz.uni-sb.de

Hepatogastroenterology 2000 Jan-Feb;47(31):90-100

The treatment of Crohn's disease depends on disease location and disease activity. It can be divided into medical and surgical treatment. While surgery is reserved for complications such as abscesses or failure of pharmacological treatment (fistulae, perianal disease, or strictures) medical treatment aims at induction and maintenance of remission. In order to achieve these goals supportive and therapeutic strategies must be used. Supportive measures include substitution of vitamins, particularly fat-soluble vitamins, and minerals in deficiencies due to resection or disease involvement of the small bowel. All patients on long-term steroids should receive calcium and vitamin D in order to prevent osteoporosis. Therapeutic options include drug treatment (corticosteroids, antibiotics, salicylates, and immunosuppressives), nutrition (parenteral or enteral), and endoscopy (dilatation of strictures). Depending on disease location different pharmacologic preparations of salicylates or corticosteroids should be used, e.g., enemas for distal colitis. The most potent drugs for long-term control are immunosuppressive agents, particularly azathioprine. It is the most widely investigated immunosuppressive agent in Crohn's disease and should be the first line treatment for patients with steroid refractory, chronic steroid dependent, fistulating, and stenosing courses. In the future, more potent drugs and better risk stratification criteria should improve the treatment of Crohn's disease.

Consumption of refined sugar by patients with Crohn's disease, ulcerative colitis, or irritable bowel syndrome.

Jarnerot G, Jarnmark I, Nilsson K.

Scand J Gastroenterol 1983 Nov;18(8):999-1002

The daily dietary consumption of refined sugar was studied in four equal-sized groups of 30 patients with Crohn's disease, ulcerative colitis (UC), irritable bowel syndrome (IBS), or minor orthopedic conditions. The latter group was matched for sex and age with the Crohn's disease group. The Crohn's disease patients consumed significantly more refined sugar (88.9 50.7 (SD) g/day) than the controls (64.3 45.6 g/day), the UC patients (64.3 38.7), or the IBS patients (59.9 33.3). Fifteen patients with Crohn's disease interviewed within 6 months of diagnosis consumed similar amounts of sugar (69.9 43.9) to those of the subjects in the other three groups. Fifteen other patients with Crohn's disease studied 7-36 months after diagnosis consumed significantly more refined sugar (107.9 41.2). These results indicate that the high sugar consumption in Crohn's disease is a secondary phenomenon without etiologic importance.

Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease.

Korzenik JR, Dieckgraefe BK. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Dig Dis Sci. 2000 Jun;45(6):1121-9.

The current hypothesis for the etiology of Crohn's disease proposes an excessive immune response, largely T-cell driven, possibly against endogenous bacteria. Standard therapy is therefore directed towards suppression of this immune response. An alternative theory of pathogenesis accounts for epidemiologic and pathophysiologic observations that have been hitherto underemphasized, namely, (1) genetic disorders with deficiencies in neutrophil function can give rise to a clinical and pathologic syndrome indistinguishable from Crohn's; (2) abnormal neutrophil function is well described in Crohn's disease; (3) a group of bacteria implicated in other chronic inflammatory disorders causes impairment of neutrophil function; and (4) 20th century environmental risk factors for Crohn's disease may directly suppress neutrophil function and may have led to a shift in the dominant gut flora with similar effects. We propose that some cases of Crohn's disease result from the interaction of environmental and genetic influences leading to impaired mucosal neutrophil function, resulting in failure to effectively clear intramucosal microbes effectively. While encompassing existing data, this hypothesis proposes a proximate defect in the mucosal immune response. If this paradigm were correct, new therapeutic approaches might involve strategies to alter intestinal flora and stimulate neutrophil function.

Influence of diets high and low in refined sugar on stool qualities, gastrointestinal transit time and fecal bile acid excretion.

Kruis W et al.

Gastroenterology 92:1483, 1987

No abstract available.

DHEA(S): the fountain of youth.

Leowattana W. Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

J Med Assoc Thai 2001 Oct;84 Suppl 2:S605-12

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are weak androgens produced primarily by the adrenal gland. Although their plasma concentrations by far exceed those of any other adrenal product, their physiological roles have not yet been determined. In plasma, where the major portion of these hormones is present in the sulfate form, it is possible that DHEAS serves as a reservoir for DHEA. Since various tissues have been shown to contain steroid sulfatases. The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years, decrease progressively thereafter, and diminish by 95 per cent around the age of 85 years. The decline of DHEAS concentrations with aging has led to the suggestion that DHEAS could play a role in itself and be implicated in longevity. Moreover, the epidemiological evidence has shown that adult men with high plasma DHEAS levels are less likely to die of cardiovascular disease. DHEA has also been shown to increase the body's ability to transform food into energy and burn off excess fat. Another recent finding involves the anti-inflammatory properties of DHEA. It has been known that DHEA can lower the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). It should be pointed out that chronic inflammation is known to play a critical role in the development of the killer diseases of aging: heart disease, Alzheimer's disease and certain types of cancer. In conclusion, DHEA or DHEAS administration combined with conventional treatment may be implicated in particular conditions to improve the quality of life.

Gut Dysfunction and Chronic Disease: The Benefits of Applying the 4R GI Restoration Program

Liska, D.J., Lukaczer, D.

2001 Oct. Applied Nutritional Science Reports, MET 558. Gig Harbor, WA: Advanced Nutrition Publications Inc. (reprint available from the Institute of Functional Medicine, Gig Harbor, WA).

Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group).

Lorenz-Meyer H, Bauer P, Nicolay C, Schulz B, Purrmann J, Fleig WE, Scheurlen C, Koop I, Pudel V, Carr L. Med. Klinik I, Stadt. Krankenhaus, Germany.

Scand J Gastroenterol 1996 Aug;31(8):778-85

BACKGROUND: There is no established therapy for maintaining remission in patients with Crohn's disease. Following different suggestions from the literature, two potential interventions for maintaining remission were tested against placebo, using either 5 g/day of a highly concentrated omega-3 fatty acid compound or a carbohydrate-reduced diet (84 g/day).

METHODS: A total of 204 patients were recruited after they had had an acute relapse. After remission (CDAI < or = 150) was attained with steroid therapy, patients were randomized to receive either omega-3 fatty acids (n = 70), placebo (n = 65), or diet (n = 69). Low-dose prednisolone was given to all patients for the first 8 weeks of intervention. CDAI and an acute-phase protein (CRP) were used as criteria for a relapse.

RESULTS: The proportion of patients without relapse within a year were similar in the placebo and active treatment group (intention-to-treat analysis: placebo, 30%; active treatment, 30%; protocol-adhering patients, 29% versus 28%). Patients did gain benefit (53%; p = 0.023) for as long as they maintained the diet. However, intention-to-treat analysis (diet group, 40%) did not show a noticeable difference when compared with placebo.

CONCLUSIONS: Omega-3 fatty acids did not show an effect on extending the remission in Crohn's disease. For the diet patients the question remains whether the noncompliant patients dropped out early because they sensed a relapse approaching or whether their condition deteriorated because they failed to comply with the diet.

Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway.

Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Department of Medicine, University of Munster, Munster, Germany.

Gastroenterology 2001 Nov;121(5):1145-57

BACKGROUND & AIMS: Treatment with a chimeric anti-tumor necrosis factor (TNF) antibody (Infliximab) has been shown to be highly efficient for patients with steroid-refractory Crohn's disease (CD). However, the mechanism of action remains largely unknown. As monocytopenia is commonly observed after treatment with Infliximab, we investigated the role of Infliximab-induced monocyte apoptosis.

METHODS: Peripheral blood monocytes from healthy volunteers and patients with chronic active CD (CDAI > 250) were isolated by density gradient centrifugation methods. Apoptosis was determined by annexin V staining DNA-laddering, and transmission electron microscopy. Activation of caspases and mitochondrial release of cytochrome C was determined by immunoblotting. Transcriptional activation of members of the Bcl-2 family have been analyzed by ribonuclease protection assay.

RESULTS: Treatment with Infliximab at therapeutic concentrations resulted in monocyte apoptosis in patients with chronic active CD in a dose-dependent manner. Infliximab-induced monocyte-apoptosis required the activation of members of the caspase-family since activation of caspase-8, -9, and -3 could be determined. Caspase activation was induced by a CD95/CD95L independent signaling pathway with mitochondrial release of cytochrome C. Cytochrome C release seemed to be triggered by transcriptional activation of Bax and Bak. Monocyte apoptosis in vivo as determined by annexin-V binding and caspase-3 activation could be shown in patients with chronic active CD as soon as 4 hours after treatment with Infliximab.

CONCLUSIONS: Monocyte apoptosis induced by Infliximab may be an important mechanism that could explain the powerful anti-inflammatory properties of Infliximab in patients with chronic active CD.

[Treatment with chimeric monoclonal antitumor necrosis factor (Infliximab) of patients with active steroid-dependent/resistant Crohn's disease and fistulas] [Article in Italian]

Martorana G, Casa A, Oliva L, Orlando A, Cottone M. Divisione di Medicina e Pneumologia, Clinica Medica R, Azienda Ospedaliera V. Cervello, Palermo.

Recenti Prog Med 2001 Jul-Aug;92(7-8):451-5

30 patients--13 with active steroid-dependent/resistant Crohn's disease (CD), 8 with active steroid-dependent/resistant disease complicated by fistulas and 9 with fistulas only (perianal or abdominal)--were treated with Infliximab. "Clinical response or remission" were defined as the reduction by 70 or more points or below 150 points of the CDAI score, respectively. As regards fistulas, "response" was defined as the reduction of 50 percent or more from baseline in the number of draining fistulas or of the quantity of drainage, "remission" as their closure. At 8 weeks 13/21 (61.9%) patients treated for active disease went on remission and 6/21 (28.5%) had a clinical response; 6/17 (35.2%) patients treated for fistulas went on remission and 8/17 (47%) had a response, while 3/17 (17.6%) didn't have any response. At 24 weeks, 9/12 (75%) patients treated for active disease and 13/16 (81.25%) treated for fistulas had a recurrence in a median time of 18.3 weeks (range, 1-36 weeks) after the first infusion.

Diet in Crohn's disease two studies of current and previous habits in newly diagnosed patients.

Mayberry JF, Rhodes J, Allan R, Newcombe RG, Regan GM, Chamberlain LM, Wragg KG.

Dig Dis Sci 1981 May;26(5):444-8

The consumption of sugar and sugar-containing foods in 32 patients with recently diagnosed Crohn's disease was significantly greater than in matched controls; the assessment was made by a questionnaire and depended upon patients recalling their eating habits. In a further study of 16 patients with Crohn's disease, all food eaten over 5 days was weighed and recorded, and no significant difference was found in the consumption of carbohydrate, protein, fats, or sugars, although the consumption of "added sugars" in patients was greater than controls. Patients who participated in both studies significantly reduced their intake of added sugar, and this was not found to correlate with either total intake of monosaccharides and disaccharides or the total carbohydrate consumption. The increased consumption of added sugar in patients with Crohn's disease does not appear to be related to other dietary abnormalities and may simply reflect a deficiency in perception of sweet taste in patients with this condition.

Immunological Aspects of Inflammatory Bowel.

McDermott RP

Seminars in Pediatric Gastroenetrology. 1:5 1990

No abstract available.

Rapid response of severe refractory metastatic Crohn's disease to Infliximab.

Miller AM, Elliott PR, Fink R, Connell W. Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia. milleram@svhm.org.au

J Gastroenterol Hepatol 2001 Aug;16(8):940-2

A case is described of a middle-aged female who developed an aggressive form of biopsy-proven metastatic Crohn's disease involving the inguinal, perineal and submammary areas. Her condition had been unresponsive to topical and systemic corticosteroids, antibiotics, immunosuppressives, and repeated surgical debridement. Administration of Infliximab resulted in a rapid clinical response with subjective improvements in pain and general well-being, and an objective decline in exudate, erythema and size of the lesions. Infliximab may be a suitable therapeutic option in patients with metastatic Crohn's disease.

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

Miura S, Tsuzuki Y, Hokari R, Ishii H. Second Department of Internal Medicine, National Defense Medical College, Tokorozawa City, Saitama, Japan.

J Gastroenterol Hepatol 1998 Dec;13(12):1183-90

Gut-associated lymphoid tissue is the major inductive site of the mucosal immune system, which is functionally independent of the systemic immune system. Both the amount and type of dietary fat modulate intestinal immune function. Absorption of long-chain fatty acids stimulates lymphocyte flux and lymphocyte blastogenesis in intestinal lymphatics. Long-chain fatty acid absorption also significantly enhances migration of T lymphocytes to Peyer's patches, possibly due to up-regulation of adhesion molecules, such as alpha4-integrin and L-selectin. Lipoproteins are involved in stimulation of lymphocyte function by both receptor-dependent and independent mechanisms. However, unsaturated fatty acids at higher concentrations have a suppressive effect on cell-mediated immunity via eicosanoid release, receptor affinity changes or interactions with intracellular signal transduction. Fat absorption also influences various other cells in the intestinal mucosa: increased cytokine release from intestinal epithelial cells follows long-chain fatty acid absorption. In Crohn's disease, elemental diets and total parenteral nutrition often induce remission, possibly by reducing antigenic load on activated immune cells in the intestine and, thus, down-regulating hyperreactive CD4 cells. Dietary oleic acid supplements caused an immunological reversal effect in the intestinal immune system of animals fed an elemental diet. An excess of long-chain fatty acids in an elemental diet, therefore, may negate its beneficial effect on gut-associated lymphoid tissues in Crohn's disease. In contrast, supplemental dietary fish oil apparently tends to prevent relapse of Crohn's disease. Because dietary fat intake is closely associated with immunological function of the intestinal mucosa, careful manipulation of dietary fat can be important in management of this disease.

Early Australian experience with Infliximab, a chimeric antibody against tumour necrosis factor-alpha, in the treatment of Crohn's disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy? The Infliximab User Group.

Mortimore M, Gibson PR, Selby WS, Radford-Smith GL, Florin TH; Schering Plough (Australia). Royal Brisbane Hospital, Queensland, Australia.

Intern Med J 2001 Apr;31(3):146-50

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) plays an important role in the pathology of Crohn's disease. Infliximab, a chimeric antibody against TNF-alpha, has been shown in controlled clinical trials to be effective in two-thirds of patients with refractory or fistulating Crohn's disease. The factors that determine a clinical response in some patients but not others are unknown. AIMS: To document the early Australian experience with Infliximab treatment for Crohn's disease and to identify factors that may determine a beneficial clinical response.

METHODS: Gastroenterologists known to have used Infliximab for Crohn's disease according to a compassionate use protocol were asked to complete a spreadsheet that included demographic information, Crohn's disease site, severity, other medical or surgical treatments and a global clinical assessment of Crohn's disease outcome, judged by participating physicians as complete and sustained (remission for the duration of the study), complete but unsustained (remission at 4 weeks but not for the whole study) or partial clinical improvement (sustained or unsustained).

RESULTS: Fifty-seven patients were able to be evaluated, with a median follow-up time of 16.4 (4-70) weeks, including 23 patients with fistulae. There were 21 adverse events, including four serious events. Fifty-one patients (89%) had a positive clinical response for a median duration (range) of 11 (2-70) weeks. Thirty patients (52%) had a remission at 4 weeks, 10 of whom had remission for longer than 12 weeks. Forty-two per cent of fistulae closed. Sustained remission (P = 0.065), remission at 4 weeks (P = 0.033) and a positive clinical response of any sort (P = 0.004) were more likely in patients on immunosuppressive therapy, despite there being more smokers in this group.

CONCLUSION: This review of the first Australian experience with Infliximab corroborates the reported speed and efficacy of this treatment for Crohn's disease. The excellent response appears enhanced by the concomitant use of conventional steroid-sparing immunosuppressive therapy.

Nutrition and gastrointestinal disease.

O'Keefe SJ. Gastrointestinal Clinic, Groote Schuur Hospital, South Africa.

Scand J Gastroenterol Suppl. 1996;220:52-9.

Nutrition and intestinal function are intimately interrelated. The chief purpose of the gut is to digest and absorb nutrients in order to maintain life. Consequently, chronic gastrointestinal (GI) disease commonly results in malnutrition and increased morbidity and mortality. For example, studies have shown that 50-70% of adult patients with Crohn's disease were weight-depleted and 75% of adolescents growth-retarded. On the other hand, chronic malnutrition impairs digestive and absorptive function because food and nutrients are not only the major trophic factors to the gut but also provide the building blocks for digestive enzymes and absorptive cells. For example, recent studies of ours have shown that a weight loss of greater than 30% accompanying a variety of diseases was associated with a reduction in pancreatic enzyme secretion of over 80%, villus atrophy and impaired carbohydrate and fat absorption. Finally, specific nutrients can induce disease, for example, gluten-sensitive enteropathy, whilst dietary factors such as fibre, resistant starch, short-chain fatty acids, glutamine and fish-oils may prevent gastrointestinal diseases such as diverticulitis, diversion colitis, ulcerative colitis, colonic adenomatosis and colonic carcinoma. The role of dietary antigens in the aetiology of Crohn's disease is controversial, but controlled studies have suggested that elemental diets may be as effective as corticosteroids in inducing a remission in patients with acute Crohn's disease. In conclusion, nutrition has both a supportive and therapeutic role in the management of chronic gastrointestinal diseases. With the development of modern techniques of nutritional support, the morbidity and mortality associated with chronic GI disease can be reduced. On the other hand, dietary manipulation may be used to treat to prevent specific GI disorders such as coeliac disease, functional bowel disease, Crohn's disease and colonic neoplasia. The future development of nutria-pharmaceuticals is particularly attractive in view of their low cost and wide safety margins.

Diet and inflammatory bowel disease: a case-control study.

Persson PG, Ahlbom A, Hellers G. Department of Epidemiology, Karolinska Institutet, Stockholm, Sweden.

Epidemiology 1992 Jan;3(1):47-52

We conducted a population-based case-control study of inflammatory bowel disease and dietary habits in Stockholm during 1984-1987. We obtained retrospective information about food intake 5 years previously by a postal questionnaire for 152 cases with Crohn's disease, 145 cases with ulcerative colitis, and 305 controls. The relative risk of Crohn's disease was increased for subjects who had a high (55 gm or more per day) intake of sucrose (relative risk = 2.6, 95% confidence interval = 1.4-5.0) and was decreased for subjects who had a high (15 gm or more per day) intake of fiber (relative risk = 0.5, 95% confidence interval = 0.3-0.9). The most striking finding was an increased relative risk of both Crohn's disease and ulcerative colitis associated with consumption of fast foods: the relative risk associated with consumption of fast foods at least two times a week was estimated at 3.4 (95% confidence interval = 1.3-9.3) for Crohn's disease and 3.9 (95% confidence interval = 1.4-10.6) for ulcerative colitis. Although coffee seemed to provide a protective effect for both diseases, there are reasons to consider this finding an artifact.

[Nutritional deficiencies and complications in chronic inflammatory bowel diseases] [Article in German]

Rath HC, Caesar I, Roth M, Scholmerich J. Klinik und Poliklinik fur Innere Medizin I, Klinikum, Universitat Regensburg. herath@t-online.de

Med Klin 1998 Jan 15;93(1):6-10

BACKGROUND: Deficiencies of vitamins and trace elements are frequent in inflammatory bowel disease. Aim of this study was to evaluate retrospectively the prevalence of these deficiencies and of liver complications in a large population.

PATIENTS AND METHODS: The records from 392 out-patients, 279 with Crohn's disease (160 female, 119 male) and 113 with ulcerative colitis (56 female, 57 male) were analyzed.

RESULTS: Deficiencies were found in 85% of patients with Crohn's disease vs 68% with ulcerative colitis during the course of the disease, predominantly a deficiency of iron and of calcium. Less frequently deficiencies of zinc, protein, cyanocobalamin, and folic acid were found. Elevated liver enzymes were seen in 38% of patients with Crohn's disease vs 27% with ulcerative colitis. In order of frequency: gamma-glutamyl-transferase, ALAT, AP, ASAT, and bilirubin. Gallstones were present in 12% of patients with Crohn's disease and 4% with ulcerative colitis. 6% of patients with Crohn's disease and 4% with ulcerative colitis had kidney stones.

CONCLUSIONS: In view of the high frequency of deficiencies in patients with inflammatory bowel disease it seems to be important to check frequently for extraintestinal complications.

Strategies targeting tumor necrosis factor in Crohn's disease.

Sandborn WJ. Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.

