Short bowel syndrome : Intestinal adaptation and medical therapy

Short bowel syndrome is a clinical entity, a consequence of significant loss of intestinal surface area, and manifests a variable picture of diarrhea, steatorrhea, malabsorprion and weight loss. Previously high mortality rates have been reduced by the early use of parenteral nutrition and have subsequently resulted in increased survival and prevalence of the condition. Ultimate patient survival is dependent on the intrinsic adaptive ability of residual intestine and this, in tum, is dependent upon length, type, functional state and the presence or absence of an ileocecal valve. The mechanisms of intestinal adaptation are not entirely understood; however, they can be grouped into three broad categories: luminal nutrition, hormonal factors, and pancreaticobiliary secretion. Medical treatment of short bowel syndrome remains supportive and centres around the control of three pathophysiological defects: decreased intestinal transit time, gastric hypersecretion, and reduced functional mucosa! surface area. CanJ Gastroenterol 1990;4(2):70-78


S URGICAL T REATMENT OF MANY
gastro intest inal diseases necessitates resection of segments of small intestine.This is well tolerated in most cases due to the in trinsic reserve of the gastrointestinal tract.However, massive intestinal resection can lead to a variable clinical picture of diarrhea, steatorrhea, malabsorption and weight loss.T his constellation of clinical events has been termed 'short bowel sy nd rome' and has been recently reviewed (1,2).
The disease states which predispose to mass ive intestinal resection are determined primarily by the age of the patient.T he infan t population must contend with necrotizing enterocolitis, atresias, volvuli and abdominal wall defects with resultant herniation and vascular compromise (3,4).The adult is more likely to be faced with repeated resection as a consequence of Crohn's disease (5 ), while in the elderly, resection is most likely due to mesenteric infarct (6).
In the past, there has been a high mortality rate assoc iated with short bowel, and thus, short bowel syndrome eleves, et a entratne une augmentation de la survie et du nombre de cas de cette affection.La survie ultime du patient depend de la capacite intrinseque d'adaptation du segment d'intestin preserve, laquelle capacite depend a son tour dela longueur, du type,de l'etatfonctionnel etde la presenceou non de la valvule lleo-caecale.Les mecanismes d'adaptation intestinale ne sont pas entierement compris mais peuvent toutefois etre classes en crois grandes categories: la nutrition au niveau des lumieres, les facteurs hormonaux et la secretion pancreaticobiliaire.Le t raitement meedical du syndrome de l'intestin court consiste surtout ~ apporter un soutien au patient et s'attache a controler trois problemes physiopathologiques: la diminution du transit intestinal, l'hypersecretion gastrique et la reduction de la surface fonctionnelle de la muqueuse.
was an e xtremely rare entity (7,8 ).Development of improved supportive care and total parenteral nutrition have prolonged survival and made this condition prevalent ( 4,(9)(10)(11).Parenteral nutrition has allowed continued intravenous feeding during intolerance to oral nutrition , and patients with extremely sh ort bowel can now exist entirely o n h o me to t al p a re nteral nutrition (12,13).
Although it is we ll known tha t residual small bowel length below 50 cm makes maintenance of adequa te nutrition difficult, the minimal length of small intestine compatible with life (withuut nutritional support) is poorly defined.In the early 1950s it was believed that survival with less than one half of the small bowel length was improbable (7,8 ).This was q uickly challenged by reports of patients surviving with shorter and shorter lengths of bowel (14)(15)(16).The first comprehensive study of sh o rt bowel syndro me in children was published in 1972 by Wilmore, in which he reviewed the outcome of 50 infants (17).He found tha t survival depended to a large extent on the presence or absence of the ileocecal valve in addition to residual intestinal length.Infants with greater than 38 cm of small bowel and an ileocecal valve had 100% long te rm survival, while chose with 15 to 38 cm had only 50% survival.Infants with less than 15 cm of bowel had l 00% mortality regardless of the status of the ileocecal valve.In the absence of an ileocecal valve, 40 cm of residual bowel was the lower limit for any degree of survival.
