Enteral nutrition (liquid feeds) for maintenance of remission in Crohn's disease

What is Crohn's disease?

Crohn's disease is a chronic inflammatory disease of the intestines that frequently occurs in the lower part of the small intestine (ileum). Symptoms include abdominal pain, diarrhoea and weight loss. When people with Crohn's disease are experiencing symptoms the disease is considered 'active'. When the symptoms stop, it is called 'remission'. When people in remission experience symptoms it is called a 'relapse'.

What is enteral nutrition?

Enteral nutrition is a feeding method where a person's daily caloric intake is delivered via a liquid diet using the GI tract. Enteral nutrition can be administered by mouth or by tube feeding, where a tube is inserted through the nose or abdomen into the stomach to deliver the liquid feed. Enteral nutrition is a form of nutritional therapy for Crohn's disease patients. The mechanism by which enteral nutrition may influence inflammation is unknown and is being studied. Enteral nutrition can be classified as elemental and non-elemental (semi-elemental and polymeric) diets. Elemental diets are composed of amino-acids (organic compounds), fats, sugars, vitamins and minerals. Elemental diets are easily absorbed and digested. Non-elemental diets are based on oligopeptide (organic compounds composed of 2 to 20 amino-acids) or whole protein sources. Non-elemental diets are best for people who can digest and absorb nutrients without difficulty.

What is 6-mercaptopurine?

6-Mercaptopurine is an immunosuppressive drug that is thought to reduce inflammation in people with Crohn's disease by blocking the immune system.

What is mesalamine?

Mesalamine is a 5-aminosalicylic acid drug. 5-Aminosalicylic drugs are thought to treat Crohn's disease by reducing inflammation in the gastrointestinal tract. These drugs are usually taken by mouth.

What did the researchers investigate?

The researchers studied whether enteral nutrition helps to maintain remission in people with Crohn's disease. The researchers also investigated whether one type of enteral nutrition was better than another (e.g. elemental vs.non-elemental) for maintaining remission in people with Crohn's disease.

What did the researchers find?

Four studies including 262 adult participants with Crohn's disease in remission were included. One study (33 participants) compared an elemental diet to a non-elemental (polymeric) diet. One study (51 participants) compared an elemental diet to a normal diet (no supplements). One study (95 participants) compared an elemental diet to 6-mercaptopurine or a no treatment control group. One study (83 participants) compared a non-elemental polymeric diet to mesalamine. The researchers searched the medical literature extensively up to 27 July 2018.

The study comparing an elemental diet to a polymeric diet found no difference in remission rates at 12 months. Six elemental diet participants were not able to tolerate the enteral nutritional formula because of taste or smell and were withdrawn from the study. Participants who received half of their total daily calorie requirements as elemental diet and the remaining half by normal diet had a lower chance of relapse at 12 months compared to participants who received a free diet. No side effects were reported in this study. The study comparing an elemental diet to 6-mercaptopurine did not show any difference in relapse rates at 12 months. There was no difference in side effect rates. The only side effect reported in the elemental diet group was surgery due to worsening Crohn's disease. Side effects in the 6-mercaptopurine group included liver injury in two participants, hair loss in one participant and surgery to treat an abscess in one participant. The study comparing a polymeric diet to mesalamine found no difference in relapse rates at six months. Two participants the polymeric diet group experienced nausea and four had diarrhoea. It is unclear if any participants in the mesalamine group had side effects. No serious side effects were reported in any of the studies.

The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the effectiveness and safety of enteral nutrition for maintenance of remission in Crohn's disease can be drawn. More research is needed to determine the effectiveness and safety of using enteral nutrition as maintenance therapy in Crohn's disease. Currently, there are four ongoing studies (estimated enrolment of 280 participants). This review will be updated when the results of these studies are available.

Authors' conclusions: 

The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of enteral nutrition in quiescent CD can be drawn. More research is needed to determine the efficacy and safety of using enteral nutrition as maintenance therapy in CD. Currently, there are four ongoing studies (estimated enrolment of 280 participants). This review will be updated when the results of these studies are available.

