Dispatches from the GUILD Conference, Series #58

Tailoring Therapy Toward the Management of Extraintestinal Manifestations of IBD: Neurological, Ocular, Cutaneous and Musculoskeletal

June 2024 • Volume XLVIII, Issue 4
Gil Y. Melmed,Paula Prieto-Jimenez

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Extraintestinal manifestations (EIM) of inflammation are common among patients with inflammatory bowel disease (IBD), many of which have distinct etiologies and treatment approaches. In the past decade, there has been a significant expansion of treatment modalities for IBD, with distinct mechanisms of action that may allow for targeting of multiple organ systems with a single agent. We review common neurologic, dermatologic, ocular, and musculoskeletal EIMs associated with IBD, and identify opportunities to address EIMs together with IBD using specific agents or therapeutic classes in order to optimally personalize treatment toward both bowel and extraintestinal inflammation. 

Extraintestinal manifestations in patients with inflammatory bowel disease (IBD) can significantly impact health-related quality of life. Advances in pathophysiology knowledge and immunomodulatory targeted therapies bring diverse treatment options for IBD and inflammatory manifestations outside the bowel which should be considered when choosing the most appropriate approach for treating both intestinal and extraintestinal manifestations of IBD. This review provides an overview of treatment approaches of IBD and extra intestinal presentations of neurological, ocular, cutaneous, and musculoskeletal manifestations. 

NEUROLOGICAL MANIFESTATIONS

Neurological extraintestinal manifestations are relatively rare in IBD. Multiple Sclerosis (MS), optic neuritis (ON) and transverse myelitis (TM) are chronic, inflammatory, demyelinating and neurodegenerative diseases, which have a heterogeneous, multifactorial, immune-mediated background caused by complex gene–environment interactions. As MS is the most common disease, most studies between IBD and CNS have been focused on MS.

Anti-TNFα therapy has been putatively associated with demyelinating syndromes.1,2 The mechanism for which anti-TNFα might potentially cause demyelination in patients with rheumatological disease and IBD is still not fully understood. Current hypotheses include an increased influx of peripheral autoreactive T cells into the CNS, dysregulation of myelin repair, downregulation of interleukin-10 and upregulation of interleukin-12 and interferon γ; and possible increase in the risk of an underlying latent infections by anti-TNFα which could lead to demyelination.6,7

Consequently, TNF inhibitors should be avoided in patients with MS or other demyelinating diseases. Some advocate that this restriction should be applied as well to first-degree relatives of patients with MS given an increased risk of developing MS, with a sibling relative risk being as high as 18 to 36.8

In patients with MS or high risk of developing demyelinating diseases, recommendations for IBD treatment depend on the type of IBD (e.g. Crohn’s disease (CD) or ulcerative colitis (UC)). For moderate to severe CD, natalizumab may be appropriate due to its effectiveness in both CD and in MS. Natalizumab is a humanized monoclonal antibody which targets the lymphocyte adhesion molecule α4β1 integrin, disrupting the interaction of α4β1 integrin with vascular adhesion molecule (VCAM) -1 and interfering with the migration of the peripheral lymphocytes from blood vessels into the CNS and into the gut lamina propria, hence its beneficial effects for both MS and CD. It is FDA approved for the treatment of relapsing – remitting MS and for CD. However, uptake of natalizumab has been limited by increased risks of progressive multifocal leukoencephalopathy (PML) through reactivation of John Cunningham (JC) virus at a rate of approximately 1 in 1000 among individuals demonstrating antibody reactivity to JC virus, a ubiquitous virus present in large proportions of the population.9 Thus, individuals with CD initiating natalizumab should not receive concomitant immunomodulators, and steroids should be tapered off within 6 months of drug initiation. Furthermore, monitoring for JC virus every 6 months is warranted while on natalizumab maintenance therapy, with shared decision-making discussions to stop therapy for patients who seroconvert while on treatment. 

Sphingosine 1-phosphate (S1P) receptor modulators are approved as disease-modifying treatments for MS and UC based on a mechanism of limiting lymphocyte trafficking to the CNS and to the gut by trapping activated lymphocytes in lymph nodes. Ozanimod is currently approved for the treatment of both relapsing and remitting MS, as well as for moderately to severely active UC in adults. Thus, ozanimod may be an appropriate treatment option for those with UC, who also have or are at-risk for MS. 

Nonspecific white matter lesions have also been described in patients with IBD without presenting concomitant CNS degenerative diseases. It has been proposed that asymptomatic white matter lesions may be correlated with anxiety and disease duration, and that these findings may serve as a biomarker of neuropsychiatric comorbidities of CD.10 These lesions are generally asymptomatic, although their pathogenesis is unknown. Several mechanisms have been proposed for their etiology including thromboembolism, immunologic abnormalities, drug side effects, malabsorption, and infections.11,12

OCULAR

Nearly 5-7% of patients with IBD experience ocular inflammation, most commonly episcleritis, scleritis or non-infectious uveitis (NIU). 

Episcleritis, or inflammation of the episclera, is the most frequent ocular EIM. It is associated with active intestinal inflammation, and usually responds to topical steroids. On the other hand, scleritis, the inflammation of the sclera, is more challenging to treat, it usually requires nonsteroidal anti-inflammatory drugs, systemic steroids or immunosuppressants. If not controlled, scleritis can lead to necrotizing scleritis, anterior scleritis and posterior scleritis with secondary potential vision loss.14 In contrast, uveitis, the inflammation of the iris, ciliary body, and choroids, is less frequently associated with IBD flares but may precede a diagnosis of IBD by months or years. Although ophthalmological manifestations are present in any type of IBD, they are more common in CD patients. 

Infliximab and adalimumab, both anti-tumor necrosis factor (TNF)-α antibodies, are frequently used first-line in patients with ocular manifestations of scleritis or uveitis. Infliximab is effective in the treatment of NIU unresponsive to other drugs, with approximately 82% of patients achieving clinical remission in a median time of 127 days. For patient with uveitis, brain magnetic resonance imaging (MRI) is indicated to screen for demyelination before the commencement of TNFα inhibitors. TNF-alpha inhibitors were shown to significantly reduce relapses, and to control scleral inflammation both rapidly and with a long-lasting effects.15,16

Most recently, therapies targeting interleukin (IL) 23 and Janus kinase inhibitor (JAK) inhibitors have emerged as treatment options for ocular EIMs. Ustekinumab, a monoclonal antibody against human IL-12/IL-23 p40 subunit, has been described in case reports for the successful treatment of non-infectious uveitis including a patient with psoriatic arthritis and psoriasis, and 2 patients with CD, including 1 with comorbid MS.17,18

Tofacitinib, a nonselective small molecule JAK inhibitor approved for UC, has been used successfully in patients with severe refractory juvenile idiopathic arthritis (JIA)-associated uveitis,19,20 but further studies are needed to show the safety and efficacy of JAK inhibitors in larger cohorts.

SKIN MANIFESTATIONS

Cutaneous extraintestinal manifestations have been described in up to 15% of patients with IBD, often preceding their IBD diagnosis and not necessarily linked with IBD disease activity. 

Erythema nodosum (EN), affecting up to 15% of those with IBD and pyoderma gangrenosum (PG), affecting up to 5% of those with IBD are the most common skin manifestations in those with CD or UC.21 It is important to note that while PG is associated with IBD, EN may be associated with a variety of conditions such as infection, medications, sarcoidosis, pregnancy, IBD, autoimmune diseases, vaccination, malignancy, and miscellaneous causes.22 PG is also linked with some degree of colonic inflammation, in up to 50% of patients underlying active disease is present, and often requires multiple therapies to achieve complete healing.23

There is an association between psoriasis and IBD, with a risk in UC patients 1.6 times higher than in the general population. Paradoxically, psoriasis can also be triggered in up to 5% of patients using anti-TNF drugs,24 and it may present in atypical locations, including new scaly and dry plaques that may be confused for eczema; therefore requiring a high suspicion by the medical provider for medication side effects. Paradoxical psoriasis may be treated with topical steroids or oral methotrexate, but if severe may require discontinuation of anti-TNF medication. 

The IL23/IL17 axis plays a critical role in the pathogenesis of skin EIMs. IL-23 stimulates the production of IL-17, an essential proinflammatory cytokine, mainly secreted by CD4+ helper T cells (Th17); therefore, biologic therapies targeting IL-23 in IBD may play a significant role in improving cutaneous inflammation such as psoriasis.26 In a similar vein, the expression of TNFα and its receptors are increased in PG and EN lesions in skin suggesting a mechanistic explanation for the effectiveness of anti-TNF therapy for these conditions.

Anti-TNFα agents, especially infliximab and adalimumab may thus be effective for some cutaneous manifestations and IBD including psoriasis and PG, and they can also be considered as sparing agents to avoid long-term side effects from systemic corticosteroids.26 Biologics against IL-23 can also be considered in patients with IBD and psoriasis, PG or EN. Considering the role of IL23 in the pathophysiology of skin inflammation, biologics such as ustekinumab, which targets IL12/23 and is approved for moderate to severely active CD and UC; and risankizumab, a humanized immunoglobulin G1 antibody targeting the p19 subunit of IL-23 approved for moderate to severe CD, may be appropriate therapeutic options for patients with IBD and concomitant psoriasis, EN, or PG.

MUSCULOSKELETAL 

Musculoskeletal involvement is the most common extraintestinal manifestations in IBD. Arthritis may affect up to 46% of patients with IBD, and its prevalence decreases with age. Patients with IBD and concomitant musculoskeletal symptoms are typically seronegative for rheumatoid factor (RF) and anti-citrullinated peptide antibodies. Seronegative spondyloarthropathies (SpA) include ankylosing spondylitis, reactive arthritis, and psoriatic arthritis (PsA). Rheumatoid arthritis (RA) has also been linked with IBD population.


CDUCMSScleritisNIUENPGPsARASpA
Anti-TNF++x++(+)(+)+++
Anti IL12/23++

(+)(+)(+)+

Anti IL-23++

(+)(+)(+)+

JAK inhibitors++

(+)(+)(+)+++
Natalizumab+
+






Sphingosine 1-phosphate 
++






Anti IL17Ax





+
+
Table 1. Advanced Therapies used for Inflammatory Bowel Disease and Extraintestinal Manifestations

Musculoskeletal conditions associated with IBD can be mainly divided into axial and peripheral arthritis (PA). Although both are present in patients with UC and CD, they are more commonly seen in CD sub-population; and while peripheral arthritis is typically correlated with active intestinal inflammation, axial arthritis is generally independent of it.

Patients with peripheral arthritis may respond to a course of nonsteroidal anti-inflammatory drugs (NSAIDs), but chronic NSAIDs use is discouraged in patients with IBD given the possibility of intestinal ulcer development and disease exacerbation; COX-2 inhibitors have been proposed as an acceptable first line treatment option for up to 14 days.27,28

Corticosteroids, on the other hand, are well known for their anti-inflammatory effects and are used in IBD as well as for peripheral arthropathies pains and flares, however they are generally ineffective for the treatment of axial arthritis and should be limited in use due to systemic side-effects. 

Sulfasalazine may be effective for peripheral and axial inflammatory arthritis, but it may be more effective in UC and peripheral arthritis than in CD. Although methotrexate has not shown efficacy in axial arthropathy either, when treating PA and CD patients, it has provided clinical improvement and may be used to achieve higher levels of anti-TNFs.29

When biologic treatments need to be considered, anti-tumor necrosis factors including infliximab and adalimumab continue to be the first line treatment as they have shown significant efficacy in both peripheral and axial arthropathy. Additional therapeutic considerations like IL12/23 and JAK inhibitors can be alternative approaches depending on the specific rheumatologic diagnosis, PsA, RA, or SpA. (Table 1.)

Ustekinumab, has shown to be effective for peripheral arthritis, including PsA, enthesitis and dactylitis, however it does not seem to be effective for treatment of axial arthropathies as SpA nor RA.30

Jak inhibitors are fast acting, oral medications, only available after not responding to TNF blockers due to safety considerations, and are effective for the treatment of SpA, RA and PsA.

Upadacitinib, a JAK inhibitor with high selectivity for JAK1 is approved for moderate to severe CD and UC as well as for moderate to severe RA, psoriatic arthritis, ankylosing spondylitis and non-radiographical axial spondyloarthropathy. Its efficacy has been demonstrated as a monotherapy with similar efficacy that combining upadacitinib with methotrexate.31,32 Tofacitinib acts by preferentially inhibiting JAK1 and JAK3, with reduced inhibition for JAK2 and tyrosine kinase 2, it is used for moderate to severe UC as well as RA, PsA and active ankylosing spondylitis.32,33

Monoclonal IgG4 antibodies directed against IL-17A such as secukinumab and ixekizumab; or against IL-17 receptor, brodalumab, are highly effective for psoriasis, enthesitis and peripheral arthritis. However, they have not only shown to be ineffective in IBD but are associated with exacerbation and new onset of IBD and colitis and its use in patients with MSK manifestations is thus not recommended.34

Summary

IBD may present with a single or multiple extraintestinal manifestations. EIMs may affect any organ system and are chronic inflammatory diseases capable of causing a major debilitating comorbidity if left untreated or partially treated. Detailed consideration of EIMs needs to be taken into account when deciding which biologic to use when co-treating IBD and EIMs. 

References

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2. Kunchok A, Aksamit AJ, Davis JM, et al. Association between tumor necrosis factor inhibitor exposure and inflammatory central nervous system events. JAMA Neurol. 2020;77(8):937-946. doi: 10.1001/jamaneurol.2020.1162

3. Kopp TI, Delcoigne B, Arkema EV, et al. Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden. Ann Rheum Dis. 2020;79(5):566-572. doi: 10.1136/annrheumdis-2019-216693

4. Li L, Aviña-Zubieta JA, Bernstein CN, Kaplan GG, Tremlett H, Xie H, Peña-Sánchez JN, Marrie RA, Etminan M. Risk of Multiple Sclerosis Among Users of Antitumor Necrosis Factor α in 4 Canadian Provinces: A Population-Based Study. Neurology. 2023 Feb 7;100(6):e558-e567. doi: 10.1212/WNL.0000000000201472. Epub 2022 Oct 28. PMID: 36307225; PMCID: PMC9946189

5. Song J, Westerlind H, McKay KA, Almqvist C, Stridh P, Kockum I, Hillert J, Manouchehrinia A. Familial risk of early- and late-onset multiple sclerosis: a Swedish nationwide study. J Neurol. 2019 Feb;266(2):481-486. doi: 10.1007/s00415-018-9163-6. Epub 2018 Dec 21. PMID: 30578428; PMCID: PMC6373346.

6. Gonzalez Caldito N. Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders. Front Immunol. 2023 Jul 7;14:1213448. doi: 10.3389/fimmu.2023.1213448. PMID: 37483590; PMCID: PMC10360935.

7. Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers. Curr Neurol Neurosci Rep. 2017 Apr;17(4):36. doi: 10.1007/s11910-017-0742-1. PMID: 28337644; PMCID: PMC5364240.

8. Mansouri B, Horner ME, Menter A. Tumor Necrosis Factor-α Inhibitor Use in Psoriasis Patients with a First-degree Relative With Multiple Sclerosis. J Drugs Dermatol. 2015 Aug;14(8):876-8. PMID: 26267733.

9. Dryden GW. Natalizumab for Moderate-to-Severe Crohn’s Disease. Gastroenterol Hepatol (N Y). 2008 Apr;4(4):296. PMID: 21960916; PMCID: PMC3093736

10. Hou J, Dodd K, Nair VA, Rajan S, Beniwal-Patel P, Saha S, Prabhakaran V. Alterations in brain white matter microstructural properties in patients with Crohn’s disease in remission. Sci Rep. 2020 Feb 7;10(1):2145. doi: 10.1038/s41598-020-59098-w. PMID: 32034257; PMCID: PMC7005825.

11. Dolapcioglu C, Dolapcioglu H. Structural brain lesions in inflammatory bowel disease. World J Gastrointest Pathophysiol. 2015 Nov 15;6(4):124-30. doi: 10.4291/wjgp.v6.i4.124. PMID: 26600970; PMCID: PMC4644876.

12. Paul T. Parks, Alexander S. Easton, “Cerebral Vasculitis in Ulcerative Colitis Is Predominantly Venular: Case Report and Review of the Literature”, Case Reports in Rheumatology, vol. 2019, Article ID 9563874, 6 pages, 2019. https://doi.org/10.1155/2019/9563874

13. Hou J, Dodd K, Nair VA, Rajan S, Beniwal-Patel P, Saha S, Prabhakaran V. Alterations in brain white matter microstructural properties in patients with Crohn’s disease in remission. Sci Rep. 2020 Feb 7;10(1):2145. doi: 10.1038/s41598-020-59098-w. PMID: 32034257; PMCID: PMC7005825.

14. Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000 Oct;130(4):469-76. doi: 10.1016/s0002-9394(00)00710-8. PMID: 11024419.

15. Ferreira, Lisia Barros MD; Smith, Anthony J. FRACP, PhD; Smith, Justine R. FRANZCO, PhD. Biologic Drugs for the Treatment of Noninfectious Uveitis. Asia-Pacific Journal of Ophthalmology 10(1):p 63-73, January-February 2021. | DOI: 10.1097/APO.0000000000000371

16. Sota J, Girolamo MM, Frediani B, Tosi GM, Cantarini L, Fabiani C. Biologic Therapies and Small Molecules for the Management of Non-Infectious Scleritis: A Narrative Review. Ophthalmol Ther. 2021 Dec;10(4):777-813. doi: 10.1007/s40123-021-00393-8. Epub 2021 Sep 2. PMID: 34476773; PMCID: PMC8589879

17. Mugheddu C, Atzori L, Del Piano M, et al. Successful ustekinumab treatment of noninfectious uveitis and concomitant severe psoriatic arthritis and plaque psoriasis. Dermatol Ther 2017; 30.

18. Chateau T, Angioi K, Peyrin-Biroulet L. Two cases of successful ustekinumab treatment for non-infectious uveitis associated with Crohn’s disease. J Crohns Colitis 2020; 14:571.

19. Miserocchi E, Giuffrè C, Cornalba M, et al. JAK inhibitors in refractory juvenile idiopathic arthritis-associated uveitis. Clin Rheumatol 2020; 39:847–851.

20. Bauermann P, Heiligenhaus A, Heinz C. Effect of Janus kinase inhibitor treatment on anterior uveitis and associated macular edema in an adult patient with juvenile idiopathic arthritis. Ocul Immunol Inflamm 2019; 27:1232–1234.

21. Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology. 2021 Oct;161(4):1118-1132. doi: 10.1053/j.gastro.2021.07.042. Epub 2021 Aug 3. PMID: 34358489; PMCID: PMC8564770.

22. Leung AKC, Leong KF, Lam JM. Erythema nodosum. World J Pediatr. 2018 Dec;14(6):548-554. doi: 10.1007/s12519-018-0191-1. Epub 2018 Sep 29. PMID: 30269303.

23. Weizman AV, Huang B, Targan S, Dubinsky M, Fleshner P, Kaur M, Ippoliti A, Panikkath D, Vasiliauskas E, Shih D, McGovern DP, Melmed GY. Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study. J Cutan Med Surg. 2015 Mar-Apr;19(2):125-31. doi: 10.2310/7750.2014.14053. Epub 2015 Mar 11. PMID: 25775631.

24. De Francesco MA, Caruso A. The Gut Microbiome in Psoriasis and Crohn’s Disease: Is Its Perturbation a Common Denominator for Their Pathogenesis? Vaccines (Basel). 2022 Feb 5;10(2):244. doi: 10.3390/vaccines10020244. PMID: 35214702; PMCID: PMC8877283.

25. Maronese CA, Pimentel MA, Li MM, Genovese G, Ortega-Loayza AG, Marzano AV. Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments. Am J Clin Dermatol. 2022 Sep;23(5):615-634. doi: 10.1007/s40257-022-00699-8. Epub 2022 May 24. PMID: 35606650; PMCID: PMC9464730.

26. Liu T, Li S, Ying S, Tang S, Ding Y, Li Y, Qiao J, Fang H. The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside. Front Immunol. 2020 Nov 17;11:594735. doi: 10.3389/fimmu.2020.594735. PMID: 33281823; PMCID: PMC7705238.

27. Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006; 4: 196-202

28. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study. Clin Gastroenterol Hepatol. 2006; 4: 203-211

29. Zochling J, van der Heijde D, Dougados M, Braun J. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis. 2006 Apr;65(4):423-32. doi: 10.1136/ard.2005.041129. Epub 2005 Aug 26. PMID: 16126792; PMCID: PMC1798100.

30. Ulusoy BÖ, Erden A, Güven SC, Armağan B, Yürekli ÖT, Özin YÖ, Omma A, Küçükşahin O. Ustekinumab in enteropathic arthritis. Immunotherapy. 2023 Jun;15(8):583-592. doi: 10.2217/imt-2022-0197. Epub 2023 Apr 5. PMID: 37020400.

31. Fonseca D, Nogueira M, Torres T. Upadacitinib for the treatment of psoriatic arthritis. Drugs Context. 2023 Feb 28;12:2022-11-6. doi: 10.7573/dic.2022-11-6. PMID: 36876156; PMCID: PMC9983629.

32. Wang, Wenfei MD1; Cleveland, Noa Krugliak MD2; Ollech, Jacob MD2; Rubin, David T. MD2. Use of Tofacitinib for the Treatment of Arthritis Associated with Ulcerative Colitis. ACG Case Reports Journal 6(9):p e00226, September 2019. | DOI: 10.14309/crj.0000000000000226

33. Momen Majumder MS, Haq SA, Rasker JJ. Tofacitinib for the treatment of inflammatory bowel disease-associated arthritis: two case reports. J Med Case Rep. 2023 Mar 1;17(1):71. doi: 10.1186/s13256-023-03796-2. PMID: 36855206; PMCID: PMC9976468.

34. Deng Z, Wang S, Wu C, Wang C. IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis. Front Pharmacol. 2023 Mar 23;14:1124628. doi: 10.3389/fphar.2023.1124628. PMID: 37033665; PMCID: PMC10076642.

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Nutrition Reviews in Gastroenterology, SERIES #14

Nutrition Therapies for Patients with an Ileoanal Pouch: A Moving Target?

June 2024 • Volume XLVIII, Issue 4
Elizabeth Wall

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An ileal pouch-anal anastomosis (IPAA) is the preferred surgical reconstruction for restoration of intestinal continuity after a total proctocolectomy; it obviates the need for a permanent ileostomy. The pouch, or continuity reservoir, is anastomosed to the sphincter-spared anus allowing for controlled passage of bowel movements (BMs). Patients with mature, properly functioning pouches can expect to pass 6-8 BMs every 24 hours. Diet after IPAA is empiric and patient-specific with the overarching goals to optimize pouch continence and nutrient/fluid absorption. Pouch inflammation is common and thought to be primarily related to an abnormal immune response to pouch dysbiosis.1 Diet may play an important role in mediating the dysbiosis and influence pouch function, though evidence of this is lacking. This article will review basic information regarding IPAA, pouch complications, diet for patients with IPAA, and recommendations for long-term micronutrient supplementation.

Introduction

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with refractory ulcerative colitis (UC) and familial adenomatous polyposis (FAP) who desire intestinal continuity after colectomy. The pouch is an alternative to a permanent end ileostomy. The most common pouch configuration is the J-shape (constructed from two limbs of distal ileum, Figure 1), though other configurations are possible based on the surgeon’s determination. To date there is a dearth of evidence to support specific dietary recommendations for patients with IPAA. Frequently, results of small studies with heterogeneous populations and endpoints, or recommendations based on patients’ observations of their responses to certain foods/food components, are used to make generalized dietary recommendations. This review will summarize the limited data and key expert recommendations to support nutrition therapies for patients with IPAA.

IPAA Construction and Function

The IPAA procedure is typically performed in two or three phases depending on the condition of the colon, specifically, and patient’s overall condition.2,3 Approximately 30-40 centimeters of the distal ileum is used to fashion the pouch that is then anastomosed to the sphincter-spared anus.4 The two-step procedure is most commonly performed; the first phase is the proctocolectomy and IPAA construction with a diverting ileostomy (DI) followed 6-8 weeks later by the second step of DI takedown.3 The three-step procedure is often reserved for patients with severe colitis, perforation, bleeding, or dysplasia; the first step is a subtotal colectomy with  end ileostomy, the second step is the completion proctectomy, IPAA construction with DI and takedown of the end ileostomy, and the third step is the takedown of the DI. 

Once bowel continuity is restored, patients will experience a period of intestinal adaptation during which their bowel habits and dietary tolerance evolve. The adaptation process can take 6-18 months following colectomy.6,7 After complete adaptation, patients can expect to pass an average of 6 bowel movements (BMs) per 24 hours; often 1 BM will occur overnight.6 Physical and emotional adjustments to the new pouch habits will vary between patients. Those with a history of severe colitis often pass fewer BMs and feel better with the pouch, however, patients with FAP typically do not have pre-operative gastrointestinal symptoms and must learn to cope with frequent BMs, reduced continence, and fecal urgency after the proctocolectomy. In either scenario, support from an experienced gastrointestinal registered dietitian nutritionist (RDN) will help patients to understand the relationships between diet, hydration, and pouch function to optimize their health and quality of life (QoL). 

