DISPATCHES FROM THE GUILD CONFERENCE, SERIES #37

A Practical Approach to Managing Immune Checkpoint Inhibitor-Induced Colitis

June 2021 • Volume XLV, Issue 6
Ruzbeh Mosadeghi,Rochelle A. Reyes,David Y. Oh,Michael G. Kattah

Read Article

INTRODUCTION

As indications for immune checkpoint inhibitors (ICIs) expand, it is critical that gastroenterologists and primary care physicians be aware of how to identify and manage associated side effects. ICIs have dramatically altered the treatment landscape and outcomes for a wide variety of cancers since they were were first approved by the Food and Drug Administration (FDA) a decade ago. ICIs are monoclonal antibodies that augment the anti-tumor immune response by blocking the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) or its ligand PD-L1. Initially approved for the treatment of advanced melanoma, their mechanism of action targets a fundamental aspect of tumor immunology, leading to FDA approval in multiple other tumors (particularly for anti-PD-1/PD-L1).1–6 While ICIs are effective, the resulting immune activation can lead to immune-mediated tissue damage in multiple organs. This review will cover the practical aspects of diagnosing and managing patients with ICIinduced diarrhea and colitis.

Immune Checkpoint Inhibitors, Adverse Events and Colitis

Immune self-tolerance is regulated in part by “immune checkpoints” that restrict exaggerated immune responses and prevent autoimmune disease. Immune checkpoint inhibitors (ICIs) inhibit these immune checkpoints and allow tumor infiltrating lymphocytes to target malignant cells. There are two major classes of ICIs targeting distinct priming and effector phases of the immune response, anti-CTLA-4 and anti-PD-1/PD-L1.1–6 In current oncologic practice, anti-PD-1/PD-L1 constitute the majority of approved tumor types for ICIs, and anti-CTLA-4 is approved as combination therapy with anti-PD-1/PD-L1 only in specific indications.1–6

While ICIs have revolutionized cancer treatment, the inhibition of checkpoint proteins can lead to immune-related adverse events (irAEs). IrAEs are thought to result from autoreactive T-cells disinhibited from attacking normal host cells. IrAEs can target multiple organs, and the gastrointestinal (GI) tract can be the target of severe or life-threatening events.4,5 Diarrhea is the most commonly reported gastrointestinal symptom of ICIs, occurring in 30-60% of patients.7 In oncologic practice, ICI-induced colitis is often defined clinically by symptoms of diarrhea without an infectious cause, as well as abdominal pain, mucus, tenesmus, hematochezia, or fever.8 In general, anti-CTLA-4 is associated with earlier-onset and more severe irAEs than PD-1/PD-L1 inhibitors, and the combination increases the incidence and severity further still.9–11 Interestingly, patients who experience an irAE of any organ system have improved overall survival compared to those without irAEs, with a specific survival benefit for GI-related irAEs.12 Data from advanced melanoma showed that patients who discontinued ICIs due to treatment-related adverse events had similar overall survival at five years compared to the overall population.1 Taken together, this implies that irAEs like ICI-induced colitis, if tolerable and responsive to treatment, are not necessarily associated with worse survival, and may in some circumstances correlate with more robust antitumor activity and a higher likelihood of favorable treatment response.

Initial Evaluation of Patients with ICI-Induced Diarrhea and Colitis

Evaluation and management of these patients have been outlined by multiple clinical practice updates, guidelines, and recommendations based on expert opinion and retrospective studies.13–19 The diagnosis of ICI-induced colitis should be considered in any patient with diarrhea and colitis symptoms occurring after ICI-initiation. ICI-induced colitis occurs with a median onset of 5-7 weeks after ICI initiation, though it can start as early as one week or over six months later.1

The first step in evaluation is to assess severity and rule out infectious causes, including Clostridiodies difficile (C.Diff) and common bacterial, viral, and parasitic pathogens. Lactoferrin and fecal calprotectin have been studied in ICIinduced colitis as non-invasive markers to help differentiate between inflammatory versus noninflammatory diarrhea.20,21 Routine labs including complete blood count, complete metabolic panel, sedimentation rate, and C-reactive protein are recommended, although their diagnostic and prognostic utility are less clear in this setting than in inflammatory bowel disease (IBD). Testing for noninfectious, non-inflammatory causes of diarrhea may include checking thyroid stimulating hormone to rule out hyperthyroidism, tissue transglutaminase (TTG)-IgA and total IgA to rule out celiac disease, and lipase and fecal elastase to rule out pancreatic insufficiency, since all have been described as rare irAEs.22 For patients with grade ≥ 2 disease who may require biologics, it is important to check for latent tuberculosis, viral hepatitis (A, B and C) and HIV. Computed tomography (CT) scans are not routinely recommended, but if there is concern for perforation or other acute pathology then a contrast-enhanced CT scan is a fast and highly informative test.13-20

Endoscopy with biopsy remains the gold standard for the diagnosis and risk-stratification of patients with suspected moderate-to-severe ICIinduced colitis. Patients with mild ICI-induced colitis may be diagnosed and treated empirically without endoscopic evaluation, especially if the non-invasive evaluation suggests a mild inflammatory non-infectious colitis (i.e., elevated fecal calprotectin and negative infectious stool studies). Endoscopic evaluation serves several purposes. First, the recommendations for moderateto- severe ICI-induced colitis involve holding immunotherapy and treating with prednisone, interventions which could unnecessarily harm patients with alternative etiologies of diarrhea. Moreover, the presence of CMV or other infectious colitis can be assessed with higher sensitivity and specificity on histology. Finally, endoscopic evaluation aids in risk stratification. High-risk features such as large ulcers >1cm, deep ulcers, and pancolitis are associated with steroid treatment failure, identifying patients who would benefit from early induction with biologics.20,23,24 ICI-induced intestinal inflammation can affect any part of the GI tract, so upper endoscopy and colonoscopy are ideal. However, retrospective studies have demonstrated that >98% of patients with ICI-induced colitis had involvement of the left (distal) colon, supporting a practice of flexible sigmoidoscopy for expedited initial evaluation.25,26

In select patients with a negative sigmoidoscopy or persistent or refractory symptoms, subsequent upper endoscopy and colonoscopy could be considered to look for more proximal colitis, gastritis, or enteritis.

ICI-induced colitis can be confirmed by histology. Common features include neutrophilic cryptitis, crypt abscesses, epithelial apoptosis, and increased intraepithelial lymphocytes. Anti-PD-1 is more likely than anti-CTLA-4 to exhibit features of lymphocytic or collagenous colitis, with some reports of chronic mucosal injury.27,28 Given the possibility of microscopic colitis, it is important to perform biopsies in multiple colonic segments even if the mucosa appears endoscopically normal.

Management of ICI-Induced Diarrhea and Colitis Based on Severity

Grade 1

Grade 1 diarrhea is defined as <4 daily stools above the patient’s baseline or mildly increased ostomy output, while grade 1 colitis is asymptomatic.8 Most society practice guidelines do not recommend GI consultation for grade 1 symptoms, although fecal calprotectin and infectious stool studies should be obtained in patients with symptoms lasting for 3 days.19 Patients with grade 1 diarrhea should be monitored closely because they may quickly progress to higher grades of diarrhea and colitis. ICIs may be held but are usually continued for mild grade 1 ICI-induced colitis.13–19 Treatment is supportive and may include loperamide and hydration, although we typically rule out infections like C.Diff before prescribing anti-diarrheal agents. If the patient’s symptoms do not improve after 3-14 days of conservative management, it is recommended to start enteric budesonide at 9mg per day for four weeks followed by a taper by 3mg every two weeks.13,18 If patients do not respond to budesonide, they should be escalated to systemic steroids with prednisone 1mg/kg per grade 2 management.13,14,16

Grade 2

Grade 2 diarrhea is defined as 4-6 stools over baseline, or moderately increased ostomy output, while grade 2 colitis is defined by abdominal pain, mucus and hematochezia.8 At this stage, ICIs are held, and GI should be consulted with consideration for flexible sigmoidoscopy in addition to noninvasive testing outlined above. Patients with grade 2 diarrhea and colitis are treated with prednisone 1mg/kg, followed by a taper over 4-8 weeks.13,18 If patients do not respond within three days of starting oral prednisone, they should be escalated to IV methylprednisolone or a biologic, either infliximab (IFX) or vedolizumab (VDZ). If patients fail to respond to IV steroids within three days, then they should be treated with a biologic. Some Grade 2 patients may respond to a single dose of a biologic followed by a steroid taper, but some may require additional induction doses.13

Grade 3 or 4

Grade 3 diarrhea is defined as ≥ 7 stools above baseline or severe increase in ostomy output, while grade 3 colitis is defined by severe pain, fever, or peritoneal signs requiring intervention, or interference with activities of daily living.8 Grade 4 diarrhea and colitis are defined by all the criteria of grade 3 but are also life-threatening.8 Most grade 3 and all grade 4 patients should be hospitalized with GI consultation, and ICIs are held. The laboratory evaluation is outlined above, including necessary tests in anticipation of biologic therapy. If there is concern for perforation or other acute pathology, a contrast-enhanced CT scan should be obtained. Patients should undergo endoscopic evaluation to assess for high-risk features. Hospitalized grade 3/4 patients are started on IV methylprednisolone 1-2mg/kg. If they fail to respond to IV steroids within 72h then they should start a biologic. Patients with grade 3/4 disease will typically require three doses of IFX or VDZ, often dosed at 0, 2, and 6 weeks.13,29,30

For grade ≥ 2 ICI-induced colitis, ICIs are held at least until patients recover and successfully taper down to a prednisone dose of ≤10mg/day.13,14,18 Repeat endoscopy is beneficial for patients with persistent symptoms, but also for risk stratifying patients who are being considered for restarting ICIs after recovering from ICI-induced colitis. While most experts recommend considering permanent discontinuation of anti-CTLA-4 for grade ≥ 2 ICI-induced colitis,13,14,18 the risks and benefits should be weighed in conjunction with the treating oncologist. PD-1/PD-L1 inhibitors are generally associated with milder ICI-induced colitis and may be restarted if patients successfully wean to ≤10mg of prednisone daily.13–16,18 Concurrent administration of maintenance IFX while resuming ICIs was reported to prevent recurrent ICI-induced colitis in a small number of patients.13,31 Therefore, treatment with IFX, or by extension VDZ, may allow ICIs to be restarted in some patients with prior ICI-induced colitis.

Evidence Supporting Various Therapies for Treating ICI-Induced Colitis

Glucocorticoids are the mainstay of treatment for patients with grade ≥ 2 ICI-induced colitis. A systematic review and meta-analysis of 1210 patients found that corticosteroids were effective in 59%.32 Several studies have identified endoscopic features associated with steroid-refractory disease, including large >1cm ulcers, deep ulcers, pancolitis, and high colitis severity scores.20,23,24 Therefore, in moderate cases without high-risk features, steroids are typically first-line. Enteric budesonide was not more effective than placebo in a randomized controlled trial for primary prophylaxis against anti-CTLA-4 induced colitis33 but is effective for patients who have features of microscopic colitis on histology or patients with persistent mild grade 1 diarrhea.13

The anti-tumor necrosis factor (TNF) IFX is one of the most commonly prescribed agents for IBD and the best characterized biologic for treating ICI-induced colitis. While it is generally safe and well-tolerated, relative contraindications include active or recurrent infections, untreated tuberculosis or HBV, moderate-to-severe heart failure, or demyelinating conditions. With regard to the risk of malignancy with anti-TNF agents, a recent metaanalysis found that the risk of new cancer or cancer recurrence in patients with a history of cancer was similar to non-biologic therapies.34 The risk may be even lower in ICI-induced colitis patients who commonly receive limited induction doses rather than long-term anti-TNF maintenance therapy. IFX appears to be effective in approximately 80% of steroid-refractory patients.24,32 There are mixed data regarding whether IFX treatment affects the efficacy of ICIs by interfering with the antitumor immune response. One retrospective study found similar overall survival in patients treated with the combination of steroids and IFX versus steroids alone,12 while another retrospective study reported that patients treated with IFX and steroids exhibited reduced overall survival compared to steroids alone.35 Nevertheless, IFX appears to be generally safe and effective in this setting.

VDZ is another option for patients with steroidor IFX-refractory disease. VDZ targets the integrin α4β7 and inhibits lymphocyte trafficking to the gut with a favorable safety profile. VDZ has been used effectively in steroid and IFX non-responders, but the response rates may be lower in IFX nonresponders as these patients likely represent a more refractory population.30 VDZ therefore is an option as both a first-line biologic in steroid-refractory patients as well as rescue therapy for IFX nonresponders.

IFX and VDZ have not been compared headto- head, so choosing between the two can depend on several factors. One retrospective cohort study suggested that patients who received VDZ for ICIinduced colitis had a shorter steroid course, shorter hospital stay, and lower recurrence of diarrhea or colitis compared to patients treated with IFX, although it is unclear if the VDZ-treated patients had less severe disease.36 Extrapolating from IBD, IFX is more effective than VDZ for moderate-tosevere disease, but VDZ is associated with fewer infectious complications.37,38 VDZ also induces a response more slowly than IFX in ICI-induced colitis, with a median response time of five days for VDZ versus two days for IFX.24,30 Given these data, our general practice is to use IFX for hospitalized patients with more severe ICI-induced colitis, and VDZ for more moderate patients, patients with relative contraindications to anti-TNF therapy, or if we anticipate needing a maintenance biologic. Given its favorable side-effect profile, VDZ may have a role for secondary prophylaxis, though more data are needed. Regardless of the agent used, prompt evaluation, diagnosis, and initiation of treatment are critical. In a retrospective study, patients treated with a biologic within 10 days from onset of symptoms were found to have shorter duration of symptoms, fewer hospitalizations, and were weaned off of steroids more easily than patients treated 10 days after symptom-onset.3

Remaining Questions in Clinical Practice

As the indication for ICIs are expanding, there are many questions remaining on how to manage ICI-induced colitis. For example, when and how to safely restart ICI therapy in patients who have recovered from ICI-induced colitis requires further investigation. Treating to complete mucosal healing,40 or concomitant administration of a biologic may reduce the risk of recurrent ICIinduced colitis, but we need more studies to determine the best approach.

Beyond IFX and VDZ, data supporting other therapies are generally limited to small case series and case reports. Tofacitinib (JAK inhibitor), ustekinumab (anti-IL-12/23), and fecal microbial transplant have been described as effective in small numbers of patients who had failed steroids, IFX, and VDZ.41–45 It will be helpful to have additional data regarding how best to prioritize biologics or other treatments for refractory patients. As we learn more about the underlying microbial, immunologic, and molecular mechanisms of ICI-induced colitis, it would be ideal to identify biomarkers of patients at highest risk for severe disease and initiate primary prophylaxis.46–49 Patients with pre-existing IBD appear to be at increased risk of developing GI irAE compared to patients without IBD.49 Given that patients with IBD respond well to ICIs,50–52 immunotherapy should not be withheld,13,16 but it will be important to determine how best to optimize control of their IBD prior to immunotherapy initiation to prevent treatment-related complications.

In conclusion, ICIs have dramatically altered the treatment of many cancers and have brought hope to many patients. By virtue of their mechanism, ICIs lead to a variety of side-effects that may portend improved efficacy against their underlying malignancy. With close monitoring, prompt diagnosis, appropriate treatment, and multidisciplinary collaboration, the associated adverse effects can generally be managed effectively.

