Short bowel syndrome: pathophysiological and clinical aspects

Pathophysiology 6 (1999) 1 19 Review article Short bowel syndrome: pathophysiological and clinical aspects Michael E. Höllwarth * Department of Pediatric Surgery, Uni ersity Klinik für Kinderchirurgie-LKH Graz, Auenbruggerplatz 34, 8036 Graz, Austria Accepted 30 November 1998 Abstract Short bowel syndrome (SBS) is characterized by maldigestion and malabsorption after extensive loss of the small bowel. Intraluminal nutrients, gastrointestinal secretions and enterohormones stimulate a process of adaptation which consists of a gradual increase in intestinal length and width, villus height, crypt depth, and absorptive capacity. Duration of treatment, incidence of complications, and overall prognosis for an individual patient depends on his age, the amount of resected bowel, which parts of the small intestine are preserved, and whether the ileocecal valve and the colon have remained intact. Dysmotility is a common symptom despite an apparently short transit time. Long-term parenteral nutrition is mandatory, until the adaptation process allows an entirely enteral nutrition, and careful monitoring and possibly continued supplementation of vitamins will be necessary even thereafter. How far the intestinal adaptation can be enhanced by additional pharmacological therapy has not yet been clarified. Surgical procedures aim at slowing down intestinal transit, increasing absorptive surface area, and/or refashioning dilated intestinal loops in order to improve peristalsis. SBS patients frequently suffer acute and chronic complications such as central venous catheter infections, chronic cholestasis and hepatic failure, bacterial overgrowth with subsequent D-lactic acidosis, and translocation of bacteria and endotoxin. Without the option of transplantation, survival rates currently reach 80%. Small bowel transplantation isolated or in combination with other organs is in constant evolution and may offer new hope for patients with an extremely short bowel. 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. Keywords: Short bowel; Intestinal adaptation; Intestinal transplantation; Bacterial overgrowth; Liver failure 1. Introduction The term short bowel was defined by Rickham [1] as a small intestinal remnant of 30%, which equals 75 cm or less of normal small bowel length in a full-term neonate. Touloukian and Walker Smith [2] published the corresponding measurements for babies of lower gestational age. In adults, normal intestinal length averages 4 6 m. Thus, adult short bowel syndrome results when less than 120 200 cm of small intestine remain after extensive resection. This amount corresponds, as in the newborn, to a loss of approximately 70% of total * Tel.: +43-316-385-3762; fax: +43-316-385-3775. E-mail address: michael.hoellwarth@kfunigraz.ac.at (M.E. Höllwarth) small bowel length. However, the antimesenteric measurements of intestinal length during surgical interventions yield highly variable results due to enormous contractibility of the bowel in length and diameter, even if touched very gently. The term short bowel syndrome (SBS) is defined by most authors as a state of significant maldigestion and malabsorption requiring a prolonged period of parenteral nutrition to provide for normal growth and development, prevent dehydration, and replace electrolytes, vitamins and trace elements due to extensive loss of the small bowel. This definition includes patients with congenital deficiencies or surgical resection of small bowel segments and those who are suffering from malabsorption due to a functional loss of absorptive surface area, e.g. after radiation injury. 0928-4680/99/$ - see front matter 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. PII: S0928-4680(98)00035-2

2 M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 The intestinal tract exhibits an astonishing ability to compensate for an extensive loss of small bowel. Adaptation to the new situation takes place with time by structural and functional changes resulting in an increased absorptive surface area and capacity. This process, however, differs markedly among individual patients depending on the remaining length of small as well as large bowel, whether the jejunum or ileum is missing, absence or presence of the ileocecal valve, and many other factors. Mechanisms supporting, and complications delaying the adaptation process have been studied extensively over the past three decades. This review presents a brief survey of the current field of basic research and summarizes clinical experience with conservative and surgical treatment modalities in patients with SBS. Most of the data presented are derived from animal studies or research performed on newborns and infants suffering from SBS, but the majority are equally relevant to the adult age group. 2. Incidence and etiology The prevalence of SBS has undoubtedly been increasing over the last two decades, since enormous progress in intensive care medicine has significantly improved the initial prognosis of patients with severe intestinal disease and/or following major surgery. The real incidence of SBS is difficult to determine since this term as mentioned above includes all forms of reduced small bowel length/function associated with a malabsorption syndrome. Mughal and Irving [3] estimated that severe SBS cases remaining dependent on longterm home parenteral nutritional support amount to two new patients per one million of the population/ year. According to Wallander et al. [4], the incidence of extreme SBS in the neonatal age group lies around 3 5 per 100 000 births/year. In infancy, most cases of SBS occur in the neonatal age group. There are many different causes which can be divided into three major groups. The first of these consists of neonates with prenatally acquired anomalies characterized by a vascular injury to the intestinal tract in utero, e.g. intestinal atresia or gastroschisis with intrauterine volvulus of the prolapsed bowel. The second group comprises postnatally acquired diseases necessitating extensive intestinal resection, e.g. necrotizing enterocolitis or malrotation/volvulus. The third group is defined by a genetically determined deficiency, e.g. in the embryological small bowel anlage causing true congenital short bowel, or in its innervation, such as total intestinal aganglionosis both very rare entities with 26 cases described in the literature for the former [5], and 41 for the latter [6]. Extensive intestinal resections leading to SBS are less frequently required in older children. Indications may be severe Crohn s disease, traumatic avulsion of the intestinal tract and/or mesenteric artery or iatrogenic lesions. The most common causes for SBS in adults are Crohn s disease, mesenteric vascular accidents due to emboli, arterial or venous thrombosis, intestinal tumors, or radiation injury (Table 1). 