Current Medical Research and Opinion
`
`ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
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`Key issues in addressing the clinical and
`humanistic burden of short bowel syndrome in the
`US
`
`Steven Hofstetter, Lee Stern & Jacob Willet
`
`To cite this article: Steven Hofstetter, Lee Stern & Jacob Willet (2013) Key issues in addressing
`the clinical and humanistic burden of short bowel syndrome in the US, Current Medical
`Research and Opinion, 29:5, 495-504, DOI: 10.1185/03007995.2013.784700
`
`To link to this article: http://dx.doi.org/10.1185/03007995.2013.784700
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`Accepted author version posted online: 12
`Mar 2013.
`Published online: 02 Apr 2013.
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`0300-7995
`doi:10.1185/03007995.2013.784700
`
`Current Medical Research and Opinion
`
`Vol. 29, No. 5, 2013, 495–504
`
`Article FT-0362.R1/784700
`All rights reserved: reproduction in whole or part not permitted
`
`Review
`Key issues in addressing the clinical and
`humanistic burden of short bowel syndrome
`in the US
`
`C opyright © 2013 Infor m a U K Lim ited
`m ercial Distribution
`U nauthorized use prohibited. Authorised users can do w nload,
`display, vie w an d print a single copy for personal use
`N ot for Sale or C o m
`
`Steven Hofstetter
`Department of Surgery, New York University School of
`Medicine, New York, NY, USA
`Lee Stern
`Jacob Willet
`LA-SER Analytica, The LA-SER Group, New York,
`NY, USA
`
`Address for correspondence:
`Lee Stern MS, LA-SER Analytica, 24 West 40th Street,
`Floor 8, New York, NY 10018, USA.
`Tel.: +1 212 686 4100; Fax: +1 212 686 8601;
`LStern@la-ser.com
`
`Keywords:
`Gastrointestinal surgery – Parenteral nutrition –
`Quality of Life – Short bowel syndrome
`
`Accepted: 26 February 2013; published online: 27 March 2013
`Citation: Curr Med Res Opin 2013; 29:495–504
`
`Abstract
`
`Background:
`The purpose of this analysis was to provide a concise report of the literature on the burden of intestinal
`failure associated with short bowel syndrome (SBS–IF) in adults, focused on clinical and humanistic issues
`important to clinicians and payers.
`
`Scope:
`A literature search was performed using the National Library of Medicine PubMed database (http://
`www.ncbi.nlm.nih.gov/pubmed) with the search term ‘short bowel syndrome’ limited to adult populations
`and English-language reports published from January 1, 1965, to January 18, 2013. Citations were
`assessed for relevance and excluded articles focused on single case studies, colon fermentation,
`absorption of medications with PN/IV, surgical technique, mesenteric artery complications/surgery, and
`transplantation focus. Additional hand searches were performed using the terms ‘short bowel syndrome’
`AND ‘cost’, and ‘home parenteral nutrition’ AND ‘cost’, along with the exclusion criteria described above.
`
`Findings:
`Despite advances in management in recent decades, SBS–IF continues to carry a high burden of morbidity
`and mortality. In the absence of sufficient intestinal adaptation following resection, many patients remain
`dependent on long-term parenteral nutrition and/or intravenous fluids (PN/IV). Although potentially life
`saving, PN/IV is costly, invasive, and associated with numerous complications and deleterious effects on
`health and quality of life. Surgical interventions, especially intestinal transplantation, are costly and are
`associated with substantial morbidity and high mortality. New therapies, which show promise in promoting
`intestinal rehabilitation and reducing dependence on PN/IV therapy, are the subject of active research.
`
`Conclusions:
`Overall, the available literature suggests that although SBS–IF affects a relatively small population, the
`clinical and humanistic burden is significant, and there is an unmet need for effective therapeutic options
`that
`target
`the underlying problem of
`inadequate absorptive capacity of
`the remaining intestine.
`Consequently, many patients with SBS–IF remain dependent on long-term PN/IV support, adding to the
`burden imposed by the underlying disorder.
