Nutritional deficiencies in inflammatory bowel disease: Therapeutic approaches

Clinical Nutrition xxx (2013) 1e7

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Review

Nutritional deficiencies in inflammatory bowel disease: Therapeutic approaches Sara Massironi a, *, Roberta Elisa Rossi a, b, Federica Alessandra Cavalcoli a, b, Serena Della Valle a, b, Mirella Fraquelli a, Dario Conte a, b a b

Gastroenterology Unit II, Fondazione IRCCS Ca’ Granda- Ospedale Maggiore Policlinico, Milan, Italy Department of Pathophysiology and Transplant, Università degli Studi di Milano, Milan, Italy

a r t i c l e i n f o

s u m m a r y

Article history: Received 3 January 2013 Accepted 24 March 2013

Background & aims: Malnutrition is common in inflammatory bowel diseases (IBD), mainly in Crohn’s disease (CD) because the small bowel is primarily affected. We reviewed the literature to highlight the importance of proper nutrition management. Methods: A PubMed search was performed for English-language publications from 1999 through 2012. Manuscripts comparing nutritional approaches for IBD patients were selected. Results: We identified 2025 manuscripts: six meta-analyses, 170 clinical-trials, 692 reviews. The study findings are discordant. In adult CD, enteral nutrition plays a supportive role, steroid therapy remaining the first choice treatment. In CD children enteral nutrition may represent the primary therapy. As regards parenteral nutrition, there are no large randomized studies, although mild improvements in morbidity have been described as a result of parenteral nutrition in malnourished surgical IBD patients. Specific micronutrient deficiencies are common in IBD. A number of factors may contribute to micronutrient deficiencies, and these include: dietary restriction, disease activity and surgery. The possible therapeutic roles of omega-3 fatty-acids, probiotics and prebiotics have been studied, but the results are still preliminary. Conclusion: Protein-energy malnutrition and micronutrient depletion are clinical concerns in IBD patients. Enteral nutrition, parenteral nutrition and micronutrient supplementation are cornerstone of the multidisciplinary management of IBD patients. Ó 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Inflammatory bowel disease Nutritional deficiencies Enteral nutrition Parenteral nutrition Protein-energy malnutrition

1. 1Introduction Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are a heterogenous group of chronic immune disorders of unclear etiology. Diet has been suggested as a potential pathogenetic factor in the development of IBD. The “Western diet” (i.e., processed and highly refined sugars and fats) is considered to be partially responsible for their increasing incidence.1e3 While UC is usually restricted to the colon, CD may affect any part of the gastrointestinal tract. As a consequence, malnutrition often occurs in cases of CD because CD mainly affects the small bowel. However, malnutrition may be observed in both UC and CD and in both the active and quiescent periods of the diseases.3 The

* Corresponding author. Gastroenterology Unit II, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via F. Sforza 35, 20122 Milano, Italy. Tel.: þ39 02 55033445; fax: þ39 02 55033644. E-mail address: [email protected] (S. Massironi).

mechanisms underlying malnutrition include reduced oral intake, increased energy requirements due to systemic inflammation, poor digestion, malabsorption due to chronic inflammation, and (mainly in CD patients) previous surgical resection or bypass of the bowel and protein-dispersion.4 Among patients with IBD, both deficiencies of macronutrients (leading to a global protein-energy malnutrition), which are less common but clinically more relevant, and deficits of specific micronutrients (nutrients required for life in small quantities) have been observed. Deficiencies of minerals, trace elements or vitamins occur for several reasons, including blood loss (iron deficiency), chronic diarrhea (hypomagnesemia) or loss of specific absorptive sites (vitamin B12).3,4 In the clinical care and management of IBD patients, nutrition plays a pivotal role, either as a supportive therapy or a primary therapy.5 It is also important to consider that poor nutritional status is a significant risk factor for postoperative complications.3 On the other hand, in recent years, the prevalence of obesity and overweight among IBD patients, especially children, has been