Acta Gastroenterol Belg 2001 Apr-Jun;64(2):170-2

Tumor necrosis factor plays an important role in mediating the inflammation of Crohn's disease. Strategies aimed at reducing tumor necrosis factor in patients with Crohn's disease include the mouse/human chimeric monoclonal antibody Infliximab, the humanized monoclonal antibody CDP571, the human recombinant tumor necrosis factor receptor fusion protein etanercept, and the small molecule thalidomide. Infliximab is effective for treating active Crohn's disease, maintaining remission, and closing fistulas. Side effects occurring in patients treated with Infliximab include human anti-chimeric antibodies, infusion reactions, formation of autoantibodies, and rarely drug induced lupus. CDP571 is effective for treating active Crohn's disease, steroid sparing, and possibly for closing fistulas and maintaining remission. Side effects occurring in patients treated with CDP571 include anti-idiotype antibodies, infusion reactions, and formation of autoantibodies. Pilot studies have suggested that etanercept and thalidomide may also be beneficial. Anti-tumor necrosis factor therapies are effective for the treatment for Crohn's disease.

Essential fatty acids in health and chronic disease.

Simopoulos AP. Center for Genetics, Nutrition and Health, Washington, DC 20009 cgnh@bellatlantic.net

Am J Clin Nutr 1999 Sep;70(3 Suppl):560S-569S

Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases.

A preliminary study of growth hormone therapy for Crohn's disease.

Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA, McKinley MJ. Department of Pediatrics, North Shore University Hospital and New York University School of Medicine, Manhasset 11030, USA. slonim@nshs.edu

N Engl J Med 2000 Jun 1;342(22):1633-7

BACKGROUND: Crohn's disease is a chronic inflammatory disorder of the bowel. In a preliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease.

METHODS: We randomly assigned 37 adults with moderate-to-severe active Crohn's disease to four months of self-administered injections of growth hormone (loading dose, 5 mg per day subcutaneously for one week, followed by a maintenance dose of 1.5 mg per day) or placebo. We instructed all patients to increase their protein intake to at least 2 g per kilogram of body weight per day. Patients continued to be treated by their usual physicians and to receive other medications for Crohn's disease. The primary end point was the change in scores on the Crohn's Disease Activity Index from base line to month 4. Scores can range from 0 to 600, with higher scores indicating more disease activity.

RESULTS: At base line, the mean (SD) score on the Crohn's Disease Activity Index was somewhat higher among the 19 patients in the growth hormone group than among the 18 patients in the placebo group (287134 vs. 213120, P=0.09). Three patients in the placebo group withdrew before their first follow-up visit and were not included in the data analysis. At four months, the Crohn's Disease Activity Index score had decreased by a mean of 143144 points in the growth hormone group, as compared with a decrease of 1963 points in the placebo group (P=0.004). Side effects in the growth hormone group included edema (in 10 patients) and headache (in 5) and usually resolved within the first month of treatment.

CONCLUSIONS: Our preliminary study suggests that growth hormone may be a beneficial treatment for patients with Crohn's disease.

Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease.

Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T Department of Internal Medicine I, University Medical Center, Regensburg, Germany.

Am J Gastroenterol 1998 Nov;93(11):2197-202

OBJECTIVES: Dehydroepiandrosterone sulfate (DHEAS) and cortisol are multifunctional adrenal hormones with immunomodulating properties. DHEAS levels were found to be very low in chronic inflammatory diseases. This study aimed to shed more light on the interrelation between DHEAS and cortisol (and humoral markers of inflammation) in chronic inflammatory bowel disease.

METHODS: DHEAS and cortisol serum levels were measured by ELISA in the serum of 66 normal subjects, 115 patients with Crohn's disease (CD) and 64 patients with ulcerative colitis (UC). Humoral markers of inflammation and disease activity scores were assessed by standard techniques.

RESULTS: DHEAS was lower in patients with CD (p < 0.005) and UC (p < 0.005) than in controls, which was, in part, dependent on previous corticosteroid treatment (p < 0.01). In CD patients, z-normalized DHEAS was inversely correlated with blood sedimentation rate (p = 0.017). Z-normalized DHEAS was negatively correlated with interleukin-6 (IL-6) in the form of a trend (p = 0.068), and z-normalized DHEAS was significantly positively correlated with hemoglobin (p = 0.001) but not with the Crohn's disease activity index. Cortisol, however, was positively correlated with blood sedimentation rate (p = 0.034) and C-reactive protein (p = 0.006). In contrast, in UC patients no such correlation of z-normalized DHEAS or cortisol and parameters of humoral inflammatory activity or Rachmilewitz index exist.

CONCLUSIONS: DHEAS as a marker of inflammation was low in CD and UC. In CD patients, low DHEAS and high cortisol serum levels were associated with higher humoral inflammatory activity. With respect to humoral inflammatory activity in CD patients, DHEAS and cortisol seem to be inversely regulated, which may have an impact on several immune functions, such as IL-6 secretion.

The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease.

Teahon K, Smethurst P, Pearson M, Levi AJ, Bjarnason I. Section of Gastroenterology, Medical Research Council Clinical Research Centre, Harrow, Middlesex, England.

Gastroenterology 1991 Jul;101(1):84-9

This study examines whether treatment of acute Crohn's disease with an elemental diet improves intestinal integrity and inflammation as assessed by a 51Cr-labeled ethylenediaminetetraacetatic acid (EDTA) permeability test and the fecal excretion of 111In-labeled autologous leukocytes, respectively. Thirty-four patients with active Crohn's disease completed a 4-week treatment course with an elemental diet. Active disease was characterized by increased intestinal permeability [24-hour urine excretion of orally administered 51Cr-EDTA, 6.4% 0.6% (mean SE); normal, less than 3.0%] and by high fecal excretion of 111In-labeled leukocytes (14.2% 1.1%; normal, less than 1.0%). Twenty-seven (80%) went into clinical remission, usually within a week of starting treatment. After 4 weeks of treatment, there was a significant decrease in both the urine excretion of 51Cr-EDTA (to 3.4% 0.5%; P less than 0.01) and the fecal excretion of 111In (to 5.7% 1.0%; P less than 0.001), indicating that such treatment is not just symptomatic. A framework for the mechanism by which elemental diet works, centering around the importance of the integrity of the intestinal barrier function, is proposed, and also appears to provide a logical explanation for some relapses of the disease.

Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease.

ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJ. Academic Medical Centre University of Amsterdam, Department of Experimental Internal Medicine, Amsterdam, the Netherlands. T.tenhove@amc.uva.nl

Gut. 2002 Feb;50(2):148-9.

BACKGROUND AND AIMS: Treatment with Infliximab induces remission in about 70% of patients with steroid refractory Crohn's disease. Because Crohn's disease is considered to be mediated by uncontrolled activation of mucosal T lymphocytes, we hypothesised that Infliximab could induce apoptosis of T lymphocytes.

METHODS: Induction of apoptosis in vivo was studied in 10 patients with therapy refractory Crohn's disease. In vitro, resting or stimulated Jurkat T cells were incubated with Infliximab.

RESULTS: Infusion of Infliximab (5 mg/kg) in steroid refractory patients with Crohn's disease induced a clinical response in 9/10 patients but did not influence expression of activation markers, homing receptors, memory cells, Fas expression, or Bax/Bcl-2 expression on peripheral blood T lymphocytes. In contrast, a significant increase in CD3 and TUNEL positive cells within colonic biopsies was detected 24 hours after infusion of Infliximab, suggesting that Infliximab stimulates apoptosis of activated T lymphocytes but not of resting T cells. To test this hypothesis, the effects of Infliximab on Jurkat T cells were investigated. We observed that Infliximab induced apoptosis and an increase in the Bax/Bcl-2 ratio of CD3/CD28 stimulated Jurkat T cells but not of unstimulated Jurkat cells.

CONCLUSIONS: Our data indicate that Infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of Infliximab in Crohn's disease.

Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2).

van Dullemen HM, van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, Woody J. Department of Hepatogastroenterology, Academic Medical Center, Amsterdam, The Netherlands.

Gastroenterology 1995 Jul;109(1):129-35

BACKGROUND & AIMS: Increased concentrations of tumor necrosis factor (TNF), a potent proinflammatory cytokine, can be shown in the mucosa of patients with active Crohn's disease. Neutralization of TNF has been shown to decrease recruitment of inflammatory cells and granuloma formation in several animal models. The aim of this study was to investigate the safety and potential efficacy of an anti-TNF monoclonal antibody in the treatment of active Crohn's disease.

METHODS: Ten patients with active Crohn's disease that was unresponsive to therapy were administered a single infusion of an anti-TNF human/mouse chimeric monoclonal antibody (cA2) in an open-label treatment protocol while the baseline anti-inflammatory therapy was continued.

RESULTS: Eight patients showed normalization of Crohn's Disease Activity Index scores and healing of ulcerations as judged by colonoscopy within 4 weeks after treatment. One patient had a perforation after colonoscopy and recovered completely after surgery. One elderly patient showed a poor response. The average duration of response after a single infusion was 4 months. No adverse experiences related to cA2 were observed.

CONCLUSIONS: The results support the hypothesis that TNF is of major importance in the pathogenesis of Crohn's disease. Treatment with cA2 was safe and may be useful in patients with Crohn's disease that is unresponsive to steroid treatment.

Dehydroepiandrosterone for the treatment of systemic lupus erythematosus.

van Vollenhoven RF. Department of Rheumatology, Karolinska Hospital, 17176 Stockholm, Sweden.

Expert Opin Pharmacother 2002 Jan;3(1):23-31

The adrenal steroidal hormone dehydroepiandrosterone (DHEA) has been studied as a potential pharmacological agent in the treatment of the autoimmune disease systemic lupus erythematosus (SLE). Both the endocrine effects (the ability to be converted peripherally to androgenic and oestrogenic sex steroids) and the immunomodulatory effects of DHEA (the production of the Th(1) cytokines, such as IL-2) suggest that this hormone could be of benefit for patients with SLE. During the past decade, five controlled clinical trials and a number of additional observational studies have been performed investigating these possibilities. The results from these studies suggest that 200 mg/day of DHEA for 7 - 12 months decreases corticosteroid requirement for the patients, the frequency of disease flares, has an anti-osteoporotic effect and has an overall beneficial effect on SLE disease activity in female patients. A small study suggested benefits for cognitive function in such patients. The side effects acne and hirsutism were seen relatively frequently (30 - 40% and 10 - 12% of patients, respectively) but in most instances were deemed mild. DHEA treatment resulted in changes in lipid profile and may have endocrine effects, the consequences of which will need to be ascertained through longer-term follow-up studies.

Does adjuvant nutritional support diminish steroid dependency in Crohn disease?

Verma S, Holdsworth CD, Giaffer MH. Dept. of Gastroenterology, Royal Hull Hospital NHS Trust, UK. sumitaverma@hotmail.com

Scand J Gastroenterol 2001 Apr;36(4):383-8

BACKGROUND: Nutritional therapy plays an important role in the management of Crohn disease, particularly during the acute phase. Nutritional supplementation may also prevent relapses during the quiescent phase of Crohn disease, though this aspect has not been widely explored.

METHODS: Thirty-three patients with Crohn disease in remission were studied. All had steroid-dependent disease. Patients were randomized to receive either elemental diet (n = 19, EO28 Extra) or polymeric diet (Forticips, n = 14). The supplement was given orally in addition to normal food in an amount to provide 35%-50% of pre-trial total calorie intake. Prednisolone was withdrawn gradually. Patients were followed up for 12 months. Failure was defined as increase in CDAI by 100 points from baseline to >200, inability to withdraw chronic steroid therapy completely, need for surgery or steroid therapy.

RESULTS: The nutritional supplement was successful in 14 (43%) patients who remained in remission for 12 months with complete withdrawal of steroids. The response to elemental diet (42%) was similar to that of polymeric diet (43%). Nutrition supplement failed in 13 (39%). Six (18%) patients were intolerant to enteral feeding because of smell and taste problems. Per-protocol analysis of data indicated that the success rate of nutrition supplement in steroid-dependent patients was 52% (14 out of 27 patients). No disease or patient-related factors helped predict the response to nutrition supplement.

CONCLUSION: Nutritional supplementation with either an elemental or polymeric diet may provide a safe and effective alternative to chronic steroid therapy in patients with steroid-dependent Crohn disease.

Intestinal permeability and the prediction of relapse in Crohn's disease.

Wyatt J, Vogelsang H, Hubl W, Waldhoer T, Lochs H. Department of Gastroenterology and Hepatology, Wahringer Gurtel, Vienna.

Lancet 1993 Jun 5;341(8858):1437-9

To see whether intestinal permeability (IP) predicted relapse in Crohn's disease, we measured IP in 72 patients with quiescent Crohn's disease using the lactulose-mannitol test. The permeability index (lactulose/mannitol) was significantly higher in patients than in controls (0.046 [SEM 0.005] vs 0.018 [SEM 0.002], respectively). Patients were followed for 1 year after the test. 26 of the 37 patients with raised permeability, but only 6 of the 35 with normal permeability relapsed within 1 year after the test (p < 0.001). The sensitivity of the permeability test as a predictor for relapse was 81%. A significant correlation was found between the value of the permeability index and the probability of relapse (p < 0.01). These results show that increases in intestinal permeability precede clinical relapses in Crohn's disease and so are an indicator of subclinical disease. The measurement of intestinal permeability may lead to a better understanding of the pathogenesis of Crohn's disease.

Schwan A.; Sjolin S.; Trottestam U.; Aronsson B.
Institute of Clinical Bacteriology, S-75122 Uppsala Sweden
Scand. J. Infect. Dis. (Sweden), 1984, 16/2 (211-215

Repeated recurrence of Clostridium difficile-associated enterocolitis is uncommon but troublesome for the afflicted patient. The patient described here received vancomycin treatment several times but always had a relapse of C. difficile enterocolitis 2-3 weeks after discontinuation of treatment. She did not form serum antibodies to C. difficile cytotoxin (toxin B). Rectal infusion of enemas prepared from fresh faeces resulted in final cure.

Reichlin B.; Gyr K.
Abt. Gastroenterol., Dept. Inn. Med., Univ. Basel Switzerland
Ther. Umsch. (Switzerland), 1980, 37/3 (194-197)

There are many interactions between antibiotics and the intestinal microflora. The purpose of this review is to focus above all on four such interactions with some clinical importance: General side-effects of antibiotics on the gastrointestinal tract are described briefly, problems of antibiotic resistance in intestinal bacteria and the new understanding of pseudomembranous colitis are explained in more detail. Finally some aspects of colonisation of the gastrointestinal tract with Lactobacillus acidus are discussed.

Bischoff S.C.; Herrmann A.; Goke M.; Manns M.P.; Von Zur Muhlen A.; Brabant G.
Dr. S.C. Bischoff, Dept. of Gastroenterology/Hepatology, Medical School of Hannover, D-30623 Hannover Germany
American Journal of Gastroenterology (USA), 1997, 92/7 (1157-1163)

A reduced bone mineral density has been reported in inflammatory bowel disease (IBD).

Objective: To assess the mechanisms of bone disease in IBD.

Methods: We studied in 90 patients (61 with Crohn's disease, 22 with ulcerative colitis, 7 with indeterminate colitis) biochemical markers of bone metabolism in serum and bone mineral density by peripheral quantitative computed tomography at the forearm.

Results: Forty-five percent of the patients had a reduced bone density (Z score < -1). Serum calcium was normal in most patients, vitamin D deficiency was documented in 17%. Osteocalcin, a serum marker of bone formation, was decreased in 26% (1.2 plus or minus 0.1 ng/ml), whereas the carboxyterminal cross-linked telopeptide of type I collagen (ICTP), a recently described serum parameter of bone breakdown, was stimulated in 38% (10.4 plus or minus 2.3 microg/L). Of 33 patients with increased ICTP levels, 19 showed a decreased bone density (Z score < -1), and 2 of them never received steroids. An active status of the underlying disease in most patients with increased ICTP levels suggests a direct effect of the underlying IBD. In the whole series of patients with a history of active disease (n = 34), 47% had signs of an increased bone degradation (ICTP > 5 microg/L; mean, 12.9 plus or minus 4.7 microg/L). Data derived from a retrospective survey of 245 patients with IBD suggest that the prevalence of bone fractures in IBD is unexpectedly high, particularly in patients with a long duration of disease, frequent active phases, and high cumulative doses of corticosteroid intake.

Conclusions: Several mechanisms may be involved in IBD-associated bone disease: (1) a high inflammatory activity directly induces bone degradation via yet unknown pathways, (2) treatment with corticosteroids may exert catabolic effects on the bone, or (3) malabsorption and vitamin D deficiency may activate bone turnover.

Wright D.H.
University Department of Pathology, Southampton General Hospital, Tremona Road, Southampton SO16 6YD United Kingdom
Bailliere's Clinical Gastroenterology (United Kingdom), 1995, 9/2 (351-369)

Neoplasms constitute the major complication of coeliac disease, and high-grade T-cell lymphoma of the small intestine (enteropathy-associated T-cell lymphoma) is the most common neoplasm in this category. HLA genotyping indicates that in patients with enteropathy-associated T-cell lymphoma have the coeliac disease associated DQA1*0501, DQB1*0201 phenotype, although additional HLA-DR/DQ alleles may represent risk factors for lymphoma development. Molecular biological and immunohistochemical studies have shown that the intestinal mucosa distant from the tumour contains clonal populations of small T cells, often of tile same clone as the high-grade T-cell lymphoma. These findings suggest that enteropathy-associated T-cell lymphoma arises in the setting of coeliac disease and evolves from reactive intraepithelial lymphocytes through a low-grade lymphocytic neoplasm to a high-grade tumour, which is usually the cause of the presenting symptoms. Most cases of chronic ulcerative enteropathy (ulcerative jejunitis) are probably part of the same disease process. If the ulceration occurs at a time when the neoplastic T-cells are of a low grade, morphological recognition of tumour cells in the ulcers may be impossible. Carcinoma of the pharynx and oesophagus, and adenocarcinoma of the small intestine, are increased in frequency in patients with coeliac disease. The increased risk of carcinoma of the oesophagus may be related to vitamin A deficiency. A number of reports have indicated an increased prevalence of various types of chronic hepatitis in patients with coeliac disease, but no coherent view of the cause of this association has emerged. Similarly, patients with coeliac disease have been reported to have various forms of fibrosing lung disease of uncertain causation. In recent years, there have been several reports, mainly from Italy, of a syndrome of epilepsy and bilateral brain calcification occurring in coeliac patients. The pathogenesis of this condition is not known and its prevalence in other communities is uncertain. Splenic atrophy occurs frequently in patients with coeliac disease and is related to the severity of the disease and degree of dietary control. Splenic atrophy predisposes to infection with capsulated bacteria, although mortality studies indicate that infection with these organisms is not a major cause of death in patients with coeliac disease.

Compston J.E.
Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ United Kingdom
Alimentary Pharmacology and Therapeutics (United Kingdom), 1995, 9/3 (237-250)

Osteoporosis is a serious complication of inflammatory bowel disease which has not received adequate recognition despite its high prevalence and potentially devastating clinical effects. Its pathogenesis remains poorly defined although corticosteroid therapy and sex hormone deficiency are likely to play a major role. Recent advances in the diagnosis and management of osteoporosis have facilitated early detection of bone loss and identified means by which this may be prevented. Bone density measurements to predict fracture risk and define thresholds for prevention and treatment should be performed routinely in patients with inflammatory disease. Hormone replacement therapy is effective in prevention of bone loss in peri- and post-menopausal patients, but the treatment of younger women and men of all ages requires further study.

Scharla S.H.; Minne H.W.; Lempert U.G.; Leidig G.; Hauber M.; Raedsch R.; Ziegler R.
Innere Medizin I, Universitatsklinik Heidelberg, Bergheimer Strasse 58, D-69115 Heidelberg Germany
Exp. Clin. Endocrinol. (Germany), 1994, 102/1 (44-49)

Inflammatory bowel disease (Crohn's disease and ulcerative colitis) is associated with decreased bone mineral density and increased risk of osteoporosis. However, the pathogenesis of this bone loss is not yet fully understood. In the present study we measured lumbar bone mineral density (by dual photon absorptiometry), serum levels of parathyroid hormone (PTH) and vitamin D metabolites, and serum markers of bone turnover (alkaline phosphatase and osteocalcin) in 15 patients with Crohn's disease and in 4 patients with ulcerative colitis. The median duration of the disease was 4 years and the median lifetime steroid dose was 10g of prednisone. We compared our results to a control group of 19 normal persons, who were matched for age and sex to the patients. We found that lumbar bone density was reduced by 11% in patients compared with control persons (Z-score -0.6 plus or minus 0.6 versus -0.1 plus or minus 0.8: p < 0.05). In patients, the serum levels of PTH, 25-hydroxyvitamin D3, and calcitriol (1.25(OH)2D3) were significantly reduced compared with control persons. Serum alkaline phosphatase activity (AP) was significantly higher in the patients and was inversely related to lumbar bone density. Osteocalcin values were not different between patients and control persons. There was also no difference in serum levels of calcium between the two groups, whereas phosphorus levels were higher in patients. We conclude that malabsorption of calcium was not a primary cause of bone loss in our patients, because we did not find secondary hyperparathyroidism. Accordingly, we did not find a severe vitamin D deficiency, since 25-hydroxyvitamin D3 levels were within the normal range. Therefore, our results favor the hypothesis that glucocorticoid therapy and/or the inflammatory process itself caused changes in bone metabolism leading to a negative bone balance with secondary reduction of PTH and calcitriol levels.

