CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:6 –10
`
`REVIEWS
`
`Short Bowel Syndrome and Intestinal Failure: Consensus
`Definitions and Overview
`
`STEPHEN J. D. O’KEEFE,* ALAN L. BUCHMAN,‡ THOMAS M. FISHBEIN,§
`KHURSHEED N. JEEJEEBHOY,储 PALLE BEKKER JEPPESEN,¶ and JONATHAN SHAFFER#
`*Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania; ‡Feinberg School of Medicine,
`Northwestern University, Chicago, Illinois; §Georgetown University, Washington, DC; 储St Michael’s Hospital, Toronto, Ontario, Canada;
`¶Rigshospitalet, Copenhagen, Denmark; and #Hope Hospital, Salford, United Kingdom
`
`Short bowel syndrome (SBS)–associated intestinal fail-
`ure is a highly disabling condition that impairs quality of
`life and social integration. Although the condition is not
`uniformly fatal, it might lead to serious, life-threatening
`complications. The basic goals of medical treatment are
`to maintain fluid, electrolyte, and nutrient balances and
`to make appropriate modifications in disease manage-
`ment to avoid side effects. Various definitions have been
`proposed for SBS and intestinal failure within the med-
`ical literature, but many focus on different aspects of the
`conditions, leading to confusion. In the past, identifying
`the cause of intestinal failure was of little consequence,
`because all patients were managed on total parenteral
`nutrition at home. However, with the recent develop-
`ment of medical therapies such as recombinant growth
`hormone, octreotide, and glucagon-like peptide-2 ana-
`logues and with improvements in small bowel transplan-
`tation, many patients can be made nutritionally auton-
`omous. To evaluate the relative efficacy of
`these
`therapies, there is now a need to develop consensus
`definitions so that patients can be properly categorized
`before therapy. To this end, a group of experts on the
`subject was convened to develop the following new
`definitions: “Intestinal failure results from obstruction,
`dysmotility, surgical resection, congenital defect, or dis-
`ease-associated loss of absorption and is characterized
`by the inability to maintain protein-energy, fluid, electro-
`lyte, or micronutrient balance.” “Short-bowel syndrome
`results from surgical resection, congenital defect, or
`disease-associated loss of absorption and is character-
`ized by the inability to maintain protein-energy, fluid,
`electrolyte, or micronutrient balances when on a con-
`ventionally accepted, normal diet.”
`
`Short bowel syndrome (SBS) is a complex disease that
`
`can result from physical loss of portions of the small
`intestine or from loss of function.1 Intestinal failure
`caused by the more severe forms of SBS is a highly
`disabling condition chiefly as a result of massive intesti-
`
`nal loss caused by surgery, trauma, or infarction and less
`commonly congenital defect or a lessening of absorptive
`surface as a result of diffuse disease. Management of SBS
`is directed toward maintaining fluid, electrolyte, and
`nutrient balances (Table 1).2,3 For the most severe forms
`of SBS, this has traditionally been accomplished with the
`use of TPN administered at home, whereas milder forms
`of the syndrome might be managed with less aggressive
`measures. These therapies have a long history of use, but
`recent advances in the treatment of SBS have begun to
`offer, for the first time, the opportunity for some patients
`to regain nutritional autonomy and be free from depen-
`dence on TPN or intravenous fluids.2
`Identifying the patients who might qualify for new
`therapeutic strategies will depend on the accuracy of
`patient diagnosis and classification, which has been com-
`plicated by the multitude of definitions that exist for
`both SBS and intestinal failure. There is currently no
`consensus within the published literature as to the def-
`inition of either of these conditions. Definition of intes-
`tinal failure has been hampered by the fact that whereas
`in Chinese failure is defined as the complete loss of
`function, in English failure can include partial loss. With
`regard to short bowel, some definitions are anatomically
`based, whereas others describe the syndrome in func-
`tional terms. To optimize the outcomes from conven-
`tional management strategies and to evaluate new ther-
`apies,
`it is important to try to establish a precise
`definition of SBS and intestinal failure.
