Short Bowel Syndrome
Richard A. Falcone Jr.
Brad W. Warner
Division of Pediatric and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
University of Cincinnati College of Medicine, Department of Pediatric Surgery, Cincinnati Children’s Hospi- tal Medical Center, Cincinnati, Ohio 45229.
Short bowel syndrome (SBS) is a term that is loosely used to define the pathophysiologic disorders that result from the removal of a large portion of the small intestine. Although this problem most commonly results from an anatomic loss or deficiency of intestinal surface area; it may also occur in the context of normal intestinal mucosal surface area due to perturbed intestinal absorption, motility, or both. The clinical syndrome leads to malnutrition, weight loss, steatorrhea, and diarrhea as a consequence of the inability of the gastrointestinal tract to absorb nutrients.
The introduction of total parenteral nutrition (TPN) (1) has resulted in a remarkable improvement in survival for patients with SBS. Unfortunately, the most common cause of death associated with SBS is TPN-induced hepatic dysfunction. However, the survival for patients with less than or equal to 40 cm of residual small bowel is routine, and long-term survival of infants with as little as 20 to 30 cm of small bowel can be expected. More recently, an infant was reported who survived off TPN with only 11 cm of small bowel and without an ileocecal valve (2). Fortunately, the dismal outcomes reported by Haymond in 1935, including a 33% operative mortality and 20% 1-year survivals, are of historic interest only. More recent estimates suggest that at least 70% of patients with SBS leave the hospital and nearly all are alive at the end of 1 year (3). The goals of management in these patients are to reduce the duration of TPN use and to intervene to maximize intestinal nutrient absorption. Multiple nutritional, hormonal, and surgical therapies have evolved to manage patients with SBS in an attempt to improve quality of life and decrease the duration of TPN dependence.
ETIOLOGY
The specific causes of SBS in the pediatric population have changed over time. Previously, the most common causes were midgut volvulus and intestinal atresia; however, in more contemporary reports, the most common cause of SBS is neonatal necrotizing enterocolitis (NEC) (4,5,6,7,8). Other causes of SBS in children include loss of bowel from mesenteric vascular occlusion, such as may occur from invasive aortic monitoring devices, neonatal aortic thrombosis, or cardiogenic emboli. Reduced perfusion states secondary to cardiogenic, hypovolemic, or septic shock, as well as the use of vasoconstrictive inotropic agents, may result in ischemic or necrotic bowel. Meconium ileus or plugging may promote the development of a volvulus with necrosis. Volvulus with intestinal necrosis may follow adhesive bowel obstruction associated with prior abdominal surgery or an intraabdominal inflammatory process.
Functional disorders in which the anatomic bowel length is normal, but motility and absorption capacity are impaired, include long-segment aganglionosis and the syndrome of idiopathic intestinal pseudoobstruction. Gastroschisis can be associated with SBS due to a combination of foreshortening of intestinal length, as well as dysfunctional peristalsis of the thickened bowel loops. Crohn’s disease may be associated with SBS because of multiple, extensive resections, bypassed absorptive mucosa due to fistulae, or impaired mucosal absorptive capacity.
Clinical Course
The normal small intestine length for a full-term infant is approximately 200 to 250 cm. In the fetus, the overall rate of growth of the gastrointestinal tract increases with age. The period of most rapid growth occurs during the third trimester. In fact, the small bowel can be expected to double in length between the second and third trimester. The rate of small intestinal lengthening due to growth alone
is rapid during infancy with continued elongation until crown-heel length (CHL) reaches about 60 cm. Slower intestinal growth then occurs between a CHL of 60 to 100 cm, and there is little change above 100 to 140 cm (9). Therefore, after massive enterectomy, consideration should be given to the expected rate of bowel lengthening due to growth alone. Further, prognosis should be based not on absolute intestinal length, but on the percentage of normal for a given gestational age following resection. Survival and complete return of gastrointestinal function may be predicted when the postresection length of intestine exceeds 5% of normal for gestational age when the ileocecal valve remains, or greater than 10% of normal if the ileocecal valve has been lost (10).
is rapid during infancy with continued elongation until crown-heel length (CHL) reaches about 60 cm. Slower intestinal growth then occurs between a CHL of 60 to 100 cm, and there is little change above 100 to 140 cm (9). Therefore, after massive enterectomy, consideration should be given to the expected rate of bowel lengthening due to growth alone. Further, prognosis should be based not on absolute intestinal length, but on the percentage of normal for a given gestational age following resection. Survival and complete return of gastrointestinal function may be predicted when the postresection length of intestine exceeds 5% of normal for gestational age when the ileocecal valve remains, or greater than 10% of normal if the ileocecal valve has been lost (10).