Gracey M.
Aboriginal Health Unit, Health Dept of Western Australia, 189 Royal Street, East Perth, WA 6004 Australia
Curr. Opin. Gastroenterol. (United Kingdom), 1994, 10/1 (88-97)

Gastrointestinal infections are common and important in infants and young children, particularly where poor hygiene and living conditions allow the spread of infectious agents. With increasing information about microorganisms that cause these infections and improved methods to detect them, many episodes that were once undiagnosed can now be attributed to previously unrecognized viruses, bacteria, and other pathogens. These advances facilitate better management and will permit more effective control and preventive strategies. This review highlights some recent reports about enterovirulent classes of Escherichia coli, including E. coli O157:H7, which causes the hemolytic-uremic syndrome and hemorrhagic colitis; Campylobacter species and a new Campylobacter-like organism (Arcobacterbutzlerlli Helicobacter pylori; Aeromonas species; and rotavirus. Important new information about intestinal parasites, including Giardia and Cryptosporidium, has emerged that should prove of practical use in diagnosis and management in places where these parasites are prevalent in children, particularly in parts of the world where HIV infection has become established. A newly described organism, so far called coccidian-like or cyanobacterium-like body, has been found in patients with prolonged diarrhea (including travelers and expatriate residents) in several countries; the name Cyclospora cayetanensis has been proposed for this organism. This year's review concludes with a short commentary on some recent reports about risk factors that predispose children to gastrointestinal infections, eg, nutritional status, domestic hygiene, maternal hygiene behavior, and young children gathered in communal facilities like day care centers. Immune function status is also important, and deficiencies of single nutrients such as vitamin A, pyridoxine, folic acid, iron, and zinc may also play a role.

Silk D.B.A.
United Kingdom
Bailliere's Clin. Gastroenterol. (United Kingdom), 1992, 6/1 (27-41)

It is clear that the nutritional state of patients with inflammatory bowel disease is often impaired and can be improved by the provision of nutritional support. Improvement in nutritional status can be achieved as effectively with enteral as with parenteral nutrition. Nutritional support appears to have no primary therapeutic effect in patients with ulcerative colitis. With regard to nutritional support in Crohn's disease, parenteral nutrition should be restricted to use as supportive rather than primary therapy. Available information now seems to suggest that most of the benefits of parenteral nutrition in Crohn's disease are related to an improvement in nutritional state rather than as primary therapy, and its use should be restricted to the treatment of specific complications of Crohn's disease, such as intestinal obstruction related to stricture formation or short bowel syndrome following repeated resection. Although some doubt exists over the efficacy of oligopeptide-containing elemental and polymeric enteral diets, the present evidence indicates that chemically defined free amino acid-containing elemental diets have primary therapeutic efficacy in the management of acute exacerbations of Crohn's disease. As such, these diets are worthy of therapeutic trial in patients with severe Crohn's disease involving the distal colon and rectum, particularly in those patients who are malnourished and who prove to be resistant to treatment with a combination of topical corticosteroids and S-aminosalicylic acid-containing compounds. Clinicians should be aware, though, that the beneficial effects are likely to be restricted to the short term, with high relapse rates by 1 year, this being particularly so in patients with distal Crohn's proctocolitis (Teahon et al, 1988). Volatile fatty acid enemas clearly have potential in the management of patients with severe steroid-resistant proctitis. Finally, one of the most important observations made in recent years is the one concerning the large losses of nitrogen that will occur in patients with inflammatory bowel disease treated with corticosteroids in the absence of adequate protein intake (O'Keefe et al, 1989). Hopefully the days of treating patients with severe inflammatory bowel disease with high dose corticosteroids and a peripheral dextrose or dextrose-saline drip have passed into history.

Janczewska I.; Bartnik W.; Butruk E.; Tomecki R.; Kazik E.; Ostrowski J.
Department of Gastroenterology, Goszczynskiego 1, P-02-616 Warsaw Poland
Hepato-Gastroenterology (Germany), 1991, 38/5 (391-395)

The aim of this study was to determine serum retinol levels in patients with inflammatory bowel disease and to attempt to elucidate the mechanism of changes in vitamin A metabolism in these disorders. It was found that in 15 patients with active ulcerative colitis, 14 patients with active Crohn's disease and in 3 operated patients with recurrent Crohn's disease serum retinol levels and retinol-binding protein were significantly lower than in controls. Concentrations of vitamin A did not depend on the localization of inflammatory bowel disease, previous ileal resections, duration of the disease or age and sex of the patients. During successful treatment of active ulcerative colitis normalization of serum retinol levels without substitution of vitamin A was observed. Repeated determinations in patients with Crohn's disease who had low serum retinol levels in an active phase of disease revealed normal vitamin A levels in an inactive phase. The absorption of vitamins A and E in patients with inflammatory bowel disease was normal. The normal serum retinol concentrations in patients with diarrhea due to irritable bowel syndrome, and in those with anorexia nervosa exclude the influence of diarrhea and body weight itself on vitamin A levels. The results of this study indicate that serum retinol levels in patients with active inflammatory bowel disease are secondary to the decreased serum retinol-binding protein concentrations, and probably depend on the increased protein catabolism in these disorders.

Albers J.W.; Nostrant T.T.; Riggs J.E.
Neuromuscular Section, Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109-0032 USA
Neurol. Clin. (USA), 1989, 7/3 (525-548)

The neurologic manifestations of gastrointestinal disease are generally thought to be uncommon, although an increasing number of previously unidentified associations are being established. These neurologic disorders may result from nutritional or non-nutritional causes. In the absence of clear malnutrition, it is likely that many of these disorders are underdiagnosed. As an example, Wernicke's encephalopathy is found at autopsy in as many as 2 per cent of brains, a very high percentage, given the rare recognition during life. The likely underdiagnosis of nutritional neurologic disorders is unfortunate because many are treatable and, more importantly, are preventable if malabsorption is suspected and appropriate supplementation initiated. For the neurologist, familiarity with the occasional association between neurologic abnormalities and specific gastrointestinal disorders is important, as is familiarity with the neurologic characteristics of disorders, such as Whipple's disease, that may present as isolated neurologic syndromes without gastrointestinal symptoms or signs. Renewed interest in selective deficiency states has resulted in identification of causative factors in several neurologic syndromes of previously presumed degenerative etiology. Recognition of the potential neurologic consequences of prolonged deficiency states also is important for the internist, because many of the syndromes are poorly reversible once symptomatic. The benefits of prevention invariably exceed those of treatment.

Fernandez-Banares F.; Abad-Lacruz A.; Xiol X.; Gine J.J.; Dolz C.; Cabre E.; Esteve M.; Gonzalez-Huix F.; Gassull M.A.
Department of Gastroenterology, Hospital de Bellvitge 'Princeps d'Espanya', Barcelona Spain
Am. J. Gastroenterol. (USA), 1989, 84/7 (744-748)

The status of water- and fat-soluble vitamins was prospectively evaluated in 23 patients (13 men, 10 women, mean age 33 plus or minus 3 yr) admitted to the hospital with acute or subacute attacks of inflammatory bowel disease. Protein-energy status was also assessed by means of simultaneous measurement of triceps skin-fold thickness, mid-arm muscle circumference, and serum albumin. Fifteen patients (group A) had extensive acute colitis (ulcerative or Crohn's colitis), and eight cases (group B) had small bowel or ileocecal Crohn's disease. Eighty-nine healthy subjects (36 men, 53 women, mean age 34 plus or minus 2 yr) acted as controls. In both groups of patients, the levels of biotin, folate, beta-carotene, and vitamins A, C, and B1 were significantly lower than in controls (p < 0.05). Plasma levels of vitamin B12 were decreased only in group B (p < 0.01), whereas riboflavin was lower in group A (p < 0.01). The percentage of patients at risk of developing hypovitaminosis was 40% or higher for vitamin A, beta-carotene, folate, biotin, vitamin C, and thiamin in both groups of patients. Although some subjects had extremely low vitamin values, in no case were clinical symptoms of vitamin deficiency observed. Only a weak correlation was found between protein-energy nutritional parameters and vitamin values, probably due to the small size of the sample studied. The pathophysiological and clinical implications of the suboptimal vitamin status observed in acute inflammatory bowel disease are unknown. Further studies on long-term vitamin status and clinical outcome in these patients are necessary.

Mattioli S.; Miglioli M.; Montagna P.; Lerro M.F.; Pilotti V.; Gozzetti G.
Istituto di Clinica Chirurgica II, Universita di Bologna, 40138 Bologna Italy
J. Parenter. Enter. Nutr. (USA), 1988, 12/6 (626-627)

A patient operated for toxic megacolon secondary to ulcerative colitis developed a Wernicke syndrome (thiamine deficiency) during the postoperative period despite the administration of the usually recommended doses of vitamin B1 during total parenteral nutrition (TPN) treatment. Vitamin B1 deficiency should be checked in order to evaluate the patients' nutritional condition before starting TPN, especially those suffering from severe chronic malnutrition. Routine administration of vitamin B1 in repletion doses may be reasonably proposed in order to avoid the development of a Wemicke syndrome which is potentially lethal in a short time if not recognized and corrected in time.

Van Noort B.A.A.; Bos P.J.M.; Klopping C.; Wilmink J.M.
Department of Ophthalmology, G2N, A.M.C., University of Amsterdam, 1105 AZ Amsterdam Netherlands
Doc. Ophthalmol. (Netherlands), 1987, 67/1-2 (45-51)

A 35-year-old man with ulcerative colitis who was receiving parenteral feeding with large amounts of glucose, suddenly developed severe optic neuropathy and oculomotor palsy. The visual acuity fell bilaterally to 0. Although it was stated that thiamine has been regularly suppleted in the preceding period, high doses of vitamin B1 were given. Visual acuity promptly returned to 1.0 but large visual field defects persisted. Later on it appeared that erroneously no vitamin B1 has been given before.

Harries A.D.; Brown R.; Heatley R.V.; et al.
Department of Gastroenterology, University Hospital of Wales, Cardiff United Kingdom
Gut (England), 1985, 26/11 (1197-1203)

Forty patients with Crohn's disease were divided into undernourished (18) and well nourished (22) groups depending on whether their midarm circumference was below or above 90% of the ideal standard. Plasma 25-(OH)D3 and the dihydroxylated metabolites, 24,25-(OH)sub 2D3 and 1,25-(OH)sub 2D3 were measured in the summer. Results were related to clinical and biochemical parameters and also compared with results from patients with ulcerative colitis and healthy subjects who served as controls. Plasma 25-(OH)D3 was reduced in the undernourished Crohn's group compared with the well nourished Crohn's group, who did not differ from the controls. Over 50% of the undernourished Crohn's group had evidence of secondary hyperparathyroidism and raised alkaline phosphatase concentrations, although concentrations of 1,25-(OH)sub 2D3 were normal. The low 25-(OH)D3 concentrations related to disease activity. It is suggested that undernourished Crohn's patients who have high levels of disease activity are at risk of vitamin D deficiency, and attempts should be made to improve their vitamin D nutrition.

Schoelmerich J.; Becher M.S.; Hoppe-Seyler P.; et al.
Department of Internal Medicine, University of Freiburg, Freiburg Germany, West
Hepato-Gastroenterol. (Germany, West), 1985, 32/1 (34-38)

A study of serum zinc and plasma vitamin A concentrations in 54 patients with Crohn's disease was performed. Compared with controls the patients had significantly lowered zinc and vitamin A concentrations. There was a marked correlation between zinc and vitamin A and the activity of the disease, as measured by the Crohn's disease activity index, and a weaker correlation with serum proteins considered to be indicators of disease activity. No correlation was found to vitamin B12 absorption, to the localization of the disease, or to previous ileal resection. The results suggest that zinc and vitamin A deficiency occurs in patients with active Crohn's disease and is not primarily caused by absorption abnormalities. Substitution might be helpful or even necessary in patients with highly active disease.

Krasinski S.D.; Russell R.M.; Furie B.C.; et al.
USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111 USA
Am. J. Clin. Nutr. (USA), 1985, 41/3 (639-643)

Vitamin K deficiency results in the appearance of abnormal prothrombin, deficient in gamma-carboxyglutamic acid, in the blood. The presence of abnormal prothrombin can be eliminated or lowered by the administration of vitamin K. Since the abnormal prothrombin antigen assay is approximately 1000-fold more sensitive than the prothrombin time for the diagnosis of vitamin K deficiency, this assay was used to evaluate patients with intestinal abnormalities. Vitamin K deficiency was found in 18 of 58 patients (31%) with chronic gastrointestinal disease and/or resection. All patients with vitamin K deficiency had either Crohn's disease involving the ileum or ulcerative colitis treated with sulfasalazine or antibiotics. Abnormal prothrombin levels returned toward normal in patients treated with vitamin K but not in patients who were not treated with vitamin K. The mean plasma vitamin E level in patients with vitamin K deficiency was significantly lower than in vitamin-K sufficient patients (p<0.01). We conclude that certain chronic forms of gastrointestinal disorders are associated with vitamin K deficiency.

Dageforde J.; Otte M.; Normann D.; et al.
Klinik fur Innere Medizin der Medizinischen Hochschule Lubeck, D-2400 Lubeck Germany, West
Arztl. Lab. (Germany, West), 1985, 31/3 (100-102)

Decreased serum levels of 25-OH-vitamin Dsub 3 are a not uncommon finding in ulcerative colitis and Crohn's disease. Exogenous factors, in particular a lack exposure, are the main causes. Vitamin Bsub 1sub 2 levels are only decreased in some Crohn patients with involvement of the ileum. This is explainable by malabsorption. Absorption of folic acid is reduced in both diseases through the interaction with salazosulfaphyridine. Organic malabsorption probably plays a minor role. Elimination of the deficiency states be means of solar irradiation and substitution therapy is necessary.

Dept. Int. Med., Univ. California, Davis, CA 95616 USA
N. Engl. J. Med. (USA), 1981, 305/25 (1513-1517)

Folate deficiency, a common occurrence in patients with inflammatory bowel disease, has been ascribed in part to the therapeutic use of sulfasalazine. However, a clear relation between the use of sulfasalazine (salicylazosulfapyridine) and the development of folate malabsorption and deficiency has not been shown. The authors designed studies to evaluate the relation of the use of sulfasalazine to folate malabsorption and deficiency in patients with ulcerative colitis. They compared the incidence of low serum folate levels in patients who were using sulfasalazine and those who were not. In a selected group of patients, the intestinal-perfusion method was used to study the effects of graded concentrations of sulfasalazine at the site of jejunal hydrolysis and luminal disappearance of folates. The data indicate that sulfasalazine inhibits the hydrolysis of polyglutamyl folate and also decreases the absorption of both polyglutamyl and monoglutamyl folates.

Dionigi R.; Guaglio R.; Bonera A.; et al.
Inst. Clin. Surg., Univ. Pavia Italy
Int. J. Clin. Pharmacol. Biopharm. (Germany, West), 1979, 17/3 (107-118)

The term 'total parenteral nutrition' (TPN) refers to the maintenance of an adequate nutritional status, normal body weight and positive nitrogen balance solely by intravenous means. It requires solutions providing calories, amino acids and other nutrients in amounts much greater than those indicated for maintenance of normal body weight. Nutrient solutions have been studied, selected and prepared in our Hospital Pharmacological Service utilizing a sterile closed system, which allows large-volume filtering, sterilizing and bottling devices. For maintenance of weight gain in adults, a basic formula is employed, which provides 1,100 Kcal/l with pure crystalline amino acids mixed with 50% anhydrous dextrose in water in a ratio of 5.8:1 (160 Kcal:1 g nitrogen). Minerals and vitamins are added to the base solution prior to use and may be increased or decreased by simple addition or omission depending on the patient's condition. This paper is based on 192 surgical patients who received TPN and have been followed in strict cooperation between the Hospital Pharmacological Service and the Surgical Department. The patients, ranging from 23 to 79 years of age, with life threatening diseases and unable to maintain adequate nutrition by the oral route, received TPN through a central catheter inserted via subclavian puncture (146 cases) or through a surgically created internal A-V fistula (46 cases). The condition of the patients generally improved within a few days after starting TPN; and weight gain, wound healing general improvement and a shorter period of hospitalization were observed. TPN could be efficiently combined with oncologic treatment, and a significant improvement of the patients' performance status and decrease of toxic side-effects due to chemotherapeutic agents were observed. TPN has been successfully applied also in patients with fistulas of the alimentary tract obtaining spontaneous closure and in patients with ulcerative colitis, showing its beneficial effect in allowing complete bowel rest for healing. No major complications or deaths could be attributed to TPN or to the route of administration.

Thomson A.B.R.; Brust R.; Ali M.A.M.; et al.
Dept. Med., Univ. Alberta, Edmonton Canada
Am. J. Dig. Dis. (USA), 1978, 23/8 (705-709)

The prevalence of iron-deficiency anemia was defined in 105 patients with inflammatory bowel disease and an appraisal made of the diagnostic value of serum ferritin for the assessment of iron stores. Iron deficiency, defined by the absence of bone-marrow hemosiderin was found with anemia in 36% of 41 patients with ulcerative colitis (UC) and 22% of 64 patients with Crohn's disease (CD). Iron deficiency without impaired erythropoiesis was detected in an additional 32% of patients with UC and 2% with CD. Anemia with plentiful bone-marrow iron was present in 33 (51%) of patients with CD, only one of whom had vitamin Bsub 1sub 2 deficiency. Red blood cell morphology, RBC indices, serum iron, and percent transferrin saturation correlated poorly with stainable marrow iron. Serum ferritin, assayed in samples from 45 patients, was <18 ng/ml in 4/12 with iron-deficiency anemia and 0/5 with absent marrow iron and a normal hemoglobin level; values >55 ng/ml were invariably associated with the presence of marrow hemosiderin. Based on a lower normal limit of 18ng/ml, the serum ferritin had an excellent predictive value (100%) but a high predictive error (32%) in the diagnosis of iron deficiency in inflammatory bowel disease. Serum ferritin >55 ng/ml ruled out iron deficiency as the basis for anemia.

Husainov O.H.
Kaf. Infekts. Bol., Tadzhik. Medinst., Dushanbe USSR
Zdravookhr.Tadzh. (USSR), 1973, 20/4 (10-12)

Investigation of 39 patients suffering from acute bacterial dysentery and 25 with an exacerbation of the chronic form revealed disturbances of the vitamin C metabolism in all cases, manifested by a low content of the vitamin in the blood and its low excretion in the urine. The degree of the changes depended on the clinical manifestations of the disease. Administration of vitamin C in therapeutic doses corrected the vitamin deficiency in acute bacterial dysentery. In patients with exacerbations of chronic dysentery the indices of the ascorbic acid metabolism failed to reach the normal values, thereby indicating more prolonged and massive vitamin therapy.

Stedman J.D.; Spyrou N.M.; Millar A.D.; Altaf W.J.; Akanle O.A.; Rampton D.S.
J.D. Stedman, Department of Physics, University of Surrey, Guildford, Surrey GU2-5XH United Kingdom
Journal of Radioanalytical and Nuclear Chemistry (Hungary), 1997, 217/2 (189-191)

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) in which there is recurrent inflammation of the mucous membranes of the colon. Inflammation is accompanied by the production of reactive oxygen species (ROS) including, amongst others, hydrogen peroxide. Selenium in the form of the selenoprotein glutathione peroxidase (GSH-Px) acts as a catalyst in the reaction which reduces hydrogen peroxide to watch. It may therefore beneficial to supplement the diets of patients who suffer from UC with selenium. In this preliminary study nine patients suffering from moderate UC were supplemented with selenium-beta tablets (300 microg Se per tablet) twice daily. Blood samples were taken at the start of the trial and at 1, 2 and 4 week intervals. Freeze-dried serum samples were analysed for their selenium content using the technique of instrumental neutron activation analysis (INAA). Samples were also analysed by particle induced X-ray emission (PIXE) to monitor other trace elements levels. Selenium concentrations were found to increase during supplementation and iron concentrations to decrease. Stool frequency was also found to improve suggesting that ROS may be important in the pathogenesis of UC.

