Abstract
Introduction
Short bowel syndrome (SBS) resulting from acute aortic dissection (AAD)-induced visceral malperfusions leads to chronic intestinal failure (CIF), necessitating patients to adopt home parenteral nutrition to prevent malabsorption. Teduglutide (TED), a glucagon-like peptide-2 analog, is a promising pharmacotherapy for intestinal rehabilitation that reduces parenteral support and improves the quality of life. Gastric mucosal necrosis, a rare gastrointestinal disorder, had never been observed as an adverse event relevant to this drug. We report a case of mucosal necrosis in the stomach after TED treatment for SBS-CIF with hepatorenal failure.
Presentation of case
A 68-year-old Japanese man who underwent massive intestinal resection for AAD experienced malnutrition and diarrhea caused by SBS-CIF. The patient received TED to improve intestinal absorption and entero-hepatic circulation besides controlling infectious diseases. Endoscopy showed mucosal hyperplasia in the stomach and duodenum 1.5 months after TED administration. The patient consented to enteral nutrition via a nasogastric tube because of anorexia. The nutritional status gradually improved after initiating enteral feeding. However, the patient experienced hematemesis 13 days after enteral feeding, and endoscopy revealed acute gastric mucosal necrosis, followed by fatal septic shock.
Discussion
For patients with SBS, TED is expected to increase intestinal absorption through epithelial proliferation. When SBS is accompanied by multiple ischemic organ failure, TED therapeutic effects remain unclear as malnutrition-associated infectious diseases are refractory, and many underlying mechanisms can be involved.
Conclusion
TED administration should be deliberately considered for patients with SBS-CIF and multiple organ failure experiencing uncontrolled systemic infection.
Keywords: Teduglutide, Short bowel syndrome, Hepatorenal failure, Acute gastric mucosal necrosis, Case report
Highlights
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SBS with hepatorenal failure caused by aortic dissection was susceptible to infection.
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Teduglutide induced gastric mucosal hyperplasia and improved nutritional status
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Unexpected gastric necrosis caused septic shock during teduglutide treatment
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Teduglutide usage should be considered for SBS with refractory infectious disease.
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Nutrition and infection care is crucial for SBS patients with multiple organ failure.
1. Introduction
Short bowel syndrome (SBS) results from extensive intestinal surgical resection owing to mesenteric malperfusion (MM). Acute aortic dissection (AAD) is a rare but potential cause of MM, with a worldwide incidence of 3.0–3.8 %. It is associated with increased hospital mortality, especially when multiple visceral organs are involved in functional failure [1,2].
In adults, SBS is the most frequent cause of chronic intestinal failure (CIF), characterized by the gut's functional inability to maintain daily water and energy requirements. Mesenteric ischemia accounts for one-third of the underlying diseases causing SBS; therefore, nutritional management is the primary treatment for SBS [3]. According to the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines, management and treatment of CIF mainly consist of home parenteral nutrition (HPN), intestinal rehabilitation, and intestinal transplantation [3,4].
Enteral nutrition (EN) may reduce the dependence on intravenous supplementation in patients with SBS-CIF receiving HPN. Moreover, pharmacotherapy enhances the absorptive capacity of the remnant bowel as intestinal rehabilitation. A glucagon-like peptide (GLP)-2 derivative, teduglutide (TED), is recommended as a primary option to reduce parenteral support and improve the quality of life in the ESPEN guidelines [4]. Since Jeppesen et al. first described the safety and effects of TED on patients with SBS [5], randomized controlled studies have been conducted to determine whether parenteral support should be reduced in these patients [6,7]. Furthermore, extension studies have been conducted to examine the long-term safety and efficacy of TED, revealing enteral autonomy in some patients with SBS-CIF [[8], [9], [10], [11]]. Contrarily, prevalent adverse events (AEs) were gastrointestinal disorders, including abdominal pain, nausea, and stoma enlargement, although no studies have identified gastric mucosal necrosis. Here, we report the case of a patient with SBS-CIF who experienced hepatorenal failure following AAD and in whom TED treatment after several months of inadequate fluid management with uncontrolled systemic infection resulted in acute gastric mucosal necrosis. This work aligns with the SCARE criteria [12].
