The Use of Enteral Nutrition in the Management of Crohn's Disease in Adults
From the * Service
d'Hépato-Gastroentérologie et Assistance Nutritive,
Hôpital Lariboisière, Assistance Publique des Hôpitaux de
Paris, France; and the Correspondence: Philippe Marteau, MD, PhD, Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris cedex 15, France. Electronic mail may be sent to philippe.marteau{at}egp.ap-hop-paris.fr. Crohn's disease is a chronic, relapsing disease and none of the treatments developed so far can cure it. Artificial nutrition is effective to both treat malnutrition when present and induce remission. However, striking advances in anti-inflammatory and immunomodulating therapies (including infliximab) and low compliance to treatment in the first trials have limited its place in the management of adults to drug-resistant patients. Randomized controlled trials show that artificial nutrition is effective in >50% of the cases in this selected population. Significant progress has recently been made to improve the palatability (and thus acceptability) of some enteral solutions, which can be consumed by the oral route and as pharmaconutrition. We reviewed the literature on enteral nutrition in adults with Crohn's disease. We present herein the results of the studies performed with antioxidants, glutamine, short-chain fatty acids, prebiotics, probiotics, low microparticle diets, and a TGFβ2 enriched formulation. The etiology of Crohn's disease (CD) remains unknown and the treatments developed so far are only symptomatic and suspensive.1 They include corticosteroids, other anti-inflammatory agents, immunosuppressive and immunomodulatory agents (purine analogs, methotrexate, infliximab, etc.), nutrition therapies, and surgical removal of the symptomatic lesions. None of them can really cure the disease and they suppress the risk of relapse or complications. The risk-to-benefit ratio of treatments has to be evaluated in every single clinical situation. Artificial nutrition, whether enteral (EN) or parenteral (PN) nutrition, has been used as primary therapy since the early 1970s in children with CD, but less often in adults despite its proven efficacy. Before the development of infliximab, the main indications were malnutrition and acute disease with steroid resistance. Nowadays, infliximab is usually recommended and often efficient in cases of steroid resistance.1 EN is proposed in cases of contraindication, inefficacy, or intolerance. We review herein the evidence for efficacy of EN, research progress, and discuss its place in the management of CD in adults.
Nutrition therapy is mandatory for patients with CD and malnutrition. Severe global denutrition has become rare.2 In a French series of 600 adult patients with moderately active CD (Crohn's disease activity index [CDAI] <200) prospectively followed for 12–18 months, 6.6% of them had a body mass index (BMI) <17 kg/m2, and only 2 patients required EN for an isolated nutrition deficiency.2 However, denutrition should not be only diagnosed in cases of low BMI, but also in cases of rapid weight loss. Some specific complications require oligoelements or vitamin supplementation, including: anemia (iron), osteomalacia or osteopenia (calcium, vitamin D), treatments with methotrexate or sulfasalazine (folic acid), fistulae or protein losing enteropathy (zinc), and ileal resection (vitamin B12). In cases of short bowel or extensive small intestinal CD, nutrition therapy should anticipate and prevent deficiencies. Some authors advocate EN rather than steroid therapy in patients suffering from active CD associated with overt osteoporosis or osteopenia.3 Only 2 retrospective studies assessed the role of preoperative artificial nutrition in CD. In a retrospective series of 103 adults who underwent bowel resection, perioperative nutrition did not significantly influence either the morbidity or the length of intestinal resection.4 The second study which concerned 108 adults (14 with exclusive EN, 25 with exclusive PN, and 69 without preoperative artificial nutrition) came to the same conclusion.5 The usual rules of perioperative nutrition should be used in patients with CD.