References

  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New Engl J Med. 2019;381(16):1535-1546. doi:10.1056/nejmoa1910836
  2. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol. 2014;34(1):1-35. doi:10.1146/annurev-immunol-032414-112049
  3. Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathology Mech Dis. 2020;16(1):1-27. doi:10.1146/annurev-pathol-042020-042741
  4. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148. doi:10.1016/j. ejca.2015.11.016
  5. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. New Engl J Medicine. 2015;372(21):2006-2017. doi:10.1056/nejmoa1414428
  6. Hodi FS, O’Day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. New Engl J Medicine. 2010;363(8):711-723. doi:10.1056/nejmoa1003466
  7. Prieux-Klotz C, Dior M, Damotte D, et al. Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management. Target Oncol. 2017;12(3):301-308. doi:10.1007/s11523-017-0495-4
  8. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) 5.0. undefined.
  9. Bellaguarda E, Hanauer S. Checkpoint Inhibitor–Induced Colitis. Am J Gastroenterol. 2020;115(2):202-210. doi:10.14309/ ajg.0000000000000497
  10. Som A, Mandaliya R, Alsaadi D, et al. Immune checkpoint inhibitor- induced colitis: A comprehensive review. World J Clin Cases. 2019;7(4):405-418. doi:10.12998/wjcc.v7.i4.405
  11. Collins M, Michot JM, Danlos FX, et al. Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies. Ann Oncol. 2017;28(11):2860-2865. doi:10.1093/annonc/mdx403
  12. Abu-Sbeih H, Tang T, Ali F, et al. The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients’ outcomes. J Immunother Precis Oncol. 2018;1(1):7. doi:10.4103/jipo.jipo_12_18
  13. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor (ICI) Colitis and Hepatitis: Expert Review. Gastroenterology. Published online 2020. doi:10.1053/j.gastro. 2020.08.063
  14. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):JCO.2017.77.638. doi:10.1200/jco.2017.77.6385
  15. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. doi:10.1186/s40425-017-0300-z
  16. Powell N, Ibraheim H, Raine T, et al. British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis. Lancet Gastroenterology Hepatology. 2020;5(7):679-697. doi:10.1016/ s2468-1253(20)30014-5
  17. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225
  18. Grover S, Rahma OE, Hashemi N, Lim RM. Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management. Am Soc Clin Oncol Educ Book. 2018;(38):13-19. doi:10.1200/edbk_100013
  19. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Ne. 2020;18(3):230-241. doi:10.6004/jnccn.2020.0012
  20. Abu-Sbeih H, Ali FS, Luo W, Qiao W, Raju GS, Wang Y. Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2018;6(1):95. doi:10.1186/s40425-018- 0411-1
  21. Berman D, Parker SM, Siegel J, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010;10:11.
  22. Prasanna T, McNeil CM, Nielsen T, Parkin D. Isolated immunerelated pancreatic exocrine insufficiency associated with pembrolizumab therapy. Immunotherapy. 2018;10(3):171-175. doi:10.2217/ imt-2017-0126
  23. Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis. 2018;24(8):1695-1705. doi:10.1093/ibd/izy104
  24. Foppen MHG, Rozeman EA, Wilpe S van, et al. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. Esmo Open. 2018;3(1):e000278. doi:10.1136/esmoopen-2017-000278
  25. Wright AP, Piper MS, Bishu S, Stidham RW. Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitor-induced colitis. Aliment Pharm Therap. 2019;49(12):1474-1483. doi:10.1111/apt.15263
  26. Herlihy JD, Beasley S, Simmelink A, et al. Flexible Sigmoidoscopy Rather than Colonoscopy Is Adequate for the Diagnosis of Ipilimumab-Associated Colitis. Southern Med J. 2019;112(3):154- 158. doi:10.14423/smj.0000000000000944
  27. Karamchandani DM, Chetty R. Immune checkpoint inhibitor- induced gastrointestinal and hepatic injury: pathologists’ perspective. J Clin Pathol. 2018;71(8):665. doi:10.1136/jclinpath- 2018-205143
  28. Hammami MB, Gill R, Thiruvengadam N, et al. Balancing the Checkpoint: Managing Colitis Associated with Dual Checkpoint Inhibitors and High-Dose Aspirin. Digest Dis Sci. 2019;64(3):685- 688. doi:10.1007/s10620-019-05534-5
  29. Johnson DH, Zobniw CM, Trinh VA, et al. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer. 2018;6(1):103. doi:10.1186/s40425-018-0412-0
  30. Abu-Sbeih H, Ali FS, Alsaadi D, et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor–induced colitis: a multi-center study. J Immunother Cancer. 2018;6(1):142. doi:10.1186/s40425-018-0461-4
  31. Badran YR, Cohen JV, Brastianos PK, Parikh AR, Hong TS, Dougan M. Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immunerelated adverse events. J Immunother Cancer. 2019;7(1):226. doi:10.1186/s40425-019-0711-0
  32. Ibraheim H, Baillie S, Samaan MA, et al. Systematic review with meta-analysis: effectiveness of anti-inflammatory therapy in immune checkpoint inhibitor-induced enterocolitis. Aliment Pharm Therap. 2020;52(9):1432-1452. doi:10.1111/apt.15998
  33. Weber J, Thompson JA, Hamid O, et al. A Randomized, Double- Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma. Clin Cancer Res. 2009;15(17):5591- 5598. doi:10.1158/1078-0432.ccr-09-1024
  34. Micic D, Komaki Y, Alavanja A, Rubin DT, Sakuraba A. Risk of Cancer Recurrence Among Individuals Exposed to Antitumor Necrosis Factor Therapy. J Clin Gastroenterol. 2017;53(1):e1-e11. doi:10.1097/mcg.0000000000000865
  35. Verheijden RJ, May AM, Blank CU, et al. Association of Anti- TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1–Treated Patients in the Dutch Melanoma Treatment Registry. Clin Cancer Res. 2020;26(9):2268-2274. doi:10.1158/1078-0432.ccr-19-3322
  1. Zou F, Shah AY, Glitza IC, Richards D, Thomas AS, Wang Y. S0137 Comparative Study of Vedolizumab and Infliximab Treatment in Patients With Immune-Mediated Diarrhea and Colitis. Am J Gastroenterol. 2020;115(1):S68-S68. doi:10.14309/ ajg.0000000000000848
  2. Dulai PS, Singh S, Jiang X, et al. The Real-World Effectiveness and Safety of Vedolizumab for Moderate–Severe Crohn’s Disease: Results From the US VICTORY Consortium. Am J Gastroenterol. 2016;111(8):1147-1155. doi:10.1038/ajg.2016.236
  3. Colombel J-F, Sands BE, Rutgeerts P, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66(5):839. doi:10.1136/gutjnl-2015-311079
  4. Abu-Sbeih H, Ali FS, Wang X, et al. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis. J Immunother Cancer. 2019;7(1):93. doi:10.1186/s40425- 019-0577-1
  5. Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to- Target strategies in IBD. Gastroenterology. Published online 2021. doi:10.1053/j.gastro.2020.12.031
  6. Esfahani K, Hudson M, Batist G. Tofacitinib for Refractory Immune-Related Colitis from PD-1 Therapy. New Engl J Med. 2020;382(24):2374-2375. doi:10.1056/nejmc2002527
  7. Bishu S, Melia J, Sharfman W, Lao CD, Fecher LA, Higgins PDR. Efficacy and outcome of Tofacitinib in Immune checkpoint inhibitor colitis. Gastroenterology. 2020;160(3):932-934.e3. doi:10.1053/j.gastro.2020.10.029
  8. Thomas AS, Ma W, Wang Y. Ustekinumab for Refractory Colitis Associated with Immune Checkpoint Inhibitors. New Engl J Med. 2021;384(6):581-583. doi:10.1056/nejmc2031717
  9. Wang Y, Ma W, Abu-Sbeih H, Jiang Z-D, DuPont HL. Fecal microbiota transplantation (FMT) for immune checkpoint inhibitor induced–colitis (IMC) refractory to immunosuppressive therapy. J Clin Oncol. 2020;38(15_suppl):3067-3067. doi:10.1200/ jco.2020.38.15_suppl.3067
  10. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591- 018-0238-9
  11. Luoma AM, Suo S, Williams HL, et al. Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy. Cell. 2020;182(3):655-671.e22. doi:10.1016/j.cell.2020.06.001
  12. Dubin K, Callahan MK, Ren B, et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockadeinduced colitis. Nat Commun. 2016;7(1):10391. doi:10.1038/ ncomms10391
  13. Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368-1379. doi:10.1093/annonc/mdx108
  14. Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME. Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease. Ann Intern Med. 2018;169(2):133. doi:10.7326/l18-0209
  15. Abu-Sbeih H, Faleck DM, Ricciuti B, et al. Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease. J Clin Oncol. 2020;38(6):576-583. doi:10.1200/ jco.19.01674
  16. Gielisse EAR, Boer NKH de. Ipilimumab in a patient with known Crohn’s disease: To give or not to give? J Crohn’s Colitis. 2014;8(12):1742-1742. doi:10.1016/j.crohns.2014.08.002
  17. Bostwick AD, Salama AK, Hanks BA. Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis. J Immunother Cancer. 2015;3(1):19. doi:10.1186/s40425-015-0064-2

Download Tables, Images & References

Medical Bulletin Board

Echosens Launches Smartexam®: Fibroscan® Software Upgrade Unlocks the True Power of Company’s Innovative and Differentiated Technology

June 2021 • Volume XLV, Issue 6

Read Article

New product and software update for existing devices available
May 12, 2021

WALTHAM, MA – Echosens, a high-technology company offering the FibroScan family of products, is pleased to announce the launch of SmartExam®, innovative technology designed to take examinations with FibroScan to an even greater level of accuracy, specificity and reliability as a non-invasive diagnostic solution for measuring liver fat and stiffness. SmartExam unlocks three key benefits for users: improved reliability in the diagnosis and monitoring of steatosis with continuous controlled attenuation parameter (CAP™); extended usage among severely obese patients with deeper assessment of liver fibrosis and steatosis; and optimized patient care with task automation features that enable physicians to dedicate more time to patient care.

“SmartExam is another example of our commitment to innovation pushing the identification and monitoring of liver disease, lifestyle change and therapeutic interventions to the next level,” says Jon Gingrich, CEO, Echosens North America. “SmartExam’s new computation method allows for a continuous measurement of CAP™ during the entire examination, which reduces variability* by 42%.** In addition, SmartExam offers a 28% increase* in probe-to-capsule distance to improve accuracy and reliability among severely obese patients.** Finally, the new task automation features guide operators through exams, making the examination process easier and faster than ever. We are thrilled to provide this innovative software to our customers.”

This critical diagnostic tool enables heath care professionals to make more informed treatment decisions about liver health and may reduce the need for expensive and more invasive testing to detect liver disease. This important upgrade provides key benefits for clinics and the patients they serve.

Estimates show that 357 million people will have nonalcoholic steatohepatitis (NASH) globally by 2030. NASH can often lead to advanced fibrosis and liver cancer, liver transplantation, increased risk of cardiovascular events and all-cause mortality. As the twin epidemics of liver disease and obesity continue to grow, and because of the prevalence and associated costs of underdiagnosed liver disease—which is now linked to over $100 billion in annual direct costs—FibroScan is gaining traction among U.S. physicians and specialists.

A nurse at French Cochin University Hospital states, “The obese population that we receive for FibroScan examinations has increased substantially in recent years. CAP has become essential to our prescribers to precisely monitor patient’s steatosis. SmartExam allows us to address complex patients and provide more reliable results.”

* CAP for pediatric patients with liver disease is only available with SmartExam capability.

** Audière et al. EASL 2020 poster #FRI-073– 42% is the variability decrease computed on a patient’s cohort scanned with the M probe.

*** Without SmartExam, the maximum recommended Probe-to-Capsula distance (PCD) is 35 mm. With SmartExam, it is 45mm, representing an increase of 28%.

**** Only for M and XL probes.

About Echosens

Echosens, the developer of FibroScan®, is an innovative high-technology company offering a full range of products and services supporting physicians in their assessment and management of patients with chronic liver diseases. FibroScan is supported by over 2,500 peer-reviewed publications and examinations are covered by Medicare, Medicaid and many insurance plans.

For more information, please visit: echosens.com

Download Tables, Images & References

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #211

Beyond the Banana Bag: Treating Nutritional Deficiencies of Alcohol Withdrawal Syndrome

June 2021 • Volume XLV, Issue 6
Brian D. Peterson,Matthew Stotts

Read Article

Excessive alcohol consumption can lead to a variety of health complications. With abrupt cessation or reduction in alcohol intake, individuals may experience alcohol withdrawal syndrome (AWS), with symptoms ranging from mild tremors to life-threatening seizures. To prevent well-described symptomatic nutritional deficiencies and severe electrolyte abnormalities, hospitalized patients are often placed on institutional protocols to manage both their withdrawal symptoms and concomitant nutrient deficiencies. These protocols often differ among health systems in their approach to nutrient replacement, primarily due to a lack of high-quality evidence for dosing. This review focuses on nutritional challenges seen in these individuals with AWS, with specific focus on immediate repletion strategies to prevent the neurologic and hematologic sequelae of common micronutrient deficiencies. This review also offers practical strategies to transition to outpatient repletion to minimize chronic nutritional deficiencies.

INTRODUCTION

Alcohol use disorder (AUD) is a common diagnosis encountered by health care providers both in the hospital and outpatient settings. The lifetime prevalence of AUD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), has increased over the last 20 years, with estimates up to 30% of non-institutionalized United States adults, leading to higher incidences of alcoholrelated health problems such as liver dysfunction and alcohol withdrawal syndrome (AWS).1,2 While patients with AUD are often admitted to hospitals for reasons other than AWS, those at high risk for AWS are often screened with the Prediction of Alcohol Withdrawal Severity Scale (PAWSS) and monitored with the Clinical Institute Withdrawal for Alcohol (CIWA). The latter scoring system correlates symptoms to the required dose of benzodiazepines or barbiturates needed to prevent life threatening symptoms of AWS.

Individuals with AUD are known to be at high risk for nutritional deficiencies and severe electrolyte derangements. Hospital protocols often include supplementing micronutrients such as thiamine, folic acid, and a variety of minerals. To date, there are few high-quality studies investigating the optimal dosing of deficient nutrients for patients treated for AWS. This lack of standardized, evidenced-based dosing strategies increases the potential that patients may receive insufficient repletion, leading to progression of nutritional deficiencies and their sequelae.

Alternatively, they may receive a longer duration of supplementation than required, leading to a high pill burden without significant benefit.

Micronutrients

Individuals with AUD may be deficient in micronutrients for a variety of reasons. In addition to heavy alcohol use often being associated with a poor diet, alcohol ingestion can directly cause malabsorption as well as electrolyte disturbances through alterations in renal tubular function.3 Providers must be aware of strategies for monitoring and replacing these micronutrients.

