Short Bowel Syndrome

Incidence and Demographics of Short Bowel Syndrome

The true incidence of SBS in the United States has not been accurately identified because there are no reliable national registries or patient databases. In addition, on review of surveys of managing gastroenterologists and nutritionists, the accurate diagnosis of SBS is often not identified in the prescription of long-term home parenteral use. The Oley Registry of home parenteral use in North America in 1992 identified 40,000 patients with the broader category of intestinal failure as the diagnosis, with only approximately 26% of cases attributed to SBS. Some patients receiving PN in the Oley Registry carried the diagnosis of radiation enteritis or malignancy, and these patients could be reclassified with SBS due to those diagnoses. In 1995, an estimate of 10,000 to 20,000 patients receiving home PN for SBS was made by Byrne et al.

It is estimated that the number of SBS patients may be in the range of 2 per million, based on extrapolation of home parenteral use for SBS patients in the United Kingdom. A more recent European survey from 1997 identified the incidence of home total parenteral nutrition (TPN) use at close to 3 per million and the prevalence greater than 4 per million. It would seem that the prevalence of SBS is lower in regions where access to specialized nutritional care is lacking, and this is likely due to under-reporting, lack of recognition of the disease process, and a resultant shorter life expectancy. The prevalence of SBS is noted to be 0.4 per million in Poland, whereas it is noted to be 30 per million in Denmark, and this may be attributed to the development of a leading IR center (IRC) in Denmark that has led to a twofold increase in the number of patients listed as receiving PN or intravenous (IV) fluid support over the past 40 years. Further underreporting of SBS incidence in both the United States and Europe can be realized when there is no accounting of patients with SBS who do not require home PN/IV support or who have been weaned off PN/IV support.

Historically, characterizing the demographics of patients with SBS is limited without a prospective national registry or database. A survey of 688 patients awaiting intestinal transplants and receiving PN/IV support revealed the diagnosis of chronic intestinal failure and 75% also had SBS identified. The age of these patients was 52.9 ± 1.52 (range, 18.5 to 88.0), with 57% women. The most common etiologies were mesenteric ischemia (27%), Crohn disease (23%), and radiation enteritis (11%). Similar findings of a median age of 52.5, a majority of females (52%), and a body mass index (BMI) of 20.7 kg/m ² was identified in a study limited to 268 SBS patients. Mesenteric infarction (43%), radiation enteritis (23%), surgical complications (12%), and Crohn disease (6%) were the common etiologies identified. Better recognition of SBS is now being seen with cooperative transplant registry data collection. SBS was identified as the most common primary indication for intestinal transplantation when 61 intestinal transplant programs in 19 countries provided data on 989 transplants in 923 patients.

Prognostic Factors in Short Bowel Syndrome

SBS is associated with short- and long-term complications that lead to significant morbidity and mortality. Historically the prime determinant of mortality in SBS patients was nutritional failure, as seen with a case-fatality rate of 37.5% in neonates, among an SBS incidence of 24.5 per 100,000 live births. The advent of effective long-term PN and indwelling central venous access in the late 1960s led to good nutritional rehabilitation with low complication rates in SBS patients. In the two decades following, widespread adoption of PN support led to a reduction in SBS mortality from nutritional failure. The current era of SBS management includes pharmacologic medical therapies, multidisciplinary IRCs, and surgical intestinal optimization and transplant procedures. These management principles have led to improvement in both morbidity and mortality rates in SBS patients. Fifty percent to 70% of patients who require PN after the initial diagnosis of SBS can be weaned off PN within 2.5 years of the referral to a specialized center. Up to 70% of pediatric SBS patients can now be discharged from the hospital and are alive 1 year after diagnosis.