IPAA Complications

The IPAA procedure is not without risk of complications; Table 1 lists the phenotypes of pouch disorders. In the acute post-operative phase infection/pelvic abscess, anastomotic leak, and small bowel (SB) obstruction/ileus are most commonly observed; complication rates are higher for patients who received systemic corticosteroids or smoked at the time of surgery.8 Long term complications are characterized by urgency/high frequency of BMs, continence problems (both seepage and difficult evacuation), fatigue, pouch failure, and reduced QoL.3 

Pouch inflammation (pouchitis) is the most common complication associated with an IPAA and affects 30–50% of patients.9 Acute pouchitis is defined as symptoms lasting < 4 weeks and is usually responsive to antibiotic therapy whereas chronic pouchitis lasts > 4 weeks. An approach to diagnosis and management of pouchitis was recently published in this journal.10 

The etiology of pouchitis is not fully understood and is likely multifactorial but thought to be primarily related to an abnormal immune response to pouch dysbiosis; though secondary factors such as Crohn’s disease, infection, ischemia, or radiation can also cause inflammation.1

Diet After IPAA 

The goals of nutrition therapy for patients with IPAA are to optimize SB absorption and to regulate passage of BMs. Patients may report that their pouch function and defecation frequency are directly related to meals and post-prandial gastrointestinal motility; though evidence is lacking with regard to specific dietary elements that directly affect pouch function.7,11 Therefore, patients and clinicians alike must take a flexible and empiric approach when developing meal plans because a patient’s food tolerances will likely change with pouch adaptation and in cases of dysfunction. 

PhenotypeClinical Features
StructuralAnastomotic leak Fistula Pelvic infection/abscess Obstruction Dilation Bezoar
InflammationPouchitis
(acute, chronic antibiotic-responsive, chronic antibiotic-refractory) Crohn’s disease-like pouch inflammation Cuffitis
FunctionalIrritable pouch syndrome Dysmotility Anopouch pain syndrome
Nutrition/metabolicAnemia Metabolic bone disease Micronutrient deficiencies
Table 1. Pouch Disorders Phenotypes1

Immediately after DI takedown, depending upon the surgeon’s opinion of the competence of the pouch and pouch-anal anastomosis, it may be recommended for the patient to follow a low fiber diet. Although evidence lacks for fiber restriction, of particular concern to surgeons are insoluble fibers (e.g., wheat or oat bran, vegetable/legume peels/shells, nuts, and seeds) that accelerate transit, increase stool bulk, and exert pressure on suture lines. Fiber restrictions should be limited to the least number of weeks necessary to prevent patients from indefinite adherence to a low fiber diet. 

Beyond the initial postoperative period, IPAA patients should advance their diet as tolerated to one that is balanced between all food groups. General guidelines for an “IPAA Diet” are lacking given significant variations in patients’ perceived tolerance to foods (see Table 2 for foods observed to effect pouch output; patients can include or limit foods based on their pouch function).7,12,13 After total colectomy absorption of nutrients and fluid is limited to the SB, thus application of the following generally accepted recommendations for those with an ileostomy may help to slow postprandial gastric emptying and intestinal transit for optimal absorption:14,15

Eat multiple (5-6) small meals daily to avoid excessive gastric and pouch distention

Include slowly fermented, gel-forming fiber (e.g., psyllium) with each meal

Avoid simple sugars in foods and beverages to reduce rapid gastric emptying of hypertonic fluid

May limit intake of lactose containing foods and beverages

Separate solid foods and liquids to optimize gastric digestion

Post-prandial rest for 20-30 minutes to increase gastric digestion and to reduce intestinal motility

Sip isotonic or hypotonic fluids between meals

Oral rehydration solutions (ORS) can promote SB absorption of sodium and water

Avoid eating 2-3 hours before bed to reduce nocturnal defecation 

If needed, take antimotility medications 20-30 minutes before meals and at bedtime

See Table 3 for more detailed interventions to improve absorption after IPAA.

Over time, patients with a well-functioning pouch may be able to tolerate larger, less frequent meals. Although evidence is limited, ingestion of foods with gel-forming fibers (psyllium, pectin, gums) may help to increase the consistency of stool and provide important substrate for microbial fermentation and production of important metabolites.14,16 A recent study looked at fruit consumption after IPAA and found that consumption of > 1.5 fruit servings daily reduced the risk of developing pouchitis,17 supporting the importance of dietary fiber consumption after IPAA.

The Mediterranean diet (MD) is known for its emphasis on plant-based foods, fish and olive oil while limiting intake of red meats, saturated fats, sweets, and sugary beverages. Research has demonstrated that the MD can reduce inflammation in chronic disease states.18 More recently, a study demonstrated that patients with IPAA (for UC) who followed the MD for 8 years had reduced fecal calprotectin levels and adherence was inversely associated with episodes of pouchitis.19 Although the exact mechanism is not understood, this data supports the recommendation that IPAA patients follow a MD pattern (Figure 2) to maintain optimal pouch function. 

Diet and Pouch Dysfunction

Pouch dysfunction can derail any progress a patient has made towards attaining a stable, healthy diet. In the case of pouchitis the combination of medical therapies (typically antibiotics are the first line of therapy as pouchitis is thought to result from microbial dysbiosis) and a shift of diet composition may provide patients symptomatic relief.1 A recent pilot study of 15 adults with active pouchitis identified a positive effect of the Crohn’s Disease Exclusion Diet (excludes processed and refined foods, includes resistant starch and fiber) in patients with strict adherence.20 Although the study was small, non-randomized, and uncontrolled, it seems hopeful that some cases of pouch inflammation may respond to diet therapy. As more is understood about the phenotypes of dysfunction, and the association between pouch function and the microbiome, it is likely that there will be opportunities for 1:1 counseling with a RDN to tailor the diet based on the nature of the pouch dysfunction and create more evidence-based recommendations for dietary therapies to alter active inflammation.7,14 

In patients with pouch dysfunction  that is more irritable in nature (frequent and/or urgent BMs, abdominal cramps, pelvic discomfort, and absence of inflammation),21 it may be reasonable to restrict highly fermentable and osmotically active carbohydrates with a low FODMAP diet (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols).14 Limitation of FODMAP consumption may reduce bacterial fermentation (gas production) of undigested carbohydrates, as well as decrease water delivery to the pouch, both of which can reduce symptoms of gas, bloating, and diarrhea/urgency. Patients with a positive response to the initial exclusion of FODMAPs should work intensively with a RDN to identify trigger foods and to re-introduce those foods that are tolerable. There is minimal evidence though to support FODMAP restriction in the management of pouchitis.22

Observed
Effects of Food		Foods and Beverages 
Stool thickeningApplesauce Banana Bread Pasta Potatoes Oatmeal Rice Peanut butter Soluble, low fermentable fiber (e.g., psyllium)
Stool thinningSpicy foods (capsaicin) Fruit and fruit juice Cabbage
Increased stool outputNuts Corn Chocolate Lettuce Fresh oranges Tomatoes Cow’s milk Alcohol Fried foods Spicy foods
Increased flatusFood with high FODMAPs  Onions, cabbage, and cow’s milk Spicy foods 
Perianal irritationCitrus fruits Spicy foods Nuts and seeds
Table 2. Foods Observed to Effect Stool Output and IPAA13,14

Fluids and Hydration

Hydration status after IPAA is often overlooked. Chronic low-level dehydration (characterized by low 24-hour urine volume, hypotension, chronic fatigue, dry mucous membranes, etc.) can affect a patient’s overall feeling of wellness and their ability to participate in life activities, not to mention the risk of nephrolithiasis and chronic kidney injury. It is recommended for adults with normal kidney function to produce at least 1,000-1,200 mL urine per day and kidney stone formers should make at least 1,500 mL per day.23,24 Attention to both fluid intake and urine output is imperative to gauge hydration and ensure long-term maintenance of normal kidney function. Without the colon to absorb sodium and water, those with an IPAA must rely mainly on SB sodium-glucose co-transporters to drag water across the mucosa.25 Consumption of isotonic fluids such as ORS and avoidance of hypertonic, sugary beverages should improve water absorption and hydration status.

ORS contain specific concentrations of sodium and sugar in water and are known to facilitate SB water absorption. Beverages that contain both sodium (50-70 mEq/L) and glucose (20-40g/L) are palatable options (Table 3).26 IPAA patients who pass high volume stool may find that sipping ORS between meals can help to achieve hydration goals.

Micronutrients

The IPAA consensus guidelines recommend lifelong monitoring of several micronutrients as well as for anemia and metabolic bone disease.1 Most notably, vitamin B12, vitamin D, and iron, are identified as micronutrients of potential concern (particularly in the early phase of IPAA and in the setting of pouch inflammation),1 although other fat soluble vitamins and divalent cations may become deficient in the IPAA population (see Table 4).4 Deficiencies can result from insufficient intake and with altered absorption in the setting of rapid transit or of villous atrophy associated with pouch inflammation.4 In particular, vitamin B12 deficiency can develop from reduced absorption and increased utilization by bacteria if pouch overgrowth/dysbiosis exists.4 Vitamin B12 deficiency can lead to permanent neurological deficits and therefore lifelong therapeutic dosing of cyanocobalamin (1,000 mcg by mouth daily or monthly subcutaneous injection) is safe and recommended. 

Evidence for monitoring and supplementation of micronutrients after IPAA does not exist. Data and guidelines for patients with inflammatory bowel disease and post-surgical malabsorption can guide clinicians when prescribing supplementation regimens. One important factor with respect to interpretation of serum/plasma micronutrient levels when inflammation exists is that reported levels are often perturbed making interpretation difficult.27 A RDN with experience in micronutrient repletion therapy, who is able to perform sequential nutrition focused physical exams, is the ideal team member to develop, institute, and monitor responses to micronutrient supplementation. Short of this, it is prudent for anyone unable to consume a balanced diet to take a daily multivitamin with mineral supplement that meets 100% of the Reference Dietary Intake (RDIs).

TherapyIntervention
DietEat 5-6 small meals Avoid overeating/drinking to prevent excessive pouch distention Use the Mediterranean diet pattern to structure meals Include plenty of plant foods with soluble fiber Oats, peas, carrots, beans, citrus fruits, apple, banana Slows gastric emptying, thickens stool, supports microbiome Eat at least  two fruit servings daily Limit foods with simple sugars  Cakes, cookies, pastries, ice cream, Italian ice Limit greasy foods Limit insoluble fiber, caffeine, and alcohol May increase BM frequency and cause watery stool
FluidsLimit fluids at meals to 4-8 ounces Sip remaining fluids between meals, throughout the day Focus in hypotonic and isotonic fluids for SB water absorption Hypotonic beverages – water, dilute juices, tea, coffee, diet drinks Isotonic beverages – ORS, e.g., Ceralyte®, Pedialyte®, DripDrop®, Trioral® Limit hypertonic beverages Cause osmotic shift of water into the intestinal lumen resulting in more volume to reabsorb Fruit juice, sweet tea, lemonade, sweetened beverages, and cocktails Oral nutrition supplements (Ensure®, Boost®)
Medications and supplementsUse antimotility agents such as loperamide to slow gastrointestinal transit Time antimotility medications 30-60 minutes before meals and bedtime Fiber supplements such as Metamucil® or Benefiber® may help thicken stool for improved continence
ActivitySit for 20-30 minutes after meals to allow for digestion and reduce intestinal motility Avoid eating 2-3 hours before bed to reduce nocturnal defecation
Table 3. Interventions to Optimize Food and Fluid Absorption After IPAA
MicronutrientMonitoring ParametersDaily Maintenance Dose¥ (Oral)Repletion Dose*
Vitamin B12Serum vitamin B12 Serum folate Plasma homocysteine Plasma methylmalonic acid1,000 mcg1,000 mcg subcutaneous injection for 5-7 days
Vitamin DSerum 25-hydroxy vitamin D18 – 70 yrs 15 mcg > 70 yrs 20 mcg100-125 mcg oral daily
Vitamin EPlasma α-tocopherol15 mg90 – 180 mg oral daily
Vitamin ASerum RetinolMen 900 mcg Women 700 mcg Pregnant 770 mcg Lactating 1300 mcg1,500 – 3,000 mcg
oral daily
IronHemoglobin Serum iron Total iron binding capacity Transferrin saturation Serum ferritinMen  8 mcg Women Premenopausal 18 mg Postmenopausal 8 mg50 – 200 mg oral daily (divided doses)
ZincPlasma zincMen – 11 mg Women – 8 mg50 mg oral daily
CalciumBone densityMen 19 – 70 yrs 1,000 mg >70 yrs 1,200 mg Women 19-50 yrs 1,000 mg >50 1,200 mgVariable based on
bone health
Table 4. Micronutrient Monitoring and Dosing Recommendations After IPAA

Conclusion

For patients with severe colitis or FAP the IPAA is a means to restore bowel continuity and avoid a permanent end ileostomy after total proctocolectomy. The procedure requires patients to adopt balanced dietary patterns, such as the MD, that include fruits, vegetables, and fiber to optimize pouch function, absorption, the microbiome, and overall health. Avoidance of excessive pouch distention from over-eating/drinking may help to control the frequency of BMs. Symptoms of irritable pouch syndrome (diarrhea dominant), rather than inflammation, may be controlled with elimination of some highly fermentable carbohydrates. Collaboration between the patient and a RDN is necessary to identify poorly tolerated foods and design the most balanced diet possible. Routine supplementation with vitamin B12 and close monitoring for micronutrient deficiencies, anemia, bone health, and hydration status is essential to ensuring optimal health and well-being. In summary, the IPAA can significantly improve the health and QoL for some patients but may require ongoing RDN support for optimization of nutrient uptake, hydration, and pouch function. 

References

1. Shen B, Kochhar GS, Kariv R, et al. Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol 2021;6:826-849.

2. McGuire BB, Brannigan AE, O’Connell PR. Ileal pouch anal anastomosis. Br J Surg. 2007;94(7):812-823.

3. Deputy M, Segal J, Reza L., et al. The pouch behaving badly: management of morbidity after ileal pouch-anal anastomosis. Colorectal Dis. 2021;23:1193-1204. 

4. Buckman SA, Heise CP. Nutrition considerations surrounding restorative proctocolectomy. Nutr Clin Pract. 2010;25:250-256.

5. Marulanda K, Purcell LN, Egberg MD, et al. Analysis of modified two-stage approach to ileal pouch-anal anastomosis without fecal diversion in pediatric patients. Am Surg. 2022;88(1):103-108.

6. Michelassi F, Lee J, Rubin M, et al. Long-term functional results after ileal pouch anal restorative proctocolectomy for ulcerative colitis. Ann Surg. 2003;238(3):433-445.

7. Ardalan ZS, Sparrow MP. A personalized approach to managing patients with an ileal pouch-anal anastomosis. Front Med. 2020;6:337.

8. Zittan E, Ma GW, Wong-Chong N, et. al. Ileal pouch-anal anastomosis for ulcerative colitis: a Canadian institution’s experience. Int J Colorectal Dis. 2017;32(2):281-285.

9. Turpin W, Kelly O, Borowski K, et al. Mucosa-associated microbiota in ileoanal pouches may contribute to clinical symptoms, particularly stool frequency, independent of endoscopic disease activity. Clin Trans Gastro. 2019;10:1-7. 

10. Hossain M, Kayal M. A review of the diagnosis and treatment of inflammatory pouch conditions.Pract Gastroenterol. 2023;47(4):17-21.

11. Groom JS, Kamm MA, Nicholls RJ. Relationship of small bowel motility to ileoanal reservoir function. Gut 1994;35:523-529.

12. Tyus FJ, Austhof SI, Chima CS, Keating C. Diet tolerance and stool frequency in patients with ileoanal reservoirs. J Acad Nutr Diet. 1992;92:861-863.

13. Quinn KP, Lightner AL, Faubion WA, Raffals L. A comprehensive approach to pouch disorders. Inflamm Bowel Dis. 2019;25(3):460-471.

14. Ardalan ZS, Yao CK, Sparrow MP, Gibson PR. Review article: the impact of diet on ileoanal pouch function and on the pathogenesis of pouchitis. Aliment Pharmacol Ther. 2020;52:1323-1340.

15. Bridges M, Nasser R, Parrish CR. High output ileostomies: the stakes are higher than the output. Pract Gastroenterol. 2019;9:20-33.

16. Sidebottom AM, Chang EB. IBD microbial metabolome: The good, bad, and unknown. Trends Endocrinol Metab. 2020;31(11):807-809.

17. Godny L, Maharshak N, Reshef L, et. al. Fruit consumption is associated with alterations in microbial composition and lower rates of pouchitis. J Crohn’s and Colitis. 2019 Sep 27;13(10):1265-1272.

18. Chicco F, Magri S, Cingolani A. et. al., Multidimensional impact of Mediterranean diet on IBD patients. Inflamm Bowel Dis. 2021 Jan 1;27(1):1-9.

19. Godny L, Reshef L, Pfeffer-Gik T, et al. Adherence to the Mediterranean diet is associated with decreased fecal calprotectin in patients with ulcerative colitis after pouch surgery. Eur J Nutr. 2020;59:3183-3190.

20. Fliss Isakov N, Kornblum J, Zemal M, Cohen NA, Hirsch A, Maharshak N. The effects of the Crohn’s Disease Exclusion Diet on patients with pouch inflammation: an interventional piolet study. Clin Gastro Hepatol 2023;21(6):1654-1656.

21. Shen B, Achkar JP, Lashner BA, et al. Irritable pouch syndrome: A new category of diagnosis for symptomatic patients with ileal pouch anal anastomosis. Am J Gastro. 2022;97:972-977.

22. Rabbenou W, Chang S. Medical treatment of pouchitis: a guide for the clinician. Ther Adv Gastroenterol. 2021;14:1-15.

23. Parrish CR, Wall EA. The clinician’s toolkit for the adult short bowel patient Part 1: nutrition and hydration therapy. Pract Gastroenterol. 2022;6:32-53.

24. Borghi L, Meschi T, Amato F, et al. Urinary volume, water, and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996;155(3):839-843.

25. Barrett KE. Water and Electrolyte Absorption and Secretion. In: Barrett KE. Ed. Gastrointestinal Physiology, 2e. New York, NY: McGraw-Hill; 2014. http://access-medicine.mhmedical.com/content.aspx?bookid=691&sectionid=45431404. Accessed February 25, 2024.

26. Wall E. ORS: The Solutions to Optimize Hydration in Short Bowel Syndrome. Practical Gastroenterology. 2020;3:24-31.

27. Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022;41:1357-1424.

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FRONTIERS IN ENDOSCOPY, SERIES #91

Endoscopic Management of Laparoscopic Gastric Sleeve Leaks

June 2024 • Volume XLVIII, Issue 4
Kelita Singh,Douglas G. Adler,Abinash Subedi,Fathima Keshia Suhail

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INTRODUCTION

Bariatric surgery is a well-established option for patients with obesity, with over 200,000 procedures performed annually in the United States. Sleeve gastrectomy comprises 58% of these surgeries.1 Gastric sleeve leaks (GSL) can occur in 1-2% of patients following laparoscopic sleeve gastrectomy.2 Leaks occur when tissue breakdown, most commonly near the anastomosis and/or suture or staple lines and can evolve into a fistula with an epithelialized tract if they do not heal in a timely manner.3 GSL are the second most common cause of mortality in patients undergoing sleeve gastrectomy, following pulmonary embolism.4

A multidisciplinary approach is important when managing these patients and should involve surgery, gastroenterology, and interventional radiology. Prompt diagnosis, classification, and treatment of GSL is essential. Techniques for managing GSL can vary based on the patient’s clinical condition, leak classification, expert experience, and availability of resources. In the presence of hemodynamic compromise, septic shock or peritonitis, further surgical management is needed. Otherwise, endoscopic treatment is preferred, due to high perioperative morbidity with surgery.5

Classification

Classification of GSL can guide management decisions. There are several proposed classification systems that are based on timing of presentation and findings on computed tomography (CT) scan. 

The Rosenthal sleeve gastrectomy leak classification system organizes leaks based on timing of presentation.6 Acute leaks are diagnosed and treated before 7 days from the operative procedure, early leaks between 1-6 weeks, late leaks between 6-12 weeks, and chronic leaks after 12 weeks. 

Sleeve leaks can also be classified according to a CT scan classification system7 which is organized by the type of collection on CT and leak visualization. (Table 1) Johari et al. proposed a validated classification system, based on CT imaging that predicts a stepwise increased risk of complication severity, increased hospital stay and salvage resection using a 2-phase modified Delphi process.8
(Table 1)

Csendes et al.Johari et al.
Type Collection on CTClass 1 Phlegmon associated with staple line
I< 5cm in LUQClass 1aPhlegmon 
II> 5cm in LUQClass 1bPhlegmon with small localized locules of gas
IIIDiffuse abdominal collectionsClass 2Fluid collection
IV Pleural (thoracic) collectionsClass 2aFluid collection with localized locules of gas
Type Staple line localization Class 2b Extensive mixed fluid and gas collection
SSuperior part of sleeve Class 3Contrast leak 
MMiddle part of sleeveClass 3aContained contrast leak 
IInferior part of sleeveClass 3bFree intraperitoneal contrast leak 

Leak VisualizationClass 4Chronic fistula 
aNo leak

bPositive leak 

Etiology

The etiologies of GSL can be due to mechanical/tissue causes or ischemic causes. It is related to an increase in intraluminal pressure which exceeds the strength of the tissue and/or staple line.9 When creating a gastric sleeve, a long staple line anastomosis is created which extends from the antrum of the stomach to the gastroesophageal junction. Leaks can form anywhere along the staple line, although most leaks occur near the angle of His, where the gastric wall is susceptible to ischemia. Relative ischemia tends to occur in this area secondary to surgical ligation of gastric arteries, relative dysmotility and increased intragastric pressure. Distal obstructions, such as concomitant gastric sleeve stenosis, can further increase intraluminal pressure and contribute to the development of leaks. 

Risk Factors

Surgical and nonsurgical risk factors contribute to the development of GSLs. Several studies have demonstrated that male gender and higher BMI, especially in super-obese patients (BMI >50 kg/m2), increase the risk of developing a GSL.2,10

Surgical risk factors relate to stapling, ischemia, gastric stenosis, and the experience of the surgeon. Meticulous tissue handling, consideration of tissue thickness, conscious stapling, avoidance of inadvertent narrowing are methods to decrease surgical risk factors.9 Additionally, surgeons performing >43 cases per year can achieve a <1% leak rate.11

Clinical Manifestations 

Clinical manifestation of GSL can range from asymptomatic leaks diagnosed with routine imaging to signs and symptoms of perforation, peritonitis, and septic shock. Fever and tachycardia are two of the most important clinical factors in the diagnosis of GSL.5 Other clinical manifestations include abdominal pain, pain radiating to the left shoulder, vomiting and tachypnea.12

Diagnosis 

Upper gastrointestinal (UGI) fluoroscopy and CT scan of the abdomen with oral contrast are the most common tests used to diagnose GSL. In a head-to-head study comparing UGI contrast studies and CT scan with oral contrast, CT was found to be superior to UGI series in the diagnosis of GSL with a sensitivity of 95% vs. 74.9% respectively.13 Endoscopy is also useful when trying to establish the characteristics of the leak such as size of the orifice.14

Endoscopic Management 

Endoscopic treatment is feasible in most patients with GSL and have been shown to facilitate healing of GSL in 74-81%14,15 of patients, with early intervention increasing the likelihood of success.15 Predictors of successful healing with endoscopic management include acute leaks that developed ≤ 3 days from the operative procedure, early endoscopic treatment < 21 days after leak diagnosis, leak size < 1 cm, and no prior history of banded gastroplasty.15 

There are various treatment options for endoscopic management of GSL. Treatment strategy depends on the characteristics of the defect and center level of experience. The size, viability of surrounding tissue, and location of the defect can be defined endoscopically to determine which closure strategy might be best to perform. Additionally, treatment of distal stenoses and removal of foreign material is important for successful treatment of GSL.16

A retrospective review of 37 patients with GSL demonstrated that 30/37 (81%) were successfully managed endoscopically. Endoscopic techniques performed included: 44% fully covered bariatric gastric stents, 34% internal pigtail plastic stents, 11% septoplasty, 5% endoluminal vacuum therapy, and 3% over-the-scope clip (OTSC).14 Other endoscopic approaches include use of tissue sealants, endoscopic suturing, and novel techniques such as use of cardiac septal occluders. Patients may require combined endoscopic modalities for successful closure, especially in patients with refractory leaks who failed initial endoscopic intervention.17

Endoscopic Internal Drainage

The presence of an intra-abdominal collection (IAC) requires drainage as they tend to be the source of sepsis. Adequate drainage can be performed internally by endoscopy, via percutaneous drains, or, less frequently, via surgery.18,19 The reported efficacy rate when EID is used as a primary intervention is 74-86%.18-20 

Endoscopic internal drainage (EID) is accomplished under general anesthesia with fluoroscopy to identify the defect within the staple line.18 One or more double pigtail stents (DPS) with a diameter of 7 or 10 French are left in place, with one end of the pigtail in the collection and the other end of the pigtail in the stomach, for several months.18-20 Follow up endoscopy with fluoroscopy can be performed after one month for stent retrieval and to determine the presence of any residual leak. In patients with persistent leaks, stents are re-inserted.18 Adverse events of EID include stent migration, seen in 46% of cases, minor gastric mucosal trauma, minor bleeding related to stent erosion, and major bleeding from nearby vessel (i.e., splenic vessels).18,20 

Endoscopic ultrasound (EUS) can also be utilized for endoscopic drainage of IAC. EUS allows determination of collection size, location, and avoidance of any intervening vessels. Drainage is accomplished by using a 19G needle, guidewire, over the wire puncture and deployment of multiple DPS or lumen-apposing metal stents (LAMS) or can simply be done via freehand technique.21  LAMS can be exchanged at 1 month with DPS, if needed.18

Self-Expanding Metal Stents 

SEMS placed is the most common endoscopic interventions used to manage GSL.22 The objective of endoluminal stenting is to divert gastric contents from the leak site and to bypass any distal stenosis if present. The ideal stent should be long enough to cover the distal end of the sleeve, including the incisura. Predictors for success include male gender, higher pre-bariatric surgery BMI, and early stenting. (25 vs. 49 days).23 (Figure 1)

The success of endoluminal stenting for GSL is between 70%-88%.22,24,25 Additionally, successful treatment of GSL with SEMS can occur in 50% of patients after a single endoscopic session.22 The most undesired adverse effect of SEMS for treatment of GSL is migration which has been demonstrated in 30-47% cases.22,24 Anti-migratory mechanisms that can be utilized include endoscopic suturing of stents, longer stent length, and the use of endoscopic clips.22 Other adverse events include stent intolerance, bleeding, foreign body obstruction, strictures, and mucosal hypertrophy. According to one group, the optimal time for stent removal is after six to eight weeks, and they proposed that shorter intervals may lead to incomplete leak closure and longer intervals may result in stent migration or mucosal hypertrophy leading to difficulty with stent extraction.25 Still, in practice many different physicians have different opinions on the optimal stent indwell time and most patients receive individualized care. 