Thiamine

Thiamine (Vitamin B1) is a common micronutrient deficiency seen in those with AUD. It is a ubiquitous water-soluble vitamin found in whole grains, meats, and fish and is absorbed in the small intestine by both active transport and passive diffusion. Only a small percentage is stored outside of the plasma, primarily in the liver. Due to its short half-life and limited stores (~ 21 days), frequent ingestion of thiamine containing foods or supplements is required.4

Thiamine deficiency is uncommon in healthy individuals, as most developed countries fortify their grains and cereals with thiamine to ensure the population meets the adult recommended daily allowance (RDA) of approximately 1.1- 1.2mg per day.5 People with AUD can become thiamine deficient through a combination of decreased intake of thiamine rich foods and decreased hepatic storage. Animal models have shown direct inhibition of duodenal transport by ingested alcohol. However, the clinical relevance is unclear with several clinical studies failing to show decreased duodenal thiamine uptake with active alcohol use.6 There are two available ways to assess thiamine status:

1. Directly measuring thiamine diphosphate serum levels

2. Measuring the function of the thiamine dependent erythrocyte transketolase enzyme7

The clinical utility of either test is unclear due to a lack of experimental data showing an association between low measured thiamine and severity of clinical symptoms. Additionally, the turn-around time is too long (7-10 days) to be useful in urgent clinical decision making.

Early symptoms of thiamine deficiency include short-term memory loss, weakness, and peripheral neuropathy. While thiamine deficiency induced congestive heart failure (wet beriberi) rarely occurs in developed countries, Wernicke-Korsakoff syndrome (WKS) is a common manifestation of thiamine deficiency in the United States.8 WKS initially presents with Wernicke’s Encephalopathy (WE), a reversible clinical syndrome characterized by a triad of altered mental status, gait ataxia, and nystagmus. If untreated, WE can progress to the chronic, irreversible neuronal changes of Korsakoff’s Syndrome (KS), characterized by retrograde and anterograde memory loss. Different studies cite the prevalence of WKS as high as 60% in patients with AUD.9 Alarmingly, about 80% of patients with WKS are diagnosed at autopsy, indicating that the syndrome often goes untreated.11 It is difficult to predict which patients are most at risk for developing symptoms of thiamine deficiency due to differences in genetic susceptibilities, alcohol consumption, and diet.Early symptoms of thiamine deficiency include short-term memory loss, weakness, and peripheral neuropathy. While thiamine deficiency induced congestive heart failure (wet beriberi) rarely occurs in developed countries, Wernicke-Korsakoff syndrome (WKS) is a common manifestation of thiamine deficiency in the United States.8 WKS initially presents with Wernicke’s Encephalopathy (WE), a reversible clinical syndrome characterized by a triad of altered mental status, gait ataxia, and nystagmus. If untreated, WE can progress to the chronic, irreversible neuronal changes of Korsakoff’s Syndrome (KS), characterized by retrograde and anterograde memory loss. Different studies cite the prevalence of WKS as high as 60% in patients with AUD.9 Alarmingly, about 80% of patients with WKS are diagnosed at autopsy, indicating that the syndrome often goes untreated.11 It is difficult to predict which patients are most at risk for developing symptoms of thiamine deficiency due to differences in genetic susceptibilities, alcohol consumption, and diet.

Folic Acid

Folic acid (Vitamin B9) is an essential nutrient obtained from leafy vegetables, broccoli, chickpeas and fortified grains. Folic acid is an important cofactor in DNA synthesis and amino acid production. The liver accounts for 50% of the total body folic acid storage with the remaining 50% stored in the blood and bone marrow. Patients with AUD become deficient through decreased dietary intake, diminished intestinal absorption, increased renal losses, and disrupted hepatobiliary conversion to active metabolites. Fortunately, folic acid deficiency is uncommon in the United States since widespread grain fortification in 1998.3

The most common sign of folic acid deficiency is macrocytic anemia without the neurologic sequelae of B12 deficiency. Replacing folate may improve macrocytic anemia, but could worsen neurologic symptoms such as dementia, depression, peripheral neuropathy, or subacute combined spinal cord degeneration if a B12 deficiency is also present. The mechanism for neurologic worsening after folic acid replacement is poorly understood so it is important to treat concomitant B12 deficiencies prior to giving folic acid.10,12 Common symptoms of folic acid deficiency include weakness, fatigue, shortness of breath and skin and hair changes.13 There is also evidence that folate deficiency and the subsequent hyperhomocysteinemia can increase the risk for alcohol withdrawal seizures.14

Magnesium

Magnesium is a dietary nutrient found in leafy vegetables, meats, and nuts. Hypomagnesemia occurs in about 30% of patients with AUD due to inadequate dietary intake, poor absorption, and alcohol-induced urinary losses.15 Importantly, magnesium plays a role in the homeostasis of other important electrolytes; hypomagnesemia can lead to both hypocalcemia by inhibiting parathyroid hormone and to hypokalemia through increased urinary losses15,16 Magnesium also plays a role in thiamine homeostasis by functioning as a cofactor for the enzyme transketolase. Patients with suspected WE who fail to improve after thiamine repletion may have a more robust response after magnesium correction.17,18 The degree of hypomagnesemia in patients presenting with AWS correlates with more severe symptoms of withdrawal and an increase in 1 year mortality.5 Symptoms of hypomagnesemia include neuromuscular manifestations (muscular weakness, tremors, positive Trousseau’s sign) and cardiac complications leading to arrhythmias and possible sudden death.15

Phosphorus

Phosphorus is an important micronutrient commonly found in meats, nuts and dairy products. Individuals with chronic alcohol use often have deficits in their total body stores of phosphorous due to inadequate dietary intake of foods rich in phosphate and frank malnutrition in some. These patients also have urinary losses from alcoholinduced renal tubular dysfunction.15 A total body deficit of phosphorus often becomes apparent after correction of underlying alcoholic ketoacidosis and glucose administration, leading to phosphate shifting into cells for glucose phosphorylation and ATP production.

Other Micronutrients

A variety of other micronutrient deficiencies have been associated with AUD, including other water-soluble vitamins such as niacin, pyridoxine, cobalamin (B12), riboflavin in addition to fatsoluble vitamins and trace elements like zinc, selenium, and iron.

Initial Acute Management

When individuals with chronic heavy alcohol use present to the hospital, providers should be aware of the potential nutritional deficiencies that are likely present and aim to adequately replete these nutrients to prevent both short and long-term clinical consequences. Malnourished patients can experience refeeding syndrome when starting nutrition repletion, leading to life threatening fluid shifts and depletion in phosphorus, magnesium, and potassium. Severely malnourished patients should be closely monitored for clinical and laboratory signs of refeeding syndrome and treated timely and effectively.19

Approach to Thiamine Repletion

Thiamine is a universal component of vitamin repletion protocols in AWS. The goal of thiamine repletion is to replenish circulating concentrations as quickly as possible to ensure central nervous system availability and both prevent and treat Wernicke’s long before it develops into Korsakoff syndrome.

The heterogeneity in alcohol consumption, genetic predisposition, and dietary intake makes it difficult to develop general thiamine replacement guidelines in patients presenting with AWS.20 A Cochrane review from 2013 revealed a lack of high-quality evidence to guide clinicians in choosing the proper dose, route, and frequency of thiamine for at risk patients.21 Currently, dosing strategies for thiamine rely on expert opinion and often differ among institutions and professional societies (Table 1). The historical dose of 100mg IV thiamine daily was arbitrarily chosen in the 1950s because it represented a high dose at that time. This dose has persisted through use of the “banana bag” for AWS, which often contained 100mg IV thiamine per bag, among other vitamins and minerals.22 This thiamine dose is likely insufficient in magnitude and dosing frequency for high-risk individuals. The plasma half-life of thiamine is approximately 1.5 hours, which leads some authors to suggest a required dosing interval of every 8-12 hours in patients at risk for WE.22,23 Notably, oral preparations should be avoided in patients with AWS due to poor intestinal absorption.24 Data from the UK National Health Service (NHS) has shown that a 5-day course of IV/IM thiamine supplementation was associated with large savings compared to shorter courses, primarily through preventing progression to Korsakoff syndrome and associated costs caring for debilitated patients in long term care facilities.25

While high-quality data on dosing regimens and duration are limited, potential guiding principles for clinicians to consider include (Table 2):

  1. Prophylactically replacing thiamine in all patients presenting with alcohol withdrawal syndrome can prevent permanent symptoms of WKS and reduce associated healthcare costs.
  2. Administering thiamine as soon as possible given evidence for developing WE after prolonged glucose administration without thiamine replacement.26
  3. Oral bioavailability in patients with AWS is poor and initial therapy should favor IV/IM repletion. Often the intravenous therapy is continued for 2-3 days before transitioning to an oral regimen.
  4. The short half-life of thiamine necessitates multiple doses per day in high-risk patients.
  5. Long term oral supplementation should be considered in individuals who remain at nutritional risk with high probability of continued alcohol misuse. Higher doses than the typical RDA are likely needed to compensate for poor absorption during active alcohol consumption (typically 100mg oral thiamine/day).

Approach to Folic Acid Repletion

The upper limit for folic acid supplementation in a healthy adult is approximately 1 mg per day.12 The bioavailability of oral supplementation approaches 100% when consumed without food or alcohol. In cases of severe, symptomatic megaloblastic anemia when enteral access is lost or difficult to obtain, IV or IM preparations can be used. There are no high-quality studies or guidelines for how long to treat with supplemental folic acid. It is reasonable in patients with mild megaloblastic anemia to supplement 1mg by mouth daily for several months until their anemia has resolved. Higher risk patients may benefit from indefinite 1mg oral folic acid supplementation. Concomitant multivitamin with minerals supplementation should be evaluated for folic acid content to avoid dosing over the recommended daily upper limit. Typical multivitamins contain about 400mcg folic acid.

Unlike thiamine, which does not seem to have adverse physiologic effects from high dosages, folic acid supplementation above the recommended daily allowance (RDA) of 1 mg by mouth daily is controversial and has been linked to increased cancer risk and neurocognitive changes in some populations.27 To date, there are no randomized controlled trials evaluating the optimal folic acid dosing strategy for patients at risk for alcohol withdrawal seizures. In 2015, the National Toxicology Program with the US Department of Health and Human Services developed a comprehensive needs assessment for further research into optimal folic acid dosing.28 This needs assessment should spur research into optimal folic acid dosing to help guide future patient management.

Approach to Magnesium Repletion

Serum magnesium levels are a poor representation of total body magnesium status because 99% of the body’s magnesium is stored intracellularly.29 However, serum magnesium is the most common test used to guide replacement. Clinicians should be aware that a normal serum magnesium level may mask a total body magnesium deficit. See Table 3 for dosing strategies. Patients with reduced renal function should receive approximately 25-50% of the recommended dosages.30 Oral dosing can be split into two daily doses to avoid causing diarrhea. Serum magnesium levels should be checked at least daily in patients with AUD or more frequently in patients with symptomatic hypomagnesemia. Of note, patients receiving multiple intravenous doses of magnesium should be monitored for EKG changes. Magnesium replacement and monitoring after hospital discharge should be considered in some patients due to total body storage depletion and continued urinary losses from alcohol induced renal tubular dysfunction.15

Approach to Phosphorus Repletion

Patients at risk for refeeding syndrome should be treated in the hospital setting due to the need for frequent laboratory monitoring.31 While ongoing alcohol use will place individuals at risk for ongoing phosphorus loss, abnormalities in the excretion of urinary phosphate typically resolves after a few weeks of ongoing abstinence. Table 3 gives an approach to managing hypophosphatemia in the inpatient and ambulatory settings. Importantly, phosphorus repletion should be enteral except in cases of extreme depletion (<1.0mg/dL) due to the risk of calcium chelation with rapid IV phosphorus administration.31

Other Micronutrient Deficiencies

In addition to the previously discussed micronutrients, there are multiple other important nutrient deficiencies in patients presenting with AWS that should be considered. These micronutrients can be replaced using a daily multivitamin with minerals (MVM), often continued indefinitely while actively consuming alcohol. Providers should realize that over the counter multivitamins may not include the essential minerals needed. Patients are encouraged to ask their pharmacist or health care provider for specific MVM recommendations.

Transition to Outpatient Management

After recovering from AWS with an initial period of aggressive micronutrient supplementation, the need for additional nutrient replacement depends on an individual’s nutritional and social needs. Factors such as employment status, social support, food insecurity, and housing status have been shown to correlate with increased alcohol use and worsened nutritional status.32 As an example, a meta-analysis from 2018 investigated the efficacy of nutritional interventions in homeless patients with AUD and found that several interventions (particularly providing meal services) could improve nutrition related behavior, although the data was insufficient in determining long term outcomes in nutrition status and disease progression.33

It is reasonable to discharge all individuals with recommendations for nutritional supplementation until they can be assessed by their outpatient provider. A complete multivitamin with minerals (MVM) is an efficient and affordable way to deliver essential micronutrients. Notably the dose of thiamine in these may be inadequate in those with ongoing heavy alcohol use.

CONCLUSION

Strategies to replete micronutrient deficiencies in patients presenting with AWS vary among institutions and individual providers due to a lack of prospective or randomized studies. Thiamine deficiency is one of the most concerning and potentially underdiagnosed nutrient deficiencies seen in this population. Thiamine replacement should be given intravenously 2-3 times a day in those who have symptoms of deficiency or are at high risk. Specific attention must be given to magnesium and phosphorous repletion based on serum levels in those at risk for refeeding syndrome. Folic acid repletion at 1 mg daily likely provides adequate treatment for deficient states. A daily MVM is a reasonable strategy to provide the remaining vitamins and minerals that are commonly deficient in this population. There are no studies examining long term benefits of outpatient nutrient replacement in patients with AUD and, hence, providers should individualize supplementation strategies based on the level of ongoing alcohol use, dietary intake, financial status and signs and symptoms of deficiency.