The prognosis of SBS is dependent on several factors, including the remaining length of functional intestine, the active presence of underlying etiologic diseases (Crohn, radiation enteritis, vasculopathy), the presence or functional continuity of the colon, and the ileocecal valve (ICV). Previously, it was felt that the ICV carried a greater role in gate-keeping transit times of intestinal loads to the colon, as well as preventing colonic reflux. However, when subsets of SBS patients are matched for length of intestinal resection, the value of the ICV appears to be primarily a marker of greater ileal or colon resection. The patient's age at presentation and the chronicity of enteral dependence are also contributing prognostic factors. Buchman reports the overall survival rate after 6 years of enteral dependence to be 65% in patients with at least 50 cm of intestine, but survival rates are much lower in patients with less than 50 cm of intestine. These patients with less residual intestine are more likely to develop PN-related complications, such as liver and kidney failure if not being permanently dependent on PN. The mortality in SBS patients with well-established PN dependence and with adequate residual intestine is less likely to be due to PN-related complications and more likely to be due to complications of their underlying disease, such as Crohn disease, cancer, and heart failure.

Normal Intestinal Physiology and Pathophysiology of Short Bowel Syndrome

The normal intestinal physiology of an intact digestive system is notable for a progressively decreasing absorptive gradient from proximal to distal. The absorptive surface area of the duodenum and jejunum is greater than that of the ileum. The proximal jejunum contains plicae circulares in greater number and thickness and with longer villi than the ileum. The absorptive surface area is also larger in the proximal intestine because the luminal diameter decreases as the gastrointestinal (GI) tract progresses from duodenum to ileum. Direct proximity to biliary and pancreatic enzymatic activity in the duodenum and jejunum is a major driver of nutrient digestion and absorption, more so than what is seen in the ileum, where bile acid resorption is a more prominent function.

The absorption of nutrients, minerals, vitamins, and amino acids is carefully distributed to preferential areas along the GI tract, as described in Chapter 71 ( Fig. 79.1 ).

The anatomy, length, and reconfiguration of the GI tract that remains after intestinal resection in the setting of SBS directly affect the proximal to distal gradient of digestion and absorption of nutrients and fluids. The small intestine has a large functional reserve capacity, and resection of up to 50% of intestinal length can be well tolerated. However, crossing the threshold of less than 200 cm of residual intestine leads to some of the clinical sequelae of SBS in at least 50% of these patients. The progression to massive intestinal loss leads to the full manifestation of SBS via the pathophysiology of loss of absorptive surface area and an increase in intestinal transit times. The clinical consequences of SBS are a result of the loss of intestinal absorption surface, the loss of site-specific absorptive areas, the loss of the ICV, and the decrease in intestinal hormone production. After major intestinal resection, larger volumes of undigested nutrients result in hyperosmotic loads entering the distal GI tract sooner, resulting in a response of increased luminal water. The resulting intense diarrhea is one of the major symptoms of the initial phase of SBS manifestation. The consequence is decreased digestion and absorption of lipids and fat-soluble vitamins, as well as emulsification and processing of cholesterol and complex fats.

Intestinal resection and reconstruction of the GI tract in the setting of SBS can be categorized into three anatomic subtypes ( Table 79.2 ). Type I is associated with significant jejunal resection and GI tract reconstruction via a jejunal-ileal anastomosis. The remnant GI tract includes at least 10 cm of terminal ileum, the ICV, and the entire colon. Type II is associated with resection of most or all of the ileum, frequently the ICV, and possibly part of the colon, usually the proximal or right colon. The GI tract in type II SBS patients is frequently reconstructed via a jejunocolic anastomosis. Type III SBS occurs with resection of all of the ileum, ICV, and the colon, with variable resection of the jejunum. The GI tract output is via an end jejunostomy, without connection to the rectum and anus.