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rising. This increase could be related to steroid therapy and a lack of physical activity. According to a recent study, overweight and obesity were observed in 23.6% of children with IBD, 20.0% with CD and 30.1% with UC.6 Given the significant impact of malnutrition on the natural history and prognosis of IBD, we provided a comprehensive review of the main patterns of malnutrition that can occur in IBD setting and reviewed the literature on nutritional approaches for IBD patients to highlight the importance of proper nutrition management. 2. Methods A PubMed search was performed for English language publications from 1999 through 2012, using the following keywords, included both medical subject heading (MeSH) terms and free language words: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nutritional deficiencies, enteral nutrition, parenteral nutrition, protein-energy malnutrition, nutritional status, nutritional sciences, and nutrition. Manuscripts that described and compared various nutritional approaches for IBD patients were selected. Reference lists from studies selected by the electronic search were manually searched to identify further relevant reports. Reference lists from all available review articles, primary studies and proceedings of major meetings were also considered. 3. Results We identified 2025 manuscripts (1782 in English language), including six meta-analyses, 170 clinical trials, and 692 reviews. Out of the 1782 remaining studies, 1470 were excluded as not pertinent on the basis of the title. Thus, 312 studies were retrieved in abstract form and 163 excluded as not pertinent on the basis of the abstract. 149 studies were obtained in full text and blindly analyzed by two authors who excluded 65 studies as not adhering to our protocol (not pertinent). We finally identified 84 studies pertinent to the review. 3.1. Nutritional assessment Nutrition assessment plays a crucial role in IBD practice and includes a combination of history-taking, clinical examination, and laboratory tests (i.e., serum albumin and iron studies).4,5 There are several markers of malnutrition; none are exclusive. The most important markers are body mass index (BMI) and weight loss, although in some recent studies, IBD patients considered wellnourished according to a conventional clinical criterion (BMI) suffered from depleted muscle mass.7 Clinicians may conduct a more comprehensive assessment that includes anthropometry and scoring systems such as the Nutrition Risk Screening (which takes into consideration weight loss (amount and duration), Body Mass Index for adults (weight in kg/height in m2), and percentile charts for children, food intake (appetite and the ability to eat and retain food) and ’stress factors’ (the effects of medical condition on nutritional requirements).8 The Subjective Global Assessment (SGA), a clinical nutritional index based on a standardized questionnaire that assesses changes in dietary intake, recent body weight changes, gastrointestinal symptoms, functional capacity, and physical signs of malnutrition (loss of subcutaneous fat or muscle mass, edema, ascites) is another widely used tool for evaluating malnutrition.9 In addition, various biochemical markers may help to detect a state of malnutrition (Table 1). However, albumin and prealbumin are negative acute phase proteins, and they decrease with an inflammatory response, independent of malnutrition. Thus, hypoalbuminemia in IBD patients could reflect active

Table 1 Biochemical markers of malnutrition. Malnutrition Parameters

Mild

Moderate

Severe

Biochemical parameters Albumin (g/dL) Transferrin (mg/dL) Pre-albumin (mg/dL) RBP (mg/dL)a Lymphocytes/mm3

3.5e3.0 150e200 18e22 2.5e2.9 1200e1500

2.9e2.5 100e149 10e17 2.1e2.4 800e1199

<2.5 < 100 < 10 < 2.1 < 800

a

RBP ¼ retinol binding protein.

disease rather than protein-energy malnutrition. Also, transferrin an acute phase protein that has been proposed as a good measure of protein status could have limited value in patients with IBD, considering that the high prevalence of inflammation and iron deficiency act as confounding factors.10 3.2. Protein-energy malnutrition Malnutrition is a state of altered functional and structural development of an organism, resulting in an imbalance between the need, the intake, and the utilization of nutrients. The pattern and severity of malnutrition depend on the duration, the activity, and the anatomical extent of the disease.5 Widely varying figures have been reported for the prevalence of malnutrition in different types of patients with IBD in different phases of illness. It has been reported that the prevalence is 20%e 85% among hospitalized patients, while the prevalence is approximately 14% and 5.7% among CD and UC patients, respectively.7,11,12 Moreover, malnutrition is more frequently observed in patients with CD (50e70%, with 65e75% of CD patients underweight at presentation5) than in patients with UC (18e62%) because the diseases affect different areas (small bowel vs. rectum). Hypoalbuminemia is found in 25e80% and 25e50% of hospitalized patients with CD and UC, respectively.4 Malnutrition in patients with CD usually develops over a long period of time (and therefore is linked to the duration of illness), whereas malnutrition in UC patients rapidly develops in exacerbated cases (and is thus linked to the activity of illness).11 A combination of factors contributes to protein-calorie malnutrition in IBD (Table 2).13 A relationship between disease activity and a reduced supply of nutrients is often observed because inflammatory mediators, including pro-inflammatory cytokines (i.e., TNFalpha), induce anorexia and cachexia. Furthermore, malabsorption, maldigestion, increased energy expenditure, and gastrointestinal protein loss may induce a relative deficiency of energy or protein, which is clinically manifested as growth failure or inadequate weight gain in children and overt malnutrition in adults. Table 2 Pathophysiology of malnutrition. Main mechanism