The next most important determinant of the clinical picture following small bowel resection is intrinsic intes-tinal adaptation (18 ).Intestinal adaptation is fe lt to be influenced by t hree factors: the type of intes tine t ha t remains; the disease state for which the resection was necessary; and the condition of the residual intestine ( 1,2 ).
Presently, treatme nt of the short bowel syndrome can be divided into two ge n e ral ca tego ries: suppo rti ve therapy and therapy to enhance intest i n a I adaptatio n .M ost trea tme nt measures, whethe r medical or surgical.are supportive in nature while awaiting intrinsic intestinal adaptation.Recent developments suggest that some modes of the rapy may e nhance or accelerate intestinal adaptation .This review will first examine intestinal adaptation fo llowing the stimulus of small bowel resection.It will then examine medical therapy for th e sho rt bowel syndrome.For the purpose of this discussion, a strict definition of short bowel syndrome as defined by length or percentage of bowel resected will be avoided because of the extre me variation in function of patients with similar residual lengths (2).The d efinitio n used will be a clinical one in which the signs and symptoms outlined above a re present.

INTESTINAL ADAPTATION
Intrinsic intestinal adaptation may be the single most important variable affecting the eventual o utcome of a patient with short bowel syndrome.Ir, in tum, is dependent upon four factors: the length, type and functional state of the residual intestine, and concomitant colonic and ileocecal valve resection, both of which are detrimental to adaptation (1 ).
It has been shown clearly by  (18,21,22 ).If the residual intestine is affected by an active disease process such as Crohn's disease o r di ffuse a rte r iosclerosis, intestinal adaptation may also be inhibited.
Adaptation is also a function of rime, and in humans it is gene rally accepted as continuing for up co two yea rs fo llowing small bowel resection ( 1,2,23 ).The definitive effects of medical or supportive therapy cannot be evaluated until after this time.
Intestinal adaptation can now be discussed from two viewpo ints: morphological and functio nal.O riginal descriptive studies of intestinal adaptation were Jone from a mo rphological viewpoint only and it has been only in the past 20 years that functional studies have heen performed to complement them.
Morphological adaptation: Macroscopic ch an ges fo llowing intestinal resection have been recognized since the classical experiments of Senn in 1888 (24) and Flint in 191 2 (25), and have been confirmed by many subseque nt studies (26-3 l ).Residual intestine undergoes d ilation and thickening of a ll o f its layers (29 ).However , whether or not there is a true increase in bowel length is controversial and may, in part, be attributed to the di fferent an imal models examined.Most authors believe that an increase in intestinal length is not pa rt of the morpho log i ca I ad ap tive response in humans (1 8,21,32).
The microscopic picture of intestinal adapta tion h as also been well described.Flint in h is classic paper ( 25) , demonstra ted that the intestinal vi lli doubled in height, and while he calculated a fourfo ld increase in mucosa!surface area, he correct!y o bserved that the number of vill i remained constant and crypt depth increased.Subsequent studies have confirmed these observations (26)(27)(28)(29)(30)(31)(32)(33)(34).
Mucosa! hypertrophy is maximal just distal to the post resectional anastomotic site and decreases further downstream (28).Although distinct mucosa!hyperplasia occurs proximal to the anastomosis, it is far less pronounced.J ej unal resection produces a 70 to 100% increase in structural and functional measurements in the residual ileum, whereas ilea! resection produces only 20 to 30% increases in structural and functional measurements in residual jejunum (27,28,(32)(33)(34)(35). Functional adaptation: The morphological adaptations observed likely contribute to functional adaptation.These functional alterations can be separated into changes in absorption and motility.
The loss of mucosa!surface area reduces the absorption sites of almost all nutrients and, as a consequence, functional adaptation is seen involving the absorption of most nutrients (21,33).There is increased segmental absorption of fluid and electrolytes (36).Oligosaccr ... rides and monosaccharides are absorbed at increasing rates when absorption is expressed per length of intestine (21,31,37).Thus it appears that absorption can be induced, suggesting the possibility of receptor recruitment (38,39).