Fully covered self-expanding metal stents (fcSEMS) have the advantage of being easily removable compared to partially covered self-expanding metal stents (pcSEMS).26 However, fcSEMS have a high migration rate, reaching up to 26-67%.27,28 The Mega stent (Taewoong Medical, Seoul, Korea) was designed as a proposed solution to overcome the problem of migration.28 It is an ultra-large fully covered stent with braided mesh and increased flexibility which allows it to conform to post-bariatric anatomy. Its design can increase compression and coaptation against the luminal wall.  Shehab et. al has demonstrated the success rate of Mega stents to be 82% with a migration rate of 18%.28 Stenting can be combined with other treatment modalities, such as over-the-scope clips, which can directly close the wall defect.29 

Through-the-Scope-Clips 

Through the scope clips (TTSC) were initially designed for the treatment of gastrointestinal bleeding. These clips can approximate the edges of a lesion and produce mechanical compression/hemostasis without creating tissue injury seen with thermal hemostatic devices.30 TTSC have been reported as a modality for management of GSL.31,32  Once the edges of the defect are approximated, one or more clips are deployed to close the defect. In a meta-analysis of 17 studies including a total of 98 patients treated with clips for GSL, 4 studies (13 patients) utilized TTSC and successful treatment was reported in 9 of 13 patients (69.2%).32 This study is limited by the inclusion of very small number of patients. The use of TTSC can be considered in stable patients with small leaks, if the leak has failed endoscopic stenting, or is not amenable to stent placement.31  

Over-the-Scope Clips 

The over-the-scope clip (OTSC) is a mechanical clipping device designed to encircle, lift, and close endoscopic defects. These clips can achieve full thickness closure of luminal defects.29 Suction or grasping can be utilized to help ensure proper placement over the entire defect. OTSC is a wall defect closure strategy for the management of GSL.  A meta-analysis reported the use of OTSC in 85 patients across seventeen papers (98 patients) with a successful closure rate of 67.1%.32 The use of OTSC is more efficient if IAC are drained prior.33 OTSC-related adverse events occur in approximately 1.7% of cases.34 These include jejunal stenosis, clip mis-deployment, and micro-perforation or free perforation if there is an underlying ulcer.33,34

As most GSL are located at the proximal end of the staple line, using an OTSC and its mounting system to maneuver and position the clip may be difficult, due to limited space. Successful deployment of an OTSC depends on the working space, size, orientation of the defect and surrounding tissue quality.35 Using OTSC as a closure device to treat GSL should be considered for small- to medium-sized defects that can easily be accessed endoscopically. (Figure 2)

Tissue Sealants

Tissue sealants are adhesives that can be used to treat gastrointestinal leaks with initial data arising predominantly from use in Roux-en-Y gastric bypass (RYGB) patients. Such products are not readily available for endoscopists, which limit its use. The most commonly used sealant used for GSL closure is fibrin glue.32 Fibrin glue mechanically occludes the stomach wall defect and aids in wound healing. It induces a cellular response to tissue damage by forming matrix-building strands which promotes neovascularization and fibroblast proliferation.36 In a 2021 systematic review and meta-analysis, 10 case series comprising 63 patients with GSL were treated with fibrin glue. In 25 patients, the sealant was delivered endoscopically with a 100% success rate. The amount of glue ranged from 2-10 cc (median 4cc). Adverse events were reported in one study and included pain and fever in 3/24 patients.32

Another example of a tissue sealant glue is cyanoacrylate. Cyanoacrylate is a highly adhesive synthetic glue with antibacterial properties that can be utilized as a tissue sealant for GSL closure.37 Only a small amount (0.5-4cc) is needed and it can be utilized in a wet environment. Despite its advantages, it’s rapid polymerization results in poor mechanical properties such as low tensile strength and brittle nature, as well as risking damage to the endoscope.37 

SurgiSIS (Cook Biotech Inc., West Lafayette, IA) is an acellular matrix biomaterial comprising porcine small intestine submucosa. It stimulates proliferation and formation of fibroblasts in the regions of wounds.38 Strips of soaked SurgiSIS material are captured within a specially designed polypectomy snare and loaded into the endoscope outside of the patient. The scope is re-inserted after which the snare is used to place the material on the defect.38 In a 2009 clinical trial, the rate of closure of 5 to 10mm wide fistulas in patients who had undergone prior gastric bypass was achieved in 20/25  patients (80%) after 3 sessions.38 Further studies are necessary to determine the efficacy of SurgiSIS in patients with leaks from sleeve gastrectomy. 

Endoscopic Suturing 

Endoscopic suturing may be considered for closure of GSL when the defect size is large and other methods are less likely successful or have failed.39 The OverStitch (Apollo Endosurgery Inc., Austin, TX) is an endoscopic suturing system, mounted over the scope, that places full-thickness sutures endoscopically. Choosing to perform endoscopic suturing for gastrointestinal leaks depends on the condition/viability/friability/etc. of the target tissue, the feasibility of placing the suture according to the shape of the defect, distance of the margins, and absence of IAC.40  

The success of closing gastrointestinal leaks with endoscopic sutures was initially reported among RYGB patients.41 Mukewar et al. reported 100% immediate clinical success rate for gastrointestinal fistula closure with endoscopic suturing, however only 40% sustained clinical success at 4 weeks after the index procedure.39 There has been limited data which observed the use of endoscopic suturing in the management of GSL. Granata et al. reported 100% clinical success rate for gastric sleeve leak patients treated with OverStitch™ endoscopic suturing (6/6 patients).40 In a 2022 randomized controlled trial, 5/15 patients with gastric sleeve leaks were managed with endoscopic suturing alone with 100% clinical success and no cases of recurrent gastric fistula during the 18 month follow up period.3 

Septotomy 

Septotomy is a relatively new procedure which allows for fluid drainage from an abscess cavity, formed secondary to a leak, into the stomach by dividing the septum that separates the abscess from the gastric lumen.42 This division equalizes the intraluminal pressures by addressing the pressure gradient that drives gastric contents from the gastric lumen into the peri gastric collection.43 These changes can result in abscess cavity collapse and healing can occur through secondary intention and epithelialization.42,43 

This procedure is performed with a forward viewing gastroscope and the leak orifice is identified. If feasible, the abscess cavity is inspected and entered for irrigation.42 Division of the septum can be performed using a needle knife, cutting knife, or other endoscopic tools.43-45 Division of the septum is complete when the entire abscess cavity communicates with the gastric lumen, allowing drainage into the lumen of the stomach.  In a small multicenter study of 9 patients with GSL treated via septotomy, the peri-gastric collections ranged in size from 3-10cm. The mean procedure time was 87 minutes and a mean of 2.3 procedures were required to achieve radiologic resolution.43 Bleeding occurred in 3 patients and was managed successfully with TTSC. All patients achieved radiologic resolution. Diaz et al. demonstrated 5 patients with GSL who were treated with septotomy combined with sleeve dilation. Clinical success was achieved in 80% of patients (4/5), and no adverse events to the procedure were identified.42 

Endoscopic Vacuum Assisted Closure 

Endoscopic vacuum assisted closure (EVAC) is a negative pressure closure technique involving the placement of a porous polyurethane sponge in the abscess cavity at the leak site. In addition to drainage, it also increases local blood flow and promotes granulation tissue formation.46,47 The Endo-SPONGE system (B. Braun, Melsungen, Germany) allows for the insertion of an open-pored sponge into the leakage cavity using an endoscope. A drainage tube is connected to the sponge and suction is applied between 75 – 120 mm Hg depending on the size of the leak.48 The sponge can be inserted in cavities from leaks with large openings (≥ 9mm). The sponge can be exchanged every 3 days via endoscopy.48 

Studies have demonstrated 85-100% success with use of EVAC for treatment of GSL.47-49 Markus et al. demonstrated a 90% healing rate with Endo-SPONGE with a mean treatment time of 17 days. GSL healing with use of a sponge was defined as wound cavity size smaller than 1 cm in radius and 2 cm in depth, after which EVAC was terminated.48 

Cardiac Septal Occluders 

Cardiac septal occluder devices (CSDO) are a novel, off-label, treatment option for the management of GSL. CSDO Amplatzer™ (St. Jude Medical, Plymouth, Minn) is a self-expandable double disk (double umbrella) closure device, made of nitinol and interwoven polyester, which promotes tissue in-growth while sealing fistulous tracts.50 In a 2020 systematic review of 22 patients with GI fistulas, in 2 patients with GSL, technical success was 100% and clinical success (after one year of follow-up) was seen in 77%. Adverse events were reported in 5 patients and included migration and fistula enlargement. Further studies are needed prior to consideration of CSDO as the first line for treatment of GSL.50

Conclusion 

Gastric sleeve leaks are common adverse events following sleeve gastrectomy. Management of these leaks should ideally occur in a multidisciplinary setting.  An endoscopic approach should be considered as a less invasive option to surgery in patients without hemodynamic compromise, septic shock or peritonitis. The endoscopic armamentarium currently provides various options, and continues to expand, serving as a minimally invasive treatment avenue for the management of GSL. 

References

References

1. Estimate of Bariatric Surgery Numbers, 2011-2021. https://asmbs.org/resources/estimate-of-bariatric-surgery-numbers

2. Stroh C, Kockerling F, Volker L, et al. Results of More Than 11,800 Sleeve Gastrectomies: Data Analysis of the German Bariatric Surgery Registry. Ann Surg. May 2016;263(5):949-55. doi:10.1097/SLA.0000000000001559

3. Negm S, Mousa B, Shafiq A, et al. Endoscopic management of refractory leak and gastro-cutaneous fistula after laparoscopic sleeve gastrectomy: a randomized controlled trial. Surg Endosc. Mar 2023;37(3):2173-2181. doi:10.1007/s00464-022-09748-z

4. Souto-Rodriguez R, Alvarez-Sanchez MV. Endoluminal solutions to bariatric surgery complications: A review with a focus on technical aspects and results. World J Gastrointest Endosc. Mar 16 2017;9(3):105-126. doi:10.4253/wjge.v9.i3.105

5. Csendes A, Braghetto I, Leon P, Burgos AM. Management of leaks after laparoscopic sleeve gastrectomy in patients with obesity. J Gastrointest Surg. Sep 2010;14(9):1343-8. doi:10.1007/s11605-010-1249-0

6. Rosenthal RJ, International Sleeve Gastrectomy Expert P, Diaz AA, et al. International Sleeve Gastrectomy Expert Panel Consensus Statement: best practice guidelines based on experience of >12,000 cases. Surg Obes Relat Dis. Jan-Feb 2012;8(1):8-19. doi:10.1016/j.soard.2011.10.019

7. Nedelcu M, Skalli M, Delhom E, Fabre JM, Nocca D. New CT scan classification of leak after sleeve gastrectomy. Obes Surg. Aug 2013;23(8):1341-3. doi:10.1007/s11695-013-1002-3

8. Johari Y, Catchlove W, Tse M, et al. A 4-tier Protocolized Radiological Classification System for Leaks Following Sleeve Gastrectomy. Ann Surg. Feb 1 2022;275(2):e401-e409. doi:10.1097/SLA.0000000000003984

9. Kim J, Azagury D, Eisenberg D, et al. ASMBS position statement on prevention, detection, and treatment of gastrointestinal leak after gastric bypass and sleeve gastrectomy, including the roles of imaging, surgical exploration, and nonoperative management. Surg Obes Relat Dis. Jul-Aug 2015;11(4):739-48. doi:10.1016/j.soard.2015.05.001

10. Benedix F, Benedix DD, Knoll C, et al. Are there risk factors that increase the rate of staple line leakage in patients undergoing primary sleeve gastrectomy for morbid obesity? Obes Surg. Oct 2014;24(10):1610-6. doi:10.1007/s11695-014-1257-3

11. Varban OA, Sheetz KH, Cassidy RB, et al. Evaluating the effect of operative technique on leaks after laparoscopic sleeve gastrectomy: a case-control study. Surg Obes Relat Dis. Apr 2017;13(4):560-567. doi:10.1016/j.soard.2016.11.027

12. Li M, Zeng N, Liu Y, et al. Management and outcomes of gastric leak after sleeve gastrectomy: results from the 2010-2020 national registry. Chin Med J (Engl). Aug 20 2023;136(16):1967-1976. doi:10.1097/CM9.0000000000002499

13. Bingham J, Shawhan R, Parker R, Wigboldy J, Sohn V. Computed tomography scan versus upper gastrointestinal fluoroscopy for diagnosis of staple line leak following bariatric surgery. Am J Surg. May 2015;209(5):810-4; discussion 814. doi:10.1016/j.amjsurg.2015.01.004

14. Deffain A, Alfaris H, Hajjar R, et al. Long-term follow-up of a cohort with post sleeve gastrectomy leaks: results of endoscopic treatment and salvage surgery. Surg Endosc. Aug 28 2023;doi:10.1007/s00464-023-10386-2

15. Christophorou D, Valats JC, Funakoshi N, et al. Endoscopic treatment of fistula after sleeve gastrectomy: results of a multicenter retrospective study. Endoscopy. Nov 2015;47(11):988-96. doi:10.1055/s-0034-1392262

16. Ge PS, Thompson CC. The Use of the Overstitch to Close Perforations and Fistulas. Gastrointest Endosc Clin N Am. Jan 2020;30(1):147-161. doi:10.1016/j.giec.2019.08.010

17. Jaruvongvanich V, Matar R, Storm AC, et al. Endoscopic management of refractory leaks and fistulas after bariatric surgery with long-term follow-up. Surg Endosc. Jun 2021;35(6):2715-2723. doi:10.1007/s00464-020-07702-5

18. Donatelli G, Spota A, Cereatti F, et al. Endoscopic internal drainage for the management of leak, fistula, and collection after sleeve gastrectomy: our experience in 617 consecutive patients. Surg Obes Relat Dis. Aug 2021;17(8):1432-1439. doi:10.1016/j.soard.2021.03.013

19. Lorenzo D, Guilbaud T, Gonzalez JM, et al. Endoscopic treatment of fistulas after sleeve gastrectomy: a comparison of internal drainage versus closure. Gastrointest Endosc. Feb 2018;87(2):429-437. doi:10.1016/j.gie.2017.07.032

20. Bouchard S, Eisendrath P, Toussaint E, et al. Trans-fistulary endoscopic drainage for post-bariatric abdominal collections communicating with the upper gastrointestinal tract. Endoscopy. Sep 2016;48(9):809-16. doi:10.1055/s-0042-108726

21. Mohan BP, Shakhatreh M, Dugyala S, et al. EUS versus percutaneous management of postoperative pancreatic fluid collection: A systematic review and meta-analysis. Endosc Ultrasound. Sep-Oct 2019;8(5):298-309. doi:10.4103/eus.eus_18_19

22. Smith ZL, Park KH, Llano EM, et al. Outcomes of endoscopic treatment of leaks and fistulae after sleeve gastrectomy: results from a large multicenter U.S. cohort. Surg Obes Relat Dis. Jun 2019;15(6):850-855. doi:10.1016/j.soard.2019.04.009

23. Murino A, Arvanitakis M, Le Moine O, Blero D, Deviere J, Eisendrath P. Effectiveness of Endoscopic Management Using Self-Expandable Metal Stents in a Large Cohort of Patients with Post-bariatric Leaks. Obes Surg. Sep 2015;25(9):1569-76. doi:10.1007/s11695-015-1596-8

24. Billmann F, Pfeiffer A, Sauer P, et al. Endoscopic Stent Placement Can Successfully Treat Gastric Leak Following Laparoscopic Sleeve Gastrectomy If and Only If an Esophagoduodenal Megastent Is Used. Obes Surg. Jan 2022;32(1):64-73. doi:10.1007/s11695-021-05467-x

25. Puli SR, Spofford IS, Thompson CC. Use of self-expandable stents in the treatment of bariatric surgery leaks: a systematic review and meta-analysis. Gastrointest Endosc. Feb 2012;75(2):287-93. doi:10.1016/j.gie.2011.09.010

26. Almadi MA, Bamihriz F, Alharbi O, et al. Use of Self-Expandable Metal Stents in the Treatment of Leaks Complicating Laparoscopic Sleeve Gastrectomy: A Cohort Study. Obes Surg. Jun 2018;28(6):1562-1570. doi:10.1007/s11695-017-3054-2

27. Garofalo F, Noreau-Nguyen M, Denis R, Atlas H, Garneau P, Pescarus R. Evolution of endoscopic treatment of sleeve gastrectomy leaks: from partially covered to long, fully covered stents. Surg Obes Relat Dis. Jun 2017;13(6):925-932. doi:10.1016/j.soard.2016.12.019

28. Shehab H, Abdallah E, Gawdat K, Elattar I. Large Bariatric-Specific Stents and Over-the-Scope Clips in the Management of Post-Bariatric Surgery Leaks. Obes Surg. Jan 2018;28(1):15-24. doi:10.1007/s11695-017-2808-1

29. Shehab HM, Hakky SM, Gawdat KA. An Endoscopic Strategy Combining Mega Stents and Over-The-Scope Clips for the Management of Post-Bariatric Surgery Leaks and Fistulas (with video). Obes Surg. May 2016;26(5):941-8. doi:10.1007/s11695-015-1857-6

30. Xavier AT, Campos JF, Robinson L, Lima EJM, da Rocha LCM, Arantes VN. Endoscopic clipping for gastrointestinal bleeding: emergency and prophylactic indications. Ann Gastroenterol. Nov-Dec 2020;33(6):563-570. doi:10.20524/aog.2020.0526

31. Ritter LA, Wang AY, Sauer BG, Kleiner DE. Healing of complicated gastric leaks in bariatric patients using endoscopic clips. JSLS. Jul-Sep 2013;17(3):481-3. doi:10.4293/108680813X13693422521999

32. Rogalski P, Swidnicka-Siergiejko A, Wasielica-Berger J, et al. Endoscopic management of leaks and fistulas after bariatric surgery: a systematic review and meta-analysis. Surg Endosc. Mar 2021;35(3):1067-1087. doi:10.1007/s00464-020-07471-1

33. Mercky P, Gonzalez JM, Aimore Bonin E, et al. Usefulness of over-the-scope clipping system for closing digestive fistulas. Dig Endosc. Jan 2015;27(1):18-24. doi:10.1111/den.12295

34. Kobara H, Mori H, Nishiyama N, et al. Over-the-scope clip system: A review of 1517 cases over 9 years. J Gastroenterol Hepatol. Jan 2019;34(1):22-30. doi:10.1111/jgh.14402

35. Aly A, Lim HK. The use of over the scope clip (OTSC) device for sleeve gastrectomy leak. J Gastrointest Surg. Mar 2013;17(3):606-8. doi:10.1007/s11605-012-2062-8

36. Bonanomi G, Prince JM, McSteen F, Schauer PR, Hamad GG. Sealing effect of fibrin glue on the healing of gastrointestinal anastomoses: implications for the endoscopic treatment of leaks. Surg Endosc. Nov 2004;18(11):1620-4. doi:10.1007/s00464-004-8803-3

37. Kotzampassi K, Eleftheriadis E. Tissue sealants in endoscopic applications for anastomotic leakage during a 25-year period. Surgery. Jan 2015;157(1):79-86. doi:10.1016/j.surg.2014.06.002

38. Maluf-Filho F, Hondo F, Halwan B, de Lima MS, Giordano-Nappi JH, Sakai P. Endoscopic treatment of Roux-en-Y gastric bypass-related gastrocutaneous fistulas using a novel biomaterial. Surg Endosc. Jul 2009;23(7):1541-5. doi:10.1007/s00464-009-0440-4

39. Mukewar S, Kumar N, Catalano M, et al. Safety and efficacy of fistula closure by endoscopic suturing: a multi-center study. Endoscopy. Nov 2016;48(11):1023-1028. doi:10.1055/s-0042-114036

40. Granata A, Amata M, Ligresti D, et al. Endoscopic management of post-surgical GI wall defects with the overstitch endosuturing system: a single-center experience. Surg Endosc. Sep 2020;34(9):3805-3817. doi:10.1007/s00464-019-07145-7

41. Overcash WT. Natural orifice surgery (NOS) using StomaphyX for repair of gastric leaks after bariatric revisions. Obes Surg. Jul 2008;18(7):882-5. doi:10.1007/s11695-008-9452-8

42. Diaz R, Welsh LK, Perez JE, et al. Endoscopic septotomy as a treatment for leaks after sleeve gastrectomy: Meeting presentations: Digestive Disease Week 2019. Endosc Int Open. Jan 2020;8(1):E70-E75. doi:10.1055/a-1027-6888

43. Mahadev S, Kumbhari V, Campos JM, et al. Endoscopic septotomy: an effective approach for internal drainage of sleeve gastrectomy-associated collections. Endoscopy. May 2017;49(5):504-508. doi:10.1055/s-0042-122012

44. Kim KH, Jung K, Kim YH, Seo KW. Endoscopic Septotomy as a Treatment for Chronic Leak after Laparoscopic Sleeve Gastrectomy. J Metab Bariatr Surg. Jun 2021;10(1):42-45. doi:10.17476/jmbs.2021.10.1.42

45. Shnell M, Gluck N, Abu-Abeid S, Santo E, Fishman S. Use of endoscopic septotomy for the treatment of late staple-line leaks after laparoscopic sleeve gastrectomy. Endoscopy. Jan 2017;49(1):59-63. doi:10.1055/s-0042-117109

46. Joo MK. Endoscopic Approach for Major Complications of Bariatric Surgery. Clin Endosc. Jan 2017;50(1):31-41. doi:10.5946/ce.2016.140

47. Leeds SG, Burdick JS, Fleshman JW. Endoluminal Vacuum Therapy for Esophageal and Upper Intestinal Anastomotic Leaks. JAMA Surg. Jun 1 2016;151(6):573-4. doi:10.1001/jamasurg.2016.0255

48. Markus A, Henrik BJ, Benedikt R, et al. Endoscopic vacuum therapy in salvage and standalone treatment of gastric leaks after bariatric surgery. Langenbecks Arch Surg. May 2022;407(3):1039-1046. doi:10.1007/s00423-021-02365-9

49. Archid R, Wichmann D, Klingert W, et al. Endoscopic Vacuum Therapy for Staple Line Leaks after Sleeve Gastrectomy. Obes Surg. Apr 2020;30(4):1310-1315. doi:10.1007/s11695-019-04269-6

50. De Moura DTH, Baptista A, Jirapinyo P, De Moura EGH, Thompson C. Role of Cardiac Septal Occluders in the Treatment of Gastrointestinal Fistulas: A Systematic Review. Clin Endosc. Jan 2020;53(1):37-48. doi:10.5946/ce.2019.030

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Feeding Tube Response in Esophagitis

May 2024 • Volume XLVIII, Issue 5

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Eosinophilic esophagitis (EoE) in young children can be associated with poor feeding as well as associated failure to thrive/failure to gain weight. Thus, use of nasogastric (NG) tube feeds as well as surgical gastrostomy tube (G-tube) feeds may be recommended to improve caloric intake as well as to provide elemental nutrition in this age group with EoE. There is minimal long-term data available regarding which pediatric patients with EoE would benefit most from NG/G-tube feeds.  

This retrospective study occurred at a tertiary children’s hospital in the United States. All pediatric patients with EoE and with a history of enteral tube feeds used as treatment for EoE from 2002 to 2021 were included. Basic patient demographics were obtained on all patients, and all patients were evaluated for both endoscopic and histologic response to enteral feeds. A total of 457 pediatric patients with EoE were identified, of which 39 pediatric patients with EoE required enteral tube feeds. The mean age of initial diagnosis of EoE for patients requiring enteral tube feeds was 6.3 ± 7.6 years, and the mean age for patients requiring enteral tube placement was 6.3 ± 9.3 years. The most common symptoms in this patient group were emesis and dysphagia. When compared to children with EoE who did not require enteral tube feeds, the patients with EoE and enteral tube feeds were significantly younger, had a significantly lower body mass index (BMI), and had a significantly lower initial Eosinophilic Esophagitis Endoscopic Reference Score (used to determine treatment response to EoE) and Endoscopic Severity Score.  

Most patients had enteral tube placement for failure to gain weight, and 19 patients (49%) required a transition from NG tube feeds to G-tube feeds. The vast amount of enteral nutrition provided to this patient group consisted of elemental formula (87%). Other therapeutics provided for this group included proton pump inhibitors, system steroids, and dupilumab. Enteral tubes remained in place for a mean of 6.8 ± 6.2 years. Most patients (92%) had enteral tube complications which were relatively mild, including tube displacement or granulation tissue formation. Most patients (71%) with enteral support achieved histologic EoE response. There was a significant increase in BMI-for-age z-scores in those patients with EoE requiring enteral feeds. Patients requiring enteral feeds prior to a diagnosis of EoE were significantly more likely to have autism or developmental delay, be non-white, and have no food allergies compared to patients with enteral feeding starting after a diagnosis of EoE. However, there was no difference in patient age, sex, or year in which EoE was diagnosed. Patients requiring initial enteral feeds due to a feeding problem had a delay of 2.2 ± 0.6 years prior to EoE eventually being diagnosed.

