Chapter 5.2.1. Short Bowel Syndrome: Half a Century of Progress

The year 1968 is often considered to be one of the most turbulent in the 20th century. It began with the Tet Offensive in the midst of the second part of the Vietnam War, it was followed by the assassination of Dr Martin Luther King, Jr, and soon after by that of Robert F. Kennedy. Mass socialist movements grew not only in the United States but also in most of European countries. The most spectacular manifestation of this was the May 1968 protests in France, in which students linked up with wildcat strikes of up to 10 million workers, and for a few days the movement seemed capable of overthrowing the government. Another event of 1968 was in August, when the Soviet army entered Prague, the capital of Czechoslovakia. However, behind those events, important happy occurrences, such as the birth of ESPGHAN and the first publication, from Stanley Dudrick and Douglas Wilmore, reporting the successful management of short bowel syndrome in neonates using parenteral nutrition (PN) (1). It started a revolution in the management of short bowel syndrome-related intestinal failure (SBS-IF). THE PIONEERS In 1967 Rickham reported his experience in Liverpool, UK, where only 7 of 17 newborns with less than 75 cm or remaining small bowel survived long term (2); these data were later confirmed in follow-up in collaboration with the Swiss group (3). In Rickham's unit at Alder Hey Hospital, PN was being used from 1962, comprised of Intralipid, 10% amino acid solution and 10% to 15% carbohydrate (glucose or fructose solution). Only a modest energy intake could be achieved, but in some cases it allowed time for gut adaptation to occur such that weaning to full enteral feeding became possible. Rickham also described using a probiotic (lactobacillus) in short bowel patients, and experimental work he undertook in rats and piglets to investigate the phenomenon of small bowel adaptation. Subsequent work on gut adaptation by Hughes et al (4) showed that in dogs total PN/compete gut rest lead to mucosal hypoplasia, and that this could be prevented by giving daily injections of cholecystokinin and secretin, possibly through a trophic effect of pancreatico-biliary secretions. Before the advent of PN, short bowel syndrome (SBS) carried a dismal prognosis. In the late 1960s, following Dudrick and Wilmore, yet another pioneer in the promotion and development of nutritional management of pediatric SBS patients in Europe was Claude Ricour, an active pediatrician and ESPGHAN member. As early as 1976 he published this letter in Journal of Pediatrics(5): “The continuous infusion technique for management of short bowel syndrome (SBS) is very interesting. At the Hospital Necker-Enfants Malades in Paris, we have used it for six years. We have employed this nutritional program in 170 children; 36 of them had a subtotal resection of the small intestine and a complete recovery ensued in 28 patients. The preliminary results have been reported as a communication in the Sixth International Congress of Dietetic. However the methods used and the indications for ‘constant rate enteral nutrition,’ about 12 cases of SBS, have been described. It is a very important nutritional approach, combined or not with total parenteral nutrition. It is not a ‘new method’ of treatment of SBS, however, as Christie and Ament have stated”(6). Indeed, PN has become the key therapeutic tool for managing SBS patients. Its aim is to achieve normal growth and development during the period of time to full intestinal autonomy. Another key ESPGHAN member, Michael Lentze, published in 1989 an important review on physiology of intestinal adaptation after intestinal resection (7). He concluded the paper as follows: “From a practical point of view, some of the substances involved such as enteroglucagon, prostaglandins and plerocercoid growth factor show some promise for future application in the management of the short-bowel syndrome. However, although adequate nutritional support and H2-receptor blocking agents can be administered, we still seem to be rather far away from being able to offer a more complete drug therapy to our patients suffering from short bowel syndrome.” WHAT IS SHORT BOWEL SYNDROME SBS is the leading cause of paediatric intestinal failure (IF). SBS-IF is characterized by a compromised bowel absorptive capacity due to severely reduced mucosal surface resulting in diarrhoea, water-electrolytes imbalance, and protein-energy malnutrition. SBS usually follows extensive surgical resection leaving the bowel length below a critical value necessary for adequate nutritional supply (8). Not surprisingly, the conditions giving rise to SBS have not really changed, although the relative importance in relation to each other has altered. Common causes still include small bowel atresia, complex gastroschisis, mid gut volvulus, neonatal necrotising enterocolitis (NEC), and long segment Hirschsprung disease. The precise anatomy of the small intestine causing IF is an important predictor of the final outcome of SBS (Fig. 1).FIGURE 1: Anatomy of small intestine causing intestinal failure in childhood.While the proportion of very preterm infants surviving has gone up the incidence of NEC has not diminished (9), generating more cases with massive gut resection resulting in SBS. A striking increase in the incidence of gastroschisis has been noted in a range of countries (10), with a small proportion of cases being complicated by intestinal atresia, or antenatal/perinatal bowel infarction. Data from the UK show a fourfold rise from 1993 to 2012 in numbers of long-term intestinal