`
`Introduction
`
`Intestinal failure associated with short bowel syndrome (SBS–IF) is a rare,
`chronic, and debilitating condition associated with either functional or ana-
`tomic loss of portions of the intestine, resulting in substantial morbidity and
`mortality1,2. A variety of overlapping definitions of SBS–IF have been promul-
`gated over the years that focus on different aspects of the condition; however, in
`2006 an international expert group published a consensus definition, which
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`states that ‘‘SBS-IF results from surgical resection, con-
`genital 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’’3. This defin-
`ition considers SBS as a subcategory of – and one of the
`major recognized causes of – the more broadly defined
`condition of intestinal failure. Importantly, it acknow-
`ledges that outcomes in SBS–IF are dependent on com-
`plex, interrelated prognostic factors regarding intestinal
`absorptive capacity, including the quality, function, and
`length of remnant bowel1,4.
`Although the symptom complex varies among patients,
`SBS–IF is characterized by diarrhea, steatorrhea, abdom-
`inal pain, electrolyte disturbances, dehydration, and mal-
`nutrition5. Management
`is
`complex,
`requiring
`an
`individualized and comprehensive approach4. The goal
`of therapy broadly focuses on symptomatic management
`along with intestinal rehabilitation to promote absorption
`of fluid and nutrients6. Numerous factors such as oral food
`intake, remnant bowel
`length and anatomy, age and
`comorbid conditions affect the remnant bowel’s ability
`to adapt following surgical resection2,4. Patients who
`cannot meet their nutritional or fluid needs through oral
`intake require long-term parenteral support: that is, paren-
`fluid (PN/IV)2.
`teral nutrition and/or
`intravenous
`However, PN/IV has limitations: in addition to its cost,
`it is associated with numerous complications, some of
`which can themselves be life threatening.
`In the past, there have been few options for the man-
`agement of SBS–IF beyond nutritional support and treat-
`ments directed at
`symptoms and complications of
`malabsorption, with surgery and transplantation reserved
`as treatments of last resort. Recently, however, new tar-
`geted therapeutic strategies have been suggested to reduce
`reliance on PN/IV by enhancing intestinal function7.
`The objective of this review is to summarize the available
`literature on the burden of SBS–IF in adult patients, with
`a focus on its clinical and humanistic burden, to provide
`a context for assessment of current management and emer-
`ging treatment approaches.
`
`The literature search yielded 382 citations. The cit-
`ations were assessed for their relevance to the topic and
`excluded articles focused on single case studies of a par-
`ticular side effect related to PN/IV, studies focused on
`colon fermentation or on absorption of medications in
`patients with PN/IV, studies that included pediatric
`patients, surgical technique papers, articles about mesen-
`teric artery complications/surgery, and articles focused
`solely on transplantation. Additional hand searches were
`performed using the terms ‘short bowel syndrome’ AND
`‘cost’, and ‘home parenteral nutrition’ AND ‘cost’, along
`with the exclusion criteria described above. Key medical
`textbook chapters also were included in the reviewed
`material. Although a comprehensive literature search
`was conducted, the review was not intended to be exhaust-
`ive or
`to provide an economic analysis of SBS–IF
`management.
`The results of this review focus on articles published
`within the last 10 years. However, older articles were con-
`sidered for inclusion if highly regarded or frequently refer-
`enced in the existing literature. Finally, the abstracts were
`reduced to 155 articles that underwent a more thorough
`review and assessment for relevance and/or redundancy,
`yielding a total of 67 citations for this article.
`Resultant articles were categorized and assessed based
`on topic. Topic areas in this review included SBS–IF epi-
`demiology and clinical burden, disease management
`(including PN/IV) and complications, new and emerging
`therapies, and SBS–IF and PN/IV-related quality of life
`(QoL) because these topics most accurately reflected the
`overall description of SBS–IF and its ramifications.
`Since the time of the initial literature review, a novel
`therapy (teduglutide) has been approved in the United
`States for the treatment of adult patients with SBS who
`are dependent on parenteral support; the primary report on
`the results of the pivotal trial of this agent, published in
`December 2012, were also included.
`
`Results
`
`Methods
`
`To characterize the current management patterns, guide-
`lines, and health outcomes among patients with SBS–IF, a
`literature search was performed using the National Library
`of Medicine PubMed database (http://www.ncbi.nlm.nih.
`gov/pubmed). The search terms were ‘short bowel syn-
`drome’ [Title] NOT pediatric [All Fields] NOT infantile
`[All Fields] NOT infant [All Fields] NOT children
`[All fields] NOT ‘case reports’ [Publication Type]. The
`inclusive dates were January 1, 1965, to January 18,
`2013. The English-language filter was applied.