2. Presentation of case
A 68-year-old man who experienced epigastric discomfort with backache was transferred to our hospital with AAD. The patient had a history of hyperuricemia. Enhanced computed tomography (CT) identified AAD involving the ramifications, resulting in stenosis of the root of the celiac artery, occlusion of the superior mesenteric artery, and right kidney infarction concomitant with MM (Fig. 1). The patient underwent emergency laparotomy, revealing ischemic bowels extending from the terminal ileum to the middle of the transverse colon, necessitating right hemicolectomy. Despite preserving the small intestine with the expectation of improved blood flow, a second-look operation identified necrotic changes in the remnant intestine. Therefore, massive intestinal resection was performed with a jejunostomy 30 cm distal from the ligament of Treitz.
Fig. 1.
Contrast-enhanced computed tomography at the initial onset of the disease. The images show aortic dissection (A) leading to stenosis of the celiac artery and occlusion of the superior mesenteric artery (B). An ischemic change was found on the upper pole of the right kidney (C), and mucosal emphysema on the ascending colon (arrows) was identified with portal venous gas (dotted circle) (D).
The patient experienced ischemic hepatorenal failure with coma (aspartate aminotransferase, 12,067 U/L; alanine aminotransferase, 3519 U/L; prothrombin time international normalized ratio [PT-INR], 2.27; creatinine, 3.51 mg/dL) and underwent prolonged continuous hemodialysis with ventilation support. Despite recovering from acute liver failure with encephalopathy, he required dialysis maintenance because of renal dysfunction (Fig. 2). Blood pressure control remained dissected aorta stable with persistent blood flows into the pseudo lumen as well as the arterial ramifications, leading to maintained perfusion in the visceral organs except for partial renal infarction 6 months after disease onset (Fig. 3).
Fig. 2.
The clinical course after disease onset. Days after the second operation and reset days after teduglutide treatment. Red arrows indicate bleeding from the stump of the transverse colon and duodenal ulcers, respectively. Green arrow indicates the timing of increased dialysis frequency.
T-bil, total bilirubin; WBC, white blood cell; CRP, c-reactive protein; Alb, albumin; ChE, choline esterase; PE, plasma exchange; CHDF, continuous hemodialysis and filtration; HDF, hemodialysis and filtration; HD, hemodialysis; TPN, total parenteral nutrition; EN, enteral nutrition.
Fig. 3.
Contrast-enhanced computed tomography 6 months after disease onset. The images show aortic dissection with persistent blood flow in the pseudo lumen (A), and blood flows into the ramifications, including the common hepatic artery (A), splenic and gastroepiploic arteries (arrows) (B), a peripheral branch of the superior mesenteric artery (C), and bilateral renal arteries (D).
Total parenteral nutrition (TPN) was administered to maintain energy requirements, and EN was initiated to prevent bacterial translocation. However, intestinal discharge from the jejunostomy increased after EN and worsened to 3 L a day despite small amounts of dietary intake (Fig. 2). He had histories of gastrointestinal bleeding by colon stump infection and duodenal ulcers leading to intermittent fasting. Because of persistent malnutrition, intraabdominal abscesses recurred repeatedly, and systemic infection gradually aggravated (Fig. 2). EN was continued solely for the symbiotic treatment owing to persistent appetite loss. The patient could not achieve a reduction in stoma discharge or the need for parenteral support even 5 months after SBS onset. Uncontrolled infection induced anorexia, worsening malnutrition, and exacerbating entero-hepatic circulation showing higher bilirubin levels (10.6–17.1 mg/dL) within the normal range of PT-INR (1.11–1.28) (Fig. 2).
We proposed the induction of TED with the patient's agreement. TED for renal dysfunction (0.025 mg/kg) was administered 6 months after SBS onset. However, the nutritional status, stoma discharge, and amount of oral intake had not changed at 1 month after TED administration (Fig. 2). Meanwhile, the patient experienced visceral dysfunction with elevated total bilirubin levels (18.9 mg/dL) and an increased dialysis frequency despite no change of arterial flows into the visceral organs on enhanced CT, which did not indicate aggravating vascular diseases but suspect deteriorating general condition.
Gastrointestinal endoscopy (GE) was performed to examine any organic diseases relevant to anorexia but identified intestinal hyperplasia in the stomach and duodenum (Fig. 4). We decided to start EN via a nasogastric tube with his consent to improve nutritional absorption and control systemic infections. Malnutrition and infection marker levels improved transiently (Fig. 2). However, he developed hematemesis 13 days after the resumption of EN, and GE showed extensive gastric mucosal necrosis (Fig. 4). Furthermore, CT identified mucosal separation from the gastric muscularis without deficient arterial flows in the stomach as well as small intestine, and any abdominal organs (Fig. 5).
