Enteral nutrition in inflammatory bowel diseases: is there a special role for elemental diets?

CllnicalNutrition (l993112 (5upp\. lI: 575-581 © Longman GroupUK LId 1993

Enteral nutrition in inflammatory bowel diseases: is there a special role for elemental diets? J. P. CEZARD and B. MESSING* Pediatric Gastroenteroloy and Nutrition Unit, Hopital Robert Debra Gastroenterology and Nutrition Unit: H6pital Seint-Lszere", Paris, France.

ABSTRACT-Enteral diets have been shown to be as effective as steroids in inducing remission of active Crohn's disease. Elemental, semi-elemental and polymeric diets produce similar results. The short periods of time over which such diets have been used have not affected the subsequent progress of the disease. The mechanism of action of enteral diets remains speculative but bowel rest together with an improvement in immunological function and nutritional status are considered to be important. Immunomodulation through the use of specific nutrients (glutamine, arginine, nucleotides, PUFA from the 006 series) could affect the inflammatory response and its recurrence but clinical trials are lacking. Parenteral nutrition and fibre free enteral nutrition is not effective in treating ulcerative colitis possibly because the colon is deprived of shortchain fatty acids (formed from fermentation of fibre), which are an important fuel for the colonocyte.

Introduction

therapy . Studies in the 1980s confirmed this hypothesis by demonstrating that artificial nutritional support could be as effective as steroids in inducing a remission of active CD (11-17). The purpose of this report is to review the role of elemental vs non-elemental diets as primary therapy for CD, and to attempt to distinguish between the possible direct effects of such diets, from the secondary effects resulting from improved nutritional status.

Inflammatory bowel diseases (IBD) include ulcerative colitis (UC) and Crohn's disease (CD). Both are characterised by acute to chronic inflammatory gut lesions, but non-intestinal manifestations occur in up to 25% of cases. 20-25% of new cases occur in children. DC and CD differ mainly by the region of the gastrointestinal tract they affect (colon vs whole respectively), the extent of transmural inflammation (mucosa vs whole gut), and the histological appearances (non-granulomatous vs granulomatous). Patients with lBO, especially those with UC (1-5), have a higher risk of developing primary schlerosing cholangitis and colonic cancer. The aetiology of DC and CD remains unknown despite intensive research, but environmental, genetic, immunological and infectious factors have been implicated (6). Therapy is largely non-specific and until the early 1970s it was based on the administration of steroids and surgery. Colectomy cures DC but surgical procedures far CD do not, because CD may recur in any part of the gastrointestinal tract. Parenteral and enteral nutrition were originally used to treat growth failure and malnutrition (7-10), but it was realised that the use of artificial nutrition in CD could control disease activity as well as some of its complications, e.g. fistulae and inflammatory masses. This led to the hypothesis that bowel rest might be a primary form of

Malnutrition and growth failure in IBD Prevalence, aetiology and assessment

A weight loss of more than 10% of usual body weight occurs in up to 70% of patients with CD and 40% of those with DC (18). Growth retardation occurs in 50% of children with CD and 15% of those with DC. Delay in the onset of puberty occurs in 25% of children (3, 19). The factors involved in the development of malnutrition in CD are summarised in Table 1. The most important general cause is probably reduced food intake, which results from disease activity, abdominal pain or discomfort, and sometimes from unjustified recommendations to reduce food intake. Bouts of diarrhoea, protein losing enteropathy and reduced absorption (or increased secretion of nutrients into the gut) contribute to malnutrition. MineraI and micronutrient deficiencies such as calcium, 75

76 ENTERAL NUTRITlON IN INFLAMMATORY BOWEL DISEASES: IS THEREA SPECIALROLEFORELEMENTAL DIETS?

Table 1 Mechanisms of malnutrition and growthfailurein Crohn•s disease - Reduction of intake +++