`Recognizing the potential ramifications of the defini-
`tions of SBS and intestinal failure in this new era of
`treatment advances, a panel of experts in gastroenterol-
`ogy and clinical nutrition was convened to re-examine
`
`Abbreviation used in this paper: SBS, short bowel syndrome.
`© 2006 by the American Gastroenterological Association
`1542-3565/06/$32.00
`PII: 10.1053/S1542-3565(05)00994-8
`
`Page 1
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`

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`January 2006
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`SHORT BOWEL SYNDROME AND INTESTINAL FAILURE 7
`
`Table 1. Clinical Consequences of SBS
`
`Jejunal resection of 50%–60% is usually well tolerated.
`Greater than 30% ileal resection is poorly tolerated.
`Severe malabsorption occurs with residual small bowel ⬍60 cm.
`Deficiencies include fluid and electrolytes (mild and moderate
`cases)/plus nutrient absorption (severe cases).
`Severe fluid and electrolyte loss is associated with end-
`jejunostomy.
`Magnesium, calcium, and zinc deficiencies are common.
`
`the definitions currently in use and to propose new
`definitions. This article summarizes their discussions,
`which examined the limitations and ambiguities sur-
`rounding current terminology in light of their experience
`with the clinical issues related to SBS.
`
`Overview of Short Bowel Syndrome
`and Intestinal Failure
`Incidence
`
`The true incidence of SBS and intestinal failure in
`the United States is unknown, in part because of the lack
`of precise definitions. Surveys of clinicians have produced
`variable figures; some practicing gastroenterologists re-
`port never having seen a patient with SBS. Undoubtedly,
`some of their patients are those who have had minor,
`well-tolerated resections, and who thus do not require
`therapy. Registries of home TPN patients generally pro-
`duce incidence figures representing the severe end of the
`SBS spectrum. The Oley Foundation estimated that
`40,000 patients with intestinal failure were receiving
`home TPN in 1992, with approximately 35% of cases
`attributable to SBS.4 Other estimates for the United
`States identify approximately 41% of SBS patients as
`dependent on parenteral nutrition (ie, they have SBS-
`associated intestinal failure) and another 12% as depen-
`dent on intravenous fluids and electrolytes alone (data on
`file; NPS Pharmaceuticals, Salt Lake City, UT; 2002).
`These figures are likely to be inaccurate, because they
`would not include patients with uncomplicated SBS.
`
`Prognostic Factors in Short Bowel
`Syndrome
`
`Among the factors associated with the prognosis
`of SBS-associated intestinal failure are the length of the
`residual small intestine, the presence of residual under-
`lying disease, the presence or absence of the colon in
`continuity and of the ileocecal valve, and the nature of
`the primary disorder; prognostic factors also include the
`age of the patient and the status of enteral dependence or
`independence.5– 8 Overall survival rates after 6 years are
`estimated to be 65% for patients with residual small
`
`intestine lengths greater than 50 cm, but survival rates
`are much lower for patients with residual lengths less
`than 50 cm.2 It is important to qualify these figures,
`because it is recognized that less than 10% of the 35%
`who die within this period are directly related to TPN
`complications, and most die of complications of the
`underlying disease, for example, cancer and heart fail-
`ure.5 Patients with shorter residual intestine are more
`likely to develop liver and kidney failure and to remain
`totally dependent on parenteral nutrition.7,9,10
`
`Bowel Adaptation
`
`The adaptation of the residual bowel is an impor-
`tant factor in determining whether the patient with a
`short bowel will progress to permanent intestinal failure
`and dependence on TPN. The adaptive process was first
`described in the 1950s and further characterized during
`subsequent decades.11–13 During the first 6 months after
`surgery, a period of gastric hypersecretion usually oc-
`curs.14,15 Other adaptive changes in SBS include mucosal
`hyperplasia, increased mucosal blood flow, and improved
`segmental absorption, together with increased pancreati-
`cobiliary secretions. Functional improvement can take up
`to 2 years.14 Thus, some patients with a short bowel
`might initially have intestinal failure and therefore be
`dependent on intravenous supplementation, but, with
`time, they might become nutritionally autonomous.