Type I SBS patients have the greatest chance of nutritional recovery over time. Although there is initial loss of the proximal to distal gradient associated with the proximal jejunum, there is greater potential for the development of functional adaptation by the ileum to reduce the severity of nutritional losses long term. The possibility of intestinal adaptation is good with type I, and the permanent need for PN is low. In type I SBS, intestinal failure and the need for permanent PN or transplant consideration occur more commonly when only less than 40 cm of jejunum (or <10% of expected intestine for gestational age in infants) remains to form the jejunal-ileal anastomosis. Clinical manifestations may be seen due to changes in intestinal endocrine regulation. Loss of cholecystokinin production in the postresection state leads to increased gastric acid hypersecretion and rapid intestinal transit time of fluids. Alteration of the intestinal pH from increased acid load can lead to reduced pancreatic enzymatic digestive capabilities. Fortunately, the acid hypersecretion postresection state can be corrected in a few weeks to months, with the addition of a proton pump inhibitor or H ₂ -blocker regimen. Type I SBS patients tend not to have dehydration issues long term because the intact colon can serve as a water reservoir and absorptive conduit. When the duodenum and at least 40 cm of jejunum are preserved, deficiencies of water-soluble vitamins are less typical because these areas of the proximal intestine can slow down water-soluble vitamin absorption times.

Type II patients typically exhibit more severe clinical manifestations of SBS due to the loss of the adaptive capacity of the ileum and the colon. More extensive ileal resections are associated with worse outcomes. When less than 65 cm of jejunum remains and no ileum, the avoidance of permanent PN dependence is poor in these type II SBS patients. Clinical manifestations occuring with ileal resections are due to disruption of the vitamin B ₁₂ and enterohepatic bile salt systems. Without the site-specific ileal B ₁₂ receptors, long-term maintenance with vitamin B ₁₂ supplements is needed. Lacking bile salt reabsorption, steatorrhea from fat malabsorption is a frequent manifestation. The persistence of unabsorbed bile salts in the colon stimulates colonic motility and secretion, further exacerbating the steatorrhea. Chronic deficiencies of the fat-soluble vitamins will lead to the expected clinical presentations—dry skin, night blindness and xerophthalmia (vitamin A), pediatric rickets and adult osteomalacia and osteoporosis (vitamin D), macular degeneration (vitamin E), and spontaneous hemorrhage and poor clotting ability (vitamin K).

Type III patients with an end jejunostomy are the most challenging to manage because they have high fluid output losses. Without both the ileum and the colon, they will have the greatest malabsorptive issues as compared with the other patients. End jejunostomy patients no longer have the water reservoir and absorptive potential of the colon but also lose ileal site-specific nutritional deficiencies. When end jejunostomy patients have less than 100 cm of jejunum remaining, there is the added issue of loss of gastric acid and intestinal secretions, resulting in a chronic net-secretory state of high fluid output. The type III patients with less than 100 cm of jejunum typically will need permanent PN/IV support.

Water losses become less of a permanent issue with an intact ileum and colon. Permeability to water is less in the ileum than jejunum because the ileum has tighter junctions and a narrower luminal surface area. Therefore less water enters the ileal lumen than the jejunal lumen in response to a hyperosmotic-loaded meal. In adaptation, the colon is capable of increasing its fluid absorption capability from approximately 1.8 to 5 L a day, or up to 400% of normal. However, patients with a resected colon (type II SBS) or with an end jejunostomy (type III SBS) may have significant water and sodium losses that may lead to acute hypotension and chronic kidney insufficiency states. Hypomagnesemia in particular may lead to muscle fatigue, cardiac dysrhythmia, and neurologic impacts from depression to seizures.

Intestinal Adaptation

Intestinal adaptation is the mechanism of GI tract functional recovery that occurs in the postresection state of SBS patients. This adaptive process begins within 24 hours of significant intestinal resection and continues over a 2-year period. The degree or success of intestinal adaptation depends on anatomic factors, such as the extent and site of intestinal resections, the patient's health and existent underlying disease processes, the mechanism of nutritional support, and regaining the endocrine regulatory mechanisms of the GI tract. Keller has identified three phases of intestinal adaptation:

• Acute phase—postresection to 4 weeks. The goal is stabilization of the patient's sequelae of diarrhea, malabsorption, and dysmotility.

• Adaptive phase—1 to 2 years. The goal is achieving maximal intestinal adaptation with a gradual increase of nutritional exposure.

• Maintenance phase—long term. Optimizing fluid balance and individualized dietary regimen. Management of acute exacerbations.