Although this is a small retrospective study, it does provide some interesting information to pursue further. For example, the finding that pediatric patients with EoE requiring enteral tube feeds having lower associated Eosinophilic Esophagitis Endoscopic Reference Scores and Endoscopic Severity Scores need further study as such patients may require more intensive feeding therapy and perhaps medical therapy. The delay in EoE diagnosis in patients with enteral feedings already in place suggests that a heightened awareness of the possibility of EoE is needed when evaluating children with feeding problems.

Borinsky S, Cameron B, Xue Z, LaFata S, Kiran A, Ocampo A, McCallen J, Lee C, Redd W, Cotton C, Eluri S, Reed C, Dellon E. Feeding Tube Placement, Complications, and Treatment Responses in a Large Eosinophilic Esophagitis.  J Pediatr Gastroenterol Nutr 2023; 77: 753-759.

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Nutritional Considerations for Hypermobile Ehlers-Danlos Syndrome

May 2024 • Volume XLVIII, Issue 5
Cheryl Iny Harris,Dacre R.T. Knight,Lisa A. Mejia,Laurie Bilyeu

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While the hallmarks of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum
disorders (HSD) are pain, joint instability, and injuries to soft tissues, most patients with hEDS and
HSD have a myriad of manifestations within the gastrointestinal tract that affect dietary tolerance
and quality of life. These include irritable bowel syndrome, functional dyspepsia, gastroparesis,
constipation, and celiac disease. Other common comorbidities include postural orthostatic tachycardia
syndrome and mast cell activation disorders, which may impact fluid and electrolyte balance, food
intolerances, and contribute to anxiety around food. Nutritional supplements are commonly used,
though research is needed to clarify their potential role in hEDS/HSD management. Patients with hEDS/
HSD benefit from the support of a multidisciplinary healthcare team. This review discusses nutritional
implications and provides practical recommendations to address the manifestations of hEDS/HSD.

Introduction

 Ehlers-Danlos syndromes (EDS) encompass a group of 14 heritable connective tissue disorders.1 The most prevalent form of EDS is hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) with hEDS/HSD appearing to be female-predominant inherited disorders.2 All types of EDS except hEDS/ HSD have identified genetic markers. HSD is also known as joint hypermobility syndrome (JHS), an older term that still appears in research. Key characteristics of hEDS/HSD are pain, fatigue, joint instability, and its consequential injuries to soft tissues.3 Patients with HSD share most of the features of hEDS, with similar symptoms, disease severity, and treatment strategies.3 Clinical features are widespread, affecting neurologic, cardiovascular, gastrointestinal, and urogynaecological systems. 

The largest prevalence study is from Wales, UK, indicating 1:500 (2%) of the general population received a formal diagnosis of hEDS or JHS.4 Both hEDS/HSD are currently underdiagnosed, with diagnosis typically taking 10+ years.5 According to an EDS worldwide survey, 97% of people with EDS report that prior to diagnosis, their healthcare team attributed their symptoms to psychological causes.6 Studies suggest the actual prevalence of hEDS/ HSD is closer to 3% of the general population.4,7 

Management of hEDS/HSD involves relieving symptoms and ensuring sufficient nutrient intake. This review focuses on gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS), functional dyspepsia (FD), gastroparesis, celiac disease, and other nutrition-related disorders, such as temporomandibular joint (TMJ) dysfunction, eating disorders (EDs), autonomic disorders such as postural orthostatic tachycardia syndrome (POTS) and mast cell activation disorder (MCAD).8 Practical applications will be emphasized (see Table 1). 

Gastrointestinal Manifestations of hEDS/HSD 

Gastrointestinal disorders are among the most common manifestations of hEDS/HSD, with studies reporting ~90% of patients experience symptoms of diseases of gut-brain interaction (DGBIs).8 GI symptoms may include dysphagia, reflux, postprandial fullness, bloating, abdominal pain, nausea, vomiting, diarrhea, and constipation. Patients often attribute symptoms to eating, which can generate food fears and changes in appetite that impact nutritional intake and contribute to disordered eating patterns.8 

Irritable Bowel Syndrome 

Research suggests that up to 62% of people with hEDS/HSD are diagnosed with a subtype of IBS (IBS-diarrhea, IBS-constipation, IBS-mixed, IBS-undefined).9 Using the ROME IV criteria, IBS is characterized by the presence of recurrent abdominal pain one day a week or more for at least 3 months and the presence of at least two symptoms related to defecation, a change in stool frequency and/or form. Visceral hypersensitivity, central sensitization, autonomic dysfunction, mast cell activation, and/or biopsychosocial factors may also contribute to symptoms of IBS. Symptomatic patients often seek nutrition guidance initially; however, organic disease must be ruled out first if there is unintentional weight loss, anemia, elevated inflammatory markers, or signs of a potential GI bleed. 

A first-line approach for IBS management is to implement the NICE (National Institutes for Health and Care Excellence) guidelines, which include:10,11 

eating regular, small meals 

eating slowly 

hydrating adequately 

avoiding excessive caffeine, alcohol, or carbonation 

avoiding more than 3 portions of fruit or juice daily 

avoiding polyols for people with loose stools 

reducing fatty foods 

limiting insoluble high fiber foods 

Research is limited on the efficacy of the NICE guidelines; however, they are often the initial strategy because of the relative ease of implementation. 

If symptoms do not improve, a secondary approach is the low FODMAP diet (LFD) (fermentable oligo, di, monosaccharides, and polyols). The LFD involves a 2–6 week guided elimination diet of osmotically active short-chain carbohydrates, followed by a structured reintroduction phase to learn potential triggers while adding in high FODMAPs, and finally, a personalization phase to maintain intake of FODMAPs that are tolerated well.10,11 Studies show the LFD reduces GI symptoms, such as bloating, abdominal pain, and diarrhea, in 57-82% of people with IBS.10 An LFD should only be undertaken with the guidance of a trained Registered Dietitian Nutritionist (RDN). 

In a study of 165 patients diagnosed with both IBS and JHS, and controls with IBS only, all subjects followed the LFD.12 Patients with JHS had greater decreases in abdominal pain and bloating. The patients who had both JHS and IBS-C showed the largest improvement on an LFD compared to IBS-C controls.12 Further studies are needed to confirm these results and understand the biological mechanism for decreased pain in patients with JHS. 

 

Irritable Bowel Syndrome
Start with the National Institutes for Health and Care Excellence (NICE) guidelines
If the NICE guidelines are not successful in alleviating symptoms, consider the low FODMAP diet with the elimination, reintroduction, and personalization phases
Functional Dyspepsia
Consider a trial limiting fatty or spicy foods, wheat, caffeine, and alcohol
Consider a Mediterranean Diet pattern to reduce intake of animal protein and increase intake of fruits and vegetables
Consider a trial of the low FODMAP diet
Have small meals throughout the day
Eat slowly and chew well
Gastroparesis 
Incorporate a small particle size diet with a focus on blending, mashing, or mincing foods
Adjust fiber intake if necessary
Increase movement after meals if possible
Have small meals throughout the day
Consume foods with fat as tolerated. Fat is sometimes tolerated best in liquid form.
Constipation
Eat two kiwifruit a day
Increase intake of soluble fiber which binds water (e.g., oats, flax) with increased fluid intake
Add foods with natural sorbitol content (e.g., prunes, dried apricots)
For IBS-C, consider a short-term trial of the NICE guidelines or the low FODMAP diet
Celiac Disease
Adopt a lifelong gluten-free diet
Monitor for nutrient deficiencies
Temporomandibular Disorders
Switch to pureed foods or soft textures if needed
Cut food into smaller pieces to ease chewing
Postural Orthostatic Tachycardia Syndrome 
Increase fluid consumption to 2-3 liters daily and increase salt up to 6-10 grams unless contraindicated
Consider a lower glycemic diet if appropriate
Monitor symptoms and tailor specific recommendations based on the patient’s needs
Mast Cell Activation Disorders
An experienced RDN should evaluate a diet journal for potential MC triggers
Consider a low histamine diet elimination and reintroduction if indicated
Table 1. Diet Recommendations for Manifestations of hEDS/HSD

Functional Dyspepsia 

The hallmarks of functional dyspepsia (FD) include decreased appetite, postprandial distress, early satiety, nausea, belching, and epigastric pain.13 Studies found that between 37-86% of patients with hEDS/HSD experience FD symptoms.13 FD often impairs dietary intake. Limited research supports small, frequent, regular meals, eating slowly, and chewing well. There is potential benefit to limiting fatty or spicy foods, wheat, caffeine or alcohol.14 Lower adherence to the Mediterranean diet pattern has been associated with worsening of symptoms in FD, thus there may be utility to adopting the Mediterranean diet, which reduces intake of animal protein and increases intake of fruits and vegetables. Also, implementing the LFD has been shown to reduce symptoms.14 

Gastroparesis 

Common gastroparesis symptoms include changes in appetite, nausea, vomiting, early satiety, and unintentional weight loss. A large case-control study compared hospitalized patients with and without EDS and found patients with EDS exhibited a 12.26 higher odds ratio of a concurrent diagnosis of gastroparesis.15 These results are supported by another study which found 52% of patients with GI symptoms and JHS were diagnosed with gastroparesis.16 Nutrition interventions to manage gastroparesis include smaller meals, modification of fiber intake, and post-prandial 

movement as tolerated to enhance motility. A small particle size diet, or altering food consistency by blending, processing or mashing food may help expand dietary tolerance (e.g., smoothies, mashed potatoes).17 

Constipation 

Constipation is common; a recent study found 73% of patients with hEDS/HSD had constipation versus 16% of controls.3 The underlying etiology of constipation in hEDS/HSD is multifactorial and includes DGBIs, delayed motility, small intestinal methane overgrowth, pelvic floor dyssynergia, medication induced constipation, and rectal hyposensitivity.8,18 Treatment should be individualized, and dietary adjustments may include eating two kiwifruit daily, gradually increasing higher fiber foods, like oats, prunes, or flaxseed, or adding soluble fiber supplements, such as psyllium husk or partially hydrolyzed guar gum.11,19 Excess fiber intake can potentially aggravate constipation, especially without concurrent adequate water intake. Patients with comorbid rectal hyposensitivity may benefit from biofeedback, which has been studied in hEDS/ HSD.18 

Celiac Disease 

One small study found that 16% of people with hEDS/HSD also had celiac disease.8 A large case control study determined the rate of celiac disease was 5.5 times higher in people with EDS than the average hospitalized patient.15 Swedish patients with EDS/JHS had an odds ratio of 2.3 of a subsequent celiac diagnosis.20 A study in children with joint hypermobility (excessively lax joints, without associated pathology) found an odds ratio of 10.9% for positive celiac serology.21 Further studies are needed; however, celiac testing is prudent for patients with symptoms or a family history. 

People diagnosed with celiac disease need to follow a lifelong, strict gluten-free diet and benefit from consultation with an RDN. Newly diagnosed patients tend to be low in vitamins A, D, E, B12, copper, zinc, folate, and iron, and anyone following a gluten-free diet may be deficient in B vitamins, folate, iron, and calcium due to lack of enrichment and fortification of gluten-free products.22 Nutrient levels should be monitored, with diet modifications and/or supplementation as indicated. 

Other Nutrition-Related Manifestations of hEDS/HSD 

A range of conditions, including TMJ, POTS, MCAD, and EDs, are frequently found in people with hEDS/HSD. These conditions contribute to the patient’s symptom burden and add an additional layer of complexity to eating. 

Temporomandibular Joint Disorders 

While the literature is limited, 40-100% of people with EDS report headache and jaw pain.23 A recent case-control study found that TMJ symptoms, including myofascial pain, headache, jaw pain, and disc displacement occurred more in people with hEDS than controls.23 Dislocations or subluxations may make chewing difficult and compromise nutritional status. Pain with oral care may exacerbate dental problems. Patients with TMJ and hEDS/HSD should be referred to an RDN to ensure adequate oral intake and appropriate food consistencies, and to knowledgeable dentists and physical therapists (PTs) as needed. 

Postural Orthostatic Tachycardia Syndrome 

POTS is a form of dysautonomia affecting approximately 30% of people with hEDS/HSD.7 It is characterized by an increase in heart rate of 30 beats per minute (bpm) in adults (40 bpm for adolescents) in the first 10 minutes when moving from a recumbent to a standing position. Patients must have symptoms of orthostatic intolerance, such as palpitations, concentration difficulties, abnormal fatigue, presyncope, or headache for 3 or more months without another explanation.24 

Nutrition changes are the cornerstones of treatment for POTS, although medication is often needed. POTS involves hypovolemia; treatment expands blood volume via increased fluids, salt, exercise, and decreased fluid pooling with compression garments.24 Over 90% of people with POTS experience GI symptoms. Most symptoms improve when sitting or recumbent; bloating, constipation and diarrhea generally do not.7,25 People with concurrent hEDS/HSD and POTS may experience a higher burden of GI symptoms compared to those with hEDS/HSD without POTS.25 

Recommendations should be tailored based on physician guidance and co-morbid illnesses, such as cardiac diseases.26,27 Unless contraindicated, the initial recommendations are 6 grams of salt and 2-3 liters of fluid.27 Patients can gradually increase salt intake up to 10 grams, with close monitoring of symptoms, and adjustments based on clinical response.24 Alcohol, caffeine, and dehydration typically worsen symptoms.26 

Two small studies investigated dietary interventions in people with POTS. In one study, 20 females with POTS (8 also had hEDS) experienced significant improvements in orthostatic and GI symptoms with a 4-week, self-reported gluten-free diet.28 Another case-control study examined 12 women with POTS who had a history of orthostatic symptoms with high glycemic foods; information on comorbid conditions such as hEDS/HSD was not provided. The study participants experienced a significant increase in tachycardia after consuming 75 grams of glucose, compared to the 13 controls.29 This preliminary research suggests a gluten-free and/or a low glycemic diet deserve further study. They may be worth exploring for motivated patients who have been screened for celiac disease and are not at risk of an ED. 

Mast Cell Activation Disorders 

Mast cells (MCs) are white blood cells found in the mucosa and throughout connective tissue and skin. MC diseases include clonal diseases, which are rare and associated with genetic mutations, and non-clonal MCADs, which include mast cell activation syndrome (MCAS).30 Typically, MCs respond to pathogens; however, in MCADs, MCs may respond to benign stimuli, such as temperature, food, chemicals, medications, physical exertion, stress, etc. and degranulate, causing an inflammatory cascade by releasing histamine, heparin, prostaglandins, and other mediators. MCAD symptoms affect multiple organ systems: gastrointestinal, neurologic, cardiovascular, dermatologic, and respiratory. Symptoms range from mild to anaphylaxis.30 

Ehlers-Danlos Syndromes 
Ehlers-Danlos Society: ehlers-danlos.com 
Ehlers-Danlos Syndrome (EDS) GP Toolkit: gptoolkit.ehlers-danlos.org 
Ehlers-Danlos Support UK: ehlers-danlos.org 
Hypermobility Syndrome Association (HMSA): hypermobility.org 
SEDS Connective: sedsconnective.org 
hEDS/HSD Diagnostic Checklist: ehlers-danlos.com/heds-diagnostic-checklist 
EDS Diet & Nutrition: ehlers-danlos.com/international-consortium-working-groups 

Physical Therapy 
Clarkson University Technologia/Leslie Russek PT, DPT, PhD: webspace.clarkson.edu/~lrussek/research.html 
Jeannie di Bon, PT: youtube.com/c/JeannieDiBonHypermobility 

Other 
Dysautonomia International: dysautonomiainternational.org 
The Mast Cell Disease Society: tmsforacure.org

The only well-researched treatment for MCADs is avoidance of known MC triggers, especially in the case of anaphylaxis, and MC stabilizing medications, such as cromolyn sodium, ketotifen, or histamine blocking medications.30 

Controversy exists over diagnostic algorithms for MCADs; however, overall, studies estimate a 24-31% overlap between MCADs and hEDS.31 MCADs have potential nutritional implications, including risks for bone loss and food restriction. A low histamine diet (LHD) is commonly 

recommended, despite a lack of research.32 Aged and fermented foods are higher in histamine, but there is no universally accepted list of low histamine foods, and no experimental studies examining the clinical impact of an LHD in people with MCAD. One survey of self-reported experiences on an undefined LHD had 51.1% reporting improvement, 19.1% reporting no change and 29.8% of people who were unsure.33 An experienced RDN should work with patients to identify patterns of foods triggering MC reactions, and advocate for the widest range of foods tolerated.34 

Eating Disorders 

Patients with GI disorders are at increased risk for developing ED and patterns of disordered eating. There is a bi-directional relationship where GI symptoms can lead to food restriction and restriction exacerbates GI symptoms. Avoidant-restrictive food intake disorder (ARFID) is an ED unrelated to weight involving fear of symptoms from eating, such as choking, pain, or nausea.35 In a 2023 study, 37.9% of people with hEDS/HSD had a positive ARFID screen using the Nine Item Avoidant/Restrictive Food Intake Disorder Screen (NIAS).36 A positive screen was associated with changing diets, skipping meals, eliminating foods, and seeking or receiving nutritional support, such as enteral feeding.36 

Patients should be screened to identify an ED, although the NIAS has not been validated for people with GI disorders.37 An experienced ED specialist can discern the difference between necessary vigilance due to pain, disease management or disordered eating. A multi-disciplinary approach is necessary, including an RDN, psychological support, and medical interventions when appropriate. 

Supplement Use in hEDS/HSD 

Supplements are widely used; however, research on utility for hEDS/HSD is lacking. Supplements should be discussed with patients reporting use or expressing interest. There are currently no evidence-based recommendations for dietary supplementation to treat hEDS/HSD, nor supplements that will benefit all patients. Supplementation regimens should be based on nutrition assessments of individual patients. Research specific to hEDS/ HSD is needed, particularly on the supplements mentioned below. 

Antioxidants 

Mantle et al. proposed a 12-nutrient and antioxidant protocol intended to address various forms of EDS in 2004.38 No trials have been published on this. Three studies explored supplement use, and 61- 81% of patients with hEDS/HSD report taking supplements.36,39,40 Patients frequently reported using vitamins C, D and magnesium in all studies and B vitamins and multivitamins in two studies.39,40 

Collagen 

Abnormal synthesis and processing of collagen proteins and the extracellular matrix (ECM) are recognized in EDS, with some of the specific proteins and genetic variants identified.41 The collagen or ECM variants associated with hEDS/ HSD have not yet been identified.2 Collagen synthesis always requires adequate dietary intake of amino acids and cofactors. However, no data suggests excess collagen from any source or type provides additional benefit for hEDS/HSD. 

Folate 

A recent review postulates that hEDS/HSD might be due to a common polymorphism known as a methylenetetrahydrofolate reductase (MTHFR) deficiency that prevents the proper usage of vitamin B9, or folate. The solution would be providing the supplemental 5-methyltetrahydrofolate and/ or decreasing folic acid supplementation.42 The authors allude to trials of folate supplementation in patients with hEDS/HSD but did not share the number of patients, the dose used, or if they confirmed that those patients had MTHFR mutations, or the wider context of interactions with the methionine cycle. There are no published trials in patients with hEDS/HSD. Further research is warranted, and more information is needed before practice guidelines can be developed. 

CONCLUSION 

Patients with hEDS/HSD experience a wide range of manifestations that impact nutrient intake, digestion, and food tolerance and will benefit from specialized nutrition guidance and having access to resources (See Table 2). Common comorbidities, such as DGBIs, other GI disorders, EDs, MCAD, and POTS add additional layers of complexity. Each patient with hEDS/HSD will need a plan tailored to their individual circumstances. Supplement usage is common, and clinicians should query about usage and evaluate its appropriateness. Clinicians should anticipate that patients will benefit from coordinated support from a multi-disciplinary team including RDNs. 

References

References
1. Malfait F, Castori M, Francomano CA, Giunta C, Kosho
T, Byers PH. The Ehlers–Danlos syndromes. Nat Rev Dis
Primer. 2020;6(1):64.
2. Scicluna K, Formosa MM, Farrugia R, Borg I. Hypermobile
Ehlers–Danlos syndrome: A review and a critical appraisal
of published genetic research to date. Clin Genet.
2022;101(1):20-31.
3. Aubry-Rozier B, Schwitzguebel A, Valerio F, et al. Are
patients with hypermobile Ehlers–Danlos syndrome or
hypermobility spectrum disorder so different? Rheumatol
Int. 2021;41(10):1785-1794.
4. Demmler JC, Atkinson MD, Reinhold EJ, Choy E, Lyons
RA, Brophy ST. Diagnosed prevalence of Ehlers-Danlos
syndrome and hypermobility spectrum disorder in Wales,
UK: a national electronic cohort study and case-control comparison.
BMJ Open.
5. Halverson CME, Cao S, Perkins SM, Francomano CA.
Comorbidity, misdiagnoses, and the diagnostic odyssey in
patients with hypermobile Ehlers-Danlos syndrome. Genet
Med Open. 2023;1(1):100812.
6. Bulbena-Cabré A, Baeza-Velasco C, Rosado-Figuerola S,
Bulbena A. Updates on the psychological and psychiatric
aspects of the Ehlers–Danlos syndromes and hypermobility
spectrum disorders. Am J Med Genet C Semin Med Genet.
2021;187(4):482-490.
7. Tai FWD, Palsson OS, Lam CY, et al. Functional gastrointestinal
disorders are increased in joint hypermobility-related
disorders with concomitant postural orthostatic tachycardia
syndrome. Neurogastroenterol Motil. 2020;32(12):e13975.
8. Thwaites PA, Gibson PR, Burgell RE. Hypermobile Ehlers–
Danlos syndrome and disorders of the gastrointestinal tract:
What the gastroenterologist needs to know. J Gastroenterol
Hepatol. 2022;37(9):1693-1709.
9. Choudhary A, Fikree A, Aziz Q. Overlap between irritable
bowel syndrome and hypermobile Ehlers–Danlos syndrome:
An unexplored clinical phenotype? Am J Med Genet C
Semin Med Genet. 2021;187(4):561-569.
10. Rej A, Avery A, Aziz I, et al. Diet and irritable bowel syndrome:
an update from a UK consensus meeting. BMC Med.
2022;20(1):287.
11. Radziszewska M, Smarkusz-Zarzecka J, Ostrowska L.
Nutrition, Physical Activity and Supplementation in Irritable
Bowel Syndrome. Nutrients. 2023;15(16):3662.
12. Fragkos KC, Keetarut K, Cox A, Eady J, Emmanuel
AV, Zarate-Lopez N. Joint Hypermobility Syndrome
Affects Response to a Low Fermentable Oligosaccharide,
Disaccharide, Monosaccharide and Polyol Diet in Irritable
Bowel Syndrome Patients: A Retrospective Study.
Gastroenterol Res. 2019;12(1):27-36.
13. Carbone F, Goelen N, Fikree A, Aziz Q, Tack J. Impact
of joint hypermobility syndrome on gastric accommodation
and nutrient tolerance in functional dyspepsia.
Neurogastroenterol Motil. 2021;33(7):e14086.
14. Amerikanou C, Kleftaki SA, Valsamidou E, et al. Food,
Dietary Patterns, or Is Eating Behavior to Blame? Analyzing
the Nutritional Aspects of Functional Dyspepsia. Nutrients.
2023;15(6):1544.
15. Brooks RS, Grady J, Lowder TW, Blitshteyn S. Prevalence
of gastrointestinal, cardiovascular, autonomic and allergic
manifestations in hospitalized patients with Ehlers-
Danlos syndrome: a case-control study. Rheumatology.
2021;60(9):4272-4280.
16. Loganathan P, Herlihy D, Gajendran M, et al. The spectrum
of gastrointestinal functional bowel disorders in
joint hypermobility syndrome and in an academic referral
center. J Investig Med. Published online November 18,
2023:10815589231210486.
17. Olausson EA, Störsrud S, Grundin H, Isaksson M, Attvall
S, Simrén M. A Small Particle Size Diet Reduces Upper
Gastrointestinal Symptoms in Patients With Diabetic
Gastroparesis: A Randomized Controlled Trial. Am J
Gastroenterol. 2014;109(3):375-385.
18. Choudhary A, Vollebregt PF, Aziz Q, Scott SM, Fikree
A. Rectal hyposensitivity: a common pathophysiological
finding in patients with constipation and associated hypermobile
Ehlers–Danlos syndrome. Aliment Pharmacol Ther.
2022;56(5):802-813.
19. Bellini M, Tonarelli S, Barracca F, et al. Chronic
Constipation: Is a Nutritional Approach Reasonable?
Nutrients. 2021;13(10):3386.
20. Laszkowska M, Roy A, Lebwohl B, Green PHR, Sundelin
HEK, Ludvigsson JF. Nationwide population-based cohort
study of celiac disease and risk of Ehlers-Danlos syndrome
and joint hypermobility syndrome. Dig Liver Dis.
2016;48(9):1030-1034.
21. Sag E, Demir F, Sag S, Guven B, Kalyoncu M, Cakir M.
Prevalence of celiac disease in children with joint hypermobility.
Acta Reumatol Port. 2021;46(2):134-139.
22. Rubio-Tapia A, Hill ID, Semrad C, et al. American College
of Gastroenterology Guidelines Update: Diagnosis and
Management of Celiac Disease. Am J Gastroenterol.
2023;118(1):59-76.
23. Bech K, Fogh FM, Lauridsen EF, Sonnesen L.
Temporomandibular disorders, bite force and osseous
changes of the temporomandibular joints in patients with
hypermobile Ehlers-Danlos syndrome compared to a healthy
control group. J Oral Rehabil. 2022;49(9):872-883.
24. Vernino S, Bourne KM, Stiles LE, et al. Postural orthostatic
tachycardia syndrome (POTS): State of the science
and clinical care from a 2019 National Institutes of
Health Expert Consensus Meeting – Part 1. Auton Neurosci.
2021;235:102828.
25. Tu Y, Abell TL, Raj SR, Mar PL. Mechanisms and management
of gastrointestinal symptoms in postural orthostatic
tachycardia syndrome. Neurogastroenterol Motil.

