Maintenance treatment with budesonide 6 mg versus 9 mg once daily in patients with Crohn's disease in remission.

BACKGROUND: In previous trials, budesonide 6 mg/day was able to prolong the time to relapse in patients with quiescent Crohn's disease and budesonide 9 mg/day was effective in active disease with limited side effects. The aim of this study was to compare the effectiveness of budesonide 9 mg vs 6 mg once daily on the maintenance of remission and occurrence of adverse events. METHODS: Double-blind, randomised trial in patients with Crohn's disease in remission. Patients were randomised to receive 6 mg/day or 9 mg/day of budesonide (Budenofalk) without concomitant treatment for Crohn's disease. Endpoints were the time to relapse and relapse rates after one year. RESULTS: Seventy-six patients were randomised to 6 mg/day and 81 patients to 9 mg/day. Survival analysis showed no differences in the time to relapse. One-year relapse rates were not significantly different (6 mg group 24%; 9 mg group 19%). Any adverse event was reported in 61 and 68% of patients in the 6 mg and 9 mg groups, respectively; none of the 12 serious adverse events were drug related. CONCLUSION: The one-year relapse rates were low and not significantly different between the group of patients treated with budesonide 6 mg vs 9 mg/day. Also, time to relapse and the number of adverse events were similar in both treatment groups.

A functional interleukin-10 mutation in Dutch patients with Crohn's disease.

BACKGROUND AND AIMS: Interleukin-10 is an anti-inflammatory and immunomodulatory cytokine. Interleukin-10 deficient mice are prone to develop chronic colitis. Administration of recombinant human interleukin-10 has been proposed to have a beneficial effect in a subgroup of patients with Crohn's disease. Recently, we found an interleukin-10 Gly15Arg mutation in a family with Crohn's disease which is associated with reduced interleukin-10 secretion by in vitro stimulated monocytes and lymphocytes. We hypothesised that this interleukin-10 mutation plays a role in maintaining the inflammatory process in Crohn's disease in some families. PATIENTS AND METHODS: We evaluated interleukin-10 Gly15Arg in 379 patients with Crohn's disease, and 75 unrelated healthy controls. Also, first degree family members of interleukin-10 Gly15Arg carriers were evaluated. Additionally, mutation carriers and their relatives were evaluated for CARD15 R702W, G908R, and 1007fs. RESULTS: Two patients with Crohn's disease were heterozygous for the interleukin-10 Gly15Arg mutation. No homozygotes were found. The Gly15Arg mutation was not observed in the controls. In first degree family members of the Crohn's disease-affected interleukin-10 Gly15Arg carriers, the mutation was found in Crohn's disease-affected as well as in their apparently healthy individuals. All family members carried one or two CARD15 mutation(s). CONCLUSION: The interleukin-10 Gly15Arg mutation is rare in patients with Crohn's disease, and is not associated with the disease in the Netherlands.

Genetic polymorphisms in biotransformation enzymes in Crohn's disease: association with microsomal epoxide hydrolase.

BACKGROUND: Mucosal biotransformation enzymes can modify toxic compounds in the gut. As chemical or oxidative stress may be involved in the aetiology of Crohn's disease, genes encoding for enzymes involved in the prevention of such stress may be candidates for genetic susceptibility to Crohn's disease. AIM: To assess the association of Crohn's disease with genetic polymorphisms in cytochrome P450 1A1, glutathione S-transferases mu-1, pi-1, and theta-1, and epoxide hydrolase. METHODS: chi(2) square analysis was used to compare frequencies of polymorphisms between 151 patients with Crohn's disease and 149 healthy controls. RESULTS: In patients, a genetic polymorphism in exon 3 of the microsomal epoxide hydrolase gene was distributed significantly different compared with controls (chi(2)=23.7; p<0.0001). All other polymorphisms tested were equally distributed between patients and controls. CONCLUSIONS: Microsomal epoxide hydrolase may play a role in the pathophysiology of Crohn's disease. Furthermore, the epoxide hydrolase gene is located on chromosome 1q, close to a region previously linked to Crohn's disease.

[Patient with refractory celiac disease and secondary lymphoma]. / Een patiënt met refractaire coeliakie en een secundair lymfoom.

A 50-year-old woman who had suffered from well-regulated coeliac disease for 16 years, presented with weight loss, soft stools and abdominal cramps. She had ulcers in the oesophagus and stomach, and in biopsies localisations of so-called enteropathy-associated T-cell lymphoma (EATL) were detected. During a staging investigation she suffered an enteric perforation and later on repeated haemorrhages, from which she eventually died. Patients with coeliac disease who do not respond to a gluten free diet or who relapse after an initial response should be investigated for the presence of a gastrointestinal malignancy. Weight loss is an important symptom. The most frequently occurring malignant complication is an EATL. This is often difficult to diagnose and the prognosis is poor, with frequent complications such as haemorrhages and perforations.