Fig. 4.
Gastrointestinal endoscopy. Intestinal mucosal hyperplasia is observed in the stomach (A) and duodenum (B) at 1.5 months after teduglutide treatment. On the other hand, extensive mucosal necrosis in the stomach (C) but not in the duodenum (D) is observed at 13 days after the resumption of enteral nutrition via a nasogastric tube.
Fig. 5.
Contrast-enhanced computed tomography at the onset of hematemesis. The images show mucosal separation from the gastric muscularis (arrowhead) (A), but blood flows into the stomach was maintained with the short gastric artery (arrow) (A), left gastric artery (arrow) (B) as well as gastroepiploic arteries (arrows) (C). The images also identified blood flows into the celiac artery spreading to common hepatic and splenic artery (D), a peripheral branch of the superior mesenteric artery (E), and bilateral renal arteries (F).
He experienced over 40 degrees of body temperature and died of septic shock 7.5 months postoperatively.
3. Discussion
This report describes a case of gastric mucosal necrosis after TED treatment in a patient with SBS concomitant with multiple organ failure following AAD. Insufficient blood flow into the stomach may have occurred during the clinical course. However, follow-up CT identified an unchanged extension of aortic dissection with stable organ perfusions during the treatment period, even though the organ functions deteriorated gradually along with exacerbated systemic infection. The patient recovered from acute liver failure transiently, but liver function decreased thereafter. This pathophysiology might be attributed to intestinal-associated liver disease caused by insufficient nutrients from the intestine. Furthermore, bacterial infection and insufficient hepatic arterial flow may exacerbate the metabolic function in the liver. Our strategy was to control the infectious disease and improve the nutritional status using TPN and EN.
Since TED has been proven to induce mucosal epithelial proliferation in animal studies [13,14], it is applied to patients with SBS with the expectation of improving water and nutrition absorption through its intestinotrophic properties [5]. Mucosal hypertrophy after TED administration has been recognized as stoma swelling [8,9], intestinal obstruction [7], and neoplasm [11] in many multicenter, randomized controlled studies investigating TED [[6], [7], [8], [9],11]. The maj08or AE associated with infection was catheter-related sepsis. However, serious AEs and mortality records have not reported any cases of acute gastric mucosal necrosis.
Patients with SBS-CIF are susceptible to infectious diseases owing to malnutrition or intestinal barrier dysfunction. The GLP-2 analog augmented the intestinal epithelial barrier by inhibiting paracellular and transcellular permeabilities concurrently with the incremental effect of epithelial growth [13] and suppression of apoptosis in the villi [14]. These effects inhibit bacterial translocation into the bloodstream, contributing to the control of infectious diseases [15]. Based on these effects, TED treatment was considered suitable for our patient to enhance water and nutrition absorption, manage systemic infection, and improve entero-hepatic circulation.
Long-standing TPN induces intestinal atrophy, and EN is a desirable route for nutrient absorption. Through its antiapoptotic effect, GLP-2 prevents intestinal degradation in TPN-fed pigs [16]. Antioxidant augmentation of the intestinal mucus by GLP-2 may be a potential mechanism to prevent intestinal atrophy [17]. However, the underlying signal transduction pathways involved in apoptosis remain undetermined owing to the possibility of cellular or receptor specificity [18,19].
Conversely, inflammation derived from endotoxins induces overproduction of nitric oxide, which plays a key role in the pathogenesis of necrotizing enterocolitis by disrupting the intestinal epithelial barrier and increasing enterocyte apoptosis [20]. Recurrent intraabdominal infection might contribute to enterocyte apoptosis through endotoxins-induced nitric oxide increment. A potential mechanism of mucosal necrosis confined in the stomach is that longer period placement of nasogastric tube induced mucosal abrasion in the stomach while TED stimulated the overgrowth of gastric mucosa, and consecutive infection into the submucosal layer occurred, leading to acute gastric mucosal necrosis. Additionally, this adverse event occurred after 2 months of TED treatment because refractory infection exacerbated reduced urinary production from his own kidneys, leading to an increased dialysis frequency at 1.5 months after TED treatment, and renal dysfunction might augment TED accumulation and accelerate the overgrowth of gastric mucosa.