`
`Adult patients with SBS–IF are highly heterogeneous, pre-
`senting with a wide range of underlying pathology, anat-
`omy,
`residual
`intestinal
`function, and psychosocial
`characteristics. In adults, SBS–IF usually occurs following
`extensive surgical resection of the small intestine, some-
`times including parts or all of the colon4,6,8. The most
`common underlying causes of SBS–IF are complications
`of Crohn’s disease that require multiple resections or
`infarction due to occlusion of the mesenteric vessels;
`other etiologies include malignancy, trauma, volvulus,
`complications of bariatric surgery, and recurrent intestinal
`obstruction or pseudo-obstruction4.
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`Epidemiology
`
`The exact incidence of SBS–IF is unknown; surveys of
`clinicians have produced a range of estimates3,4. Home
`PN/IV, for which SBS is a frequent indication, often
`serves as a surrogate marker for epidemiologic measure-
`ments. The most recent prevalence estimate in the
`United States is from 1992, based on extrapolated data
`from the Oley Foundation Home Parenteral and Enteral
`Nutrition Registry. At that time, it was estimated that
`about 40,000 US patients per year required home PN/IV
`support. Approximately 35% of the patients in the Oley
`registry had a diagnosis of SBS, yielding an estimate of
`10,000 to 15,000 patients with SBS–IF9. It should be
`noted, however, that the number of patients may be sub-
`stantially greater than this estimate because some patients
`dependent on PN/IV support because of malignancy or
`radiation enteritis may meet the criteria for a diagnosis
`of SBS–IF10. In addition, these estimated patient numbers
`do not reflect individuals with SBS–IF who had never
`required home parenteral support or for whom home par-
`enteral support could be successfully discontinued.
`European data suggest a projected incidence of two
`individuals per million per year in the United States10.
`A multicenter survey conducted in 1997 indicated that
`the incidence in Europe was approximately three individ-
`uals per million population per year with prevalence of
`approximately four per million, representing a modest
`increase from data collected in 199311. Another multi-
`center assessment outlined the demographic features of
`the SBS–IF population in Western Europe. In 41 centers
`from nine countries that enrolled 688 adults (418 years of
`age), the average age of patients with SBS was 52.9 years;
`more patients were female (57%) than male (43%)12.
`Mortality estimates for the SBS–IF population are high.
`According to Schalamon et al., overall SBS–IF-related
`mortality in adults ranges from 15% to 47% depending
`on patient age, underlying disease, and duration of PN/
`IV13. A recent US study by Boland et al. in 2010 estimated
`1 and 5 year mortality rates to be 17% and 32%, respect-
`ively14. An earlier study by Messing et al. in a French
`population reported 2 and 5 year mortality estimates of
`14% and 25%, respectively15. In multivariate analysis, sur-
`vival was related negatively to end enterostomy, small
`bowel length 550 cm, and arterial infarction as a cause
`of SBS, but not to parenteral support dependence. The
`latter was
`related negatively to post-duodenal
`small
`bowel lengths 550 and 50–99 cm and to absence of ter-
`minal ileum and/or colon in continuity. Cutoff values of
`small bowel lengths separating transient and permanent
`intestinal failure were 100, 65, and 30 cm in end enteros-
`tomy, jejunocolic, and jejunoileocolic type of anastomosis,
`respectively. A review of 210 postoperative cases of SBS in
`the United States evaluated over 20 years revealed that
`25% were caused by a postoperative complication; 67%
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`Current Medical Research and Opinion
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`Volume 29, Number 5 May 2013
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`of those patients required long-term parenteral support
`(all patients with remnants 560 cm required parenteral
`support), and 13% of patients died8.
`
`Impact of malabsorption
`
`One of the major consequences of SBS–IF is malabsorp-
`tion leading to dehydration and malnutrition. The severity
`of malabsorption and which deficiencies are present
`depend primarily on the remnant bowel length and anat-
`omy, among other factors16. Underlying conditions, such
`as active Crohn’s disease, may also impede the intact
`bowel from adapting16,17. The presence of colon in con-
`tinuity affects outcome because following resection the
`colon becomes an important digestive organ4.
`Patients considered to be at the highest nutritional risk
`typically have one of the following: an end jejunostomy
`with 5115 cm of small intestine remaining; a jejunocolic
`or ileocolic anastomosis with 560 cm of small intestine
`remaining; or a duodenostomy or a jejunoileal anastomosis
`with535 cm of small intestine remaining18.