Parenteral structured triglyceride emulsion improves nitrogen balance and is cleared faster from the blood in moderately catabolic patients.

BACKGROUND: Most postoperative patients lose net protein mass, which reflects loss of muscle tissue and organ function. Perioperative parenteral nutrition may reduce the loss of protein, but in general, with conventional lipid emulsions a waste of protein still remains. METHODS: We compared the effects on nitrogen balance of an emulsion containing structured triglycerides, a new type of synthesized triglycerides, with an emulsion of a physical mixture of medium- and long-chain triglycerides as part of parenteral feeding in moderately catabolic patients. The first 5 days after placement of an aortic prosthesis patients received total parenteral nutrition (TPN) providing 0.2 g of nitrogen per kg body weight per day; energy requirement was calculated using Harris and Benedict's equation, adding 300 kcal per day for activity. Twelve patients were treated with the structured triglyceride emulsion and 13 patients with the emulsion of the physical mixture of medium- and long-chain triglycerides. The design was a randomized, double-blind parallel study. RESULTS: In the patients who completed the study, the mean cumulative nitrogen balance over the first 5 postoperative days was -8+/-2 g in 10 patients on the structured triglyceride emulsion and -21+/-4 g in 9 patients on the emulsion of the physical mixture of medium- and long-chain triglycerides; the mean difference was 13 g of nitrogen (95% confidence interval 4 to 22, p = .015) in favor of the structured triglyceride emulsion. On the first postoperative day serum triglyceride and plasma medium-chain free fatty acid levels increased less during infusion of the structured triglyceride emulsion than with the physical mixture emulsion. CONCLUSIONS: The parenteral structured triglyceride emulsion improves the nitrogen balance and is cleared faster from the blood, compared with the emulsion of the physical mixture of medium- and long-chain triglycerides, in moderately catabolic patients.

Eosinophilic gastroenteritis treated with non-enteric-coated budesonide tablets.

A patient who presented with upper abdominal pain, nausea and ascites together with peripheral eosinophilia is described. Based on a surgical full-thickness biopsy of the antrum, the diagnosis of eosinophilic gastroenteritis was made. Treatment with prednisone resulted in a clinical response, but the prednisone dose could not be lowered below 5 mg. We preferred to treat the patient with corticosteroids with minimal systemic side effects. As there was gastric involvement, we could not give enteric-coated budesonide capsules. Therefore, we treated the patient with budesonide tablets, which were designed originally for use as a clysma but now are given orally. With this treatment regimen, the patient has been in remission for more than 2 years.

Tc-99m-PEG-Liposomes for the evaluation of colitis in Crohn's disease.

In the present study, the potential role of 99mTc-PEG-liposome to determine the extent and severity of active disease of Crohn's colitis was investigated. Patients suspected of having an exacerbation of Crohn's disease underwent a 99mTc-PEG-liposome scan (740 MBq, imaging at 4 and 24 h p.i.). A barium enema or endoscopy was performed as the standard verification procedure. Disease activity indices (Clinical Disease Activity Index and Van Hees Activity Index) were calculated. In seven patients positive images of colon segments affected by Crohn's colitis were obtained using 99mTc-PEG-liposomes. Only a moderate relation between 99mTc-liposome scan grading and verification procedures was found (Spearman rank r = 0.22). In accordance with previous studies, no significant correlation was found between the clinical disease activity indices and the verification procedures. This study was prematurely terminated because of unacceptable side-effects in 3 out of 9 patients, which occured almost immediately after starting the infusion. The complaints consisted of dyspnea and facial erythema. The symptoms were self-limiting when the infusion was stopped. In conclusion, the extent of Crohn's colitis can be established non-invasively with 99mTc-PEG-liposome scintigraphy. However, in view of the encountered side-effects, the PEG-liposomal preparation may have to be modified.

The value of methods to determine zinc deficiency in patients with Crohn's disease.

BACKGROUND: The serum zinc concentration is frequently applied for the assessment of zinc deficiency, but this concentration is also influenced by other factors. The aim of this study was to compare various methods of assessing the zinc status in patients with Crohn' s disease. METHODS: Serum levels of zinc, serum alkaline phosphatase activity, and zinc in various types of cells were related to factors potentially inducing zinc deficiency: the number of liquid stools, weight loss, bowel resection, and the extent and severity of inflammation. RESULTS: Thirty-one patients with more or less active Crohn's disease were included. In 68% of these patients the serum zinc concentration was less than the reference level, and it was correlated with the extent of bowel resection and the van Hees Index but not with the Crohn's Disease Activity Index. Serum alkaline phosphatase activity was correlated with bowel resection. Zinc in blood cells was poorly correlated with factors inducing zinc deficiency. CONCLUSION: A decrease of serum zinc concentration is frequently seen in active Crohn's disease. This study suggests that the determination of zinc in blood cells is not superior to the determination of the serum zinc concentration and serum alkaline phosphatase activity.

Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications.

The prevalence of malnutrition and its predictive value for the incidence of complications were determined in 155 patients hospitalized for internal or gastrointestinal diseases. At admission, 45% of the patients were malnourished according to the Subjective Global Assessment (physical examination plus questionnaire), 57% according to the Nutritional Risk Index [(1.5 x albumin) + (41.7 x present/usual weight)], and 62% according to the Maastricht Index [(20.68 - (0.24 x albumin) - (19.21 x transthyretin (prealbumin) - (1.86 x lymphocytes) - (0 04 x ideal weight)]. Crude odds ratios for the incidence of any complication in malnourished compared with well-nourished patients during hospitalization were 2.7 (95% CI: 1.4, 5.3) for the Subjective Global Assessment, 2.8 (1.5, 5.5) for the Nutritional Risk Index, and 3.1 (1.5, 6.4) for the Maastricht Index. Odds ratios were reduced to 1.7 (0.8, 3.6), 1.6 (0.7, 3.3), and 2.4 (1.1, 5.4), respectively, after a multivariate analysis that included disease category and disease severity. Because the confounding factors adjusted for are not only a measure of the severity of the disease but may also be influenced by malnutrition itself, the actual risk for complications due to malnutrition could be higher than the adjusted odds ratios. In conclusion, malnutrition was frequent in patients with gastrointestinal disease and other internal diseases at the time of admission. The severity of malnutrition in the patients predicted the occurrence of complications during their hospital stay and this association was not completely explained by confounding factors.

Specificity of indexes of malnutrition when applied to apparently healthy people: the effect of age.

Protein-energy malnutrition is thought to be widespread in hospitalized patients. However, the specificity of indexes used to assess malnutrition is uncertain. We therefore assessed the rate of false-positive diagnoses of malnutrition when biochemical-anthropometric indexes were applied to healthy subjects. Nutritional status was assessed in 175 healthy blood donors (aged 44.2 +/- 13.4 y) and in 34 highly fit elderly volunteers (aged 74.7 +/- 3.6 y) participating in the Nijmegen Four Days Walking March. We investigated both the Nutritional Risk Index [(1.489 x albumin) + (41.7 x present/usual weight)] and the Maastricht Index [20.68-(0.24 x albumin, g/L)-(19.21 x serum transthyretin, g/L)-(1.86 x lymphocytes, 10(6)/L)-(0.04 x ideal weight)]. We found previously that 52-64% of nonsurgical hospitalized patients were malnourished according to these indexes. In the present study, 1.9% of the 209 volunteers had apparent malnutrition according to the Nutritional Risk Index and 3.8% according to the Maastricht Index. The prevalence of apparent malnutrition in the elderly volunteers was 5.9% and 20.6%, respectively. The rate of false-positive diagnoses was acceptably low in those aged < 70 y with both the Nutritional Risk Index and the Maastricht Index; therefore, the use of these indexes will not cause a clinically significant increase in the prevalence of malnutrition because patients who are not malnourished are included. The high percentage of spurious malnutrition in the elderly limits the use of the Maastricht Index to subjects aged < 70 y.

Serum alkaline phosphatase activity during zinc deficiency and long-term inflammatory stress.

A decrease in serum zinc can be caused by a real zinc deficiency but can also be caused by an apparent zinc deficiency, e.g. in inflammatory stress. The aim of this study was to evaluate the diagnostic power of serum alkaline phosphatase (AP) activity in the discrimination between pathophysiologic states of "real" and "apparent" zinc deficiency. A decrease in serum zinc was induced in growing and adult rats, by providing a diet low in zinc and by causing inflammatory stress. AP activity was determined using reagents low or enriched in zinc. Serum AP was decreased in zinc-deficient adult rats (P < 0.01). In zinc-deficient growing rats AP activity was not different from normal rats but AP activity decreased rapidly. In the same growing rats a significant difference was found in AP activities determined using buffers low and enriched in zinc (P < 0.001) between both groups of rats. After inducing inflammatory stress a decrease in AP activity (P < 0.01) and serum zinc (P < 0.001) was seen during the first few days. After the initial phase of inflammation AP activity normalized, serum zinc showed a rise which after correction for the decrease in serum albumin reached the level of the control rats. A difference in AP activity in buffers low and enriched in zinc was observed only during the first few days after induction of inflammatory stress (P < 0.001). Probably the method of measurement of the difference in enzyme activity, using buffers low and enriched in zinc, can be used as an indication for zinc deficiency in situations with changing AP enzyme concentrations. AP activity is decreased during the initial phase of inflammatory stress due to a decrease in serum zinc.