Effect

Anorexia Abdominal pain, nausea, vomiting Restricted diets Reduced absorptive surface due to inflammation, resection, bypass and fistulae Increased intestinal loss Exudative enteropathy Occult/overt blood loss Diarrhea Hypermetabolic state Drug interaction

Decreased food intake

Nutrient malabsorption

Protein loss Iron deficiency Increased loss of Zn2þ, Kþ, Mg2þ Alteration of resting energy expenditure Anorexia, nausea, test alteration, proteolysis, interaction with nutrient absorption/utilization

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S. Massironi et al. / Clinical Nutrition xxx (2013) 1e7 Table 3 Micronutrient deficiencies in IBD (ulcerative colitis, UC and Crohn’s disease, CD). Micronutrients

Prevalence (%) in UC

CD

Iron Folic acid Vitamin B12 Potassium Calcium Magnesium Vitamin A Vitamin D Zinc Selenium

81 35 5

39 54e67 48 6e20 13 14e33 11e50 75 40e50 35e40

10 26e93 35

Although protein-calorie malnutrition incidence is decreasing, nutritional support should be established in the majority of IBD patients.4 3.3. Micronutrient depletion Micronutrient depletion is common in patients with IBD, and its frequency depends on the extension and the activity of the disease; it is more commonly observed in CD than in UC (Table 3).4,14 Nutritional deficiencies can occur early in the disease process and may be clinically apparent at the time of diagnosis.4 The mechanisms underlying micronutrient deficiencies are similar to those described for malnutrition. In this case, the reduced intake is often related to restrictive diets prescribed by physicians or by the patients themselves. These restrictive diets, which usually exclude milk, dairy products, and fiber, do not offer any clinical benefit but lead to calcium and folate deficiencies.15 For UC or CD patients in remission, a healthy balanced diet with necessary dietary restrictions should be encouraged. During relapses accompanied by diarrhea, it is prudent for patients to temporarily reduce their oral intake of dietary fiber, although this practice is not supported by controlled trials.5 Furthermore, there is currently no evidence to support the use of a low-lactose diet for patients with UC or for patients with CD confined to the large bowel. A recent study16 demonstrated an increased prevalence of lactose intolerance in patients with CD, but lactose malabsorption may be related to bacterial overgrowth in the small bowel and increased transit time, independent of duodenal lactase activity. Some studies have suggested screening for lactose malabsorption with a hydrogen breath test16 in patients with CD involving the small bowel who present with persistent diarrhea.6 Because some nutrients are digested and absorbed at specific sites within the gastrointestinal tract,17 the activity and localization of the disease determine the risk of specific micronutrient deficiencies (e.g., vitamin B12 deficiency in patients with terminal ileitis or calcium and iron deficiencies in patients with disease of the proximal small bowel). Furthermore, patients who have previously undergone a resection of the small bowel tract are at risk of specific micronutrient deficiencies depending on the extent and location of the bowel removed, since different micronutrients are adsorbed at specific site through the small bowel tract. Particularly, vitamin B12 deficiency occurs in case of resection of the terminal ileum, whereas calcium and iron, which are absorbed in the jejunum, are deficient in case of proximal bowel resection.17,18 3.4. Iron deficiency Between 36% and 90% of adults with IBD develop iron deficiency, which is likely the main cause of anemia in IBD patients.19 Anemia (defined as hemoglobin level < 12 g/dl for women and <13 g/dl for