`Resection of the first part of the small intestine (duo-
`denum) by itself is rare and does not lead to SBS–IF, but it
`may cause dumping syndrome, poor tolerance of certain
`sugars, and malabsorption of calcium,
`iron, and folic
`acid16. Malabsorption due to resection of the jejunum is
`often transient because the last section of the small intes-
`tine (i.e., the ileum) can adapt rapidly to take over the
`jejunum’s functions, including fat absorption19. However,
`survival may be limited if only a few centimeters of the
`jejunum are present17. The ileum is not able to compensate
`for the lack of enterohormones normally produced by the
`jejunum that aid in the regulation of gastric secretion16.
`Consequent increased acidity may cause damage to the
`mucosa, decreased transit, and inactivation of pancreatic
`enzymes, leading to poor absorption of lipids and proteins
`and potentially, steatorrhea16. Patients with jejunum
`resection may also experience transient electrolyte and
`fluid imbalance, as well as chronically low absorption of
`nutrients and excess sodium loss16.
`The effects of malnutrition from SBS–IF range from
`weight loss to distinct clinical syndromes related to various
`micronutrient and macronutrient deficiencies (calcium;
`magnesium; potassium; selenium; zinc; iron; vitamin B12;
`vitamins A, D, and K; carbohydrates; lactose; protein; and
`fat among others)16,17,19–22. Malnutrition impairs the
`function of all body systems, leading to diminished over-
`all health and QoL. Patients with malnutrition may be
`more susceptible to disease and have a greater propensity
`to experience complications
`from surgery or
`illness.
`Loss of muscle mass is associated with weakness and fati-
`gue, and loss of body fat produces a feeling of coldness;
`gaunt appearance; dry, wrinkled skin; and dull hair,
`leading
`patients
`to
`appear
`to
`age
`prematurely.
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`Moreover, malnutrition may cause mood changes, such as
`apathy, depression, and irritability, which may in turn
`affect patients’ willingness to adhere to treatment2.
`In addition to essential nutrients, medications may
`be malabsorbed, complicating comorbid conditions2,10.
`Reduced fluid absorption in the distal regions of the
`bowel may induce severe dehydration and diarrhea10,16,21.
`This, combined with sodium deficiency, may lead to hypo-
`tension and acute renal failure6,23. Malabsorbed bile salts
`may enter the colon and stimulate water and fat secretion,
`causing diarrhea. Moreover, bile salt deficiency may
`lead to fat malabsorption, resulting in steatorrhea19.
`Gallbladder stasis often leads to gallstones, especially
`in male patients. Hypocalcemia is common and may
`cause bone demineralization and altered mental status23.
`Other possible complications include metabolic acidosis,
`hyperammonemia, hypomagnesemia, reduced carbohy-
`drate fermentation, and renal stones6,16,19,21,24.
`
`Impact of PN/IV
`
`All patients with SBS initially need intravenous fluids and
`electrolytes, with the goal of gradually discontinuing par-
`enteral support once the patient is taking oral nutrition2.
`PN/IV support is usually given at night for an average of 5
`(range, 3–7) days per week4,13,25. Overnight infusions can
`improve nitrogen balance and result in decreased satiety,
`thereby leading to increased food intake during daylight
`hours; however, they can also be disruptive to sleep pat-
`terns because of frequent bathroom visits or discomfort
`from the procedure.
`Many patients, especially those with very short intes-
`tinal remnants, require life-long parenteral support2. A
`longer duration of PN/IV support is associated with an
`increased probability of continued dependency. One
`assessment found that patients have a 95% probability of
`irreversible intestinal
`failure after 2 years of PN/IV
`dependency15. Patients who are dependent on PN/IV are
`at risk for severe, chronic complications and death.
`
`Complications account for an estimated 15% to 20% of
`all deaths among patients on long-term PN26.