References

  1. Grant BF, Goldstein RB, Saha TD, et al. Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72(8):757-766.
  2. Grant BF, Chou SP, Saha TD, et al. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 2017;74(9):911-923.
  3. Medici V, Halsted CH. Folate, alcohol, and liver disease. Mol Nutr Food Res. 2013;57(4):596-606.
  4. Osiezagha K, Ali S, Freeman C, et al. Thiamine deficiency and delirium. Innov Clin Neurosci. 2013;10(4):26-32.
  5. Maguire D, Talwar D, Burns A, et al. A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with alcohol withdrawal syndrome. J Transl Med. 2019;17(1):384.
  6. Rees E, Gowing LR. Supplementary thiamine is still important in alcohol dependence. Alcohol. Jan-Feb 2013;48(1):88-92.
  7. Whitfield KC, Bourassa MW, Adamolekun B et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
  8. Arts NJ, Walvoort SJ, Kessels RP. Korsakoff’s syndrome: a critical review. Neuropsychiatr Dis Treat. 2017;13:2875-2890.
  9. Donnino MW, Vega J, Miller J, et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50(6):715-721.
  10. Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19995-20000.
  11. Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry. 1986 ;49(4):341-5.
  12. Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol. 2014;120:927-943.
  1. National Institutes of Health Office of Dietary Supplements (2021, January 15). Folate. Ods.od.nih.gov/factsheets/Folate- HealthProfessional/.
  2. Bleich S, Degner D, Bandelow B, et al. Plasma homocysteine is a predictor of alcohol withdrawal seizures. Neuroreport. 2000;11(12):2749-2752.
  3. Palmer BF, Clegg DJ. Electrolyte Disturbances in Patients with Chronic Alcohol-Use Disorder. N Engl J Med. 2017;377(14):1368-1377.
  4. Ayuk J, Gittoes NJ. How should hypomagnesaemia be investigated and treated? Clin Endocrinol (Oxf). 2011;75(6):743-746.
  5. Traviesa DC. Magnesium deficiency: a possible cause of thiamine refractoriness in Wernicke-Korsakoff encephalopathy. J Neurol Neurosurg Psychiatry. 1974;37(8):959-962.
  6. Peake RW, Godber IM, Maguire D. The effect of magnesium administration on erythrocyte transketolase activity in alcoholic patients treated with thiamine. Scott Med J. 2013;58(3):139- 142.
  7. Friedli N, Odermatt J, Reber E, et al. Refeeding syndrome: update and clinical advice for prevention, diagnosis and treatment. Curr Opin Gastroenterol. 2020 Mar;36(2):136-140.
  8. Thomson AD, Marshall EJ. The natural history and pathophysiology of Wernicke’s Encephalopathy and Korsakoff’s Psychosis. Alcohol Alcohol. 2006;41(2):151-158.
  9. Day E, Bentham PW, Callaghan R. Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. Cochrane Database Syst Rev. 2013 Jul 1;2013(7):CD004033.
  10. Flannery AH, Adkins DA, Cook AM. Unpeeling the Evidence for the Banana Bag: Evidence-Based Recommendations for the Management of Alcohol-Associated Vitamin and Electrolyte Deficiencies in the ICU. Crit Care Med. 2016;44(8):1545-1552.
  11. Tallaksen CM, Sande A, Bøhmer T, et al. Kinetics of thiamin and thiamin phosphate esters in human blood, plasma and urine after 50 mg intravenously or orally. Eur J Clin Pharmacol. 1993;44(1):73-78.
  12. Thomson AD. Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke- Korsakoff syndrome. Alcohol Alcohol Suppl. 2000;35(1):2-7.
  13. Wilson EC, Stanley G, Mirza Z. The Long-Term Cost to the UK NHS and Social Services of Different Durations of IV Thiamine (Vitamin B1) for Chronic Alcohol Misusers with Symptoms of Wernicke’s Encephalopathy Presenting at the Emergency Department. Appl Health Econ Health Policy. 2016;14(2):205-215.
  14. Schabelman E, Kuo D. Glucose before thiamine for Wernicke encephalopathy: a literature review. J Emerg Med. 2012;42(4):488-494.
  15. Pieroth R, Paver S, Day S, et al. Folate and Its Impact on Cancer Risk. Curr Nutr Rep. 2018;7(3):70-84.
  16. National Toxicology Program US Department of Health and Human Services (2015, August). Identifying Research Needs for Assessing Safe Use of High Intakes of Folic Acid. https:// ntp.niehs.nih.gov/ntp/ohat/folicacid/final_monograph_508.pdf
  17. Auyk J, Gittoes NJL. How should hypomagnesemia be investigated and treated? Clin Endocrinol (Oxf). 2011 Dec;75(6):743-6.
  18. Assadi F. Hypomagnesemia: an evidence-based approach to clinical cases. Iran J Kidney Dis. 2010 Jan;4(1):13-9
  19. Reber E, Friedli N, Vasiloglou MF, et al. Management of Refeeding Syndrome in Medical Inpatients. J Clin Med. 2019;8(12).
  20. Santolaria F, Perez-Manzano JL, Milena A et al. Nutritional assessment in alcoholic patients. Its relationship with alcoholic intake, feeding habits, organic complications and social problems. Drug Alcohol Depend. 2000 Jun 1;59(3):295-304.
  21. Ijaz S, Thorley H, Porter K. Interventions for preventing or treating malnutrition in homeless problem-drinkers: a systematic review. Int J Equity Health. 2018 Jan 16;17(1):8.
  22. Knudsen AW, Jensen JEB, Norgaard-Lassen I, et al. Nutritional intake and status in persons with alcohol dependencey: data from an outpatient treatment programme. Eur J Nutr. 2014 Oct;53(7):1483-92.
  23. The ASAM Clinical Practice Guideline on Alcohol Withdrawal Management. J Addict Med. May/Jun 2020;14(3S Suppl 1):1-72.
  24. Haber P. Guidelines for the Treatment of Alcohohol Problems. Australian Government Department of Health and Ageing. June 2009. Online ISBN: 1-74186-977-3.
  25. Lingford-Hughes AR, Welch S, Peters L et al. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from the BAP. J Psychophamacol. 2012 Jul;26(7):899-952.
  26. Galvin R, Brathen G, Ivashynka A, et al. ESNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010 Dec;17(12):1408-18.
  27. National Collaborating Centre for Mental Health (UK). NICE Clinical Guidelines, No 115. Alcohol-Use Disorders: Diagnosis, Assessment, and Management of Harmful Drinking and Alcohol Dependence. Leicester (UK): British Psychological Society; 2011.
  28. Thomson AD, Cook CCH, Touquet R et al. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke’s encehpalopathy in the accident and Emergency Department. Alcohol Alcohol. Nov-Dec 2002;37(6):513-21.
  29. Thomson AD, Guerrini I, Marshal J. The evolution and treatment of Korsakoff’s syndrome: out of sight, out of mind? Neuropsychol Rev. 2012 Jun;22(2):81-92.

Download Tables, Images & References

GUIDELINES FOR AUTHORS

Guidelines for Authors

June 2021 • Volume XLV, Issue 6

Read Article

Practical Gastroenterology publishes articles for the primary care physician, and your article should therefore have a nuts-and-bolts slant. We urge you to keep the nonspecialist in mind as you write your article. We cannot stress strongly enough the importance of focusing your article on information that will be useful and instructive to the primary care physician. In this regard, it would be helpful for you to emphasize prevention and cost (of tests, drugs, surgery, hospital stay, procedures, techniques, etc.) whenever and wherever possible.

We offer the following list to help you conform to our mechanical requirements:

  1. Please submit one copy of your manuscript as a Microsoft Word file, typed on 8½″ × 11″ pages with 1″ margins, double-spaced throughout, including references, tables and figure legends. Ideally, the length of the manuscript should be 2000–2500 words (10–13 pages). Manuscripts should be submitted via e-mail to: PracticalGastro@aol.com
  2. Manuscripts must be submitted as Microsoft Word files without automatic footnoting and as final format documents (without indications of markup).
  3. Tables should be submitted with titles. If the table has been previously published, identify the source and provide all information that would be included in a standard reference list (see below), along with indication that permission to republish has been obtained. It is your responsibility to obtain permission.
  4. Figures and illustrations (photographs, drawings, charts) help explain the text, add to the visual appeal of the published article, and are very welcome. Each table should have a title, and each figure should have an accompanying legend. If figures and illustrations have been previously published, you should identify the source and provide all information that would be included in a standard reference list (see below), along with indication that permission to republish has been obtained. It is your responsibility to obtain permission. All figures and illustrations must be supplied in JPEG format and must be identified as Figure 1, Figure 2, etc. When e-mailing figures and illustrations, do not embed them into a text document. Each JPEG should be sent as a separate document attached to the e-mail. Tables, figures and Illustrations should not be submitted as Excel spreadsheets or in Power Point.
  5. The title page should include the names, addresses, phone numbers, complete titles and affiliations of all authors.
  6. A color head-shot photograph of each author should accompany the manuscript. These will be published with your article. These must be submitted as JPEG files.
  7. An abstract of 125–150 words should also accompany your paper. This will be published at the beginning of your article. Please do not exceed the 150-word limit.
  8. References should be used sparingly and cited in the body of the paper using consecutive superscript (raised) numbers. The references section should be numbered consecutively in the order in which the references are cited in the text. References should follow AMA style, and journal names should be abbreviated according to Index Medicus practice. Inclusive page ranges should be indicated. The following references illustrate AMA style:
  1. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416.
  2. Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med. 2008;168:378-81.
  1. Articles will be copyrighted upon publication by Practical Gastroenterology Publishing, Inc. The manuscript must not have been published previously. Each article we publish is subject to review by members of our Editorial Board. Articles are also subject to final editing.

Download Tables, Images & References

A SPECIAL ARTICLE

Benign Rectal Strictures: A Review Article

June 2021 • Volume XLV, Issue 6
Ammar Ahmad,Padmini Krishnamurthy

Read Article

The aim of this review article is to assess the various etiologies and different management techniques for benign rectal strictures. A systematic review was performed using PubMed central using the keywords that included ‘benign’, ‘stricture or strictures’, and ‘rectum, rectal, or anorectal’. Retrospective studies, prospective studies, case series, and case reports describing etiology or management of benign rectal strictures were included in this review article. A total of 730 cases of benign rectal strictures were identified in 79 articles. Anastomotic stricture was the most common cause of benign rectal strictures. Different techniques were used to manage benign rectal strictures including Hegar dilation, balloon dilation, stent placement, microsurgery, or other surgical techniques. The initial technique used for management was dependent on the provider as there are no clear guidelines for management of benign rectal strictures.

INTRODUCTION

Benign rectal strictures can be iatrogenic after a major colorectal surgery or spontaneous due to medical conditions. The most common cause of benign rectal strictures are anastomotic strictures. Rectal strictures behave differently from colonic strictures due to rectum’s anatomical relation with the anal canal, proximity to pelvic organs, and unique blood supply. Different management techniques such as surgical repair, endoscopic balloon dilation, rectal stent placement, medical treatment alone, or a combination of treatments have been used to treat benign rectal strictures. In this article, we describe the etiologies and management of benign rectal strictures.

Methods

A PubMed Central search was carried out, using the search term (benign) AND (stricture or strictures) AND (rectum or rectal or anorectal). Only articles that described strictures known to be benign at the time of diagnosis were included. Retrospective studies, prospective studies, case series, and case reports were included. Content from references found in the articles were included if deemed relevant. In total, 79 articles are included in this review article.

Clinical Presentation

Rectal strictures can present with minor symptoms to progressive constipation and on occasion, obstipation. Symptoms include left lower quadrant abdominal pain, increased frequency of bowel movements, difficulty in defecation, feeling of inadequate evacuation, pencil-thin stools, anal pain, and fecal urgency. Stenosis is often defined as inability to pass a 12mm diameter sigmoidoscope1 or narrowing to less than one-finger breadth by digital rectal examination.2

Etiology of Rectal Strictures

Anastomotic strictures are the most common cause of benign rectal strictures. Non-operative etiologies of rectal strictures include inflammatory bowel disease, rectal ischemia, sexually transmitted disease, radiation, endometriosis, pelvic actinomycosis, chronic suppository usage, and solitary rectal ulcer.3–17 Few cases of strictures have been reported after submucosal endoscopic dissection.18

Anastomotic Rectal Strictures

Post-operative anastomotic strictures develop in 3 to 30% of patients undergoing colorectal resection.3,19-22 Anastomotic rectal strictures are predominantly seen following resection of rectal cancer with colorectal or coloanal anastomosis (with residual rectal cuff). Other surgeries that can lead to anastomotic rectal strictures include hemorrhoidectomy and colorectal resection for extensive diverticular disease.1,22 Rectal strictures are more likely to form after stapled anastomosis compared to hand-sewn anastomosis.22–27 Ischemia, post-operative anastomotic leakage, and postoperative radiation are major risk factors for development of anastomotic strictures.2,19,22,28,29 Other contributing factors include obesity, incomplete “doughnut” construction, low-lying anastomosis, and post-operative infection.19,30 Temporary diverting ileostomy or colostomy may contribute to anastomotic strictures due to absence of dilation of anastomosis by fecal stream.31–33

Inflammatory Bowel Disease (IBD)

Anorectal strictures are more commonly seen in Crohn’s disease but can also be seen in ulcerative colitis. They are frequently present with fistulizing disease and proctitis.8,34 Rectal stricture in ulcerative colitis may portend development of cancer. The pathophysiology remains speculative since both inflammatory and fibrotic components frequently occur in anorectal strictures in patients with inflammatory bowel disease. The presence of anorectal strictures in Crohn’s disease is a predictor of poor outcomes.9

Miscellaneous Etiologies of Rectal Strictures

Radiation Induced Rectal Strictures

Rectal stricture is a rare complication of pelvic irradiation. Chronic radiation proctitis has been reported in up to 20% of patients receiving radiation of the pelvis, and rectal stricture occurs in about 1 to 15% of these cases.35 Radiation causes histologic alterations such as obliterative endarteritis, tissue ischemia and necrosis leading to submucosal collagen deposition. These changes result in transmural fibrosis and formation of rectal strictures.2

Infectious Rectal Strictures

Sexually transmitted infections (STIs) due to anal intercourse have been reported to cause rectal strictures in both HIV and non-HIV patients. Lymphogranuloma venereum caused by chlamydia trachomatis is the most frequently reported sexually transmitted infection to cause rectal strictures.5 A case report implicating HSV-2 as the cause of benign rectal stricture has been reported.4 These strictures can occur in HIV patients even with CD4 counts > 200 x 106/L. Biopsies with histological evaluation using special stains and serology is used to confirm diagnosis.5 Rare cases of rectal strictures due to actinomycosis infection have also been reported due to contiguous spread from intrauterine devices.10,17

Foreign Body Strictures

Benign rectal strictures can develop due to reactive inflammation and fibrosis around a foreign body.6 Strictures can develop following rectal administration of cation binding resins such as sodium polystyrene sulfonate or calcium polystyrene sulfonate and are usually diagnosed by presence of characteristic crystals on histology.36 Chronic suppository usage is also noted to cause anorectal stenosis and strictures due to chronic reactive inflammation.11,12

Endometriosis

Endometriosis should be suspected in women presenting with rectal stricture at a young age without any other explanation for the stricture. These patients generally have menstrual irregularity and cyclic abdominal pain that worsens during menstruation. The presence of ectopic endometrial tissue in the muscularis propria and subserosa or mesentery is thought to be the cause of the stricture.7

Solitary Rectal Ulcer Syndrome

Solitary rectal ulcer Syndrome is a benign disease that is often missed as a cause of rectal bleeding. It is thought to occur due to chronic hypoperfusion leading to ischemic injury to the rectal mucosa. Rarely, it can lead to stenosis or stricture of the rectum. Symptoms generally include chronic constipation, abdominal pain, rectal bleeding, and mucosal discharge.14,37

Ischemic Rectal Stricture

Ischemic proctitis is rare because the rectum has abundant blood supply and rich collaterals. A stricture due to ischemic proctitis develops due to acute compromise in blood flow usually in the setting of hypovolemic shock in patients with inadequate collateral circulation around the rectum.38

Complication of Submucosal Dissection

Endoscopic submucosal dissection is widely used as a minimally invasive treatment for colorectal neoplasms. It can help avoid surgical treatments that can result in anal dysfunction and the need for permanent colostomy. Although rare, endoscopic submucosal dissection can result in the formation of a stricture when the lesion being resected is large and extends into the lower rectum.18

Medical Management of Strictures

Management of benign rectal stricture depends on the etiology and often requires endoscopic or surgical intervention. Infectious strictures due to chlamydia or actinomycoses heal well with antibiotic treatment.4,5 Rectal strictures due to inflammatory bowel disease have a healing rate of 59% with anti-tumor necrosis factor- agents with or without immunomodulators.9 It is important to biopsy strictures occurring after surgical resection of colorectal cancer and strictures related to IBD to rule out cancer.9 Stool softeners and laxatives are often needed, with high fiber diet even after resolution of stricture.22

Specific Management of Strictures

Treatment of benign rectal strictures can be difficult and usually requires multiple modalities. These include dilation with Hegar or bougie dilators, endoscopic interventions (balloon dilation, stent placement), or surgical treatment. Case reports, small case series, and retrospective studies comprise most of the published literature.Consequently, novel methods may have to be used keeping in mind maximum benefit and safety of the patient. Mechanical dilation or endoscopic methods are attempted first, as surgical treatment is difficult and has high risk of end-colostomy.

