Short Bowel Syndrome

Abstract

Purpose of Review:

Short gut syndrome is life-altering and life-threatening disease resulting most often from massive small bowel resection. Recent advances in understanding of the perturbed physiology in these patients have translated into improved care and outcomes. This paper seeks to review the advances of care in SBS patients.

Recent Findings:

Anatomic considerations still predominate the early care of SBS patients, including aggressive preservation of bowel and documentation of remnant bowel length and quality. Intestinal adaptation is the process by which remnant bowel changes to fit the physiologic needs of the patient. Grossly, the bowel dilates and elongates to increase intestinal weight and protein content. Architectural changes are noted, such as villus lengthening and deepening of crypts. In addition, gene expression changes occur that function to maximize nutrient uptake and fluid preservation. Management is aimed at understanding these physiologic changes and augmenting them whenever possible in an effort to gain enteral autonomy. Complication mitigation is key, including avoidance of catheter complications, bloodstream infections, cholestasis, and nutrient deficiencies.

Summary:

Multidisciplinary teams working together towards intestinal rehabilitation have shown improved outcomes. Today’s practioner needs a current understanding of the ever-evolving care of these patients in order to promote enteral autonomy, recognize complications, and counsel patients and families appropriately.

Introduction

Short bowel syndrome (SBS) and resultant intestinal failure is a clinically-diagnosed disorder of macronutrient and micronutrient absorption [1]. Though this syndrome most often results from significant small bowel resection, the clinical manifestations and severity are only loosely based on remaining bowel length. SBS can result in life-altering and life-threating sequelae due to an inability to maintain protein, fluid, electrolyte or micronutrient needs via enteral nutrition. This can result in multiple complications, including failure to thrive, sepsis, and death. Significant research has improved our understanding of the pathophysiology and has resulted in improved patient outcomes.

Etiology of SBS

The most common causes of pediatric SBS are intestinal atresias, necrotizing enterocolitis, gastroschisis, volvulus, long segment Hirschsprung disease, and inflammatory bowel disease [2]. Rarer disorders of intestinal failure in patients with normal intestinal length include intestinal motility disorders such as chronic pseudo-obstruction and disorders of intestinal epithelial cells.

Anatomic Considerations

Initial prognostic criteria of the severity of SBS after small bowel resection are related to: (a) remnant bowel length, (b) loss of ileum and/or ileocecal valve, (c) loss of colon, and (d) intestinal continuity.

Because remnant bowel length is an important predictive factor, it is important to document this in operative reports. In addition, the quality of remaining bowel should be noted – for instance, segments of bowel that may be strictured or abnormally dilated. In general, infants with a small bowel length less than 75 cm are at risk of developing SBS [3]. For reference, term infants are estimated to have ~150–250 cm of small bowel length [3, 4]. Bowel length doubles in the third trimester, an important consideration when understanding the sequelae of bowel resections in premature infants.

The ileum is the most adaptable part of the small bowel and thus preservation of the ileum versus the jejunum is less like to yield negative impact of resection [5]. The ileum is able to better adapt by increase villus surface area (including villus height and crypt depth) and increasing its length, diameter and motor function, effectively increasing its ability to absorb nutrients [6, 7]. The ileum is also specialized in its vitamin B12 absorption, bice acid absorption, and fluid absorption as compared to the jejunum [8]. Further the ileal epithelium has recently been demonstrated to differentiate into more proximal jejunal epithelium after massive bowel resection [9].

Preservation of the ileocecal valve (ICV) in short gut syndrome is associated with improved outcomes in small series, though the data is not as strong in adults as in children [10]. Goulet et al. evaluated children needing parenteral nutrition (PN) and revealed a longer duration of PN and lower likelihood of weaning from PN in those patients who had their ICV resected [11, 12]. The ICV slows passage of small bowel contents, both fluid and nutrients, into the colon, thus increasing small bowel transit time. Additionally, the ICV prevents reflux of colonic contents into the small bowel and may help to limit small bowel intestinal overgrowth (SIBO) [13, 14]. SIBO can exacerbate fat malabsorption and diarrhea because of reduced bile acid and B12 absorption.

When compared to the small bowel, the colon has the slowest transit time and is most efficient at retaining sodium and water. Thus patients who undergo massive small bowel resection and do not have a colon – for instance, those with an end jejunostomy – lose significant volume for their gastrointestinal tract and are at high risk for dehydration. The colon can also absorb nutrients via fermented carbohydrates. Thus some SBS patients with a colon can be placed on a high-carbohydrate diet and absorb up to 50% of their energy requirements via their colon [15, 16]. Despite this, studies in infants and children have failed to show a consistent benefit to colon retention in predicting enteral autonomy [17, 18].