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men, according to World Health Organization 2008) is found in 16% of outpatients and up to 68% of admitted patients.19 Iron deficiency has a significant negative impact on quality of life and can lead to abnormal growth and inadequate cognitive development in children and adolescents. Although a low ferritin level is usually considered the best indicator of iron deficiency, it can be normal or increased in response to inflammation. Thus, it has been suggested that the threshold for defining a low serum ferritin level should be increased to 100 mg/L in the presence of inflammation.19 Oral iron supplementation has been shown to improve quality of life without negatively impacting the disease course; intravenous supplementation is needed only in selected cases: severe anemia (defined as hemoglobin <10 g/dL), need for fast recovery in mild anemia, intolerance to oral iron, and failure of oral iron.19 Both intravenous and oral iron can effectively supplement hemoglobin in the setting of iron-deficiency anemia and there is no evidence that intravenous iron is more effective than oral iron supplementation in raising hemoglobin levels. Moreover, common side effects of oral iron (i.e. nausea, abdominal pain, or diarrhea) are mainly related to relatively high dosing of elemental iron (>120 mg/d). According to recent clinical trials, low doses of iron (i.e. 60 mg elemental iron per day) are as efficacious as higher doses, with fewer side effects. In IBD patients, both oral iron and intravenous iron are effective in treating anemia. Moreover, there is no convincing evidence that oral iron activates or exacerbates IBD-related clinical symptoms. The use of a low starting dose of oral iron, such as one ferrous sulfate tablet per day, for treatment of iron deficiency is worthy of consideration.20 3.5. Folate deficiency Folate deficiency affects 20e60% of IBD patients, according to recent studies. Changes in medical therapy (e.g., reduced use of sulfasalazine) and increasing folate intake through supplements or food have most likely decreased the prevalence of the deficiency, though low-residue diets with insufficient intake of dietary fiber reduce oral intake of folic acid.5,21 In addition, treatment with sulfasalazine (but not with the other aminosalicylates, such as mesalamine) may exacerbate folate deficiency because it competes with the folic acid present in the intestinal lumen, rendering it unavailable for absorption.4 Methotrexate treatment may also contribute to folate deficiency because methotrexate is an antagonist of folic acid.21 Therefore, folate deficiency can cause and worsen anemia in IBD patients.5 Moreover, folic acid is an essential co-factor in the metabolic route of homocysteine-methionine, and folate deficiency may result in hyperhomocysteinemia, which may explain the increased incidence of thromboembolic events observed in CD and UC patients.4,21 Thus, folic acid supplementation is generally recommended if a low level of serum folate is detected in routine blood tests or if patients are receiving therapy with methotrexate or sulfasalazine.4 3.6. Vitamin B12 deficiency Vitamin B12 deficiency, which can exacerbate anemia, has been reported in approximately 20% of both adult and pediatric CD patients.21 The prevalence rises to 48% among patients with terminal ileitis, and it is nearly 100% among patients undergoing >100 cm ileal surgical resection.17 The absorption of vitamin B12 requires an intact ileum to absorb the B12eIF complex; thus, the factors that contribute to vitamin B12 deficiency include the location of the disease, the presence of a terminal ileum resection, and bacterial overgrowth.21 Finally, vitamin B12 is a crucial co-factor in the homocysteinee methionine metabolic pathway, and low serum vitamin B12 levels

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are an independent risk factor for hyperhomocysteinaemia.5 Vitamin B12 serum levels should be frequently monitored in all patients with ileal disease and in those who have undergone an ileal resection. If patients do experience a vitamin B12 deficit, they should receive supplementation via the parenteral route (i.e., by intramuscular injection). 3.7. Calcium and vitamin D deficiency Approximately 13% of adults with CD and 10% of patients with UC have a calcium deficiency. This deficiency could be related to the binding of calcium to unabsorbed fatty acids in the intestinal lumen, to the reduced absorptive surface after a resection of the ileum tract and the resulting vitamin D deficiency or to restrictive diets that exclude milk and dairy products. Calcium deficiency contributes to bone loss, and osteoporosis is a common nutritional complication of IBD. In cases involving corticosteroid therapy, the prevalence of osteopenia and osteoporosis are 51e 77% and 17e28%, respectively.22 Therefore, a total daily intake of 1.5 g of dietary calcium should be encouraged for all IBD patients.5 For patients with inadequate dietary calcium intake, oral supplementation with 500e1000 mg of calcium may be prescribed.22 Furthermore, among CD patients, low levels of vitamin D have been associated with bone disease, independently of exogenous glucocorticoid administration.23 On the other hand, vitamin D plays an important role in regulating the immune system by inhibiting adaptive immunity, therefore it has been suggested that vitamin D deficiency may be involved in the pathogenesis of IBD.23 Moreover, a recent study24 confirmed the potential role of vitamin D as mediator in the pathogenesis of CD and, possibly, UC; Ananthakrishnan and colleagues have shown that higher plasma levels of 25(OH)vitamin D reduce the risk of incident IBD, particularly CD.25 Thus according to the available data, vitamin D3 supplementation is recommended not only because it may help increase bone mineral density in patients with IBD5,22 but also for its possible therapeutic effects.25