`The most common complication of this invasive ther-
`apy is catheter-related infection27, a cause of up to 70% of
`PN-related deaths6. Septicemia, in particular, is of major
`concern and has been associated with approximately 70%
`of hospitalizations among patients receiving PN. On aver-
`age, these patients experienced an infection once per 31
`months28. The evidence suggests PN/IV patients require
`one to two hospital readmissions per year26, with 0.34
`catheter sepsis events per catheter-year and 0.07 catheter
`occlusions per catheter-year29. Venous thromboses and
`catheter occlusions often occur and prevent adequate
`PN/IV support1,6. Fracture or breakage, pinch-off syn-
`drome, placement complication, and various other com-
`plications may also result from the central venous catheter
`(Table 1). Preliminary results suggest that including etha-
`nol locks as part of the PN/IV protocol may substantially
`reduce bloodstream infections; however, because some
`patients have developed thromboses, caution should be
`taken30.
`Abnormal biochemical liver function and associated
`liver complications are common and may be a factor in
`PN-related mortality6,31,32. An estimated 15% of patients
`dependent on PN/IV have end-stage liver disease (ESLD),
`for which the prognosis is poor. As Chan et al. found
`among 42 patients with PN/IV (mean follow-up, 6.7
`years), six had ESLD, with a 100% mortality rate32. In
`general, the longer the duration of PN/IV dependence,
`the greater the increase in risk of developing ESLD.
`Buchman et al. reported that the majority of patients rely-
`ing on PN/IV for more than 5 years will develop significant
`liver disease (severe fibrosis, cirrhosis, bilirubin 43.5 mg/
`dL for41 month, ascites, portal hypertension or liver fail-
`ure with factor V550%)4. Promising new data suggest that
`intestinal-failure-related liver disease may be treated with
`lipid therapy modulation33. However, the findings are
`investigational and future research is required. In addition,
`vitamin and mineral deficiencies are common in PN/IV
`
`Table 1. Short bowel syndrome complications.
`
`Central Venous
`Catheter Related
`
`Parenteral Support
`Related67
`
`Infection
`Occlusion
`Breakage
`Central vein thrombosis
`
`Hepatic
`Biliary
`
`Bowel Anatomy Related67
`
`Other Considerations2,4,6
`
`Susceptibility to disease
`Appearance of premature aging
`Apathy, depression, irritability, confusion
`High costs involved in care
`Impaired quality of life
`Increased risk of mortality
`
`Malabsorptive diarrhea
`Malnutrition and dehydration
`Fluid and electrolyte disturbances
`Micronutrient deficiency
`Essential fatty acid deficiency
`Small bowel bacterial overgrowth
`D-lactic acidosis
`Oxalate nephropathy
`Renal dysfunction
`Metabolic bone disease
`Acid peptic disease
`Anastomotic ulceration/stricture
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`patients34–37. Specifically, iron-deficiency anemia occurs
`frequently and may require regular, small doses of iron to
`be added to the PN formula38. PN/IV-induced cholestasis
`is less common in adults than children and occurs in vir-
`tually all patients with comorbid Crohn’s disease. If not
`corrected, cholestasis may lead to chronic and irreversible
`liver disease31.
`In addition to the clinical burden of complications,
`PN/IV also carries a substantial cost burden. Annual reim-
`bursement for home parenteral nutrition services across all
`clinical settings in the United States has been estimated at
`approximately $2.3 billion, a figure that does not include
`the costs paid for related healthcare services or for non-
`reimbursed expenditures39. Per patient, mean annual reim-
`bursements to healthcare professionals have been reported
`to range from $100,000 to $250,000, with reimbursement
`for PN/IV-related hospitalizations ranging from $10,000 to
`$196,000 and costs for supplies and infusion solutions ran-
`ging from $75,000 to $122,000. Annual non-reimbursed
`costs were $4716 per family for an average of 36 healthcare
`appointments for home PN/IV treatment per year. These
`additional costs do not reflect indirect costs such as lost
`income or additional out-of-pocket non-reimbursed
`expenses associated with PN/IV.
`
`Current management options
`
`The immediate goals of SBS–IF management are to
`increase intestinal absorption, decrease diarrhea, and pre-
`vent dehydration, with the ultimate goal being intestinal
`rehabilitation to reduce and ideally eliminate PN/IV
`dependence. Nutritional support remains the cornerstone
`of treatment. In addition to PN/IV, patients require a
`hyperphagic diet with appropriate oral
`rehydration,
`and vitamin and mineral supplementation along with
`pharmacotherapy to manage symptoms and complications
`of SBS–IF.