The clinical course of patients with SBS involves several stages. There is an initial perioperative period of extreme fluid and electrolyte loss. This is followed by initial enteral feeding and a period of intestinal adaptation. Finally, a chronic or plateau stage is reached after 1 to 2 years if the adaptive intestinal response is inadequate. It is this final phase when the persistent problems of malabsorption, diarrhea, parenteral nutrition, and chronic nutritional deficiencies occur. The initial postoperative management is therefore directed toward fluid and electrolyte replacement. Large volumes of fluid may be lost from an ostomy, and replacement with a solution containing comparable electrolyte composition may be required to avoid fluid and electrolyte imbalance. The early postoperative care may be further complicated by the need for reoperation because of intraabdominal infections and/or fistulae. This early stage generally lasts about 1 to 2 weeks (11).
By removing specific portions of the small bowel, certain complications become more prevalent. Jejunectomy produces no permanent defect in the absorption of macronutrients and electrolytes because the ileum is capable of taking over these absorptive functions. Several of the intestinal hormones responsible for inhibiting gastric secretion are distributed mainly in the jejunum, and therefore, jejunectomy is more likely to result in gastric hypersecretion (11). In contrast, the ileum has a pronounced effect in slowing intestinal transit. Thus, ileal resection generally results in more rapid intestinal transit. The ileum is also an essential site for the absorption and recycling bile salts. As such, bile salt waste is associated with extensive ileal resection. Under these circumstances, the bile salt pool becomes depleted, leading to a high incidence of cholelithiasis and malabsorption of fat (11). It is for this reason that prophylactic cholecystectomy may be beneficial in the setting of SBS. The malabsorption of fat leads to deficiency of fat-soluble vitamins A, D, E, and K. In addition, vitamin B12 malabsorption after ileal resection may necessitate parenteral vitamin B12 on a monthly basis (12).
Patients with SBS are also at increased risk of developing hyperoxaluria, and this is associated with nephrolithiasis. Rarely, children with extensive small bowel resections may develop D-lactic acidosis. This occurs secondary to alterations in colonic pH and inhibition of the growth of Bacteroides species of bacteria. This leads to the increased growth of acid-resistant anaerobes capable of producing D-lactate.
The final stage following massive small bowel resection is the plateau phase, which occurs following maximal adaptation. This stage is generally reached within 1 to 2 years from the time of resection. It is during this final stage that decisions regarding additional surgical intervention are generally undertaken. Remedial surgical procedures may be indicated earlier in the face of the appearance of liver dysfunction or failure to advance enteral calories.
INTESTINAL ADAPTATION
Following massive small bowel resection (SBR), adaptive changes in the remaining intestine are detected as soon as 48 hours (13). This process probably continues for more than 1 year in humans. The adaptive response is mediated primarily by a mitogenic signal culminating in significantly taller villi, deeper crypts, and greater caliber and length of the intestine. In face of massive SBR, these morphologic alterations serve to expand the mucosal digestive and absorptive surface area (14). The key elements that control enterocyte proliferation and intestinal adaptation are incompletely understood. The magnitude of the adaptive response is directly related to the time interval following resection (13,15) and the amount of intestine removed. The degree of adaptation is greater after proximal SBR when compared with a distal resection of similar magnitude.
Studies by Loran et al. confirmed that the augmented villus height and crypt depth are the result of increased proliferation and accelerated cellular migration along the villus (16,17). Furthermore, similar villus cell densities, unaltered RNA/DNA ratios, and increased protein content suggest it is epithelial hyperplasia rather than hypertrophy that accounts for these changes (16,17). The increase in crypt epithelial cell proliferation occurs shortly after surgical resection.
Previously, it was believed that the increased cell proliferation during intestinal adaptation was balanced simply by the natural loss of senescent enterocytes from the villi into the intestinal lumen. However, more recent work has highlighted the importance of apoptosis or programmed cell death in the cellular homeostasis of the intestinal epithelium (18). Helmrath et al. reported significantly increased rates of crypt apoptosis in the remnant ileum of mice that had undergone SBR when compared with control mice (15).