failure patients, with an increase in the proportion with SBS rising from 27% to 50% (11). WHAT CHANGED IN THE MANAGEMENT? During the 1980s, many children dependent on PN for long periods of time experienced high rates of sepsis, cholestatic liver disease, bone disease, and mortality. The high rate of mortal complications raised serious doubts about the safety of PN which ultimately led to intestinal transplantation being considered as the final solution for the SBS-IF. With the advent of tacrolimus the following decade saw the onset of the European perspective in intestinal transplantation (see Chapter 5.2.4). Nevertheless, following the pioneer period, an increasing number of infants and children survived after extensive intestinal resection (12). Case report and cohort follow-up studies from USA and Europe allowed identification of factors influencing the outcome: the underlying diagnosis, the type of segments preserved a long-term stoma versus a primary anastomosis, the presence of the ileo-caecal valve and the age of the patient at the time of surgery (13–19). Goulet from the team of Claude Ricour in Paris (13) reported outcomes in 87 patients with major gut resection; they were divided into group 1 with less than 40 cm remaining bowel, and group 2 with 40 to 80 cm. Underlying disorders included 36 atresia, 22 volvulus, 10 gastroschisis, 11 NEC, and 8 with other conditions. Survival was 92% in group 2 and 67% in group 1; overall more than 90% survived. Outcome was better after 1980 following the introduction of a home PN service. Nutritional support teams (NST) developed in response to the increasing sophistication of medical interventions, in order to share knowledge and skills, provide management advice and act as an expert resource across different departments (20). The care of children with SBS was aimed at maintaining growth and development while promoting adaptational changes in the gut that would facilitate eventual weaning from PN, as well as avoiding recognised complications such as catheter-related blood stream infection and intestinal failure–associated liver disease. NST commonly brought together nurse, dietician, gastroenterologist, surgeon, and pharmacist with clinical chemist, speech and language therapist, and interventional radiologist also closely involved. The “nutrition nurse specialist” was crucial, and often the starting point of the team, being a novel appointment employed solely to foster effective nutritional support. This role was shown to be cost effective through having an important impact on complications such as catheter-related blood stream infection (21). Nutrition nurse specialists subsequently played a key role in the development of home PN services, training carers, coordinating with community services, and supporting families at home. In some centres, pharmacists took on PN prescribing functions, and the development of computer-assisted PN prescribing facilitated the provision of individualised feeding regimens (22). An evaluation of children referred for consideration of intestinal transplantation (mostly with SBS) suggested that those who had been cared for in a medical unit without NST were less well nourished, had more CVC related complications and experienced greater early mortality than those cared for by a multidisciplinary team (23). Quality standards in some countries such as the UK now dictate that specialist gastroenterology services have to include an NST. CONTROVERSIES IN SHORT BOWEL SYNDROME FEEDING MANAGEMENT The management of SBS aims to promote the adaptation of the remnant intestine, which is a physiological process. The role of PN is to maintain optimal nutritional status during the time required for the intestinal adaptation to achieve intestinal autonomy. The GI tract should be used for feeding as much and as early as possible since it is the most physiological and safest route to provide nutrition. However, PN should not be stopped until adequate intake and growth can be achieved with oral feeding (OF) and/or enteral tube feeding (ETF). The optimal strategy for enteral feeding, OF versus ETF and bolus versus continuous, remains a matter of debate (24). A European group of expert agreed in promoting as much OF as possible allowing the maintenance of sucking and swallowing functions along with the interest and enjoyment associated with eating thus helping to prevent eating disorders (24). Moreover, OF promotes the release of epidermal growth factor (EGF) from salivary glands and increases gastrointestinal secretion of trophic factors (25). As emphasized by the Rotterdam group, breast-feeding should be encouraged (26). Human milk (HM) contains a number of factors supporting the developing neonate's immune system including nucleotides, EGF, immunoglobulin A, and leucocytes (27). Very few studies involved the choice of an “ideal” formula for SBS patients. In Europe, only Ksiazyk et al provided data showing the tolerance and efficiency of polymeric diets (28). However they are not usually used. Extensively hydrolysed formulas are preferred with the advantage of containing short peptides easily absorbed as well as medium-chain triglycerides (MCT) (24). Amino acid–based formulas (AABF) are generally used in the treatment of food allergies or in case of milk protein hydrolysate intolerance. True food allergies have been rarely documented in children with SBS (29). In spite of 2 retrospective studies reporting that the use of an AABF was associated with earlier weaning off PN and also a reduced rate of allergies (30,31), the very small sample sizes and the lack of control groups do not support the recommendation