Table of Contents  

Goulet and Abboud: Short bowel syndrome

Introduction

Intestinal failure (IF) is caused by the critical reduction of functional intestinal mass below the minimal amount necessary for adequate functioning of digestion and absorption in order to cover body nutrient and fluid requirements for maintenance in adults and growth in children.1 Causes of IF are divided into three main categories: (1) short bowel syndrome (SBS), (2) neuromuscular disorders affecting the gut motility (Hirschsprung’s disease and chronic intestinal pseudo-obstruction) and (3) mucosal diseases (microvillus inclusion disease and tufting enteropathy).2

Definition and causes of short bowel syndrome

Short bowel syndrome is the leading cause of IF. It is characterized by a state of malabsorption resulting from a massive reduction of the absorptive surface following extensive small bowel resection. SBS requires parenteral nutrition (PN), which allows the child to grow while the remaining small intestine adapts.3

Causes of SBS (Table 1) can be congenital, due to intestinal atresia, which can involve any portion of the small intestine and colon, and can be isolated or multiple. Another congenital form is gastroschisis, in which SBS is caused by abnormal intestinal development and resection of the ischaemic parts of the intestine. Hirschsprung’s disease can lead to SBS when the aganglionosis extends to a large part of the small intestine. Among the acquired forms, necrotizing enterocolitis is the most frequent cause, with resections most frequently involving the ileum as well as the proximal colon. Midgut volvulus may manifest early in life as a result of malrotation with congenital bands, as well as later in life primarily as a result of tumours. Later SBS may be due to trauma or vascular abnormalities. Inflammatory bowel disease should no longer be thought of as a cause of SBS.

TABLE 1

Aetiology of SBS

Prenatal Neonatal Postnatal
Atresia (unique or multiple) Midgut volvulus (midgut or segmental) Midgut volvulus (malrotation, bands or tumour)
Apple peel syndrome Necrotizing enterocolitis Complicated intussusception
Midgut volvulus (malrotation) Arterial thrombosis Arterial thrombosis
Segmental volvulus (with omphalomesenteric duct or intra-abdominal bands) Venous thrombosis Inflammatory bowel disease
Abdominal wall defects Post-trauma resection
Gastroschisis Extensive angioma
Extensive Hirschsprung’s disease

Incidence and mortality

The incidence of neonatal SBS and mortality is difficult to determine accurately because of the rarity of the condition, variation in the definition of SBS between institutions, and the difficulty experienced by tertiary care referral centres in accurately determining the population and of achieving complete follow-up of a cohort. The Canadian Collaborative Study Group, using administrative health care data, in 2004 estimated the incidence of neonatal SBS to be 24.5 per 100,000 live births, although the incidence was much higher in infants born before 37 weeks’ gestation than in term-born newborns (353.7/100,000 live births vs. 3.5/100,000 live births).4 The overall mortality rate of a neonate with SBS was found to 37.5%, with 60% attributed to intestinal failure-associated liver disease. The Intestinal Failure Consortium in the USA reported5 on 272 infants followed for 25.7 months (range 11.2–40.9 months). The cohort experienced 8.9 new catheter-related bloodstream infections per 1000 catheter-days. The cumulative incidence of enteral autonomy, death and intestinal transplantation was 47%, 27% and 26%, respectively. Recent data from our home-PN cohort of 156 SBS infants and children show a survival rate > 98% (unpublished data).

Anatomical variants of short bowel syndrome

Anatomically, three forms of SBS have been described, characterized by the length of post-duodenal residual small intestine, and eventual anastomosis with the colon (Figure 1): type 1, enterostomy; type 2, jejunocolic anastomosis; and type 3, jejuno-ileal anastomosis (the most favourable form) with a preserved ileum, ileocaecal valve (ICV) and the entire colon.7

FIGURE 1

Anatomical variants of SBS. Adapted from Nuzzo et al., 2014.6

HMJ-705-fig1.jpg

This classification is based on the ability of the small intestine to adapt; the length of the remaining small intestine is important to provide an intestinal adaptation sufficient to wean the patient off PN. It is not only the length of the remaining bowel that is important for achieving PN weaning, but also the part of the bowel involved in resection. Although the ileum has a greater adaptive capacity than the jejunum, massive ileal resection has a significantly worse impact than jejunal resection as the ileum plays an important role in electrolyte and water absorption, as well as absorption of vitamin B12 and bile salts.8 The presence of the colon is another important factor, because of its bacterial content, which plays a crucial role in the ‘final’ digestion of unabsorbed nutrients and nutrition by providing trophic factors, mainly short-chain fatty acids (SCFAs) (e.g. butyrate), for the colon as well as the remaining small bowel.7