Specific members of the bcl-2 gene family appear to be important in the regulation of resection-induced enterocyte apoptosis. Stern et al. reported a significant reduction in the antiapoptosis protein bcl-w coincident with an
increase in the expression of the proapoptosis member of the bcl-2 family bax in the remnant intestine following SBR (19). Further, this group reported that the increase in postresection apoptosis was prevented in bax-null mice (20). Bax therefore appears to be a key regulator of postresection apoptosis.
increase in the expression of the proapoptosis member of the bcl-2 family bax in the remnant intestine following SBR (19). Further, this group reported that the increase in postresection apoptosis was prevented in bax-null mice (20). Bax therefore appears to be a key regulator of postresection apoptosis.
In addition to various morphologic changes, the remnant intestine undergoes functional adaptation to counteract the acute loss of digestive and absorptive capacity after resection. Like the structural alterations, changes in enterocyte function are more prominent after a proximal intestinal resection. Because diarrhea is a common complication of massive intestinal resections, adaptive increases in sodium and water absorption are particularly important. Active Na+/substrate transporters, Na+/H+ exchangers (NHE), and passive Na+ channels facilitate sodium absorption and the subsequent passage of water and chloride (21). NHE activity, as well as mRNA and protein levels of the NHE-3 isoform, are increased in the residual intestine after resection (21). The Na+/glucose cotransporter is the primary mechanism for sodium transport in the small bowel (22). Schulzke et al. found a 2.5-fold increase in glucose-dependent sodium absorption per centimeter of intestine following 70% SBR in rats (23).
Multiple mechanisms and mediators have been proposed to be required for the initiation and maintenance of the postresection adaptation response. There is strong evidence to implicate a role for luminal nutrients, gastrointestinal secretions, and humoral factors in the genesis of adaptation. Further, the nutritional status of the host, as well as neural, bacterial, and mechanical factors, have become more clear recently.
The important contributions of luminal nutrients to the adaptive response of the intestine is underscored by the observations that gut mucosal atrophy is associated with starvation and is reversed by refeeding. Further, under normal conditions, indicators of adaptation such as bowel wall thickness, villus height, and crypt depth are greatest in the proximal jejunum and decrease as one moves toward the terminal ileum. This aboral gradient coincides with the nutrient composition of the ingested luminal contents. Because absorption of luminal carbohydrate, fat, and protein is virtually completed in the jejunum, the ileal mucosa is not normally exposed to high concentrations of these nutrients. In fact, surgical transposition of a segment of the ileum into the more proximal intestinal stream results in structural and functional “jejunalization” of the transposed ileum (24).
The most compelling evidence that luminal nutrients play a significant physiologic role is the observation that postresection adaptive changes in animals receiving only parenteral nutrition are attenuated (25). However, it is likely that the effect of luminal nutrients is indirect, including hormones, various gastrointestinal secretions, intestinal peristalsis, and mucosal blood flow. An indirect effect of luminal nutrients is best demonstrated in experiments where enteral feeding of an animal results in reversal of mucosal atrophy within a Thiry-Vella loop, which is not in continuity with the remainder of the gastrointestinal tract (26).
Not only is the presence of luminal nutrition important for adaptation, but also the composition of the nutrients. More complex nutrients require more metabolic energy to absorb and digest. They appear to induce the greatest adaptive response, the so-called functional workload hypothesis (27). Enteral fats appear to be the most effective of the trophic macronutrients in inducing adaptation. More specifically, longer-chain and more unsaturated fats may provide an even greater stimulus for adaptation (28). Further, supplementation of the enteral diet with pectin (a source of short-chain fatty acids) has revealed an enhanced adaptation response.
Another important luminal nutrient to consider is glutamine, an enterocyte-specific fuel. Enteral supplementation with glutamine after intestinal resection in animal and human models has yielded conflicting results (29,30). It appears that glutamine contributes to the proliferative effects of several different endogenous growth factors such as epidermal growth factor (EGF) (31) and insulinlike growth factor-1.