`Because of the capacity for the remaining bowel to
`adapt, most of the intestine has to be lost before intes-
`tinal failure occurs. Evidence of loss of function includes
`vitamin B12 deficiency, malabsorption of bile acid and
`fat-soluble vitamins in isolated ileal resection, and the
`inability to maintain hydration and electrolyte stability.
`
`Management of Short Bowel Syndrome
`
`The management of SBS has recently been re-
`viewed.1 It is appropriate here to highlight some general
`principles (Table 2)2,3 as they relate to the issue of
`disease definition.
`Management of the malabsorption associated with SBS
`varies with the degree of severity. In mild cases, malab-
`sorption can be overcome by increasing oral intake. In
`more severe situations, absorption can be enhanced with
`the use of antimotility agents that prolong nutrient-
`mucosa contact and, therefore, fractional absorption. Di-
`gestive function is far better preserved than absorptive
`function, because enzymes are secreted well in excess of
`requirements, and carbohydrate and protein digestion is
`virtually complete in the duodenum. In the extreme
`situation, for example, with the loss of all but the jeju-
`num (the end-jejunostomy syndrome), diet and drug
`therapy cannot maintain fluid, electrolyte, and nutrient
`
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`8 O’KEEFE ET AL
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`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 1
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`Table 2. General Management Strategies for SBS
`
`Fluids
`Avoid drinking water without food
`Spread fluid intake throughout the day
`Sip liquids
`Restrict hypotonic fluids
`Drink oral rehydration solution containing salt and carbohydrates
`Diet
`Eat small, frequent meals balanced in nutrient content
`Add salt to the diet (only for patient with colon in continuity)
`Increase quantity of food intake
`Follow a high complex-carbohydrate diet (patients with a colon)
`Avoid osmotically active sweeteners, which might cause diarrhea
`Drugs
`Use antimotility agents
`Use antisecretory agents
`Consider growth factors to enhance adaptation and absorption
`Surgery
`Small bowel transplantation
`Bowel-lengthening procedures
`
`NOTE. These are based on current practice.2,3 Management strate-
`gies might differ for SBS patients with or without a colon.
`
`balances. Patients then become dependent on intrave-
`nous therapy. A state of permanent intestinal failure
`exists when patients remain dependent on intravenous
`therapy beyond the 2 years or so that are generally
`sufficient for intestinal adaptation. This group of patients
`needs to be identified early, because they will die without
`intravenous support and close metabolic and nutritional
`monitoring. Clear definition of the condition of SBS-
`associated intestinal failure is therefore important.
`
`Evolution of Definitions: Short
`Bowel Syndrome and Intestinal
`Failure
`The reported “normal” length of the small intes-
`tine varies considerably from 300 – 850 cm.1,16 Al-
`though evidence suggests that patients with less than
`200 cm of small bowel are likely to develop intestinal
`failure, this number is of little use in clinical practice,
`because outcome depends on the prognostic factors al-
`ready mentioned, important among which are the qual-
`ity of bowel remaining and whether the large bowel has
`been conserved. For example, loss of bowel in a patient
`with Crohn’s disease or from radiation injury is likely to
`be far more serious than loss of bowel as a result of
`trauma.
`The preservation of the colon is often a critical deter-
`minant of whether a patient will manage without intra-
`venous supplements, because the colon helps conserve
`fluid and electrolytes and can salvage malabsorbed car-
`bohydrate
`and protein through bacterial metabo-
`lism.17–20 These points were well-illustrated by the anal-
`ysis by Carbonnel et al6 of 103 patients whose residual
`
`bowel lengths ranged from 17–150 cm. Overall, the
`length of bowel remaining correlated with the patient’s
`degree of nutritional autonomy (ie, independence from
`intravenous nutrition), but the configuration of the re-
`maining bowel, namely whether there was any ileum or
`colon in continuity, also affected the prognosis. This
`study reported a high risk for loss of nutritional auton-
`omy under conditions of (1) ⬍35 cm of jejunum remain-
`ing in patients with jejunoileal anastomoses, (2) ⬍60 cm
`remaining in patients with jejunocolic anastomoses, and
`(3) ⬍115 cm remaining in patients with end-jejunosto-
`mies. Remarkably similar cutoff levels were reported by
`Messing et al7 on the basis of an analysis of 124 patients
`with short bowel (⬍150 cm of small intestine remain-
`ing).