Dilation by Hegar Dilators

Hegar dilators, often used by surgeons in the initial management of benign rectal strictures, are least invasive and most cost-effective mode of treatment. Dilation is usually started with 14-20 French dilators and is gradually increase up to a maximum of 60 French dilators.29,39 Based on our review of literature, Hegar dilators were effective in 56.1% of the cases (Table 2).

Endoscopic Balloon Dilation

For a majority of the cases, endoscopic balloon dilation is considered the first line of treatment. It can be performed using through the scope hydrostatic or combined endoscopic-fluoroscopic pneumatic balloon dilators.22,24,40,41 Dilation under fluoroscopic guidance allows for better visualization and control over the process and ability to increase the balloon diameter as needed.40 Based on our review, balloon dilation has an overall success rate of 77.5% (Table 2). Dilation is considered successful when a 13mm colonoscope can be passed easily through the stricture with resolution of symptoms.24 Recurrence of symptoms occurred in 60% of cases after one dilation session. Consequently, on average two to three dilation sessions are required to achieve successful results.42–47 More dilation sessions are generally required for low lying rectal strictures.18 If successful results are not achieved in five or more dilation sessions, alternative methods should be pursued.48 There are no guidelines for time intervals between dilation sessions and is typically four weeks or more.40 In high-grade strictures, with a lumen < 7 mm, argon plasma coagulation or laser can be used to make a small incision that allows the endoscope to pass through the stricture for balloon dilation.22,49 Endoscopic balloon dilation is especially effective for shorter strictures, usually < 2 cm in length with low complication rates.50–52 Perforation is reported in about 1.1% of cases and abscess is reported in 0.2% of cases.53

Stent Placement for Rectal Strictures

Stent placement is usually the next option for treatment of rectal strictures that do not resolve with endoscopic balloon dilation. They are usually used for strictures longer than 2 cm.55,56 Most of the published literature on stents are case reports and case series. Three different types of stents have been used for rectal strictures: fully covered selfexpanding metal stents, uncovered metal stents, and biodegradable stents.4,56–60 Uncovered metal stents are rarely used due to risk of mucosal hyperplasia leading to re-occlusion. Additionally, uncovered stents cannot be removed via endoscopic method, resulting in the need for surgery.55

Fully covered self-expanding metal stents are most frequently used due to low tissue ingrowth and ease of removal.61 Based on our review, the success rate of fully covered self-expanding metal stents was 68.5% (Table 2). Migration of the stent was the most common complication and was reported in 31% of the cases. In some cases, migration occurs after stricture has sufficiently dilated.62 In a case series of four patients, migration was avoided with “upside-down” deployment of fully covered self-expanding metal stents.61 Rare complications such as stent fracture, coloenteric fistula, and perforation have been reported.56,62,63 Less serious complications of rectal stent placement include abdominal pain, rectal pain, and tenesmus.60,61 It is unclear as to how long metal stents should be left in place, and removal has been reported as early as four weeks to as late as 30 months.57,62

Biodegradable stents have been predominantly used for esophageal strictures.56,64,65 They are more flexible, do not have to be removed as they usually self-disintegrate, and have a mean patency of 4 months.56,66 Since they tend to be wider and longer, they are poorly tolerated in strictures closer to the anus. Based on our review, the success rate of biodegradable stents was 66.7% (Table 2). Migration was the most common complication, occurring in 27% of cases. Acute intestinal obstruction due to stent migration occurred in one case and required emergent surgical intervention.55

Surgery for Rectal Strictures

Surgery is the last resort for treatment of benign rectal strictures since there is a high risk of endcolostomy and creation of permanent stoma. About 28% of patients have refractory strictures requiring surgical correction.68 Several minimally invasive surgical options have been reported for refractory benign rectal strictures, especially involving the lower rectum. These include transanal minimally invasive surgery (TAMIS), transanal endoscopic microsurgery (TEM), laparoscopic stricturoplasty using transanal radial linear cutter, and transanal stapler resection of stricture.69–78 Resection with re-anastomosis is more successful in upper rectal strictures (>10 cm from anal verge), although coloanal anastomosis for mid and lower rectal strictures (within 10 cm of anal verge) have also shown satisfactory long-term functional results.68,79 Some recalcitrant rectal strictures in Crohn’s disease may need proctectomy and creation of a stoma.8

CONCLUSION

Benign rectal strictures are a common complication of rectal anastomotic surgeries but can also be caused by other etiologies such as Crohn’s disease, ischemia, infection, complication of endoscopic submucosal dissection, endometriosis, and chronic suppository usage. Management of rectal strictures is based on underlying etiology and may include both endoscopic and/or surgical interventions. This article provides guidance for the treatment of benign rectal strictures in different clinical scenarios.

References

  1. Petersen S, Hellmich G, Schumann D, Schuster A, Ludwig K. Early rectal stenosis following stapled rectal mucosectomy for hemorrhoids. BMC Surg. 2004;4:6. Published 2004 May 21.
  2. Karanikas M, Touzopoulos P, Mitrakas A, et al. Benign postradiation rectal stricture treated with endoscopic balloon dilation and intralesional triamcinolone injection. Case Rep Gastroenterol. 2012;6(3):583-589.
  3. Idrees S, Naseer S, Hartmann E, et al. Treatment of benign rectal strictures with proctoplasty. Am Surg. 2015;81(3):E134-E135.
  4. Pérez Sánchez LE, Hernández Barroso M, Hernández Hernández G. Rectal inflammatory stenosis secondary to Chlamydia trachomatis: a case report. Rev Esp Enferm Dig. 2017;109(9):668.
  5. Pinsk I, Saloojee N, Friedlich M. Lymphogranuloma venereum as a cause of rectal stricture. Can J Surg. 2007;50(6):E31-E32.
  6. Elmoghrabi A, Mohamed M, Wong K, McCann M. Proctalgia and colorectal stricture as the result of a 2-year transit of a retained rectal chicken bone: a case presentation and review of the literature. BMJ Case Rep. 2016;2016:bcr-2016-215913. Published 2016 Jun 20.
  7. Katsikogiannis N, Tsaroucha A, Dimakis K, Sivridis E, Simopoulos C. Rectal endometriosis causing colonic obstruction and concurrent endometriosis of the appendix: a case report. J Med Case Rep. 2011;5:320. Published 2011 Jul 20.
  8. Linares L, Moreira LF, Andrews H, Allan RN, Alexander- Williams J, Keighley MR. Natural history and treatment of anorectal strictures complicating Crohn’s disease. Br J Surg. 1988;75(7):653-655.
  9. Brochard C, Siproudhis L, Wallenhorst T, et al. Anorectal stricture in 102 patients with Crohn’s disease: natural history in the era of biologics. Aliment Pharmacol Ther. 2014;40(7):796-803.
  10. Ratliff DA, Carr N, Cochrane JP. Rectal stricture due to actinomycosis. Br J Surg. 1986;73(7):589-590.
  11. Van Gossum A, Zalcman M, Adler M, Peny MO, Houben JJ, Cremer M. Anorectal stenosis in patients with prolonged use of suppositories containing paracetamol and acetylsalicylic acid. Dig Dis Sci. 1993;38(11):1970-1977.
  12. Tannouri F, Lalmand B, Zalcman M, et al. Role of the doublecontrast barium enema in rectal stenosis due to suppositories containing paracetamol and acetylsalicylic acid. Eur Radiol. 1998;8(7):1217-1220.
  13. Agrawal V, Joshi MK, Jain BK, Gupta A. Unusual rectal stricture. Trop Gastroenterol. 2008;29(1):44-45.
  14. Gruber M, Füglistaler I, Zettel A, Fox M, Manz M. An Unusual Cause of Rectal Stenosis. Case Rep Gastroenterol. 2016;10(2):406-409. Published 2016 Aug 9.
  15. Mata A, Galindo A, Díaz J, Marijuan JL, Aguilera MJ. Estenosis ano-rectal completa por supositorios de paracetamol y salicilamida [Complete anorectal stenosis due to paracetamol and salicylamide suppositories]. Rev Esp Enferm Dig. 1995;87(6):463-464.
  16. Haj M, Nasser G, Loberant N, Cohen I, Nesser E, Eitan A. Pelvic actinomycosis presenting as ureteric and rectal stricture. Dig Surg. 2000;17(4):414-417.
  17. Spickett GP, Kipping RA. Pelvic actinomycosis presenting with rectal stricture. J R Soc Med. 1985;78(8):674-676.
  18. Sako T, Toyonaga T, Nakano Y, et al. Endoscopic submucosal dissection involving the anal canal presents a risk factor for postoperative stricture. Surg Endosc. 2021;35(3):1307-1316.
  19. Nepal P, Mori S, Kita Y, et al. Radial incision and cutting method using a transanal approach for treatment of anastomotic strictures following rectal cancer surgery: a case report. World J Surg Oncol. 2019;17(1):48. Published 2019 Mar 14.
  20. Xinopoulos D, Kypreos D, Bassioukas SP, et al. Comparative study of balloon and metal olive dilators for endoscopic management of benign anastomotic rectal strictures: clinical and cost-effectiveness outcomes. Surg Endosc. 2011;25(3):756-763.
  21. Albertsmeier M, Rittler P, Hoffmann RT, Spelsberg F. Treatment of a completely obstructed colonic anastomotic stricture using a CT-guided endoscopic rendezvous technique. Endoscopy. 2011;43 Suppl 2 UCTN:E5-E6.
  22. Suchan KL, Muldner A, Manegold BC. Endoscopic treatment of postoperative colorectal anastomotic strictures. Surg Endosc. 2003;17(7):1110-1113.
  23. Araujo SE, Costa AF. Efficacy and safety of endoscopic balloon dilation of benign anastomotic strictures after oncologic anterior rectal resection: report on 24 cases. Surg Laparosc Endosc Percutan Tech. 2008;18(6):565-568.
  24. Ambrosetti P, Francis K, De Peyer R, Frossard JL. Colorectal anastomotic stenosis after elective laparoscopic sigmoidectomy for diverticular disease: a prospective evaluation of 68 patients. Dis Colon Rectum. 2008;51(9):1345-1349.
  25. Luchtefeld MA, Milsom JW, Senagore A, Surrell JA, Mazier WP. Colorectal anastomotic stenosis. Results of a survey of the ASCRS membership. Dis Colon Rectum. 1989;32(9):733-736.
  26. MacRae HM, McLeod RS. Handsewn vs. stapled anastomoses in colon and rectal surgery: a meta-analysis. Dis Colon Rectum. 1998;41(2):180-189.
  27. Brennan SS, Pickford IR, Evans M, Pollock AV. Staples or sutures for colonic anastomoses–a controlled clinical trial. Br J Surg. 1982;69(12):722-724.
  28. Zhang B, Zhuo GZ, Tian L, et al. Zhonghua Wei Chang Wai Ke Za Zhi. 2019;22(8):755-761.
  29. Lee SY, Kim CH, Kim YJ, Kim HR. Anastomotic stricture after ultralow anterior resection or intersphincteric resection for very low-lying rectal cancer. Surg Endosc. 2018;32(2):660-666.
  30. Sun X, Qiu H, Wu B, Lin G, Shi H, Xiao Y. Zhonghua Wei Chang Wai Ke Za Zhi. 2018;21(6):666-672.
  31. Virgilio C, Cosentino S, Favara C, Russo V, Russo A. Endoscopic treatment of postoperative colonic strictures using an achalasia dilator: short-term and long-term results. Endoscopy. 1995;27(3):219-222.
  32. Graffner H, Fredlund P, Olsson SA, Oscarson J, Petersson BG. Protective colostomy in low anterior resection of the rectum using the EEA stapling instrument. A randomized study. Dis Colon Rectum. 1983;26(2):87-90.
  33. Waxman BP, Ramsay AH. The effect of stapler diameter and proximal colostomy on narrowing at experimental circular stapled large bowel anastomoses. Aust N Z J Surg. 1986;56(10):797-801.
  34. Fields S, Rosainz L, Korelitz BI, Panagopoulos G, Schneider J. Rectal strictures in Crohn’s disease and coexisting perirectal complications. Inflamm Bowel Dis. 2008;14(1):29-31.
  35. Theis VS, Sripadam R, Ramani V, Lal S. Chronic radiation enteritis. Clin Oncol (R Coll Radiol). 2010;22(1):70-83.
  36. Marginean EC. The Ever-Changing Landscape of Drug- Induced Injury of the Lower Gastrointestinal Tract. Arch Pathol Lab Med. 2016;140(8):748-758.
  37. Over H, Ulker A, Baysal C, Dağli U. Endoscopic balloon dilation of strictures complicating solitary rectal ulcer syndrome. Endoscopy. 1997;29(5):427-429.
  38. Iida T, Ohkubo Y, Kubo T, et al. A case of a rectal stricture related to ischemic proctitis following rupture of an aortic aneurysm. Endosc Int Open. 2018;6(2):E186-E189.
  39. Kashkooli SB, Samanta S, Rouhani M, Akbarzadeh S, Saibil F. Bougie dilators: simple, safe and cost-effective treatment for Crohn’s-related fibrotic anal strictures. Can J Surg. 2015;58(5):347-348.
  40. De Lange EE, Shaffer HA Jr. Rectal strictures: treatment with fluoroscopically guided balloon dilation. Radiology. 1991;178(2):475-479.
  41. Venkatesh KS, Ramanujam PS, McGee S. Hydrostatic balloon dilatation of benign colonic anastomotic strictures. Dis Colon Rectum. 1992;35(8):789-791.
  1. Saxena P, Azola A, Kumbhari V, Kalloo AN, Khashab MA. EUS-guided rendezvous and reversal of complete rectal anastomotic stenosis after Hartmann’s reversal. Gastrointest Endosc. 2015;81(2):467-468.
  2. Barker JA, Hill J. Incidence, treatment and outcome of rectal stenosis following transanal endoscopic microsurgery. Tech Coloproctol. 2011;15(3):281-284.
  3. Placer C, Urdapilleta G, Markinez I, et al. Estenosis anastomóticas benignas en la cirugía radical del cáncer de recto. Resultados del tratamiento con dilatación hidrostática [Benign anastomotic strictures after oncologic rectal cancer surgery. Results of treatment with hydrostatic dilation]. Cir Esp. 2010;87(4):239-243.
  4. Johansson C. Endoscopic dilation of rectal strictures: a prospective study of 18 cases. Dis Colon Rectum. 1996;39(4):423-428.
  5. Campbell DM, Geraghty JG, McBride K, Murphy JJ, MacErlean D. Radiologically controlled balloon dilatation of rectal strictures. Clin Radiol. 1991;44(2):77-78.
  6. Di Giorgio P, De Luca L, Rivellini G, Sorrentino E, D’amore E, De Luca B. Endoscopic dilation of benign colorectal anastomotic stricture after low anterior resection: A prospective comparison study of two balloon types. Gastrointest Endosc. 2004;60(3):347-350.
  7. Skreden K, Wiig JN, Myrvold HE. Balloon dilation of rectal strictures. Acta Chir Scand. 1987;153(10):615-617.
  8. Reddy RA, Venkatasubramaniam AK, Khursheed A, Latimer J, Tabaqchali MA. Dual interventional approach of endoscopic reboring in completely stenosed rectal anastomosis using radiology guidance: a novel technique. Colorectal Dis. 2009;11(1):49-52.
  9. Milsom JW, Mazier WP. Classification and management of postsurgical anal stenosis. Surg Gynecol Obstet. 1986;163(1):60-64.
  10. Garcea G, Sutton CD, Lloyd TD, Jameson J, Scott A, Kelly MJ. Management of benign rectal strictures: a review of present therapeutic procedures. Dis Colon Rectum. 2003;46(11):1451- 1460.
  11. Ravo B, Amato A, Bianco V, et al. Complications after stapled hemorrhoidectomy: can they be prevented? Tech Coloproctol. 2002;6(2):83-88.
  12. Ragg J, Garimella V, Cast J, Hunter IA, Hartley JE. Balloon dilatation of benign rectal anastomotic strictures — a review. Dig Surg. 2012;29(4):287-291.
  13. Yuan X, Liu W, Ye L, Wu M, Hu B. Combination of endoscopic incision and balloon dilation for treatment of a completely obstructed anastomotic stenosis following colorectal resection: A case report. Medicine (Baltimore). 2019;98(26):e16292.
  14. Lamazza A, Fiori E, Sterpetti AV, Schillaci A, Scoglio D, Lezoche E. Self-expandable metal stents in the treatment of benign anastomotic stricture after rectal resection for cancer. Colorectal Dis. 2014;16(4):O150-O153.
  15. Repici A, Pagano N, Rando G, et al. A retrospective analysis of early and late outcome of biodegradable stent placement in the management of refractory anastomotic colorectal strictures. Surg Endosc. 2013;27(7):2487-2491.
  16. Gornals JB, Albines G, Trenti L, Mast R, Frago R. EUS-guided recanalization of a complete rectal anastomotic stenosis by use of a lumen-apposing metal stent. Gastrointest Endosc. 2015;82(4):752.
  17. Oztas E, Saygili F, Ulas M, Disibeyaz S. Endoscopic Treatment of the Coloanal Anastomotic Dehiscence and Stricture: Stenting Via Rendezvous Technique. Surg Laparosc Endosc Percutan Tech. 2018;28(5):e88-e90.
  18. Law WL, Choi HK, Chu KW, Tung HM. Radiation stricture of rectosigmoid treated with self-expanding metallic stent. Surg Endosc. 2002;16(7):1106-1107.
  19. Cereatti F, Fiocca F, Dumont JL, et al. Fully covered selfexpandable metal stent in the treatment of postsurgical colorectal diseases: outcome in 29 patients. Therap Adv Gastroenterol. 2016;9(2):180-188.
  1. Testoni PA, Fanti L, Antonucci E, Dabizzi E. Inverted “upsidedown” esophageal fully-covered self-expanding metal stent is effective for temporary treatment of colorectal strictures: a pilot case series. Endosc Int Open. 2019;7(6):E818-E823.
  2. Forshaw MJ, Maphosa G, Sankararajah D, Parker MC, Stewart M. Endoscopic alternatives in managing anastomotic strictures of the colon and rectum. Tech Coloproctol. 2006;10(1):21-27.
  3. Modarai B, Forshaw M, Parker MC, Stewart M. Self-expanding metallic stents in the treatment of benign colorectal anastomotic strictures: a word of caution. Tech Coloproctol. 2008;12(2):127- 129.
  4. Dederichs F, Knüdeler S, Nolte W, Iesalnieks I. Behandlung einer postoperativen Rektumstenose mittels eines selbstexpandierenden resorbierbaren Polydioxanon-Stents [Treatment of a postoperative rectal stenosis with a self-expanding biodegradable polydioxanone stent]. Z Gastroenterol. 2013;51(5):437- 439.
  5. Pérez Roldán F, González Carro P, Villafáñez García MC, et al. Usefulness of biodegradable polydioxanone stents in the treatment of postsurgical colorectal strictures and fistulas. Endoscopy. 2012;44(3):297-300.
  6. Rejchrt S, Kopacova M, Brozik J, Bures J. Biodegradable stents for the treatment of benign stenoses of the small and large intestines. Endoscopy. 2011;43(10):911-917.
  7. Martínez Alcalá F, Martínez-Alcalá García FR, Sánchez- Yague A, Martínez-Alcalá García A, Ciria Avila JA, Perez Pozo JM. Treatment of a benign, anastomotic refractory rectal stricture with an AXIOS stent. Endoscopy. 2015;47 Suppl 1 UCTN:E413-E414.
  8. Schlegel RD, Dehni N, Parc R, Caplin S, Tiret E. Results of reoperations in colorectal anastomotic strictures. Dis Colon Rectum. 2001;44(10):1464-1468.
  9. Valdés-Hernández J, Del Rio FJ, Gómez-Rosado JC, et al. TAMIS repair of a rectal stenosis not treatable by endoscopy. Tech Coloproctol. 2018;22(11):891.
  10. Baatrup G, Svensen R, Ellensen VS. Benign rectal strictures managed with transanal resection–a novel application for transanal endoscopic microsurgery. Colorectal Dis. 2010;12(2):144-146.
  11. Pabst M, Giger U, Senn M, Gauer JM, Boldog B, Schweizer W. Transanal treatment of strictured rectal anastomosis with a circular stapler device: simple and safe. Dig Surg. 2007;24(1):12- 14.
  12. Anvari M. Endoscopic transanal rectal stricturoplasty. Surg Laparosc Endosc. 1998;8(3):193-196.
  13. Kato K, Saito T, Matsuda M, Imai M, Kasai S, Mito M. Successful treatment of a rectal anastomotic stenosis by transanal endoscopic microsurgery (TEM) using the contact Nd:YAG laser. Surg Endosc. 1997;11(5):485-487.
  14. Gomes da Silva R, Hanan B, Fonseca LM. Treatment of Anastomotic Stricture of a Handsewn Coloanal Anastomosis With Transanal Approach. Dis Colon Rectum. 2017;60(7):755.
  15. Bong JW, Lim SB. Transanal minimally invasive surgery as a treatment option for a completely occluded anastomosis after low anterior resection: A new approach to severe anastomotic stenosis. Asian J Endosc Surg. 2019;12(2):175-177.
  16. Kawaguti FS, Martins BC, Nahas CS, et al. Endoscopic radial incision and cutting procedure for a colorectal anastomotic stricture. Gastrointest Endosc. 2015;82(2):408-409.
  17. Araki Y, Kishimoto Y, Sato Y, et al. Transanal dilation using circular stapling for benign rectal stenosis: report of a case. Kurume Med J. 2002;49(3):149-151.
  18. Kawak S, Turaihi H, Bjordahl P. Transanal stricturoplasty: a minimally-invasive approach to a challenging problem. J Surg Case Rep. 2019;2019(3):rjz087. Published 2019 Mar 29.
  19. Yi BQ, Wang ZJ, Zhao B, et al. Zhonghua Wai Ke Za Zhi. 2013;51(7):577-581.