3. Intestinal physiology Adequate digestion and absorption depends on the active mucosal surface of the intestinal tract. Three anatomical modifications amplify its surface area 500 600-fold to what would be provided by a simple cylinder: first, the plicae circulares of Kerckring which are most prominent in the upper jejunum, second, the villi which are significantly higher in the duodenum and proximal jejunum than in the ileum (0.8 vs. 0.5 mm), and third, the microvilli covering the luminal surface of the enterocytes [7]. All together, the gut has a mucosal surface area of some 400 m 2 in the adult, therefore large reserves of absorptive and digestive capacity are available. In addition to morphological differences, a functional graduation from the proximal to the distal small bowel exists as well: activity of microvillus enzymes and absorptive capacity are both several fold higher per unit length in the proximal as compared to the distal intestine [7,8]. Intestinal secretions and oral fluid intake reach approximately 8 9 l/day in the adult. About 80% of these are re-absorbed in the small intestine, 18% in the colon, and only 100 200 ml/day are excreted with the stools. After ingestion of food, luminal isotonicity is rapidly achieved in the upper jejunum either by water secretion (hypertonic meal) or water absorption (hypotonic meal). An isotonic aqueous medium is essential for proper digestion and absorption. Water absorption Table 1 Incidence of SBS 36 Necrotizing enterocolitis Neonates a Intestinal atresia 21 Volvulus/malrotation 19 Gastroschisis and volvulus/atresia 10 Hirschsprung s disease 7 Trauma 1 Others 6 Adults b Crohn s disease 42 Mesenteric infarction/embolism 24 Radiation enteritis 14 Others (polyposis, volvulus, trauma, ulc. colitis, 20 pseudo-obstruction) a Adapted from Ref. [8]. b Over 100 cases collected from the literature. %

M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 3 from isotonic chyme is a passive process closely coupled with electrolyte movements taking place primarily in the duodenum and jejunum. It can take a transcellular or paracellular route, with predominance of the latter in the upper intestinal tract, as in this localization the intercellular pores are significantly larger than in the ileum (diameter of tight junctions: 8 and 4 Å, respectively) [7]. Carbohydrate digestion begins in the oral cavity by salivary amylase and proceeds in the duodenum by pancreatic amylase. The intermediate products, mostly oligosaccharides and disaccharides, must be further hydrolyzed by membrane bound brush border enzymes to monosaccharides before they can be absorbed, either by an active transport system as for glucose and galactose, or by facilitated diffusion (fructose). The capacity of the brush border enzymes is much higher in the jejunum than in the ileum, possibly a consequence of the considerably greater length of the villi in the upper part of the intestine. Dietary carbohydrates consist of starch, dietary fiber and various sugars. Approximately 80% are absorbed in the small intestine, the remainder mostly complex carbohydrates and fiber pass into the colon where they are almost completely fermented to short chain fatty acids (SCFA), such as butyrate, by the bacterial flora [9]. SFCA represent a major source of energy for the colonocyte, stimulate intestinal mucosal growth, and enhance water and sodium absorption within the colon [10]. Protein is broken down in the stomach and duodenum by pepsin and pancreatic peptidases. The resulting oligopeptides are either hydrolyzed to amino acids by brush border enzymes, or transported as di- and tripeptides into the enterocyte where further hydrolyzation to free amino acids takes place. While most of the proteins are absorbed in the jejunum and ileum, a small amount (approximately 2% of diet and host derived proteins, the latter from protein rich secretions, mucus, and epithelia) reach the colon undigested to undergo fermentation by bacteria resulting in SCFA as well [10]. Triglyceride and lipid digestion starts in the stomach and continues in the proximal small bowel where pancreatic lipase and colipase play a major role. Secretin and cholecystokinin from the duodenal and jejunal mucosa stimulate pancreatic secretions, bile flow and gallbladder contraction. In the first step fats are emulsified in the stomach and in the duodenum to form smaller droplets of lipids with an increased surface area upon which pancreatic lipase and colipase can act. Long chain triglycerides are hydrolyzed to yield one monoglyceride and two fatty acids. Liver derived bile salts mainly conjugated with glycine and taurine are capable of forming micelles. These are spheric associations of watersoluble bile salts on the outside with hydrophobic long chain fatty acids filling the interior compartment. They gain access to jejunal and ileal enterocytes by passive diffusion. Fat soluble vitamins, such as vitamins D, E, A, and K, are absorbed by the same transport mechanism. Medium and short chain fatty acids are sufficiently soluble in the aqueous phase to be absorbed without incorporation into bile salt micelles. In contrast to carbohydrates and proteins which partly reach the colon undigested under normal conditions, lipids are almost entirely absorbed within the small bowel. Bile salts are re-absorbed to 95% in the ileum and resecreted by the liver several times during a meal, a circle which is called the enterohepatic circulation (EHC). It maintains the bile salt pool at a relatively constant level. In contrast, bilirubin is deconjugated in the distal small bowel or colon and either precipitates as an insoluble calcium salt if calcium is available or is converted to urobilinogen which undergoes a limited EHC. Normal motility is a major factor for uneventful digestion and absorption. The small intestine exhibits three different patterns of postprandial contractions: rhythmic segmentations, propulsive peristalsis, and tonic contractions, all of them