`Function is not dependent on length alone, because
`150 cm of diseased bowel might function less well than
`75 cm of healthy intestine, as indicated above. For this
`reason, some definitions of SBS and intestinal failure have
`been based on measurements of the functional capacity of
`the remaining bowel. A study of 48-hour nutritional
`balance studies in patients dependent on home TPN, as
`compared with patients who were nutritionally autono-
`mous, demonstrated that intestinal failure could be pre-
`dicted by an absorption rate below 1.4 kg/day of wet
`weight and 84% of the calculated basal metabolic rate
`(4.9 megajoules [1171 kilocalories]/day of energy).18 It is
`important to note that nutritional balance studies are
`very difficult to perform accurately in practice because
`they require the analysis of duplicate food portions and
`accurate stool collections. Furthermore, dietary intake
`rate can influence intestinal transit and therefore absorp-
`tion rates. Consequently, dietary intake needs to be
`standardized to reveal reproducible measurements. Other
`investigators used the plasma citrulline test as an alter-
`native measure of intestinal function.21 Noting that cit-
`rulline in the fasting state can only be synthesized by the
`small intestine and is not incorporated into body pro-
`teins, they proposed that fasting plasma citrulline con-
`centration should provide an index of residual functional
`enterocyte mass. Although the low plasma concentration
`of citrulline represents a potential problem in achieving
`an accurate determination, automated ion exchange chro-
`matography specifically standardized for citrulline mea-
`surement has enhanced the precision and accuracy to
`⬍5%, making the test a practical measure of enterocyte
`function or mass. By equating citrulline levels to absorp-
`tion, they suggested that a concentration of ⬍5 ␮mol/L
`indicates intestinal failure and predicts dependence on
`TPN.
`
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`January 2006
`
`SHORT BOWEL SYNDROME AND INTESTINAL FAILURE 9
`
`Table 3. Medical Appropriateness of Small Bowel
`Transplantation
`
`Category I
`TPN failure because of venous thrombosis, recurrent sepsis, and
`liver failure
`Category II
`Small bowel
`SBS with intestinal failure
`Defective intestinal motility (hollow visceral myopathy,
`neuropathy, and/or total intestinal aganglionosis)
`Impaired enterocyte absorptive capacity (microvillus inclusion
`disease, selective autoimmune enteropathy, radiation
`enteritis, extensive inflammatory bowel disease, and/or
`massive intestinal polyposis)
`Failure of a previously transplanted small bowel graft
`Small bowel/liver
`Irreversible failure of the liver and intestine
`Liver failure associated with total thrombosis of the
`protomesenteric system
`Multivisceral
`Combined organ failure and/or premalignant conditions of the
`gastrointestinal tract
`Extensive thrombosis of the splanchnic vascular system
`Massive gastrointestinal polyposis
`Generalized hollow visceral myopathy or neuropathy
`Contraindications
`Life expectancy ⬍5 years because of age-related debilitation
`and comorbidities
`Ability to ingest oral nutrition
`Unresectable malignancy
`Serious, uncontrolled psychiatric illness that would hinder
`compliance at any stage of the transplant process
`Neurologic disease independent of the disease process being
`treated
`Drug or alcohol addiction
`Human immunodeficiency virus positivity
`Active and/or life-threatening infections that are uncorrectable
`Severe body/organ system disease unrelated to the
`transplanted organs
`Inability or unwillingness of the individual or legal guardian to
`give signed consent and to comply with regular follow-up
`requirements
`
`NOTE. This is an example of where a precise definition of SBS with
`intestinal failure will help in assessing candidacy. (Based on Blue-
`Cross BlueShield Medical Policy Reference Manual, 2005.)
