There are numerous definitions for short-bowel syndrome (SBS). The simplest definition is that there is inadequate intestine to maintain normal nutrition by eating. Because infants and children require increased calories to grow and develop, SBS can have a more devastating effect in these patients.
Before the availability of total parenteral nutrition (TPN, food delivered into the veins), most infants and children with SBS died from malnutrition. The true incidence of SBS is unknown. A Canadian study suggested that it is present in 4.8 per 1 million people. SBS typically is the result of a catastrophic event involving the small intestine and possibly the colon (large intestine). NEC and midgut volvulus from malrotation are the two most common causes of SBS. Other causes are listed in Table 1.
| Table 1: Course of Short-Bowel Syndrome in Infants and Children |
| Necrotizing enterocolitis Midgut volvulus from malrotation Multiple intestinal atresias Gastroschisis Trauma Inflammatory bowel disease |
Normal Physiology
The small intestine is completely formed by 20 weeks’ gestation. Most of its growth prior to birth occurs in the third trimester. Before 27 weeks’ gestation, the average length of the small intestine is 115 cm. This length increases to approximately 250 cm with a diameter of 1.5 cm after 35 weeks’ gestation. In contrast, the adult intestine is 600 to 800 cm in length and 4 cm in diameter. The mucosal surface area increases with age. Infants have 950 cm2; adults have 7500 cm2.
The intestine has an enormous capacity to absorb secretions and ingested fluids (Figure 1). There is extra intestine normally which is why a major loss of the intestine may not result in SBS. Absorption occurs through the lining (mucosa) of the small intestine. Nutrients, vitamin B12, calcium, iron, and bile acids are absorbed through the cells of this lining. Mucus covers the surface of the mucosa cells and acts as a trap to hold nutrients in contact with the cell surface. Mucus also acts as a bacterial barrier.
Figure 1. Intestinal function by site. After removal of the intestine, other sites may adapt to assume those functions, as there is overlap of some absorptive function between sites. |
Pathophysiology
In patients with SBS, intestinal function depends on multiple factors (Table 2).
| Table 2: Factors Influencing Intestinal Function in Short-Bowel Syndrome |
| Total remaining small intestinal length Etiology of intestinal loss Intestinal loss before versus after birth Remaining intestine (jejunum or ileum) Presence of the ileocecal valve (valve between the large and small intestine) Length of time from removal of the intestine |
The most crucial factor is the length of the remaining intestine. Removal of the stomach, jejunum, or colon is better tolerated than removal of the ileum (last part of the small intestine). The stomach digests nutrients by the action of acid and enzymes and produces “intrinsic factor,” which is essential for vitamin B12 absorption. The stomach reacts to massive loss of intestine by secreting large volumes of high acid–containing stomach juices at least for a time.
The jejunum (first part of the small intestine) is the site of absorption of most nutrients and minerals, such as calcium, magnesium, and iron. With removal of the jejunum, there is loss of some of the enzymes that break down sugars, which decreases sugar absorption. Unfortunately, bacteria can use these unabsorbed sugars and produce lactic acid. The absorption of the increased lactic acid can lead to increased acid in the bloodstream.
Fat and protein digestion may be reduced if the jejunum is gone. Calcium and magnesium losses are increased. If there is adequate ileum (last part of the small intestine) remaining after loss of the jejunum, however, the loss of the jejunum is better tolerated.
Carbohydrate, protein, fluid, and electrolytes are also absorbed in the ileum. The ileum is the principal source of absorption of bile acids; vitamin B12; and the fat- soluble vitamins A, D, E, and K. Removal of most of the ileum results in vitamin B12 and fat-soluble vitamin deficiencies and diarrhea. The diarrhea is from both the large volume of fluid passed into the colon (large intestine), and the unabsorbed bile salts can cause the colon to release water. Loss of these bile salts can also result in a decrease in fat absorption since the bile salts help the intestine to absorb fats.
The ileocecal valve (valve between the small and large intestine) slows the progress of intestinal fluids into the colon. It also increases the pressure gradient between the ileum and the colon to prevent the colon fluids with high concentrations of bacteria from moving back up into the small intestine.
Removal of the large intestine has minimal effect on digestion and absorption. The colon is the site of absorption of fluid and sodium and the excretion of potassium and bicarbonate. In SBS, the presence of the colon is of value because it increases the absorption of fluids and electrolytes (normal chemicals in the blood stream such as sodium, potassium, chloride, and bicarbonate) and decreases diarrhea.