`
`Symptomatic management
`A variety of adjunctive medications are used to
`help manage the burdensome symptoms associated with
`SBS–IF (Table 2). Diarrhea,
`steatorrhea, and other
`
`digestive problems may be severe. Drugs that inhibit gas-
`tric acid secretion (e.g., proton pump inhibitors), antiper-
`istaltic
`agents
`(e.g., opioids),
`antidiarrheal
`agents,
`somatostatin analogs, and bile salt binders may be admin-
`istered to reduce stool output2,6,40. Antisecretory drugs
`may reduce diarrhea shortly after surgery but may not be
`effective long term and do not aid in eliminating PN/IV
`support supplements2,6,41. Diphenoxylate/atropine is less
`frequently prescribed because of its potential for anti-
`cholinergic activity (e.g., dry mouth). Somatostatin ana-
`logs may be useful as antidiarrheal therapy in patients with
`high-output jejunostomies or ileostomies, but in patients
`who need permanent PN/IV the effect may be insignifi-
`cant42. Malabsorbed bile salts and fatty acids may contrib-
`ute to diarrhea by stimulating water and sodium secretion
`from the colonic mucosa. Cholestyramine may be admin-
`istered to reduce bile malabsorption but may unintention-
`ally cause fat malabsorption41. Pancreatic agents in turn
`may be administered to aid in fat absorption2,4,43. For
`patients who exhibit electrolyte imbalance, especially
`those with stool output of 3 L/day or more, oral rehydration
`solutions may be advised4,40. In particular, sodium loss can
`be significant, for which oral rehydration solutions con-
`taining
`sodium and glucose
`(per World Health
`Organization specifications) may be administered.
`
`Intestinal rehabilitation
`Intestinal adaptation, the innate process of the remaining
`bowel’s attempt to regain absorptive capacity, begins
`almost immediately following extensive resection and is
`generally thought to occur over 1 to 2 years3. During adap-
`tation, the intestine hypertrophies, resulting in structural
`and functional changes that enhance its capacity for nutri-
`ent absorption. These changes include an increase in villus
`height, crypt depth, enterocyte proliferation, enzyme
`activity, and apoptosis44. Although there is minimal
`lengthening of the small bowel, increases in villus height
`and diameter effectively increase the absorptive surface of
`the intestine.
`Patient
`factors associated with adaptation include
`younger age,
`length of
`remaining bowel, adequate
`
`Table 2. Selected symptomatic therapies used in the management of short bowel syndrome.
`
`Therapeutic Class
`
`Effect
`
`Examples
`
`Antidiarrheals40,44
`Proton pump inhibitors6,40
`
`Reduce stool volume
`Reduce gastric secretion
`
`Bile salt binders40
`Narcotics40,44
`Antibiotics4,40
`
`Pancreatic enzymes6,43,44
`Endocrine metabolic agent6,42,68
`Oral rehydration solutions40,44
`
`Reduce level of malabsorbed bile salts
`Antiperistaltic agents
`Prevent infection, reduce diarrhea, increase
`bile salt reabsorption, prevent bacterial overgrowth
`Digest fats
`Reduces diarrhea
`Hydration
`
`Loperamide, diphenoxylate/atropine
`Omeprazole, lansoprazole, pantoprazole,
`esomeprazole
`Cholestyramine, colesevelam, colestipol
`Codeine, paregoric, morphine
`Metronidazole, tetracycline, ampicillin
`
`Lipase
`Octreotide
`Electrolyte replacement
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`mesenteric blood flow, presence of the ileocecal valve, and
`lack of comorbid conditions4. PN/IV support is needed
`when adaptation is inadequate to meet the patient’s nutri-
`ent and/or fluid needs. However, because of the drawbacks
`of chronic PN/IV therapy, there has been considerable
`interest in recent years in the development of targeted
`treatment strategies that go beyond symptomatic manage-
`ment to promote intestinal rehabilitation and improve
`absorption. Although oral food intake plays an important
`role in stimulating intestinal adaptation, a number of non-
`nutrient factors,
`including several gut hormones, are
`thought to be involved in the process4. Glucagon-like pep-
`tide 2 (GLP-2) appears to play a key role, although other
`factors may also be involved, including growth hormone,
`epidermal growth factor, GLP-1, enteroglucagon, chole-
`cystokinin, gastrin, insulin, and neurotensin4,23.
`
`Human growth hormone
`Human growth hormone was the first agent to be approved
`by the US Food and Drug Administration (FDA) specif-
`ically for short-term use in patients with SBS. Its actions
`on the gut may be direct or mediated via the local or sys-
`temic production of insulin-like growth factor-1 (IGF-1).