Intestinal continuity is important so that all potential absorptive and digestive mucosa is exposed to luminal nutrient. Therefore, closing stomas earlier than later can help facilitate weaning from the need for parenteral nutrition.

Intestinal Adaptation

Following intestinal resection, there are physiologic changes by the remaining bowel, both on the macroscopic and microscopic levels, in order to increase absorptive capacity and retain some of the lost function from the resected bowel. In children, the process begins shortly after surgery and can continue for years after resection. Epithelial hyperplasia can be observed within one day of bowel resection, including lengthening of remaining villi [19].

On a gross level, the remnant bowel will dilate and elongate, resulting in increased intestinal weight and protein content. Villus lengthening and microvilli proliferation is well-documented. Total enterocyte number is increased [20]. Hypertrophy of the muscle layers leads to an increase in bowel wall thickness. The ileum demonstrates more adaptive capacity than the jejunum. Further, adaptive changes in the jejunum are functional rather than structural – mostly related to transporter activity and enzyme activity [21].

On a microscopic level, brush border membrane activity is upregulated. Changes can occur with fluidity and permeability and regulation of trans-membrane transporters [5, 22]. Intestinal angiogenesis leads to new blood vessel growth to the bowel [23]. Changes in gene expression lead to an increased expression of intestinal growth factors [24, 25, 26].

Enteral nutrition is the best stimulant of intestinal adaptation, stimulating changes that are not seen exclusively with parenteral nutrition [27, 28]. Enteral nutrients, specifically fat, stimulate intestinal adaptation via trophic gastrointestinal hormones, the most widely studied of which is glucagon-like peptide 2 (GLP-2). This intestinal growth factor is produced by L cells in the ileum and colon [29]. This has led to the production of teduglutide, a long-acting GLP-2 analogue that is given to adults with PN-dependent short bowel syndrome and has shown benefit in reducing PN needs [30, 31]. Other growth factors that have been studied extensively, in addition to GLP-2, include growth hormone, insulin-like growth factor 1, epidermal growth factor, glucocorticosteroids, thyroid hormone, and leptin [32].

Microbiome and Bacterial Overgrowth

Patients with SBS have significant alterations in the gut microbial community [33]. Investigations into the fecal microbiome of SBS patients show that diversity is reduced and the relative abundance of Proteobacteria, especially Enterobacteriaceae, is significantly increased [34, 35]. Increased Proteobacteria has recently been associated with shorter bowel length and decreased linear growth in pediatric SBS patients [36]. Lactobacillus species are also increased. These microbiome changes are more pronounced in patients who are dependent on PN [37].

Small-intestinal bacterial overgrowth (SIBO) is a common complication in SBS associated with significant morbidity [38, 39]. In patients without SBS, the proximal small bowel has relatively less bacterial colonization, mostly with aerobes [13]. SBS patients can have overgrowth in areas of dilated bowel and a relative increase of the anaerobic bacterial population, leading to SIBO, which clinically manifests by decrease nutrient absorption. This occurs by bacterial deconjugation of bile acids, damage to the mucosa surface via inflammation, and direct competition of vitamin B12. SBS patients are also prone to D-lactic acidosis from gram-positive anaerobic overgrowth, mostly Lactobacilli, which can lead to neurologic sequelae [40]. Treatment of this unusual lactic acidosis involves antibiotics, carbohydrate restriction, and correction of acidosis [41].

Complications of SBS

One of the keys to management of SBS is multidisciplinary treatment to avoid, if possible, and treat complications. Multidisciplinary teams include pediatricians, gastroenterologists, surgeons, neonatologists, dieticians, licensed independent providers, nurses, pharmacists, speech therapists, and social workers. Multiple studies have shown the benefits of these teams working as part of intestinal rehabilitation programs to reduce morbidity and mortality [42, 43].

Acute complications of short bowel syndrome include diarrhea, dehydration, electrolyte issues, obstruction, and catheter associated complications – including malfunction and blood stream infection. Acute postoperative diarrhea is often a function of the extent of resection. Thus to prevent this complication, and SBS, preservation of bowel length is a priority for all surgeons.

Central venous catheters (CVC) become a lifeline for patients who are PN-dependent. Extreme care in catheter maintenance in required to prevent complications such as catheter breakage, occlusion, or infection. When serial catheter complications lead to loss of reliable central venous access, intestinal transplantation may need to be considered.

SBS patients can be at risk for CVC-related bloodstream infections from their altered flora. Bacterial translocation from altered gut epithelial barriers can increase risk for CVC infection [44]. Davidovics et al. have even concluded that the altered microbiome of SBS patients is itself a risk factor for bacterial translocation [34]. The highest risk for CVC-related infection occurs during the first month of home PN and in children younger than one year of age [45]. Training parents in basic catheter care is crucial: the line should not be submerged in water, protective covers should be used when bathing. When signs of infection are present, immediate evaluation is warranted, usually requiring blood cultures, intravenous antibiotics, and inpatient admission [46]. Efforts are made to preserve the catheter in order to preserve central access sites.