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The Basics of Liver Transplantation for the Primary Care Provider and the General Gastroenterologist 

May 2024 • Volume XLVIII, Issue 5
Phoenix Fung,Michael Babich

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Liver transplant remains a well-established treatment that can drastically improve the survival and quality of life for patients with end-stage liver disease and certain hepatic malignancies. It is crucial for the primary care provider (PCP) and/or general gastroenterologist to understand the basics of liver transplantation as they play an important role in the management of patients with liver disease. Timely identification and referral to a transplant center is key. We are providing the PCP with an overview of liver transplantation indications, evaluation process, and management factors to consider prior to transplant. We want to highlight the importance of identification of potential liver transplant candidates who may benefit from early referral as well as provide information on evolving trends and advances in the liver transplant process. By raising liver transplantation knowledge, we can improve patient outcomes, facilitate timely referral, and ensure comprehensive care for patients throughout the transplantation process.

Introduction 

Despite the advances in the management of chronic liver disease, liver transplantation remains a definitive life sustaining treatment for patients with severe acute or advanced chronic liver disease despite best medical therapy. It is important for the provider to be aware of the basics of the liver transplant process as they are often the gatekeepers to help screen patients requiring referral for liver transplantation. The process of liver transplantation is often both complex and multifaceted requiring a multidisciplinary approach between multiple healthcare professionals, including the PCP. This article aims to educate providers who treat patients with liver disease with an overview of the indications for liver transplantation, the evaluation process, and the pre-transplant management of patients during the waiting list period. Learning the principles of liver transplantation and management of patients with chronic liver disease can facilitate improved outcomes of patients. In addition, this paper serves to provide basic clinical updates within the last decade on liver transplantation for practitioners who manage cirrhosis. 

Liver Transplant Statistics

The first successful human liver transplant was performed in 1963 by Dr. Thomas Starzl. Since then, over 200,000 liver transplants have been performed in the United States (US) in the past 35 years. According to the Organ Procurement and Transplantation Network (OPTN), the liver is the second most transplanted organ. Between 2019-2022, the average number of liver transplants per year in the US was between 7,000-8,000 for deceased donors and 400-500 for living donors. Despite the COVID-19 pandemic, 8,906 liver transplants were performed in the United States in 2020, which was more than in any previous year.1 The average wait time for liver transplant can range widely, from a few days to up to 5 years depending on the urgency. As of April 2023, there were approximately 10,000 patients listed for liver transplant. Liver transplant recipients had a five-year survival rate of >70%, compared to 15% for patients receiving medical therapy alone, emphasizing the life-saving impact of transplantation.2

Chronic non cholestatic liver disorders
Chronic hepatitis C
Chronic hepatitis B
Autoimmune hepatitis
Alcohol-related liver disease
Cholestatic liver disorders
Primary biliary cirrhosis
Primary sclerosing cholangitis
Biliary atresia
Alagille syndrome
Nonsyndromic paucity
  of the intrahepatic bile ducts
Cystic fibrosis
Progressive familial intrahepatic cholestasis
Metabolic disorders causing cirrhosis
Alpha-1-antitrypsin deficiency
Wilson disease
Nonalcoholic steatohepatitis
  and cryptogenic cirrhosis
Hereditary hemochromatosis
Tyrosinemia
Glycogen storage disease type IV
Neonatal hemochromatosis
Metabolic disorders causing severe
  extrahepatic morbidity
Familial amyloid polyneuropathy
Primary Hyperoxaluria
Urea cycle defects
Disorders of branched chain amino acids
Hepatocellular carcinoma
Hepatoblastoma
Fibrolamellar hepatocellular carcinoma
Hemangioendothelioma
Fulminant hepatic failure
Budd-Chiari syndrome
Metastatic neuroendocrine tumors
Polycystic disease
Retransplantation

Alcohol associated liver disease was the leading indication for transplant in 2020. Other common categories for adult liver transplantation are hepatitis C virus infection, hepatocellular carcinoma (HCC), acute liver failure, and non-alcoholic steatohepatitis (NASH) according to the 2019 OPTN.3

Research has revealed disparities in liver transplant access and outcomes based on ethnicity. A study published in the American Journal of Transplantation found that Hispanic and African American patients faced a higher risk of waitlist mortality and lower chances of receiving a liver transplant compared to Caucasian patients.4 A significant gender disparity also exists in the donor pool. In the United States, approximately 62% of deceased liver donors are male, while only 38% are female. 

Timing of Referral for Liver Transplant Evaluation

Who is a Candidate for Liver Transplantation?

Patients with severe acute or advanced chronic liver disease for which medical therapy has reached maximization should be evaluated for liver transplantation.5 The main population that the PCP should focus on referring for liver transplantation are patients with decompensated cirrhosis, cirrhotic patients with MELD (Model for End Stage Liver Disease) score ≥ 15, and patients with significant quality of life issues secondary to their end stage liver disease. Hepatic decompensation develops due to progressive portal hypertension from cirrhosis, with varying presentations, such as hepatic encephalopathy, ascites, variceal bleeding, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension. Patients who develop hepatic decompensation in the form of variceal bleeding, hepatic encephalopathy, or ascites have significantly reduced survival compared to cirrhotic patients who are well-compensated. The median survival of persons with compensated cirrhosis is 9-12 years compared to 2 years in persons with decompensated forms of liver disease. In a patient with compensated cirrhosis, the rate of decompensation is 5-7% per year.6 Providers should be screening for hepatic decompensations in a routine and systematic fashion. 

The PCP should be aware of the definition of fulminant or acute liver failure and recognize the need for expedited inpatient evaluation in a liver transplantation center. Fulminant liver failure is the rapid hepatic deterioration with development of hepatic encephalopathy and coagulopathy in patients who do not have underlying liver disease. If the adult patient has fulminant liver failure, and anticipated life expectancy of less than 7 days without liver transplant, in an intensive care unit, and acute onset of hepatic encephalopathy with one of the following criteria: (1) ventilator dependence (2) required dialysis or (3) INR >2, then the patient qualifies for Status 1A. When listed as Status 1A, the OPTN prioritizes the search for first available liver donors by expanding the criteria from regional to national. For the purposes of this paper, we would like to focus on recognition of indications for liver transplant referral for patients with chronic liver disease in the outpatient setting.

There are clinical considerations to help determine successful liver transplant candidacy. Oftentimes, the patient has to be sick enough, where transplant would increase survival odds, but not too ill where they would not be expected to survive the operation and the immediate postoperative period. Patients must be able to demonstrate the insight and willingness to comply with a complex medical regimen required post-transplantation, particularly the need to take chronic immunosuppressive medications to prevent allograft rejection and prophylactic antibiotics/antivirals to prevent infection. Patients cannot have other severe comorbid conditions that could potentially compromise the graft or patient survival. These evaluations will occur in the transplant center through a comprehensive multidisciplinary team approach. 

Understanding the Basics

Classification of Liver Disease Severity

The Child-Turcotte-Pugh Score and the MELD-3.0 scoring system help classify the liver disease severity and need for liver transplantation evaluation. The Child-Turcotte classification system was developed in 1964 to risk-stratify patients undergoing shunt surgery for portal hypertensive decompression. In 1972, Pugh modified the Child-Turcotte system, and it became known as the Child-Turcotte-Pugh (CTP) score. Components of the CTP score include the serum total bilirubin, serum albumin, INR, presence/quantity of ascites, and presence/grade of encephalopathy. CTP score has been shown to accurately predict surgical outcomes in patients with cirrhosis and portal hypertension. In addition, clinicians have widely used this tool to assess the risk of short-term mortality in cirrhotic patients. Overall, the 30-day post operative mortality following abdominal surgery of a cirrhotic patient with CTP score A is 10%, CTP score B is 30% and CTP score C is 76–82%. One year survival is 45% in CTP score C, compared to 95% and 80% in CTP score A and CTP score B, respectively.7 Patients with CTP-C scores are the sickest, and special attention should be focused on this group. 

Model of End Stage Liver Disease (MELD) Score is another prognostic scoring system which estimates the survival probability of a patient with end-stage liver disease. It is calculated using the serum bilirubin, serum creatinine, and INR. United Network for Organ Sharing (UNOS) manages the United States transplant allocation system and uses the MELD score for organ recipient priority. In 2002, the MELD score was adopted by UNOS for deceased liver organ allocation. The MELD scores range from 6 to 40, which correspond to 3-month survival odds of 90% and 7%, respectively. In January 2016, the MELD score was further modified to incorporate serum sodium to create the MELD-Na equation as hyponatremia in cirrhosis is a marker of increased liver transplant waitlist mortality.8 Further adaptations of the MELD score have been utilized to reduce wait time death of patients on the transplant list and make listing more equitable. In July 2023, the MELD 3.0 score was implemented to reduce liver transplant wait list mortality by accounting for female sex, serum albumin, and a lowered serum creatinine cut-off from 4.0 mg/dL to 3.0 mg/dL. The new scoring system addresses the disparity that females have had consistently lower transplant rates historically.9

The PCP should use prognostic score systems of CTP score and MELD-3.0 score to risk stratify cirrhotic patients. Patients with decompensated cirrhosis or MELD-3.0 ≥ 15 are recommended to be referred to a liver transplant center for evaluation due to their high risk of morbidity and mortality. 

Indications for Liver Transplant Evaluation

Liver transplantation can restore quality of life and prolong patient survival. Progressive advancements in care of liver transplant patients show favorable short and long term outcomes. Graft survival is 91.2% at 1 year, 76.5% at 5 years, and 56.4% at 10 years.10 The main indications for liver transplantation are decompensated liver disease, acute liver failure, primary unresectable hepatic malignancy, inherited metabolic liver disease, and retransplantation. Chart 1 provides an inclusive list of indications for liver transplantation. 

The Evolving Liver Transplantation Population

The most recent American Association of the Study of Liver Disease (AASLD) Guidelines has modified nomenclature to change “alcoholic” to “alcohol-associated” cirrhosis to help reduce the stigma associated with the disease faced by patients and family members.11 Alcohol-associated liver disease is the most common indication for liver transplant in the United States at present. Alcohol-associated liver disease has surpassed hepatitis C as the leading indication for liver transplant in the United States in the last several years. Since the introduction of well tolerated direct acting antivirals with substantial rates of hepatitis C eradication, there is a reduction in the need for liver transplantation and development of hepatocellular carcinoma in this subset of patients.12

Alcohol-associated liver disease and metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as non-alcoholic steatohepatitis (NASH) are projected to be the leading indications for liver transplantation in the near-future.13 Obesity and metabolic syndrome are risk factors for development of metabolic dysfunction associated liver disease (MASLD), which can progress to MASH and cirrhosis. The rate of obesity has doubled in the last 30 years worldwide, with the growth rate within the United States being one of the highest. Patients added to the transplant wait list with NASH as an indication increased by 170% between 2004 and 2013.14 It is predicted that MASH will be the leading indication for liver transplant in the U.S. over the next 10 to 20 years.15 Up to 25% of patients with MASH will progress to cirrhosis with increased risk of hepatocellular carcinoma development, therefore early diagnosis and management may curb the need for liver transplantation. Patients with MASH-induced cirrhosis can be a challenging population to manage due to comorbid conditions such as severe cardiovascular disease, which can preclude transplantability. Metabolic clinics for weight loss and early referral for bariatric surgery may be an option to help reduce MASLD-associated fibrosis but is not recommended in decompensated liver disease. Potential pharmacologic treatments for MASH are being studied. Resmetirom, an oral liver-directed thyroid hormone receptor beta–selective agonist, has been recently FDA approved for patients with stage 2-3 fibrosis secondary to MASH, which has been shown to be helpful in hepatic fibrosis regression.16

Alcohol-induced hepatitis is one of the most severe manifestations of alcohol-associated liver disease, with high morbidity and mortality. Liver transplantation may be considered as a last option for patients with alcohol-induced hepatitis when medical treatment has failed or is contraindicated. Many liver transplant centers require six months of alcohol abstinence prior to evaluation for liver transplantation. Due to the risk of significant morbidity and mortality without transplantation during that 6-month period, predictors have been studied in the US and Europe to identify a subset of patients with low risk of recidivism. Select patients with severe alcohol-induced hepatitis who fail to respond to medical therapy should be considered for liver transplant.17 The most favorable factors associated with low risk of recidivism include: alcohol induced hepatitis as initial hepatic decompensating event, good social support, insight to severity of disease, absence of severe psychiatric disorders, recent life stressor, prolonged duration of abstinence prior to transplantation, stable employment, and a covenant to adhere to life-long alcohol abstinence.18 Although there are similar favorable one and three years survival outcomes in patients transplanted for alcohol induced hepatitis compared to other indications for liver transplant, the cumulative incidence of persistent alcohol use post-transplant was 10% in the first year and 17% by the third year, with increasing alcohol use associated with increased mortality over time, based on recent studies.19 Further longitudinal studies need to be performed to elucidate the generalizability of these outcomes. 

MELD Exception Points

OPTN prioritizes organ allocation based on medical necessity using the MELD-3.0 score, with higher scores given higher priority access to the donated organs. MELD exception points are granted in certain liver diseases when the severity of the liver disease is not reflected by the calculated MELD score. Typically, the morbidity and mortality is higher in this population subset and the patient is “sicker than the MELD” score. These indications include hepatocellular carcinoma, hilar cholangiocarcinoma, primary hyperoxaluria, metabolic disorders of the urea cycle, hepatopulmonary syndrome, portopulmonary hypertension, cystic fibrosis, and familial amyloid polyneuropathy. If the patient meets specific inclusion criteria, they are OPTN waitlisted with a MELD score equivalent to the median MELD at transplant within the surrounding transplant centers minus 3 points (MMaT-3). The median MELD is calculated from within 150 nautical miles surrounding each donor hospital in the country and is applied to the exception point score for any transplant candidate receiving liver offers from that donor hospital. Patients with primary hyperoxaluria and metabolic diseases, such as urea cycle disorders or organic acidemia, meeting criteria receive MELD exception equivalent to the MMaT.20,21

Hepatocellular Carcinoma

Hepatocellular carcinoma in a cirrhotic patient is an important indication for liver transplant. A landmark trial by Mazzaferro showed a 4-year post-liver transplant survival benefit of 75% with recurrence-free survival of 83% when the liver cancer was confined to the “Milan criteria”.22  Hepatocellular carcinoma within “Milan criteria” includes one lesion ≤ 5 cm, or three lesions < 3 cm without metastasis. Hepatocellular carcinoma is diagnosed based on cross sectional CT or MRI with confirmation of tumor dimensions by a radiologist in an OPTN approved transplant center. These patients are eligible for MELD exception points if they meet criteria. HCC can be treated with locoregional therapy while awaiting transplantation. Hepatocellular carcinoma that is beyond the Milan criteria limits can be attempted to be down-staged by loco-regional treatment so as to be brought within Milan criteria, and then can be reconsidered for transplantation without sacrificing post-transplant survival.23

Cholangiocarcinoma

Cholangiocarcinoma is a bile duct cancer with increased risk of development in patients with underlying primary sclerosing cholangitis (PSC). In general, intrahepatic cholangiocarcinoma is a relative contraindication to liver transplant due to the aggressive nature of the malignancy with poor post-transplant survival. For patients undergoing curative surgical resection, there are high rates of recurrence up to 60-70%. Five-year survival for patients with resectable disease is 20-40%.24 Patients with hilar cholangiocarcinoma are likely not candidates for resection due to the anatomical location of tumor being in the area of the hepatic duct and its bifurcation. The Mayo Clinic has created a highly selective protocol using neoadjuvant chemotherapy prior to liver transplant for early stage unresectable, non-metastatic perihilar cholangiocarcinoma. The five-year survival after liver transplant is 73%, based on their protocol.25 For consideration of liver transplant for perihilar cholangiocarcinoma, UNOS requires the transplant institution to have an approved written treatment protocol, and grants MELD exception points if the patient is suitable. 

HRS – New Nomenclature

Hepatorenal syndrome (HRS) is defined as renal failure in a person with cirrhosis in the absence of intrinsic renal disease. Previous nomenclature of Type 1 HRS is now termed HRS-acute kidney injury (HRS-AKI). Patients with HRS-AKI have a rapid deterioration in renal function with very high morbidity and mortality. AKI is defined as an increase in serum creatinine ≥ 0.3 mg/dL from baseline within 48 hours or a ≥ 50% increase in serum creatinine within the last 7 days.26 After ruling out intrinsic renal disease and post-renal obstruction as a cause, and after failing to improve with 48 hours of intravascular volume repletion, this entity would be considered HRS-AKI. Patients with HRS-AKI should have an expedited referral for liver transplantation. HRS-AKI is usually reversible after liver transplantation. HRS Type 2, now termed HRS-chronic kidney disease (HRS-CKD), is a more gradual impairment in renal function that is less severe than type 1 HRS and is seen typically in patients with refractory ascites, which are resistant to diuretics. The definition of HRS-CKD requires the patient to meet HRS criteria and have eGFR < 60 ml/min per 1.73 m2 for ≥ 3 months, in absence of other structural causes. Select patients with chronic kidney disease and liver disease should be considered for combined liver-kidney transplantation. 

Contraindications for Liver Transplantation

An important concept of liver transplantation is to recognize contraindications to liver transplantation. Universal absolute contraindications include severe cardiopulmonary disease, active extrahepatic malignancy, metastatic hepatocellular carcinoma, uncontrolled sepsis, brain death, AIDS, active alcohol or illicit substance abuse, persistent noncompliance or lack of social support, and anastomotic barriers to liver transplantation.27 Many transplant centers require a minimum alcohol abstinence of 6 months with substance dependence program attendance. Literature suggests the risk of recidivism is lower in patients who complete at least 6 months of sobriety compared to those with shorter periods.28 The recommendation remains controversial, as other studies suggest the length of pre-transplantation abstinence is a relatively poor predictor of post-transplantation abstinence.29 An exception to the “six-month rule” may be considered when patients are being transplanted for alcohol-induced hepatitis in a center with a protocol for this situation. Conversely, hepatic function may improve with alcohol abstinence in patients with alcohol-induced cirrhosis to the extent a transplant is less urgent.30

Relative Contraindications

Physiologic, not chronologic, age should be considered in a patient undergoing liver transplant evaluation. There has been an increasing median age of patients being evaluated and waitlisted for transplantation. Registrants for UNOS liver transplant waitlist aged ≥ 65 years increased from 8% in 2002 to 17% in 2014.31 Post transplant survival for patients over age 65, compared to younger cohorts, was overall lower in earlier studies.32,33 More recent studies do not indicate higher rates of mortality or lower graft survival in young compared to elderly liver recipients in early transplant outcomes, however increased malignancy rates are seen in older patients.34

It is also feasible that being transplanted at an older age is associated with increased morbidity and mortality due to natural shorter life expectancy in older patients. A detailed evaluation to assess for functional and nutritional status, as well as medical comorbidities including cardiopulmonary status and malignancy, is highly recommended. In the absence of significant comorbidities, age > 70 years is not a contraindication for liver transplant.

Patients will need curative treatment for isolated primary extrahepatic malignancy with oncologic clearance prior to liver transplant. Typically, there is a waiting period to ensure absence of tumor recurrence after definitive treatment prior to transplant listing. There is heightened concern for risk of tumor recurrence for patients with prior malignancy who are on long-standing immunosuppression after transplant. The Israel Penn database is a collection of patients who developed malignancy after organ transplants. Based on the Israel Penn data, malignancies which have a low risk of recurrence are incidental renal tumors, lymphoma, testicular, cervical, and thyroid cancers. Malignancies with intermediate risk of recurrence are uterine, Wilms’ tumor, colon cancer, prostate, and breast cancer. Tumors associated with a high risk of recurrence include bladder cancer, sarcoma, melanoma, symptomatic renal cancer, and myelomas.35 A judicious individualized, multidisciplinary approach by the transplant team is used to decide on optimal candidates and timing of listing. 

Although AIDS is a contraindication for transplant, HIV patients are eligible for transplantation in the presence of adequate immune function with CD4 >100/µL with undetectable viral load at the time of liver transplant. Co-management with an infectious disease specialist is recommended.5

Class III obesity (body mass index (BMI) ≥ 40) is a relative transplant contraindication. It is associated with coronary artery disease, hyperlipidemia, diabetes mellitus, renal dysfunction, and obstructive sleep apnea.5 Obesity increases the risk of perioperative complications and length of post-operative hospital stay and reduces long term survival. Primary graft non function, immediate, 1-year, and 2-year mortality were significantly higher in the morbidly obese group. Five-year mortality was significantly higher both in the severely and morbidly obese subjects, mostly due to cardiovascular events.36 Weight loss is recommended prior to transplant in patients with class III obesity. While patients with severe obesity and/or metabolic-associated fatty liver disease can be considered for bariatric surgery, this is contraindicated in decompensated liver disease due to risk of worsening hepatic dysfunction with surgery. Studies investigating the performance of gastric sleeve placement simultaneously with liver transplant, to assist with weight management, demonstrate safety and may be helpful in long term total body weight loss.37

Patients with severe ascites can be seen as “overweight”, but this should not be confused for obesity as oftentimes that patient has co-existing anasarca and sarcopenia.  The presence of ascites is associated with an increased risk of postoperative morbidity and mortality post-transplant. A study performed by Leonard et al. showed that correction of BMI for ascites volume placed 11-20% of the studied patients who received a liver transplant into a lower BMI classification. It was calculated that each liter of ascites removed during the transplant was associated with a 7% increased relative risk of mortality.38 Special care should be utilized to prevent further malnutrition, as patients with ascites will still require high protein diets as cirrhosis is a catabolic state. 

Underweight patients also pose a concern, as patients at both extremes of BMI have significantly higher wait list mortality and worse liver transplant outcomes as compared with those with normal BMI (18.5 to <25). Underweight patients (BMI < 18.5) have higher risk of hemorrhagic complications and cerebrovascular events. Overweight patients (BMI > 40) have a higher risk of infectious complications and cancer events. Given this disparity, innovative means are required to target high risk groups.39 A comprehensive nutrition assessment and dietary management should be utilized in patients who are at extremes of BMI to help minimize complications. 

Understanding the General
Liver Transplant Evaluation Process 

Patients should be referred to a liver transplant center if there is decompensated liver disease or MELD-3.0  ≥ 15. The PCP should be familiar with their local transplant centers. Oftentimes, there will be local outreach clinics if the nearest center is distant. The patient should understand that a referral does not mean they will be automatically listed for a liver transplant. Generally, the multidisciplinary transplant team consists of the transplant hepatologist and surgeon, nurse coordinator, financial coordinator, social worker, psychiatrist, dietician, physical therapist, anesthesiologist, and pharmacist, all of whom will interact with the patient. During the initial evaluation, the transplant process will be discussed with the patient, and individual evaluations performed. The patient’s motivation and insight to comply with medication therapy and long term follow up, social support, functional and nutritional status, and substance abstinence duration are assessed. The hepatologist ensures medical management has been maximized and appropriate treatments are up to date. The transplant surgeon evaluates surgical contraindications for liver transplant, as well as suitability for living donor evaluation if applicable.  Standard blood tests, including blood type, screening for liver disease, and determining the infection status of HBV, HCV, EBV, CMV, VZV, RPR, and HIV are performed. Status of tuberculosis exposure is typically performed with interferon-gamma release assay (i.e., Quantiferon gold) or tuberculin skin testing. Cardiopulmonary testing may include echocardiogram, cardiac stress test, heart catheterization as needed, and pulmonary function testing. These are used to screen for significant valvular disease, heart failure, coronary artery disease, significant respiratory diseases, hepatopulmonary syndrome, and portopulmonary hypertension. Testing is based on individualized risk. Cross sectional abdominal imaging with CT or MRI are performed to rule out intra- and extra-hepatic malignancy, especially hepatocellular carcinoma, and anatomic contraindications. Standard preventative care measurements such as age- and indication-appropriate malignancy screening with mammogram, colonoscopy, low dose contrast CT chest, and pap smear are reviewed. Screening for osteoporosis with DEXA scan and vitamin D levels are incorporated into the process. Dental exam should be completed to assess for necessary extractions prior to transplant. After an extensive evaluation is completed and the patient/family comprehends the aspects of the transplant process, the multidisciplinary team discusses whether the patient should be waitlisted for organ transplant. 

Understanding Liver Donation

Deceased Donor vs. Living Donor 

Transplanted livers may be received from a living or a deceased donor. Almost 20% of patients on the US waiting list die or become too sick for the transplant. Deceased liver donation remains the primary source of organs for liver transplantation. However, the scarcity of deceased donor organs has led to the utilization of living donors to expand the donor pool to provide timely transplants for recipients. Deceased liver donors are typically individuals who have experienced irreversible brain damage or cardiac arrest and are declared legally brain dead. These donors are often individuals who have registered as organ donors or have consented to donation through their families. The process involves meticulous matching of the donor liver with a suitable recipient based on factors such as blood type, body size, and urgency of need. Organs from deceased donors are carefully preserved and transported to the recipient’s transplant center. 

Living donor liver transplantation (LDLT) occurs when an individual readily volunteers to donate a portion of their liver to someone in need. This is possible because of the liver’s incredible ability to regenerate. Candidates being considered for living donor transplantation will need to meet evaluation criteria set forth by the transplant center. The decision to accept a liver donor is determined by a multidisciplinary team in a transplant center.