Download Tables, Images & References

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #210

Vitamin D Replacement in Adults: Current Strategies in Clinical Management

May 2021 • Volume XLV, Issue 5
Ronak M. Patel,Lindsay Bazydlo,Sue A. Brown,Alan C. Dalkin

Read Article

Vitamin D, a prohormone, is needed for proper calcium homeostasis and potentially a host of additional physiologic functions. With changes in diet and an age-related decline in dermal production of vitamin D, practitioners often encounter patients with varying degrees of vitamin D insufficiency or deficiency. It is imperative to recognize and treat vitamin D deficiency before it manifests with detrimental effects on the body. This review will provide background on the physiology of vitamin D, common causes of hypovitaminosis D and conclude by providing a practical guide to vitamin D replacement and monitoring in common clinical scenarios.

INTRODUCTION

Vitamin D plays a critical role in human health. Well recognized is the importance of vitamin D in the absorption of calcium and phosphate mineral and the subsequent actions on bone mineralization, bone strength, and fracture protection.1 In recent years, increasing preclinical evidence supports a role for vitamin D in a multitude of extra-skeletal physiological functions while low vitamin D levels have been linked in observational studies to immune dysfunction, malignancies (e.g. breast, colon, prostate), skeletal muscle strength, cardiovascular, and glycemic regulation.2,3 Despite these associations, randomized controlled trials are either lacking or do not consistently find that vitamin D supplementation alters most of these non-skeletal outcomes.4-7 However, it is generally agreed that perturbations in vitamin D metabolism can have an important impact on human health and hence screening for, and adequately treating, vitamin D deficiency is important for general health purposes.8

There exist two primary sources of vitamin D in humans: dermal production of vitamin D3 (cholecalciferol) and nutritional supplementation with either vitamin D3 or vitamin D2 (ergocalciferol). Shortfalls in dietary intake, reduction in ultraviolet light exposure needed for dermal biosynthesis of vitamin D, age-related decline in dermal production of vitamin D, disorders altering the gastrointestinal absorption of fats, and conditions that accelerate the metabolism of vitamin D stores can all predispose an individual to vitamin D deficiency. It is not surprising that hypovitaminosis D can be present in a wide array of clinical scenarios.

Conversely, while wide-spread supplementation of milk, juices, cereal, and daily multivitamins and calcium preparations with vitamin D is part of a general health approach to prevent vitamin D deficiency, over-replacement with vitamin D can have adverse consequences. Excess absorption of calcium and phosphate can predispose to hypercalciuria and nephrolithiasis and much less commonly, calcium mineral deposition of soft tissues and organs such as the kidney, thereby adversely altering function. It is the purpose of this article to:

  1. briefly review the physiology and regulation of vitamin D activity
  2. identify common clinical conditions in adults in which an evaluation of vitamin D status is indicated
  3. review commercially available assays for vitamin D with their specific advantages and limitations,
  4. propose a practical therapeutic plan for adults that includes monitoring and treatment goals that are generally acceptable for most patients with vitamin D deficiency

Physiology of Calcium Homeostasis and the Role of Vitamin D

The central player in the regulation of calcium is parathyroid hormone (PTH). PTH synthesis and secretion are directly regulated by the extracellular calcium concentration via the Calcium-sensing receptor (CaSR) through an inhibitory mechanism. Activation of the CaSR results in a reduction in PTH. Conversely, hypocalcemia increases PTH. Target organs for PTH action include the bone and kidney. PTH increases bone turnover and osteoclast action to release calcium and phosphorus into the circulation. In terms of renal actions, PTH enhances resorption of filtered calcium thereby limiting renal losses of calcium. In addition, and relevant to this review, PTH drives conversion of stored 25-hydroxyvitamin D (calcidiol) into the active metabolite 1,25-dihydroxyvitamin D (calcitriol) via the actions of 1-alpha hydroxylase (CYP27B1). Calcitriol, in turn, enhances gastrointestinal absorption of calcium and phosphorus in the small bowel, though there may be a small contribution of calcidiol in this regard. In addition, and to a more modest degree, calcitriol favors bone mineralization and the deposition of calcium mineral into newly formed bone (osteoid). The increase in circulating calcium then feeds back at the level of the parathyroid gland to inhibit further PTH secretion

Stored vitamin D, i.e. calcidiol, is the product of 25-hydroxylation by the hepatocytes. Both vitamin D2 and D3 , regardless of their source, are fully and rapidly converted to calcidiol such that measurement of cholecalciferol or ergocalciferol is not practical. Calcidiol circulates attached to a vitamin D binding protein (high affinity, low capacity) and albumin (low affinity, high capacity), both products of hepatic biosynthesis. While the capacity to synthesize calcidiol from the parent compounds is generally well in excess of normal physiologic needs, severe hepatic dysfunction and end-stage liver disease can be associated with vitamin D deficiency due to a decline in calcidiol production.

Due to the feedback regulation described above, vitamin D toxicity due to excess ingestion of calcidiol is unlikely. If calcidiol levels rise above the normal range, calcium feedback to the parathyroid glands inhibits parathyroid hormone release, via activation of the CaSR, which in turn reduces the conversion of calcidiol to calcitriol. In effect, thereby preventing further enhancement in calcium absorption. None-the-less, excess levels of vitamin D (> 80 ng/mL) can increase circulating calcium levels which results in hypercalcemia and hypercalciuria and a long-term risk of nephrolithiasis.

Clinical Presentation of Vitamin D Deficiency, Differential Diagnosis and Laboratory Testing in Adults

The majority of patients with vitamin D deficiency have few, if any signs or symptoms related to the condition. Over the long term, reductions in vitamin D can lead to a reduction in circulating calcium, secondary hyperparathyroidism, increased bone remodeling and mobilization of calcium from bone. Severe vitamin D deficiency can result in osteomalacia that is often asymptomatic, but in some can be associated with diffuse bone pain. In addition, enhanced bone fragility can present with fracture from a ground level fall. The associated laboratory studies include a reduced 25-hydroxyvitamin D, normal or lownormal calcium levels, elevated PTH and alkaline phosphatase levels and a reduced 24-hour urinary calcium excretion rate.

There remains some discussion on the proper diagnostic nomenclature for patients with hypovitaminosis D. The Endocrine Society’s practice guidelines9 detail three categories:
1. Vitamin D sufficiency: 25-hydroxyvitamin D of > 30 ng/mL (75 nmol/L)
2. Vitamin D insufficiency: 25-hydroxyvitamin D between 21-29 ng/mL (51-74 nmol/L)
3. Vitamin D deficiency: 25-hydroxyvitamin D of < 20 ng/mL (<50 nmol/L)

It is important to note that the biologic contributions of either vitamin D2 or vitamin D3 are similar and hence differentiation between the two forms is not important for diagnostic purposes. Of greater import, measurement of 1,25-dihydroxyvitamin D (calcitriol) is not included in the identification of vitamin D deficient patients. Calcitriol levels are maintained in the normal range even in the presence of severe calcidiol deficiency and will not reflect many patients’ vitamin D balance.

A full discussion of the causes of vitamin D insufficiency and deficiency is beyond the scope of this manuscript. In overview, malabsorptive conditions predispose to deficiencies of all fatsoluble vitamins. Infectious etiologies (e.g. C. Difficile), inflammatory (e.g. ulcerative colitis) and iatrogenic (e.g. bariatric surgery) all can result in substantial reductions in vitamin D stores. In addition, with aging, dermal production of cholecalciferol declines and hence even reasonable UV light exposure may not be sufficient to maintain normal 25-hydroxyvitamin D levels.

It is also important to mention that there are acute causes of vitamin D deficiency. In patients receiving care in an intensive care unit for severe illness, there is some data suggesting that 25-hydroxyvitamin D levels may abruptly drop below the reference range.10,11 That said, data supporting a benefit for urgent restoration of vitamin D levels is lacking. Hence, we neither check vitamin D levels, nor add vitamin D replacement in this patient population.

Measurement of Vitamin D

An immunoassay can use a variety of detection techniques and 2 methods for the measurement of 25-hydroxyvitamin D are chemiluminescence and radioactivity. Chemiluminescent immunoassays can be automated and allow for a faster turn-around time, with the downside being that it is unable to distinguish between 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and is reported only as a total 25-hydroxyvitamin D level. Radioactivity as a detection method is becoming less common but radioimmunoassays (RIA) are still available. In general, immunoassays tend to underestimate the concentration of 25-hydroxyvitamin D2 due to a lower affinity of the antibody for this analyte compared to 25-hydroxyvitamin D3. Liquid chromatography tandem mass spectrometry is a popular choice for measuring 25-hydroxyvitamin D, as it separates and measures 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 individually and has been established as the gold standard to which chemiluminescent and RIA assays are compared.