Brush border enzymes also show adaptive changes with increase in total activity per segment; however, the specific activity of the enzymes is not altered and may even decrease in vitro (38,40).It has been suggested that brush border membrane enzymes may be induced earlier along the villus so that enterocytes are functional at an earlier stage of development (29,41).Recently, however, studies by Menge and Chaves (42) on disaccharidase activity in post resectional rat mucosa showed maintenance of the normal enzymatic gradient along the villus and emphasized that the cells are probably not functional immature cells.The function of individual enzymes may be more dependent on the total enzyme activity levels in the residual segments prior to resection, as specific enzyme systems are not uniformly distributed throughout the bowel.Despite these changes in brush border enzymes, the lipid composition ( total free fatty acids, total bile acids, total cholesterol, total and individual phospholipids, and the ratio of total phospholipids to total cholesterol) of brush border membrane was found to be similar in control resected intestine (43).
Adaptation to the absorption of amino acids and peptides also occurs following intestinal resection.The brush border becomes much more efficient at protein utilization, increasing both absorption and peptidase activity as expressed per unit length (21,33,38).Again, this is probably secondary to mucosa!hyperplasia (41).
Adaptation to lipid digestion and absorption is more difficult to assess due to the confounding problem of bile acid pool losses.It appears that there is an increase in the absorption of free fatty acids, mono-and diglycerides per unit length of residual intestine (21).
As seen with the morphological adaptive response to intestinal resection, the functional adaptive response of the ileum is greater than that of the jejunum.In the normal intestine, jejuna!absorption of nutrients is greater than the ileum.With jejuna!resection, the ileum adapts to absorb nutrients at nearly the same or increased rate relative to normal jejunum ( 44 ).Following ilea! resection, residual jejunum undergoes a small degree of adaptation.The increase in absorptive function is not as marked and it cannot assume the specialized ilea! functions of bile salt and vitamin B12 absorption (21,33).Interestingly, as ilea!enterocytes undergo adaptive hyperplasia, there is a supranormal absorption of both vitamin B12 and bile acids as expressed per unit length of intestine, although this appears to be of little clinical consequence (21).
As the major cause for malabsorption in the short bowel syndrome is the loss of mucosa[ surface area, the morphological changes of adaptation to increase the residual surface area are understandable.Similarly, maintaining the functional capacity of the short gut requires that the intestine absorbs more per unit length.Clinically, functional adaptation is observed as the patient with short bowel syndrome slowly recovers tolerance to oral feeds with diminishing diarrhea and steatorrhea (1,2,18).
The second functional adaptation involves intestinal motility.Transsection of the proximal bowel separates the duodenal pacemaker from the residual intestine ( 4 5).Uncoordinated peristalsis, combined with dilation of the intestine leads to ineffective forward propulsion and mixing.This results in bacterial overgrowth, impaired mixing of chyme, poor digestion and alteration in transit time.
There is recent evidence that the ileum acts as a brake on proximal intestinal transit.Initial studies by Snell ( 46) first described the association between steatorrhea and small bowel hypomotility.In a recent experiment, Spiller et al ( 4 7) demonstrated that the instillation of fat into the ileum caused a delay in transit time of jejuna!contents ( 4 7).The effect was not seen with the instillation of either carbohydrate or protein solutions.This may further explain why jejuna!resection is clinically better tolerated than ilea!resection, as a residual ilea I segment can still exert this braking effect on intestinal transit.

MECHANISMS OF ADAPTATION
How does intestinal adaptation occur?There is no single theory which explains all of the experimental evidence.Three major factors proposed are: luminal nutrition, hormonal or systemic factors, and pancreaticobiliary secretions.Luminal nutrition: Evidence for the importance of luminal nutrition in the adaptive response following resection is best illustrated in three situations.