`
`With the recent development of potent forms of hor-
`mone and gut peptide therapies such as growth hormone,
`octreotide, and glucagon-like peptide-2,2,22–24 which
`have the potential to improve intestinal function suffi-
`ciently for some patients with intestinal failure to be
`weaned off home TPN, there is an urgent need to de-
`velop a practical working definition of SBS-associated
`intestinal failure. The same is true for the selection of
`patients with SBS–intestinal
`failure for small bowel
`transplantation. Table 3, which summarizes the medical
`appropriateness of small bowel transplantation (based on
`BlueCross BlueShield), illustrates this point, because the
`Category 2 candidacy for isolated small bowel transplan-
`tation is dependent on proof of small bowel intestinal
`failure. Existing definitions have certain limitations.
`
`Current Definitions
`
`The National Institute of Diabetes and Digestive
`and Kidney Diseases defines intestinal failure as “reduced
`absorption of nutrients from the gastrointestinal tract
`resulting in the need for parenteral nutrition for surviv-
`al.”25 This definition lacks precision, because it would
`include patients with anorexia, who also have inadequate
`absorption not because of intestinal failure but because of
`the inability or unwillingness to eat. Fleming and Rem-
`ington18 have defined intestinal failure as the “reduction
`in the functioning gut mass below the minimal amount
`necessary for adequate digestion and absorption of food.”
`This is a far more encompassing definition because it
`includes the need for loss of intestinal mass.
`
`Proposed New Definitions
`Recognizing the limitations and overlap in cur-
`rent definitions of conditions related to short bowel and
`intestinal failure, our group convened for the purpose of
`developing consensus definitions for both intestinal fail-
`ure and SBS-associated intestinal failure to help practic-
`ing gastroenterologists categorize patients with short
`bowel and to provide uniformity of view when register-
`ing such patients with regulatory authorities or assessing
`their response to novel forms of therapy. The panel
`considered SBS as only one cause of the broader condition
`of intestinal failure (Figure 1).
`
`Short Bowel Syndrome
`
`The proposed new definition for SBS takes into
`consideration all of the previously noted factors and
`characteristics but makes SBS a subcategory of the
`broader condition of intestinal failure. “Short-bowel syn-
`drome–intestinal failure results from surgical resection,
`
`Figure 1. A new definition of SBS associated with intestinal failure.
`
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`10 O’KEEFE ET AL
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`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 1
`
`congenital defect or disease-associated loss of absorption
`and is characterized by the inability to maintain protein-
`energy, fluid, electrolyte or micronutrient balances when
`on a conventionally accepted, normal diet.”
`
`Intestinal Failure
`
`The proposed new definition for intestinal failure
`builds on the concepts noted above. “Intestinal failure
`results from obstruction, dysmotility, surgical resection,
`congenital defect, or disease-associated loss of absorption
`and is characterized by the inability to maintain protein-
`energy, fluid, electrolyte, or micronutrient balance.”
`
`Conclusions
`Consensus working definitions of SBS and intes-
`tinal failure have been proposed in this review to help the
`practicing gastroenterologist manage patients with in-
`testinal failure caused by massive intestinal loss and, at
`the same time, to help in the evaluation of novel phar-
`macologic therapies.
`
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`
`Address requests for reprints to: Stephen J. D. O’Keefe, MD, MSC,
`University of Pittsburgh, Division of Gastroenterology, Hepatology, and
`Nutrition, 200 Lothrop St, Mezzanine Level C-Wing, Pittsburgh, PA
`15213. e-mail: sjokeefe@pitt.edu; fax: 412-648-9378.
`Dr Jeppesen has served as a consultant for NPS Pharmaceuticals.
`Funding for the meeting of the panel of experts was provided by
`NPS Pharmaceuticals, Salt Lake City, Utah. The views contained are
`solely those of the expert panel.
`
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