A study comparing measurements from different laboratories using either highperformance liquid chromatography (HPLC), RIA, or automated chemiluminescent assays for measurements of serum 25-hydroxyvitamin D demonstrated that the degree of variability of the results between methods and between laboratories, even when using the same method, confounded the diagnosis of vitamin D insufficiency.12 Specifically, some chemiluminescent and RIA assays were found to underestimate the contribution of 25-hydroxyvitamin D2 to total circulating 25-hydroxyvitamin D levels. Since ergocalciferol (vitamin D2) is often used for treatment of hypovitaminosis D, the inability to measure 25-hydroxyvitamin D2 could result in apparent laboratory failures in assessing therapeutic responses and/or lead to a misdiagnosis of vitamin D insufficiency or deficiency. Increases in unmeasured vitamin D could potentially result in dose escalation and subsequent dangerous consequences such as hypervitaminosis D. As a result, we suggest ascertaining the specific assay for 25-hydroxyvitamin D used by your own laboratory, not only during diagnosis (although measurement of only 25-hydroxyvitamin D3 in that setting would be of little harm), but also when monitoring response to treatment.

Strategies for Vitamin D Replacement

While many preparations of vitamin D and its metabolites are available to restore normal circulating levels of vitamin D, cholecalciferol and ergocalciferol are used more frequently as they are less expensive and, in particular, cholecalciferol is readily available to most patients in overthe-counter formulations (Table 1). While the biological activities of the two forms of vitamin D are comparable, in our practice cholecalciferol is generally the preferred formulation for vitamin D supplementation as there is data to suggest that it is more effective than ergocalciferol at increasing total 25-hydroxyvitamin D levels.13-15 This observation may be due to a predictable decrease in vitamin D3 level seen in patients treated with ergocalciferol.16 We do not utilize calcitriol in most instances unless the patient manifests clinical signs of hypocalcemia, have hypoparathyroidism (and the associated deficit in renal 1-hydroxylation) or if they would be more likely to absorb calcitriol (e.g. following bariatric surgery).

In adult patients without malabsorption, but with vitamin D deficiency (25-hydroxyvitamin D of < 20 ng/mL (<50 nmol/L)), we initially treat with 2,000-6,000 international units (IU) cholecalciferol daily or 50,000 IU of ergocalciferol (or cholecalciferol) weekly for 6-8 weeks.9 Once the course of therapy is complete, we repeat testing including a 25-hydroxyvitamin D level along with a measurement of serum calcium. In addition, in patients with secondary hyperparathyroidism prior to treatment, normalization of PTH levels can confirm adequacy of replacement, though we elect to do this infrequently to reduce cost and recognizing that changes in PTH levels can lag behind changes in vitamin D levels. Once replete, the vitamin D dose is reduced to a maintenance regimen generally of 2,000 IU/day cholecalciferol, or 50,000 IU of ergocalciferol (or cholecalciferol), every 14-30 days, and levels are again repeated in 2-3 months. We feel the majority of these patients are at a relatively high risk of repeat vitamin D deficiency in the future, and they are counseled that this is life-long therapy. Of note, in obese individuals, steady state levels may take a longer time to reach and hence we often delay repeat measurement for an additional 1-3 months.

Patients who have vitamin D insufficiency (25-hydroxyvitamin D between 21-29 ng/mL (51-74 nmol/L)) may be replaced with 400-2,000 IU cholecalciferol per day to achieve normal 25-hydroxyvitamin D levels. In general, we do not recommend high dose vitamin D without documentation of vitamin D deficiency as there are emerging data to suggest routine use of this type of supplementation in vitamin D replete individuals may not be beneficial.17

In patients with malabsorptive states, higher doses of vitamin D may be needed, even as high as 6,000 IU-10,000 IU daily of cholecalciferol or 50,000 IU twice weekly of ergocalciferol(or cholecalciferol) for short-term use.9 Once replete,these patients usually continue on slightly reduced or in some cases the same dose of vitamin D long term to avoid recurrence of vitamin D deficiency. We often follow vitamin D and calcium levels every 3-6 months going forward to ensure adequate replacement and less often once stable.

In addition, there are special patient populations that may benefit from treatment with metabolites of vitamin D. Patients with liver disease may have impairment of 25-hydroxylation of vitamin D and these patients may benefit from calcidiol (25-hydroxyvitamin D).18,19 Similarly, patients with severe renal disease or end-stage renal disease (ESRD, beyond stage 3) may have impairment in 1-hydroxylation of 25-hydroxyvitamin D and may benefit from calcitriol (1,25-dihydroxyvitamin D).20 Vitamin D analogs are often used in the ESRD patient population to reduce the sequelae of severe secondary hyperparathyroidism and the decision whether to treat a low 25-hydroxyvitamin D level is complex. Indeed, in many instances, we do replace these patients with cholecalciferol or ergocalciferol, to potentially reduce the effects of secondary hyperparathyroidism, even while recognizing that calcium balance is not significantly altered as a result.

Summary

Vitamin D has an important role in many physiological functions, most prominent and well established are its roles in calcium homeostasis and bone health and deficiency may be asymptomatic. Screening patients for vitamin D deficiency should be performed in individuals presenting with low bone mineral density. Cholecalciferol (D3 ) is the preferred replacement supplement, inexpensive, and readily available over-the-counter. Monitoring the success of vitamin D replacement is key and needs to be tailored to the patient in light of the vitamin D preparation to ensure sufficiency and avoid toxicity. The treatment plans outlined within this manuscript should provide practitioners with safe and effective means to restore vitamin D levels to the normal range.

References

  1. Dawson-Hughes B, Harris SS, Krall EA et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670-6.
  2. Pilz S, Gaksch M, Kienreich K, et al. Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial. Hypertension 2015;65:1195-1201.
  3. Mitri J, Dawson-Hughes B, Hu FB, et al. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr 2011;94:486-94.
  4. Bischoff-Ferrari HA, Vellas B, Rizzoli R, et al; DO-HEALTH Research Group. Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial. JAMA 2020;324:1855-1868.
  5. Pittas AG, Dawson-Hughes B, Sheehan P, et al; D2d Research Group. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med 2019;381:520-530.
  6. Shea MK, Fielding RA, Dawson-Hughes B. The effect of vitamin D supplementation on lower-extremity power and function in older adults: a randomized controlled trial. Am J Clin Nutr 2019;109:369- 379.
  7. Giustina A, Adler RA, Binkley N, et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Rev Endocr Metab Disord 2020;21:89-116.
  8. Lips P, Bilezikian JP, Bouillon R. Vitamin D: Giveth to Those Who Needeth. J Bone Min Res Plus 2019;4:e10232.
  9. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011;96:1911–1930
  10. Czarnik T, Czarnik A, Gawda R, et al. Vitamin D kinetics in the acute phase of critical illness: A prospective observational study. J Crit Care. 2018;43:294-299.
  11. Waldron JL, Ashby HL, Cornes MP, et al. Vitamin D: a negative acute phase reactant. J Clin Pathol. 2013;66(7):620-2.
  12. Binkley N, Krueger D, Cogwill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab, 2004; 89:3152-3157.
  13. Tripkovic L, Lambert H, Hart K, et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr 2012;95:1357-64.
  14. Heaney RP, Recker RR, Grote J, et al. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab 2011; 96:E447-52.
  15. Trang HM, Cole DE, Rubin LA, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 1998;68:854-858.
  16. Lehmann U, Hirche F, Stangl GI, et al, Bioavailability of Vitamin D2 and D3 in Healthy Volunteers, a Randomized Placebo-Controlled Trial. J Clin Endocrinol Metab 2013;98,4339–4345,
  17. Burt LA, Billington EO, Rose MS, et al. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA 2019;322:736-745. Erratum in: JAMA 2019;322:1925.
  18. Cianferotti, L, Cricelli, C, Kanis, JA et al. The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Endocrine 2015;50:2–26.
  19. Brandi ML, Minisola S. Calcidiol [25(OH)D3]: from diagnostic marker to therapeutical agent. Curr Med Res Opin 2013;29:1565-72.
  20. Zand L; Kumar R. The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease. Endocrinology & Metabolism Clinics of North America. 46(4):983-1007, 2017

Download Tables, Images & References

LETTER TO THE EDITOR

Re: Nutrition Issues in Gastroenterology, Series #205 Enhanced Recovery After Surgery and Immunonutrition: An Evidence-Based Approach

May 2021 • Volume XLV, Issue 5

Read Article

Dear Carol Rees Parrish MS, RDN:

We read with great interest the article titled, “Enhanced Recovery After Surgery (ERAS) and Immunonutrition (IMN): An EvidenceBased Approach” by Friedman & Thiele in your December 2020 issue.1 We appreciate the importance of this area of on-going research and the work that went into putting such an article together. However, after our review, we believe this article contains some important omissions and interpretation inaccuracies of the literature (particularly those in Table 2) that could skew the overall interpretation of the benefits of IMN to the reader.

In Table 2, Friedman & Thiele inaccurately report the study design and results of Thornblade et al., 2017.2 First, this was not a randomized controlled trial (as the title of Table 2 and inclusion criteria would suggest) but rather a prospective cohort study. Secondly, Thornblade et al. states “Although differences in serious adverse events were non-significant (RR = 0.76, 95% CI: 0.49- 1.16), prolonged length of stay (RR = 0.77, 95% CI: 0.58-1.01 p = 0.05) was lower in those receiving IMN.” Friedman & Thiele report in Table 2 that the “IMN group had increased LOS”.

Table 2 also references a study by HamiltonReeves et al. published in 2016.3 HamiltonReeves et al. published two manuscripts from their pilot study; one in 2016 and one in 2018.3,4 The data in Table 2 are the findings from the 2018 article, not the 2016 article as indicated. In 2016, Hamilton-Reeves et al. reported, “Participants receiving specialized IMN had a 33% reduction in postoperative complication rate (95% CI: 1-64; p = 0.060) and a 39% reduction in infection rate (95% CI: 8-70; p = 0.027) during late-phase recovery.”3 These positive findings were omitted in Friedman & Thiele’s review.

Friedman and Thiele also omitted positive results from Uno et al., 2016.5 In addition to reporting a significant decrease in postoperative infectious complications and serum IL-6, Uno et al., also reported that length of stay was significantly shorter, and severity of complications was significantly lower in the IMN group compared to control.5 These inaccuracies and omissions of positive findings may mislead the reader about the results reported by recent trials of IMN. Additionally, the publications listed in Table 2 are not included in the reference list making it difficult for readers to identify the primary source of these findings.

Friedman & Thiele raise the concern that, “there is some data that IMN can be harmful in certain populations” yet, mortality outcomes of recently published trials were not reported by Friedman & Thiele. Mortality rates were monitored in 9 of the 12 studies listed in Table 2.2,5-12 Of these nine studies, seven reported no difference in mortality between groups.2,5-10 The remaining two studies reported higher mortality in the control groups.11-12 Specifically, Lewis et al., stated that “death within 30 days postoperative was twice as high for those in the standard nutrition group versus the IMN group, with no deaths in the perprotocol analysis for those in the IMN group” and Klek et al. reported significantly increased mortality with standard nutrition compared to IMN at three months (16.7% versus 0.0%, p = 0.004).11-12 We echo Friedman & Thiele’s concerns about small sample sizes in these recently published trials, however, given the importance of this outcome, we believe it is an unfortunate omission of this review.

Friedman and Thiele highlight three societies which recommend or have favorable guidance on IMN use including the European Society for Clinical Nutrition and Metabolism (ESPEN), the American College of Surgeons Strong for Surgery Campaign and the American Society for Enhanced Recovery. Unfortunately, they omit that other societies also have recent guidelines which support the use of IMN. For example, the 2016 guidelines from the American Society for Parenteral and Enteral Nutrition and Society of Critical Care Medicine suggest the routine use of an immune-modulating formula (containing both arginine and fish oil) in the surgical ICU and the 2018 ERAS Guidelines for Colorectal Surgery state that perioperative IMN is beneficial with a strong recommendation grade.13,14

Finally, regarding the “Oxepa® experience,” mentioned by Friedman & Thiele, it is worth clarifying that the subsequent RCT performed by Rice et al., did not use Oxepa® as their intervention.13 Instead, this intervention consisted of bolus feedings of omega-3 fatty acids, g-linolenic acid, and antioxidants provided twice per day. Importantly, the control formula was isocaloric, but not isonitrogenous to the intervention.15 In fact, Rice et al., reported that the control formula contained five times more protein than the intervention formula (20g protein/240ml versus 3.8g protein/240ml, respectively). Given these prominent differences in study design, the results of Rice et al. do not necessarily negate the findings reported by Pontes-Arruda, et al. as is implied by Friedman & Thiele.16

Although we highlight these concerns, we agree with Friedman & Thiele that all research should adhere to the scientific method and be challenged by peer-review regarding scientific design, analysis, and interpretation and add that this caution should be practiced regardless of funding source. We also agree that further health economics and outcomes research will prove meaningful moving forward. It is essential to critically review healthcare practices to ensure that patients are provided the best possible care within the context of growing cost constraints. We truly appreciate the opportunity to discuss our concerns in order that your readers have the most accurate data when making decisions with their patients regarding immunonutrition.

Katie N. Robinson, PhD, MPH, RD

Medical Science Liaison
Scientific and Medical Affairs
Abbott Nutrition, Columbus, OH, USA

Beth Besecker, MD, MBA

Director of Medical Affairs
Adult Nutrition, U.S.
Abbott Nutrition, Columbus, OH, USA

References

References

  1. Thiele R, Friedman J. Enhanced Recovery After Surgery (ERAS) and Immunonutrition: An Evidence-Based Approach. Practical Gastroenterology. 2020:27.
  2. Thornblade LW, Varghese Jr TK, Shi X, et al. Preoperative immunonutrition and elective colorectal resection outcomes. Dis Colon Rectum. 2017;60(1):68.
  3. Hamilton-Reeves JM, Bechtel MD, Hand LK, et al. Effects of immunonutrition for cystectomy on immune response and infection rates: a pilot randomized controlled clinical trial. Eur Urol. 2016;69(3):389-92.
  4. Hamilton-Reeves JM, Stanley A, Bechtel MD, et al. Perioperative immunonutrition modulates inflammatory response after radical cystectomy: results of a pilot randomized controlled clinical trial. J Urol. 2018;200(2):292-301.
  5. Uno H, Furukawa K, Suzuki D, et al. Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection. Surgery. 2016;160(1):228-36.
  6. Mudge LA, Watson DI, Smithers BM, et al. Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer. Br J Surg. 2018;105(10):1262-72.
  7. Hogan S, Solomon M, Rangan A, et al. The Impact of Preoperative Immunonutrition and Standard Polymeric Supplements on Patient Outcomes After Pelvic Exenteration Surgery, Taking Compliance Into Consideration: A Randomized Controlled Trial. JPEN J Parenter Enteral Nutr. 2020;44(5):806-14.
  8. Gade J, Levring T, Hillingsø J, et al. The effect of preoperative oral immunonutrition on complications and length of hospital stay after elective surgery for pancreatic cancer–a randomized controlled trial. Nutr. Cancer. 2016;68(2):225-33.
  9. Kanekiyo S, Takeda S, Iida M, et al. Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy. Nutrition. 2019;59:96-102.
  10. Martin II RC, Agle S, Schlegel M, et al. Efficacy of preoperative immunonutrition in locally advanced pancreatic cancer undergoing irreversible electroporation (IRE). Eur J Surg Oncol. 2017;43(4):772-9.
  11. Lewis S, Pugsley M, Schneider C, et al. The Effect of Immunonutrition on Veterans Undergoing Major Surgery for Gastrointestinal Cancer. Fed Pract. 2018;35(Suppl 4):S49.
  12. Klek S, Scislo L, Walewska E, et al. Enriched enteral nutrition may improve short-term survival in stage IV gastric cancer patients: A randomized, controlled trial. Nutrition. 2017;36:46- 53.
  13. McClave SA, Taylor BE, Martindale R, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
  14. Gustafsson UO, Scott MJ, Hubner M, et al. Guidelines for perioperative care in elective colorectal surgery: Enhanced Recovery After Surgery (ERAS®) society recommendations: 2018. World J Surg. 2019;43(3):659-95.
  15. Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-81.
  16. Pontes-Arruda A, DeMichele S, Seth A, et al. The use of an inflammatio-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr. 2008;32(6):596-605

Download Tables, Images & References

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #36

Inflammatory Bowel Disease Therapies and Pregnancy and Neonatal Outcomes: Results from the PIANO Registry

May 2021 • Volume XLV, Issue 5
Florence-Damilola Odufalu,Uma Mahadevan

Read Article

Pregnant women with inflammatory bowel disease (IBD) are at higher risk for adverse pregnancy outcomes, and disease activity is a major determinant of these adverse outcomes. Controlling disease activity prior to conception and through the postpartum period is critical to improve health outcomes for both mother and child. However, due to misconceptions and a lack of robust safety data, discontinuation of IBD therapies during pregnancy can occur. Effective management of pregnant IBD patients is complex and requires a multidisciplinary approach. This update reviews the results from the prospective, 13 year Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry addressing common questions and concerns regarding IBD pregnancy and therapeutics, and maternal and fetal outcomes with respect to disease activity, infections, and infant growth and development.