When luminal nutrition is withheld by starvation, with or without maintenance of parenteral nutrition, the intestinal mucosa atrophies (48,49).This intestinal atrophy can be reversed by the reinstitution of oral nutrition (50).Second, exclusion of the intestine from the luminal stream by creation ofThiry-Vella fistulas, or with intestinal bypass, causes atrophy in the defunctioned intestine ( 44,51).Furthermore, Jacobs et al (51) showed that the institution of elemental Vivonex (Norwich-Eaton) solution into a Thiry-Vella fistula not only prevented atrophy but induced mucosa!hypertrophy.Third, transplantation of the ileum to a more proximal position in the gut exposes the ileum to a greater volume of luminal nutrients with a resultant ilea! mucosa) hypertrophy and functional adaptation.The jejunum which is now lying downstream from the ileum undergoes slight hypoplasia (52).
The relative importance of luminal nutrients in the adaptive response to resection is unknown.Studies by Morin (53) in rats showed that the oral infusion of only 20% of the total daily caloric requirements as long chain triglyceride fat prevented intestinal atrophy in rats maintained on parenteral nutrition.Protein and carbohydrate when infused in a similar manner had only a partial sparing effect.
Whether the effect of luminal nutrients on intestinal adaptation is mediated directly or indirectly through parac, me or endocrine responses remains to be determined ( 54).Hormonal factors: Not all facets of intestinal adaptation are adequately explained by the effects of luminal nutnt1on.Mucosa!hyperplasia proximal to an anastomosis and the hypertrophic effect of intestinal resection on a previously constructed Thiry-Vella loop suggest that other mechanisms must be present (28,55).
Perhaps the strongest evidence for the existence of humeral factors is the parabiotic rat studies and the cross-circulation experiments in pigs.In these experiments, paired animals are either cross-circulated with each other's blood on a continual ( the rat) or intermittent (the pig) basis.When one animal in the pairing undergoes a small bowel resection, mucosa!adaptation is seen in both the resected animal and its partner (56,57).
The search for the elusive humeral factor has led through a number of hormones from the gut and elsewhere.Initial investigations centred around the hormone gastrin, as many authors felt that this was the trophic hormone of the gut (58,59).The observation of elevated gastrin levels in animal models of short bowel syndrome suggested an indirect association (60).Yet gastric hypersecretion and hypergastrinemia were not found universally, and several studies demonstrated a lack of correlation between levels of serum gastrin and observed intestinal adaptation (61,62).Furthermore, there was no hyperplasia observed in patients with Zollinger-Ellison syndrome or pernicious anemia, conditions which have high serum gastrin levels.It is now felt that the trophic effects of gastrin are limited to gastric and duodenal mucosa!growth with little or no effect on small intestinal adaptation (62,63).
Cholecystokinin and secretin have also been postulated as possible intestinal trophic factors (21,33).Unfortunately, it is difficult to separate the direct effects of these hormones from those of the pancreaticobiliary secretions which they stimulate.Exogenous cholecystokinin and secretin given to dogs maintained on total parenteral nutrition prevented the intestinal hypoplasia which normally occurs on total parenteral nutrition ( 64).Weser et al (65) in trying to delineate which hormone was more important, found that cholecystokinin given alone in parenterally fed rats was the trophic hormone in the cholecystokininsecretin mixture.However, in another experiment, Hughs (66) gave synthetic cholecystokinin octapeptide to rats in a high and low dosage scheme only to find that there was no effect on the intestinal mucosa in either case but a marked effect on pancreatic growth.The divergent results with cholecystokinin may relate to differences in amino acid sequence between synthetic and natural fragments examined.
Prolactin has also been investigated as a prospective agent due to the mucosa I hyperplasia seen with lactating rats.Muller (67)  Hormone profiles in models of intestinal adaptation have consistently shown elevation of the hormone enteroglucagon (68)(69)(70).Enteroglucagon, though structurally similar to pancreatic glucagon, is produced in the intestine with maximal concentrations in the ileum and the colon (54,71).A classic case report by Gleeson et al in 1971 (72) demonstrated intestinal mucosa!hyperplasia in a patient with a renal cell enteroglucagon-secreting tumour.Following surgical removal of the tumour and return to normal enteroglucagon levels, the patient's intestinal mucosa reverted to normal (73 ).Experiments by Bloom and Dowling (21) in rats with extracts made from the tumour confirmed that the tumour products caused mucosa[ hypertrophy.Jacobs et al (74) examined enteroglucagon levels in three models of rat intestinal adaptation: resection, lactation and cold-induced hyperphagia.