serving to mix and slowly propagate the chyme through the bowel. During the interdigestive period a coordinated series of contractile activity the migrating motor complex (MMC) sweeps down the length of the small bowel. Feeding interrupts the MMC and re-initiates the three types of contractions described above. Mucosal polypeptides and/or transmitters such as cholecystokinin (CCK) and bombesin stimulate intestinal motility, others including somatostatin, peptide YY, VIP, glucagon, and nitric oxide exert inhibitory effects [11]. Other features of intestinal motility are the so called ileal brake and colonic brake. These represent reflex mechanisms slowing down gastric emptying and increasing transit time in the upper small bowel when a substantial amount of chyme reaches the ileum or colon. They are believed to be mediated by hormones such as peptide YY, enteroglucagon, and others [12 14]. Most of the nutrients are absorbed in the small intestine and only a minor volume of residue enters the colon. Transit from one to the other is regulated by the ileocecal junction which consists of a valve and a sphincter. When the ileum becomes distended, reflex relaxation of the sphincter allows the passage of the ileal contents into the colon. In contrast, when the cecum gets distended, the sphincter constricts leading to closure of the mucosal valve. Furthermore, the ileocecal valve is thought to prevent backwash of bacteria from the colon into the ileum, thus inhibiting bacterial overgrowth of the small intestine, but this has not been confirmed by recent animal experiments (see Section 4). 4. Pathophysiology Following intestinal resection, the symptoms of an individual patient depend on the absorptive capacities as

4 M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 well as on inborn characteristics of the remaining bowel. In normal human individuals, most of the nutrients are digested and absorbed within the first 150 cm of the jejunum [15]. This observation correlates with the fact that patients with SBS can maintain nutritional balance on oral feeding more easily when more than 100 cm of jejunum are preserved [16]. Gastric secretions and acid production, as well as serum gastrin levels, are elevated in SBS patients during the initial phase. Spontaneous normalisation occurs 6 12 months after the loss of small bowel [17]. The capacity of water and electrolyte absorption in SBS patients does not depend on the residual amount of small intestinal tract alone, but to a great extent on the presence or absence of colon as well [15]. Loss of up to 50% of the small bowel rarely induces significant water or electrolyte imbalance. Water soluble vitamins (B 1, B 2, B 6, and C) are absorbed along the entire small intestine and therefore, sufficient uptake depends largely on the remaining length. Carbohydrate break-down into small oligo- or disaccharides is a major contributory factor to the intraluminal osmotic load which can lead to a significant loss of fluid in SBS patients. Extensive small bowel resection also results in a decrease of microvillar lactase activity and may cause lactose intolerance and D-lactic acidosis [18,19]. Furthermore, undigested fiber, carbohydrates and proteins, undergo a fermentation process in the colon to yield SCFA, which on one hand may provide a significant source of calories if most of the colon is preserved. On the other hand the osmotic load especially of the carbohydrates may contribute substantially to diarrhea if only a little colon remains [10]. Protein absorption in patients with SBS can be effectively increased by adaptation and may reach 60 80% of normal, unless there is mucosal dysfunction due to bacterial overgrowth or Crohn s disease. Products of protein digestion contribute very little to the osmotic load because they are largely absorbed as diand tripeptides, and only partially hydrolyzed to amino acids within the intestinal lumen. Fat malabsorption is a common feature in patients with SBS because absorption depends on the remaining small bowel length as well as on the available bile acid pool. The relatively large molecules of undigested fat have little osmotic effect. In short bowel situations with a depleted bile salt pool hydrolyzed fatty acids and bile salts reach the colon. The former bind to calcium to form calcium stearate, preventing calcium absorption. Subsequently, oxalate which is normally excreted with the feces bound to intraluminal calcium gets absorbed in increased amounts, leading to oxaluria and eventually kidney stone formation [20]. Microbial deconjugation of bile acids in the colon, on the other hand, stimulates chloride secretion, diarrhea, and oxalate absorption as well [15]. Similarly due to the consumption of enteric calcium by undigested fatty acids the deconjugated enteric bilirubin remains in solution. Brink et al. [21] have demonstrated in ileectomized rats a significant EHC of unconjugated bilirubin and significantly increased secretion rates of bilirubin into bile. This observation may explain the 10% incidence of biliary sludge formation and gallstone diseases in SBS-patients [22]. Resection of the jejunum induces only a transient reduction of absorption of all nutrients, as the ileum can adapt very rapidly. Due to a smaller pore size, it is also more restrictive to transmucosal water movement and, therefore, can tolerate an osmotic load better. More serious consequences result from resection of the ileum. The ileum is responsible for absorbing all the water that has been secreted in the upper intestinal tract following a hypertonic meal. If the ileum is resected, this water spills over into the colon. Although the colon can increase water and solute absorption up to 400% of normal, there is a limit to the excess that may be reabsorbed [23]. The surplus of water results in diarrhea. Another consequence of ileal resection is life-long malabsorption of vitamin B 12 due to the loss of site-specific receptors. Furthermore, the ileum is the major site of bile salt absorption. Significant ileal resection results in a depletion of the bile acid pool leading to a disturbed micelle formation, malabsorption of fat and fat soluble vitamins (A, E, D, and K), and steatorrhea. Increased synthesis of lithogenic bile salts entails the formation of sludge and calculi in the biliary tree. In regard to intestinal motility, massive resection of the upper small bowel results in delayed gastroduodenal emptying, a