of using AABF in SBS patients. The small number of SBS patients as well as their heterogeneity precludes the design of randomized controlled trials investigating both, the type of the diet and the mode of its administration. Therefore, the current clinical practice is based more on expert opinion and experience based on large cohorts, than on evidence-based medicine. The European view has been published by ESPGHAN members, d’Antiga and Goulet (32), and the ESPGHAN Working Group on Intestinal Failure (33). INTESTINAL MICROBIOTA: THE BLACK BOX The Yin and Yang of the Colon The role of the colon, as well as the intestinal microbiota, are crucial for the prognosis of the SBS by reducing loss of energy and by producing trophic factors (34). In animal models, supplementation of an elemental diet with pectin, which is fermented to short-chain fatty acids in the colon, improved adaptation of the small intestine and the colon in SBS (35). PN with short-chain fatty acids reduced mucosal atrophy and intestinal immune dysfunction following massive small bowel resection (36). Interesting results have been obtained by Finkel et al by infusing pectin-supplemented elemental diet (37). However, clinical manifestations such as abdominal distension, bloating and nausea—due to fermentation in the colon—may impair daily life and should be monitored. They are the consequences of the intestinal malabsorption leading to huge load of undigested CHO reaching the colon. This condition may be worsened by hyperphagia or aggressive tube-feeding with the risk of developing d-lactic acidosis, a rare complication of the colonic hypermetabolism (38). Small Intestinal Bacterial Overgrowth and Cholestasis Cholestatic liver disease (CLD) has been shown to be more frequent in the SBS patients than in any other IF conditions (39). It is generally accepted that CTF offers the advantages of optimal digestion and absorption rate (26). However, continuous infusion changes the intestinal motility pattern by missing fasting period (40). Significant dysmotility—impairing intestinal bacterial clearance—leads to small intestinal bacterial overgrowth (SIBO) with subsequent enterotoxin release or Gram-negative sepsis. SIBO and cholestasis are common, especially in patients without ileo-caecal valve and in those with abnormal motility (eg, intestinal atresia, gastroschisis, NEC). Aggressive continuous ETF is often attempted with the aim of weaning the child off PN, thought to be the cause of liver injury. These patients present with dilated loops of bowel containing residual nonabsorbed nutrients. This strategy results in increasing SIBO that can cause mucosal inflammation and increased permeability leading to sensitisation and allergy as well as bacterial translocation, sepsis, and cholestasis (32) (Fig. 2). Interestingly, a group of Finish paediatric surgeons demonstrated, recently, the link between small bowel dilation, mucosal damage, bowel-derived bloodstream infections, and hepatic injury (41). In addition, overaggressive ETF may also result in abdominal discomfort, intestinal distension, and loss of self-regulation of intake leading to eating disorders. IFALD occurrence is a strong limiting factor in continuing PN. Fish oil–based lipid emulsions have been shown to reverse cholestasis (42–44), and the studies on their efficacy have been recently reviewed by the ESPGHAN Committee on Nutrition providing recommendations for their use in chronic IF patients (45). Both their availability and SBS-IF management improvements might explain why, in Europe, the rate of end stage IFALD leading to death or liver-intestine transplantation is much lower than reported by the US Intestinal Failure consortium (46).FIGURE 2: Cover of JPGN February 2013 illustrating the concept of SIBO causing gastrointestinal and nutritional disorders as well as liver disease.Dysbiosis as a New Paradigm The evolution of knowledge on the gut microbiota leads to changes in paradigms and terminology. SIBO should not be neglected or confused with what it is now referred to as “intestinal dysbiosis.” Available data are limited, but the study by Joly et al has opened this field by showing “imbalances” in the gut microbiota of adults with SBS, therefore suggesting “intestinal dysbiosis” (47). Two recent European studies have been conducted in children with SBS (48,49). The faecal microbiome of children with SBS was different from that of controls with a significant abundance of gamma-proteobacteria and bacilli (48). Overall, these studies seem to report a decreased bacterial diversity associated with a reduction or dominance of some bacterial species. These characteristics appear to be correlated with the level of PN dependence and the use of gastrointestinal decontamination. Ulcerations in the small intestine in the vicinity of ileocolonic anastomosis are rare and relatively unknown complication of SBS, especially in children, as reported by 2 groups from Paris (50,51). These ulcerations appear as externalized or occult gastrointestinal hemorrhages (hypochromic microcytic anemia). The pathophysiology is not known but it could be caused by dysbiosis and, perhaps by a specific bacterium. The role of NOD2/CARD15 mutations has been suggested (51). HOW TO ENHANCE BOWEL ADAPTATION AND INTESTINAL AUTONOMY Do Surgeons Have the Answer? Surgical approaches aimed at maximising gastrointestinal digestive and absorptive function are crucial to the management of SBS. These include stoma closure and restoration of bowel continuity together with resection of strictures and closure of fistula. There are situations where surgical interventions aimed at reducing