In all cases the concentration of emeroglucagon was greatest in the ilea[ mucosa.When enteroglucagon concentration was expressed as quantity per unit weight of mucosa, there was also a marked increase.This suggests that either there were more enteroglucagon-producing cells in the intestine, or the cells were making enteroglucagon at an increased rate.
The definitive proof for a trophic effect of emeroglucagon resides in the ability of pharmacological doses to promote intestinal adaptation.Several experiments have been performed thus far with singularly disappointing results (75).It may be that enteroglucagon is not the trophic hormone but has a permissive effect on the adaptive process.
Other hormones examined as potential mediators of adaptation include epidermal growth factor, vasoactive intestinal peptide, peptide YY and the trophic peptide polyamines: putrescine, spermidine and spermine ( 7 6-78).Only the latter family of compounds have been shown to correlate with the adaptive phenomena.The enzyme omi thine decarboxylase seems to be activated by adaptation and is the rate-limiting step in the synthesis of polyamines.The role and importance of these peptides in in-testinal adaptation is unknown at the present time.Pancreaticobiliary secretions: Some of the effects of pancreaticobiliary secretion have been outlined in the previous section on the hormones cho lecystokinin and secretin.It is not known whether the effect of pancreaticobiliary secretion is separate from the effect of these hormones (79).O riginal studies by Altman and Leblond (80), in which bile and pancreatic secretions were diverted to isolated loops of ileum, demonstrated mucosa!hyperplasia with increases in villus size.Later experiments with the intraluminal infusion of previo usly isolated pancreatic juice showed a trophic mucosa!effect (81 ).The adaptation seen in these early experiments are now fe lt to be due to the protein load given intraluminally and are explained by the effects of luminal nutrition.
Experiments with pancreaticobiliary diversion in rats showed that post resectional ilea! hyperplas ia could be further enhanced by pancreaticobiliary diversion to the midpo int in the intestine (80,81).U nfortunately, the expected hypoplasia of the proximal jejunum did not happen and, in fact, the mucosa became somewhat hyperplastic wi th increases in villus height, mucosa!mass and absorptive surface area.These latter observations have cast some doubt o n the re lat i ve importa n ce of pancreaticobiliary secreti on in the adaptive process.Most authors feel that although there is no question as to the trophic effects of pancreaticob iliary secretion on the pancreas, the effects on the intestine are minimal and of little consequence in intestinal adaptation (79,(82)(83)(84).Other factors: Several other factors have been looked into as possible mediators of adaptation (21 ).Changes in mucosa!bloodflow may be the final common pathway to all the changes of adaptation.LaPlace (85) demonstrated the abo lishmen t o f t he adapt ive response to partial bowel resection after vagotomy in a pig model, but little else is known of the role neural factors play.Also of interest is the effect of changing luminal bacterial flora, and additional trophic factors from the saliva, stomach and duodenum (33 ).Further investigation is needed to determine the relative importance of these factors.

TREATMENT
Aside from malnutrition and weight loss there are many metabolic complications which may arise from the short bowel syndrome.These include gastric hypersecretion (86) , watery d iarrhea, malabsorpcion of fat and the fa t-soluble vitamins with accompanying steatorrhea, hypokalemia and renal and oxalate stone formation (87-89 ), d ivalent cation deficiencies (calcium, magnesium and zinc) (90), formation of lith ogenic bile with c h o lesterol gallstone formation (91)(92)(93), essential fatty acid deficiency ( 1) and vitamin B12 deficiency.The individual clinical picture is, therefore, variable both in its fo rm and severity.