The first trials using nutrition therapies in CD were published in the 1970s. Three meta-analyses have been performed on data available from randomized controlled trials (RCT) assessing EN as a primary treatment of CD in adults. Their main conclusions were that: 1) EN is effective in inducing remission in about 50%–70% of moderate CD flare-up; 2) EN is significantly less effective than steroids in adults; 3) EN and PN are equally effective to achieve remission; 4) nonelemental diets are as effective as elemental EN.6-8 Compliance is an important factor that often impairs the clinical response to EN in adults. In the meta-analysis of the RCT comparing EN to steroids performed by Anne Griffiths in 1995, 21% of patients allocated to EN were noncompliant. The pooled odds ratio related to compliance toward EN was 0.57 (0.35–0.94) compared with steroids.7 The percentage of patients intolerant of EN varied from 18%–41% in early trials that proposed EN by oral route9-12 and from 0%–13% in studies that exclusively delivered EN through nasogastric tubes.13-19 This stimulated research to improve the acceptability of EN by oral route and significant progress was made concerning the palatability of some products. Modulen IBD (Nestlé, Vevey, Switzerland) was well accepted in 28 out of 29 children with CD who received an 8-week course by exclusive oral route in a prospective trial.20 All of them received the allocated volume (1950–3000 mL) within the first week. Ramirez et al21 performed in a multicenter retrospective study among 45 adult patients who received Modulen IBD for CD. The tolerance of this EN solution by oral route was fair and the acceptability was better in the patients receiving it as supplements vs exclusive nutrition support.
Several hypotheses have been tested in recent years to improve the efficacy and acceptability of EN in CD, most of them based on a pharmaconutrition concept.
Lipid Composition of Enteral Nutrition
Antioxidant Vitamins
Glutamine
Butyrate
Prebiotics and Probiotics
Low Microparticle Diet
TGF-β2-rich Enteral Nutrition Solution
In addition to malnutrition correction or diets for stenosis and short bowel syndrome, EN has a significant efficacy in adults with acute CD. Practitioners should be aware of this efficacy, especially in the cases of failure or contraindication of medical therapies including corticosteroids, immunosuppressing, and immumodulating (infliximab) drugs. Research trials should continue to develop and assess better-tolerated oral feeding solutions and improve their composition. Treatment strategies including EN in association with drugs should also be evaluated. Received for publication December 6, 2004. Accepted for publication February 15, 2005.
DiscussionDr Meier: Thank you very much for this nice presentation. I really think you should do this prospective trial if you already have the network and the experience in some centers. Maybe as an adjuvant treatment, an oral Modulen supplement with a nice flavor. This could be another choice to help these patients.Dr Marteau: I did not mention that 44 out of the 45 patients could drink it. Of course I don't know because it is a retrospective study to how many patients we proposed this treatment and how many could not drink it before. So this has also to be looked at. Dr Meier: You mentioned that denutrition is decreasing but still about 25%–30% have nutrition deficits during an acute attack of Crohn's disease. When you can supplement them with adequate nutrition support I think they will have at least a benefit on quality of life and maybe on inflammation. Dr Marteau: You are right. It is also good to underline that BMI is not the only way to ascertain that there is denutrition, and when there is a rapid loss of weight, there is also denutrition. Adult physicians are not aware enough of the diagnosis of denutrition and of its severity on the prognosis of other diseases. Dr Meier: That is really a big problem: the awareness of nutrition by physicians. But that is the reason why we are having this meeting, to learn about this. Dr Walker-Smith: This is extremely encouraging because you have taken a very adverse group of patients although they are retrospective and I think it is astonishing that you have got 50%. I would hope that you would give your adult patients the opportunity in a more formal way of studying this with an acute relapse because we have heard in the pediatric dimension that the best results are with the new acute attack. It is no doubt, when adult patients become aware of the option they often choose it. Prof Roy Pounder, in an anecdotal experience, who was still unenthusiastic for steroids, was almost forced sometimes by former children who are now his patients that he offered them steroids they said, "no, I don't want steroids, I want a trial of enteral nutrition." The key thing in children is that in the first 24–48 hours they can be made to feel better, and a lot of these patients are treated at home. I do think that, as with the children, if you are going to do a proper trial you ought to have the effort of having the patients in a supporting environment, getting through that first 24–48 hours until you get that feeling of improvement. Can an adult patient, although it does interfere with life, be convinced to take a week or 2 weeks of exclusive enteral nutrition? Exclusive nutrition in a planned trial for 2 weeks