Successful intestinal adaptation depends on morphologic changes in the residual intestine's microanatomy. The absorptive capacity may be increased by several hundred percent from increased mucosal surface, as well as increased absorption per surface area. In the postresection state the acute phase is marked by hyperemia of the bowel wall. Increased blood flow to the remnant intestine may be seen for up to 4 weeks after resection. Hyperemic changes promote mucosal hyperplasia, with resulting increased number and size of crypts and villi in the ileum. The normal ileum is typically exposed to fewer luminal nutrients than the jejunum. Taking advantage of the ileum's adaptive capability, therapeutic stimulation via planned and gradual exposure of macronutrients to ileal intestinal mucosa leads to a net increase in the absorptive surface area. Intestinal wall lengthening, luminal diameter increase, and wall thickening can occur in the ileum. Such adaptive growth of intestinal length and diameter is most prominent in premature babies with SBS. After morphologic changes occur over the initial 2-year period, there is evidence of retention of these features—Joly has reported that there is a 35% increase in crypt depth and a 22% increase in cell numbers and crypts in type II jejunocolic anastomosis patients up to 9.8 years after resection, as compared with healthy controls.

Functional changes in intestinal enterocytes are further key elements of increasing absorptive capacity. Differentiation of specialized mucosal cells may occur, thereby optimizing electrolyte (sodium, calcium) transport and exchange processing. Such differentiation occurs at the microvilli level. Functional adaptation occurs in the remnant colon through the process of hyperfermentation of undigested carbohydrates by colonic bacteria. Carbohydrate conversion to short-chain fatty acids (SCFAs), which are then absorbed in the colon, has proved to be an energy preservation mechanism.

Slowing small bowel transit time and thereby lengthening the time of contact between nutrients and the absorptive surface area is a change that improves quality of life. Although diarrhea is a prominent feature of the acute phase, long-term success in fluid, electrolyte, and nutritional balance can be achieved during the adaptive phase with deceleration in intestinal transit time.

Although calorie maintenance can be achieved with PN, the intestinal structural integrity can only be maintained via enteral stimulation. Lack of enteral nutrition leads to mucosal atrophy, blunting of villi and crypts, changes in brush border integrity, and increased fluid permeability. Intestinal adaptation is highly dependent on the luminal presence of nutrients. Increased complexity of nutrients seen by the remnant intestine promotes greater adaptation, by promotion of pancreaticobiliary secretions, stimulation of neurohormonal endocrine release, and ongoing use of the absorptive surface area. For example, long-chain triglycerides induce intestinal hyperplasia to a greater extent than medium-chain triglycerides. Certain nutrients are more valuable in the promotion of intestinal adaptation.

Glutamine is the primary energy source for enterocyte growth and metabolism. Studies that have examined the utility of glutamine in intestinal adaptation show modest benefit clinically. Glutamine added as a supplement to PN does reduce the severity of PN-induced intestinal atrophy. In contrast, glutamine added as part of a nutritional dietary regimen does not seem to yield measurable structural intestinal changes, such as villous growth. The lack of glutamine-driven effect may be due to the greater complexity of the luminal nutrients of the existing dietary regimen. The combination of glutamine with growth hormone (GH) is perhaps more valuable clinically. Studies of SBS patients receiving GH plus glutamine show greater long-term fluid and electrolyte maintenance as well as reductions in PN/IV volume requirements compared with patients receiving GH alone. A Cochrane meta-analysis of human trials indicated that GH, with or without glutamine, improves energy absorption and weight gain in SBS patients, but such benefits were lost when GH therapy was discontinued.