Burke A.; Lichtenstein G.R.; Rombeau J.L.
Prof. J.L. Rombeau, Department of Surgery, Hospital University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 USA
Bailliere's Clinical Gastroenterology (United Kingdom), 1997, 11/1 (153-174)

The role of diet in the aetiology and pathogenesis of ulcerative colitis (UC) remains uncertain. Impaired utilization by colonocytes of butyrate, a product of bacterial fermentation of dietary carbohydrates escaping digestion, may be important. Sulphur-fermenting bacteria may be involved in this impaired utilization. Oxidative stress probably mediates tissue injury but is probably not of causative importance. Patients with UC are prone to malnutrition and its detrimental effects. However, there is no role for total parenteral nutrition and bowel rest as primary therapy for UC. The maintenance of adequate nutrition is very important, particularly in the peri-operative patient. In the absence of massive bleeding, perforation, toxic megacolon or obstruction, enteral rather than parenteral nutrition should be the mode of choice. Nutrients may be beneficial as adjuvant therapy. Butyrate enemas have improved patients with otherwise recalcitrant distal colitis in small studies, Non-cellulose fibre supplements are of benefit in rats with experimental colitis. Eicosapentaenoic acid in fish oil has a steroid-sparing effect which, although modest, is important, particularly in terms of reducing the risk of osteoporosis, but it seems to have no role in the patient with inactive disease. gamma-Linolenic acid and anti-oxidants also are showing promise. Nutrients may also modify the increased risk of colorectal carcinoma. Oxidative stress can damage tissue DNA but there are no data published at present on possible protection from oral anti-oxidants. Butyrate protects against experimental carcinogenesis in rats with experimental colitis. Folate supplementation is weakly associated with decreased incidence of cancer in UC patients when assessed retrospectively. Vigilance should be maintained for increased micronutrient requirements and supplements given as appropriate. Calcium and low-dose vitamin D should be given to patients on long-term steroids and folate to those on sulphasalazine.

Campbell J.M.; Fahey G.C. Jr.; Lichtensteiger C.A.; Demichele S.J.; Garleb K.A.
G.C. Fahey Jr., Division of Nutritional Sciences, Department of Animal Sciences, University of Illinois, Urbana, IL 61801 USA
Journal of Nutrition (USA), 1997, 127/1 (137-145)

Evidence supports a pathogenic role of arachidonic acid-derived inflammatory mediators within the gastrointestinal tract of patients with inflammatory bowel disease. The purpose of this study was to assess the effects of an ulcerative colitis nutritional formula (UCNF) containing oligosaccharides, fish oil, gum arabic and antioxidants on plasma and colonic phospholipid fatty acid and prostaglandin profiles in pigs. Twenty-four growing barrows in two replications were equally randomized among four killing times (d 0, 7, 14 and 21), and one of two diets, a control and the UCNF. Diets contained comparable levels of protein, fat, and nonstructural carbohydrate and met 100% of the energy requirements of the pig. Intake and body weight were recorded daily while blood, urine and tissue samples were collected at time of kill. Within 1 wk of ingestion of the UCNF, the composition of plasma phospholipid fatty acids showed an increase in 20:5(n- 3) and 22:6(n-3) (P < 0.0001) and a decrease in 20:4(n-6) and 18:2(n-6) (P < 0.0001). Similar effects were observed for the phospholipids in the colonic and cecal mucosa. Plasma prostaglandin E was unaffected by treatment, whereas thromboxane B2 and 6-keto-prostaglandin F(1alpha) levels were significantly decreased after 7 d of UCNF ingestion. Ingestion of the UCNF resulted in a suppression in the synthesis of proinflammatory prostaglandins by cecal and colonic mucosal cells. Levels of colonic and cecal prostaglandin E, 6- ketoprostaglandin F(1alpha) and thromboxane B2 were significantly decreased after 7 d of UCNF ingestion. These changes may have been mediated by rapid increases of (n-3) fatty acids into cellular phospholipids. Dietary supplementation with the UCNF may prove beneficial for patients with ulcerative colitis by modulating colonic prostaglandin synthesis.

Lashner B.A.; Provencher K.S.; Seidner D.L.; Knesebeck A.; Brzezinski A.
USA
Gastroenterology (USA), 1997, 112/1 (29-32)

Background and Aims: Two case-control studies have shown that folate may protect against neoplasia in ulcerative colitis. This historical cohort study was performed to better define this association. Methods: The records of 98 patients with ulcerative colitis who had disease proximal to the splenic flexure for at least 8 years were reviewed. Documented folate use of at least 6 months was deemed a positive exposure. Results: Of the patients, 29.6% developed neoplasia and 40.2% took folate supplements. The adjusted relative risk (RR) of neoplasia for patients taking folate was 0.72 (95% confidence interval (CI), 0.28-1.83). The dose of folate varied with the risk of neoplasia (RR, 0.54 for 1.0 mg folate; RR, 0.76 for 0.4 mg folate in a multivitamin compared with patients taking no folate). Folate use also varied with the degree of dysplasia (RR for cancer, 0.45; RR for high-grade dysplasia, 0.52; RR for low-grade dysplasia, 0.75 compared with patients with no dysplasia) (P = 0.08). Conclusions: Although not statistically significant, the RR for folate supplementation on the risk of neoplasia is <1 and shows a dose-response effect, consistent with previous studies. Daily folate supplementation may protect against the development of neoplasia in ulcerative colitis.

Candy S.; Borok G.; Wright J.P.; Boniface V.; Goodman R.
Gastro-intestinal Clinic, Department of Medicine, Groote Schuur Hosp., Univ. Cape Town, Cape Town South Africa
South African Medical Journal (South Africa), 1995, 85/11 (1176-1179)

Debate exists about the role of diet in both the aetiology and the management of ulcerative colitis. To examine the latter, a group of patients with documented ulcerative colitis was studied at the Groote Schuur Hospital Gastro-intestinal Clinic. A total of 18 subjects, 9 female and 9 male, were randomised into active or control groups and followed up weekly for 6 weeks. Subjects in the control group were asked to document but not alter their intake of food and drink. Those in the experimental group had their diets systematically manipulated to exclude foods that appeared to provoke symptoms. The symptoms, sigmoidoscopy and biopsy findings of all subjects were compared before and after. 'Remission' was defined as the passage of normal stools with absence of rectal bleeding. 'Improvement' was defined as a decrease in the number of diarrhoeal stools and/or a diminution of rectal bleeding. At the end of the trial the diet group displayed significantly fewer symptoms than did the controls (P = 0.009; Fisher's exact test). Sigmoidoscopic findings improved in 8 subjects in the diet group compared with 2 of the controls. Histological findings improved in 3 of the diet group as well as in 3 of the controls. There were no foods that provoked symptoms in all patients, though spiced and curried foods and fruits, especially grapes, melon and the citruses, commonly caused diarrhoea. In only 2 patients were symptoms reproduced consistently on reintroduction of a particular food, pork in 1 case and yellow cheese in another.

Fujita T.; Sakurai K.
First Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105 Japan
British Journal of Surgery (United Kingdom), 1995, 82/6 (749-751)

Intact intestinal epithelium and associated lymphatic tissue act as body defences against luminal toxins. This barrier may become threatened or compromised in inflammatory bowel disease, leading to an increase in mucosal permeability and subsequent translocation of endotoxins. The effect of oral glutamine on gut mucosal ornithine decarboxylase activity and on endotoxin levels in portal vein blood was studied in a guinea-pig model of carrageenan- induced colitis. Despite failure to show induction of ornithine decarboxylase activity by glutamine administration, the mean endotoxin level of portal vein blood in guinea-pigs fed a glutamine-enriched elemental diet was 25.3 pg/ml compared with 71.2 pg/ml in animals given a standard elemental diet (P<0.01). A glutamine-enriched elemental diet may be therapeutically beneficial in patients with inflammatory bowel disease.

Nagel E.; Bartels M.; Pichlmayr R.
Klinik fur Abdominal, Transplantationschirurgie, Konstanty-Gutschow-Stras se 8, D-30625 Hannover Germany
Langenbecks Archiv fur Chirurgie (Germany), 1995, 380/1 (4-11)

Nutritional therapy for ulcerative colitis (UC) is controversial. Studies are usually designed to investigate total parenteral (TPN) or total enteral nutrition (TEN), and before these can be compared it is necessary to differentiate between the different therapeutic aims. The aims of artificial nutritional support in patients with UC are the readjustment of the nutritional status, possible remission of disease activity, and decrease in the incidence of surgical intervention or postoperative complication. Owing to the heterogeneity of the results published so far, it is still difficult to compare studies. Nevertheless, they indicate that the extent and severity of the colitis and the patient selection are of paramount importance in the implementation of nutritional therapy. Positive effects of TPN reported from non-controlled studies were not confirmed by controlled trials. Moreover, TPN was no more effective than an oral diet. Regarding remission rates or operative interventions needed, TPN had more side effects than and no defined advantages over TEN. TEN seems to be useful for certain patients. In some patients with UC, it seems to be accompanied by fewer postoperative complications. However, a definitive conclusion on the effects of TEN or TPN is not yet possible. In this context, certain fatty acids may have an important role in the treatment of UC. In prospective, randomized and controlled studies omega-3 fatty acids were found to be therapeutically useful. A reduction of the steroid doses needed is particularly important. Another therapeutic approach in distal UC is seen in the rectal administration of short chain fatty acids.

Frankel W.L.; Choi D.M.; Zhang W.; Roth J.A.; Don S.H.; Afonso J.J.; Lee F.- H.; Klurfeld D.M.; Rombeau J.L.
Harrison Department of Surgery, University of Pennsylvania Hospital, 34th and Spruce Street, Philadelphia, PA 19104 USA
J. Parenter. Enter. Nutr. (USA), 1994, 18/1 (55-61)

Clostridium difficile colitis is a disabling complication in critically ill patients who commonly receive broad-spectrum antibiotics and liquid diets. To date, there is no experimental model specifically designed to investigate the effects of liquid diets on this type of colitis. The addition of fiber to liquid diets normalizes gut structure and improves absorptive function in selected conditions of intestinal dysfunction. The purposes of this study were the following: (1) to develop a reproducible model to examine the interaction of acute C difficile-induced colitis and liquid diets, (2) to determine whether the addition of soy fiber to a liquid diet improves disease, and (3) to investigate possible mechanisms of fiber-mediated disease improvement. Syrian hamsters were pair-fed with either a polymeric liquid diet or the same diet with 1.4% soy fiber for 10 days. Animals were given either clindamycin and C difficile (to produce ileocecitis), or equivalent volumes of saline. Mean survival time and systematic stool examinations for C difficile toxin positivity, liquidity, and percent water were performed to determine the effect of soy fiber on disease. Survival time was prolonged by 34% (p < .05), and C difficile toxin positivity and stool liquidity were significantly reduced (p < .05) with fiber. Additional animals were studied to determine possible mechanisms for improved survival in fiber-supplemented animals. Cecal histology, colonic water absorption, cecal microflora, and gastric to anus transit time were measured in these animals. Colonic water absorption and gastric to anus transit time were significantly increased (p < .05) and decreased (p < .05) with fiber, respectively. A hamster model of C difficile ileocecitis has been designed to investigate the effects of liquid diets. Fiber supplementation prolongs survival in this model due in part to a delay in onset of C difficile infection and improved colonic water absorption.

Grimminger F.; Fuhrer D.; Papavassilis C.; Schlotzer E.; Mayer K.; Heuer K.-U.; Kiss L.; Walmrath D.; Piberhofer S.; Lubbecke F.; Kramer H.-J.; Stevens J.; Schutterle G.; Seeger W.
Department of Internal Medicine, Justus-Liebig-University, Klinikstrasse 36, D-6300 Giessen Germany
Eur. J. Clin. Invest. (United Kingdom), 1993, 23/11 (706-715)

N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d-1 fish oil-derived lipid emulsion (eicosapentaenoic acid (EPA), 4.2 g; docosahexaenoic acid (DHA), 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake. In contrast, erythrocyte membrane enrichment in EPA and DHA occurred only after the prolonged (2 month) period of dietary n-3 lipid supplementation. Ex vivo stimulation of neutrophils with A23187 showed progressive increase in 5-series leukotriene- and 5-HEPE-generation during both periods of n-3 lipid infusion, in parallel with the rise of plasma EPA contents. Maximum 5-series/4-series leukotriene ratios surpassed 0.25. Similarly, ratios of thromboxane B3/B2 liberated from ex vivo stimulated platelets surpassed 0.4 during ongoing n-3 lipid infusion. The profound changes in fatty acid profiles and lipid mediator generation may be related to the reduction in colitis activity observed during the periods of intravenous n-3 lipid supplementation.

Ross E.
Department of Internal Medicine, Tufts University School of Medicine, Boston, MA 02111 USA
Nutr. Rev. (USA), 1993, 51/2 (47-49)

Recent studies suggest that marine fish-oil supplements, which are rich in n-3 fatty acids, may reduce the inflammation associated with ulcerative colitis. Fish oils may exert their beneficial effects by shifting eicosanoid synthesis to less inflammatory species or by modulating tissue levels of certain cytokines.

Heimburger D.C.; Colby F.; Benitez L.; Raiten D.J.; Butterworth C.E.
Department of Nutrition Sciences, University of Alabama, Birmingham, AL 35294 USA
Ann. New York Acad. Sci. (USA), 1992, 669/- (87-96)

The notion that requirements for folic acid may be higher in some tissues than others, resulting in localized deficiencies in spite of blood levels in the normal range was first suggested by the observation of megaloblastic changes in the cervical epithelium that responded to folate supplementation. Theoretically, such deficiencies may arise from elevated folate turnover in response to rapid tissue proliferation or repair; inactivation or alteration of its function by external agents such as tobacco, alcohol, or drugs; or altered metabolism or tissue uptake caused by an inborn error. Marginal dietary intake could aggravate these effects on cells at risk. Evidence for the possible existence of localized folate deficiencies in the aerodigestive tract includes lower circulating folate levels in smokers as compared with nonsmokers; yet lower circulating levels in smokers with bronchial metaplasia; lower folate levels in scrapings of the buccal mucosa of smokers than non-smokers; apparent improvement in bronchial atypical metaplasia in smokers supplemented with folic acid; lower erythrocyte folate levels and higher prevalence of cellular features compatible with folate deficiency in geographic areas and individuals in South Africa at high risk for esophageal cancer; and a trend toward a lower prevalence of colonic dysplasia in ulcerative colitis patients who use folic acid supplements. These observations, as well as animal and in vitro studies, also suggest that folate deficiency may be co-carcinogenic. Further research in this area will be aided by the development of animal models of localized folate deficiency and of methodologies capable of measuring folate levels in minute quantities of tissues and exfoliated cells.

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Aslan A.; Triadafilopoulos G.
Gastroenterology Section, Martinez VA Medical Center, 150 Muir Road, Martinez, CA 94553 USA
Am. J. Gastroenterol. (USA), 1992, 87/4 (432-437)

Arachidonic acid metabolites formed by both the cyclooxygenase and lipoxygenase pathways may contribute to the clinical diarrhea and colitis of inflammatory bowel disease. Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa, and these levels tend to correlate with severity of the disease. In this study, we evaluated the efficacy of ingestion of fish oil n-3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. Eleven patients with ulcerative colitis of mild to moderate severity were studied in a 8-month, double-blind, placebo-controlled, crossover trial of dietary supplementation with fish oil, which provided about 4.2 g of omega-3- fatty acids per day. A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mucosal leukotriene B4 production was measured by radioimmunoassay. Mean disease activity index declined 56% for patients receiving fish oil and 4% for patients on placebo (p < 0.05). There were no statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels. All patients tolerated fish oil ingestion and showed no alteration in routine blood studies. No patient worsened; anti-inflammatory drugs could be reduced or eliminated in eight patients (72%) while receiving fish oil. We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis but is not associated with significant reduction in mucosal leukotriene B4 production, compared with placebo therapy. Further studies are needed to elucidate the mechanism of action and optimal dose and duration of fish oil supplementation in ulcerative colitis.

Simopoulos A.P.
The Center for Genetics, Nutrition and Health, 2001 S Street, NW, Washington, DC 20009 USA
Am. J. Clin. Nutr. (USA), 1991, 54/3 (438-463)

Several sources of information suggest that man evolved on a diet with a ratio of omega6 to omega3 fatty acids of similar 1 whereas today this ratio is similar 10:1 to 20-25:1, indicating that Western diets are deficient in omega3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Omega-3 fatty acids increase bleeding time; decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability, thus decreasing the tendency to thrombus formation. In no clinical trial, including coronary artery graft surgery, has there been any evidence of increased blood loss due to ingestion of omega3 fatty acids. Many studies show that the effects of omega3 fatty acids on serum lipids depend on the type of patient and whether the amount of saturated fatty acids in the diet is held constant. In patients with hyperlipidemia, omega3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol; furthermore, they consistently lower serum triglycerides in normal subjects and in patients with hypertriglyceridemia whereas the effect on high-density lipoprotein (HDL) varies from no effect to slight increases. The discrepancies between animal and human studies most likely are due to differences between animal and human metabolism. In clinical trials eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oils along with antirheumatic drugs improve joint pain in patients with rheumatoid arthritis; have a beneficial effect in patients with ulcerative colitis; and in combination with drugs, improve the skin lesions, lower the hyperlipidemia from etretinates, and decrease the toxicity of cyclosporin in patients with psoriasis. In various animal models omega3 fatty acids decrease the number and size of tumors and increase the time elapsed before appearance of tumors. Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants. Because omega3 fatty acids are essential in growth and development throughout the life cycle, they should be included in the diets of all humans. Omega-3 and omega6 fatty acids are not interconvertible in the human body and are important components of practically all cell membranes. Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake. Therefore appropriate amounts of dietary omega6 and omega3 fatty acids need to be considered in making dietary recommendations, and these two classes of PUFAs should be distinguished because they are metabolically and functionally distinct and have opposing physiological functions. Their balance is important for homeostasis and normal development. Canada is the first country to provide separate dietary recommendations for omega6 and omega3 fatty acids.

O'Morain C.A.
Department of Gastroenterology, Meath/Adelaide Hospitals, Peter Street, Dublin 8 Ireland
Scand. J. Gastroenterol. Suppl. (Norway), 1990, 25/172 (29-34)

The aetiology of inflammatory bowel disease (IBD) remains unknown, and many methods of treatment have been advocated. Patients with IBD are often nutritionally deficient and in negative nitrogen balance. The cause is multifactorial and includes decreased intake and absorption due to previous resection or mucosal involvement or increased exudation. General recommendations of vitamin and mineral supplements are usually made for these patients. Diet may have a more fundamental role in the aetiology and treatment of Crohn's disease, although this is not certain. Several controlled studies have confirmed that an elemental diet is as effective as steroids in inducing a remission in patients with acute Crohn's disease. Bacteria have also been implicated in the aetiology of Crohn's disease. Dietary measures may alter the intestinal flora and could result in a decrease of toxin production, which has been shown to correlate with clinical improvement. Although elemental diets are not effective in the treatment of ulcerative colitis, dietary measures may still be important. Preliminary studies suggest that eicosapentaenoic acid, which inhibits the production of mediators of inflammation by competing with enzymes in the arachidonic acid pathway, may be effective. Recent findings of increased faecal bile acids in patients with long-standing ulcerative colitis who developed dysplasia or carcinoma suggest that dietary measures may counteract these developments. It does appear that nutritional therapy in patients with IBD has both a primary and adjunctive role.

Jenkins H.R.; Pincott J.R.; Soothill J.F.; et al.
Department of Gastroenterology, The Hospital for Sick Children, London United Kingdom
Arch. Dis. Child. (England), 1984, 59/4 (326-329)

Forty six children presented with colitis between 1977 and 1981, and all 8 of those below the age of 2 years had food allergic colitis which resolved completely after exclusion of certain foods. In most of the 8 the onset was soon after starting foods other than breast milk. The most common offending food was cows' milk protein, but soya (3 cases) and beef (1 case) were also implicated. A history of allergy in the child or family was common as were blood eosinophilia, high concentrations of serum IgE, and positive IgE antibodies. Colonoscopic appearances were distinctive and biopsies showed a noticeable increase in eosinophils and IgE-containing cells in the lamina propria. We suggest that food allergy is the major cause of colitis in infancy and that an exclusion diet is the treatment of choice.