seems to be related to an increased risk of bone fracture and liver toxicity.18,27 3.9. Other nutritional deficiencies Among IBD patients, a deficit of antioxidant agents, including ascorbic acid, beta-carotene, and vitamin E, has been observed. However, the precise clinical implications of these deficiencies, as well as the advantages of supplementation, have yet to be clearly elucidated. Moreover, according to some studies reported in the literature, supplementation of vitamin E could be responsible for an increase in the mortality rate among IBD patients, which discourages the indiscriminate use of supplements with high antioxidant content.28 Other nutritional deficiencies include iron, zinc, and selenium. Because zinc plays a pivotal role in wound healing, zinc deficiency may be a co-factor in patients with chronic fistulas.4,18 Moreover, zinc is a co-factor for superoxide dismutase; consequently, it may protect against oxidative cellular damage.5 Selenium has been shown to influence the expression of different pro-apoptotic genes linked to p53, nuclear factor kappa B (NF-kB) and stress signal pathways that play an important role in the pathogenesis of inflammation and in the early stages of cancer development29; selenium supplementation might be therefore included in the nutritional management of IBD patients. In conclusion, although a large percentage of IBD patients consume multivitamins and antioxidant vitamin supplements, currently, there is not sufficient evidence to support the use of these supplementations, except for documented specific deficiencies. Moreover, there are no current guidelines for assessment of micronutrient deficiencies in IBD patients. Considering the paucity of studies and the conflicting results reported, it is necessary to consider both the potential benefits and also the possible harmful effects of this supplementation.30 4. Nutritional therapeutic approaches 4.1. Dietary interventions

3.8. Fat-soluble vitamin deficiency Because bile acids are selectively absorbed in the terminal ileum, CD patients with terminal ileum disease or ileal resection may experience fat-soluble vitamin (i.e., A, D, E, and K) deficiencies as a consequence of bile acid and fat malabsorption. Moreover, the use of specific drugs such as cholestyramine, which binds bile acids, may exacerbate this deficiency. Vitamin K is a known cofactor for carboxylation of multiple proteins, including blood coagulation factors but also osteocalcin. There have been few studies addressing vitamin K status in IBD patients, although because of malabsorption and dietary restrictions, IBD patients may be at risk for vitamin K deficiency and some studies reported low serum and bone vitamin K levels in patients with longstanding CD.18,26 However, currently there is not sufficient evidence to support the use of vitamin K supplementation in IBD patients to prevent or treat bone disease; instead, increased dietary vegetables and legumes should be advised in all IBD patients who can tolerate these to promote bone health.18 An increased prevalence (about 16%) of hypovitaminosis A (defined as serum vitamin A < 20 mg/dl) or E (defined as serum vitamin E < 5 mg/l) has been documented both in CD and UC patients and a relationship between disease severity and the frequency of vitamin A or E deficits has been observed among CD patients.27 However, supplementation with fat-soluble vitamins is not routinely recommended for IBD patients. In particular, excessive vitamin A supplementation should be avoided because high intake