Medical Management

The main goals of medical management of SBS are the optimization and maintenance of

• nutritional absorption

• fluid and electrolyte balance

• vitamin and trace element retention

• nutritional and weight maintenance

In the acute phase after intestinal resection, attention must be paid to the dominant clinical issue of massive diarrhea and attendant fluid and electrolyte loss. The first few postoperative days require IV fluid replacement of losses, preferably using lactated Ringer with glucose solution (dextrose 5% [D5]). A schedule of replacement of water-soluble vitamins and trace elements must be instituted. Gastric acid hypersecretion should be controlled with proton pump inhibitor and H ₂ -blocker therapy for the first 6 months. Occasionally, the somatostatin analogue octreotide is useful to reduce the intraluminal fluid load, especially in the type III patients with end jejunostomies. Diarrhea may be controlled with the judicious use of intestinal motility inhibition agents, such as loperamide. Cholestyramine is useful in promoting bile salt retention and should be used to reduce cholerheic diarrhea. Sepsis control and correction of postoperative infection is critical to preventing ileus and early intestinal atrophy. Metronidazole is useful in the prevention of small bowel bacterial overgrowth (SBBO). A regular schedule of maintenance drug therapy is recommended in the acute phase for SBS patients ( Table 79.3 ).

Enteral nutrition should begin by postoperative day 4 to 5, via a low continuous infusion via nasal/percutaneous feeding tube, or by oral intake. The institution of early enteral feeding may be tempered by surgical concerns about ongoing ischemic changes in the massive vascular accident patient or for anastomotic integrity, peritoneal infection, or septic shock. Initial assessment of the adequacy of early enteral nutrition may be difficult because initial use of the remnant GI tract will lead to apparent worsening of diarrhea. The nutritional load will typically exceed immediate remnant absorptive capacity. A goal of 30 to 40 kcal/kg per day should be sought, but, given potential malabsorption rates of 30%, up to 45 to 60 kcal/kg per day may be the input level of enteral nutrition.

Enteral nutrition over the first 3 to 4 weeks after resection should progress with a structured program of increasing nutrient loads, first with isotonic salt-glucose solutions. Similarly, the nutritional program should introduce elemental level amino acids early on, including glutamine. Medium-chain triglycerides are preferred in the acute phase, for patients with a preserved colon, but not in type II or III SBS patients. For type II or III patients, a dietary balance of 40% to 50% carbohydrates and 30% to 40% lipids is recommended ( Table 79.4 ).

In the beginning of the adaptive phase, past the 4-week point, dietary expansion begins with long-chain triglycerides, free fatty acids, and carbohydrates such as maltose, saccharose, and pectin. Proteins should comprise approximately 20% of the diet. In patients with an intact colon, soluble dietary fibers can be degraded by colonic bacteria to yield SCFAs and provide a supplementary energy supply of up to 500 to 1000 kcal/day. These patients benefit from a carbohydrate-rich diet but should avoid lipids. Soluble fibers also promote better formed stool production as opposed to insoluble fibers, which can promote diarrhea.

Steadfast attention and maintenance of elemental levels, particularly magnesium and calcium, is also required at the early adaptive stage. Calcium supplementation should be at the 800- to 1200-mg/daily oral. Oxalates in the diet should be avoided to prevent the development of oxalate nephrolithiasis. Development of metabolic acidosis may be treated with addition of bicarbonate during the first few months of the adaptation phase. Oral magnesium supplementation may not be possible, due to the laxative effect of enteral magnesium.

A generic formula of PN may be started in the early postoperative period, with tailoring to an individual PN formula after the first week, dependent on review of electrolyte levels. In the first two phases of SBS recovery, the desired PN balance consists of 3 to 5 g/kg per day carbohydrates, 1.5 g/kg per day protein, and 1 g/kg per day lipids. Progression to the maintenance phase is with an emphasis of reduction/termination of PN. If intestinal adaptation is mature and the balance between delivery and loss of nutrients is equilibrated, these patients may regain substantial quality of life. The widespread adoption of PN led to significant reduction in morbidity and mortality in SBS patients in the 1970s. One-year survival of SBS adult patients on PN was recognized to be 91%, but leveling off at 86% at 5 years. The long-term utility of PN is counterbalanced by PN-related complications, such as indwelling catheter–associated septic and venous thrombotic events, as well as the development of PN-associated liver disease (PNALD). Fifteen percent of PN-dependent patients will develop end-stage liver disease, which carries a 100% mortality rate within 2 years of diagnosis.