The widespread use of ethanol lock has lessened the burden of CVC-related infections in children [47]. This involves instilling 70% ethanol in the catheter when it is not being used for PN. This therapy is usually initiated after the first CVC-related bloodstream infection; its frequency can be increased during an active infection. Caution should be utilized as some studies have noted increased occlusive and thrombotic events with the use of ethanol locks [48].

Similarly, standardized protocols can be used to decrease mechanical complications. Occlusion can be treated by thrombolytic agents. Physical damage to CVCs should be minimized through educational efforts aimed at parents and caregivers, including avoidance of clamping and use of sharp objects near the catheter. If damaged, repair kits can be attempted to salvage the catheter. If CVC replacement is required, guide wires can be used to maintain the same anatomic location in order to preserve other central access sites.

Intestinal failure-associated liver disease (IFALD) is one of the most dreaded complication of chronic PN dependence. Liver disease is progressive and can lead to cirrhosis, jaundice, and liver failure necessitating liver and small bowel transplantation. The pathogenesis of this disease is not well understood but likely involves proinflammatory cytokines such as toll-like receptor 4 in hepatic inflammation and farnesoid X receptor in bile acid synthesis [49]. The most severe disease is generally encountered in the neonatal population, especially in those patients with necrotizing enterocolitis [50]. Several best practices have emerged to avoid and minimize the effects of IFALD. Enteral nutrition should be aggressively maximized. Avoidance of sepsis is also important. Cycling of PN and lipids can help to minimize liver injury. Lipid emulsions with lower ratios of omega-6 to omega-3 fatty acids (fish – derived oil versus animal and plant oils) decrease inflammation and improve bile flow [49]. Lipid-reduction strategies have been beneficial in treatment of IFALD as well as preventing the onset of IFALD [51, 52]. Alternative sources of intravenous lipid emulsions, including fish oil-based products, have also served to decrease IFALD [53, 54]. Recent studies of SBS in which PN is not provided has revealed liver injury [55]. This would suggest that intestinal resection alone is a major contributor to the pathogenesis of IFALD

SBS patients also suffer from an increased incidence of gallstone disease, likely due to bile stasis and alterations in bile composition [56]. Oral ursodeoxycholic acid may be used to minimize gallstone formation, although the data for this practice is weak. Some authors advocate for prophylactic cholecystectomy in SBS patients to avoid the sequelae of gallstone disease [57]. Because of gastric hypersecretion early after small bowel resection, the use of acid suppressing medication – either histamine receptor antagonists or proton pump inhibitors – are recommended for the first few months after surgery [10]. However, in the absence of ongoing peptic disease, these medicines should be weaned after a period of a few months after resection. Gastric hypersecretion will self-resolve and chronic treatment with acid suppression medication leads to adverse microbiome and metabolic bone health as well as decreased vitamin B12 absorption [58].

SBS places children at great risk for nutrient deficiencies. Transition to full enteral nutrition without PN supplementation can further exacerbate this risk. The most common deficiencies are fat soluble vitamins – A, D, E, and K, as well as zinc and iron [59, 60]. Other complications include hyperoxaluria, eosinophilia within the GI tract, GI bleeding, oral aversion, adhesive bowel disease, and financial hardship to the family.

Management

Management for SBS is aimed at mitigating the following issues: fluid and electrolyte loss, inadequate protein/carbohydrate/fat absorption, inadequate vitamin and mineral absorption, and poor weight gain. Early management in the first few months after resection is aimed at maintaining volume status, preventing electrolyte abnormalities, and maintenance of nutrition status via PN [61]. PN in the early phase delivers the vast majority of the patient’s energy, as the remaining bowel is recovering from surgery and has not yet undergone complete intestinal adaptation [62]. Modern regimens seek to prevent IFALD through various lipid manipulations discussed above early in the PN course.

Fluid balance is precarious early after resection, given GI loss and lack of adaptation. Stomal losses of fluids and electrolytes should be measured and replaced. Electrolytes such as sodium, potassium, chloride, and magnesium must be monitored and repleted vigorously. As discussed earlier, acid suppression in the early months is key to combat the acid hypersecretion following resection. Lack of suppression leads to reduced pH, leading to difficulty in fat absorption.

Growth failure is common amongst children with SBS, especially infants. Though resting energy expenditure is the same in infants with SBS as other infants, malabsorption necessitates a 30–70% increase in calorie intake to maintain growth [63, 64].