Adaptation of the Intestine
Loss of a significant amount of the small intestine produces changes in the bowel called intestinal adaptation. The result is an increase in the intestinal surface area of the inside lining (mucosa) of the intestine and an increase in absorption and digestion. The inside lining of the intestine is made of strands of mucosa (villi) that increase the surface area. (Figure 2)
Figure 2. The Biarchi procedure for making the intestine longer. The enlarged, dilated intestine is divided down the middle after the blood vessels feeding it are separated to one side or the other. The ends are then hooked up. The enlarged intestine now becomes longer and fairly normal in .... |
The first and most significant adaptive change is an increase in growth of the villi. The villi are longer and thicker. The inside diameter of the intestine also increases. However, there is only so much increase in diameter of intestine and size of the villi that can occur. A number of growth factors and other still undefined factors are responsible for causing this adaptation. The most important site of adaptation is the small intestine; however, enlargement of the villi also occurs in the large intestine, resulting in an increase in water and electrolyte absorption.
Although the specific mechanisms that cause adaptation are not known, there is information on factors that influence adaptation. (Table 3) Providing enough calories to support growth and development is important. The villi get smaller in patients getting calories only from TPN exclusively. This condition can be reversed by feeding small amounts of nutrition into the stomach or intestines, typically referred to as trophic feeds.
| Table 3: Factors Influencing Intestinal Adaptation |
| Factors in the bloodstream Hormones (gastrin, cholecystokinin, glucagon) Intestinal factors (e.g., epidermal growth factor, hepatocyte growth factor, glucagon-like peptide-2, interleukin-11) |
| Gastrointestinal (stomach, intestine) secretions Pancreatic secretions Intestinal secretions Bile |
| Nutrients in the intestine From outside sources (food) From within the intestine |
Normal secretions in the gastrointestinal (stomach and intestines, GI) tract increase adaptation. Bile duct and pancreatic secretions help the small intestine mucosa grow.
Perhaps the most important influence on intestinal adaptation is hormones, growth factors, or cytokines. At present, the only substances that have reached clinical trials are human growth hormone and glucagon-like peptide-2 (GLP-2). There is not yet enough data to determine if these substances increase adaptation of the intestine.
The means by which cells of the mucosa adapt is still unclear. There is increasing evidence that putrescine, spermidine, and spermine may play a crucial role. Experimentally, massive removal of the small bowel results in an increase in these “polyamines” and the enzyme that controls polyamine synthesis, ornithine decarboxylase (ODC). If ODC is blocked after small bowel removal, polyamine concentrations are markedly reduced, and increase in the size of the villi and the mucosal cells does not occur.
Management of Short Bowel Syndrome
In the early period after intestinal loss, attention is directed toward keeping the fluids and electrolytes in the body normal. TPN (food delivered into the bloodstream) is begun. Excess secretions, which are lost through stomas or diarrhea, must be replaced. Blood levels of calcium, magnesium, trace elements, and vitamins and blood pH (acid) must be monitored. Fat (40% of calories) is given into the bloodstream daily or at least three times per week.
As soon as GI function has returned, intestinal feeds are introduced gradually. This is usually accomplished through a gastrostomy (feeding tube placed directly in the stomach) or nasogastric tube (tube placed through the nose into the stomach). Infants and young children must be fed at least in part orally, however, to establish their ability to suck and eat. Because adaptation begins early after loss of intestine, small amounts of feeds are started early to stimulate adaption of the intestine. Small volumes of liquid feedings are introduced first. A trial-and-error method maximizes the results.
Use of elemental diets (where all the nutrients are broken down into simplified forms that can be easily absorbed) have become increasingly popular to feed patients with SBS. These diets have the advantage of being better absorbed. However, more complex diets are more trophic (promoting growth) to the GI tract and help increase adaptation. The decision to use one formula over the other depends on each individual child.
Most diets that are well-tolerated with SBS contain peptides as the major protein source and forms of glucose as the sugar source. Long-chain triglycerides and short-chain fatty acids are important and should be added gradually to the diet because they stimulate mucosal growth. In the past, patients were not fed complex fats because of the fear of increasing diarrhea. Several clinical studies have shown that this is incorrect. One type of fat, medium-chain triglycerides, are absorbed readily through the intestine.
The volume and complexity of feedings are increased gradually. Consideration should be given to adding fiber to the diet, particularly pectin. Vitamins B12, A, D, E, and K may be required. As more nutrients are absorbed, the amount of TPN that is given is decreased. During hospitalization and at home, stools should be monitored periodically for reducing substances which indicate that sugars are not being absorbed, amount of water, frequency of stools, volume, and the presence of undigested fat.