Multiple experimental observations contribute to the notion that endogenous gastrointestinal secretions are important for adaptation. Similar to the previous arguments related to luminal nutrition, there is a declining aboral gradient in bowel thickness from the origin of the pancreaticobiliary secretions (ampulla of Vater) toward the ileum. Transposition of the ampulla to areas more distal in the gastrointestinal tract results in villus hyperplasia beyond the transposed ampulla. Bile alone has been demonstrated to stimulate intestinal RNA and DNA content when directly delivered to the mid-small bowel, but the effect seems to be more profound when combined with the pancreatic secretions. In other studies, pancreatic secretions seem to be more trophic to the intestinal mucosa when compared with bile.
Further evidence that pancreaticobiliary secretions are important for postresection adaptation is the observation that somatostatin, an agent that dramatically diminishes the output of endogenous gastrointestinal secretions, also inhibits the adaptation response. The inhibitory effect of somatostatin is reversible with growth factor administration in vivo (32). However, the results of an in vitro study suggest that somatostatin perturbs the proliferative effects of growth factor administration (33). Along these lines, it is unclear what component(s) of the pancreaticobiliary secretions may be trophic to the intestinal mucosa. Because many growth factors are concentrated within the pancreaticobiliary secretions, it is possible that these are the necessary constituents for mucosal stimulation.
Increased serum or tissue levels of multiple hormones, growth factors, and cytokines after massive SBR have been taken as support for the concept that these factors play a
role in the pathogenesis of adaptation. Coupled with these observations, exogenous administration of many of these substances has been shown to enhance various components of the adaptation response. One of the more compelling experiments to substantiate the contribution of hormones to adaptation is the parabiosis model. In animals that share a common circulation, it has been shown that intestinal resection in one animal induces adaptive changes in the intestine of the unoperated animal (34). The most important circulating factor(s) is unknown, but this question is presently under intense investigation.
role in the pathogenesis of adaptation. Coupled with these observations, exogenous administration of many of these substances has been shown to enhance various components of the adaptation response. One of the more compelling experiments to substantiate the contribution of hormones to adaptation is the parabiosis model. In animals that share a common circulation, it has been shown that intestinal resection in one animal induces adaptive changes in the intestine of the unoperated animal (34). The most important circulating factor(s) is unknown, but this question is presently under intense investigation.
Although a multitude of hormones and growth factors have been proposed to mediate postresection adaptation, there is significant evidence to support the hypothesis that EGF and its intestinal receptor [epidermal growth factor receptor (EGFR)] are crucial (35). Similar to other known trophic substances, exogenous administration of EGF enhances adaptation. The optimal route (orogastric gavage), dose (50 μg per kg per day), and timing of EGF administration (immediately following intestinal resection, not prior to or after adaptation had already taken place) in a murine model of SBR have been detailed. Following a 50% proximal enterectomy, there is evidence for increased expression of mRNA and protein, as well as activation of the ileal EGFR. The direct effect of EGF on the intestine was proven by demonstrating that transgenic mice with targeted intestinal overexpression of EGF “superadapt” to massive small bowel resection. In these mice, EGF was overexpressed only in the remnant intestine, without affecting serum levels of EGF.
However, surgical removal of the major source of EGF in the mouse (bilateral submandibular gland resection) prior to SBR resulted in a significantly blunted adaptation response in the remnant ileum (36). Exogenous EGF rescued this impaired adaptation. Adaptation after intestinal resection is substantially impaired in a mutant strain of mice with defective EGFR signaling (37). Taken together, the evidence accumulated in the murine model for intestinal resection would strongly support the hypothesis that EGF and the intestinal EGFR are requisite for the normal adaptation response.
Glucagon-like peptide 2 (GLP-2) is another intestinotrophic peptide that has been shown to enhance intestinal adaptation (38). The glucagon-like peptides are synthesized in and released from enteroendocrine cells in the small and large intestine. In rat models of massive small bowel resection, GLP-2 has been shown to produce significant increases in segmental and mucosal wet weight. In addition, crypt-villus height and mucosal sucrase activity are enhanced postresection following the administration of GLP-2. GLP-2 appears to enhance adaptation by both increased cellular proliferation and decreased crypt epithelial cell apoptosis (39).
In a clinical study of short bowel patients, GLP-2 has been shown to provide modest improvement in intestinal absorption and nutritional status (40). Despite these limitations, the data supporting potential use of GLP-2 for the pharmacologic management of SBS is encouraging.
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