"'Anorexia '"Abdominal pain "'Diarrhea - Increased intestinal losses "'Protein losing enteropathy *Bleeding "'Malabsorption "'Proteins. carbohydrates. lipids?" - Malabsorption "'Minerals (Ca, Mg, Fe. Zn) "'Vitamins (Folic acid. B12. D. K) "'Bacterial overgrowth *111erapeutic interaction *Inflammation - Increased needs "'Growth (children) "'Streroids (protein)

magnesium, potassium, zinc, iron, vitamin D and vitamin B12 are common. They may occur singly, but usually they occur in combination, or in association with protein-energy malnutrition (3, 18, 19,22). Nutritional assessment is important for both adults and children. In adults, the percentage change from usual weight should be recorded, and in children weight for height should be monitored. Biochemical as well as anthropometric measurements may also be useful, especially when made concurrently with an assessment of disease activity, e.g. Harvey-Bradshaw or Best indices. Among the biochemical markers that may be useful in assessing nutritional status/disease activity are full blood count, concentration of circulating proteins (albumin, transthyretin, and acute phase protein such as C reactive protein and orosomucoid), iron and calcium. In children, an assessment of bone age and pubertal development are important especially in deciding when to initiate artificial nutritional support (3, 23). In adults subjective global assessment of nutritional status is valuable (22). Studies of body composition have drawn attention to the significantly reduced calcium content of bone in 25% of patients with CD. Bioelectrical impedance and whole body electromagnetic conductance may be used in assessing the amount of fat and fat-free mass within the body, although the latter technique is restricted to only a few centres. Treatment of growth failure and malnutrition

Enteral and parenteral nutrition have been repeatedly shown to improve malnutrition and growth failure resulting from CD (3, 22-24), and to induce a remission of active disease. The absence of a clear cut efficacy of artificial nutritional support in causing remission of active DC, has limited its use in this condition (25, 26). Indeed postponing curative surgi-

cal procedures so that nutritional status could be improved has been reported to increase morbidity and mortality (22), presumably because of unchecked disease activity. In children with growth retardation the potential for catch up growth is time dependent and time limited. Therefore early and aggressive nutritional support is indicated, to control disease activity and reverse the growth retardation. If oral supplements fail to produce benefit, cyclic nocturnal enteral nutrition is indicated especially in prepubertal children (27). Home tube feeding can be used either continuously or intermittently(27-29). Although catch up growth has been successfully obtained with various types of feeds - elemental, semi-elemental, or polymeric (9, 27, 29) - controlled studies to assess the relative merits of various types of diets have not been critically evaluated. In adults with active CD, elemental diets can induce a remission, even in those who are resistant to other forms of treatment (11-17) including steroids. However, in order to induce a significant reduction in disease activity, the elemental diets frequently have to be administered for a minimum of 3 weeks. Since an improvement in nutritional status is detectable during this period, it has been suggested that the subsequent suppression of the disease activity is due to an improvement in nutritional status. In our opinion this seems a doubtful assertion, especially since a clear cut response may occur quickly with such diets, or following administration of parenteral nutrition, which rests the bowel. Furthermore, polymeric diets seem to be generally more effective than elemental diets in improving nutritional status, but they are not more effective in controlling intestinal inflammation (11-17).

Efficacy of enteral nutrition in reducing disease activity Controlling exacerbations

Parenteral or enteral nutrition is reported to reduce disease activity in no more than 25% of patients with DC, but up to 80% in CD (8-10, 22, 26). At least 5 controlled trials have demonstrated the efficacy of elemental diets in achieving partial or total remission of exacerbations of CD (11, 30-33). In these studies, which are summarised in Table 2, a comparison is made with the standard form of treatment, namely administration of steroids. Despite the variable number of patients in each study (n = 19-42) and the variable period of treatment (5-6 weeks), the mean success rate in compliant patients was high (78%).

CLINICALNUTRITION 77 Tallie 2

Controlled Trial s: Elemental diets (ED) vs Steroid

treatment (ST) in Crohn's disease

Patients Treatment % success (n) Period rate week ED ST

O'Morain (II) Savarymutu (30) Seidman (31) Ohada (32) Gorand (33)

21

4 1.5 3 6 4

37 (32)

19 20 42 (33)

82 52 (69) 80 80 50 (86)

Statistica l Difference

80 81 67 30 95

NS NS NS <0.05 NS

Number in brackets take into account only the compliant patients.