Cosnes J.; Tello H.; Le Quintrec M.; et al.
Service d'Hepato Gastroenterologie, Hopital Rothschild, F-75571 Paris Cedex 12 France
Gastroenterol. Clin. Biol. (France), 1983, 7/12 (1003-1009)

In order to assess the effectiveness and potential limitations of continuous enteral nutrition (CEN) to correct denutrition related to underlying digestive diseases, 10 nutritional criteria were measured weekly in 92 undernourished patients fed with CEN for a 3-7 week period. All the patients received a standard non-elemental diet providing a mean daily energy intake of 52.8 kcal/kg BW (36.5 kcal/kg BW by tube feeding and 16.3 kcal/kg BW orally). The influence of preexisting intestinal malabsorption, hypercatabolic status, and post-radiation or inflammatory bowel disease was studied by an a posteriori classification of patients in one of the six following groups: I (no limiting factor), II (malabsorption), III (catabolic disease), IV (catabolic disease and malabsorption), V (colitis), VI (enteritis). During CEN, 8 patients had transient and one had persistent vomiting while 3 developed bronchopneumonia. Gains in body weight, triceps skinfold, midarm muscle circumference, creatinine-height index, urinary sodium and serum transferrin were significant as early as the 2nd week of CEN. Serum albumin and cholesterol, hemoglobin, and total count of lymphocytes were not significantly affected. Sixty-five patients (71 per cent) had an objective nutritional improvement and mean spontaneous oral intake increased from 17.8 to 28.7 kcal/kg BW per day. Significant increase of oral intake and objective nutritional improvement were observed in each group, but a longer period of CEN was necessary to achieve this result in groups II, IV and VI. These results a) confirm that CEN is an effective and well tolerated nutritional treatment in gastrointestinal patients, b) describe the kinetics of nutritional improvement during CEN, and c) show that, in the alimentary conditions of this study, malabsorption, hypercatabolic disease or inflammatory enteropathy are not a contra-indication to the use of CEN. In chronic denutrition CEN must be administered during at least 3 weeks and prolonged until nutritional autonomy is obtained.

Wensinck F.; Custers-Van Lieshout L.M.C.; Poppelaars-Kustermans P.A.J.; Schroder A.M.
Dept. Med. Microbiol., Erasmus Univ., Rotterdam Netherlands
J. Hyg. (England), 1981, 87/1 (1-12)

The faecal flora of patients with Crohn's disease was compared with that of healthy subjects. In patients with terminal ileitis, numbers of anaerobic gram-negative and coccoid rods (species of Eubacterium and Peptostreptococcus) were higher than in the controls whereas anaerobic gram-positive rods and cocci and aerobes occurred in normal numbers. The composition of the flora was neither influenced by duration of the disease nor by ileocaecal resection. In healthy subjects and patients, a chemically defined diet induced only slight changes in the flora. Thus, the flora in terminal ileitis although stable was permanently abnormal. In patients with Crohn's colitis, abnormally low numbers of anaerobes were found in patients with severe, bloody diarrhoea while aerobic counts were normal. The flora in patients with mild colitis was similar to that in terminal ileitis. It is suggested that the abnormal flora composition might be an expression of the genetic predisposition to Crohn's disease.

Axelsson C.; Jarnum S.
Div. Gastroenterol., Med. Dept. P, Rigshosp., Univ. Copenhagen Denmark
Infusionsther. Klin. Ernahr. (Switzerland), 1977, 4/6 (313-318)

During a 4-year period 59 patients were treated with an elemental diet (Vivasorb(Reg.trademark)) for 1-6 weeks. The great majority (41 patients) were suffering from chronic inflammatory bowel disease. The indication for treatment was insufficient remission on prednisone 10-60 mg daily for 1-4 weeks or no remission after a high dose of prednisone (6O-120 mg) for 1-4 weeks. Remission was obtained in 14 patients on elemental diet and a constant or decreasing dose of prednisone and in another 6 on elemental diet and a high dose of prednisone. Thus, a total of 2O patients (50%) remitted. This includes 12 out of 24 with ulcerative colitis, and 8 out of 17 with Crohn's disease. It was not possible to demonstrate significant differences between the groups having moderate and severe disease activity, or between those with topographically restricted and with extensive lesions. The remission was long. During this treatment of patients with chronic inflammatory bowel disease there occurred a significant reduction in faecal bulk, frequency of bowel movements, and the ESR (erythrocyte sedimentation rate). A number of parameters, including serum protein and albumin, remained greatly reduced. Moreover, there was a significant decrease in serum urea and in the renal excretion of urea, due to the low nitrogen content of Vivasorb(Reg.trademark). Treatment of patients with intestinal fistulae (13 patients), the short bowel syndrome (6 patients), intractable diarrhoea (4 patients), recurrent pancreatitis (2 patients) and hyperlipaemia (2 patients) gave good results in several, but far from all cases. In particular, no effect was obtained in patients having the short bowel syndrome.

Goschke H.; Buess H.; Gyr K.; et al.
Dept. Inn. Med., Univ., Basel Switzerland
Schweiz.Med.Wschr. (Switzerland), 1977, 107/2 (43-49)

21 patients with gastroenterological disease and indication for the use of intravenous nutrition received an elemental diet (ED) for 5-44 days. In 6 out of 8 patients with exacerbation of Crohn's disease remissions were achieved, apart from 3 persistent fistulas. In 5 out of 9 cases with various primary diseases and postoperative intestinal fistulas, spontaneous healing was observed. Furthermore, 2 patients with ulcerative colitis, 1 with radiation enteritis and 1 with pancreatitis were treated with ED. On ED, hemoglobin increased from 11.3 + or - 0.4 (m + or - SEM) to 12.0 + or - 0.5 g% (p <0.01) and serum albumin from 2.7 + or - 0.1 to 3.4 + or - 0.1 g% (p <0.001). Nitrogen requirements were studied in 11 patients receiving various quantities of ED. Nitrogen balance was found to be in equilibrium or positive in 7 patients, and negative in 4. In one patient with severe ulcerative colitis, fecal nitrogen losses were higher than urinary nitrogen losses. The unpleasant taste of ED resulting from free amino acids limited the ED supply in 3 patients and led to premature ending of ED administration in 3 other patients. In such cases ED may be given by nasogastric tube feeding. From the results presented it appears that ED is indicated in Crohn's disease and intestinal fistulas. However, the results obtained require confirmation by further observations and comparison with an intravenously fed control group.

Falchuk K.R.; Falchuk Z.M.
Dept. Med., Massachusetts Gen. Hosp., Peter Bent Brigham Hosp., Boston, Mass. USA
Gastroenterology (USA), 1975, 69/2 (503-506)

A patient with selective immunoglobulin A deficiency, severe ulcerative colitis, and malabsorption had a flat jejunal mucosa demonstrated by peroral biopsy. Treatment at different times with a gluten free diet for the jejunal lesion and corticosteroids for the ulcerative colitis, led to improvement of the malabsorption. A great jejunal biopsy demonstrated histological improvement of the jejunal mucosa, even though the colitis remained active. The occurrence of immunoglobulin A deficiency in a patient with ulcerative colitis and gluten sensitive enteropathy is uncommon.

Ito T.
I Dept. Int. Med., Hirosaki Univ. Sch. Med., Hirosaki Japan
Hirosaki Med.J. (Japan), 1974, 26/2 (167-186)

A comparative study of the absorption of various kinds of fatty acids and corresponding triglycerides and a study of MCT metabolism in experimental animals is presented. Time lapse absorption of MCT and LCT was studied in fasted albino rats by giving orally sup 1sup 4C labeled fatty acid preparations. Octanoic acids were mostly absorbed within an hr but only 32% of palmitate. The absorption of sup 1sup 4C labeled glycerol trioctanoate was studied. Small intestines of the dog were ligated and segmented into 3 parts (upper, middle and lower). Of the 3 segments, the middle showed the fastest absorption of glycerol trioctanoate 1 sup 1sup 4C. Experiments in dogs with indwelling cannulas in the thoracic ducts showed that only 5.21 x 10sup -sup 2 muCi of administered glycerol trioctanoate 1 sup 1sup 4C was transported to the lymphatics in 120 min. The radioactivity in the lipids of albino rat liver was studied 60 and 120 min after an oral administration of glycerol trioctanoate 1 sup 1sup 4C. The radioactivity of the lipid fraction was 1.3% of all activity that was absorbed. Nearly 54.1% of the radioactivity of lipids from liver slices was detected in phospholipids and 36.8% in triglycerides but in free fatty acids and cholesterol esters the activity was extremely low. The radioactivity of administered glycerol was detected in the form of sup 1sup 4COsub 2 as early as 15 min after ingestion and this activity increased abruptly after 30 min and in 75 min it reached 21.3% of the administered dose and 28% of the total absorbed glycerol. Clinical study was performed to evaluate MCT therapy in 10 patients, 7 of them with postoperative malabsorption syndrome, one with liver cirrhosis, one with pancreatic cyst and one with postoperative ulcerative colitis. After a control period, 150 g of MCT was added daily to the diet of the patients. Because of the untoward effects, the MCT regimen was discontinued in 3 cases. The other 7 patients treated for more than a mth showed an increase in body weight of over one kilogram on average. Abnormally low serum cholesterol and albumin in a patient attained a normal range after one month of MCT administration. sup 1sup 3sup 1I triolein test improved and the frequency of bowel movements decreased in all patients. To achieve clinical effectiveness, MCT was continuously administered for at least a mth. In patients with malabsorption syndrome, there was an increase in body weight, serum cholesterol and serum albumin, a decrease in frequency of bowel movements and an improvement in the nature of the stool.

Jarnum S.
Med. Afd. P, Gastroenterol. Afsnit, Rigshosp., Kobenhavn Denmark
Ugeskr.Laeg. (Denmark), 1974, 136/17 (912-920)

Crohn's disease attracts increasing interest on account of its many clinical and pathophysiological aspects and because it seems to be becoming more frequent. Based on case material of 179 patients with Crohn's disease treated in hospital over a 10 yr period, certain epidemiological, clinical and pathophysiological features are discussed. Diagnostic accuracy is considered high. Thus the small intestine was involved in approximately 90%. However, the case material is selected and, therefore, less suited for an epidemiological study. One third was transferred from other hospitals, one fourth lived in Copenhagen, one third in Jutland. Copenhagen citizens in the case material represented a 'minimal' prevalence of 7.8 per 100,000 inhabitants in Copenhagen City, and the total case material a prevalence of 3.6 per 100,000 in the whole country. Owing to selection the true prevalence must be considerably higher. There were 50% more women than men. The pathophysiological characteristics of Crohn's disease are largely due to its liability to involve the ileum. Enterogenous vitamin Bsub 1sub 2 malabsorption occurred in 67% of 118 patients studied. It was also present in 11% of 70 patients with ulcerative colitis. Extensive intestinal resection is another, less frequent consequence of Crohn's disease. Studies in 24 patients subjected to extenseive but intestinal resection (75-270 cm) showed Bsub 1sub 2 malabsorption to occur only after ileal resection, whereas decreased serum folic acid developed mainly following jejunal resection. The serum protein pattern shows a characteristic bun nonspecific change. Albumin and often transferrin are decreased, orosomucoid increased. Immunoglobulin levels are within normal range, but higher in patients who respond favourably to medical treatment than in patients who do not. Intestinal plasma protein loss is almost consistently present. Treatment of Crohn's disease should be a combined and harmonized surgical medical undertaking. Resection is now preferred to 'by pass' interventions. Medical treatment comprises specific and individualized treatment. Specific treatment aiming at suppression of the inflammatory process is possible with salicylazosulfapyridine which is effective in mild and moderate cases, glucocorticoids which may have a dramatic effect in severe cases without obstruction, and, possibly, immunosuppressive agents, the value of which is still disputable. Individualized medical treatment covers a wide range of therapeutic measures: vitamin substitution (especially vitamin Bsub 1sub 2), electrolytes, bile acid binding resin to counteract cholegenic diarrhoea, dietary fat restriction (40 g fat per day) in the short bowel syndrome, symptomatic therapy with analgetic, spasm relieving and constipating drugs. Complete parenteral nutrition or treatment with 'elementary diet' may be beneficial in selected, severe cases, in particular when intestinal fistulas are present.

Tasev T.; Nedkova Bratanova N.; Nikolov N.; et al.
Kat. Gastroenterol. Dietet., ISUL, Sofia Bulgaria
Vatr.Bolesti (Sofia) (Bulgaria), 1973, 12/2 (24-31)

The results are reported from simultaneous clinical, morphological and enzymological examinations of 105 patients with different gastrointestinal diseases. The quantitative determination of lactase, maltase and invertase in homogenate of jejunal mucous membrane was carried out by the Dahlquist method. A decrease of lactase was found in 65.45% of the patients with non specific chronic enteritis, of maltase on 56% and invertase in 43.9%. In patients with gastric resection the figures for these 3 examinations were 45.4%, 25% and 33.3%; and in patients with ulcerative colitis in 55.5%, 57.14% and 25% resp. Comparison of the data after disaccharide loading and the quantitative enzyme determination showed a certain parallelism in 2/3 of the cases. No correlation was established between the morphological investigations and enzyme values. The excluding of non tolerated disaccharides from the diet for a relatively longer time led to clinical improvement and restoration of jejunal mucous membrane with the exception of lactase, the disaccharide content was elevated.

Breuer R.I.; Soergel K.H.; Lashner B.A.; Christ M.L.; Hanauer S.B.; Vanagunas A.; Harig J.M.; Keshavarzian A.; Robinson M.; Sellin J.H.; Weinberg D.; Vidican D.E.; Flemal K.L.; Rademaker A.W.
Dr. R.I. Breuer, Evanston Hospital, Special GH Laboratory, 2650 Ridge Avenue, Evanston, IL 60201 USA
Gut (United Kingdom), 1997, 40/4 (485-491)

Background - Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. Aims - To assess the efficacy of topical SCFA treatment in ulcerative colitis.

Patients and Methods - 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial.

Results - Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (<6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores.

Conclusions - Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.

Williams C.N.
CRC, Dalhousie University, 5849 University Avenue, Halifax, NS B3H 4H7 Canada
Can. J. Gastroenterol. (Canada), 1993, 7/2 (196-199)

There are many issues and controversies concerning nutrition in inflammatory bowel disease (IBD). Most authorities now accept that total parenteral nutrition (TPN) is useful, both as primary and adjunct therapy in the management of patients with Crohn's disease, but only useful as adjunct therapy in patients with acute flare-ups of ulcerative colitis. In both, there is a role for TPN in preparing patients for imminent surgery. In comparison with TPN, defined formula (elemental diet) therapy has less complications, is easier to monitor, is less costly, and gives equivalent results. Several controlled trials have shown that elemental diet therapy is as useful as prednisone in inducing remission in patients with active Crohn's disease. Elemental diets have been compared with polymeric diets in patients with Crohn's disease, and have been shown to be effective; recently a semi-elemental diet has also been shown to be as effective as elemental diet, but with a conferred benefit of maintaining essential fatty acid levels. Elemental diets do not appear to be effective in closing fistulas. If the problems of palatability and, in some patients, nausea, vomiting, abdominal cramps and diarrhea persist, these can be overcome to some extent by flavour changes, chilling, gradual introduction and counselling or nasogastric tube feeding. Recently, fish oils have been used in patients with IBD. There is suggestive evidence that they are of benefit in patients with ulcerative colitis but not in Crohn's disease. There is a suggestion that fish oils have a steroid-sparing effect which, if confirmed, will be of great potential benefit to patients with ulcerative colitis.

Greenfield S.M.; Green A.T.; Teare J.P.; Jenkins A.P.; Punchard N.A.; Ainley C.C.; Thompson R.P.H.
Gastrointestinal Laboratory, The Rayne Institute, St Thomas' Hospital, London SE1 7EH United Kingdom
Aliment. Pharmacol. Ther. (United Kingdom), 1993, 7/2 (159-166)

In a placebo-controlled study, 43 patients with stable ulcerative colitis were randomized to receive either MaxEPA (n = 16), super evening primrose oil (n = 19), or olive oil as placebo (n = 8) for 6 months, in addition to their usual treatment. Treatment with MaxEPA increased red-cell membrane concentrations of eicospentaenoic acid (EPA) at 3 months by three-fold and at 6 months by four-fold (both P < 0.01), and doubled docosahexaenoic acid (DHA) levels at 6 months (P < 0.05). Treatment with super evening primrose oil increased red-cell membrane concentrations of dihomogamma-linolenic acid (DGLA) by 40% at 6 months (P < 0.05), whilst treatment with placebo reduced levels of DGLA and DHA at 6 months (both P < 0.05). Clinical outcome was assessed by patient diary cards, sigmoidoscopy and histology of rectal biopsy specimens. Super evening primrose oil significantly improved stool consistency compared to MaxEPA and placebo at 6 months, and this difference was maintained 3 months after treatment was discontinued (P < 0.05). There was however, no difference in stool frequency, rectal bleeding, disease relapse, sigmoidoscopic appearance or rectal histology in the three treatment groups. Despite manipulation of cell-membrane fatty acids, fish oils do not exert a therapeutic effect in ulcerative colitis, while evening primrose oil may be of some benefit.

Hawthorne A.B.; Daneshmend T.K.; Hawkey C.J.a; Belluzzi A.; Everitt S.J.; Holmes G.K.T.; Malkinson C.; Shaheen M.Z.; Willars J.E.
Department of Therapeutics, University Hospital, Nottingham NG7 2UH United Kingdom
Gut (United Kingdom), 1992, 33/7 (922-928)

The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentanoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore-stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.

Hillier K.; Jewell R.; Dorrell L.; Smith C.L.
Clinical Pharmacology Group, Faculty of Medicine, University of Southampton, Southampton SO9 3TU United Kingdom
Gut (United Kingdom), 1991, 32/10 (1151-1155)

The incorporation of the fatty acids in fish and olive oil into the colonic mucosa of patients with inflammatory bowel disease was examined during 12 weeks' dietary supplementation with the oils, and the influence on colonic mucosal prostaglandin and thromboxane generation was measured. With a dietary supplement of 18 g fish oil daily, concentrations of the major polyunsaturated fatty acids in fish oil, eicosapentaenoic acid and docosahexaenoic acid, were significantly raised in mucosal lipids. The first time these were measured, after three weeks' supplementation, the mean increases in eicosapentaenoic and docosahexaenoic acid were seven fold and 1.5 fold respectively, and these increases were maintained during the 12 week study. Arachidonic acid values fell throughout the study and this reduction was significant at 12 weeks. Mucosal prostaglandin E2 (PGE2), thromboxane B2, and 6-keto prostaglandin F(1alpha) synthesis were suppressed, and this reached significance (p < 0.05) at three and 12 weeks for PGE2 and at 12 weeks for thromboxane B2. The predominant fatty acid in olive oil is oleic acid. Supplementation with 18 g/day resulted in a significant increase in oleic acid in colonic mucosa at 12 weeks (p < 0.05) and a fall in stearic acid and docosahexaenoic acid; there was no significant change in eicosanoid synthesis. It is concluded that colonic lipids and prostaglandin and thromboxane synthesis can be readily altered by dietary supplementation with fish oil. The extent of incorporation of the fatty acids present in oils is dependent upon the individual fatty acid.

Krizek V.; Sadilek L.
Vyzkumny Ustav Balneologicky, Marianske Lazne Czech Republic
Fysiatr. Revmatol. Vestn. (Czech Republic), 1993, 71/4 (195-212)

1. Carlsbad mineral water is a hydrogencarbonate-sulphur containing thermal water with a mineralization of cca 6.4 g.l-1. It is drunk at the springs in the spa and is bottled under the name 'Mlynsky pramen' (Mill spring).

2. 28-day controlled clinical trial comprising two weeks of drinking Carlsbad water was to provide new information on the suitability of this water in nephrourological indication.

3. The trial comprised 16 experimental subjects, mostly suffering from urolithiasis, four suffered from gout. During the first and fourth week the subjects drank 1.5 litres of ordinary drinking water, during the second and third week the same amount of Carlsbad water. The standard diet which was the same every week made it possible to compare the excretion of minerals and other substances during individual periods in the course of the investigation.

4. Drinking of Carlsbad water induced desirable diuresis. The demand of a diuresis of more than 2 l.d-1 was met only by 52 to 55% of the daily amounts.