Medications Used for Small Bowel Syndrome
Reducing Stomach Acid Output
There is evidence that gastric (stomach) hypersecretion (making too many secretions) complicates the first phase of adaptation to the SBS. In addition to aggressive monitoring and replacement of fluid and electrolyte losses, early medical treatment should address this problem. In the early postoperative period, antacids or sucralfate may be given via a nasogastric tube (and later by mouth) to reduce the elevated risk of ulcer disease. Cimetidine or ranitidine (Zantac) can be especially useful in decreasing water and sodium losses related to the hypersecretion. Clinically, we typically use cimetidine in doses of 10 to 20 mg/kg/day orally or intravenously divided every 6 hours. If a stronger medicine is required to reduce stomach output, proton-pump inhibitors such as omeprazole (Prilosec) can be used. Oral and intravenous omeprazole have been shown to decrease stool weight and sodium losses in SBS patients. In children, omeprazole can be given, 0.6 to 0.7 mg/kg once or twice daily.
Antimotility and Antisecretory Agents
Medications that slow peristalsis (pushing of food along by the intestines) and increase the time that it takes for food to get through the intestine (transit time) have been used for several decades to treat SBS. By prolonging transit time, there is a longer contact time between nutrients and the cells using the intestine (mucosa), allowing for better absorption and less diarrhea.
Loperamide hydrochloride is one such medicine that weakens transit time in the small bowel and colon. In children, this agent is safely administered with few side effects.
Diphenoxylate (Lomotil) is another antidiarrhea medicine that is well absorbed. It contains atropine to discourage drug abuse by producing undesirable side effects at higher doses. Because diphenoxylate in children has been linked to cases of serious brain, breathing, or heart side effects it is important to use this medication cautiously.
As feedings into the stomach or intestine are gradually increased, if a second medicine is required in addition to loperamide, it is possible to add another drug, such as codeine (0.5 to 1.0 mg/kg per dose orally every 6 hours) to slow small intestine peristalsis further. Tincture of opium (Paregoric) also may be effective and has the benefit of easily being slowly increased just a few drops at a time to achieve the desirable effects, while minimizing the risk of side effects.
The treatment plan should be individualized for each patient based on the length of the remaining intestine, the presence of the ileocecal valve, and the length of the colon. Treating SBS patients, especially patients lacking an ileocecal valve, with antimotility agents may increase the risk of bacterial overgrowth in poorly functioning, dilated enlarged portions of intestine. Diagnosis of bacterial overgrowth in patients experiencing increased pain and diarrhea means that these intestinal slowing medicines should be stopped and a course of antibiotics (usually oral metronidazole) should be started.
The absence of the terminal ileum (last part of the small intestine) increases diarrhea as a result of the high concentration of bile salts and acids which make it to the colon. This is because most of these bile salts and acids are absorbed by the last portion of the small intestine. Colonic bacteria change the bile salts, which stimulates the secretion of water and electrolytes into the colon (large intestine). Agents that bind bile acid, such as cholestyramine, can be effective in treating diarrhea when bile salts and acid are a problem.
Somatostatin is a hormone that inhibits a number of functions of the GI system. Somatostatin and its synthetic version, octreotide, can decrease the formation of gastric acid, decrease how fast food empties from the stomach, and reduce gallbladder contraction, pancreas function, bowel motility, and small intestinal secretions.
Increasing the time it takes for food to move all the way through the intestines (intestinal transit time), and reducing intestinal secretions can result in improved absorption of food, decreased loss of fluids and electrolytes, and is thought to be the mechanism by which somatostatin is beneficial.
Somatostatin and octreotide have been shown to decrease intestinal fluid losses in SBS patients. Because octreotide has a long duration of action and may be given via injections into the fat under the skin, it has been proposed as a potential long-term treatment to improve the lifestyle of SBS patients. Its use in this population has not been studied extensively, however, and the mechanism by which somatostatin benefits patients with SBS is unclear.
It is important to recognize that octreotide can cause possible side effects of abdominal pain, nausea, increased incidence of gallstones, facial flushing, and headache. At this time, the role of octreotide in managing SBS patients seems limited. However, patients whose intestinal output is greater than their oral intake can benefit from the administration of octreotide.
Glutamine and Growth Hormone (GH)
Glutamine and GH, as individual agents and when used together, have been extensively studied in humans with SBS. Glutamine is an energy source for the mucosa (lining of the gut). Experiments have shown that glutamine stimulates the intestinal cells to grow. Adding glutamine to parenteral nutrition encourages the mucosa to grow following massive small bowel removal.
Administration of GH has been shown to increase bowel growth in animal studies. GH also has been shown to induce small bowel lengthening in newborn piglets.
However, five studies of growth hormone use in humans have been performed with mixed results. Human GH is approved by the U.S. Food and Drug Administration for SBS. However, it is unclear if the drug is effective.
Numerous animal studies of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1) suggest that these factors stimulate intestinal adaptation in patients with SBS. EGF is a hormone secreted by the salivary glands and some of the cells of the small intestine. Numerous studies have shown that hepatocyte growth factor (HGF) is also a powerful growth factor for the small intestine. Future clinical trials are necessary to study the roles of these and other growth factors as potential treatments for SBS.