Along with the assignment of an Independent Living Donor Advocate (ILDA) by the recovery hospital, the evaluation and selection of an adult liver donor involves a comprehensive assessment of their medical and psychosocial health status to determine eligibility. The ILDA, either an individual or a team, must be qualified and understand the full transplant protocol of the recovery hospital, function independently of the recipient’s team, advocate for the donor, and ensure that the donor has received all information required to make an informed decision. The living donor must undergo psychosocial testing with a team of psychiatrists and psychologists prior to organ recovery to ensure that there are no detrimental psychosocial issues (including high risk behaviors, mental health issues, substance use disorders, etc.) that precludes organ donation or would affect long term recovery. This team also must determine that the donor is free of coercion, can make informed decisions, and understands the long and short term psychological and medical risks.40 Advantages of living donor liver transplantation (LDLT) include reduced wait time for the recipient, use of a graft with minimal ischemic time, and sufficient time to plan for an elective surgery. The evaluation process is otherwise similar to deceased donor.41

Surgical techniques for living donor liver transplantation involve the partial resection of the donor’s liver, either the right or left lobe, which can regenerate to near-normal size and function in both the donor and recipient within a few months. With regards to outcomes, graft failure occurs in 5.9% (6 months), 7.9% (1 year), 14.7% (3 year), 20.7% (5 year), and 40.6% (10 year) of deceased donor recipients. There is a slightly lower graft failure rate for living donor recipients: 4.9% (6 months), 7.4% (1 year), 12.2% (3 year), 23.7% (5 year), and 36.7% (10 year). It is notable that overall recipient mortality has continued to improve over the last decade.42

Given the current allocation policies in the United States, patients with MELD scores <15 on the waiting list rarely receive a liver in a timely fashion. Patients with low MELD scores must rely on either living donors or expanded-criteria deceased donors if they are to receive a transplant. In the landmark Adult-to-Adult Living Donor Liver Transplantation Cohort (A2ALL) study, the survival benefit of an LDLT was demonstrated at MELD-Na scores less than 15.43

An ideal patient for LDLT would be one with a low MELD score but decreased quality of life due to underlying end stage liver disease. Life altering manifestations from end stage liver disease, such as refractory hepatic encephalopathy, ascites/hepatic hydrothorax, sexual dysfunction, sarcopenia, and pruritus can occur, and are not reflected in the MELD 3.0 score. A study performed in the United States by Jackson et al. showed significant survival benefit of LDLT in patients with end-stage liver disease, even at MELD-Na scores as low as 11. For patients with low MELD scores and significant quality of life issues from liver disease, LDLT is a good alternative to waiting for a deceased donor as it will significantly increase survival compared with remaining on the waitlist.44

Although the number of living donor transplants performed annually has increased slowly over the years, it still accounts for only about 5% of liver transplants in the United States.45 Of the 8,906 liver transplants performed in the US in 2020, 7,979 (89%) patients received organs from a deceased donor and 425 (11%) from a living donor.46

Medical Management of Patients
Awaiting Liver Transplantation 

The matching of a donor and recipient is prioritized based on recipient MELD score per UNOS and compatible ABO blood type. As such, the waitlist time for liver transplant is variable. For patients with low MELD scores, waitlist time can be years, between listing and getting called for their transplant. It is therefore essential to continue management of the cirrhotic patient during this time period to help reverse or delay the need for transplant. The management of the cirrhotic patient can be complex. It is recommended to communicate with the transplant team for major medical decisions, however “day to day” management of portal hypertension, HCC surveillance, counseling on substance dependence and tobacco cessation, weight loss counseling for obese patients, screening for malnutrition and monitoring of functional status, vaccination for Hepatitis A and B, and preventative measures such as ensuring PAP smear, mammogram, colonoscopy and DEXA scan are up to date can be performed by the PCP. Early referral for liver transplant is recommended for patients with alcohol-related liver disease to facilitate prompt treatment for substance addiction. 

PCPs should recognize that non-transplant peri-operative risk is substantially increased in patients with decompensated cirrhosis, especially CTP class C. PCPs should consult with the transplant hepatologist/transplant team prior to any, particularly abdominal, surgery to weigh the risks and benefits, as surgery can increase morbidity and mortality. In addition, patients should be counseled on eating a high protein diet to counteract sarcopenia and development of hepatic encephalopathy. Typically, the recommended protein intake is 1.2 to 1.5 g/kg per day, based on ideal body weight, with protein included with each meal and snack. A protein-based bedtime snack can reduce the incidence of sarcopenia.47

Summary

In conclusion, it cannot be overstated that liver transplantation is a life-saving procedure for patients with acute or chronic end-stage liver disease. The evaluation process involves a comprehensive assessment of a patient’s medical history, comorbidities, and psychosocial factors that play a key role in identification of suitable candidates for this life saving procedure. The decision to undergo liver transplantation is complex and requires a collaborative approach involving multiple healthcare professionals. As a PCP, the understanding of key aspects of the evaluation process is crucial for recognizing patients who may benefit from liver transplantation and ensuring their timely referral to transplant centers. Candidates for liver transplant referral include, but are not limited to, patients with acute liver failure, decompensated liver disease, primary unresectable hepatic malignancy, inherited metabolic liver disease, and MELD score ≥ 15. The role of the primary care provider does not end with timely referral to transplant centers, but also involves being knowledgeable about pre-transplant management, including optimizing patient health, managing complications, and providing appropriate long term follow up. PCPs can make a significant difference in improving patient quality of life and long-term survival rates by actively participating in the care of patients with chronic liver disease. By collaborating closely with transplant teams and staying updated on the indications, evaluation criteria, and potential contraindications, PCPs can enhance patient outcomes and contribute to the overall success of liver transplantation. 

References

References

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Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838–51. 

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D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217-31. 

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Londono MC, Cardenas A, Guevara M, et al. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007;56(9):1283-90. 

Kim WR, Mannalithara A, Heimbach JK, et al. MELD 3.0: The model for end-stage liver disease updated for the modern era. Gastroenterology. 2021;161(6):1887-1895.e4. 

Kwong A, Kim WR, Lake JR, et al. OPTN/SRTR 2018 annual data report: liver. Am J Transplant 2020;20(Suppl s1): 193-299.

Crabb DW, Im GY, Szabo G, et al. Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance from the AASLD. Hepatology. 2020;71(1):306-33.

Belli LS, Perricone G. Adam R, et al. Impact of DAAs on liver transplantation: Major effects on the evolution of indications and results. An ELITA study based on the ELTR registry. J Hepatol. 2018;69(4):810-17. 

Fleming JA, Kim WR, Brosgart CL, Terrault N. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology 2017;65(3):804-12. 

Wong R, Aquilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547-55. 

Charlton M, Burns J, Pedersen R, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011; 141: 1249-1253. 

Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509. 

Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011;365:1790–1800. 

Im GY, Kim-Schluger L, Shenoy A, et al. Early Liver Transplantation for Severe Alcoholic Hepatitis in the United States–A Single-Center Experience. Am J Transplant. 2016;16:841–849. 

Lee BP, Mehta N, Platt L, et al. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis. Gastroenterology. 2018;155(2):422-30.e1. 

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OPTN. Accessed October 8, 2023. https://optn.transplant.hrsa.gov/media/amdkjmg0/1379-faq-mmat-at-donor-hospital-sorting-changes

Mazzaferro V, Regalia E, Doci R, Andreola S, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular in patients with cirrhosis. N Engl J Med. 1996; 334:693-699. 

Yao F, Ferrell L, Bass N, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33(6):1394-403. 

Bekki Y, Ahrens D, Takahashi H, Schwartz M, Gunasekaran G. Recurrent Intrahepatic Cholangiocarcinoma- Review. Front Oncol. 2021; 11:776863.

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Mahmud N. Selection for Liver Transplantation: Indications and Evaluation. Current Hepatology Reports. 2020;19:203-212.

Osorio R, Ascher N, Avery M, et al. Predicting recidivism after orthotopic liver transplantation for alcoholic liver disease. Hepatology. 1994;20:105–10. 

Foster P, Fabrega F, Karademir S, et al. Prediction of abstinence from ethanol in alcoholic recipients following liver transplantation. Hepatology. 1997;25(6):1469-77. 

Veldt B, Lainé F, Guillygomarc’h A, et al. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol. 2002;36:93–98. 

Su F, Yu L, Berry K, et al. Aging of liver transplant registrants and recipients: trends and impact on waitlist outcomes, post-transplantation outcomes, and transplant-related survival benefit. Gastroenterology. 2016;150(441–53):e6. 

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Schwartz J, Pappas L, Thiesset H, et al. Liver transplantation in septuagenarians receiving model for end-stage liver disease exception points for hepatocellular carcinoma: The national experience. Liver Transpl. 2012;18:423–433. 

Dolnikov S, Adam R, Cherqui D, Allard M. Liver transplantation in elderly patients: what do we know at the beginning of 2020? Surg Today. 2020;50(6):533-539. 

Witherow BA, Roth GS, Carrozza MA, et al. The Israel Penn International Transplant Tumor Registry. AMIA Annu Symp Proc. 2003:1053. 

Nair S, Verma S, Thuluvath P. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105-9. 

Zamora-Vales D, Watt K, Kellogg T, et al. Long-term outcomes of patients undergoing simultaneous liver transplantation and sleeve gastrectomy. Hepatology. 2018;68(2):485-95. 

Leonard J, Heimbach JK, Malinchoc M, Watt K, Charlton M. The impact of obesity on long-term outcomes in liver transplant recipients—results of the NIDDK liver transplant database. Am J Transplant. 2008;8:667-72. 

Dick AA, Spitzer AL, Seifert CF, et al. Liver transplantation at the extremes of the body mass index. Liver Transpl. 2009;15(8):968–77. 

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Berg CL, Merion RM, Shearon TH, et al. Liver transplant recipient survival benefit with living donation in the model for end stage liver disease allocation era. Hepatology. 2011;54(4):1313-21. 

Jackson WE, Malamon JS, Kaplan B, et al. Survival Benefit of Living-Donor Liver Transplant. JAMA Surg. 2022;157(10):926–932. 

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Endoscopic Therapy for Refractory Benign Esophageal Strictures

May 2024 • Volume XLVIII, Issue 5
Douglas G. Adler,Zheyuan Jenny Wang

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The management of refractory benign esophageal strictures (RBES) presents a formidable clinical challenge, necessitating frequent interventions to ameliorate symptoms and enhance the quality of life for affected individuals. Among the array of available endoscopic therapeutic modalities for RBES, esophageal dilation stands out as the primary treatment approach, with both balloon dilators and bougies demonstrating high rates of technical success and satisfactory clinical resolution. Despite its efficacy, approximately 30-40% of strictures recur following dilation, prompting exploration into adjunctive therapies such as steroid injections, incisional therapy, stent placement, and the application of mitomycin C. Triamcinolone injections have emerged as an option, reducing stricture recurrence rates and improving dysphagia scores, particularly in refractory anastomotic strictures. However, the literature reports conflicting findings regarding their efficacy, underscoring the need for further investigation. Similarly, stent placement, including the use of self-expanding metal stents (SEMS) and lumen-apposing metal stents (LAMS), offers viable alternatives, albeit with concerns regarding migration rates and adverse events. Furthermore, self-dilation, while rarely employed, presents a patient-centered approach that can be both safe and effective when appropriately implemented. Despite these advancements, several knowledge gaps persist, necessitating further research to refine treatment strategies, optimize clinical outcomes, and enhance the overall management of RBES. This literature review aims to synthesize existing evidence, identify areas of agreement and disagreement, and delineate avenues for future investigation to address these critical gaps in understanding and practice.

Dilation

Esophageal dilation remains the primary treatment for RBES as patients with RBES often require multiple dilations.,,  Most strictures are successfully treated with endoscopic dilation, however approximately 30-40% recur. There are several methods of performing esophageal dilation. These vary by the type of dilator used and the way it is passed through the esophagus to the level of the stricture itself. Generally, dilation can be categorized as either balloon or mechanical (bougie-type). Balloon dilators can be passed through-the-scope (TTS) or over a guidewire. Placement can be verified by direct visualization via endoscopy, and/or via fluoroscopy.1,4 TTS balloons come in a variety of sizes and are in widespread use. (Figure 1) The most common type of bougies in current use are Savary-Gilliard (SG) or Maloney dilators. Modern bougies, made of polyvinyl chloride, are generally passed over a wire, frequently with additional fluoroscopic guidance, across a stricture where they exert radial and longitudinal pressure on the stricture. It should be noted that using balloon dilation is technically easier, but the cost is higher as balloons are one time use devices. SG and Maloney dilators are not disposable and can be used repeatedly and are more cost effective over time.4 There is no statistical difference between the balloon dilation and SG dilators in terms of clinical resolution of esophageal strictures., Repeated dilation treatment by balloons and bougies was found to have an overall clinical success rate of 70.9% in a 2019 retrospective analysis.7 Another study found successful dilation, defined as the ability to expand the esophageal lumen to accommodate a 42F (14 mm wide) catheter, was attained in 93.5% of patients undergoing endoscopic dilation.10

Among the adverse events associated with dilation for benign esophageal strictures are perforation, bleeding, bacteremia, and (rarely) esophageal fistula. The perforation rate has been reported between 0.1 – 0.4%, which no clear evidence of different perforation rates for mechanical versus balloon dilators.1 Significant bleeding and bacteremia are rare adverse events. Furthermore, data suggests no significant difference in adverse event rates between the use of balloon dilators and other methods, underscoring the safety and efficacy of both approaches in clinical practice.8 Numerous individuals encounter challenges with traditional interventions such as balloons and bougies in managing refractory strictures, necessitating the exploration of additional and alternative therapeutic modalities.

Steroid Injection

Triamcinolone, a long-acting and semi-viscous corticosteroid agent, has been utilized as an adjunctive therapy to enhance the efficacy of dilation in the treatment of refractory strictures, or as standalone therapy. Most investigators utilize triamcinolone acetate or acetonide at concentrations of 10 mg/mL, although higher concentrations of 40 mg/mL have also been employed. The volume of injection has varied across studies, ranging from 0.5 mL to 2.8 mL. Additionally, betamethasone and dexamethasone preparations have been utilized, with no discernible differences in outcomes reported among different steroid formulations. 

Triamcinolone injections are indicated for refractory strictures where conventional dilation techniques have proven ineffective. The precise mechanism of action of triamcinolone in stricture management remains unclear. However, studies suggest that corticosteroids decrease the fibrotic healing that appears to occur after dilation.9 Triamcinolone injections have shown potential results in reducing stricture recurrence rates and improving dysphagia scores, particularly in patients with refractory anastomotic strictures.9, Meta-analysis has not demonstrated consistent improvement in dysphagia scores among patients receiving steroid injections, but the interpretation of these findings is limited due to the high heterogeneity of the data. Studies have reported a significant decrease in the Periodic Dilation Index (PDI), which is defined as the number of dilations required/duration of time in months, among patients receiving intralesional steroid injections alongside dilation therapy.11 Triamcinolone may prove beneficial in managing RBES, potentially reducing the frequency of necessary dilations. There is currently no standardized protocol for the number of triamcinolone injection sessions. The optimal dosing regimen and injection technique may vary based on the specific characteristics of the stricture and individual patient factors.9 The literature presents conflicting results regarding the efficacy of triamcinolone injection in the management of patients with RBES. Pereira-Lima et al. reported a significant increase in the number of dysphagia-free patients after 6 months and an improvement in dysphagia scores in a double-blind randomized study consisting of 19 patients. In contrast, the double-blind study of 60 patients conducted by Hirdes et al. failed to replicate these results. 

While endoscopic triamcinolone injections are generally well-tolerated, adverse events may include intramural infection, yeast esophagitis, and perforation. Due to the low number of adverse events, statistical analysis was not possible in a 2018 meta-analysis that analyzed the effect of intralesional steroid injections in addition to endoscopic dilation of benign refractory esophageal strictures.11 

Incisional Therapy

Incisional therapy represents an additional option for patients with RBES. This therapeutic approach entails the use of electrocautery or mechanical devices to directly incise or cauterize the fibrotic stricture itself. The fundamental principle underlying this modality mirrors that of dilation, involving the disruption or displacement of circumferential fibrotic tissue and collagen fibers to facilitate the restoration of a satisfactory lumen diameter and prevent reformation of scar tissue. 

Needle knife incision is the most commonly employed technique. This technique employs a needle-knife catheter, widely used for ERCP, to perform electrosurgical incisions in a radial manner around the stricture. (Figure 2) The determination of the length and quantity of incisions is tailored to each specific stricture. Typically, an average of 4-12 radial incisions is required for ideal treatment.13 Optimal outcomes are typically observed with short-segment strictures measuring less than 1 cm such as Schatzki rings or anastomotic strictures. With long segment strictures, complete removal of the stricture rim may not always be feasible. In a prospective outcome study, 87.5% of patients had neither subjective dysphagia nor endoscopic recurrence at a 24 month follow up after incisional therapy.

Potential adverse events associated with incisional therapy include pain, bleeding, and perforation. The perforation or hemorrhage rate associated with balloon or bougie dilation ranges from 0.1% to 0.4%,1 while the perforation rate with endoscopic incision therapy falls within the range of 0% to 3.5%, with no reported evidence of significant bleeding.13

Stents

Self-Expanding Metal Stents

Endoscopic stent placement has emerged as mainstay of treatment for managing RBES. It is widely recognized as a safe procedure and is frequently used as a first-line therapy option. Stents commonly employed in therapy include partially covered self-expanding metal stents (PCSEMS), fully covered self-expanding mental stents (FCSEMS), LAMS, and biodegradable stents (where they are commercially available). Stents are deployed under endoscopic and/or fluoroscopic guidance, depending on the patient and the type of stent used, with placement confirmation via endoscopy. Alternatively, direct visualization can guide stent placement without fluoroscopic assistance.

SEMS were introduced into clinical practice approximately three decades ago. PCSEMS and FCSEMS have both been evaluated for treatment of RBES. Presently, temporary placement of SEMS is commonplace in the management of RBES. (Figure 3) It has been recommended by one study that FCSEMS should be left in place for up to 12 weeks to minimize the risk of hyperplastic tissue and stent embedment, but in practice many patients require longer stent indwell times and treatment should be individualized. Both PCSEMS and FCSEMS were found to have a high technical success rate and short-term clinical efficacy. There was no statistical difference between PCSEMS and FCSEMS. Adverse events linked to PCSEMS encompass stent migration and tissue ingrowth. Conversely, FCSEMS primarily presents stent migration as the main adverse event. Stent migration persists as a significant concern and represents a primary factor prompting re-intervention with SEMS. 

Migration rates were observed to be 17.6% for PCSEMS post-placement and 17.4% for FCSEMS, as reported in a 2015 retrospective case review.18 A different 2016 multicenter study reported stent migration in 44.4% of patients with SEMS. Additionally, a literature review published in 2017 documented stent migration in 11.9% of patients treated with SEMS, while 20.3% experienced tissue in-growth or overgrowth. Another multicenter study conducted in 2016 reported a notable stent migration rate of 44.4% among patients receiving SEMS.  It should be stressed that stent migration is not always an adverse event per se. If the stricture responds to stenting, and the lumen opens up appropriately, there may no longer be a stenosis there to help anchor the stent in place. 

Biodegradable stents have emerged as a potential solution to address adverse events associated with SEMS and self-expandable polymer stents (SEPS), although these devices are not currently available in the United States. Two main types of biodegradable stents have been developed: knitted poly-L-lactic acid monofilaments, although no longer available, and the SX-ELLA BDS composed of semicrystalline biodegradable polymer known as polydioxanone. These stents offer constant radial force over a period of 4-5 weeks, allowing sufficient time for treating underlying esophageal diseases, while their progressive hydrolysis-mediated self-degradation prevents tissue overgrowth.22 Notably, their complete dissolution within 11-12 weeks obviates the need for endoscopic removal. Adverse events such as bleeding and chest pain have been reported. It is worth noting that BDS are associated with a higher incidence of major adverse events (28.6%) compared to FCSEMS and SEPS (10.6% and 14.3% respectively).22 Further prospective randomized trials are warranted to compare the clinical effectiveness of BDSs with FCSEMS. These trials should aim to determine the optimal duration of stent placement, evaluate the value of repeat stenting over extended periods, and assess the cost-effectiveness alongside patient satisfaction. A 2012 prospective multicenter study comparing FCSEMS, SEPS, and BDS revealed no significant differences in the clinical success of all three stent types. However, BDSs and FCSEMS demonstrated superiority over SEPS in several variables, including the dysphagia-free period, long-term improvement, and the number of reinterventions required.16 It should be noted that SEPS are no longer in clinical use. 

Lumen-apposing metal stents (LAMS)

LAMS were initially designed for the management of pancreatic fluid collections, chosen for their anti-migratory property attributed to their saddle-shaped design. Over time, their clinical applications have expanded greatly beyond their initial indications, owing to several benefits such as offering multiple different diameters, short stent lengths, and facilitating simple stepwise deployment, which enhances technical success. These devices can be used effectively to treat short-segment RBES. (Figure 4) Comparative effectiveness studies have demonstrated that LAMS procedures are both feasible and safe, yielding good clinical outcomes. Technical and clinical success rates have been reported at 98.6% and 79.7%, respectively.23 Notably, the migration rate with LAMS stands at 10.6%, significantly lower than that observed with SEMS.24 Moreover, LAMS have exhibited superior clinical outcomes compared to FCSEMS and BDS. However, adverse events associated with LAMS include perforation, discomfort prompting early removal, stent migration, bleeding, and stricture reformation. 

In a 2020 multicenter study comparing 15 mm and 20 mm stents, stent migration (15.6%) was the most common adverse event with 15 mm LAMS, but pain (14.3%) was the most common adverse event with 20 mm LAMS. Moving forward, future research endeavors aim to provide more extensive data on long-term outcomes and explore the utility of LAMS in managing refractory strictures, thereby guiding device refinement, and enhancing clinical practice.

Mitomycin C

Mitomycin C, a chemotherapeutic agent primarily employed in the treatment of malignancies such as esophageal, anal, breast, and bladder cancer, possesses pharmacological properties that make it a potential candidate for scar modulation.3 In the context of esophageal strictures, mitomycin C is administered either topically at the site of the stricture or injected directly into the stricture following dilation. The typical dosing regimen involves diluting 0.4 mg/mL of mitomycin C in 1 mL of saline, which is then divided into aliquots of 0.5 mL each. These aliquots are injected into the four quadrants of the narrowest part of the stricture.3 Despite its potential benefits, the administration of mitomycin C is not without risks, as adverse events such as intense pain, necrosis, and ulceration have been reported. However, while no longer widely practiced, there is published literature reporting the use of this agent in patients with corrosive esophageal strictures refractory to repeated endoscopic dilation.

Self-Dilation

Self-dilation represents a patient-centered approach to the management of strictures, aiming to empower patients with the ability to actively participate in their own care. Self-dilation is offered to patients with esophageal strictures refractory to other treatments such as endoscopic dilation, incisional therapy, or stent placement.28 Techniques for safe and effective self-dilation typically involve educating patients either in the clinic or during their hospital stay, if admitted, within 48 hours following endoscopic dilation. Patients are instructed to begin self-dilation with a Maloney dilator that is either the same size or one size smaller than the dilator used during their typical endoscopic dilation procedure. Patient selection criteria include those with recurrent strictures after dilation, many of which are proximal, and individuals who have failed previous treatments such as Savary or balloon dilation, or those who have undergone dilation combined with intralesional steroid injections or incisional therapy., Despite the potential benefits, patients may exhibit reluctance to engage in self-dilation due to concerns regarding pain or perforation. Nevertheless, self-dilation offers a safe, effective, and cost-efficient treatment option for appropriately selected patients with refractory strictures. In a 2013 small retrospective study, esophageal self-dilation was successful in treatment of 90% of patients. Another 2018 retrospective study showed comparable results, with a technical success rate of 94% and median number of endoscopic dilation procedures dropping from 17 over a median period of 9 months to 1.5 procedures after initiation of self-dilation. Further research is needed to refine patient selection criteria and optimize the implementation of self-dilation protocols in clinical practice.

Conclusion

The management of RBES continues to pose a significant clinical challenge, often requiring repeated interventions to alleviate symptoms and improve quality of life for affected individuals. The array of endoscopic therapeutic modalities available for RBES includes dilation, steroid injections, incisional therapy, stent placement, and the use of mitomycin C. While each approach offers distinct advantages and potential drawbacks, several key agreements and disagreements have emerged from the existing body of literature. Endoscopic dilation, whether performed with balloon dilators or bougies, remains the primary treatment modality for RBES, demonstrating high rates of technical success and an acceptable rate of clinical resolution. Triamcinolone injections have shown promise in reducing stricture recurrence rates and improving dysphagia scores, particularly in refractory anastomotic strictures. However, conflicting findings regarding the efficacy of triamcinolone injection underscore the need for further research to elucidate its true effectiveness. Discrepancies in reported stent migration rates highlight the necessity for standardized protocols and further investigation into optimal stent selection and placement techniques. Self-dilation is rarely undertaken although when appropriately implemented this approach offers a safe, effective, and cost-efficient treatment option for selected patients with refractory strictures. Overall, while significant progress has been made in the endoscopic management of RBES, several knowledge gaps persist, warranting additional research to refine treatment strategies and optimize clinical outcomes in this challenging patient population. 