Therefore, clinicians should carefully consider the patient's general condition and indications for a hormone analog with intestinotrophic properties before administration.
Careful management of nutrition and infection is crucial for treating patients with SBS experiencing insufficient nutritional absorption and refractory infectious diseases with multiple organ dysfunction.
4. Conclusion
Our experience with a patient undergoing SBS-CIF concomitant with multiple organ failure following AAD revealed acute gastric mucosal necrosis as an unexpected AE associated with TED during infection-related organ dysfunction. TED is beneficial for reducing parenteral support and improving the quality of life of patients with SBS-CIF. Therefore, carefully administering TED with nutritional and infectious management is crucial, particularly in cases of uncontrolled infection with multiple visceral organ failure.
Funding
This research received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contribution
Tohru Takahashi contributed to the conception and design of the study, acquisition, analysis, and interpretation of the data, as well as manuscript drafting.
Taku Maejima and Dai Miyazaki equally contributed to the acquisition of the data.
Susumu Fukahori contributed to the data analysis.
Masahiro Hagiwara contributed to the conception and design of the study and interpretation of the data. All authors critically revised the manuscript, agreed to be fully accountable for ensuring integrity, and have read and approved the final version of the manuscript.
Guarantor
Tohru Takahashi – corresponding author
Consent
Written informed consent was obtained from the patient's family for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Statement of ethical approval
This study was approved by the Tokushukai Group Ethics Committee (No: TGE02432-012) and was carried out in accordance with the Helsinki Declaration Principles.
Conflict of interest statement
None.
Acknowledgments
We would like to thank Editage (www.editage.jp) for English language editing.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijscr.2024.109524.
Appendix A. Supplementary data
The following are the supplementary data related to this article.
Supplementary Fig. 1.
Contrast-enhanced computed tomography at the initial onset of the disease. Blood flows were identified in the peripheral branches of the superior mesenteric artery and inferior pancreatico-duodenal artery.
Supplementary Fig. 2.
Gastrointestinal endoscopy at 13 days after the resumption of enteral nutrition via a nasogastric tube.
A small hematoma was identified on the right piriform fossa, but esophageal mucosal surface appeared to be normal.
Data availability
The article's data will be shared by the corresponding author upon reasonable request.
References
- 1.Di Eusanio M., Trimarchi S., Patel H.J., Hutchison S., Suzuki T., Peterson M.D., et al. Clinical presentation, management, and short-term outcome of patients with type a acute dissection complicated by mesenteric malperfusion: observations from the international registry of acute aortic dissection. J. Thorac. Cardiovasc. Surg. 2013;145:385–390.e1. doi: 10.1016/j.jtcvs.2012.01.042. [DOI] [PubMed] [Google Scholar]
- 2.Jaffar-Karballai M., Tran T.T., Oremakinde O., Zafar S., Harky A. Malperfusion in acute type a aortic dissection: management strategies. Vasc. Endovascular Surg. 2021;55:721–729. doi: 10.1177/15385744211017116. [DOI] [PubMed] [Google Scholar]
- 3.Pironi L., Arends J., Bozzetti F., Cuerda C., Gillanders L., Jeppesen P.B., et al. ESPEN guidelines on chronic intestinal failure in adults. Clin. Nutr. 2016;35:247–307. doi: 10.1016/j.clnu.2016.01.020. [DOI] [PubMed] [Google Scholar]
- 4.Cuerda C., Pironi L., Arends J., Bozzetti F., Gillanders L., Jeppesen P.B., et al. ESPEN practical guideline: clinical nutrition in chronic intestinal failure. Clin. Nutr. 2021;40:5196–5220. doi: 10.1016/j.clnu.2021.07.002. [DOI] [PubMed] [Google Scholar]
