Editorials
`
`Teduglutide and Short Bowel Syndrome: Every Night Without Parenteral
`Fluids Is a Good Night
`
`See “Teduglutide reduces need for parenteral
`support among patients with short bowel syn-
`drome with intestinal failure,” by Jeppesen PB,
`Pertkiewicz M, Messing B, et al, on page 1473.
`
`Short bowel syndrome (SBS) is characterized by either
`
`a congenital or acquired absence of a substantial
`portion of the small intestine. Those patients whose re-
`sultant malabsorption is insufficient to maintain nutri-
`tional or fluid autonomy (eg, fecal energy and/or fluid
`losses are greater than absorption) are deemed to have
`intestinal failure (IF). Although most nutrient absorption
`occurs within the proximal 100 –150 cm of jejunum,1
`intestinal transit time is very rapid, allowing for limited
`nutrient– epithelial contact time. Such individuals are
`among the most complex and challenging to manage
`patients of any gastrointestinal disease. Particularly diffi-
`cult to manage are those patients with a proximal jeju-
`nostomy, who may actually secrete more fluid than they
`ingest.2 Adult patients typically have ⬍200 cm of residual
`small bowel, with or without their colon, although ab-
`sorption is dependent not only on the length of bowel,
`but the overall surface area and function. Underlying
`etiologies may include multiple small bowel resections for
`diseased or obstructed bowel including Crohn’s disease,
`trauma, mesenteric vascular catastrophes, or volvulus. Eti-
`ologies in children may also include congenital disorders
`such as intestinal atresia, malrotation, and gastroschisis.
`In part, because the underlying diseases resulting in SBS
`are a heterogeneous group, there is no ICD-9 code and, as
`such, there are no reliable estimates as to the number of
`individuals with SBS or SBS/IF in the United States.
`Estimates based on European registries and other data-
`bases have suggested the number of such patients in the
`United States may be in the 10,000 –20,000 range.3
`Patients with SBS/IF depend on artificial nutrition
`and/or fluid support to maintain life. This may require
`them to infuse parenteral fluids (parenteral support [PS])
`overnight for 3–7 days per week, and in some cases,
`during the day as well. This therapy has substantial im-
`plications for employment, activities, sleep, and finances.
`Furthermore, medical management may differ depending
`on whether a given patient has residual colon in continu-
`ity with the remaining small intestine or not.
`Numerous complications from SBS or its therapy may
`develop. Most notorious among these is IF-associated
`liver disease.4 IF-associated liver disease is the leading
`indication for intestine and intestine–liver transplanta-
`
`GASTROENTEROLOGY 2012;143:1416 –1434
`
`tion, a procedure that may be life-saving and eliminate
`dependence on parenteral fluids, but may cost upwards of
`$1 million, although often $250,000 –$500,000 for the
`procedure and initial hospitalization in addition to med-
`ications, follow-up clinical visits, and treatment of com-
`plications such as infections or acute and chronic rejec-
`tion and additional surgery. One year of parenteral
`nutrition (PN), discounting treatment for laboratory
`studies, nursing and physician visits, and treatment of
`complications and hospitalizations (generally 1–2 times
`annually), often costs the health care system $100,000 –
`$125,000.5
`Animal models suggest that, after massive intestinal
`resection, the intestine begins to adapt, whereby the in-
`testine lengthens a modest amount, but may increase in
`diameter and surface area significantly. This process is
`more pronounced in the ileum after a jejunal resection
`wherein villi lengthen and crypts deepen.6-8 These findings
`are supported by limited human data,9-12 wherein diar-
`rhea decreases over time after onset of SBS.10 In fact,
`conventional management13 of these patients, perhaps
`not always widely practiced owing to its relative complex-
`ity and unfamiliarity among clinicians,14 combined with
`the patient’s own innate ability for adaptation, can lead to
`elimination of PN in 50% of patients within 6 months of
`their resection.15
`Growth hormone was the first medication approved by
`the US Food and Drug Administration (in 2003) specifi-
`cally for use in patients with SBS receiving specialized
`nutritional support “in conjunction with optimal man-
`agement”13 based on a 2-center controlled trial, although
`there was no placebo group and subjects received addi-
`tional interventions in addition to growth hormone. In-