Oral nutrition in the stable SBS patient should consist of many small meals, with an emphasis on a high-fat diet and moderate fluid intake with meals. Accounting for chronic malabsorption rate reduction from the acute 30% potential, the maintenance diet should still be balanced to achieve target absorption rate of 30 to 40 kcal/kg per day. The transition to the high-fat diet of the maintenance phase may yield recurrence of steatorrhea symptoms for which the patient should be prospectively counseled and managed appropriately.

Novel drug therapy for SBS includes the use of teduglutide for PN-dependent patients. Teduglutide is the recombinant human analogue of glucagon-like peptide 2 (GLP-2). Both GLP-1 and GLP-2 are intestine-trophic hormones released by the endocrine L cells in the ileum and colon. Upregulation of GLP-1 and GLP-2 synthesis is seen after ileal resection if there is remaining colon in a jejunocolic configuration. These GLP hormones promote villous height and crypt cell mass increase. In a randomized placebo-controlled phase III trial, the use of 0.05 mg/kg/day SQ of teduglutide led to a significant decrease in weekly PN volume requirements of 32% versus 21% in the placebo group ( P < .001) by 24 weeks. Teduglutide-associated PN volume reduction also led to improved quality-of-life scores among SBS patients. The increased crypt cell mass growth caused by teduglutide raises the concern for promotion of neoplastic growth, and therefore a prospective colonoscopy prior to teduglutide therapy is recommended to exclude active intestinal malignancy.

Multidisciplinary Intestinal Rehabilitation

Although the population of SBS patients may be small, they have complex pathophysiology and require an intense focus of care to lead successful lives without morbidity and mortality. A newer paradigm in the care of SBS patients is multidisciplinary IR at a specialized intestinal care center. These IRCs offer SBS patients a comprehensive management approach that recognizes the nutritional management challenges and short- and long-term complications and transitions patients from medical/pharmacologic management to surgical interventions of intestinal reconstruction or transplant.

Clinical pathways are triggered with an SBS patient from the initial postsurgical phase, the IR phase, with monitoring for complications ( Fig. 79.2 ). An IR program's well-established clinical pathways are tailored to the individual SBS patient with an emphasis on patient education. In addition to the fluid, nutritional, and medical management in the initial postsurgical phase of SBS, educational counseling is oriented toward the patient's understanding of the major lifestyle changes ahead, as well as broadening familiarity of the program's services and capabilities of support. Understanding the intestinal remnant and configuration, as well as the patient's underlying health, leads to the formulation of a detailed nutritional assessment of the degree of short- and long-term nutritional deficits.

Specialized IRCs typically have a gastroenterology program director with nutritional, medical, pharmacy, surgical, interventional radiology, and social work team members ( Fig. 79.3 ). Pathways are developed in a coordinated fashion to seamlessly hand off the SBS patient from one major transition point to the next—for example, specialist referral for an acute complication, or surgical referral for transplantation in the setting of intestinal failure ( Table 79.5 ). One such important transition point is the first discharge from the hospital to a home care environment. A specialized IR program will have established protocols of communication between the patient, the nutrition specialist (PN/enteral nutrition/fluid support), the pharmacist (for relevant medications), and the social worker. Patient recognition of symptom exacerbations (e.g., dehydration, diarrhea, cramping) is prospectively co-managed to reduce severity or minimize hospital readmissions.

Studies indicate that IRCs are capable of delivering improved outcomes in SBS patients. Nehme compared 211 patients whose PN was managed by a dedicated nutritional support team (NST) against 164 patients whose PN was managed by a variety of individual physician providers, over a 2-year period. The NST group had a catheter complication rate of 3.7% versus 33.5% in the non-NST group. Catheter sepsis rates were 1.3% in the NST group and 26.2% in the non-NST group. NST management led to a 50% decrease in complication rates when compared with the group managed by individual physicians ( P < .001). Such coordinated care of the SBS patient on PN may yield cost savings of $4.20 for every $1.00 assigned to the use of a NST.

Complications of Short Bowel Syndrome

In addition to the specific nutritional, metabolic, and fluid deficiencies associated with SBS, there are several notable and specific complications that arise in the management of these patients.