- 5.Jeppesen P.B., Sanguinetti E.L., Buchman A., Howard L., Scolapio J.S., Ziegler T.R., et al. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54:1224–1231. doi: 10.1136/gut.2004.061440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Jeppesen P.B., Gilroy R., Pertkiewicz M., Allard J.P., Messing B., O’Keefe S.J. Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut. 2011;60:902–914. doi: 10.1136/gut.2010.218271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Jeppesen P.B., Pertkiewicz M., Messing B., Iyer K., Seidner D.L., O’Keefe S.J., et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012;143:1473–1481.e3. doi: 10.1053/j.gastro.2012.09.007. [DOI] [PubMed] [Google Scholar]
- 8.O'Keefe SJ, Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B. Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure. Clin. Gastroenterol. Hepatol. 2013;11:815–23.e1–3. 10.1016/j.cgh.2012.12.029. [DOI] [PubMed]
- 9.Schwartz L.K., O’Keefe S.J., Fujioka K., Gabe S.M., Lamprecht G., Pape U.F., et al. Long-term teduglutide for the treatment of patients with intestinal failure associated with short bowel syndrome. Clin. Transl. Gastroenterol. 2016;7 doi: 10.1038/ctg.2015.69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Iyer K.R., Kunecki M., Boullata J.I., Fujioka K., Joly F., Gabe S., et al. Independence from parenteral nutrition and intravenous fluid support during treatment with teduglutide among patients with intestinal failure associated with short bowel syndrome. JPEN. J. Parenter. Enteral Nutr. 2017;41:946–951. doi: 10.1177/0148607116680791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Seidner D.L., Fujioka K., Boullata J.I., Iyer K., Lee H.M., Ziegler T.R. Reduction of parenteral nutrition and hydration support and safety with long-term teduglutide treatment in patients with short bowel syndrome-associated intestinal failure: STEPS-3 study. Nutr. Clin. Pract. 2018;33:520–527. doi: 10.1002/ncp.10092. [DOI] [PubMed] [Google Scholar]
- 12.Sohrabi C., Mathew G., Maria N., Kerwan A., Franchi T., Agha R.A. The SCARE 2023 guideline: updating consensus surgical CAse REport (SCARE) guidelines. Int. J. Surg. 2023;109(5):1136–1140. doi: 10.1097/JS9.0000000000000373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Benjamin M.A., McKay D.M., Yang P.C., Cameron H., Perdue M.H. Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse. Gut. 2000;47:112–119. doi: 10.1136/gut.47.1.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Tsai C.H., Hill M., Asa S.L., Brubaker P.L., Drucker D.J. Intestinal growth-promoting properties of glucagon-like peptide-2 in mice. Am. J. Physiol. 1997;273:E77–E84. doi: 10.1152/ajpendo.1997.273.1.E77. [DOI] [PubMed] [Google Scholar]
- 15.Kouris G.J., Liu Q., Rossi H., Djuricin G., Gattuso P., Nathan C., et al. The effect of glucagon-like peptide 2 on intestinal permeability and bacterial translocation in acute necrotizing pancreatitis. Am. J. Surg. 2001;181:571–575. doi: 10.1016/S0002-9610(01)00635-3. [DOI] [PubMed] [Google Scholar]
- 16.Burrin D.G., Stoll B., Jiang R., Petersen Y., Elnif J., Buddington R.K., et al. GLP-2 stimulates intestinal growth in premature TPN-fed pigs by suppressing proteolysis and apoptosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2000;279:G1249–G1256. doi: 10.1152/ajpgi.2000.279.6.G1249. [DOI] [PubMed] [Google Scholar]
- 17.Lei Q., Bi J., Wang X., Jiang T., Wu C., Tian F., et al. GLP-2 prevents intestinal mucosal atrophy and improves tissue antioxidant capacity in a mouse model of total parenteral nutrition. Nutrients. 2016;8:33. doi: 10.3390/nu8010033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Yusta B., Boushey R.P., Drucker D.J. The glucagon-like peptide-2 receptor mediates direct inhibition of cellular apoptosis via a cAMP-dependent protein kinase-independent pathway. J. Biol. Chem. 2000;275:35345–35352. doi: 10.1074/jbc.M005510200. [DOI] [PubMed] [Google Scholar]
- 19.Koehler J.A., Yusta B., Drucker D.J. The HeLa cell glucagon-like peptide-2 receptor is coupled to regulation of apoptosis and ERK1/2 activation through divergent signaling pathways. Mol. Endocrinol. 2005;19:459–473. doi: 10.1210/me.2004-0196. [DOI] [PubMed] [Google Scholar]
- 20.Chokshi N.K., Guner Y.S., Hunter C.J., Upperman J.S., Grishin A., Ford H.R. The role of nitric oxide in intestinal epithelial injury and restitution in neonatal necrotizing enterocolitis. Semin. Perinatol. 2008;32:92–99. doi: 10.1053/j.semperi.2008.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
The article's data will be shared by the corresponding author upon reasonable request.