In addition to this classification, the age of the child is a determining factor in the adaptation process. In fact, at birth the small bowel length is 250 cm (standard deviation 40 cm), and the increase in length is maximal during the first year of life. This explains the more favourable outcome in neonates than in children. Moreover, the length of the small bowel doubles during the last trimester of gestation, which means that, for the same remnant of small intestine length, the prognosis differs between a premature and full-term neonate.3

Intestinal adaptation after resection

Bowel adaptation is a physcological remodelling process involving luminal and humoral factors. It aims to improve the absorptive surface and capacity of the remnant bowel. Increase in the intestinal mass and surface area occurs through enterocyte and crypt cell proliferation, with taller villi and deeper crypts which defines intestinal mucosa hyperplasia, and intestinal hypertrophy of the smooth muscle layers (Figure 2). These adaptive processes ultimately lead to dilatation and elongation of the small intestine, with resorptive performance increasing up to full enteral adaptation. These processes are influenced by various factors (Figure 3), such as gastrointestinal growth factors (EGF, IGF-1, GLP-2) and cytokines, in addition to tissue factors including immunity, blood flow, neural influences and gut.3

FIGURE 2

Adaption of the remnant intestine.

HMJ-705-fig2.jpg
FIGURE 3

Factors of remnant intestine adaption. CCK, cholecystokinin.9

HMJ-705-fig3.jpg

In the colon, when present, the remaining electrolytes are absorbed from the digestive lumen. The microbiota of the colon also plays a major role, metabolizing fibre and other non-digested substrates, such as carbohydrate, to SCFAs (mainly acetate, propionate and butyrate). Butyrate represents not only source fuel for the colonic epithelial cells, but is also a factor stimulating the release of GLP-2 from L-cells in the terminal ileum and cecum. Studies have shown that butyrate is the most important SCFA responsible for the adaptation of the colon, by promoting hypertrophy of the colonocytes and reducing apoptosis.7 This explains why patients with SBS in whom the colon is preserved experience less faecal energy loss than those who do not have a colon. SCFAs have not only local effects on the colon, but also a trophic effect on enterocytes;7 in fact, whenever there is an enterostomy with a remaining colon, it is very important to establish intestinal continuity as soon as possible to promote water–electrolyte reabsorption and energy salvage, and therefore to achieve earlier weaning off PN.

Depending on the severity of IF, full enteral autonomy might be achieved only very slowly, if at all, especially in patients with short remnant small intestine with no ICV and no colon.

Predictor of outcome in short bowel syndrome

The goal of the management of SBS-related IF is to enable enteral autonomy and wean the patient off PN by means of a multidisciplinary approach, while preserving growth in children. Many studies are currently investigating how to reliably predict if and when a child can be successfully weaned off PN (see Figure 4).

Management of SBS aims to preserve the physiological process of SB adaptation and child growth by combining long-term PN and home PN and oral feeding by using semi-elemental diets (protein hydrolysates) containing small peptides and medium-chain triglycerides that are easily absorbed.8

One predictor widely used is the remnant bowel length, whether or not the ICV and the colon are present. However, the precise determination of small bowel length is difficult. Bowel inflammation (i.e. necrotizing enterocolitis) or extensive adhesion (i.e. gastroschisis) may explain such a difficult measurement. Moreover, during early life the small intestinal length is physiologically increasing. As a matter of fact, increased surface area resulting from post-intestinal resection adaptation would not be reflected in the static measure of length obtained during a single operation. Finally, both technical difficulties of precise measurements and physiological bowel lengthening, potentially limit the use of length measured at the time of surgery as a completely reliable biomarker.10 However, actuarial analysis of PN dependency shows the difference according to the type of SBS and the length of remnant small intestine (see Figure 4).

FIGURE 4

Duration of PN dependency according to anatomical variants of SBS (data from 156 patients) from the Paris-Necker Intestinal Rehabilitation Center. SBL, small bowel length.