Two substances probably have the greatest potential as growth factors for the small intestine. GLP-2 belongs to a specific class of compounds called proglucagon-derived peptides. Studies have shown that GLP-2 and GLP-2α increase growth of the mucosa and absorptive function in rats. Preliminary studies in adults also support its possible role in the treatment of SBS. Clinical trials are now under way to evaluate the role of GLP-2 in patients with SBS. No trials have yet to be performed in children.
Continued research may allow clinicians to employ growth factors to definitively treat SBS.
Surgery
Reduction of transit time of food through the intestines: A number of surgical techniques have been used to slow transit time or to increase the mucosal surface area for improved absorption. These include turning a portion of the intestine backwards so that it impedes forward motion of the intestinal contents, and creating recirculating loops – both of which have fallen into disfavor. The creation of an artificial ileocecal valve, however, may reduce transit time and may have some benefit to the patient.
Small Intestine Tapering: Removing some of the extra portions of the dilated (enlarged) small intestine prevents the intestinal fluid from sitting in a big piece of intestine like a cesspool (stasis) and bacterial overgrowth (the bacteria flourish in the “cesspool”) and malabsorption. By reducing bacterial overgrowth, bloodstream infection also may be decreased. This procedure has been used frequently. It has allowed some patients to be able to eat fully and to discontinue TPN, but the results reported have not been uniformly good.
Intestinal Lengthening: Two methods are now available to lengthen the intestine. Bianchi originally described intestinal lengthening. Because the blood vessels leading to the intestine separate and course to either side of the intestine, the blood vessels and the intestines that they feed can be separated (Figure 2). So, the enlarged (dilated) small intestine can be split into two parallel portions, each with its own blood supply. This reduces the size of the dilated intestine by half and doubles its length. An intestinal stapling device helps to divide the intestine. A few successful cases have been reported in which the patients have been able to fully eat after this operation with a decrease in infection.
Figure 3. The STEP procedure. A staple which divides the intestine after stapling either side is used to make an “accordion” of the intestine that makes it longer and a fairly normal size. |
More recently a STEP (serial transverse enteroplasty) procedure has been used (Figure 3). This procedure can also lengthen the intestine. For both of these operations the intestine must be enlarged. Risks include infection, narrowing of the intestine and redevelopment of a dilated intestine.
Intestinal Pacing: Pacing of the small intestine by electrodes implanted in the gut slows intestinal transit time and increases the time that the food is in contact with the lining of the intestine. This procedure has been effective in the treatment of experimental SBS, but there are no reported clinical cases.
Small Intestine Transplantation: Small intestine failure or inadequate intestinal length leads to the indications for small intestine transplantation in (1) patients with SBS, (2) patients who are unable to be maintained on intestinal feedings and who are developing liver disease as a result of needing to use TPN, or (3) patients who have problems with having a place to get the TPN into the veins so that TPN is no longer possible. Improved immunosuppressive medications, which include tacrolimus and cellcept, as well as a better means of identifying rejection of the intestine, have improved survival.
The complications of small intestine failure are numerous. Infections (in large part from bacteria passing through the intestine into the bloodstream), lymphoproliferative disease (overgrowth of white blood cells) from the effects of aggressive immunosuppression, and bouts of rejection are common and life-threatening.
Rejection is a major issue in small intestine failure. Differentiating between infection and rejection can be difficult. Small intestine transplant biopsy remains the standard, but this can be wrong. Also, interpretation of what constitutes histologic evidence of rejection has changed.
A report from the University of Pittsburgh indicated a 1-year graft and patient survival of 60 to 70%. However, long-term results may well be much lower. Patients surviving small intestine failure were free of TPN in 92% of cases. In the pediatric age group, small intestine transplant was more successful. This was not true for infants younger than age 2 years, however. Rejection occurred in 92% of patients. Because the incidence of death occurring while on the waiting list is still 50%, in some patients isolated liver transplants have been done.
Prognosis
Numerous series of SBS patients have been reported with survivals ranging from 50% to 80%. Adaptation did not seem to be related to the presence or absence of the ileocecal valve or even a particular length of intestine unless it was 20 cm of small intestine or less.
The management of SBS has changed considerably since the 1970s. Before TPN there was little hope for survival. Current, the modalities discussed offer an acceptable-to-good quality and quantity of life. TPN provides appropriate caloric needs. Improved feeding formulas can help to increase the absorptive ability of the small intestine, and surgical procedures, especially intestinal lengthening, may maximize intestinal absorption.
The results of small intestine transplant are improving, and when indicated, this procedure offers an acceptable option. The most promising approach for the future is the use of growth factors to stimulate growth of the intestinal cells and to improve their ability to absorb nutrients. Because most SBS patients adapt within 2 years after resection, ample time should be allowed for adaptation to occur before small intestine transplant is considered.
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