mechanism which is thought to be an important mechanism for lengthening intestinal transit time [24]. After 80% of mid-intestinal resection in dogs, propagation of the interdigestive MMC is significantly slowed and its frequency decreased [25]. All these changes in motility prolong the contact of ingested foodstuff with the mucosal remnants, but may also promote bacterial overgrowth. A variety of congenital malformations characterized by primarily impaired intestinal motility, such as intestinal atresia, gastroschisis with or without intrauterine volvulus or extensive aganglionosis rapidly lead to bacterial overgrowth, especially if associated with SBS. The time required for weaning these patients off parenteral nutrition is significantly longer and the survival rate is significantly reduced in comparison with other causes of neonatal SBS, e.g. after necrotizing enterocolitis or malrotation/volvulus of an otherwise healthy bowel [26]. Resection of the ileum also causes loss of the ileal brake. Consequently, nutrients spend less time in the

M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 5 stomach and in the upper intestinal segments. Due to shorter contact, absorption is reduced, and an unusually large fluid load imposed onto the distal remnants [14,27]. Resection of the ileocecal valve is commonly thought to have detrimental effects by allowing backwash of bacteria, thus enhancing bacterial overgrowth in the small intestine [2,28]. In contrast, experimental short bowel models in rats have shown that additional resection of the ileocecal valve reduces bacterial overgrowth within the intestinal remnants and attenuates bacterial translocation significantly, as compared to ileal resection alone [29,30]. These findings are, if not supported, at least not contradicted either by a recent retrospective analysis of children with SBS in which there was no evidence of a relationship between the occurrence of bacterial overgrowth (and colon length) and the presence or absence of the ileocecal valve [31]. Further studies are required to elucidate the effects of the loss of the ileocecal valve in SBS-patients with normal and abnormal motility of the remaining intestine. 5. The process of intestinal adaptation Adaptation is the term characterizing the pathophysiological process which follows extensive intestinal resection. It includes, firstly, morphological changes of the intestinal remnants leading to an increase of the surface area, secondly, functional changes resulting in an augmentation of the absorptive capacity of the remaining enterocytes, and thirdly, reduction of motility slowing down the transit of chyme. In animal studies, an increase of blood flow to the remaining bowel has been observed as early as 24 h after an 80% mid-intestinal resection, and perfusion of the ileal remnant stayed elevated for at least 4 weeks [32]. Hyperemia is followed by an increase of the DNA content leading to mucosal hyperplasia, and finally an increase of villus height and crypt depth [33]. The latter response is more pronounced in the ileum than in the jejunum, which may be explained by the fact that the remainder of the jejunum in an SBS faces the usual composition and osmolarity of intestinal contents while the ileal mucosa is confronted with a substantially different composition of chyme that enhances mucosal adaptation. The morphological changes eventually result in an impressive increase in length and diameter of the intestinal remnant [34 36]. Adaptive growth in regard to length and diameter of the remaining bowel also occurs in humans with SBS. This is most pronounced in premature babies [37]. Epithelial hyperplasia following massive small bowel resection is observed as well, while villus hypertrophy and crypt depth accretion is not [38]. Nevertheless, adaptation results in an augmentation of the functional capacity of the microvillus transport mechanisms and allows more than 70% of patients to be completely weaned off parenteral nutrition eventually provided that enough intestine remains to undergo adaptation towards sufficient growth of absorptive surface area. Apart from these ongoing changes in the small intestinal remnant, water and solute absorption is also enhanced in the intact colon, colonic bacteria hyperferment undigested carbohydrates and proteins, and the resulting SCFA fulfill an important role as energy providers and apparently, as additional promoters of adaptation [39,40]. Peristalsis in grossly dilated intestinal loops slows down and is characterized by ineffective to and fro movements. The weak propulsion of luminal contents increases the contact time of nutrients with the mucosa, but excessive stagnation of chyme will eventually result in bacterial overgrowth. Although the exact mechanisms responsible for the process of intestinal adaptation are not fully elucidated, it is well accepted that nutrients, gastrointestinal secretions, and enterohormones are key factors to support the underlying physiological forces. 5.1. Nutrients The presence of food in the lumen of the gut is the most important factor for the morphological and functional integrity of the mucosal layer [41,42]. Absence of food together with total parenteral nutrition leads to decreased villus height and crypt depth, impairment of gut barrier function, and increased translocation of endotoxin and bacteria [43 45]. Enteral nutrients stimulate gastrointestinal secretions and hormones that are known to exert trophic effects on the mucosa. The process of intestinal adaptation depends on the type and complexity of the nutrients administered. In general, the higher the workload required for digestion and absorption, the more potent is the stimulus for adaptation [46]. Long chain triglycerides, especially those with highly unsaturated fatty acids, such as menhaden oil, stimulate adaptation more than medium chain triglycerides. Furthermore, undigested enteral proteins enhance adaptation better than protein hydrolysates, and disaccharides are more effective than their constituent monosaccharides [19,47]. Pectin, a carbohydrate fiber, has also been shown to re-enforce the adaptation process in animals, and possibly in humans, too [48,49]. Pectin undergoes fermentation to SCFA within the colon. These may be the essential mediators of the positive influence of pectin a hypothesis supported by recent studies confirming the trophic effects of SCFA s on the intestinal tract [40,50].