`consistent results have been reported in previous clinical
`trials. Nevertheless, PN requirements could be reduced by
`approximately 2 L or 1 night weekly.16 The use of this
`growth factor has been limited, largely owing to concerns
`with regard to efficacy and the fact that only short-term
`use was approved. The effects of growth hormone on
`human intestinal absorption are unknown, although it
`enhances reabsorption of sodium in the distal nephron.17
`Notably, patients with acromegaly have a heightened risk
`for development of colonic adenomas in humans, al-
`though malignancy has not been reported.18
`A myriad of other growth factors may be involved in the
`process of postresection intestinal adaptation, including
`hepatocyte growth factor, vascular endothelial growth fac-
`tor, cholecystokinin, transforming growth factor, epider-
`mal growth factor, gastrin, insulin, insulin-like growth
`factor-1, neurotensin, keratinocyte growth factor (KGF),
`
`Page 1
`
`

`
`and glucagon-like peptide-2 (GLP-2).19 GLP-2’s own ac-
`tions may be modulated by some of these peptides, in-
`cluding transforming growth factor-␤, insulin-like growth
`factor-1, and KGF.20-22 Each of these extracellular growth
`factors have the potential for human use. Epidermal
`growth factor is no longer commercially manufactured
`and KGF is used only for the treatment of mucositis
`currently. GLP-2 is among the first of these peptides
`evaluated in humans with SBS/IF.
`GLP-2 is released from L cells in the distal small bowel
`and colon in response to food ingestion, but its release is
`severely blunted in patients with SBS/IF and ileal resec-
`tion,23 although meal-stimulated release is enhanced in
`patients with a preserved colon.24 It promotes intestinal
`epithelial growth via increased cellular proliferation
`through activation of the Wnt signaling pathway, which
`leads to nuclear translocation of ␤-catenin,25 and de-
`creased apoptosis and epithelial growth may also be en-
`hanced through increased mesenteric blood flow.26
`Normal digestion and absorption depends on a gradual
`emptying of nutrients from the stomach into the small
`intestine, wherein mixing with pancreatic enzymes and
`bile occurs. Rapid gastric emptying may result in inade-
`quate mixing, insufficient enzymatic digestion, and im-
`paired nutrient digestion. GLP-2 increases gastrointesti-
`nal transit time, and this may be among the mechanisms
`by which its use leads to decreased diarrhea.27 The use of
`native GLP-2 has resulted in less chronic dehydration, the
`major factor in the development of IF-associated nephrop-
`athy in patients that require long-term PN,28 among patients
`with SBS.29 GLP-2 may also exert a beneficial effect on bone
`health as well,30 which is adversely affected during SBS/IF.31
`However, the actions of the native hormone are limited
`by rapid degradation by dipeptidypeptidase IV, leading
`to a very short half-life. A long-acting analog, more
`resistant to this enzyme, h(Gly2)GLP-2[1-33] (teduglu-
`tide) was developed by the substitution of a glycine
`residue for an alanine in position 2.
`In this issue of GASTROENTEROLOGY, Jeppesen et al32
`report the results of a phase III double-blind, placebo-
`controlled trial of teduglutide for the purposes of enhanc-
`ing nutrient and fluid absorption and weaning parenteral
`fluids in 86 patients with SBS/IF. This study was con-
`ceived because of discrepant results from an earlier place-
`bo-controlled multinational study wherein a higher dose
`of teduglutide (0.1 mg/kg per day) seemed to be slightly
`less effective than the 0.05 mg/kg dose used in the current
`study, although a significant difference for the lower dose
`was not achieved when compared with placebo.33
`Jeppesen et al32 are to be congratulated for completing
`an extremely complex, multinational study in a very com-
`plicated group of patients, in fact the largest prospective
`study ever in this patient population. Patients were re-
`quired to have received PS ⱖ3 times weekly and for a
`
`Editorials, continued
`
`minimum of 12 months immediately preceding the study
`to qualify for inclusion. This could have included PN or
`intravenous fluid and electrolytes alone. A strength of the
`study was the pretreatment PS optimization whereby in-
`dividual patient fluid volumes were stabilized to achieve a
`urine output of 1–2 L/day over a period of 4 –16 weeks
`before randomization. That ensured as much as possible
`that the baseline PS volume was required and stable,
`although unlike in the previous study,33 there was no
`specific attempt at weaning PN before randomization.