monitoring the CRP, would be reasonable in adult practice. I saw in the last year or 2 in my practice at least 2 or 3 children with steroid side effects. They had been put first on steroids and the referring physicians were astonished when I referred them back because they had gone into remission on enteral nutrition, off steroids. So these children who are getting side effects with steroids were getting better with enteral nutrition. The terrible side effects of steroids I think is one of the things that people sometimes do forget. The very first patient I saw was a former child who had got on for years and years and had many of the side effects of steroids, a short stature, muscle wasting, acne, all the features, and we tend to forget that. I think you have to offer your adult patients the choice in the trial of a regime which is without side effects and there I think is one of the most powerful things to argue when we are looking at this. Adults are different but there are similarities to older children and often we are talking about adolescents and university students. Anecdotally I am aware of students who are feeling bad before examinations, perhaps anxiety, they get onto full exclusive nutrition, perhaps it is a matter of 2 or 3 days, and they are able to get through the examinations. Dr Marteau: I agree although we know that nutrition is an efficient treatment for acute episodes, we are often not good enough to convince our patients to use it and we probably need psychologists in our teams both to try to work with the patients and to try to work with the physicians to help us. The second point is that when we treat an adult with Crohn's disease we have in mind not only the acute episode, in the first days, but we try to look further. We know that the risk of relapse is very high, so that is why we are very open to treatments, which can go on for longer time. Initially infliximab was just considered as an acute treatment and nothing beyond, but now we begin with infliximab and we don't stop it until at least 1 year. So probably the next treatment will come and offer this opportunity: to be a chronic treatment and will again have its place before nutrition. Another point is that I do believe in combination treatment and adding nutrition in our drug strategies. Dr Huggett: I am sorry I didn't pick it up very clearly. What was the difference between the supplemental use of the enteral nutrition and the exclusive use in terms of the outcome? Was there a big difference in terms of efficacy? Dr Marteau: There was not a significant difference. Probably it is not as strong information here as it is a retrospective study and as the patients were taking drugs also. Dr Meier: What is the highest percentage of patients who go on with infliximab treatment after you have done the 0, 2, 6, week application? In which patients do you continue and in which do you stop it? Dr Marteau: I would not have answered that 6 months ago, but clearly now we go on in our team. In other words, we do not stop infliximab when we begin it, at least for 1 year. And now the research strategy is to answer the question what should we do after 1 year. What do we stop? Infliximab, azathioprine? Nothing? I guess the main idea is to try stop azathioprine. Dr Meier: It is a very effective but a very expensive treatment. In France it is paid by the insurance without problems? Dr Marteau: I agree with you, that is why we were so reluctant to do that (to use them chronically). We initially only treated the patients on demand. However after many communications, some communications saying that this way of treating the patients is very dangerous, that we induce antibodies against infliximab and that the patients will get less efficacy from the drug in the future, more side effects, and it is true. So progressively, of course we gain expertise, in groups such as a group called GETAID in France. We meet very often to discuss the way we treat our patients and now the majority of us, when we begin infliximab, we treat for 1 year. However I can say that we do not use this strategy very often, for the moment I guess that 3% of our patients with Crohn's disease in France receive infliximab. So it means that we wait, we really concentrate on the resistant patients, resistant not only to corticosteroids but also to immunosuppressants, and for the patients with open fistulae and severe perianal disease. Dr Powell-Tuck: I am just a little bit puzzled by some of the discussion. I think one thing that needs to be quite clear is that we are quite clear in adult practice that enteral nutrition is effective, from many controlled trials in the management of acute Crohn's disease. Our problems are much more the composition of these feeds in order to optimize whether it should be elemental or polymeric, what the fat composition should be, whether it should have TGF-β in it or not. These are the questions that we don't have answers to and we should hear more. I think also there is a fascinating opportunity. As you mention, the fish oil and remission or maintenance and I totally agree with Rob, maintenance or remission is a terrific challenge and very difficult to study in controlled trials, and the fish oil must remain of interest, and the fascinating role of antioxidants. The antioxidant situation in inflammatory bowel disease should be assessed. I often wish I was in the