References

References

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. Lee TH, Lee SH, Park JY, Lee CK, Chung IK, Kim HS, Park SH, Kim SJ, Hong SJ, Lee MS. Primary incisional therapy with a modified method for patients with benign anastomotic esophageal stricture. Gastrointest Endosc. 2009 May;69(6):1029-33. doi: 10.1016/j.gie.2008.07.018. Epub 2009 Feb 11. PMID: 19215919.
. Canena JM, Liberato MJ, Rio-Tinto RA, Pinto-Marques PM, Romão CM, Coutinho AV, Neves BA, Santos-Silva MF. A comparison of the temporary placement of 3 different self-expanding stents for the treatment of refractory benign esophageal strictures: a prospective multicentre study. BMC Gastroenterol. 2012 Jun 12;12:70. doi: 10.1186/1471-230X-12-70. PMID: 22691296; PMCID: PMC3447662.
. Boregowda U, Goyal H, Mann R, Gajendran M, Patel S, Echavarria J, Sayana H, Saligram S. Endoscopic management of benign recalcitrant esophageal strictures. Ann Gastroenterol. 2021;34(3):287-299. doi: 10.20524/aog.2021.0585. Epub 2021 Jan 27. PMID: 33948052; PMCID: PMC8079876.
. Gangloff A, Lecleire S, Di Fiore A, Huet E, Iwanicki-Caron I, Antonietti M, Michel P. Fully versus partially covered self-expandable metal stents in benign esophageal strictures. Dis Esophagus. 2015 Oct;28(7):678-83. doi: 10.1111/dote.12260. Epub 2014 Aug 29. PMID: 25168061.
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. Suzuki T, Siddiqui A, Taylor LJ, Cox K, Hasan RA, Laique SN, Mathew A, Wrobel P, Adler DG. Clinical Outcomes, Efficacy, and Adverse Events in Patients Undergoing Esophageal Stent Placement for Benign Indications: A Large Multicenter Study. J Clin Gastroenterol. 2016 May-Jun;50(5):373-8. doi: 10.1097/MCG.0000000000000500. PMID: 26905604.
. Repici A, Vleggaar FP, Hassan C, van Boeckel PG, Romeo F, Pagano N, Malesci A, Siersema PD. Efficacy and safety of biodegradable stents for refractory benign esophageal strictures: the BEST (Biodegradable Esophageal Stent) study. Gastrointest Endosc. 2010 Nov;72(5):927-34. doi: 10.1016/j.gie.2010.07.031. PMID: 21034894.
. Gkolfakis P, Siersema PD, Tziatzios G, Triantafyllou K, Papanikolaou IS. Biodegradable esophageal stents for the treatment of refractory benign esophageal strictures. Ann Gastroenterol. 2020 Jul-Aug;33(4):330-337. doi: 10.20524/aog.2020.0482. Epub 2020 Apr 13. PMID: 32624652; PMCID: PMC7315705.
. Jain D, Patel U, Ali S, Sharma A, Shah M, Singhal S. Efficacy and safety of lumen-apposing metal stent for benign gastrointestinal stricture. Ann Gastroenterol. 2018 Jul-Aug;31(4):425-438. doi: 10.20524/aog.2018.0272. Epub 2018 May 7. PMID: 29991887; PMCID: PMC6033762.
. Giri S, Vaidya A, Kale A, Jearth V, Sundaram S. Efficacy of lumen-apposing metal stents for the management of benign gastrointestinal stricture: a systematic review and meta-analysis. Ann Gastroenterol. 2023 Sep-Oct;36(5):524-532. doi: 10.20524/aog.2023.0819. Epub 2023 Jul 3. PMID: 37664226; PMCID: PMC10433256.
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Kiwifruit in the Clinic: Nutritional Insights and Evidence-based Applications for Constipation

April 2024 • Volume XLVIII, Issue 4
Jason Nasser,Barbara Hollander,Bianca W. Chang

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Chronic constipation is a common presenting concern in primary care and gastroenterology clinics. Multiple factors can contribute to constipation, including dietary habits, physical activity, dehydration, medication side effects, systemic diseases, and pelvic floor dysfunction. While many new medications have been developed, patients are often interested in conservative and natural remedies to medical illnesses. Rich in fiber and protease enzymes, in addition to a plethora of micronutrients, kiwifruits hold a unique ability to retain water and bulk feces. By virtue of unique proteolytic enzymes, they can further aid in digestion and promote food transit. Recent studies underscore the efficacy of consuming two kiwifruits daily in addressing functional constipation and constipation-predominant irritable bowel syndrome symptoms through alleviating constipation as well as abdominal pain, bloating, and dyspepsia. This article will review the evidence in support of kiwifruit use for constipation management as well as provide suggestions for sustainable incorporation into the diet.

Introduction

Chronic constipation is a common gastrointestinal disorder, affecting 8-12% of adults in the U.S.; its prevalence increases with age and is twice as common among women.1 In clinical practice, constipation is most simplistically and pragmatically defined as unsatisfactory defecation in the setting of reduced stool frequency, hardened stool consistency, and/or difficulty with stool evacuation. Patients can further report straining, prolonged time spent on the toilet, a sensation of incomplete emptying, or the requirement of manual maneuvers to remove stool. It is often associated with other gastrointestinal symptoms, including abdominal discomfort, pain, bloating, and distention. When such symptoms persist for more than a month, constipation is considered chronic. Kiwifruit offers patients a natural alternative in the management of constipation, abdominal pain, and dyspepsia with randomized controlled trials supporting its efficacy. 

Why does chronic constipation happen?

The pathophysiology of constipation is multifactorial, and it is paramount to evaluate for identifiable causes and risk factors. While some risk factors are unmodifiable, such as older age and female sex, many risk factors can be reversed, including low dietary fiber intake, dehydration, physical inactivity, and medication adverse effects.

A common etiology of constipation that is often associated with a delay in diagnosis is the spectrum of evacuation disorders. These include structural disorders that create a mechanical obstruction, such as enteroceles, rectoceles or rectal intussusception, and those associated with the dissipation of the defecatory force, such as in descending perineum syndrome and rectal prolapse. Functional evacuation disorders, namely dyssynergic defecation, may manifest as paradoxical involuntary contraction or non-relaxation of the anal sphincter and puborectalis muscle during defection and/or inadequate abdomino-rectal propulsive force generation. Given the prevalence of dyssynergic defecation, estimated in some studies to affect nearly 20% of patients with chronic constipation, it is recommended to perform anorectal manometry early in the course of evaluation, especially if the patient exhibits symptoms suggestive of an evacuation disorder.2 This is further supported by the efficacy of biofeedback therapy, which can be upwards of 70%.3 Aside from defecatory dysfunction, chronic constipation subtypes include functional constipation and constipation-predominant irritable bowel syndrome, as well as slow transit constipation and normal transit constipation. 

Constipation can also be secondary to medications and systemic diseases, as shown in Table 1. It is worth noting that constipation can precede the identification of the underlying disorders’ primordial symptoms, particularly in scleroderma, Parkinson’s, and neuropathy.

How is chronic constipation managed?

In managing constipation, the initial approach often hinges on dietary modifications, promotion of physical activity, and over-the-counter fiber supplementation.4 Although general guidance emphasizes increasing fiber through dietary staples like whole grains, fruits, and vegetables, few natural foods have been tested in clinical trials to validate their individual benefits for constipation management. Nevertheless, the spotlight is gradually shifting towards functional foods. These are foods that are recognized to provide health advantages beyond basic nutrition, with examples including aloe, rhubarb, figs, prunes, and kiwifruit.5 

The typical management of constipation typically follows the order of:

Lifestyle modifications, including dietary changes, increased physical activity, and hydration

Laxatives: 

Bulk-forming laxatives (such as psyllium and methylcellulose, the latter being a non-fermentable, synthetic fiber)

Osmotic laxatives (such as polyethylene glycol and milk of magnesia)

Stimulant laxatives (such as bisacodyl and senna, whose long-term use is avoided)

Prescription medications:

Chloride channel activators (lubiprostone)

Guanylate cyclase-C agonists (linaclotide and plecanatide)

Sodium/hydrogen exchange inhibitors (tenapanor)

5-HT4 serotonin receptor agonists (prucalopride)

Ingested vibrating capsules. 

Peripherally acting mu-opioid receptor antagonists (or PAMORAs; methylnaltrexone and naloxegol) for patients with opioid-induced constipation

While lifestyle modifications are often taken for granted, certain dietary modifications, like the addition of kiwifruit, are often underutilized and can be introduced into the management of constipation at any point in the course of treatment.

How does kiwifruit help constipation?

Kiwifruit is available in two main varieties: green and gold. The green kiwifruit (Actinidia deliciosa, cultivar Hayward) and the gold kiwifruit (Actinidia chinensis, cultivar Zesy002) are the two most widely consumed varieties. Over the past few years, they have gained traction as a dietary intervention for various gastrointestinal concerns, particularly constipation. This food’s nutritional profile has many potential mechanisms explaining its laxative benefits, in addition to being generally regarded as a nutrient-dense, low-calorie fruit considering its high fiber, water, and micronutrient content, as highlighted in Table 2. 

Fiber and water content – One green kiwifruit of around 80g contains 2.4g of fiber while a similar gold kiwifruit contains 1.1g of fiber.6 As a reference, the USDA 2020-2025 dietary guidelines for Americans recommends 14g of fiber per 1000 calories. Americans should thus, on average, consume between 25-30g of fiber per day. Two green kiwifruits per day provide around 20% of the daily recommended intake of fiber. The fiber content of kiwifruit is approximately one-third soluble fiber, mainly composed of pectic polysaccharides which are fermentable fibers; and two-thirds insoluble fiber mainly composed of cellulose and hemicellulose which are non-fermentable and fermentable fibers. The insoluble fiber content is thought to stimulate water secretion and thereby improve stool transit time, while the soluble fiber binds to water, creating a gel that helps to soften and bulk the stool.7 Kiwifruit’s fiber content is particularly unique in its capacity to swell, passively increasing its volume in water, and in its elevated water retention capacity, distinguishing it from other high-fiber fruits like apple and even psyllium husk.8 

Simple Carbohydrate content – Green kiwifruit contains approximately 7g of sugars, split evenly between glucose and fructose, while the sweeter-tasting gold kiwifruit contains 10g of sugars with a similar distribution of glucose and fructose.9 Given the absence of polyols and oligosaccharides, kiwifruit is an appropriate addition to a low fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet. This stands in contrast to other fruits recommended for constipation such as prunes, which are high in sorbitol and may lead to bloating, diarrhea, and discomfort in patients unable to digest sorbitol. A small study showed that ingestion of 2 kiwifruit was not associated with increases in hydrogen or methane levels on breath testing, consistent with this notion.10 

Protein and amino acids -While kiwifruit is not a high-protein food, with under 1g protein per fruit, the proteins and amino acids contained within it are significant.9 Actinidin, the primary protein in kiwifruit, is a protease enzyme that can aid digestion. Remarkably, actinidin remains stable against pepsin degradation and displays broad proteolytic action, especially in the acidic environment of gastric pH.11 It has been shown to quickly digest ingested proteins, with evidence of improving gastric emptying time.12,13 While the protein concentrations of most kiwifruit cultivars are comparable, there is a marked variation in their enzymatic activity.13 Specifically, the green kiwifruit actinidin’s proteolytic activity is much greater (about eight times greater) than that of the SunGold™ kiwifruit.11,13 Gold kiwifruit varieties other than the SunGold™ variety have little to no actinidin.13 Beyond actinidin, kiwifruit houses other proteins and derivatives like kiwellin, kissper, and thaumatin-like protein, which have also been shown to exhibit anti-inflammatory, anti-bacterial, and anti-fungal activities.14 Interestingly, the kiwifruit’s kissper protein exhibits ion channel-like, pore-forming properties, suggesting that modulation of the intestinal membrane permeability may be one of the mechanisms for alleviating constipation.15 

Micronutrients – While they may not contribute to its laxative effect, the kiwifruit is an excellent source of vitamins, particularly vitamin C, vitamin E, and folate. It is also rich in other antioxidants, such as phenolics and carotenoids, including lutein, violaxanthin, and β-carotene.6 Furthermore, it is a significant source of potassium, containing around 6 mEq of potassium per kiwifruit.6 

Evidence Supporting Kiwifruit for Constipation

Historically, knowledge of kiwifruit’s gastrointestinal benefit can be traced back to the Tang Dynasty (circa 600 AD).6 A pioneering human study in 2001 offered evidence on this matter, revealing that kiwifruit improved bowel movement frequency, consistency, volume, and ease of defecation among healthy elderly participants.16 Subsequent studies have echoed these positive findings, particularly among patients with functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C), the latter being characterized by abdominal pain. In these studies, participants typically consumed 2-3 kiwifruits daily from either the green or gold variety, though some trials explored the impact of powdered kiwifruit extract.

In a recent 2023 international multicenter, randomized crossover study of patients with FC and IBS-C, the consumption of two peeled green kiwifruit per day (providing 6g of fiber) as compared to 7.5g of psyllium fiber was associated with an increase in the number of complete spontaneous bowel movements (CSBM), at an increase of 1.5 CSBM per week for FC and 1.7 CSBM per week for IBS-C.17 On the other hand, psyllium was associated with a non-significant increase of 0.7 CSBM per week for FC and a significant increase of 1.3 CSBM for IBS-C. Comparing the improvement with kiwifruit to that with psyllium showed kiwifruit to be superior (overall increase in CSBM of 1.7 vs. 0.9, p=0.038).17 There was also a statistically significant improvement in stool consistency and straining for both kiwifruit and psyllium, again showing kiwifruit to be superior.17 Another similarly designed study from New Zealand was published in 2022, comparing two gold kiwifruits to 7.5g of psyllium fiber.18 Findings revealed comparable efficacy between the interventions with an increase of approximately 1 CSBM weekly for gold kiwifruit and around 1.5 weekly for the psyllium (p=0.63 in comparing interventions).18 Chey et al., found that two green kiwifruit daily were associated with a mean increase of 1 CSBM weekly.19 In contrast, 12g psyllium provided an increase of 1.7 CSBM weekly and prunes offered 2.19 Beyond the number of bowel movements, kiwifruit intake also improved stool consistency, reduced straining, and mitigated the sensation of incomplete evacuation.19 Of note, for those with constipation, an improvement of over 1 CSBM weekly constitutes a clinically meaningful amelioration. 

The Impact of Kiwifruit on Symptoms Associated with Constipation

A 2022 systematic review delved into kiwifruit’s benefits in gastrointestinal symptoms other than constipation.20 They found that there was good evidence supporting a positive influence of kiwifruit, particularly green kiwifruit, on abdominal discomfort and pain (good evidence, medium-high quality), abdominal distention and bloating (medium evidence, medium quality), disrupted swallowing and reflux (good evidence, high quality), and indigestion or dyspepsia (good evidence, high quality).20 The evidence supporting gold kiwifruit in this context was weaker, with low evidence for abdominal discomfort/pain and disrupted swallowing/reflux, no evidence for abdominal distention/bloating, and good evidence only for indigestion/dyspepsia. 

Evidence Regarding Kiwifruit Extracts

Despite the evidence showing the benefit of kiwifruit for constipation, studies investigating the effect of kiwifruit supplements (often freeze-dried powders) have not shown similar benefits. 21 It is likely that components of the fresh fruit are crucial to derive its benefits. However, the single positive randomized controlled trial that demonstrated evidence supporting kiwifruit supplements used Kivia powder containing ZyactinaseTM at a dose of 5.5g per day, compared to other studies which used 0.6g to 1g of other kiwifruit extracts.21,22 This study found improvements in the frequency and consistency of bowel movements as well improvements in abdominal discomfort, flatulence, and urgency.22 As such, the benefit appears to be related to dosage and extract formulation, similar to how the benefit of fresh kiwifruit is related to the quantity and strain of the ingested fruit. 

How to Apply Research Results in the Clinic

In clinical settings, we recommend presenting kiwifruit as a potential treatment option, especially for patients with mild symptoms and those reluctant to take medications. Patients can be counseled to eat two to three kiwifruits per day, ideally of the green Hayward variety, as the evidence is strongest for this cultivar. The gold cultivar may be offered as well if the green variety is not palatable, but the supportive evidence is weaker. There is some evidence that consuming the kiwifruit flesh with its skin may enhance the beneficial effects on gastrointestinal symptoms, although most studies were performed on peeled kiwifruit.23 Therefore, we suggest deferring the choice to the patient given the unappetizing texture of the skin. While there is no evidence regarding the timing of consuming the fruits, it is likely that consuming the fruit near meals may be beneficial given their potential digestive benefits.

From Clinic to Bowl –
How to Make it Sustainable

Kiwifruit is generally palatable and well-received. In a 2021 study by Chey et al., only 7% of those assigned to consume kiwifruit for constipation reported dissatisfaction, in comparison to 17% for prunes and 38% for psyllium.19 While kiwifruit can easily be enjoyed on its own, strategies to avoid taste fatigue can include the creative methods of incorporated kiwifruit into the diet as described in Table 3. It is also worth noting that while most studies specify that fruits were ingested whole, there is no evidence to suggest that blending kiwifruit is detrimental. Juicing, on the other hand, is not recommended as the juice extraction process removes most of the fruit’s fiber content. Similarly, baking kiwifruit is not ideal as the heat is likely to denature the enzymes, detracting from its benefits.24 

Conclusion

The management of chronic constipation can be challenging. Given the compelling evidence, kiwifruits should be added to the healthcare provider’s therapeutic toolkit. A daily intake of two green kiwifruits offers a promising option for constipation management through enhancing stool frequency, consistency, and ease of evacuation. Kiwifruits are further likely to benefit associated symptoms of abdominal pain, bloating, indigestion, and reflux. While their palatability is generally well-received, it can be pivotal to proactively discuss the potential for taste fatigue with patients to improve sustained treatment adherence. Two kiwifruits a day may truly keep the gastroenterologist away. 

References

References

1. 

Suares NC, Ford AC. Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation in the Community: Systematic Review and Meta-analysis. Am J Gastroenterol. 2011;106(9):1582-1591. 

2. 
Tanner S, Chaudhry A, Goraya N, et al. Prevalence and Clinical Characteristics of Dyssynergic Defecation and Slow Transit Constipation in Patients with Chronic Constipation. J Clin Med. 2021;10(9):2027. 

3. 
Lee HJ, Boo S-, Jung KW, et al. Long-term efficacy of biofeedback therapy in patients with dyssynergic defecation: results of a median 44 months follow-up. Neurogastroenterol Motil. 2015;27(6):787-795. 

4. 
Chang L, Chey WD, Imdad A, et al. American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation. Gastroenterology. 2023;164(7):1086-1106. 

5. 
Singh P, Tuck C, Gibson PR, Chey WD. The Role of Food in the Treatment of Bowel Disorders: Focus on Irritable Bowel Syndrome and Functional Constipation. Am J Gastroenterol. 2022;117(6):947-957. 

6. 
Richardson DP, Ansell J, Drummond LN. The nutritional and health attributes of kiwifruit: a review. Eur J Nutr. 2018;57(8):2659-2676. 

7. 
Bellini M, Tonarelli S, Barracca F, et al. Chronic Constipation: Is a Nutritional Approach Reasonable? Nutrients. 2021;13(10):3386. 

8. 
Sims IM, Monro JA. Fiber: Composition, Structures, and Functional Properties. Vol 68.; 2013.

9. 
Sivakumaran S, Huffman L, Sivakumaran S, Drummond L. The nutritional composition of Zespri® SunGold Kiwifruit and Zespri® Sweet Green Kiwifruit. Food chemistry.2018;238:195-202. 

10.
Chen AGY, Offereins MSL, Mulder CJ, Frampton CM, Gearry RB. A Pilot Study of the Effect of Green Kiwifruit on Human Intestinal Fermentation Measured by Hydrogen and Methane Breath Testing. J Med Food. 2018;21(12):1295-1298. 

11.
Grozdanovic MM, Ostojic S, Aleksic I, Andjelkovic U, Petersen A, Gavrovic-Jankulovic M. Active actinidin retains function upon gastro-intestinal digestion and is more thermostable than the E-64-inhibited counterpart. J Sci Food Agric. 2014;94(14):3046-3052.

12.
Montoya CA, Rutherford SM, Olson TD, et al. Actinidin from kiwifruit ( Actinidia deliciosa cv. Hayward) increases the digestion and rate of gastric emptying of meat proteins in the growing pig. Br J Nutr. 2014;111(6):957-967. 

13.
Kaur L, Mao B, Bailly J, Oladeji O, Blatchford P, McNabb WC. Actinidin in Green and SunGold Kiwifruit Improves Digestion of Alternative Proteins—An In Vitro Investigation. Foods. 2022;11(18):2739. 

14.
Bayer SB, Gearry RB, Drummond LN. Putative mechanisms of kiwifruit on maintenance of normal gastrointestinal function. Crit Rev Food Sci Nutr. 2018;58(14):2432-2452. 

15.
Ciardiello MA, Meleleo D, Saviano G, et al. Kissper, a kiwi fruit peptide with channel-like activity: Structural and functional features. J Pept Sci. 2008;14(6):742-754. 

16.
Rush EC, Patel M, Plank LD, Ferguson LR. Kiwifruit promotes laxation in the elderly. Asia Pac J Clin Nutr. 2002;11(2):164-168. 

17.
Gearry R, Fukudo S, Barbara G, et al. Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort-Results of an International Multicenter Randomized Controlled Trial. Am J Gastroenterol. 2023;118(6):1058-1068. 

18.
Bayer SB, Heenan P, Frampton C, et al. Two Gold Kiwifruit Daily for Effective Treatment of Constipation in Adults—A Randomized Clinical Trial. Nutrients. 2022;14(19):4146. 

19.
Chey SW, Chey WD, Jackson K, Eswaran S. Exploratory Comparative Effectiveness Trial of Green Kiwifruit, Psyllium, or Prunes in US Patients With Chronic Constipation. Am J Gastroenterol. 2021;116(6):1304-1312. 

20.
Bayer SB, Frampton CM, Gearry RB, Barbara G. Habitual Green Kiwifruit Consumption Is Associated with a Reduction in Upper Gastrointestinal Symptoms: A Systematic Scoping Review. Adv Nutr. 2022;13(3):846-856. 

21.
van der Schoot A, Creedon A, Whelan K, Dimidi E. The effect of food, vitamin, or mineral supplements on chronic constipation in adults: A systematic review and meta-analysis of randomized controlled trials. Neurogastroenterol Motil. 2023;35(11):e14613. 

22.
Udani JK, Bloom DW. Effects of kivia powder on Gut health in patients with occasional constipation: a randomized, double-blind, placebo-controlled study. Nutr J.2013;12(1):78. 

23.
Eady SL, Wallace AJ, Hedderley DI, Bentley-Hewitt KL, Butts CA. The Effects on Immune Function and Digestive Health of Consuming the Skin and Flesh of Zespri® SunGold Kiwifruit (Actinidia Chinensis var. Chinensis ‘Zesy002’) in Healthy and IBS-Constipated Individuals. Nutrients.2020;12(5):1453.

24.
Zhu X, Kaur L, Boland M. Thermal inactivation of actinidin as affected by meat matrix. Meat Sci.2018;145:238-244.

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MAUNA KEA TECHNOLOGIES PARTNERS WITH METRODORA TO CREATE FIRST U.S. CENTER OF EXCELLENCE FOR THE USE OF CELLVIZIO® TO IDENTIFY AND TREAT FOOD INTOLERANCE IN ADULTS

MAUNA KEA TECHNOLOGIES PARTNERS WITH METRODORA TO CREATE FIRST U.S. CENTER OF EXCELLENCE FOR THE USE OF CELLVIZIO® TO IDENTIFY AND TREAT FOOD INTOLERANCE IN ADULTS

Cellvizio Food Intolerance Test (C-FIT) delivers real-time, in vivo visibility to accurately identify food intolerance in patients suffering from Irritable Bowel Syndrome (IBS)

Metrodora will serve as Center of Excellence for patient care and physician training to enable broad access to this breakthrough procedure

Paris, Boston and Salt Lake City, March 6, 2024 – Mauna Kea Technologies (Euronext Growth: ALMKT), inventor of Cellvizio®, the multidisciplinary probe and needle-based confocal laser endomicroscopy (p/nCLE) platform, and Metrodora Institute, a leading multispecialty healthcare institute, today announced the formation of a new partnership. This collaboration aims to establish Metrodora Institute as the first U.S. Center of Excellence that will serve as the model of patient care and physician training on the use of Cellvizio for identifying and treating food intolerances in patients suffering from Irritable Bowel Syndrome (IBS). The Cellvizio Food Intolerance Test (C-FIT) offers a groundbreaking approach to diagnosing food intolerances, providing a real-time visualization of the intestinal barrier during a food challenge.

In the United States, about 10-15%[1] of the general adult population suffers from IBS, a condition reportedly linked to atypical food intolerance in the majority of cases, characterized by a group of symptoms including abdominal pain, bloating, and changes in bowel habits (diarrhea, constipation, or both). This condition significantly affects the quality of life of those affected who often face a protracted and distressing journey of medical consultation that could last 2 to 3 years on average with no guaranteed path to identifying the underlying cause of their symptoms.

“This partnership is perfectly aligned with our strategic ambition and represents a significant step forward in expanding the use of Cellvizio in the food intolerance markets. The Cellvizio U.S. Center of Excellence at the Metrodora Institute serves as a key driver in increasing awareness among the medical and patient communities about C-FIT, positioning it as a benchmark method for food intolerance detection”,  said Sacha Loiseau, Ph.D., Founder, Chairman and Chief Executive Officer of Mauna Kea Technologies. “There is an urgent, unmet need for the immense pool of IBS patients who endure debilitating daily complications. It is crucial to swiftly extend the C-FIT procedure to as broad an audience as possible.”

Metrodora was established in 2021 as a multidisciplinary care and research center for people with neuroimmune disorders, including neurogastrointestinal disorders. Metrodora’s state-of-the-art ambulatory surgery center in Salt Lake City, Utah, offers advanced diagnostic and therapeutic procedures to evaluate and treat a range of complex and routine conditions.