5. Drinking of Carlsbad water led to slight alkalization of the urine from pH 5.8 to 6.8 with a corresponding decline of titratable acid and ammonia in urine. Acid-base indicators in blood were not affected.

6. Calciuria rose by 4 to 7%, magnesiuria, on the other hand, declined slightly. The Ca/Mg quotient in urine rose insignificantly. The blood levels of calcium and magnesium declined slightly. It was not possible to confirm analogous effects to those described formerly by Stransky.

7. A 20% rise of natriuria was recorded and elevated inorganic sulphaturia by 45 to 57%. The urinary potassium excretion increased slightly. The chloride excretion, on the other hand, declined by 8.5%. Serum electrolytes did not display major changes.

8. The tolerance of the Carlsbad water drinking cure - 3 times 0.5 l - was good. The water had a minor purgative effect. The daily frequency of bowel movements increased by 36 to 60% and there was a higher proportion of loose but not diarrhoeal stools.

9. Uricaemia declined by 17% and uricuria by 13 to 16%. The uric acid clearance declined by 7 to 11%. In the four patients suffering from gout analogous effects were recorded as in subjects without gout. No uricosuric effect was found.

10. During the drinking cure in the investigated non-diabetic subjects the morning blood sugar and insulin level were not affected.

11. The Carlsbad water drinking cure is indicated in particular in urate and cystine urolithiasis. It will be useful to use the drinking cure more frequently to ensure primary and secondary prevention of oxalate lithiasis in gastroenterological patients with malabsorption syndromes, in conditions following intestinal bypasses, jejunostomies, similarly as in the prevention of urate lithiasis in ulcerative colitis, in particular after operations such as ileostomies, colectomies etc.

12. The Carlsbad water drinking cure, in particular larger amounts, must be indicated carefully in conditions where the ingestion of sodium or alkalization of urine are not desirable.

Ferraris L.; Karmeli F.; Eliakim R.; Klein J.; Fiocchi C.; Rachmilewitz D.
Department of Medicine, Hadassah University Hospital, Mount Scopus, PO Box 24035, Jerusalem 91240 Israel
Gut (United Kingdom), 1993, 34/5 (665-668)

Generation of platelet activating factor by intestinal mucosal epithelial cells and lamina propria mononuclear cells was evaluated to elucidate the possible role of this mediator in the pathogenesis of inflammatory bowel disease. Epithelial and lamina propria mononuclear cells were isolated from surgical specimens from control, Crohn's disease, and ulcerative colitis patients. Platelet activating factor was extracted from highly purified cell preparations with 80% ethanol after stimulation with and without 0.2 uM calcium ionophore A23187 and was measured by platelet aggregation assay. Both cell types generated platelet activating factor activity and this was generally comparable for epithelial and lamina propria cells. Basal and stimulated platelet activating factor activity of epithelial and lamina propria cells from ulcerative colitis but not Crohn's disease patients was appreciably higher than that of control. Stimulation with calcium ionophore increased appreciably platelet activating factor activity in lamina propria cells from all groups. In contrast, only epithelial cells from ulcerative colitis showed an appreciable increase after calcium ionophore induction. These results suggest that epithelial cells are important contributors to intestinal platelet activating factor generation under normal and inflammatory conditions and that epithelial cells actively play a part in the pathogenesis of ulcerative colitis.

Kirsner J.B.
Department of Medicine, University of Chicago, Chicago, IL USA
Dis. Mon. (USA), 1991, 37/11 (673-675)

Once regarded as medical curiosities, ulcerative colitis and Crohn's disease have achieved a remarkable change in status recently and today are among the more compelling of all human illnesses. The cause(s) of inflammatory bowel disease (IBD) are not known. Genetic, environmental, microbial, and immunologic factors are involved, but the precise mechanisms are obscure. The incidence of ulcerative colitis is relatively stable, while Crohn's disease continues to increase in frequency. In 10% to 15% of patients, it is hard to differentiate between ulcerative colitis and Crohn's colitis, however, problems with diagnosis usually resolve with time and repeated examinations. In part I of his two-part monograph on IBD, Dr. Kirsner addressed the nature and pathogenesis of the disease. Increased study of ulcerative colitis and Crohn's disease in recent years has generated new knowledge regarding their etiology. Part I focused on microbial, immunologic, and genetic mechanisms of, and the inflammatory process involved in the disease. In this part, Dr. Kirsner deals with the clinical features, course, and management of IBD, based on the author's 55 years of experience with these problems and supplemented by critical examination of the recent (1988-1990) literature. Particular attention is directed to the symptoms and physical findings of ulcerative colitis and Crohn's disease. The laboratory, radiologic, endoscopic, and pathologic features, and the many systemic complications. IBDs are mimicked by several enterocolonic infections and other conditions making differential diagnosis necessary. Inflammatory bowel disease in children and the elderly conforms to conventional clinical patterns modified by the health circumstances of the respective age groups. Because the cause of IBD has not been established, current medical therapy is facilitative and supportive rather than curative. The principles of medical treatment are approximately the same for ulcerative colitis and Crohn's disease. Treatment emphasizes a program rather than a drug and also considers the individuality of the therapeutic response. A clearer understanding of dietary and nutritional needs, including hyperalimentation and electrolyte and fluid balance, aids treatment. Antidiarrheal and antispasmodal preparation and sedatives are prescribed for symptom relief. The bowel inflammation is controlled with sulfasalazine or the newer 5-amino-salicylic acid (5-ASA) compounds, antibacterial drugs for complications of Crohn's disease and IBD, adrenocortical steroids, and the immunosuppressive compounds 6-mercaptopurine (6MP), azathioprine, and cyclosporine, as determined in each patient. The surgical procedures available for treatment of ulcerative colitis include total protocolectomy and ileostomy or ileoanal anastomosis. In Crohn's disease of the small bowel, the usual approach is intestinal resection and reanastomosis. Strictureplasty is possible in some instances of stenotic intestinal disease. For treatment of Crohn's colitis, procedures include total proctocolectomy, total colectomy with ileal anastomosis, and occasionally, segmental resection of the large intestine. Chronic IBD requires prolonged observation, periodic adjustments in therapy, and colonic and radiologic surveillance. The prognosis of ulcerative colitis and Crohn's disease is much improved over the years, but a cure has not yet been found reemphasizing the need for further investigation of these challenging diseases.

Harries A.D.; Brown R.; Heatley R.V.; et al.
Department of Gastroenterology, University Hospital of Wales, Cardiff United Kingdom
Gut (England), 1985, 26/11 (1197-1203)

Forty patients with Crohn's disease were divided into undernourished (18) and well nourished (22) groups depending on whether their midarm circumference was below or above 90% of the ideal standard. Plasma 25-(OH)D3 and the dihydroxylated metabolites, 24,25-(OH)sub 2D3 and 1,25-(OH)sub 2D3 were measured in the summer. Results were related to clinical and biochemical parameters and also compared with results from patients with ulcerative colitis and healthy subjects who served as controls. Plasma 25-(OH)D3 was reduced in the undernourished Crohn's group compared with the well nourished Crohn's group, who did not differ from the controls. Over 50% of the undernourished Crohn's group had evidence of secondary hyperparathyroidism and raised alkaline phosphatase concentrations, although concentrations of 1,25-(OH)sub 2D3 were normal. The low 25-(OH)D3 concentrations related to disease activity. It is suggested that undernourished Crohn's patients who have high levels of disease activity are at risk of vitamin D deficiency, and attempts should be made to improve their vitamin D nutrition.

Bellaiche G.; Le Pennec M.P.; Slama J.L.; Ley G.; Choudat L.; Giacomini T.; Godefroy Y.; Paugam B.
Service de Gastroenterologie, Ctr. Hosp. General Robert Ballanger, Boulevard Robert-Ballanger, 93602 Aulnay-Sous-Bois Cedex France
Annales de Gastroenterologie et d'Hepatologie (France), 1996, 32/1 (11-17)

The goal of this study was to evaluate the contribution of sigmoidoscopy with bioptic microbiology to the etiologic diagnosis of acute diarrhea in adults. Patients and methods. Sixty-five patients with acute diarrhea were included prospectively from February 1993 to November 1994. Ages ranged from 17 to 83 years. In each patient, two stool samples were cultured and three examined for parasites. Clostridium difficile toxin was looked for in the 18 patients who had taken antimicrobials before onset of the diarrhea. Sigmoidoscopy with collection of biopsy specimens for bacteriologic cultures was performed routinely. Results. A pathogenic organism was identified in 35 patients (54%). Eighteen patients (28%) had positive stool cultures. Clostridium difficile toxin was detected in six patients. Colonic biopsy cultures were positive in 26 patients (40%). Endoscopic findings established the diagnosis of pseudomembranous colitis with negative tests for C. difficile toxin in two patients, diverticulitis in one, ischemic colitis in two, and cryptogenic colitis in seven. Conclusions. Sigmoidoscopy ensured the diagnosis in over 72% of cases of acute diarrhea. This investigation complements stool cultures and should be done routinely in adults with severe acute diarrhea.

Patterson M.; Healy G.R.; Shabot J.M.
Gastroenterol. Div., Dept. Med., Univ. Texas Med. Branch, Galveston, Tex. 77550 USA
Gastroenterology (USA), 1980, 78/1 (136-141)

The diagnosis of amoebiasis presents problems, particularly if one relies on finding the organism. Thus, serologic tests are expedient. A gel diffusion precipitin test (GDP), commercially available, simple to perform, and inexpensive, was compared with the indirect hemagglutination test (IHA). 257 Patients' sera were tested; 14 had amoebic colitis, 21 had amoebic liver abscess, 63 had suspected amoebic liver abscess, and 46 had inflammatory bowel disease. GDP tests were positive in 85% of amoebic colitis and 95% of amoebic liver abscess patients; IHA was positive in 91% of amoebic colitis and 94% of abscess patients. Within 6 mo, GDP tests became negative in 66% of patients. IHA tests were observed positive up to 20 yr. The performance characteristics of diagnostic methods for amoebiasis, fecal examination, IHA and GDP, show serologic tests have superior sensitivity and predictive value in recognizing invasive disease.

Solomon G.E.
Mount Sinai Sch. Med., City Univ. New York, N.Y. 10029 USA
Mt.Sinai J.Med. (USA), 1976, 43/5 (602-624)

The currently available clinical and laboratory data (119 references) make it still premature to conclude that IBD represents an autoimmune process. None of the 6 definitive criteria for autoimmune disease have been well established for either chronic ulcerative colitis (CUC) or Crohn's disease (CD). Nevertheless, there is a good deal of available data which supports an autoimmune etiology. Virtually all of the ancillary findings which Sell labels as presumptive evidence for autoimmune disease have been demonstrated in IBD. These include: a morphologic picture consistent with known allergic reactions; the demonstration of antibody or a positive delayed skin reaction; a depression of complement during any stage of the disease; a beneficial effect from agents known to inhibit some portions of an allergic reaction (steroids, radiation, anti-metabolites, etc.); an association with other possible autoimmune diseases; identification of a reasonable experimental model in animals that mimics the human disease: an increased familial susceptibility to the same or other autoimmune disease; and an association between the disease state and specific HLA (human histocompatibility antigen) types (Sell, S; Immunol., Immunopathol., and Immunity, New York, 1972). A framework, consistent with the available data, in which these criteria are satisfied consists of a breakdown of colonic mucosal barriers, which might represent a distinct immunizing event in which the underlying enteric lymphatic tissue becomes exposed to coliform antigens. Following immunization, a latent period might ensue during which sensitized cells or antigen or both communicate with the systemic immune system, possibly via Peyer's patches. Clones of cells programmed to respond to the coliform antigen are produced, possibly in the thymus, and migrate to the lamina propria of the enteric tract. Subsequent exposure to coliform antigen or cross-reacting colonic antigens causes release of lymphotoxin from these sensitized lymphocytes resulting in local cytolysis. Damage to mucosal cells leads to the release of mucosal cell antigens and further compromises the mucosal barrier, allowing a self perpetuating reaction in which the inflammatory process leads to the release of those antigens which initiated the inflammation. These antigens, both bacterial and colonic, have been fairly well identified. The evidence for a transmissable agent may well represent a transfer of the sensitive state by cells from an affected individual to a normal individual, and the periods of remission which punctuate IBD may represent the temporary induction of tolerance by optimal concentration of antigen. Although these proposed mechanisms are purely speculative, they are useful in that they clearly point out those areas to which future research must be directed.

Fabia R.; Ar'Rajab A.; Johansson M.-L.; Willen R.; Andersson R.; Molin G. Bengmark S.
Dept. of Surgery, Lund University, S-221 85 Lund Sweden
Scand. J. Gastroenterol. (Norway), 1993, 28/2 (155-162)

The potential beneficial effect of exogenous administration of Lactobacillus on acetic acid-induced colitis was evaluated in the rat. Colitis was induced by instillation of 4% acetic acid for 15 sec in an exteriorized colonic segment. This produced uniform colitis with a threefold increase in myeloperoxidase (MPO) activity of the colonic tissue (an index of neutrophil infiltration) and a sixfold increase in plasma exudation into the lumen of the colon (mucosal permeability) as evaluated 4 days after acetic acid administration. Intracolonic administration of L. reuteri R2LC immediately after acetic acid administration, at a dose of 5 ml of 7 x 107 colony-forming units (CFU)/ml in two forms: either as pure bacterial suspension or as fermented oatmeal soup, prevented the development of colitis. Thus, the morphologic score, MPO activity, and mucosal permeability were almost normalized by Lactobacillus treatment. Initiating the treatment 24 h after acetic acid administration or using lower doses of 1 ml for 3 consecutive days resulted in a smaller protective effect. We conclude that exogenous administration of L. reuteri R2LC prevents the development of acetic acid-induced colitis in the rat.

Besterman H.S.; Mallinson C.N.; Modigliani R.; et al.
Dep. Med., R. Postgrad. Med. Sch., London W12 0HS United Kingdom
Scand. J. Gastroenterol. (Norway), 1983, 18/7 (845-852)

We have studied fasting levels and the response to a standard test breakfast of blood glucose and several gut hormones in 24 patients with ulcerative colitis, in 14 patients with Crohn's disease, and in 14 healthy control subjects. Patients with ulcerative colitis had significantly elevated fasting human pancreatic polypeptide (HPP) concentrations, and both basal and postprandial levels of gastrin, gastric inhibitory polypeptide (GIP), and motilin were greater than normal. In contrast, patients with Crohn's disease had normal gastrin levels but had increased fasting and postprandial levels of GIP and motilin and, in addition, of enteroglucagon, compared with controls. These patients also had greater than normal HPP concentrations 30 min after the breakfast. Normal levels of insulin, pancreatic glucagon, neurotensin, and vasoactive intestinal polypeptide were found in both groups of patients. Much remains to be known about the pathophysiology of these two debilitating diseases, and the abnormal release of gut hormones may be of importance.

Rutgeerts P.; Ghoos Y.; Vantrappen G.
Dept. Med., Univ. Hosp. St Rafael, 3000 Leuven Belgium
Eur. J. Clin. Invest. (England), 1982, 12/2 (135-143

The metabolism of cholic acid and chenodeoxycholic acid was studied in seventeen patients with non-operated Crohn's disease, eleven ileitis and six ileocolitis patients. The turnover of cholic acid was significantly increased in patients with ileitis (k = 2.0 + or - 1.13 dayssup -sup 1; P < 0.001) and ileocolitis (k = 0.91 + or - 0.47 dayssup -sup 1; P < 0.005) as compared to normals (k = 0.35 + or - 0.19 dayssup -sup 1). Although chenodeoxycholic acid was better preserved in the enterohepatic circulation than cholic acid its turnover was also significantly faster in ileitis (k = 0.81 + or - 0.56 dayssup -sup 1; P < 0.005) and ileocolitis patients (k = 0.62 + or - 0.18 dayssup -sup 1; P < 0.01) than in normals (k = 0.20 + or - 0.09 dayssup -sup 1). The fractional turnover of cholic acid was related to the length of ileal involvement (r = 0.761; P < 0.001; n = 17). Patients with Crohn's ileitis tended to preserve normal fasting total bile acid pools by increased synthesis of primary bile acids and efficient absorption of deoxycholic acid and ursodeoxycholic acid by the normal colon. Patients with active ileocolitis had decreased total fasting pool sizes (2.62 + or - 1.83 mmol; P < 0.001) as compared to normals (7.69 + or - 1.61 mmol). In these patients there was no increase in bile acid synthesis as compared to normals and secondary bile acids were absent frome bile. It is concluded that the colon has an important role in maintaining the fasting pool size to a normal level in the presence of an interrupted enterohepatic circulation of bile acids due to ileal disease.

Vantrappen G.; Ghoos Y.; Rutgeerts P.; Janssens J.
Lab. Gastrointest. Pathophysiol., Dept. Med. Res., Univ. Leuven Belgium
Gut (England), 1977, 18/9 (730-735)

The pool size and composition of bile acids were studied in 13 unoperated patients with uncomplicated Crohn's disease, 10 patients with ulcerative colitis, and 10 normal subjects. Many patients with Crohn's disease had in their bile a significantly increased amount of ursodeoxycholic acid. The bile acid pool size was significantly decreased and the ratio of glycine to taurine conjugates was significantly increased in the Crohn's disease patients. The reduction in bile acid pool size was related to the activity of the disease. The disorders of bile acid metabolism suggest that the intestinal involvement in Crohn's disease is much more extensive than can be demonstrated by careful radiological examinations.

Lenz K.
Med. Dept. P, Div. Gastroenterol., Rigshosp., Copenhagen Denmark
Scand.J.Gastroent. (Norway), 1976, 11/8 (769-775)

Bile acid and vitamin Bsub 1sub 2 malabsorption were evaluated in 34 cases of ulcerative colitis. Twenty four patients were non operated and 10 patients were colectomized. The postprandial duodenal bile acid concentration was abnormally low in 13 of 24 non operated cases and found to be correlated to the activity of the disease. Two of six patients subjected to colectomy had a reduced bile acid concentraion. Bile acid absorption was assessed by the cholyl glycine 1 sup 1sup 4C breath test combined with faecal analysis. The sup 1sup 4C excretion in breath was abnormally elevated in only one of the patients in the total material. The faecal sup 1sup 4C output was related to the disease activity in the non operated group. Patients colectomized for ulcerative colitis had an extremely high excretion of isotope in the ileal effluent, from 15 to 81 per cent of the dose given. The faecal sup 1sup 4C output was correlated with the duration of the ileostomy and the mass of ileal discharge. Vitamin Bsub 1sub 2 malabsorption was only present in five patients. It is concluded that patients with ulcerative colitis during the active phase of the disease have bile acid malabsorption, and patients colectomized for ulcerative colitis have an abnormal high bile acid deconjugation in the ileal effluent.

Grimes D.S.
Dept. Med., Withington Hosp., Manchester United Kingdom
Lancet (England), 1976, 1/7956 (395-397)

A diet high in refined carbohydrate is implicated in the aetiology ofsome diseases of the colon i.e., diverticular disease, irritable bowel syndrome, ulcerative colitis, non occlusive ischaemic colitis, and pseudomembranous colitis. It is suggested that spasm of the smooth muscle is the common pathogenetic mechanism in these colonic diseases. The strength of the spasm producing increased pressure in the colonic lumen or wall and the length of time for which the colon has been affected are believed to determine the type of disease resulting. A diet high in refined carbohydrate allows the intense muscle spasm to occur because the physical buffering effect of faecal bulk is considerably reduced.

Ellestad Sayed J.J.; Nelson R.A.; Adson M.A.; et al.
Dept. Ped., Univ. Manitoba, Winnipeg USA
Amer.J.Clin.Nutr. (USA), 1976, 29/12 (1333-1338)

To investigate further an apparent relationship between chroniculcerative and granulomatous colitis and pantothenic acid deficiency,colonic tissues obtained at the time of colectomy in 29 patients with these disorders were assayed for pantothenic acid and for coenzyme A (CoA) activity. For comparison, normal colonic tissues free of pathological lesions were obtained from 31 patients having colectomy for carcinoma or diverticulitis. Plasma, red blood cells, and colonic mucosa were assayed microbiologically for free and total pantothenic acid. The activity of CoA in colonic mucosa was determined by assaying the acetylation of sulfanilamide. Concentrations of free, bound and total pantothenic acid in blood and in colonic mucosa did not differ between the two groups of patients. Bound pantothenic acid increased linearly with total pantothenic acid. Colonic mucosa concentrated free pantothenic acid to about 50 times the level of blood, and pantothenic acid in red cells was similar to the concentration in plasma. Compared to normal gut mucosa, CoA activity was markedly low in mucosa from patients with chronic ulcerative or granulomatous disease despite the presence of normal amounts of free and bound pantothenic acid. A block in the conversion of bound pantothenic acid to CoA in diseased mucosa is suggested.