Both medical and surgical treatment of short bowel syndrome have been designed to control or improve three bas ic pa thoph ys io log ical d efects: decreased mucosa!absorptive surface area, gastric hypersecret io n , a nd decreased intestinal transit time.Most fo rms of treatment are suppo rtive while the process of intestinal adaptation is occurring.Nevertheless, recent forms of treatment are being developed to enhance intest inal adaptation as well.
Medical treatment is designed to d irectly address gastric hypersecretion and decreased intestinal transit time.Indirectly, it addresses the loss of intestinal absorptive surface area by the add ition of ancillary nutritional support.Increasing effective absorption: The loss of effective mucosa!absorptive surface area underlies most of the signs and symptoms of short bowel syndrome.
Perhaps the greatest advance in sup, portive therapy o f sh o rt bowe l syndrome has been the introduction of total parenteral nutrition (10)(11)(12)94).T o ta l parenter a l nutritio n allows provision of calories to a patient unable to tolerate oral feeding and is responsible for the increase in patient survival with short bowel syndrome.It provides time while intestinal adaptation occurs, and in the case of extreme shore bowel can provide all calories and n utrients indefinitely (94,95).T otal parenteral nutrition is not without its problems.Venous access on a long term basis may be d ifficult due to recurrent sepsis and veno us obstruct ion ( 94).Also, long term total parenteral n utrition especially in the ped iatric population leads to liver fail ure from cho lescasis (96,97).At present, the main causes of death in the pediatric shore bowel population are sepsis and liver fai lure seconJary to total parenteral nutrition (97).
The recognition that luminal nutritio n is necessary fo r the aJ apcive response co resection has made the use of low residue, part ially hydrolyzed, high caloric oral feeds an integral part of t he t reatme nt of sh o rt bowel syndrome.T his is one of the few treatments which can be classified as both supportive and enhancing intestinal adaptation.T o effect maximal adaptation, patients should be started on oral feeds as soon as they can be tolerated, even if only a small part of the total calo ric intake is consumed in th is manner.T here is no agreement as to the actual composi tion of the oral diet.A high carbohydrate and protein diet has generally been recommended due to the severe malabsorpcion of complex dietary fats.
Unfo rtunately, much of the early work was done in uncontrolled situations and the osmotic effect of high carbo hydrate diets was not appreciated.Some authors have recently shown that the restriction of fa t may not he as imporcan c as o nce believed (98,99).Studies by Woolf et al ( 100) on eight patients wi th shore bowel synJrome comparing high carbohydrate and high fat diets showed no d iffe rence in the abso rp tio n of fl uid, e lectro lytes, divalent cations or calories.In an extension of this work, they demonstrated chat patients stabilized for one year on an oral diet do not need co restrict fat in take.Th ere was virtually no difference in the malabsorption of fat, carbohydrate, protein or total calories on a controlled test diet containing 46% of total calories as fat ( 100).T hey do suggest, however, that oral intake should be increased to 35 to 40 kcal/kg of body weight and that the divalent cations (calcium, magnesium and zinc) require oral supplementation due to increased CAN J GASTROENTEROL VOL 4 No 2 M ARCH/APRIL 1990 intestinal losses.Lactose intolerance is common in short bowel syndrome, and patients should be advised to limit exposure to milk products.Mineral and vitamin supplements arc required in nearly all cases (87).Recently, 1t has been demonstrated that both jejuna!and colonic uptake ofhexoses and I ipids can be modified by variations in the fat content of the diet ( I 01-103 ).Whether these dietary manipulations will prove to be of benefit in humans with short bowel syndrome remains to be determined.
When there has been a significant loss of ilea I length, bile acids cannot be re-absorbed in the distal ileum and thus are lost to the colon.This loss of bile acids has two consequences.First, if increased bile acid synthesis in the liver cannot compensate for bile acid loss, then a decrease in luminal concentration of bile acids results in impaired micellar fo rmation and subsequent diminished fat absorption.In this case, oral bile acid supplementation may increase the size of the bile salt pool (87).
Second, the presence of bile acids in the colon has a direct stimulatory effect on water Jc!cretion by colonic mucosa.Th is choleretic diarrhea can be treated with cholesryramine, which binds bile acids in the lumen, decreasing their secretory activity in the colon (104)(105)(106)(107).