“We couldn’t be more excited about being named the first U.S. Center of Excellence for implementing and serving as a healthcare model for the C-FIT procedure,” said John Wirthlin, CEO, Metrodora Institute. “Many patients live with undiagnosed food intolerances, simply because existing testing methods cannot identify the underlying issues. Our vision is that Metrodora Institute will adopt novel technologies like Cellvizio to improve the lives of the patients we serve.” 

About Mauna Kea Technologies

Mauna Kea Technologies is a global medical device company that manufactures and sells Cellvizio®, the real-time in vivo cellular imaging platform. This technology uniquely delivers in vivo cellular visualization which enables physicians to monitor the progression of disease over time, assess point-in-time reactions as they happen in real time, classify indeterminate areas of concern, and guide surgical interventions. The Cellvizio® platform is used globally across a wide range of medical specialties and is making a transformative change in the way physicians diagnose and treat patients. 

[1]

Hungin APS, Tack J, Mearin F, Whorwell PJ, Dennis E, Barghoui V. Irritable bowel syndrome (IBS): prevalence and impact in the USA – the truth about IBS (T-IBS) survey. Am J Gastroenterol. 2002; 97:242. (Poster #460)

For more information, visit:

maunakeatech.com

2024 Sherman Prize
Now Accepting Nominations

Honoring Excellence in Crohn’s and Colitis

BOCA RATON, Florida, March 11, 2024 – The Bruce and Cynthia Sherman Charitable Foundation announced today that the Sherman Prize is now accepting nominations for 2024. Now in its ninth year, the Sherman Prize, which recognizes and rewards those who have gone above and beyond in the fight to overcome Crohn’s disease and ulcerative colitis, also known as the inflammatory bowel diseases (IBD), has honored the outstanding achievements of 24 extraordinary IBD professionals.

“The Sherman Prize is the highest recognition of the talent and achievements in the field of IBD today,” said Dr. Maria T. Abreu, 2024 Selection Committee Chair and 2019 Sherman Prize Recipient. “Honoring the innovators who have devoted their careers to helping those who suffer from Crohn’s disease and ulcerative colitis elevates their work and inspires others to excel, which is why the Sherman Prize is so meaningful. This is a great opportunity for our colleagues to nominate outstanding individuals who are pushing the boundaries of treatment and care.”

All nominees are evaluated by the Sherman Prize Selection Committee. In 2024, Chair, Dr. Abreu is joined by:

Dr. Jessica Allegretti, Brigham and Women’s Hospital, 2020 Sherman Prize Emerging Leader Prize recipient.

Dr. Stephen Hanauer, Northwestern University Feinberg School of Medicine.

Dr. James Lewis, University of Pennsylvania, 2016 Sherman Prize recipient.

Dr. Uma Mahadevan, University of California San Francisco, 2022 Sherman Prize recipient.

Bruce Sherman said, “Since we launched the Sherman Prize in 2016, my wife Cynthia and I have been proud to honor the visionaries who share a deep commitment to addressing the unmet challenges of Crohn’s and colitis and lead the scientific research that not only improves the quality of life for people with IBD today but lays the foundation for greater discoveries in the future. We hope that by rewarding these achievements, the Sherman Prize may inspire excellence in others.”

Nominations may be submitted at ShermanPrize.org through May 24. The 2024 Prize recipients will be announced in the Fall and honored at the Prize presentations during the Advances in IBD (AIBD) conference in Orlando, Florida, December 10.

About the Sherman Prize

In 2016, Bruce and Cynthia Sherman established the Sherman Prize to provide national recognition and financial prizes to pioneering IBD professionals who exemplify excellence in Crohn’s disease and ulcerative colitis. Since its inception, the Sherman Prize has honored 24 IBD practitioners from diverse specialties.

Two $100,000 Sherman Prizes are awarded annually to IBD clinicians, surgeons, researchers and/or academics, recognizing exceptional and pioneering contributions that transform the care of people with IBD. Sherman Prize recipients are accomplished experts changing the paradigm in IBD and inspiring future innovators through their achievements.

A $25,000 Sherman Emerging Leader Prize is awarded to an IBD clinician, surgeon, researcher, academic, or physician assistant, who, while early in his or her career, has contributed to an advancement and shows great promise for significant future contributions.

Selection decisions are made by the Board of Directors, following an extensive review and evaluation by the Prize Selection Committee, which is comprised of five of the nation’s preeminent IBD specialists.

For eligibility guidelines and to nominate an individual doing exceptional work on behalf of people with IBD, please visit:

ShermanPrize.org

Pancreatic Duct Leaks

Pancreatic Duct Leaks

April 2024 • Volume XLVIII, Issue 4
Nicole D. Ferrante,Monica Saumoy

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INTRODUCTION

Pancreatic duct (PD) leaks can occur in the setting of acute or chronic pancreatitis, trauma, or pancreatic resection. Their clinical manifestations vary widely depending on the underlying etiology and the site and extent of PD disruption. Sequelae of PD leaks include peripancreatic and pancreatic fluid collections (PFCs), as well as internal and external pancreatic fistulas. Small PD leaks may resolve with conservative management alone, but other therapeutic options include endoscopic, radiologic, surgical, and combined approaches necessitating a multidisciplinary care team. The role of endoscopic retrograde cholangiopancreatography (ERCP) is primarily to provide a therapeutic intervention to PD leaks and their sequelae. Over time, the role of endoscopic therapy for PD leaks has expanded with comparable effectiveness to surgical and radiologic approaches. Currently, the mainstay of endoscopic therapy involves transpapillary pancreatic duct stenting to bridge the site of PD disruption. In this article, we review the pathophysiology, epidemiology, clinical manifestations, diagnosis, and approach to endoscopic management of PD leaks. (See Figure 1.)

PATHOPHYSIOLOGY AND CLASSIFICATION 

PD leaks result from disruption of the pancreatic ductal system, which can be seen in the setting of acute or chronic pancreatitis, abdominal trauma, and as a complication of pancreatic resection or peripancreatic surgery. (See Figure 2.) Activation of proteolytic enzymes, pancreatic autodigestion, and the production of proinflammatory cytokines are felt to play key roles in the pathogenesis of acute pancreatitis.1 While the exact mechanism is unknown, pancreatic duct disruption is likely a secondary effect of pancreatic inflammation in patients without trauma or prior instrumentation. Disruption of the PD results in the leakage of pancreatic fluid, which may contribute to autodigestion of pancreatic parenchyma.1 PD leaks can also occur in the setting of chronic pancreatitis either because of superimposed acute pancreatitis or increased intraductal pressure from obstructing PD stones or strictures. Lastly, PD leaks can occur as a result of direct injury to the PD from abdominal trauma, pancreatic resection, or inadvertent pancreatic injury during abdominal surgery. The American Association for the Surgery of Trauma grading system grades pancreatic injury based on the location of PD injury and degree of ductal involvement.2 Postoperative pancreatic fistulae are defined and graded based on the 2016 International Study Group of Pancreatic Fistula consensus definitions.3

Persistent leakage of pancreatic fluid can erode into neighboring structures and spaces resulting in the formation of PFCs and pancreatic fistula. The classification of PFCs has changed over time and is currently based on the time that they develop in relation to pancreatitis onset and the presence of necrosis.4 Pancreatic fistula are abnormal connections between the pancreatic ductal epithelium and another epithelial surface. Fistula are traditionally classified as internal or external, as well as anatomically based on the site of involvement. Internal pancreatic fistula can result from pancreatic fluid erosion into the peritoneal space (pancreaticoperitoneal fistula), pleural space (pancreaticopleural fistula), mediastinum (pancreaticomediastinal fistula), pericardial space (pancreaticopericardial fistula), bronchial tree (pancreaticobronchial fistula), biliary tract (pancreaticobiliary fistula), stomach (pancreaticogastric fistula) and nearby small or large bowel (pancreaticoenteric or pancreaticocolonic fistula). External pancreatic fistula, or pancreaticocutaneous fistulas, result from communication between the pancreas and the skin, and are most commonly iatrogenic secondary to drains placed via interventional radiology or surgery. 

EPIDEMIOLOGY

PD disruption and its sequelae are most commonly seen in the setting of severe acute pancreatitis, though the true incidence of PD leaks is unknown as small leaks may be clinically silent.5–7 Disconnected pancreatic duct syndrome (DPDS) represents the most severe form of PD disruption with complete transection of the main PD resulting in a portion of the pancreas (usually the tail) becoming isolated from the remainder of the pancreas.8,9 It is most commonly seen in the setting of necrotizing pancreatitis with up to 10-30% of patients developing DPDS, though the true incidence is not known.5,6

PD leaks can also occur post-operatively after pancreatic resection or inadvertent pancreatic injury during surgery of nearby organs such as the spleen, left kidney, colon, and left adrenal gland. (See Figure 3.) In the setting of pancreatic resection, PD leaks can complicate up to 5-29% of cases depending on the health of the underlying pancreatic tissue, extent of pancreatic resection, and main PD diameter.10–13

Lastly, PD leaks can be seen in the setting of pancreatic injury from abdominal trauma. The incidence of pancreatic injury is up to 5% after blunt abdominal trauma and up to 30% after penetrating abdominal trauma, with the most common complication being pancreatic fistula.14–19  

CLINICAL MANIFESTATIONS

The clinical manifestations of PD leaks vary widely and are driven by the underlying etiology, the site of the PD leak, the extent of PD disruption, rate of secretion of pancreatic fluid, and the presence of pancreatic fistula.20 (See Figure 4.) In acute pancreatitis, the initial presentation is largely driven by the etiology and severity of the pancreatitis, whereas the sequelae of PD disruption play a greater role as the clinical course evolves. Generally, low-grade leaks can be asymptomatic, precipitate pancreatitis, or evolve to become pseudocysts whereas severe leaks and their sequelae are more likely to be symptomatic. Depending on the size, location, and presence of superinfection, PFCs may present as nonspecific gastrointestinal symptoms, sepsis/septic shock, gastric outlet obstruction, or biliary obstruction. DPDS typically presents as a refractory PFC or pancreatic fistula, as the isolated portion of the pancreas continues to secrete pancreatic fluid that is unable to be secreted appropriately into the GI tract.

The clinical manifestations of pancreatic fistula are highly variable depending on the distant site of communication. Pancreaticocutaneous fistulas are usually the most obvious, as they present with visible leakage of pancreatic fluid from the skin with or without skin excoriation. Pancreaticoperitoneal fistulas result in pancreatic ascites with varying degrees of abdominal symptoms and can be complicated by peritonitis. Pancreaticoenteric fistulas can present with gastrointestinal (GI) bleeding, diarrhea, or malabsorption. Thoracopancreatic fistulas can result in cough, dyspnea, chest pain, dysphagia, mediastinitis, and pneumonia depending on the site of involvement. Because pancreatic fluid is high in bicarbonate and protein, PD leaks can cause a metabolic acidosis, dehydration, and malnutrition, especially in the setting of high-grade leaks. 

DIAGNOSIS 

Accurate identification and characterization of PD disruption is important in guiding the approach to management. Currently, there are no consensus guidelines for the diagnosis of PD leaks. ERCP is traditionally considered the gold standard for confirming the presence, severity, and site of PD disruption, which is defined by contrast extravasation from the pancreatic ductal system. (See Figures 5-7.) The potential for ERCP to cause pancreatitis and superinfection, and the improvement in noninvasive imaging modalities, has resulted in ERCP being primarily reserved for cases where endotherapy is warranted in the setting of a diagnostic evaluation.21 Generally, the diagnostic approach is determined by the clinical presentation.

In the setting of acute pancreatitis, contrast-enhanced computerized tomography (CT) is often obtained as part of the initial diagnostic workup. Clinical worsening should prompt repeat CT imaging to evaluate for the development of PFCs and pancreatic necrosis. Identification of a PFC suggests that a PD leak is present, and its location may suggest the site of PD disruption. (See Figure 8.) Serial imaging demonstrating a persistent or enlarging PFC further supports the presence of an ongoing PD leak, which can be confirmed with magnetic resonance cholangiopancreatography (MRCP), secretin-enhanced MRCP (S-MRCP), or ERCP. In the setting of DPDS, S-MRCP has high sensitivity for identifying the site of ductal disruption and may additionally visualize the disconnected portion of the pancreas.22 In the setting of chronic pancreatitis, CT is often used in the initial diagnosis of chronic pancreatitis and to evaluate for calcified PD stones, PD strictures, and sequelae of PD leaks in the case of symptom progression.23

Similarly, internal pancreatic fistula can be suggested by findings on cross-sectional imaging and, in the case of pancreatic ascites and pancreaticopleural fistulas, can be confirmed by the presence of a high fluid amylase in the peritoneal and pleural fluid, respectively. (See Figure 9.) The diagnosis of external pancreatic fistula and post-operative PD injury is often more straightforward, as they typically present as persistent fluid output from a percutaneous or surgical drain. Fluid analysis demonstrating a fluid amylase that is >3x upper limit of normal (ULN) supports the diagnosis, and a fistulogram is rarely necessary for diagnostic purposes.3

Occasionally, sequelae of PD disruption may present in the absence of a clear inciting event. If a patient presents with a PFC in the absence of preceding pancreatitis, a general approach involves obtaining cross-sectional imaging (CT or MRI) with or without EUS for fluid analysis to rule out a neoplasm.

MANAGEMENT

PD leaks and their sequelae can result in fluid and electrolyte imbalance, malnutrition, and sepsis; thus, conservative medical therapy plays a key role in management and may result in resolution of low-volume PD leaks. A multi-disciplinary approach is essential to identify patients that might benefit from endoscopic, radiologic, surgical, or multimodal therapy. 

Overview of Endoscopic Therapy

ERCP can be used to effectively treat PD leaks and their sequelae. The presence of a PD leak is not a strict indication for endotherapy, as low-grade leaks may resolve with conservative management alone; thus, a key step is to identify patients that would benefit from an endoscopic approach to management. Still, in practice, most patients with PD leaks come to endotherapy at some point in their clinical course. Important considerations include whether there is evidence of an ongoing PD leak, PFC, or necrosis. 

Relative indications for endotherapy of presumed or definite PD leaks and their sequelae include: 

Persistent or worsening PD leak despite conservative management 

Symptomatic PFC 

Superinfected PFC 

The mainstay of endoscopic therapy for PD leaks and their sequelae involves transpapillary pancreatic duct stenting to bridge the site of PD disruption and/or transmural drainage of associated PFCs. If a leak cannot be crossed with endoscopic transluminal stenting, which usually occurs in the setting of DPDS, surgery or interventional radiology approaches may be indicated. (See Figure 10.) 

Transpapillary Drainage

Transpapillary drainage involves an ERCP with insertion of a PD stent that bridges the site of PD disruption. (See Figures 11-13.) Bridging the site of PD disruption with a PD stent promotes physiological flow of pancreatic fluid into the duodenum rather than through the site of PD disruption and correlates with successful outcomes.24,25 Additionally, PD stents can be used to bypass areas of ductal obstruction due to PD stones and strictures. The stent diameter depends on the PD diameter and should not exceed the diameter of the upstream PD.26 While pancreatic sphincterotomy is not required for stent insertion, it can be used to facilitate stone extraction and PD stricture dilation and is often performed if the need for repeated PD access is anticipated in the future. Optimal stent duration/indwell time is unclear and depends on the etiology of the PD leak and operator preference. In cases where the upstream portion of the PD is unable to be accessed, a shorter stent can be placed, with a plan to re-attempt ERCP to bridge the leak at a later date. In most case series, PD stents were left in place for 4-8 weeks with shorter durations being associated with an increased risk of recurrence or failure and longer durations being associated with stent occlusion and ductal changes in a previously otherwise normal PDs, but this has not been universally reported.24,25,27–29 Importantly, many patients need, and tolerate, long PD stent indwell times without any evidence of duct injury. Lastly, transpapillary drainage can be used to drain PFCs that communicate directly with the main PD. This technique involves placing the distal aspect of the stent directly into the PFC and is supported by case-series that have demonstrated its effectiveness, though it is not the preferred route of drainage.30,31 (See Figure 14.) Even if the PD does not clearly communicate with the PFC, a PD stent can still help to prevent backfilling of the PFC and can promote resolution.

Transmural Drainage

Transmural drainage directs PFC contents into the stomach or duodenum, which decompresses the PFC and promotes healing of the PD leak. This technique involves transmural puncture of a mature PFC through the gastric wall (cystgastrostomy) or duodenal wall (cystenterostomy) and placement of one or more stents to allow for drainage of the contents into the GI tract. (See Figure 15) Transmural drainage is performed during esophagogastroduodenoscopy (EGD) with or without EUS guidance, although in current practice the use of EUS is almost universal. EUS allows for the identification of blood vessels and solid debris and is the preferred approach, especially in the absence of an obvious area of extrinsic compression.32,33 Effective drainage of liquefied PFCs has been reported with the placement of double-pigtail plastic stents, biliary SEMS, or lumen apposing metal stent (LAMS).34–41 Currently, there are no consensus guidelines for stent selection and duration and, thus, this is left at the discretion of the endoscopist. Typically, cross-sectional imaging is performed 4-8 weeks later to confirm PFC resolution followed by stent removal 6-8 weeks after radiographic resolution of the PFC.21 If percutaneous drains were also placed, they are typically removed before the transmural drains to minimize the risk of developing external PF. If the PFC contains solid necrotic material, this can also be debrided endoscopically via direct endoscopic necrosectomy (DEN). 

Pancreatic Leak from Acute Pancreatitis 

In the setting of acute pancreatitis, PFCs are classified according to the time they develop in relation to onset of pancreatitis and the presence of necrosis.4 Briefly, acute PFCs are seen earlier in the course of pancreatitis, lack a definable wall, and are either predominantly fluid-filled (acute PFCs) or contain some component of solid necrotic debris (acute necrotic collections).4 Most acute collections resolve spontaneously but if drainage is necessary, endoscopic drainage is often not recommended in the absence of a definable outer wall. Occasionally, acute collections evolve into pancreatic pseudocysts or WON which contain a well-defined wall.4 Distinguishing between pseudocysts and WON is important, as this will inform therapeutic management. 

Options for the endoscopic management of pseudocysts include transpapillary drainage, transmural drainage, or a combination of the two.21 The approach depends on the collection’s size, proximity to the gastric or duodenal wall, and communication with the main PD. Smaller pseudocysts (≤ 6cm) that communicate with the main PD can be effectively managed with transpapillary drainage alone.42,43 Outcomes have otherwise been variable due to heterogeneity in PFC nomenclature and varying patient populations. More recently, evidence has emerged regarding the lack of additional benefit with transpapillary drainage among individuals with successful transmural drainage of PFCs.44,45 Transmural drainage has become increasingly popular over time, with SEMS and especially LAMS being widely utilized with excellent reported outcomes.39,40 Percutaneous drainage can also be performed but is associated with pancreaticocutaneous fistulae (which can become chronic); thus, it is typically reserved for PFCs that are either immature or not amenable to transmural drainage because of their location.21 In regards to timing, endoscopists may choose to perform an ERCP and place a PD stent if there is an active PD leak either at the time of transmural drainage or later in the patient’s course, as transmural drainage alone may result in healing of the leak.44 

Whereas pseudocysts are predominantly fluid filled, WON contains solid debris which cannot be effectively drained with a transpapillary approach. The preferred approach to endoscopic management is transmural drainage and necrosectomy with a “step-up” approach to potentially include percutaneous drainage and/or surgical debridement, although this last step is rarely required.

Pancreatic Leak from Chronic Pancreatitis

In the setting of chronic pancreatitis, PD disruption can occur from either an episode of acute on chronic pancreatitis, or ductal obstruction secondary to PD stones or strictures. The most common indication for endotherapy in chronic pancreatitis is to alleviate abdominal pain that is felt secondary to PD obstruction and to treat PD leaks, and is supported by international consensus guidelines.46 Similar to PD leaks from acute pancreatitis, PD stents can bridge the site of PD disruption and bypass areas of obstruction, thus restoring endoluminal flow of pancreatic duct secretions.  

External Pancreatic Fistula

External pancreatic fistula are most commonly iatrogenic due to surgery or percutaneous drainage of PFCs, and are rarely due to penetrating abdominal trauma. Endoscopic therapy is typically reserved for persistent pancreaticocutaneous fistulae despite initial attempts at conservative management, as the majority of low-volume leaks will close with conservative therapy. Conservative management includes enteral feeding, which has been shown to improve fistula closure rates.47 The use of somatostatin analogs for prevention and treatment of pancreatic fistula has been extensively studied with mixed results; thus, it is typically reserved for patients with high-output fistulas in the absence of contraindications.48,49 If fistula output fails to decrease with conservative management, MRCP or S-MRCP should be performed prior to evaluate for DPDS. In the absence of DPDS, transpapillary stent placement can be performed to facilitate closure of external PF and is supported by case series.50–55 In addition, case series have described combined endoscopic and percutaneous rendezvous approaches to internalizing external fistulae but this should only be attempted at expert centers.56 Surgery is rarely necessary and typically reserved for inaccessible superinfected PFCs, bleeding from pseudoaneurysms, failure of endoscopic methods, and clinical instability.

Internal Pancreatic Fistula

As previously discussed, internal pancreatic fistulae can communicate with the peritoneum, pleural space, bowel, biliary tree, or other thoracomediastinal spaces. The approach to therapy depends on the type of fistula and whether or not there is an associated pseudocyst. Pancreatic ascites and high-amylase pleural effusions were initially managed with conservative management consisting of bowel rest, diuretics, octreotide, and large-volume paracenteses and thoracenteses with suboptimal success and recurrence.57–59 Transpapillary stenting has proven to be effective in multiple case series, so long as the site of PD disruption can be bridged with the stent.27,60–64 In the presence of a concomitant pseudocyst, transmural drainage alone may result in resolution of pancreatic ascites and pleural effusions.65 Surgical options include partial pancreatectomy, enteropancreatic anastomosis, or Roux-en-Y cystojejunostomy if concomitant pseudocysts are present, but is associated with up to 10% mortality and 15% recurrence rates.12,57,66,67 

Pancreatic fistulization into the bowel can also occur. While pancreaticoenteric fistulas in the upper GI tract appear to be effectively managed with conservative therapy, pancreaticocolonic fistulas are associated with higher mortality rates due to associated sepsis and/or GI bleeding.68,69 For stable patients, endoscopic therapy can be considered, as case series have reported acceptable rates of success with transpapillary stent placement and transmural drainage of associated PFCs.70,71 Of note, specialized centers have described the use of transcolonic necrosectomy, SEMS placement, and over-the-scope clip closure of pancreatoenteric fistulas but this should only be attempted at expert centers.72–74 Surgical management, which often includes diverting ileostomy or colostomy, should be considered in patients who fail endoscopic therapy or develop clinical instability or GI bleeding. 

Lastly, pancreatobiliary fistulae are a rare complication of PD leaks, which may result in cholestasis or cholangitis/sepsis. Similar to the above, case reports and case series have reported successful outcomes with different combinations of transmural drainage of associated PFCs, transpapillary PD stent placement, and biliary stent placement in the presence of cholestasis or cholangitis.75,76 Based on limited case series, an endoscopic approach appears to be safe and effective, with surgical biliary reconstruction reserved for patients who fail endoscopic therapy. 

Disconnected Pancreatic Duct Syndrome

DPDS most commonly manifests as a PFC or pancreaticocutaneous fistula that is refractory to conservative management. The management of DPDS is complex and has not been standardized. Traditionally, it involves distal pancreatectomy or internal drainage via Roux-en-Y pancreaticojejunostomy with the disconnected segment.8 More recently, there has been interest in endoscopic and multimodal approaches.77 For DPDS-associated PFCs, percutaneous drainage alone carries the risk of pancreaticocutaneous fistula formation. Alternatively, transmural drainage allows for enteral drainage of the upstream pancreatic secretions that are unable to drain transpapillary. In these instances, transmural drains are often left in place indefinitely with favorable outcomes.8,78,79 Lastly, interventional radiology-guided percutaneous embolization of the disconnected portion of the PD with cyanoacrylate or other agents has been described in case series.80 Currently, there is no consensus regarding optimal nonsurgical management in these patients due to a lack of robust comparative studies. Important limitations of previous studies are the inclusion of patients with partial duct disruption, which may skew the findings in favor of endoscopic therapy, and varying definitions of DPDS and endoscopic success. In a recent systematic review, endoscopic transmural drainage was found to be superior to transpapillary drainage with comparable success rates of >80% when compared to surgical management, analogous to previous systematic reviews and meta-analyses.81–83 Should endoscopic therapy be attempted, it is important to consider a step-up approach for patients who fail minimally invasive treatment. 

Traumatic PD Leaks 

Traumatic PD leaks can present similarly to PD leaks from other etiologies. The role of ERCP in traumatic PD leaks has not been established. As with other clinical scenarios, ERCP is useful when the suspicion of PD disruption is high and endotherapy can be performed. Case series have described the utility of early ERCP to assess PD anatomy, which may influence immediate surgical management.84,85 If the PD leak is identified at a later presentation, they typically present as smoldering pancreatitis or a PFC, the management of which is described above. 

CONCLUSION

It is important to be able to identify PD leaks and understand the indications and contraindications for endotherapy. While small PD leaks may resolve with conservative management alone, larger leaks often require additional therapy for which the options include endoscopic, radiologic, surgical, and combined approaches. The majority of PD leaks can be managed effectively without surgery, but a multidisciplinary approach to therapy is recommended to identify patients that require step-up therapy. The mainstay of endoscopic therapy for PD leaks and their sequelae involves transpapillary pancreatic duct stenting to bridge the site of PD disruption and/or transmural drainage of associated PFCs. Importantly, current evidence for the management of PD leaks is limited to case series, retrospective observational studies, and expert opinion; therefore, prospective studies are needed to inform clinical practice guidelines. 

ACKNOWLEDGEMENTS

We would like to thank Drs. Ricardo Morgenstern, Kashyap Panganamamula, Nuzhat Ahmad, and Galen Leung for providing images.

References

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