Murch S.H.; MacDonald T.T.; Walker-Smith J.A.; Levin M.; Lionetti P.; Klein N.J.
Dept. Paediatric Gastroenterology, St Bartholomew's Hospital, London EC1A 8BE United Kingdom
Lancet (United Kingdom), 1993, 341/8847 (711-714)

We have studied the distribution and nature of sulphated glycosaminoglycans (GAGs) within normal and inflamed intestine. There is increasing evidence that these negatively charged polysaccharides, which both regulate the ability of albumin to leave the vasculature and inhibit thrombosis, may be affected by inflammatory cells and their products. We obtained samples of freshly resected intestinal tissue from eight controls, eleven patients with Crohn's disease, and six with ulcerative colitis. Sulphated GAGs were detected by means of a gold-conjugated poly-L-lysine probe, and the tissue density of anionic sites was assessed semiquantitatively by means of a Lennox graticule. In normal intestine there was staining in the vascular endothelium and the subepithelial basal lamina and throughout the extracellular matrix of the lamina propria and submucosa. Tissue from the patients with inflammatory bowel disease showed inflammation macroscopically and on histology. There were profound abnormalities of extracellular matrix GAGs, limited to the mucosa in ulcerative colitis and greatest in the submucosa in Crohn's disease. There was also substantial loss of GAGs from the subepithelial basal lamina in both disorders and from the vascular endothelium in submucosa in Crohn's disease. The extent of local GAG disruption was associated with the distribution of macrophages immunoreactive for tumour necrosis factor alpha and the activation marker RM 3/1. We suggest that inflammatory disruption of vascular and connective tissue GAGs may be an important pathogenetic mechanism, contributing to the leakage of protein and fluid, thrombosis, and tissue remodelling seen in inflammatory bowel disease.

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Stone O.J.
18700 Main Street, Huntington Beach, CA 92646 USA
Med. Hypotheses (United Kingdom), 1990, 31/2 (99-103)

Shortly after the introduction of sulfa drugs, sulfapyridine was found tohave unique therapeutic properties, unrelated to antibacterial activity. Later, sulfones were found to share the same properties. The disorders initially improved were dermatitis herpetiformis, pyoderma gangrenosum, subcorneal pustular dermatosis, acrodermatitis continua, impetigo herpetiformis and ulcerative colitis. They were also sometimes helpful in many other disorders. They are effective in select disorders characterized by edema followed by granulocytic inflammation or edema followed by vesicle or bullae formation. The sulfones work in low doses in leprosy and their mode of action is not fully understood. Several pieces of experimental information are available. It is proposed that these drugs are entering or influencing the protein moiety of glycosaminoglycans and decreasing tissue viscosity. This decreased tissue viscosity prevents edema and dilution of tissue fluid and decreases acute inflammation and vesicle and bullae formation.

Symonds D.A.
Dept. Pathol., US Publ. Hlth Serv. Hosp., Baltimore, Md. USA
Arch. Pathol. Lab. Med. (USA), 1978, 102/3 (146-149)

The glycosaminoglycans from normal colonic mucosa and colons with avariety of inflammatory diseases, as well as benign and malignant neoplasms were analyzed. Normal colonic mucosa contains predominantly chondroitin sulfates and dermatan sulfate. Increases in the levels of hyaluronic acid and heparan sulfate, as well as substantial increases in the amount of total glycosaminoglycans were characteristic of invasive colonic adenocarcinoma. Lesser elevations in the amount of total glycosaminoglycans and hyaluronic acid and heparan sulfate were present in neonatal colonic mucosa, villous adenoma, ulcerative colitis, and mucosa adjacent to carcinoma. The degree of elevation was proportional to the dysplastic potential. Since dysplastic lesions have scant connective tissue, the epithelial component of colonic neoplasms may contribute to these neoplasm-related alterations in glycosaminoglycan composition.

Siegel J.
7410 Long Point Rd, Houston, Tex., 77055 USA
Ann. Allergy (USA), 1981, 47/2 (92-94)

That inflammatory bowel disease (IBD) is just another possible facet of allergy is shown by the alleviation of IBD following allergy testing and treatment. This is further borne out by the findings in a survey (questionnaire) of local members of the National Foundation of Ileitis and Colitis (NFIC) in which 70% of individuals with IBD listed other symptoms which were judged to be 'Possibly Allergic.'

Aitola P.T.; Soppi E.T.; Halonen P.J.; Laine S.T.; Matikainen M.J.
Dept. of Surgery, Tampere University Hospital, P.O. Box 2000, FIN-33521 Tampere Finland
Scand. J. Gastroenterol. (Norway), 1994, 29/7 (646-650)

Background: The levels of antibodies against cow's milk proteins inulcerative colitis (UC) were used to study whether mucosal inflammation leads to immune recognition, as a marker of enhanced permeability, of dietary proteins. A further purpose was to study the effect of proctocolectomy on the serum antibody levels against cow's milk proteins and their relation to biochemical and histologic liver abnormalities associated with ulcerative colitis.

Methods: Serum antibody levels against six cow's milk proteins, alpha-casein, alpha-lactalbumin (LA), beta-lactoglobulin A (LGA), beta-lactoglobulin B (LGB), bovine serum albumin (BSA), and whole milk powder (MP) were determined before and after (mean, 24 months) proctocolectomy in 125 patients with ulcerative colitis. Simultaneously, serum liver enzymes were analyzed. A liver biopsy specimen was also obtained at proctocolectomy.

Results: Before proctocolectomy IgA antibody levels were significantly increased against all antigens except BSA. Increased levels of IgM antibodies against LGA, LGB, and BSA were also detected. IgG antibodies were significantly increased only against LGA. After proctocolectomy IgA and IgM antibody levels decreased significantly (p < 0.05) against LGA, LGB, and LA, whereas IgG antibodies increased significantly (p < 0.01). In the patient group with abnormal liver histology (n = 9) the IgA antibodies to all cow's milk proteins were significantly higher (p < 0.02) than in the group with normal liver histology both before and after proctocolectomy. The IgA antibody levels showed a significant positive correlation with alanine amino-transferase and gamma-glutamyltransferase (r value from 0.460 to 0.721, p value from < 0.05 to < 0.01), but not with alkaline phosphatase.

Conclusions: These results suggest that the inflamed mucosa in UC allows the antigenic contents of the bowel to escape. Proctocolectomy alters the antibody levels against certain milk proteins, which may serve as a model to suggest that proctocolectomy, probably by eliminating inflammation, may have positive effects by reducing the foreign pathogenic antigen and immune complex load.

Paganelli R.; Pallone F.; Montano S.; et al.
Cattedra di Immunologia Clinica, Clinica Medica III, Policlinico Umberto I, I-00161 Roma Italy
Int. Arch. Allergy Appl. Immunol. (Switzerland), 1985, 78/1 (81-85)

We studied the class-specific antibody response to the cow's milk antigenbeta-lactoglobulin (beta-LG) in sera from patients with ulcerative colitis and Crohn's disease. IgG and IgM to beta-LG were significantly higher in patients when compared to healthy non-atopic controls, whereas IgA values were similar, and specific IgE absent in all groups. No correlation between IgG- and IgM-containing immune complexes was found with the corresponding isotype of antibody to beta-LG; however, IgM complexes correlated with serum total IgM in ulcerative colitis. In these patients, IgG antibodies were higher in active cases, whereas IgM increased in patients without signs of disease activity. Antibody titers did not correlate with disease duration or administration of antiinflammatory drugs. This pattern of anti-beta-LG reactivity suggests that the presence of intestinal lesions may be revealed by the selective increase of some antibody isotopes to orally administered antigens. Enhanced mucosal permeability may be studied by this type of serological analysis.

Prudden J.F.; Balassa L.L.
Dept. Surg., Coll. Phys. Surg., Columbia Univ., New York, N.Y. USA
Semin.Arthritis Rheum. (USA), 1974, 3/4 (287-321)

Catrix is a material with proven clinical safety and efficacy in thetreatment of important chronic inflammatory conditions. Among these entities the authors have had the most experience with osteoarthritis, psoriasis, anal and perianal conditions, and inflammatory bowel disease. The results in the rheumatic diseases, while still preliminary, are encouraging and deserve intensive further investigation. An expansion of these studies should provide important new information about the nature and treatment of many diseases for which there is no present nontoxic therapy of value.

Mielants H.; Veys E.M.
Department of Rheumatology, University of Ghent, B-9000 Ghent Belgium
J. Rheumatol. (Canada), 1985, 12/2 (287-293)

In an open study, sulfasalazine was given to 15 HLA-B27 positive patientswith asymmetrical pauciarticular arthritis and enthesopathies resistant tononsteroidal antiinflammatory drugs (NSAID). In 11 patients, long lasting remission of inflammatory and biological variables was obtained after 3 to 12 months of treatment. In the other 4 patients significant improvement of the clinical and biological variables was observed. In the 7 patients on whom ileocolonoscopy was performed, inflammatory signs were seen in the terminal ileum or ileococcal valve, suggestive of inflammatory bowel disease (IBD). It is generally accepted that sulfasalazine improves the intestinal symptoms of IBD; our study suggests that it is also beneficial in HLA-B27 related arthropathies resistant to NSAID. No significant adverse reactions were encountered. These findings are encouraging but have to be confirmed in a double blind controlled study.

Mielants H.; Veys E.M.; Cuvelier C.; et al.
Department of Rheumatology, University of Ghent, B-9000 Ghent Belgium
J. Rheumatol. (Canada), 1985, 12/2 (294-298)

Ileocolonoscopy and microscopic examination of ileum biopsies wereperformed on 35 patients with reactive arthritis, with asymmetricalpauciarticular arthritis and enthesopathies. Ileocolonoscopy was alsoperformed on 26 patients with ankylosing spondylitis (AS) and on 19 control patients with rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus and psoriatic arthritis. In the reactive group, ileocolonoscopy showed macroscopic inflammation in 16 cases and abnormal microscopic examination in all but 2 cases, even in patients without gastrointestinal disorders. In the 2 patients with sexually acquired disease, the gut was normal. In the AS group, inflammation was observed in the B27 negative and positive patients with peripheral joint involvement. Occasionally, ileal signs were seen in the HLA-B27 positive patients without peripheral joint involvement. None of the controls showed signs of gut inflammation. Ileocolonoscopy may be of value in detecting subclinical forms of bowel inflammation.

Ramakrishna B.S.; Varghese R.; Jayakumar S.; Mathan M.; Balasubramanian K.A.
Dr. B.S. Ramakrishna, Dept. of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore 632004 India
Journal of Gastroenterology and Hepatology (Australia), 1997, 12/7 (490-494)

Oxygen free radicals produced by neutrophils are important in thepathogenesis of mucosal damage in ulcerative colitis. Vitamin A, vitamin E and cysteine in the plasma can scavenge free radicals. In the present study, plasma levels of vitamin A, vitamin E, cysteine, cystine and protein-bound cysteine were measured in active ulcerative colitis before and immediately after treatment of the active disease, and correlated with disease severity, extent and activity. Plasma vitamin A and cysteine were significantly reduced in active ulcerative colitis compared with controls. Levels of vitamin E, cystine and protein-bound cysteine were not significantly altered in active ulcerative colitis. Vitamin A and cysteine concentrations returned to normal levels (P< 0.05) within 2 weeks of treating active colitis. There were significant negative correlations between clinical severity and the plasma concentrations of vitamin A and cysteine. Plasma cysteine levels also correlated inversely to disease extent. Depletion of the circulating antioxidants, vitamin A and cysteine, in active ulcerative colitis is likely to be important in the pathophysiology of the disease.

Wasser T.E.; Reed J.F.; Moser K.; Robson P.; Faust L.; Fink L.L.; Wunderler D.
Research Department, The Lehigh Valley Hospital, Cedar Crest and I-78, Allentown, PA 18105-1556 USA
Canadian Journal of Gastroenterology (Canada), 1995, 9/3 (131-136)

Using the Harvard/Willett Semi-Quantitative Food Frequency Questionnaire (H/WSQFFQ), nutritional information was gathered on patients enrolled in an inflammatory bowel disease (IBD) registry. The registry lists 320 patients positive for either ulcerative colitis (n = 124) or Crohn's disease (n = 196). The sample was limited to those 19 to 84 years old (meanplus or minusSD 48.57plus or minus14.98), and comprised 136 males and 184 females. Using a battery of indices, quality of life, disease activity and general well-being were also assessed. Nutritional intake values from the Harvard-Willett data were compared with recommended dietary allowances (RDA) tables by sex age group (19 to 24 years, 25 to 50, 51 and older) to discover any intake deficiencies. Results showed that IBD patients were below RDA guidelines for vitamin E, calcium, magnesium, zinc iodine and selenium. Females were below RDA guildelines for iron while men were below for vitamin B6. There were also some deficiencies according to age in males and two nutrient deficiencies were seen by age group in women. There were no deficiencies by sex or age for vitamins A, C, D and niacin. There were no observed nutrient intake differences between ulcerative colitis and Crohn's disease groups. Patients receiving vitamin or mineral supplementation showed significant decreases in quality of life, regardless of diagnosis (Crohn's disease or ulcerative colitis) group. The H/WSQFFQ is a useful tool for assessment of the nutritional status of the IBD patient because it not only provides valuable measurement data to the clinician, but also adds to patient awareness about nutritional problems associated with IBD.

Cetiner S.; Gorgulu S.; Kaymakcioglu N.; Sen D.
Genel Cerrahi Anabilim Dali, GATA, 06018 Etlik, Ankara Turkey
Bulletin of Gulhane Military Medical Academy (Turkey), 1994, 36/4 (452-457)

One of mediators which have been implicated as the cause of tissue injury in ulcerative colitis is the free oxygen radicals. In this study, it is investigated to induce experimental ulcerative colitis in this group. Vitamin E was administered IP at the same time with, before, before and after Mitomycin C in groups 3, 4 and 5 respectively. In group 2 than group 1, it was observed significantly meaningful histopathological alterations in colonic mucosa and meaningful decrease superoxide dismutase (SOD) levels in plasma (p < 0.01). While meaningful histopathological alterations in colonic mucosa were observed in groups 3 and 5 than group 1 (p < 0.05), but it is not as severe as group 2 and there was not meaningful difference SOD levels in plasma (p < 0.05). In group 4, histopathological alterations in colonic mucosa which were not as severe as group 2, but more severe than groups 3 and 5 and meaningful decrease SOD levels in plasma were observed (p > 0.05). As a result, free oxygen radicals are effective in the pathogenesis of experimental ulcerative colitis. Vitamin E, an antioxidant agent, appears to be a good choice in the treatment of the experimental ulcerative colitis.

Lauritsen K.; Laursen L.S.; Bukhave K.; Rask-Madsen J.
Department of Medical Gastroenterology, Odense University Hospital, Odense, DK-5000 Odense C Denmark
Pharmacol. Toxicol. (Denmark), 1987, 61/4 (246-249)

To determine whether supplementation with the physiological radical scavenger, vitamin E, would modulate arachidonate metabolism in human inflammation, we performed equilibrium dialysis of rectum in eight patients with active ulcerative colitis confined to the rectum. The patients, all off drug treatment, were supplemented with 1920 IU/day of alpha-tocopherol and had rectal dialysis done at entry and after three and 14 days. Luminal concentrations of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), determined by radioimmunoassay in purified dialysates, were significantly raised compared to healthy controls. Supplements caused no change in these levels either at day 4 or 15, although serum-tocopherol showed a 3-fold increase. Also disease activity was unaffected. This failure of vitamin E supplementation to suppress the mucosal release of PGE2 and LTB4 in active inflammation does not encourage controlled trials of the effect of oral vitamin E in ulcerative colitis.

Krasinski S.D.; Russell R.M.; Furie B.C.; et al.
USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111 USA
Am. J. Clin. Nutr. (USA), 1985, 41/3 (639-643)

Vitamin K deficiency results in the appearance of abnormal prothrombin, deficient in gamma-carboxyglutamic acid, in the blood. The presence of abnormal prothrombin can be eliminated or lowered by the administration of vitamin K. Since the abnormal prothrombin antigen assay is approximately 1000-fold more sensitive than the prothrombin time for the diagnosis of vitamin K deficiency, this assay was used to evaluate patients with intestinal abnormalities. Vitamin K deficiency was found in 18 of 58 patients (31%) with chronic gastrointestinal disease and/or resection. All patients with vitamin K deficiency had either Crohn's disease involving the ileum or ulcerative colitis treated with sulfasalazine or antibiotics. Abnormal prothrombin levels returned toward normal in patients treated with vitamin K but not in patients who were not treated with vitamin K. The mean plasma vitamin E level in patients with vitamin K deficiency was significantly lower than in vitamin-K sufficient patients (p<0.01). We conclude that certain chronic forms of gastrointestinal disorders are associated with vitamin K deficiency.

Galvez J.; Cruz T.; Crespo E.; Ocete M.A.; Lorente M.D.; Sanchez de Medina E.; Zarzuelo A.
J. Galvez, Department of Pharmacology, School of Pharmacy, University of Granada, Poligono de Cartuja s/n, E-18071, Granada Spain
Planta Medica (Germany), 1997, 63/5 (409-414)

The effect of the flavonoid rutoside on acetic acidinduced rat colitis was studied. Rats were pretreated orally with different doses of the flavonoid (10, 25, and 100 mg/kg) 48, 24, and 1 hour prior to colitis induction and examined for colonic damage 24 hours later. Colonic inflammation was characterized by gross and microscopical injury, bowel wall thickening, abolition of fluid absorption, glutathione depletion, enhanced leukotriene B4 synthesis, and increased levels of myeloperoxidase and alkaline phosphatase activities. Rutoside treatment (25 and 100 mg/kg) reduced histologic injury and prevented the increase in alkaline phosphatase activity, but it had no effect on myeloperoxidase levels or leukotriene B4 synthesis. In addition, glutathione depletion was effectively counteracted at the dose of 25 mg/kg, whereas fluid absorption was achieved at the highest dose assayed. It is concluded that rutoside has an acute antiinflammatory activity in this model which may be related to a putative direct protective effect on intestinal cells, mainly enterocytes, in which the antioxidative properties of the flavonoid may play a role.

De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A.
F.S. De Medina, Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada Spain
Journal of Pharmacology and Experimental Therapeutics (USA), 1996, 278/2 (771-779)

Quercitrin was tested for acute and chronic anti-inflammatory activity in trinitrobenzenesulfonic acid-induced rat colitis. The inflammatory status was evaluated by myeloperoxidase, alkaline phosphatase and total glutathione levels, leukotriene B4 synthesis, in vivo colonic fluid absorption, macroscopical damage and occurrence of diarrhea and adhesions. Treatment with 1 or 5 mg/kg of quercitrin by the oral route reduced myeloperoxidase and alkaline phosphatase levels, preserved normal fluid absorption, counteracted glutathione depletion and ameliorated colonic damage at 2 days. Increasing or lowering the dose of the flavonoid resulted in marked loss of effect. The acute anti-inflammatory effect of quercitrin is unrelated to impairment of neutrophil function or lipoxygenase inhibition, and it may be caused by mucosal protection or enhancement of mucosal repair secondary to increased defense against oxidative insult and/or preservation of normal colonic absorptive function. When tested in chronic colitis (2 and 4 weeks), quercitrin treatment (1 or 5 mg/kg . day) decreased colonic damage score and the incidence of diarrhea, and normalized the colonic fluid transport. All other parameters were unaffected. The chronic effect of the flavonoid is apparently related to its action on colonic absorption, although it can be partly secondary to its acute beneficial effect.

Bokkenheuser V.
Department of Pathology, St. Luke's-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025 USA
Clin. Infect. Dis. (USA), 1993, 16/Suppl. 4 (S427-S434)

Anaerobic bacteria include the most pathogenic of microorganisms. Their primary function, however, is hardly to cause illness. They rarely are involved in epidemics or in clinically significant infections. Some organisms, e.g. lactobacilli, control the normal vaginal ecosystem, and the intestinal anaerobes probably are instrumental in restraining the growth of Clostridium difficile in human carriers. The main role of anaerobes appears to be the provision of catabolic enzymes for organic compounds that cannot be digested by enzymes of eukaryotic origin. They are needed for the catabolism of cholesterol, bile acids, and steroid hormones; they hydrolyze a number of flavonoid glycosides to anticarcinogens; and they detoxify certain carcinogens. Anaerobic enzymes are used industrially in the production of cheese; the conversion of starch to sweeteners; and the transformation of sawdust, wood chips, and waste paper to fuel. Indeed, the anaerobes may well be the gene bank on which future generations of eukaryotic organisms will rely to adapt successfully to an ever-changing world.