6 M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 5.2. Gastrointestinal secretions Gastric juice, bile, intestinal and pancreatic secretions are supposed to stimulate the adaptation process [42,51]. Whether their effects are caused by the secretions themselves or simply by the fact that they contain proteins imposing an additional workload on the enterocytes has not yet been clarified. 5.3. Trophic factors In response to enteral nutrients and secretions a large number of trophic polypeptides and other mediators are secreted. Although the mechanisms by which they work are barely understood, some of them have recently attracted attention regarding their possible clinical value in promoting adaptation in SBS patients. Gastrin was the first hormone that was demonstrated to exhibit trophic effects on the small bowel [52]. Gastrin is released from the G-cells of the antrum after ingestion of food. Gastrin blood levels significantly rise after jejunal resection. This might be due to the decrease of gastric inhibitory polypeptide and vasoactive polypeptide normally secreted from the small bowel. Currently it is assumed that gastrin acts as a trophic hormone only in the very proximal small bowel with little or no effects in the distal part of the intestine where most of the adaptation process takes place [47]. Hypergastrinemia after extensive resection may even prove disadvantageous by causing gastric hypersecretion and imposing a substantial fluid load onto the intestinal remnant. It also decreases the duodenal ph and inactivates most of the pancreatic enzymes [53,54]. Enteroglucagon is synthesized in the ileum and in the proximal colon. It has been shown to exert a remarkable trophic effect on the intestinal tract in animal experiments and in humans [55]. Immuno-neutralization by monoclonal antibodies, however, failed to block this adaptive response [56]. Recent evidence suggests that precursors of enteroglucagon may be the proteins responsible for adaptation since ileal proglucagon m- RNA increases rapidly after intestinal resection [57]. Lately glucagon-like peptide 2 has been shown to stimulate villus hyperplasia in rats. Thus, this could alternatively be the hormone exerting the enteroglucagon effect [58]. Bombesin also induces mucosal proliferation in rats, especially after injury by pre-treatment with methotrexate or atrophy due to feeding an elemental diet or saline solutions [59]. Human growth hormone (GH) is a single chain polypeptide consisting of 191 amino acids. It is secreted by the anterior pituitary gland and exerts direct and indirect metabolic effects, the latter by the production of insulin-like growth factors. It has significant anabolic effects including nitrogen retention, enhanced ileal mucosal amino acid transport, enhanced sodium and water absorption, and promotion of mucosal hyperplasia in animals [60,61]. Although the exact mechanisms remain unclear, it has been shown that GH exerts its effect at the molecular level by increasing nutrient carrier protein m-rna expression, e.g. GH up-regulates glutamine uptake in SBS rabbits by increasing the number of transport proteins available, and thus the maximal transport capacity and velocity V mx [62]. Epidermal growth factor (EGF) is a 53 amino acid polypeptide secreted by the salivary glands and the duodenal Brunner s glands. It increases DNA synthesis and cellular proliferation [63]. EGF induced up-regulation of intestinal electrolyte and nutrient transport has been demonstrated in a number of animal experiments using a SBS model [64]. EGF receptors are found throughout the small bowel [65]. The combination of GH and EGF enhanced microvillus height, glucose, glutamine and leucine transport in the jejunum, while uptake of alanine and arginine were increased in the ileal remnant following massive enterectomies in rabbits [62]. The improved absorption of all of above substrates has profound beneficial effects on intestinal mucosal metabolism and function. Insulin-like growth factor-i (IGF-I) is synthesized primarily in the liver but also in intestinal tissues. Production is stimulated by enteral feeding itself and/or indirectly by GH which exerts many of its anabolic actions via generation of IGF-I in the liver and other peripheral tissues [66]. IGF-I receptors have been identified in all segments of the gastrointestinal tract. IGF-I stimulates DNA and RNA synthesis and cellular amino acid uptake [67]. The endogenous GH-IGF-I system is an important regulator of small intestinal growth and adaptation [68]. Combining recombinant IGF-I administration with enteral glutamine supplementation synergistically increases ileal mass during intestinal adaptation in rats [66]. The latter study demonstrated that either substance enhances small intestinal hyperplasia on its own, but the combination of both proved significantly more effective. In addition, IGF may also promote colonic adaptation by stimulating fluid and electrolyte absorption [69]. Transgenic mouse models have confirmed the importance of GH and IGF in regulating the intestinal mass [70]. Although the absorption of substrates was clearly enhanced by intraluminal administration of EGF and IGF-I, no changes of villus crypt ratio, mean number of villi, and mean villus height were found in rats after 14 days of treatment following 80% mid-intestinal resection [71]. Among the amino acids glutamine (GL) plays an important role in the maintenance of intestinal structure and function by providing the energy required by cells with a rapid turnover, such as macrophages or enterocytes. It is synthesized in practically all tissues, acts as a precursor of protein synthesis, and is an