Read the full abstract...
Background: 

Prevention of relapse is a major issue in the management of quiescent Crohn's disease (CD). Current therapies (e.g. methotrexate, biologics, 6-mercaptopurine and azathioprine) may be effective for maintaining remission in CD, but these drugs may cause significant adverse events. Interventions that are effective and safe for maintenance of remission in CD are desirable.

Objectives: 

The primary objectives were to evaluate the efficacy and safety of enteral nutrition for the maintenance of remission in CD and to assess the impact of formula composition on effectiveness.

Search strategy: 

We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and clinicaltrials.gov from inception to 27 July 2018. We also searched references of retrieved studies and reviews.

Selection criteria: 

Randomised controlled trials (RCTs) including participants of any age with quiescent CD were considered for inclusion. Studies that compared enteral nutrition with no intervention, placebo or any other intervention were selected for review.

Data collection and analysis: 

Two authors independently screened studies for inclusion, extracted data and assessed methodological quality using the Cochrane risk of bias tool. The primary outcome was clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included anthropometric measures (i.e. height and weight), quality of life (QoL), adverse events, serious adverse events and withdrawal due to adverse events. We calculated the risk ratio and 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference and 95% CI. A random-effects model was used for the statistical analysis. We used the GRADE criteria to assess the overall certainty of the evidence supporting the primary outcome and selected secondary outcomes.

Main results: 

Four RCTs (262 adult participants) met the inclusion criteria. One study (N = 33) compared an elemental diet to a non-elemental (polymeric) diet. One study (N = 51) compared a half elemental diet to a regular free diet. Another study (N = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group. One study (N= 83) compared a polymeric diet to mesalamine. Two studies were rated as high risk of bias due to lack of blinding or incomplete outcome data. The other two studies were judged to have an unclear risk of bias. The studies were not pooled due to differences in control interventions and the way outcomes were assessed.

The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to adverse events is uncertain. Fifty-eight per cent (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57% (8/14) of participants in the polymeric diet group (RR 1.01, 95% CI 0.56 to 1.84; very low certainty evidence). Thirty-two per cent (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95% CI 0.59 to 159.93; low certainty evidence). Anthropometric measures, QoL, adverse events and serious adverse events were not reported as outcomes.

The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates is uncertain. Thirty-five per cent (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64% (16/25) of participants in the free diet group (RR 0.54, 95% CI 0.30 to 0.99; very low certainty evidence). No adverse events were reported. This study reported no differences in weight change between the two diet groups. Height and QoL were not reported as outcomes.

The effect of an elemental diet compared to 6-MP on relapse rates or adverse events is uncertain. Thirty-eight per cent (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23% (7/30) of participants in the 6-MP group (RR 1.61; 95% CI 0.73 to 3.53; very low certainty evidence). Three per cent (1/32) of participants in the elemental diet group had an adverse event compared to 13% (4/30) of participants in the 6-MP group (RR 0.23, 95% CI 0.03 to 1.98; low certainty evidence). Adverse events in the elemental diet group included surgery due to worsening CD. Adverse events in the 6-MP group included liver injury (n = 2), hair loss (n = 1) and surgery due to an abscess (n = 1). No serious adverse events or withdrawals due to adverse events were reported. Weight, height and QoL were not reported as outcomes

The effect of a polymeric diet compared to mesalamine on relapse rates and weight is uncertain. Forty-two per cent (18/43) of participants in the polymeric diet group relapsed at 6 months compared to 55% (22/40) of participants in the mesalamine group (RR 0.76; 95% CI 0.49 to 1.19; low certainty evidence). The mean difference in weight gain over the study period was 1.9 kg higher in the polymeric diet group compared to mesalamine (95% CI -4.62 to 8.42; low certainty evidence). Two participants in the polymeric diet group experienced nausea and four had diarrhoea. It is unclear if any participants in the mesalamine group had an adverse event. Height, QoL, serious adverse events and withdrawal due to adverse events were not reported as outcomes.

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