HMJ-705-fig4.jpg

Plasma citrulline levels, reflecting functional intestinal cells, may be used as predictor of bowel capacity. Citrulline is a free circulating amino acid found in human plasma. Almost all of the plasma citrulline is produced by the metabolism of glutamine and proline in small bowel enterocytes. Plasma citrulline has been correlated with small bowel enterocyte mass and small bowel absorptive capacity. The value of this assessment is debated, as plasma levels may contrast with the clinical situation suggesting poor feeding tolerance. Such a biomarker should be associated with other criteria such as intestinal absorption rate (steatorrhea, total energy losses) and the growth of the child for adapting PN intake. Plasma citrulline levels are clearly not sufficient for distinguishing patients with likely long-term PN or in need of intestinal transplantation.11

A third predictor is the estimation of the absorptive capacities of the remaining small bowel by calculating faecal energy losses. A faecal calorimetry is compared with calories consumed in food, indirectly reflecting the percentage of calories absorbed by the intestine.12

Special therapies for short bowel syndrome

For patients who cannot be weaned off PN after several months or years of dependency, some medical therapies for the treatment of IF have recently emerged: recombinant human growth hormone (rhGH) and glucagon-like peptide 2 (GLP-2). A number of open trials in paediatric patients have shown that these are effective as long as treatment continues, but not once the drugs have been discontinued;13,14 there are no data on the long-term use of rhGH. rhGH is not intestine specific and probably exerts its intestinal trophic effects via insulin-like growth factor 1, thus increasing the incidence of type 2 diabetes, and perhaps has effect on tumorigenesis.

The endogenous peptide GLP-2 is secreted by intestinal cells at the level of the terminal ileum, enhancing nutrient absorption and increasing mucosal surface area, but has a short half-life because it is degraded by the enzyme dipeptidyl peptidase IV. Teduglutide is a human recombinant GLP-2 analogue in which a single amino acid substitution extends its half-life, allowing daily subcutaneous dosing; several studies have shown promising results with teduglutide therapy in adults with SBS.15 Currently, teduglutide is approved for the short-term treatment of SBS in adults and it will be soon available for infants and children.

Surgery also plays an important role in the treatment of IF, especially when impaired intestinal motility together with aggressive tube feeding leads to excessive dilatation of the remnant bowel. This can cause stasis, which promotes small intestinal bacterial overgrowth (SIBO). SIBO contributes to malabsorption, bacterial translocation with systemic infection and, ultimately, intestinal failure-associated liver disease (Figure 5; see also ‘Patient-related factors for cholestatic liver disease’).3 Surgical treatment involves intestinal lengthening using one of two main techniques. Bianchi’s longitudinal intestinal lengthening and tailoring (LILT) consists in dividing the dilated bowel into two separate pieces, following which the two bowel loops are joined to create an anastomosis, while serial transverse enteroplasty (STEP) consists in serial transverse application of a linear stapler on alternate sides, creating a ‘zigzag’, longer, but narrower, intestinal channel (Figure 6).16

FIGURE 5

Harmful consequences of aggressive tube feeding in SBS with intestinal mobility.

HMJ-705-fig5.jpg

It is difficult to compare LILT and STEP because no randomized trials are available and SBS patients are very heterogeneous. The time to wean off PN after such lengthening procedures are more or less similar with both techniques. STEP may achieve more rapid weaning by sometimes increasing the bowel length to > 100% of the original length, while Bianchi LILT results in only doubling of the original length.17

If other treatments fail, the final option for reversing IF is intestinal transplantation. This is necessary when caloric intake is less that half of the estimated requirements, accompanied by growth failure, loss of central venous access, worsening liver function or recurrent sepsis.3,18

Patient-related factors for cholestatic liver disease

  • Prematurity and low birthweight.

  • Causes of intestinal resection impairing intestinal motility:

    • intestinal atresia;

    • gastroschisis;

    • necrotizing enterocolitis.

  • Lack of enteral feeding.

    • Total PN.

  • Dysruption of enterohepatic biliary acid cycle.

    • Proximal stoma, ileal resection.

  • Intestinal stasis and bacterial overgrowth

    • Obstruction, dysmotility, lack of ileocaecal valve, aggressive tube feeding.

Conclusion

In conclusion, adaptation after intestinal resection is a physiological process that should be promoted by maintaining optimal nutritional status from PN and develop bowel function by the early use of oral feeding. The colon and its microbiota are key players in gut physiology. Absence of the colon (SBS type 1) makes intestinal autonomy unlikely unless the length of the remnant small bowel is sufficient (> 100 cm). Management of SBS should be adapted to each case according to anatomical variants, feeding tolerance, growth and any complication related to intestinal failure or parental nutrition. IF/PN complications may be prevented by appropriate management and the use of ‘modern’ PN practices, including the use of fish oil-based lipid emulsion.19,20 Home PN is the cornerstone of management,21,22 and early referral to a specialized centre is mandatory in order to avoid critical situations with recurrent sepsis, lack of venous accesses and end-stage liver disease.23,24

FIGURE 6

Non-transplant surgery for SBS.

HMJ-705-fig6.jpg

References

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