`In the current study, patients were randomized to re-
`ceive teduglutide 0.05 mg/kg per day or placebo injected
`daily. The primary endpoint was the percentage of en-
`rolled patients that achieved a consistent reduction in PS
`volume of 20%–100% from baseline at both week 20 and
`week 24. A 20% decrease equates to the reduction of PS
`from 6 to 5 nights per week, a very profound improve-
`ment for an individual patient. Given the disparity be-
`tween daily fluid volumes (ⱖ1.5– 8 L daily), it would have
`been inappropriate to have used the absolute decrease in
`number of days of infusion as the primary endpoint.
`Secondary endpoints in the study included the mean
`percentage and absolute volume decrease in PS and the
`number of patients and the time they required on study
`medication to be completely weaned from PS.
`Attempts to wean PS were made at the discretion of
`individual investigators in increments of 10%–30%, begin-
`ning after 2 weeks of therapy, and then every 4 weeks for
`the remainder of the 24 week study. As we generally do in
`clinical practice, urine output was collected for 48 hours
`(including a night when PS were not administered if ⬍7
`nights per week) before each study visit. This volume had
`to exceed the baseline value before further weaning would
`be considered. Discontinuing an entire day of PS was
`considered based on the weekly volume reduction, but the
`choice was left up to the investigator and patient.
`There were 27 of 43 (63%) responders in the teduglutide
`group compared with 13 of 43 (30%) in the placebo group
`(P ⬍ .02) with differences between the group-specific
`responder rate at each visit. There was a nonsignificant
`trend toward a greater response rate in those patients with
`residual colon in continuity with their remaining small
`bowel. PS volume reduction was 4.4 ⫾ 3.8 L per week in
`the teduglutide group versus 2.3 ⫾ 2.7 L per week in the
`placebo group. At baseline, subjects received an average of
`nearly 2 L/d, so it was not surprising that no subjects were
`completely weaned from PS; however, the number of
`patients who achieved ⱖ1 full day off PS in the teduglu-
`tide group was more than double that in the placebo
`group (54% vs 23%; P ⬍ .047). PS was not completely
`eliminated in any patient. An earlier and more aggres-
`sive PS weaning protocol than that utilized in the
`previous teduglutide study33 may have accounted for a
`
`1417
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`Page 2
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`

`
`Editorials, continued
`
`more significant decline in PS volume in the current
`investigations.
`Consistent with an increase in intestinal mass, plasma
`citrulline concentration increased significantly only in the
`teduglutide group. Previous studies with teduglutide have
`shown it reduces the volume of diarrhea,34 although this
`effect was not evaluated in the most recent investiga-
`tion.32 It is to be noted that some patients with SBS/IF
`have sufficient nutrient absorption, but are unable to
`consume sufficient fluids to make up for dramatic losses,
`and as such require parenteral fluid and electrolytes, but
`not PN. Might these patients respond better to teduglu-
`tide? The data were not broken out. In addition, the effect
`of teduglutide on micronutrient absorption and potential
`independence from intravenous micronutrient supple-
`mentation was not evaluated.
`Some patients failed to respond to teduglutide. Why
`did that occur? Because most L cells are located in the
`ileum and colon, patients with resection of those portions
`of bowel would presumably have lower native meal-stim-
`ulated serum GLP-2 concentrations and thereby might
`have a greater response to exogenous administration.
`However, there was a trend toward a greater response in
`patients with colon, although this difference did not at-
`tain significance. Given that nutrient absorption is a fac-
`tor of not only percentage absorption, but oral intake,
`might teduglutide be more effective if administered post-
`prandially rather than pre-prandially to avoid potential
`development of gastroparesis and early satiety? In addi-
`tion, there were a substantial number of patients with
`Crohn’s disease enrolled in the study. In a previous study,
`teduglutide was shown to be a potentially useful therapy
`for Crohn’s disease, but only at a much greater dose
`(ⱖ0.15 mg/kg per day).35 Differential efficacy in patients
`with Crohn’s disease owing to direct effects of inflamma-
`tion on response to GLP-2, and therefore on mucosal
`repair and adaptation is, therefore, uncertain.