M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 7 Fig. 1. Adaptive growth 4 weeks after 80% midintestinal resection in rats: the left side shows the ileum without treatment, the right side shows the stimulation of growth by a PgE 2 compound (identical magnification) [80]. important mediator in a large number of metabolic pathways [72]. GL is continuously released from skeletal muscle, but in chronic illness the tissue consumption exceeds skeletal muscle production, and plasma and intracellular concentration of this amino acid decreases. As a result GL has recently been considered a conditionally essential amino acid which cannot be sufficiently synthesized by cells during catabolic states. Therefore, patients after major trauma or in chronic catabolic states will benefit from GL supplementation [72,73]. The intestinal mucosa is able to extract large amounts of GL from the circulation. Recent studies have provided biochemical and morphological evidence that GL might protect the small bowel against noxious agents by, on the one hand, acting as a specific survival factor in enterocytes while, on the other, its deprivation induced apoptosis in intestinal epithelial cells of rats [74]. In regard to SBS, it has been shown that GH increases GL uptake after intestinal resection in the jejunal remnant by 100% [66]. While studies by Vanderhoof and coworkers [75,76] could not confirm a role for GL or GH as trophic agents for the intestinal tract, a large number of other investigations have demonstrated a protective role of GL for maintaining the gut structure and barrier function during critical illness in animals and humans [77,78]. There is evidence that GL exerts trophic effects not only on the small intestine but also on the colon in patients with SBS [61,66,72]. Prostaglandin (Pg) E 2 and polyamines have also been shown to stimulate cell proliferation in animal experiments by increasing blood flow and DNA synthesis [79]. Four weeks of feeding a synthetic Pg E 2 compound stimulated adaptive growth in short bowel rats by inducing significant intestinal growth in length and diameter, and by increasing villus length and crypt depth [80] (Fig. 1). Finally, testosterone has been shown to enhance adaptation after small bowel resection in cats [81]. 6. Clinical management 6.1. Medical treatment: The clinical course of SBS can be divided into three stages which require individual management: the acute phase, the adaptation phase, and the maintenance phase. The acute phase the duration of which depends on the underlying disease is characterized by insufficient absorption, dysmotility, diarrhea, and gastric hypersecretion. Therapeutic measures are guided by the underlying disease process and the severity of illness of the patient, and primarily aimed at restoring and maintaining fluid, electrolyte and acid base equilibrium. The following adaptation phase is slower in humans compared to animals and often takes more than a year to reach its peak unrelated to the absolute length of intestinal remnants [19]. Treatment strategies during this phase include parenteral nutrition and carefully balanced, stepwise increasing enteral feeding. Diligence and patience are necessary prerequisites to reach the maximum of what can be achieved in a given patient. Surgical methods can only support the adaptation process and must be evaluated very carefully. Finally follows the maintenance phase in patients with a constant malabsorption rate of 30% or more, during which a surplus of enteral calories has to be consumed daily, supplemented by vitamins, trace elements and minerals, adapted to the individual demands [15] (Table 2). Parenteral nutrition is a key factor in treatment and is usually necessary for many months. For its delivery a central venous line is essential, constituting a life-saving measure for patients with SBS. Catheter related complications, of which infections represent a major one, must be minimized. Meticulous handling of the indwelling catheter is of paramount importance in the care of SBS patients. An established catheter sepsis must be treated

8 M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 Table 2 Therapeutic algorythm of SBS vigorously with systemic antibiotics, and by removal of the catheter if antibiotics fail to control infection. Balanced fluid and electrolyte solutions must cover the basic demands and replace losses via a nasogastric tube, from an enterostomy, or due to excessive diarrhea. Existing nutritional deficiencies should be restored by adequate supplementation of carbohydrates, protein, and fat. Calorie intake in children needs to be continuously advanced to accommodate the increasing demands of the growing organism. Growth in weight, height and head circumference are the basic parameters to ensure adequacy of parenteral nutritional solutions and enteral feeding. In newborns and small infants an infusion running continuously over 24 h is most appropriate. In contrast, when older patients take at least 20% of their total calorie requirements by the enteral route, intermittent parenteral feeding can be attempted and the intervals increased as long as serum glucose levels are maintained. In the older age groups and in adults a 12-h infusion time is usually well tolerated. Finally, parenteral nutrition can be restricted to the nocturnal period. The possibility of home parenteral nutrition considerably improves the quality of life for the patients and their families allowing a more normal lifestyle, and substantially reduces hospital costs. Enteral feeding is usually introduced by continuous infusion via a gastric or jejunal tube as soon as the intestinal remnants resume normal motility. This avoids gastric distension and offers a constant load of carrier proteins to the microvilli. Elemental diets are started in a low concentration and are slowly increased to 0.67 kcal/ml in infants, and 1.0 kcal/ml in children and adults [47]. A high carbohydrate content represents a substantial osmotic load and may cause diarrhea. A stool volume, which increases by 50% compared to baseline is an indication to reduce the amount and/or concentration of enteral feedings. Stool samples positive for reducing substances also suggest that enteral feeding should not be advanced and carbohydrate uptake should be reduced. In infants with normal colon length, a decrease of stool ph below 5.5 signals carbohydrate malabsorption. Protein hydrolysate diets are beneficial due to their higher content of di- and tripeptides. In infants up to 6 months, protein containing diets might cause a protein sensitive enteritis/allergy. Therefore, amino acid formulas are preferred. Medium chain triglycerides are water soluble and can be absorbed without the need for bile acid micelle formation, but their efficiency in enhancing the adaptation process is far lower in comparison to long chain fatty acids. Therefore, elemental diets in pediatrics contain both medium and long chain fatty acids, the mixture probably being the most efficacious for stimulation of adaptation. As soon as the infant s condition improves, oral