stasis in very dilated bowel, possibly decreasing SIBO (with its negative effects on digestion, absorption, and the liver) in the process and increasing contact time between luminal nutrients and mucosa might improve overall absorption. The most common procedures are Longitudinal Intestinal Lengthening and Tapering (LILT) developed by Adrian Bianchi in Manchester, UK (52) and Serial Transverse Enteroplasty (STEP) mostly used in North America (53). The precise indications and the potential benefits of these procedures remain a matter of debate (54,55). LILT involves longitudinal splitting of the small bowel remnant along its mesenteric and anti-mesenteric border, ending up with 2 tubes of bowel of identical length each with their own blood supply, which are then joined together (52). STEP is a newer and less complex technique that involves serial transverse application of a stapler, from opposite directions to create a zig-zag channel (53); unlike LILT, no anastomosis is needed, and the mesenteric blood supply is not put at risk. If the bowel re-dilates, a further STEP procedure can be undertaken. Unfortunately there are no surgical techniques that can reliably increase small bowel surface area, and by so doing rapidly achieve more than the background process of gut adaptation. Plasma citrulline is a marker of small bowel enterocyte mass (56,57). It increases significantly within the first weeks following the STEP procedure (58), suggesting that, by reducing SIBO, it restores small intestinal mucosa integrity and improves villous size. Surgical bowel-lengthening should be considered in any chronically PN-dependent patient when there is substantial bowel dilatation and symptoms of SIBO, regardless of the remaining bowel length. Hormonal Therapy The role of recombinant human growth hormone (rhGH) alone or in combination with glutamine has been investigated by ESPGHAN members in PN-dependent children with SBS (59,60). Despite some decrease in PN requirements during treatment these trials showed little benefit on body composition and mucosal absorption in the long term. Glucagon-like peptide 2 (GLP-2) is produced by the L-cells of the terminal ileum in response to luminal nutrients and has a trophic effect on the intestine, promoting absorption and adaptation (61). Clinical trials suggest it has the potential to decrease PN dependency in patients with SBS when given as a daily subcutaneous injection. A 12-week, open-label study, involving the Great Ormond Street Hospital in London, enrolled SBS PN-dependent patients aged 1–17 years (62). It has been concluded that Teduglutide (GLP-2 analogue) was well tolerated at 0.025 or 0.05 mg/kg per day and was associated with trends toward reductions in PN requirements and advancements in enteral feeding. However, study limitations included its short-term, open-label design, small sample size and heterogeneity of both patients and management because of the multicentre study. Monocenter trials are required for addressing recommendations and extend the use of GLP-2 analogue (eg, Teduglutide Revestive) at a dose of 0.05 mg/kg per day. The research group of Shamir has shown oral insulin to be beneficial in animal models (63), and some preliminary observational trials have shown beneficial effects in children with SBS (64). It might be interesting to use other trophic factors such as EGF, insulin-like growth factor-1 (IGF-1) or GLP-1 in SBS-IF. CURRENT PERSPECTIVES Tremendous progresses have been achieved during the last half a century, changing the face of SBS-IF. Significant contributions have been provided by both sides of the Atlantic Ocean, even if clinical practices often differ (8,24,26,32,65,66). SBS-IF moved from a high mortality condition to a model of intestinal physiology and PN efficiency promoting new concepts and paradigms for the daily clinical practice, lending special importance on preserving oral skills and improving the quality of life. Nevertheless, some patients still remain at risk of developing irreversible IFALD due to extremely short bowel or type 1 SBS, mostly caused by very long segment Hirschsprung disease. In spite of availability and safety of home-PN improving their quality of life, those patients are candidates for hormonal treatment that is already available, intestinal transplantation that showed limits or tissue engineering that might be one hope for the future. As management strategies of these patients are aimed at preventing the need for small bowel transplantation by avoiding the life-threatening complications of PN, effective interventions to reduce the incidence of NEC and congenital bowel defects will be needed to reduce the numbers of patients with SBS. Progress may come from further understanding of molecular and genetic influences on congenital gastrointestinal anomalies, recently reviewed (67). Gene regulatory factor X6 (RFX6) is possibly linked with intestinal atresias, while gastroschisis may be due to improper closure of a body fold impeding the merging of the yolk sac stalk with the connecting stalk, resulting in the intestine rather than the umbilical cord herniating into the amniotic cavity with the vitelline duct. Polymorphisms in genes for intracellular adhesion molecule 1 (ICAM1), endothelial nitric oxide synthetase 3 (NOS3), atrial natriuretic peptide (NPPA) and alpha-adducin (ADDI) may be involved. The risk of gastroschisis appears higher in children with ICAM1 and NOS3 single-nucleotide polymorphisms with mothers who smoked in pregnancy. It has been hypothesised that tobacco impairs VEGF-NOS3 and ICAM1 signalling leading to defective angiogenesis and vascular remodelling.