Although some data suggest that dietary factors play a role in the onset and the course of IBD, recommendations other than following a healthy and varied diet cannot currently be made for most patients. Prescribing a low-residue diet, poor in insoluble fiber, may be advisable during acute flares of IBD, particularly in patients with stricturing CD or severe UC attacks.31 Recently, several hypotheses about the possibility that some specific nutrients can modulate inflammation have been suggested. In details, the anti-inflammatory effects of n-3 (omega-3 fatty acids, fish oil) have been suggested to be beneficial in chronic inflammatory disorders such as inflammatory bowel disease.32 At present, data are available mainly about the beneficial effect of n-3 polyunsaturated fatty acids (PUFAs) and fermentable fiber [the main source of shortchain fatty acids (SCFA)], during the remission/quiescent phase of both CD and UC.12 3 PUFAs are metabolized to 3-series prostaglandins and thromboxanes and 5-series leukotrienes, which generally lead to less grade of inflammation and exert antiinflammatory effects when compared with their n-6 PUFA counterparts. However, according to a recent systematic review,32 there is insufficient evidence to recommend the use of omega 3 for IBD patients, even though a marginal significant benefit of n-3 therapy for maintaining remission and a substantial safety have been reported. Fermentable fiber generates much less residue than insoluble fiber, and it is fermented by colonic microflora, yielding several products, such as SCFA, mainly butyrate, than can be of benefit in IBD. Butyrate is the main metabolic substrate for colonic epithelial cells, and there are in vitro-evidences, suggesting that butyrate is

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able to down-regulate the production of pro-inflammatory cytokines, to promote the restoration of intracellular Reactive Oxygen Specie (ROS) balance, and the activation of NF-kB.33 Moreover, according to several in vivo-studies, rectal administration of butyrate or mixtures of SCFA were reported to decrease inflammation in patients with active UC.33 On the other hand, Kovarik et al. found that peripheral blood monucluear cells (PBMC) from IBD patients, compared to healthy individuals, are less sensitive to the inhibitory effect of n-butyrate when stimulated via toll like receptor (TLR) 2 engagement.34 As regards nutritional interventions, available data are not always consensual partially due to the incomplete knowledge of pathogenic mechanisms underlying IBD development; further studies are therefore needed to improve nutritional therapeutic approach and to provide unique nutritional guidelines. 4.2. Enteral nutrition (EN) Enteral nutrition (EN) has been studied either as nutritional support against malnutrition or as the primary therapy for CD because it may help to control disease activity.35 4.2.1. EN for nutritional support As nutritional support, EN has defined indications. It should be used under the following conditions: severe malnutrition, moderate malnutrition with food intake expected to be insufficient for > 5 days, ordinary nutritional status with insufficient food intake > 10 days or moderate/severe hypercatabolism.36,37 EN is preferred over parenteral nutrition (PN) as a method of nutritional repletion because it is associated with a lower incidence of serious complications and lower costs. Moreover, the presence of luminal nutrients has been shown to be an important trophic factor for intestinal mucosa, and it may prevent bacterial translocation and preserve gastrointestinal function. Contraindications to the use of enteral feeding include massive hemorrhage, bowel perforation, short bowel syndrome, intestinal obstruction, and toxic megacolon. Whenever EN is contraindicated, PN must be prescribed.11 Furthermore, a possible positive long-term effect of EN is under study. It has recently been suggested that nutritional therapy may reduce mucosal inflammation,38 although the pathogenetic mechanisms are far from being clearly understood. In particular, whereas steroids seem to be ineffective in promoting mucosal healing, there is increasing evidence supporting positive long-term effects of nutrition on mucosal healing and the normalization of inflammatory markers, with rates between 44 and 74%.38 Moreover, supplementary EN has also been shown to be effective in maintaining remission among CD patients, which indicates a suppressive effect on clinical and endoscopic disease activity. Data on nutritional support in UC patients are still limited, particularly related to nutrition interventions and the maintenance of remission in UC patients. Malnutrition is less common in cases of UC, and it is mainly observed among patients with chronically active disease that is resistant to traditional medical therapy,3 which is considered an independent risk factor for surgical outcomes.39 4.2.2. EN as primary therapy EN might be an effective therapeutic approach to CD because of its anti-inflammatory effect, which usually predicts an improvement in nutritional status (i.e., normalization of inflammatory markers within three days).40 Several mechanisms have been proposed, but none has been proven as the primary mode of action.36 EN could provide caloric nutritional support with a low antigenic load (semi- and elemental diet) and little fat (in particular with low levels of u6 eicosanoids, in favor of relatively high