Fernandez-Banares F.; Mingorance M.D.; Esteve M.; Cabre E.; Lachica M.; Abad-Lacruz A.; Gil A.; Humbert P.; Boix J.; Gassull M.A.
Department of Gastroenterology, Hospital Universitari 'Germans Trias I Pujol', Carretera del Canyet 2/n, 08916 Badalona Spain
Am. J. Gastroenterol. (USA), 1990, 85/12 (1584-1589)

Serum levels of zinc, copper, and selenium, and alkaline phosphatase activity were prospectively studied in 29 patients with inflammatory bowel disease. Fifteen patients had extensive active colitis (active colitis group). Seven patients had active, and seven cases inactive small bowel or ileocecal Crohn's disease (small bowel disease group). Ninety-three healthy subjects acted as controls. Serum trace element levels were considered in relation to vitamin A and E levels, nutritional parameters, the activity of the disease, and the recent intake of steroids. The effect of total enteral nutrition on serum trace elements was studied in seven cases. Serum zinc levels were lower and serum copper levels higher in the active colitis group than in controls (p = 0.0007, and p = 0.02, respectively). More than 50% of patients with active colonic or small bowel disease showed zinc levels below the 15th percentile of the control group. Serum zinc levels correlated with plasma vitamin A in acute colitis (r = 0.67; p = 0.006), and with both serum albumin concentration (r = 0.76; p = 0.002) and disease activity score (r = -0.67, p = 0.009) in patients with small bowel disease. The copper:zinc ratio was higher in the active colitis group than in controls (p = 0.002). In spite of the increase in serum albumin levels and the decrease in disease activity, serum zinc levels remained low after total enteral nutrition. The implications of the abnormal trace element status in patients with inflammatory bowel disease are discussed.

Gee M.I.; Grace M.G.A.; Wensel R.H.; et al.
Department of Food and Nutrition, Faculty of Home Economics, University of Alberta, Edmonton, Alta. Canada
J. Am. Diet. Assoc. (USA), 1985, 85/12 (1591-1599)

Dietary intakes of two groups of gastrointestinal patients, one group with inflammatory bowel disese (IBD) - Crohn's disease or chronic ulcerative colitis - and the other with functional disorders (FD) - irritable bowel syndrome, nonulcer dyspepsia or gastroesophageal reflux disease, were assessed by means of 48-hour recalls. The relationships between dietary intake and anthropometric and biochemical measurements were examined. The IBD group had lower mean serum albumin and hemoglobin levels (p < .05); however, FD patients had less adequate diets. The mean energy intake of women with FD was significantly lower than that of women with IBD (p < .05) and was associated with inadequate or marginal intakes of many nutrients. Comparison of nutrient intakes between the IBD and FD groups revealed a significantly lower mean intake of folate, ascorbic acid, and vitamin A for women with FD than for women with IBD (p < .05). In general, women had poorer diets and a higher prevalence of abnormal biochemical parameters than men. One notable feature of the dietary pattern of the women was that they consumed less meat than the general population consumed. Increasing meat consumption would improve the intake of many nutrients, including protein and iron. The results of this study suggest that more attention should be given to the adequacy of dietary intakes of gastrointestinal patients in general and of women in particular.

Pirzer U, Schonhaar A, Fleischer B, Hermann E, Meyer zum Buschenfelde KH
First Department of Medicine, University of Mainz, Germany.
Lancet 1991 Nov 16;338(8777):1238-9

Intestinal T lymphocytes are normally unresponsive to microbial and recall antigens in vitro, whereas the same antigens induce strong immune responses in peripheral-blood-derived T cells. We obtained T lymphocytes from peripheral blood and from the non-inflamed and inflamed intestinal mucosa of 6 patients (3 male, 3 female; mean age 33 years) with Crohn's disease. The T cells were stimulated in vitro with a range of microbial antigens. Whereas T cells from normal mucosa were unresponsive, those from inflamed mucosa had a proliferative response comparable to that of the peripheral-blood-derived T cells. These findings suggest that physiologic unresponsiveness to luminal antigens is abrogated in the inflammatory lesions of Crohn's disease patients. Infiltrating T lymphocytes may therefore mediate chronic inflammation on encountering the many antigens present in the intestine.

Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T
Department of Internal Medicine I, University Medical Center, Regensburg, Germany.
Am J Gastroenterol 1998 Nov;93(11):2197-202

OBJECTIVES: Dehydroepiandrosterone sulfate (DHEAS) and cortisol are multifunctional adrenal hormones with immunomodulating properties. DHEAS levels were found to be very low in chronic inflammatory diseases. This study aimed to shed more light on the interrelation between DHEAS and cortisol (and humoral markers of inflammation) in chronic inflammatory bowel disease.

METHODS: DHEAS and cortisol serum levels were measured by ELISA in the serum of 66 normal subjects, 115 patients with Crohn's disease (CD) and 64 patients with ulcerative colitis (UC). Humoral markers of inflammation and disease activity scores were assessed by standard techniques.

RESULTS: DHEAS was lower in patients with CD (p < 0.005) and UC (p < 0.005) than in controls, which was, in part, dependent on previous corticosteroid treatment (p < 0.01). In CD patients, z-normalized DHEAS was inversely correlated with blood sedimentation rate (p = 0.017). Z-normalized DHEAS was negatively correlated with interleukin-6 (IL-6) in the form of a trend (p = 0.068), and z-normalized DHEAS was significantly positively correlated with hemoglobin (p = 0.001) but not with the Crohn's disease activity index. Cortisol, however, was positively correlated with blood sedimentation rate (p = 0.034) and C-reactive protein (p = 0.006). In contrast, in UC patients no such correlation of z-normalized DHEAS or cortisol and parameters of humoral inflammatory activity or Rachmilewitz index exist.

CONCLUSIONS: DHEAS as a marker of inflammation was low in CD and UC. In CD patients, low DHEAS and high cortisol serum levels were associated with higher humoral inflammatory activity. With respect to humoral inflammatory activity in CD patients, DHEAS and cortisol seem to be inversely regulated, which may have an impact on several immune functions, such as IL-6 secretion.

Christl SU Eisner HD Dusel G Kasper H Scheppach W.
Dig Dis Sci (1996 Dec) 41(12):2477-81I

It has been shown that feces of patients with ulcerative colitis uniformly contain sulfate reducing bacteria. Sulfide produced by these bacteria interferes with butyrate-dependent energy metabolism of cultured colonocytes and may be involved in the pathogenesis of ulcerative colitis. Mucosal biopsies from the sigmoid rectum of 10 patients (no cancer, polyps, inflammatory bowel disease) were incubated with either NaCl, sodium hydrogen sulfide (1 mmol/L), a combination of both sodium hydrogen sulfide and butyrate (10 mmol/L), or butyrate. Mucosal proliferation was assessed by bromodeoxyuridine labeling of cells in S-phase. Compared to NaCl, sulfide increased the labeling of the entire crypt significantly, by 19% (p < 0.05). This effect was due to an expansion of the proliferative zone to the upper crypt (compartments 3-5), where the increase in proliferation was 54%. Sulfide-induced hyperproliferation was reversed when samples were coincubated with sulfide and butyrate. The study shows that sodium hydrogen sulfide induces mucosal hyperproliferation. Our data support a possible role of sulfide in the pathogenesis of UC and confirm the role of butyrate in the regulation of colonic proliferation and in the treatment of UC.

Motley RJ Crawley EO Evans C Rhodes J Compston JE.
Gut (1988 Oct) 29 (10):1332-6

The rate of spinal trabecular bone loss during one year was measured in 54 patients with inflammatory bowel disease. The mean change in spinal bone mineral content was -5.1 mg/ml K2HPO4, representing 3% of the initial bone mineral content. The rate of bone loss showed a significant negative correlation with body mass index (r = -0.276, p less than 0.05) but no other significant correlations were found with other clinical or biochemical indices, including the total amount of prednisolone taken during the course of the study. Eleven patients had bone loss greater than 15 mg/ml/year; these included four non steroid-treated patients, two of whom had disease confined to the large bowel. The results indicate rapid rates of bone loss in some patients with inflammatory bowel disease over the course of one year. Although steroid therapy and malnutrition are likely to be contributory factors in some patients, other as yet unidentified risk factors also operate. The rapid bone loss observed in some patients emphasises the need for effective prophylactic regimes.

Marcus R Butterfield G Holloway L Gilliland L Baylink DJ Hintz RL Sherman BM.
J Clin Endocrinol Metab (1990 Feb) 70(2):519-27

We evaluated the effects of recombinant human GH (rhGH) in 16 men and women more than 60 yr of age. After 10 days of dietary equilibration and control collections, subjects were randomly assigned to receive 0.03, 0.06, or 0.12 mg/kg rhGH by daily injection for 7 days. A brisk rise in circulating somatomedin-C (insulin-like growth factor-I) occurred in all subjects, and this rise was dose dependent. RhGH produced striking changes in nitrogen retention, sodium excretion, and the parathyroid-vitamin D axis. Twenty-four-hour urinary nitrogen excretion decreased from 8.00 +/- 0.33 to 5.01 +/- 0.33 g (P less than 0.001), and sodium excretion decreased from 45.9 +/- 2.96 to 21.2 +/- 3.48 mmol/day (P less than 0.001). Serum calcium concentrations did not change, but serum inorganic phosphorus levels of 1.08 +/- 0.04 mmol/L at baseline increased significantly after rhGH treatment to 1.33 +/- 0.04 mmol/L (P less than 0.001). Increases were also observed in circulating PTH (53.2 +/- 6 vs. 39.5 +/- 4.2 ng/L; P less than 0.01) and calcitriol (82.8 vs. 65.8 pmol/L; P less than 0.05). A rise in serum osteocalcin (10.3 +/- .86 vs. 8.0 +/- 0.5 micrograms/L; P less than 0.05) was accompanied by increased urinary excretion of hydroxyproline (628 +/- 63 vs. 406 +/- 44 mumol/day; P less than 0.01). Despite the reduction in sodium excretion, marked increases were observed in urinary calcium (6.04 +/- 0.97 vs. 3.27 +/- 0.40 mmol/day; P less than 0.01). rhGH significantly impaired oral glucose tolerance and reduced insulin sensitivity, but was otherwise well tolerated and produced no systematic changes in weight or blood pressure. The results of this study indicate that RhGH requires further study as a potential agent for attenuating or reversing the loss of muscle and bone in elderly people.

Almallah YZ, Richardson S, O'Hanrahan T, Mowat NA, Brunt PW, Sinclair TS, Ewen S, Heys SD, Eremin O
Department of Surgery, University of Aberdeen, United Kingdom.
Am J Gastroenterol 1998 May;93(5):804-9

OBJECTIVES: Recently, it has been postulated that patients with ulcerative colitis have altered natural cytotoxicity, in particular natural killer (NK) and lymphokine-activated killer (LAK) cell activities. These cellular mechanisms have been postulated to play an etiological role in the pathogenesis of the disease process. We have shown previously that the essential fatty acids (EFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) specifically inhibit natural cytotoxicity. Our aim was to evaluate the role of omega-3 EFA in the modulation of natural cytotoxicity and disease activity in patients with distal procto-colitis.

METHODS: In this pilot study patients were randomized into two groups. Each patient received either fish oil extract (EPA, 3.2 g, and DHA, 2.4 g) (n = 9) or sunflower oil (placebo) (n = 9) daily in a double-blind manner for 6 months. Monthly assessments of disease activity (clinical and sigmoidoscopic scores) and histological evaluation of mucosal biopsies were carried out. Also, the circulating levels and activities of NK and LAK cells, using flow cytometric analysis (CD16+ CD56+) and in vitro 51 chromium release assays (K562), respectively, were monitored.

RESULTS: After 6 months' supplementation with EFA, there was improvement in the clinical activity compared with pretreatment evaluation. There was significant reduction in the sigmoidoscopic and histological scores in the EFA group compared with the placebo group. Essential fatty acid supplementation for 6 months also induced significant reduction in the circulating numbers of CD16+ and CD56+ cells and the cytotoxic activity of NK cells, compared with the placebo group.

CONCLUSIONS: This pilot study has demonstrated that omega-3 fatty acids can suppress natural cytotoxicity and reduce disease activity in patients with distal procto-colitis. These findings suggest a therapeutic strategy for managing patients with inflammatory bowel disease.

Mascolo N, Izzo AA, Autore G, Maiello FM, Di Carlo G, Capasso F
Department of Experimental Pharmacology, University of Naples, Federico II, Naples, Italy.
J Pharmacol Exp Ther 1995 Jan;272(1):469-75

Eicosanoids and platelet-activating factor (PAF) production increases in experimental colitis. Both eicosanoids and PAF seem to arise from similar membrane phospholipids. To support both these suggestions we have investigated whether a fat-free diet, which should alter production of eicosanoids and PAF, affects experimental colitis. Essential fatty acid deficient (EFAD) rats were obtained by putting 4-week-old animals on a fat-free diet for 3 months. Experimental colitis was induced by a single intracolonic administration of 2 ml of 4% acetic acid. One to seven days later the animals were sacrificed and the colon removed to assess macroscopically and histologically intestinal damage. Eicosanoids and PAF levels were also measured in the mucosa scrapings by specific radioimmunoassay. The injury to the colon was more evident in control rats compared with EFAD rats. Besides colonic tissue of control rats showed a highly significant increase of PGE2, LTB4 and PAF, compared with levels in EFAD rats. Our results indicate that fat-free diet reduces tissue damage, and at the same time PGE2, LTB4 and PAF colonic content.

Simopoulos AP
Center for Genetics, Nutrition and Health, Washington, DC.
Am J Clin Nutr 1999 Sep;70(3 Suppl):560S-9S

Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases.

Han PD, Burke A, Baldassano RN, Rombeau JL, Lichtenstein GR
University of Pennsylvania School of Medicine, Philadelphia, USA.
Gastroenterol Clin North Am 1999 Jun;28(2):423-43, ix

This article reviews the nutritional aspects of inflammatory bowel disease (IBD) including the mechanisms and manifestations of malnutrition and the efficacy of nutritional therapies. Nutrient deficiencies in patients with IBD occur via several mechanisms and may complicate the course of the disease. Nutritional status is assessed by clinical examination and the use of nutritional indices such as the Subjective Global Assessment of nutritional status. Nutritional intervention may improve outcome in certain individuals; however, because of the costs and complications of such therapy, careful selection is warranted, especially in patients presumed to need parenteral nutrition.

Nieto N, Fernandez MI, Torres MI, Rios A, Suarez MD, Gil A
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Granada, Spain.
Dig Dis Sci 1998 Dec;43(12):2676-87

The intrarectal administration of trinitrobenzene sulfonic acid in rats induces ulcerative colitis, which results in histological alterations of colonic mucosa, severe modification of the cellular antioxidant defense system, and enhanced production of inflammatory eicosanoids. This study evaluated the influence of different dietary fatty acids, i.e., monounsaturated, n-3, and n-3 + n-6 polyunsaturated fatty acids, on the recovery of the colonic mucosa histological pattern, the cellular antioxidant defense system of colon, and PGE2 and LTB4 colonic mucosa contents in a model of ulcerative colitis induced by intrarectal administration of trinitrobenzene sulfonic acid. Administration of dietary n-3 polyunsaturated fatty acids led to a minimum stenosis score, a higher histological recovery, lower colon alkaline phosphatase and gamma-glutamyltranspeptidase activities, and lower mucosal levels of PGE2 and LTB4 compared with the other two experimental groups. However, glutathione transferase, glutathione reductase, glutathione peroxidase, and catalase activities were lower in the group treated with n-3 polyunsaturated fatty acids than in the groups fed with either the monounsaturated or the n-6 + n-3 polyunsaturated enriched diet. We conclude that n-3 polyunsaturated fatty acids can be administered to prevent inflammation in ulcerative colitis, but they cause a decrease in the colonic antioxidant defense system, promoting oxidative injury at the site of inflammation.

Akisu M, Baka M, Coker I, Kultursay N, Huseyinov A
Department of Pediatrics, Ege University Medical School, Izmir, Turkey
makisu@hotmail.com
Biol Neonate 1998;74(1):31-8

Necrotizing entercolitis (NEC) is an important neonatal disease with a high mortality rate. Inflammatory mediators, such as mainly platelet-activating factor (PAF), leukotrienes (LT) and tumor necrosis factor play an important role in the genesis of NEC. Diets in omega-3 (n-3) fatty acids appear to have an antiinflammatory effect, which is thought to be due to decreased active prostaglandins and leukotrienes production after incorporation of these fatty acids into cell membrane phospholipids. We investigated the protective effect of fish oil (source of n-3 fatty acids) on hypoxia-induced model of NEC. Young mice were divided into three groups; group 1 mice were fed standard chow (n-3 fatty acids-free), group 2 was fed a chow supplemented by 10% fish oil for 4 weeks. Group 3 mice served as control. We examined the intestinal lesions by light microscopy and measured intestinal tissue PAF and LB4 levels in hypoxia-induced model of NEC. Significantly increased intestinal PAF and LTB4 levels were found in group 1 mice when compared to group 2 and group 3 mice. The histopathology of the intestinal lesions in group 1 animals was characteristic of ischemic injury. In the n-3 fatty acids-supplemented animals these lesions were milder. The present study shows that endogenously released PAF and LTB4 play an important role in mediating hypoxia-induced intestinal necrosis. The present study also suggests that dietary supplementation with n-3 fatty acids suppress intestinal PAF and LTB4 generation in hypoxia-induced bowel necrosis. The intestinal protective effect of n-3 fatty acids in an experimental model of NEC may open new insight into the treatment and prevention of NEC in neonates.

Hunter JO
Addenbrooke's Hospital, Gastroenterology Research Unit, Cambridge, UK.
Eur J Gastroenterol Hepatol 1998 Mar;10(3):235-7

During the past 20 years there has been growing interest in the importance of nutritional factors in the pathogenesis of inflammatory bowel disease. There are so far no definite links between ulcerative colitis and diet, but links with Crohn's disease have been studied by both epidemiologists and clinicians. Epidemiological studies, although retrospective, have suggested that patients with Crohn's disease eat more sugar and sweets that control individuals; however, when dietary sugar is restricted, there is little clinical benefit. The clinical approach to nutrition in Crohn's disease has been by the use of elemental diets, which will produce symptomatic and objective remission in up to 90% of compliant patients. Those who return to normal eating soon relapse but, in some studies, have enjoyed prolonged remission on exclusion diets. The foods excluded have been not sugar, but predominantly cereals, dairy products and yeast. Attention has now switched to the possible harmful role of fat in Crohn's disease. The efficacy of elemental feeds appears to depend not on the presentation of nitrogen but on the amount of long chain triglyceride present. Increases in recent years in the frequency of Crohn's disease in Japan have been correlated with increased dietary fat intake, and a recent study suggested that W-3 fatty acids, which are metabolized by immunomodulatory leukotrienes and prostaglandins, may have a beneficial role to play. The links between nutrition and Crohn's disease have now become strong and the role of fat may be the most exciting of all.

[Article in Spanish]
Jorquera Plaza F, Espinel Diez J, Olcoz Goni JL
Seccion de Digestivo, Hospital de Leon, Espana.
Nutr Hosp 1997 Nov-Dec;12(6):289-98

Malnutrition is a very common situation in patients inflammatory with intestinal disease (IID), which can be caused by a multitude of factors. It has been shown that nutritional support not only improves the nutritional condition of the patients, but in Crohn's disease it also has an effect on the activity of the disease, although this effect is smaller than that of steroids. Elemental diets are no more efficient than polymeric diets except under very special circumstances, but they are more expensive and patients tolerate them worse. A digestive pause is not recommended unless there is an absolute contraindication for the use of the digestive tract. Therefore, parenteral nutrition, which is more expensive and can cause serious complications, will be reserved for very specific indications. The use of fish oil supplements, either because it competes with arachidonic acid and prevents the initiation of the inflammatory cascade, or because it decreases the production of cytokines, has shown to be potentially useful in inflammatory intestinal disease, and this must be confirmed by further studies. Short chain fatty acids enemas have shown promising results in distal ulcerative colitis but the lack of homogeneity in the studies makes it necessary for these results to be consolidated in new studies. Nutritional support is especially interesting in children with inflammatory intestinal disease given that the growth retardation which is often seen in severe cases, can be controlled by adequate enteral or parenteral diets.