position to study more, but I am not. So we are quite clear it works, it is the detail and all these things in the maintenance and remission of IBD which are the big issues. And I totally agree on the importance of the psychology, of not our patients but of drug orientated doctors. Dr Marteau: It is true we know it works. But since we use it, not the first line treatment, we have also to provide data to convince our colleagues and patients that it works in the way we want to use it, that means in resistant patients. And if we have data showing that it couldn't work and that the patients need surgery and so on it would be important to know that. Dr Triantafyllidis: I would like to add our experience on the use of Modulen IBD in adult patients with Crohn's disease. So far we have treated 24 patients in my department with mild to moderate Crohn's disease and we came almost to the same conclusion as you. And I would like to add that there was also an increase in the calcium level. Probably this was due to the increased level of albumin and the fall of fibrinogen level and platelet number. We also included patients with fistulas and we saw good results. We are going to submit it as a letter to the editor because of the lack of control group. I totally agree with you. I wonder what is your experience in this group of 45 patients with fistulas? Dr Marteau: I don't know the details, I cannot answer. I will transmit your request to Simon Ramirez so he can communicate further and can give the results. I don't think nutrition is very efficient in the perianal fistulae, but for abdominal fistulae, there is usually a stenosis below the fistula and our medical treatments are not efficient. Of course with a draining of the fistula it can be decreased, but we cannot avoid surgery. So in our mind it is more preparation of surgery which can include nutrition for sure, and then we have to make a better diagnosis of denutrition and the need for perioperative strategies, but not as a single treatment. Dr Beattie: Would you consider offering enteral nutrition as a treatment option for newly diagnosed acute Crohn's disease. Particularly I am thinking about young adults in their early 20s when they have had symptoms for some time and would be in the latest stages of pubertal growth, and so there would be good evidence they are still laying down calcium for example, which will have an impact on their life long osteoporosis risk. I am just thinking that there is so much more awareness now than 10 years ago about the toxicity of steroids long-term. Don't you think it should now be a shift in adult practice to actually offering this as a treatment option because it is a treatment option that we know works at diagnosis? I am aware that there is evidence from yourself and there is also evidence from data published by Verma's group which highlights this important sub-group: which is steroid dependant adults who do well on enteral nutrition because of its primary effect. I wonder what your thoughts were, would you in a prospective trial for example consider offering enteral nutrition as a first line treatment for newly diagnosed young adults with Crohn's. Dr Marteau: It is not easy. What we try to do is first to avoid steroids. In general, in all the forms with mild to moderate symptoms we try to use budesonide, 5-aminosalicylic acid and so on. Then we address situations where this first line treatment doesn't work, so we are 2 weeks into treatment, or 4 weeks for a first line treatment; or if the disease is severe from the beginning, which is not very often. Then the choice is nutrition vs steroids vs infliximab. I would be interested to read the paper. I don't think I can convince my colleagues in the GETAID to participate in the trial. I am convinced the problem is: does it really fit with what the patients expect? Because as adults they decide, and they look at the Internet and they want this treatment and they want to go skiing next week or they will ask about the risk of relapse. Dr Beattie: Still the issue is that there are the steroid toxic effects. And the issue with regard to lifestyle is that the children on enteral nutrition generally get back to school very quickly and that is the same way with adults on enteral nutrition. They could generally get them back to work pretty quickly. Dr Marteau: And the way we behave, it is not a good way, I know, but we give calcium plus vitamin D and we perform DEXA and when there is osteopenia or osteoporosis we discuss this. So probably there are other strategies, and, of course, we live in a world of evidence based medicine so we want randomized control trials proving that something works. We are contacted every week by a new company developing a new biologic treatment of Crohn's disease with the hope that it will be very effective, very well tolerated, and so on. So there is a high competition for nutrition. As a physician, in my everyday practice I know enteral nutrition works, and we can use it in some patients, but in how many, that is a difficult question. Dr Meier: But still the nutrition status plays a role. A negative nutrition status affects the outcome and if nutrition is not the only therapy, it is one thing to consider in parallel in all these patients, and this is neglected most of the time. We have all these expensive treatments but we often neglect the nutrition status. It must be our