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concentrations of u3), stimulate intestinal trophism, modify bowel flora, and/or promote “intestinal rest” (because mixtures available for EN are completely absorbed in the jejunum). Despite the pathophysiological assumptions, whether EN is actually an effective therapeutic approach to CD remains unclear. Several studies, including meta-analyses, have been published in the literature, but the results have been controversial. Among the six published meta-analyses, four describe corticosteroids as being more effective than EN for treating active CD,41e44 but the remaining 2 studies (including pediatric trials only) report that steroids are as effective as EN.45,46 According to the available data, it is likely that several other patient characteristics and disease characteristics contribute to therapeutic management decisions, which may include enteral nutritional therapy as an option. Thus, there are inadequate data provided to confirm or refute EN using the results of the meta-analyses. Therefore, EN would be used mainly as a nutritional support for malnourished adults, usually in combination with steroids, which are considered to be the gold standard therapy for CD. In the pediatric setting, however, where corticosteroids should be avoided because of their toxicity, EN could become the first-line approach. However, there is still a debate about the differing results obtained in adult and pediatric populations. First, the reported data come from two different populations in terms of age, disease localization (the majority of children have ileal CD, which is most likely to respond to EN as a primary therapeutic approach), disease duration (pediatric studies include mostly first diagnoses), and strict adherence to EN (which is far superior in the pediatric setting). Hanai et al. recently published a prospective study to assess EN as a safe and effective alternative to immunomodulator agents. The study shows that as a maintenance therapy in patients with CD, EN is nearly as effective as 6-mercaptopurine with fewer side effects; therefore, it is a safe candidate for long-term maintenance therapy.47 Moreover, whether EN is more effective than a placebo among adults is still being debated because randomized trials directly comparing nutritional intervention to a placebo are rare. However, EN efficacy, reported at approximately 40%, has been compared with the remission rate (approximately 25%) in the placebo group in other drug trials for CD. These results indirectly suggest that EN is effective in inducing remission.46 In any case, even among children, for whom EN is considered a first-line therapy because it has good efficacy in prompting remission, beneficial effects on growth, and fewer adverse effects, there are no specific guidelines on the choice of enteral formula. Further studies on different enteral formulations (elemental, immuno-nutrition, gut-specific nutrients) and on combinations of enteral and drug therapy are needed. In severe acute cases of UC, although there are no data supporting a nutritional approach as a first-line therapy, EN may play a significant role, whereas PN is reserved for patients in whom EN is contraindicated or likely to fail. 4.3. Parenteral nutrition PN in IBD patients is mainly indicated to correct malnutrition. Because EN has been shown to be at least as effective as PN, but with lower costs and fewer side effects, the current indication for PN support is restricted to a small group of IBD patients for whom enteral feeding has failed or is contraindicated.13 The main indications for PN include intestinal obstruction, toxic megacolon and enterocutaneous fistulas with elevated gastrointestinal output (>400 mL/die). In addition, PN is usually indicated in cases of intractable vomiting, severe stenotic disease, short bowel syndrome (SBS) or gastrointestinal perforation. In terms of wound healing and reconstitution of the small bowel, PN shows no

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advantages when compared to EN. On the other hand, oral/enteral nutrition is assumed to stabilize the organic function of the small intestine more quickly.3 Moreover, there is no advantage to PN if the disease is chronically active because, according to the official guidelines of the American Gastroenterological Association (AGA), an increased rate of remission is not usually achieved with PN. PN has no influence on the surgical intervention rate for CD, and it is not helpful to bypass the intestinal passage to achieve clinical remission.48 PN support could be useful in cases of severe malnutrition and for pre- and post-operative nutritional support in both CD and UC patients. The pre-operative use of total PN has been shown to improve serum albumin and body weight in patients with CD, although its impact on post-operative morbidity and mortality remains unclear.5 According to some retrospective studies, CD patients supported with pre-operative total PN have experienced fewer post-operative complications, an improved clinical course, and a decrease in the length of bowel requiring resection, but these benefits were achieved at the expense of a longer hospitalization period.48 When PN is indicated, it should be administered via an appropriate catheter inserted with full aseptic technique; the central venous catheterization is associated with an increased risk of several complications, such as sepsis, venous thrombosis, pneumothorax, and lymphatic duct damage. In patients with long-lasting and severe malnutrition, it is important to cautiously introduce PN and to carefully monitor patients for the risk of re-feeding syndrome. Although it has not been clearly demonstrated, a continuous infusion is usually preferred at the beginning in the most compromised patients, shifting to cyclical delivery once the patient becomes more stable, allowing periods of independence from PN, and offering better opportunities for social interaction.3,4 4.3.1. Home parenteral nutrition5 The most common indication for home PN in IBD is SBS with chronic intestinal failure, which is frequently a consequence of multiple small bowel resections due to CD. SBS occurs when there is less than 150e200 cm of viable jejunum left, which is inadequate to sustain the absorption of fluids, electrolytes, and nutrients. In patients with SBS, PN dependence is influenced by the length of the remaining small bowel and the type of the digestive circuit of anastomosis. The reported cut-off values of small bowel lengths separating transient and permanent intestinal failure are < 100 cm for end-enterostomy, <65 cm for jejunocolic, and <30 cm for jejunoileocolic type of anastomosis.49 Home PN requires comprehensive education for the patient and the support of a dedicated multi-disciplinary team. Although home PN delivers life-saving nutritional support to patients with SBS, it is associated with significant morbidity and potentially life-threatening complications (e.g., catheter-related, metabolic, gastrointestinal, hepatic, renal and skeletal complications) that often require hospitalization.50 Studies have reported that home PN is significantly associated with an increased quality of life, improvement in serum albumin and transferrin levels, and a reduction of oral steroid dependence. Conversely, it does not seem to influence body weight or the need for surgery among CD patients.50 4.3.2. PN as primary therapy Bowel rest, as a result of total parenteral nutrition (TPN), has been shown to reduce intestinal inflammation and decrease disease activity in selected patients with CD. Several retrospective analyses have examined the benefits of TPN as a primary therapy for CD, particularly for patients who have had little success with other medical/nutritional strategies, although the data are still controversial. Initial TPN-induced remission occurs in approximately 54%