Enteral nutrition is crucial to management of SBS. Early enteral feeding, even trophic feeds, promotes intestinal adaptation and can decrease PN needs [65]. Oral feeding can help to prevent feeding aversion. Feeds can and should be initiated as soon as the patient is stabilized from bowel resection, often days after surgery. Advancement should be persistent and as rapidly tolerated by the patient. In infants, breast milk should be used whenever possible. In addition to the known immunologic benefits, breast milks bolsters the mucosal barrier and its trophic factors aid in intestinal adaptation [66, 67]). Breast milk may also lead to decreased rates of IFALD via an as yet undiscovered mechanism [68]. Stool output must be monitored to prevent dumping. Surgical enteral access may be beneficial in these patients as continuous feeds are often better tolerated, especially in the months after resection. Conversion to bolus feeding typically occurs after >50% of energy requirements are achieved enterally and may have some physiologic benefit [69].

Pharmacologic therapy can be used as an adjunct to enteral feeding. Supplementation of vitamins and minerals are crucial, especially fat soluble vitamins and vitamin B12. Bile acid sequestrants can be beneficial in patients with bile acid diarrhea, most commonly seen in patients who have had their terminal ileum resected [70]. Other agents may be used to control diarrhea, including loperamide, octreotide, and clonidine. Discussed earlier, teduglutide is a GLP-2 analogue approved for adults with SBS that may facilitate greater intestinal adaptation responses.

Multiple surgical procedures have been described in order to surgically lengthen the bowel in order to increase bowel surface area [71]. The Bianchi procedure, also known as the longitudinal lengthening and tailoring (LILT) procedure was the first published procedure. In this procedure, bowel is lengthened based on the leaflets of the mesentery. It requires multiple anastomoses and is difficult to perform if the bowel caliber is variable [72]. The STEP procedure, serial transverse enteroplasty procedure, is a surgery in which the bowel is tapered with staples in order to increase length and improve absorptive capacity [73]. It may be beneficial in decreasing D-lactic acidosis by preventing stasis [74]. Data regarding optimal timing for surgical intervention is lacking. Early intervention may prevent the adaptation and lengthening that is occurring physiologically. Late intervention may expose the patient to unnecessary PN-related complications [75]. Despite this variety, small series do support the use of bowel lengthening procedures in SBS [76, 77].

As management of SBS has improved, the number of patients needing small bowel and/or multivisceral transplants has significantly decreased [78]. Patients needing referral to a transplant center include those with severe IFALD, those patients who few or no venous access options, or patients with recurrent CVC infections.

Frontiers in SBS

The past few decades have seen significant basic science and clinical work that has improved the care of SBS patients. In 1999, Messing et al. published that in patients with <100 cm of intestinal length, 45% would require lifelong PN with a five-year mortality of approximately 25% [79]. That same year, Bianchi published that the long term survival of patients requiring intestinal lengthening procedures, a heterogeneous population but nevertheless a good indicator, was 45% [80]. In the 1990s, the overall five-year survival of patients requiring intestinal transplantation was ~50% at five years [81, 82, 83].

There is now greater understanding of the pathophysiology behind short gut syndrome, the complications thereof, and the basic science behind intestinal adaptation. This, in combination with advent and proliferation of quality intestinal rehabilitation centers, has led to improved outcomes for SBS patients. In 2013, Stanger et al. published an increase in patient survival from 22% to 42% when compared with historical controls [43]. Fullerton et al. published a five-year survival of nearly 90% in 2016 [84]. Similar advances have been described patients with ultrashort small bowel syndrome, described as <10 cm of small bowel [85]. Even those patients who undergo intestinal or multivisceral transplantation now have improved outcomes, though long term outcomes are still disappointing [86].

Despite these substantial gains in patient outcomes, there remain predictors of poor outcomes that can be considered while counseling patients towards less aggressive interventions or redirection to comfort measures. In a 2018 survey of pediatric surgeons and neonatologists, 73% of providers recommended comfort measures only for a premature infant with midgut volvulus regardless of remaining bowel length; 54% recommended comfort measures in the same clinical scenario with a full-term infant [87]. In the current era with improved survival, there is a clear need to educate frontline practitioners of modern-day outcomes in order to change counseling practices and aggressively treat SBS patients.

Research efforts have allowed us to parse out differences in intestinal adaptation between the duodenum, the jejunum, and the ileum, further stratifying our understanding of adaptation on the molecular level [88]. There is growing interest in circadian rhythmicity of gene regulation of intestinal transporters [89]. Research into tissue engineering yields promise not only for potential sources of bowel for implantation but is also aiding in understanding of intestinal adaptation and the molecular signaling involved in this process [90].

Conclusions

Short bowel syndrome was once a condition that was uniformly fatal. Our understanding of intestinal adaptation and the complications of SBS has led to improved care for these patients. Nevertheless complications persist and result in severe morbidity and mortality. Recent advancements in care, both bench research and clinical measures, have yielded improved outcomes. We must continue on this trajectory in order to ameliorate the sequelae of short bowel syndrome.