educational goal to improve the awareness of these points. Dr Damiao: I would like to address a very practical issue, which is that in many situations and many places in the world the expensive treatments are covered by insurance and you don't have enteral nutrition covered by insurance. So when the doctor tries to choose the best treatment, of course he will choose the treatment that is covered by the insurance. So I think we should discuss this also with the authorities, showing them the importance of enteral nutrition in selected patients, and at least we should have enteral nutrition as an option in the therapeutical profile that is covered by insurance. Probably many people here have this problem, sometimes many doctors don't prescribe enteral nutrition simply because it is not covered by the insurance. Dr Meier: That is a very good point. Dr Marteau: I agree, it is our responsibility to have this fight, it is not an easy fight but there is data to help. Dr Meier: And the funny thing is that most of the time parenteral nutrition, which is much more expensive and with many more complications, will be reimbursed whereas enteral nutrition is not. That is really a big problem. Dr Saavedra: There is both direct and indirect cost from whatever our therapy is and whatever the disease is. From that point of view, one of the things that we do not inject in all the trials that we are talking about is cost. Cost for the health care system, and for the individual, should be part of the outcome of all the trials that we are talking about. That still needs to be done. To that point the only way we ultimately could demonstrate or utilize nutrition in many places, and I would say the majority in the near future, is demonstrating that there is efficacy and that that efficacy is also associated to a potential reduction in cost. In many places enteral nutrition may be more expensive because you do require support, you do require additional personnel, you do require additional time to talk to the patient, and that is also part of the cost. So all those factors need to be incorporated into what the assessment of the therapy is. As we have with newer drugs which are obviously more expensive, some of them eventually lower in price, and the same thing happens with nutrition. Nutrition at the beginning can be very expensive because there is a huge investment in time and in effort, and in the psychologist or social worker that you sometimes need. In all the trials that we are proposing need to be done, in terms of demonstrating the efficacy with double blinded randomized fashion, never is cost considered in the outcomes, and it needs to be there. Dr Marteau: You are right, and there was a paper a few years ago in Gastroenterology saying that one-third of the cost of Crohn's disease was 5-aminosalicylic acid, and as mentioned yesterday the evidence for its efficacy is low for active disease and near to zero for maintenance of remission. Dr Barabino: You mentioned the use of fish oil in the treatment of Crohn's disease. I just would like to make a comment about that. The Italian Pediatric IBD group did a randomized double blind trial in mild Crohn's disease, fish oil vs placebo, and we found that the fish oil is much more efficient in maintaining remission vs placebo. The data are not published yet. Dr Meier: But they will be published somewhere, or as an abstract? Dr Barabino: There was an abstract in ESPGHAN about 2 or 3 years ago, and now we are trying to publish the data, and we presented the paper at the Digestive and Liver Disease meeting. Dr Meier: The study was done only in children? Dr Barabino: All children. Dr Marteau: What was the dose and the nature of the fish oil? Dr Barabino: 3 g of fish oil EPA and DHA for 3 months. Dr Marteau: With vitamin E or without? Dr Barabino: No, without. Dr Gassull: I have a couple of comments about the trials, and the difficulty to do these. For example, in trying to organize at least 3 large trials on the effects of enteral nutrition in Crohn's in adults and getting >60 or 70 patients, trying to include 10 or 15 hospitals, there is a big reluctance by the adult gastroenterologists to take on this challenge. In our hospital, people have been working with me for years so they are used to doing it, but even in this situation it is getting very difficult. So it means that we need to have more evidence, more pressure or more education to gastroenterologists on the effects of nutrition. Because the problem is if you try to perform a parenteral nutrition trial, you don't get enough patients. I think one of our mistakes is that we are dealing with the concept of nutrition and replenishment and we are treating malnutrition, we are not treating nutrition in this sense, we are using nutrients as a therapy. This is an important concept. The second point is about the cost. It is not only the cost of hospitalization, surgery and drugs, it is also the social cost, they lose their work and things like this, and probably it represents 50% of the cost of IBD. So all this should be taken into account along with the direct cost.
Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 4 suppl,
S166-S172 (2005) This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
|
 |
|
Top
CORRECTION OF MALNUTRITION AND...
ENTERAL NUTRITION TO INDUCE...
B reduces the productions of TNF and proinflammatory cytokines
messenger RNA)