Another 3 studies which aimed to assess the efficacy of semi-elemental diets relative to steroid treatment in inducing partial or total remission in CD (12, 34, 35), are summarised in Table 3. In two of these the semi-elemental diets induced a lower remission rate than steroids. The overall remission rate in compliant patients receiving semi-elemental diets was 65%. This result is lower than that obtained with elemental diets (78%), but the mean of all studies combined is as high as 75% . However, of the 5 controlled studies that have compared elemental and polymeric diets (14-17, 36) , only one reported a better success rate with the elemental diet (14). Furthermore, Table 4 indicates that the mean success rate with the two types of diets were similar (62% elemental vs 57% polymeric). Interestingly, the decline in disease activity might occur earlier with the elemental diet (14) and steroid therapy (12) compared with the semi-elemental diet. Table 3 Controlled Trials: Semi-elemental diets (SED) vs Steroid treatment (ST) in Crohri 's disease Patients Treatment (n) period (week) Sanderson (34) 17 95 (75) Malchow (35) Lochs (12) 107 (100)

% success rate SED ST*

6

88

6

41 (66)

6

52 (60)

Statistical difference

86 NS 73 <0.05 (NS) 79 <0.01 «0.05)

Number in brackets take into account only the compliant patients. Table 4 Controlled trials: Elemental diets (ED) vs Non-elemental diets (NED) in Crohn's disease Patients Treatment (n) period (week) Giaffer (14 ) Rigaud (17) Raouf (15) Park (16) Middleton (36) (P)

~

30 30 24

14 29

1.5 4 3 4 2

% success rate

ED

NED"

75 67 69

36 73 73 86 73

57 79

Statistical difference

(P) (P) (P) (P) (SED)

Polymeric diets(SED ) ~ Semi elemental diet .

0.05 NS NS NS NS

From the above it can be concluded that enteral diets are able to control exacerbations of CD within 3-6 weeks in 57-78% cases, which is probably similar to the results of steroid therapy. The variability in response is related to the variable severity and duration of disease activity. and the extent of gastrointestinal involvement. Colonic disease is less responsive than ileitis (6). The effects of artificial nutrition (37-39) in patients with steroid dependent disease and those with subacute exacerbations of CD who are resistant to usual forms of treatment, are far from clear (37-39). This is partly due to the difficulties in analysing the few data that are available, and partly because of the confounding effects of concurrent therapy in the form of steroids (38, 39) or parenteral nutrition (39). As many as 70% of patients enrolled in some of these studies were receiving varying doses of steroids (38, 39). Since no significant difference in response rate was found between enteral or parenteral nutrition on the one hand, and combination of parenteral nutrition and oral feeding on the other, it is tempting to conclude that nutritional support , irrespective of whether it is enteral or parenteral, is more important than bowel rest in inducing the 58-71 % response rate (38).

Maintenance ofremission after controlof exacerbations Since patients claim to be intolerant to certain types of foods , it was suggested that exclusion of these foods from the diet can improve the clinical course of CD (40). However, this assumption was not supported by the results of a multicentre prospective study (41). Other workers have investigated the long-term relapse of CD (at I and 3 years) after initial control of exacerbations with either steroids or artificial nutrition (13, 33). The results of the two treatments were comparable, which implies that a short period of enteral or parenteral nutrition does not modify the course of CD (3, 22). However, in another study the use of an enteral supplement in undernourished adults with active CD, was reported to improve nutritional status as well as disease activity 3 months after the start of supplement (4 1). Furthermore , studies involving long-term use of enteral nutrition, either continuously or intermittently, suggests an improvement in disease activity (9, 27, 42). Potential use of enteral nutrition in control of disease activity: elemental versus non-elemental diets The use of enteral diets in controlling acute ex-

78 ENTERAL NUTRITION IN lNFLAMMATORY BOWEL DISEASES: IS THEREA SPECIALROLEFORELEMENTAL DlETS1

Table 5 Physiopathological mechanismsin Crohn's disease

Environmental factors - Smoking,drugs (acetornlnophen). tooth paste - Simple sugars - Alimentary antigens - Infectiousagents (mycobacteria,viruses) Increasedintestinal permeability Abnormalgut immunological response - Alteration of antigenpresentingcell (Hl.A Classe II) - Reduction of suppressor T cells - Increasedlevel ofIg G2 x ~ cells and cytotoxic T cells (CD8, CD25) - Increased expressionof cytokines(ILl, IL6. TNF. IFN, lL2) - Increasednon cytokine inflammatorymediators (prostaglandins and leukotrienes) - Increasedproductionof oxygen free radicals

acerbations of CD to the same extent as the standard steroid therapy, has resulted in new insights into the multifactorial pathogenesis of IBD (14, 17). The main pathophysiological mechanisms implicated in Crohn's disease (Table 5) have been extensively reviewed (19, 23, 44). Aspects specifically related to artificial nutrition, especially enteral nutrition (Table 6), are discussed below. Comparison between different enteral formulae