M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 9 feeding of small amounts of diet three or four times daily should be attempted so that the child learns to suck, taste, chew and swallow properly with the aim of avoiding the problem of total refusal of any oral intake, not infrequently encountered after long term total parenteral nutrition (TPN) and enteral tube feeding. For the maintenance phase in adults, Wilmore et al. [82] recommend a special diet supplying approximately 55 60% of total calories from carbohydrates, 20 25% from fat, and 20% from protein with calories and proteins equally distributed into six meals. Blood levels of vitamins, trace elements and minerals must be checked regularly and any deficient substance supplemented either orally or parenterally as appropriate. Dietary modifications are recommended depending on the individual situation. Patients suffering from SBS with the colon intact benefit from a high fiber intake because the colon is capable of fermenting carbohydrates. On the contrary, patients who have had the large bowel removed or excluded may fare better with a diet rich in fat providing a high energy concentration with a relatively small osmotic load [10]. Triglycerides with highly unsaturated long-chain fatty acids such as menhaden oil have exerted more trophic effects on the intestinal remnants after resection than other long chain fatty acid containing oils in animal experiments [83]. In addition, recent studies in rats have shown that SCFA supplementation of TPN enhances morphological and functional aspects of adaptation [40]. From these results, one might speculate that further modifications of TPN formulas for humans might stimulate intestinal adaptation even before the introduction of enteral feeding. In addition to carefully balanced nutrition, some patients with SBS benefit from additional pharmacological treatment. This may improve mucosal function and stimulate the adaptation process, or prevent/reduce complications of the disease itself or of adverse effects of long-term parenteral nutrition. As mentioned above adequate GL supply appears mandatory during critical illness. Administration of GL dipeptide enriched intravenous feeding solutions and GL enriched formulas for enteral nutrition have been shown to exert trophic effects on the human gut [84]. The combination of GL and GH together with a specialized diet has been used in a group of patients whose intestinal absorptive surface area had been considered inadequate to become independent of parenteral nutritional support [61,82]. After 4 weeks of treatment, half of the patients thrived on enteral feeding alone. Predictors of a favorable outcome in this study included greater bowel length, lower body weight, and, especially, association of the two resulting in a high bowel length/body weight ratio. While GL or GH alone had only marginal effects, the combination of both together with the special diet proved highly efficient [61]. However, a major criticism of this uncontrolled study has been directed to the fact that the trophic impact of the special enteral diet was not evaluated in isolation. Thus, nonspecific effects of aggressive enteral feeding could not be differentiated from a selectively pharmacological benefit [47]. An otherwise similarly set up, but double blind placebo-controlled randomized trial resulted in only modest improvement of electrolyte absorption and discrete delay in gastric emptying, while small bowel morphology, macronutrient absorption and fecal losses remained unaltered [85]. Ellegard et al. [86] performed a randomized double-blind crossover study comparing recombinant human GH with placebo in 10 adults with SBS. Following GH administration serum levels of IGF-1 doubled, and body weight and lean body mass increased, but significant alterations of the absorptive capacity for water, protein, or other nutrients could not be detected. In recent animal experiments, neither GL nor GH stimulated gut adaptation [76]. It thus remains controversial whether GL and/or GH supplementation should be recommended in the treatment of SBS and there remains a need for controlled clinical trials in order to elaborate which agents have a lasting impact and thus prove beneficial for the long term. Gastric hyperchlorhydria during the early phase after extensive loss of intestine can be suppressed successfully either with H 2 receptor antagonists or with proton pump inhibitors, thereby improving absorption and reducing high output diarrhea [87]. Rapid intestinal transit can be slowed by opioid medication. In this group loperamide has proved effective and safe to use in the pediatric age group even over a long period of time. Another agent, octreotide acetate, a somatostatin analogue which essentially inhibits all exocrine and endocrine gastrointestinal secretions, is apt to improve quality of life in patients with predominantly secretory losses, and has been judged beneficial in at least some patients on long-term treatment [88]. Unfortunately, it has more side effects in comparison to loperamide and is rather expensive. Interference with the adaptation process has been discussed, but recent work has not supported this fear [89]. Cholestyramine binds bile acids and prevents choleretic diarrhea induced by an excess of bile salts in the colon. While thus reducing diarrhea, it may increase stearrhoea. Ursodeoxycholic acid is supposed to counteract additional hepatic damage by restricting the absorption of potentially toxic bile acid metabolites from the colon [90]. Of course, the latter considerations only apply if the colon is present. In patients with ileal resection but an intact colon, urinary oxalate levels should be monitored. Dietary oxalate restriction is to be recommended in patients with high levels of oxaluria. A surplus of calcium ingestion provides additional oxalate binding capacity. In order to avoid metabolic bone disease, calcium, vitamin D, and alkaline phosphatase levels in the serum should also be checked periodically, as well as the other fat soluble vitamins, and vitamin B 12 if the terminal ileum is lacking.