`The placebo response was also substantially greater in
`the current study compared with the previous study.33
`This may have been related to a less aggressive PS weaning
`protocol before randomization. The current study used an
`“optimization” period only to stabilize urine output over
`a wide range (1–2 L daily). Perhaps some patients simply
`continue their adaptation phase much longer than others,
`although only 6 patients in the teduglutide group and 8
`patients in the placebo group were ⬍2 years out (the
`previous study’s exclusion criteria) since their last bowel
`resection. We are not told whether these patients re-
`sponded differently to treatment.
`Predictors of response to teduglutide need to be either
`determined or developed. Jeppesen et al32 found that the
`length of the residual bowel was not a factor. Perhaps one
`might be a baseline meal-stimulated serum GLP-2 con-
`centration. This was unfortunately not investigated in any
`
`1418
`
`of the teduglutide or native GLP-2 studies to date despite
`the provision of standardized meals in an earlier study.34
`A study in children has identified a concentration of
`serum GLP-2, below which a need for PN can be pre-
`dicted.36 The presence of comorbid conditions that in-
`clude the health of the residual bowel and perhaps un-
`derlying pathology, mesenteric blood flow, and age are
`likely all important cofactors.
`As would be expected in the SBS/IF patient population,
`there were many adverse events in the study reported in
`this issue of GASTROENTEROLOGY, although these were
`equally distributed across
`teduglutide and placebo
`groups. Only 2 patients in the teduglutide group and 3 in
`the placebo group terminated the study owing to treat-
`ment-emergent adverse events (in both cases, abdominal
`pain that resolved within 3 days of study withdrawal in
`the teduglutide group). Abdominal pain and distention,
`nausea, peripheral edema, dyspnea, and nasopharyngitis
`were slightly more common in patients who received
`teduglutide. Stomal changes, primarily related to enlarge-
`ment, were evident in a significant minority of patients in
`the teduglutide group as would be expected, given the
`hyperplastic effect of the medication on intestinal epithe-
`lial tissue as well as previous reports.33,34 The observation
`that 1 patient may have developed a transient bowel
`obstruction during treatment with teduglutide seems in-
`conceivable to be related to the medication in the absence
`of an unrecognized pretreatment bowel obstruction given
`that teduglutide does not fertilize the growth of monster
`villi, but its use should be tempered in patients with bowel
`strictures, stomas with small lumens, or partial bowel
`obstructions.
`Concern has been raised about the potential for GLP-2
`to stimulate development of colonic adenomas in rodent
`models. The number of adenomas increased in mice
`treated with the chemical carcinogen 1,2 dimethylhydra-
`zine,37 although studies in different models, the APC-
`min/⫹ mouse, nude mice with colon cancer xenografts, or
`in GLP-2 receptor-transfected cancer cells.38 A more recent
`investigation in azoxymethane-treated mice found develop-
`ment of colonic dysplasia and adenocarcinomas in animals
`that had been chronically treated with h(Gly2)GLP-2[1-33].39
`Although the risk for malignancy is hypothetical in humans,
`and colonoscopy is difficult in these patients, colonoscopy
`should be considered at baseline for those patients with
`residual colons and perhaps even as frequently as annually
`while on therapy until more long-term safety data are
`available. This risk must be balanced against quality-of-
`life improvements, and decreased complications related to
`enhanced absorption and, therefore, portal nutrient cir-
`culation, and decreased catheter access, which may lead to
`decreased infection risk. In addition to intestine and co-
`lon, GLP-2 receptors have been found in lung, the hind-
`brain, and the hypothalamus.40 Although, to date, clini-
`
`Page 3
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`

`
`cally detectable effects have not been observed in these
`organs, the potential exists that chronic administration of
`GLP-2 could have either beneficial or detrimental effects.