Despite wide variation in the composition of enteral diets (Table 7), their effects on the activity of CD are similar (see above). The composition of the diets differs in nitrogen source, in the proportion of nitrogen as amino acids peptides and protein, and amino acid composition, especially with respect to glutamine and arginine which are absent from some feeds. The feeds also differ in the type of fats they contain, and their content of emulsifying agents and polyunsaturated fatty acids (PUFA). Such differences produce much Table 6 Potentialmechanismsof action of artificial (parenteral, elemental and semi-elemental diets) in Crohn's disease

Bowel restand intestinal adaptation - Decreased gut metabolic activity - Changesin gut blood flow and motility - Decreasedpancreatico-biliary secretion - Distal small bowel atrophy (animals) . - Decreasedavailabilityof: glutamine,SCFAs, purine nucleotides, PUFAs Immunological effects - Decreaseddietary antigens. - Changesin fecal flora? - Decreasedlymphatic flow - Changes in inflammatory mediatorsynthesis - Changesin cell mediated immunity Nutritionaleffects - Increasednitrogenand caloric intake - Correction of micronutrientdeficiencies

greater variability in the integrity of the gastrointestinal tract than in nutritional status. The response of the intestinal tract is obviously important especially if it is already ulcerated and associated with impairment of its barrier function (6). The diets, which are nearly sterile, provide luminal nutrition to the gut,with a reduced antigenic load or inflammatory processes, so that they will induce a remission of CD. Further research in this area is needed to assess the most appropriate dietary composition. Medical and surgical bowel rest , divers ion colitis and the use of specific intestinal fuels

The small intestine and colon are put to rest when artificial nutrition is used, especially parenteral nutrition. With enteral nutrition, bowel rest is incomplete because of the continuous gastric delivery of predigested aseptic foods, which may contain some protein and bacterial antigenic loads. Bowel rest is more complete with elemental diets than non-elemental diets. With elemental diets the distal small intestine 'rests' more than the proximal part. Consequently, during enteral feeding only the proximal small intestine is luminally nourished, so that the distal part can be regarded as being 'fasted' or deprived of luminal nutrients (22). There is an analogy between this form of medical bowel rest , and the surgical bowel rest. The surgery, which was already being performed more than 20 years ago, aimed to divert the faecal stream in patients with colitis . Instillation of chyme but not its ultrafiltrate , into the diverted colon worsened the histological appearances, and in some cases produced exacerbations of CD (see (22) for review). When the colon is diverted surgically for more than a few months , a colitis may paradoxically develop (diversion colitis) (48). This colitis may respond to instillation into the colon of short-chain fatty acids (SCFA), especially butyrate which is normally an important fuel for epithelial cells of the colon (48, 49). Glutamine is also a fuel for colonocytes but it Table 7

Main diets used in Crohn's disease

14-18% Amino acids 70--80% Dextrine maltose 1-10% Lipids Vivonex-EO 28-Enteronutril 14-18% Semi elementaldiets Oligopeptides from proteins 40--60% Dextrine maltose Lipids (%-0/.LeT -- \I.I- !h MCT) 12-40% Survimed- Peptisorb-Reabilan Proteins (milk. meat, soja) 14-18% Polymeric diets Dextrine maltose 40--50% Lipids (LCT > 70%) 30-4 0% Enteral 400-Ensure-Fortison-Realmentyl-Triosorbon-Vital