10 M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 6.2. Surgical options The primary aim of surgical interventions is restoration of the bowel continuity as soon as possible in order to allow all remaining intestinal segments to take part in the adaptation process. Following this, the majority of patients will finally adapt to full enteral feeding and not require additional operations [22]. Surgery, then, only comes into play again to deal with complications such as mechanical obstruction and ileus, or if adaptation is impaired by one of the following problems: (1) the absorptive surface area is too small to allow enteral feeding, (2) intestinal transit is too fast to allow sufficient absorption of nutrients, or (3) dysmotility in grossly dilated loops entails stagnation of chyme (Table 3). Augmentation of the absorptive surface area has been attempted almost exclusively in animal experiments by autologous mucosal transplantation into demucosed intestinal loops, which have undergone mucosectomy or attachment of longitudinally opened bowel loops to other structures (liver, muscle) across the surface of which mucosal growth ensues [91,92]. Digestive and absorptive function of this neomucosa is considerably lower compared to native mucosa, however, and peristalsis is virtually lacking as to be expected in the absence of the muscular layers of the normal bowel wall [93]. So far, none of these techniques has proved successful in the long run. Intestinal transplantation (TPX) is, of course, the most effective method to increase absorptive area. This procedure can be categorized into two classes: isolated intestinal TPX, and combined small bowel and liver TPX. The latter represents the only chance of survival for SBS patients with irreversible liver failure and end stage liver disease. Indications for TPX of the small bowel alone are less clear cut, but is to be considered in infants with very little or no small bowel who are expected to always be dependent on TPN and subsequently are bound to develop progressive liver failure, as well as in patients with recurrent sepsis and/or very difficult venous access [4,94]. Until recently the results Table 3 Surgical strategies in SBS patients To increase To increase absorptive sur- To improve peripassage time face area stalsis Antiperistaltic segment Colon interposition Intestinal valves Artificial invagination Serosa patching Mucosa transplantation Small bowel TPX Tapering Tapering and lengthening of intestinal TPX had been poor, mainly due to a high rejection rate. With the introduction of new drugs, such as Tacrolimus and OKT3 in addition to steroids, promising progress has been achieved with the 1 year transplant survival rate approaching 75% in recent series [47]. It is hoped that the adverse effects of these new immunosuppressive agents, which include lymphoproliferative diseases related to EBV infections reaching an incidence of 20%, can be minimized [95]. A variety of surgical procedures to lengthen intestinal transit time have been invented and applied in humans [96]. Reversed (antiperistaltic) intestinal segments have been used in over 40 patients, and in most of them a delay of chyme transport was achieved and increased absorption documented. However, all of these reports are anecdotal, and so far it remains uncertain whether these effects will be maintained. Long term follow up is mandatory to answer this question. Intestinal valves and sphincters have been created in a few humans, mostly children, with doubtful results. A segment of colon can be interposed in the small bowel, more proximally in the isoperistaltic direction, or in an antiperistaltic manner distally [97]. In a series of 11 children and one adult (11 isoperistaltic forms), promising results were observed in six. Chemically induced bowel denervation slowed intestinal transit and improved weight gain and survival in rats after 80% bowel resection [98]. Dilated intestinal loops with inefficient peristalsis and stagnant chyme are a common problem in patients with SBS, either as a consequence of the underlying pathology, e.g. remnants after multiple atresias, or following initially effective adaptive growth that finally overshoots to result in large dilated bowel segments with insufficient and undirected motility. Bianchi [99] introduced a very interesting procedure consisting of longitudinal division of the dilated part into two separate segments each comprising one half of the circumference. Both segments remain viable because the mesenteric vessels divide extramurally into branches supplying either side of the bowel separately. The two halves are then refashioned to tubes of normal intestinal diameter which are lined up in the isoperistaltic direction and anastomosed to one another yielding twice the length of the original part (Figs. 2 and 3). Bianchi s method [100] has been used in more than 50 infants. It has proved successful when performed in a later stage of the disease on so called self-selected survivors, i.e. patients in stable general condition free of other severe complications. Kimura and Soper [101] described a similar method dividing the dilated bowel segment horizontally. As this would devitalize the antimesenteric half by cutting off its feeding vessels, it is necessary to attach the submucosal layer of this part to another organ liver or abdominal muscle in the first step in order to parasitize the blood supply. Once perfusion is adequate,

M.E. Höllwarth / Pathophysiology 6 (1999) 1 19 11 7.1. Central enous catheter complications The ability to provide long-term parenteral feeding through a central venous line is one of the major achievements in modern medicine. However, disadvantages of long-term parenteral nutrition include the risk of bacterial contamination of the inserted catheter. Although infants are more prone to recurrent catheter sepsis, all age groups may be affected. After insertion of a central venous line its outer surface is rapidly coated by a thin layer of fibrin, albumin and platelets. This fibrinous sheath has been suspected to contribute to catheter infection by providing a surface area onto which bacteria preferentially adhere. However, recent experiments comparing fibrin coated with uncoated catheters did not confirm the fibrin coat to represent an additional risk factor [104]. The inner surface behaves differently due to its contact with hyperosmolar solutions and blood. Clot formation can be observed rapidly and may cause either occlusion of the catheter or protrusion of thrombotic material Fig. 2. Longitudinal division of an enlarged intestinal segment in a newborn. The vessels are divided according to their distribution to the right and left side. the horizontal division can be performed. Continuity is restored by isoperistaltic anastomosis, as by Bianchi. Finally, intestinal refashioning can be achieved surgically by tailoring the antimesenteric side of a dilated loop, either by resection of abundant wall provided that enough absorptive area remains available and stasis is the only problem or by infolding the excessive part of the intestinal circumference in a longitudinal way [102,103]. 7. Chronic complications Despite the progress in intensive care medicine and long-term parenteral nutrition, many complications do occur in patients with SBS, some of which are life threatening. The most important problems will be discussed in this section: central venous catheter related problems, liver failure, and bacterial overgrowth and translocation. Fig. 3. The sketch shows how the two separated halfs of the intestine can be anastomized in a prograde fashion during bowel lengthening procedure.