of patients,11 and symptomatic relapses are common (occurring in approximately 60% of TPN-treated patients within 2 years).11 On the other hand, PN does not seem to be effective as a primary therapy for UC, as the initial response rate is 37e41%, and only 12% of patients experience stable remission over 12e64 months.11

5. Conclusion Nutritional deficiencies, resulting in an inability to maintain adequate body weight, malnutrition and growth failure in children, were historically considered to be the main nutritional problems for IBD patients. Advances in diagnostics and medical therapies have partially decreased their incidence, although nutritional deficiencies continue to be clinically relevant, particularly for children. Although classical treatments of IBD (including glucocorticoid therapy, anti-inflammatory drugs, immunosuppressives, and more recently, biologic agents) are efficient in minimizing inflammation and inducing prolonged remission, their long-term effects on growth and height remain controversial, in some cases reflecting deleterious effects on nutrition status. Nutritional support for malnourished IBD patients is indicated either as a supportive strategy or as a first-line treatment, and the enteral route is the first choice whenever possible. Among adults, EN has been shown to be effective in both active CD and in maintaining remission as a complement to corticosteroids, which remain the milestone of treatment. Among children, in whom long-term steroid therapy is contraindicated, nutrition therapy seems to be as effective as steroids. On the other hand, micronutrient depletion continues to affect the majority of IBD patients. Its frequency depends on the extent and the activity of the disease, and it is more commonly observed in CD than in UC patients.4 Finally, recent studies6 suggest that obesity may be linked to an increased use of surgery, suggesting a more aggressive disease course. In this perspective, the addition of steroid therapy and the lack of physical activity may further aggravate the problem, despite not having a clear direct action. The excessive inflammatory response characteristic of obese patients may also contribute to the progression of intestinal disease. A complete nutritional assessment and nutritional support, including EN, PN and micronutrient supplementation, is therefore an important aspect of the treatment of IBD patients, highlighting the importance of multidisciplinary management of individual patients.

Financial disclosures None.

Conflict of interest None.

Acknowledgments Statement of authorship: MS and RRE planned the work; RRE, CF and DVS performed the literature search; MS and RRE wrote the first draft of the manuscript; MS, RRE and CF edited subsequent versions of the manuscript; CD corrected the final version; MS, RRE, FM and CD wrote the revised version of the manuscript. Finally all authors read and approved the final manuscript.

Please cite this article in press as: Massironi S, et al., Nutritional deficiencies in inflammatory bowel disease: Therapeutic approaches, Clinical Nutrition (2013), http://dx.doi.org/10.1016/j.clnu.2013.03.020

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Please cite this article in press as: Massironi S, et al., Nutritional deficiencies in inflammatory bowel disease: Therapeutic approaches, Clinical Nutrition (2013), http://dx.doi.org/10.1016/j.clnu.2013.03.020