Elemental diets

CLINICAL NUTRITION 79

is probably more important for the small intestine (45-57). Experimental studies suggest that the colon derives as much as 75% of its specific fuels from the luminal side, and 25% from the vascular side, while enterocytes derive about 50% of their specific fuels from both sources (45, 48). It is suggested that in colitis the colon is deprived of SCFA (either through reduced fermentation in the large bowel - e.g. decreased 'fibre' intake - or from an inability to metabolise butyrate normally, as shown experimentally). The successful use of diets enriched with fibre (which produce SCFA in the colon) in treating chemically induced colitis, and the successful use of butyrate enemas in human proctitis (49), are consistent with this hypothesis. Glutamine provides nitrogen for nucleic acid synthesis and stimulates protein synthesis in rapidly dividing cells such as surface enterocytes, cells within intestinal crypts and lymphocytes (45). Animal studies have suggested an important role of pharmacological doses of glutamine in preventing, a) translocation of bacteria from the intestinal lumen to the systemic circulation, especially in parenterally fed rats that have intestinal atrophy, and b) intestinal lesions including ulceration produced by the cytotoxic drug 5fluoruracil (46, 47). Animal studies also suggest that purine nucleotides may have potent trophic effects (50, 51). However, until now the use of gut specific fuels in enteral and parenteral nutrition for the treatment of IBD has been limited and a specific fuel deficit for the small or large intestine affected by CD has not been demonstrated. Therefore it is tempting to suggest tentatively that neither parenteral nor enteral nutrition supplemented with some of the above fuels, may produce benefit in the same way as in ulcerative colitis. Indeed, artificial nutrition deprived of gut specific fuels has the effect of producing bowel rest and partial healing of bowel affected with CD.

Immunomodulation through enteral diets The currently available referenced drugs that are used to prevent exacerbations or relapse of lED are immunosuppressive. Furthermore, many studies have emphasised the specific role of individual nutrients on immunity. Taken together these observations suggest that it may be possible to modify the pathogenic mechanisms involved in Crohn's disease by dietary manipulation (addition or removal of specific dietary components). Various antigens, derived either from food proteins or bacteria, may trigger an inflammatory response in the bowel affected with CD (43, 52, 53). Increased permeability occurs in active CD (54), and micro-vas-

culitis has been recently recognised as a primary histologicallesion in the submucosa of patients with CD (55). Furthermore, endotoxaemia is frequently present in patients with CD who have an ulcerated mucosa, and in the rat systemic liposaccharides from various bacteria induce microvasculitis in the gut (56). In addition enteral feeding alone is associated with decreased intestinal permeability in CD (57). Oral bacterial and food protein antigen loads are obviously reduced when using elemental or semi-elemental diets. Therefore, it is tempting to speculate that the efficacy of enteral nutrition in CD is linked to a decreased antigen load, and an improvement in immunological defences is associated with improved micronutrient and protein status (41). In this respect glutamine and arginine are fascinating amino acids since they are potent activators of polymorphonuclear cells and T cells (45, 58, 59). The fact that some enteral diets do not contain glutamine does not mean that the gut is deprived of such a fuel since the gut can extract glutamine from the circulation. Furthermore, the turnover of 15N-glutamine is substantial in the post-absorptive state although it is increased by enteral feeding (60). The main lipids used in enteral nutrition are triglycerides from negative sources, which are rich in PUPA's of the W6 series. They are precursors of arichidonic acid, which is further metabolised to prostaglandins (PG) and leucotrienes (LT). PGE 2 and LTB4 are potent non-specific pro-inflammatory agents which have been implicated in the pathogenesis of CD (61). In contrast, PUPA's from the (03 series, which is abundant in fish oil, may further decrease the inflammatory response (62-64) by decreasing production of PG~ and I~ through, a) relative depletion of the membrane content of (06 fatty acids, and b) increasing products of eicospentanoic acid (fish oil is rich in this acid) (LTB4, GPI3 , TXA 3) , which are formed via the cycle-oxygenase pathway. This' last group of substances are less pro-inflammatory than their (06 counterparts (62). Therefore, manipulation of fatty acid pattern of elemental diets is an available therapeutic approach for IBD (61). Overall, decreased antigen load, decreased intestinal inflammatory response and permeability, as well as non-specific improvements in intestinal and systemic immune functions might playa prominent role in indicating the remissions of CD in patients receiving elemental or semi-elemental diets. References I. SircusW, Natural history of Cohn's disease - overview. In: AllanR N, Keighley M R B. Alexander-Williams J, eds.

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