Zinc exchange by blood cells in nearly physiologic standard conditions.

Determination of zinc concentrations in white blood cells has been used to establish zinc deficiency. During pathological conditions changes in zinc concentrations in these blood cells were observed. However, these investigations were hampered by the low amount of zinc in this form per mL blood. Earlier we demonstrated that, in the case of zinc deficiency, the uptake of zinc was increased, using the in vitro exchange of zinc by the various blood cells with extracellular zinc labeled with 65Zn in fairly physiologic conditions. In case of inflammation, no increase in zinc uptake by erythrocytes was seen, indicating that this method probably can be used to differentiate real from apparent zinc deficiency. Only during the first days of the inflammatory process, probably representing the redistribution phase during which zinc moves from the serum to the liver, a small increase in in vitro zinc uptake was seen in mononuclear cells (MNC) and polymorphonuclear cells (PMNC). Earlier papers raised some questions; e.g., is the uptake part of an exchange process and can the efflux of zinc by the cells be measured by the same method; what is the influence of time on the process of zinc uptake; what is the magnitude of the uptake of zinc by the cells compared to the zinc concentration in the cells; and, what is the influence of temperature on the uptake of zinc? In the present study, the influence of incubation time and temperature on the uptake of zinc by human and rat blood cells and on the release of zinc by rat blood cells was studied. At least three phases of uptake of zinc in the various cells were found by varying the incubation time--a fast phase during the first half hour, probably caused by an aspecific binding of zinc on or in the cell membrane; a second fast uptake between 60-330 min, probably caused by an influx of zinc in the cell as part of the exchange process of zinc; and a slow third phase after 5.5 h, in which probably the in- and efflux of the rapidly exchangeable intracellular pool is more or less equilibrated. For mononuclear cells, polymorphonuclear cells, and erythrocytes of rats, the rapidly exchangeable intracellular pool is 40%, 53%, and 10%, respectively, of the total zinc content of the cells. This study is also performed in human cells; in human cells the exchangeable pool of mononuclear cells and erythrocytes is 17 and 3.5% of the total zinc content of the cells, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

The in-vitro uptake of zinc by blood cells in rats with long-term inflammatory stress.

The aim of the present study was to investigate the in vitro uptake of zinc by blood cells, in an attempt to distinguish between those conditions in which low plasma zinc concentrations are due to inflammatory stress, and those which are due to true zinc deficiency. Inflammation induced by intramuscular injection of turpentine caused a significant reduction in plasma albumin concentrations, which persisted until the end of the study (2 weeks). It also caused a reduction in the plasma zinc concentration which was most marked during the first few days. A smaller difference persisted until the end of the study. When the serum zinc concentration was corrected for the hypoalbuminaemia, the changes in serum zinc concentration after the first 4 days of turpentine were small and mainly non-significant. The in vitro uptake of zinc by erythrocytes obtained from animals with inflammation did not increase, whereas the uptake was increased in cells obtained from animals with true zinc deficiency. Therefore this study suggests a method that can probably differentiate between an apparent zinc deficiency due to inflammatory stress and a real zinc deficiency, but additional experiments to validate this method should be performed.

Zinc uptake by blood cells of rats in zinc deficiency and inflammation.

In zinc deficiency, the function of leukocytes is impaired. However, the results of studies on the zinc concentration of blood cells in zinc deficiency are conflicting, probably in part because of technical and analytical problems. The aim of this study was to investigate, under standard conditions, the uptake of 65Zn-labeled zinc by blood cells, taken from zinc-deficient rats and from rats in which an inflammation is induced. In both conditions, the serum zinc concentration is reduced. In clinical practice, this makes it difficult to determine whether the decrease in serum zinc is the result of a real or an apparent zinc deficiency. In stress, like an inflammatory disease, the decrease of zinc reflects an apparent zinc deficiency because of redistribution of serum zinc into the liver and because of decrease in serum albumin concentration. Over 70% of the serum zinc is bound to albumin. Blood cells from zinc-deficient and control rats were isolated using a discontinuous Percoll gradient and incubated under nearly physiological conditions in a 65Zn-containing medium. A significant increase in the in vitro uptake of 65Zn-labeled zinc by the blood cells of zinc-deficient rats was seen: erythrocytes 1.3, mononuclear cells 2.0, and polymorphonuclear cells 2.6 times the control values. During inflammation, no change in 65Zn-labeled zinc uptake by erythrocytes and mononuclear cells was demonstrated after 2 d, although the serum zinc and albumin concentrations were decreased, but a small but significant increase in zinc uptake by polymorphonuclear cells was observed. This study of 65Zn uptake in vitro under standard conditions may prove of value for distinguishing in patients real zinc deficiency from apparent zinc deficiency owing to, e.g., stress, although additional experiments should be performed.