Decreasing gastric hypersecretion: The increase in gastric secretion after extensive intestinal resection has been described for many years in animal and human models.Initial observations in humans came from the surgical literature where patients with previous vagotomies and gastrectomies for ulcers did better than others after extensive bowel resection (108,109).Subsequently, gastric hypersecret1on has not been shown in humans universally, and many authors doubt its existence or feel that it is only a temporary problem (86,104).Certainly, the high levels of gastrin seen postoperatively do not correlate with levels of gastric secretion (110,111).
The introduction of Hz receptor antagonists has made surgical treatmentof gastric hypersecretion obsolete.Studies have shown both c imetidine (112-115) and ranitidine (116) to be effective in controlling gastric hypersecretion associated with short bowel syndrome.
Cimetidine may also have an effect on intestinal adaptation completely separate from its effect on gastric secretion.Studies by Cortot et al ( 117) show an increase in nutrient absorption with cimeti<line in patients with short bowel syndrome.Cimeti<line has also been shown to increase villus length and reduce steatorrhea ( 118).It has been postulated that the effects of cimetidine are a consequence of enhanced crypt cell production rate or a <lirect trophic effect on the bowel; however, neither theory has been proven conclusively (119,120).
Slowing intestinal transit: The mcrease in intestinal transit time associated with short bowel syndrome 1s due both to a loss of intestinal length and an alterauon in intestinal motility.The resultant loss of contact time with the absorptive mucosa!surfaces and digestive enzymes causes further compromise of intestinal digestion and absorption of nutrients.Medical therapy designed to decrease intestinal mottl1ry has, in the past, been base<l on narcotics or narcotic analogues such as codeine and diphenoxylate.These drugs act directly on intestinal smooth muscle to decrease perista lsis.Recently, lopernmide has been shown to be as effective as codeine 111 altering intestinal transit with far fewer side effects.It appears to act hy increasing nonpropulsive motor activity in both the fasting and postprandial states, enhancing retention of chyme within the small bowel (121-123).
Somatostatin is one of the major inhibitory hormones of the gut and has a marked effect on gastric secretion through direct inhibition of both gastrin and intestinal motility ( 124 ).
Long acting synth etic somatostatin analogues have been shown to increase intestinal transit time and have been used to decrease diarrhea and ileostomy outputs (125,126).Unfortunately, che effect of somatostatin analogues appears to be only transient ( 127).Furthermore, a study by Holmes (128) in rats demonstrated that somatostatin has an inhibitory effect on the hyper-CAN J GASTROENTEROL VOL 4 No 2 MARCH/APRIL 1990 Short bowel syndrome: Medical therapy plastic response co ileal resection and inhibits nutrient absorption.For these reasons, somatostatin has limited use in short bowel syndrome at present.

CONCLUSIONS
Although the factors which influence intestinal adaptatton after massive intestinal re~ection arc well known, their relative contributtons ro the final clinical picture are not clear.Furthermore, no single theory adequately expla ins the mechanism of intestinal adaptatio n .More than likely, several mechanisms are at work.With this gap in knowledge, it is not surprising that medical therapy to this point has been rel atively ineffective in manipulating intestinal adaptation.Present therapy is supportive, control-!mg symptoms which arise from the hasic pathophysiologic <lefects of sho rt bowel syndrome: <lecrcased intestinal transit time, gastric hypersecretion, and reduced mucosa!surface area.Until there 1s a better understanding of the mechanisms of intestinal adaptation in short bowel syndrome, a llowing active intervention, the c linician will be forced to rely largely on the intrinsic abi lity of the residual intestine to adapt.
used two models of hyperprolactinemia and, in the face of mammary hyperplasia and documented hyperprolactinemia, found no change in villus height, crypt depth, mucosa!wet weight or DNA content per unit length of intestine.CAN J GASTROENTEROL VOL 4 No 2 MARCH/APRIL 1990 Short bowel syndrome: Medical therapy