`Is teduglutide a “game changer?” Few treatments in
`SBS are. The only patients who will be able to discontinue
`PS completely will be those who are on the borderline
`between nutritional autonomy and PS dependence. Po-
`tentially, teduglutide may help some patients who sit on
`that “fence” from actually needing PS to begin with. What
`happens when teduglutide is stopped? Some preliminary
`evidence suggests the effects on adaptation may be per-
`sistent,41 although an earlier study noted histologic
`changes that trended toward baseline within 4 weeks of
`discontinuation.35 Possibly longer treatment than that
`reported in this issue of GASTROENTEROLOGY is required.42
`The advent of teduglutide, like most other new therapies,
`represents an incremental improvement in the care of
`patients with SBS/IF and likely will allow the clinician an
`additional option for patient management. Every night
`without PN is a good night, but whether teduglutide is a
`true “game changer” is not clear. Teduglutide does have
`the potential to improve quality of life for patients with
`SBS/IF, although a fully validated measure of quality of
`life in these patients awaits full development. I think we
`should look forward to the availability of teduglutide as a
`treatment for patients with SBS/IF and now we also
`eagerly await the development of longer acting analogs, as
`well as other growth factors such as HGF and KGF.
`The future is a truly artificial, or artificially grown and
`harvested, intestine; even intestinal transplantation repre-
`sents but a bridge at best. Although advances have been
`made, the practical aspects of a truly functional artificial
`gut— or even one constructed from a patient’s own stem
`cells, remains far from a clinical reality. In the meantime,
`teduglutide represents a significant, although incremental
`improvement in the treatment armamentarium for pa-
`tients with SBS/IF.
`ALAN L. BUCHMAN
`Glencoe, Illinois
`
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`
`Reprint requests
`Address requests for reprints to: Alan L. Buchman, MD, MSPH,
`AGAF, 959 Oak Drive, Glencoe, Illinois 60022.
`e-mail:
`.
`
`Conflicts of interest
`Dr Buchman is a former consultant for NPS pharmaceuticals.
`© 2012 by the AGA Institute
`0016-5085/$36.00
`
`Familial Visceral Myopathies: From Symptom-Based Syndromes to
`Actin-Related Diseases
`
`See “Segregation of a missense variant in en-
`teric smooth muscle actin ␥-2 with autosomal
`dominant familial visceral myopathy,” by
`Lehtonen HJ, Sipponen T, Tojkander S, et al,
`on page 1482.
`
`Mammals have genes that encode 6 different actin
`
`isoforms expressed in a developmental and tissue-
`specific fashion.1 These actins include 2 striated muscle
`(skeletal and cardiac), 2 smooth muscle (vascular and
`visceral), and 2 non-muscle actins. Isoelectic focusing sep-
`arates these actins into ␣- (skeletal, aortic smooth, and car-
`diac), ␤-, and ␥1- and ␥2- (cytoplasmic and enteric smooth
`muscle, respectively) actins. These actins share a high degree
`of structural homology, with no 2 actins differing in struc-
`ture from one another by ⬎5%. Furthermore, in mammalian
`cells, from 2 to 4 of the different actins may be simultane-
`ously present in the same cell. G-Smooth muscle actin is the
`
`1420
`
`major actin found in visceral smooth muscle, and this report
`by Lehtonen et al2 of the association of a mutation in this
`actin with familial visceral myopathy is significant for 2
`reasons. It is the first report of a human disease associated
`with this particular actin isoform and it means that now
`mutations in each of the 6 different actin isoforms have been
`shown to cause human disease.3–7 What is particularly inter-
`esting, and it is true for the mutation focused on here, is that
`in a number of cases, different diseases are caused by muta-
`tions at the same site in different actins. For example, the
`R148S mutation in ␥-smooth muscle actin causes familial
`visceral myopathy, whereas the mutation to C in ␣-smooth
`muscle actin causes thoracic aortic aneurysm and dissec-
`tion.4 The R258 mutation to either H or C in ␣-smooth
`muscle actin causes thoracic aortic aneurysm and dissec-
`tion,4 whereas in ␤-nonmuscle actin, an R to W mutation at
`the same site causes Baraitser–Winter syndrome.6 In a third
`example, a V370A mutation in ␥-nonmuscle actin causes
`autosomal-dominant nonsyndromic deafness, DFNA20/26,7
`
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