`Clinical studies have administrated growth hormone to
`enhance the transmucosal transport of water, electrolytes,
`and nutrients45,46. In a double-blind, randomized con-
`trolled trial enrolling 41 patients dependent on PN/IV,
`patients treated with growth hormone plus glutamine for
`4 weeks were able to achieve significant mean reductions
`in PN/IV volume and frequency (P50.001 vs glutamine
`alone) and were able to sustain these reductions over a 3
`month period47. Nevertheless, growth hormone has not
`been consistently demonstrated to promote intestinal
`adaptation.
`
`GLP-2 analog
`A novel
`intestinotrophic agent, teduglutide, another
`trophic factor that appears to promote intestinal adapta-
`tion, was recently approved for treatment of adults with
`SBS who are dependent on parenteral support. This dipep-
`tidyl peptidase IV resistant GLP-2 analog has a unique
`mechanism of action, mimicking the actions of naturally
`occurring human GLP-2, a peptide known to increase
`intestinal and portal blood flow and inhibit gastric secre-
`tion48, to target the malabsorption that is the underlying
`defect of SBS–IF. In a phase II study, teduglutide was
`shown to induce structural changes in the intestinal
`mucosa (including increased villus height and crypt
`depth) and to increase absorption of fluids, electrolytes,
`and nutrients and reduce fecal fluid loss49.
`A subsequent phase III placebo-controlled trial was
`undertaken to assess the percentage of patients able to
`achieve 420% reduction in PN/IV volume at 24 weeks
`
`after the initiation of therapy, an endpoint chosen because
`it had the potential to translate into one additional day off
`PN/IV support50. This multicenter, multinational, pla-
`cebo-controlled study is the largest reported to date in
`this rare condition. It enrolled 86 patients with SBS–IF
`who had been dependent on PN/IV for a minimum of
`12 months before the start of the study: the mean duration
`of PN/IV dependence was 6.3 years, and more than half
`of patients (46/86) required infusions 7 days/week50. A
`total of 63% (27/43) of
`teduglutide-treated patients
`achieved the primary endpoint, compared with 30%
`(13/43; P¼ 0.002) of patients randomized to placebo50.
`Statistically significant differences in PN/IV fluid needs
`became apparent as early as 8 weeks after starting therapy;
`these changes were sustained or increased throughout the 6
`month study period.
`Importantly,
`significantly more
`patients treated with teduglutide had at least 1 day off
`PN/IV compared with placebo (54% vs 23%; P¼ 0.005)50.
`
`Emerging therapies
`Additional promising therapies continue to emerge, with
`the most notable being treatments with epidermal growth
`factor (EGF)23. Clinical trials of recombinant EGF have
`demonstrated an increase in carbohydrate absorption and
`tolerance to enteral feeding, although these results were
`transient51. Studies involving GLP-1-based treatments
`have also been undertaken, specifically with the GLP-1
`agonist exenatide. Data have been published in a popula-
`tion of five patients treated with exenatide; although a
`small
`sample, all patients demonstrated immediate
`improvement in bowel form and frequency. In addition,
`three of the five were able to become independent from
`PN/IV support52. Although these results are promising,
`further research in a larger population is warranted to
`define the ideal regimen and its efficacy and safety.
`
`Surgery
`A number of surgical interventions have been designed to
`improve intestinal absorption and bowel function. Because
`of dilation of the intestine over time in SBS–IF patients
`and associated deleterious effects on motility, tapering
`enteroplasty may be necessary, and indeed has been
`found to improve intestinal function. Various procedures
`have been developed to prolong intestinal transit, includ-
`ing intestinal elongation, colonic transposition, and intes-
`tinal valve placement. Success rates vary and numerous
`complications, such as obstruction, anastomotic leak,
`and valve necrosis, may follow surgery. Nevertheless, up
`to 80% of patients show clinical
`improvement; this
`approach may be especially beneficial to patients who
`are refractory to, are not able to tolerate, or become
`addicted to pharmaceutical treatments intended to slow
`transit53.
`
`500 Burden of SBS in the US Hofstetter et al.
`
`www.cmrojournal.com ! 2013 Informa UK Ltd
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`Intestinal transplantation is reserved for patients who
`cannot