Introduction

The peak age of onset of inflammatory bowel disease (IBD) is during the third decade of life, overlapping with reproductive years. Women with IBD are more likely to have adverse pregnancy complications, further exacerbated by active maternal disease.1 Although most patients with IBD have uncomplicated prenatal and postpartum courses, active disease complicates approximately 30% of pregnancies.2 Therefore, controlling maternal disease activity throughout pregnancy with stable pharmacologic therapy is a high priority. However, there remains concern about the safety of IBD therapies with respect to both mother and child. Medication non-adherence remains high in the pregnant IBD population and has the potential to worsen outcomes.3 This update highlights maternal and neonatal outcomes from the large multicenter prospective cohort, Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO).4

The recent publication of the PIANO registry data in Gastroenterology is a product of over a decade of research and 1500 pregnancies among women with IBD followed prospectively throughout pregnancy and the first four years of the infant’s life. Patients were enrolled across the U.S. through the Crohn’s Colitis Foundation Clinical Research Alliance. The primary objective of the PIANO registry is to address whether exposure to thiopurines, biologics and combination therapy (monoclonal antibodies and thiopurines) in pregnant women with IBD leads to an increase in specific adverse outcomes.

Pregnancy Outcomes

The investigators from the PIANO registry studied adverse outcomes during the prenatal and postpartum period. The study enrolled 1712 pregnant women with IBD, including Crohn’s Disease (CD), Ulcerative Colitis (UC) and IBD indeterminate. Of those, 1490 completed pregnancy with 1431 live births. The cohort had a higher number of patients (62%) with Crohn’s Disease. This is in comparison to the prevalence of 37 to 246 cases per 100,000 persons for ulcerative colitis and from 26 to 199 cases per 100,000 persons for Crohn’s Disease.5 The median disease duration was 8.3 years. The cohort included women with exposure to infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, ustekinumab, mercaptopurine, azathioprine, or combination therapy.

Pregnancy outcomes examined included spontaneous abortion (SAB), preterm birth (<37 weeks), stillbirth, intrauterine growth restriction (IUGR), small for gestational age (SGA), low birth weight (LBW) (<2500 g), abruptio placenta, eclampsia/preeclampsia, cesarean delivery, Neonatal Intensive Care Unit (NICU) stay at birth and congenital malformations. Adverse pregnancy outcomes are outlined in Table 1. Overall, there were no differences in rates of pregnancy complications comparing those exposed to biologics and thiopurines and those not exposed to these medications. Similar findings were observed even when comparing pregnancies in mothers with IBD without any IBD medication exposure, biologic exposure excluding the 3rd trimester, and biologic exposure throughout pregnancy and through birth. This highlights that sustained IBD therapy throughout the duration of pregnancy does not increase maternal or infant complications.

There has been a rapid increase in Cesarean delivery since 1996, with rates in the general population as high as 33%.6 When active perianal disease is present (usually in CD), there is up to a 10-fold increased risk for fourth-degree laceration and elective Cesarean delivery is recommended.7 In the PIANO cohort, Cesarean delivery was observed in 43% of enrolled participants. Women on biologics or on combination therapy had higher rates of Cesarean delivery compared to the unexposed population. Active or severe IBD was the most common indication for Cesarean delivery for women with and without biologic or thiopurine exposure. However, in women on combination therapy, perianal disease was the most common indication for Cesarean delivery.

Disease Activity

The PIANO registry explored the impact of disease activity on both maternal and infant outcomes. UC mothers had significantly lower rates of remission per trimester and higher rates of flares compared to CD mothers. This finding is consistent across several studies as discussed in a meta-analysis of 14 studies, which found a significantly higher risk ratio of active disease during pregnancy in patients with UC who commenced pregnancy with active disease (55%) compared with those whose disease was in remission at conception (36%) (risk ratio, 2.0; 95% confidence interval, 1.5–3; P < .001).8 The higher rates of increased disease activity during pregnancy in UC compared to CD is interesting and may point to a mechanistic difference in response to the pregnancy state or may suggest the mothers with UC are undertreated compared to CD.

Results from PIANO also determined that the first trimester represents the period with the highest rate of flare. This was more pronounced in women with IBD not on therapy. Prior studies also correlate with these findings, demonstrating that discontinuation of anti-TNF before week 24 increases the risk of disease flare.9,10 In the PIANO cohort, higher rates of disease activity was associated with risk of spontaneous abortion (HR 3.41, 95% CI 1.51-7.69). These findings highlight that priority should be given to treating active disease in pregnancy and the critical role of preconception planning and a stable therapeutic regimen for improved pregnancy outcomes.

Infections

Pregnancy represents a unique immunologic state and dysregulation of immunological mechanisms is increasingly implicated in the pathogenesis of preterm birth, infections and other pregnancy related complications.11 Consequently, pregnancy presents many challenges for making decisions on how to approach and prevent infectious diseases. In pregnant women with IBD, there is a lack of data regarding rates of infections for mother and child with exposure to immunosuppressive therapies.

Birth, and the first few months of life, represent a critical time where children have vulnerable immune systems and are more susceptible to infection. In this critical time, part of the infant immunity is reliant on maternal antibodies that cross the placenta, and most of this transfer occurs during the third trimester. With the exception of certolizumab, biologics (monoclonal antibodies) actively cross the placenta.12,13 The effect of biologics presence in the neonate and the effect on the developing immune system raises several concerns about infection risk. Results from the TEDDY study suggested exposure to anti-TNFα drugs in utero does not increase the risk of severe infections in children born to mothers with IBD.9 Outcomes from the PIANO cohort confirmed that there was no increase in serious, non-serious or any infection in the first year of life in infants with thiopurine, biologic or combination therapy exposure (Figure 1). The majority of infections were non-serious, consisting primarily of otitis media and upper respiratory infections. Serious infections were rare, consisting of febrile illnesses requiring antibiotics, sepsis or hospitalization. Preterm birth was the only independent risk factor for infection (OR 1.73, 95% CI 1.19-2.51). Infection rates did not differ by individual biologic agent.

In nursing mothers receiving biologic therapy, very low levels of drug are detected in breastmilk.14,15 When compared to infants that were not breastfed, breastfed infants in PIANO with biologic exposure did not have higher rates of infection or reduction in achievement of developmental milestones.15

Daycare attendance among the general population is associated with an increased risk of serious and non-serious respiratory and gastrointestinal infections in the first years of life. Through the PIANO cohort, longitudinal information was examined in mother-child pairs. Overall, as expected, children in daycare had a higher rate of any infection. However, there was no difference in serious infections compared to those not in daycare. Biologic use was not associated with increase in infection in children attending daycare.16

It is well established that IBD patients on immunosuppression, particularly on combination therapy, are at risk for reduced or inadequate vaccine response.17 Data from the PIANO cohort has shed light on the long-term outcomes of vaccine response in infants with in utero exposure to biologics (monoclonal antibodies), thiopurines and combination therapy. In a study by Beaulieu, Ananthakrishnan et. al, data from infants born in the PIANO cohort demonstrate that the rates of adequate serologic response to Haemophilus influenzae B (HiB) and tetanus vaccines were similar among infants born to women on biologic therapy compared to those who were not exposed during pregnancy.18 There was also no association between cord blood or infant serum concentrations of biologics and adequacy of vaccine titers.18

Subgroup analysis of the TREAT registry demonstrated that anti-TNFa may be associated with increased maternal complications including infection.19 The rate of serious infections among those who had received infliximab was significantly higher than those who were not treated with infliximab (1.37 per 100 patient-years vs .65; RR [95% CI], 2.15[1.442–3.210]; P < .001), however this was confounded by disease activity as patients in the infliximab-treated group were more likely to be receiving prednisone, immunomodulators, and narcotic analgesics.19 In the PIANO cohort, maternal postpartum infections were rare. The incidence of perineal trauma and poor wound healing is not significantly different in the IBD patient population compared to the general population.20

Infant Growth and Development

Epidemiological studies have shown that infants exposed to stress in the womb are at higher risk of impaired cognitive development and growth restriction. A recent study by Stoye et al. examined the impact of maternal stress and found that chronic maternal stress state in pregnancy is associated with microstructure and structural connectivity of the newborn amygdala, a region of functional importance for early social development and emotion regulation.21

Studies in childhood growth and development are often difficult to ascertain causality, as there are several host factors and socioeconomic factors that contribute to growth and development. The PIANO study examined differences in infant growth and developmental milestones at 12 months of age by drug exposure. Overall, there were no differences in height or weight outcomes by drug exposure, or in odds of being very low for length or weight, controlling for preterm birth and maternal disease activity. There were also no differences in developmental milestones in the first year of life by exposure status within the cohort or compared to validated Ages & Stages Questionnaire norms. However, scores of biologic and/or thiopurine exposed infants were slightly higher than the general population in some categories.22

Congenital Malformation

The risk of congenital malformations related to biologic and thiopurine exposure were addressed in the PIANO cohort. Of the 1431 live births observed, 133 (9%) infants had congenital malformations. No pattern of congenital malformations was suggested based on IBD and medication exposure. The observed rate of congenital malformations was higher than reported in national observation estimates of congenital malformation prevalence data, but not different by drug of exposure. This increased rate is likely secondary to the close monitoring of each participant over one year and strict inclusion and classification of congenital malformations.23

Summary

Pregnant women with IBD are at higher risk for adverse complications of labor and delivery. This risk is heightened by active disease, emphasizing the importance of controlling disease activity prior to conception and through delivery. However, there remains concern about the safety and approach for managing IBD therapies during pregnancy, as well as the impact on the developing fetus and long-term outcomes. The PIANO registry clarified this risk to provide IBD patients and providers important safety information and guidance. The PIANO registry provides clear long-term safety data on mother and child demonstrating that biologic, thiopurine or combination during pregnancy is not associated with increased adverse maternal or fetal outcomes at birth or within the first year of life, and likely the first four years of life as well. With this collection of safety data, providers can advise that women with IBD on biologics, thiopurines or combination therapy should continue this regimen throughout pregnancy and the post-partum period to maintain remission for the health of the mother and the child. Future studies in PIANO will use the existing infrastructure to look at new therapies for IBD and will continue to follow children out to 18 years of age.

References

  1. Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007;133(4):1106-1112.
  2. Caprilli R, Gassull MA, Escher JC, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations. Gut. 2006;55 Suppl 1:i36-58.
  3. Mountifield RE, Prosser R, Bampton P, Muller K, Andrews JM. Pregnancy and IBD treatment: this challenging interplay from a patients’ perspective. J Crohns Colitis. 2010;4(2):176-182.
  4. Mahadevan U, Long MD, Kane SV, et al. Pregnancy and Neonatal Outcomes after Fetal Exposure To Biologics and Thiopurines among Women with Inflammatory Bowel Disease. Gastroenterology. 2020.
  5. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-1517.
  6. Martin JA, Hamilton BE, Osterman MJK. Births in the United States, 2019. NCHS Data Brief. 2020(387):1-8.
  7. Hatch Q, Champagne BJ, Maykel JA, et al. Crohn’s disease and pregnancy: the impact of perianal disease on delivery methods and complications. Dis Colon Rectum. 2014;57(2):174-178.
  8. Abhyankar A, Ham M, Moss AC. Meta-analysis: the impact of disease activity at conception on disease activity during pregnancy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38(5):460-466.
  9. Chaparro M, Verreth A, Lobaton T, et al. Long-Term Safety of In Utero Exposure to Anti-TNFalpha Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study. Am J Gastroenterol. 2018;113(3):396-403.
  10. Truta B, Leeds IL, Canner JK, et al. Early Discontinuation of Infliximab in Pregnant Women With Inflammatory Bowel Disease. Inflamm Bowel Dis. 2020;26(7):1110-1117.
  11. PrabhuDas M, Bonney E, Caron K, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol. 2015;16(4):328-334.
  12. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology. 2016;151(1):110-119.
  13. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of antitumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-292; quiz e224.
  14. Lahat A, Shitrit AB, Naftali T, et al. Vedolizumab Levels in Breast Milk of Nursing Mothers With Inflammatory Bowel Disease. J Crohns Colitis. 2018;12(1):120-123.
  15. Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure Concentrations of Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and Development. Gastroenterology. 2018;155(3):696-704.
  16. Long MD, Siegel CA, Abraham BP, Chiorean M, Mahadevan U. Day Care Attendance and Infectious Complications in Children Born to Mothers with Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. 2021.
  17. Mamula P, Markowitz JE, Piccoli DA, Klimov A, Cohen L, Baldassano RN. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(7):851-856.
  18. Beaulieu DB, Ananthakrishnan AN, Martin C, Cohen RD, Kane SV, Mahadevan U. Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines. Clin Gastroenterol Hepatol. 2018;16(1):99-105.
  19. Lichtenstein GR, Feagan BG, Mahadevan U, et al. Pregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report. Am J Gastroenterol. 2018;113(11):1678-1688.
  20. Lewin SM, Martin C, Scherl E, Stein DJ, Ganguly EK, Mahadevan U. 161 – Risk Factors for Poor Wound Healing after Episiotomy and Perineal Laceration: Results from the Piano Registry. Gastroenterology. 2018;154(6, Supplement 1):S-45.
  21. Stoye DQ, Blesa M, Sullivan G, et al. Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner. Elife. 2020;9.
  22. Mahadevan U, Martin CF, Chambers C, et al. 1 Achievement of Developmental Milestones Among Offspring of Women With Inflammatory Bowel Disease: The PIANO Registry. Gastroenterology. 2014;146(5, Supplement 1):S-1.
  23. Mai CT, Isenburg JL, Canfield MA, et al. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 2019;111(18):1420-1435.

Download Tables, Images & References

FROM THE PEDIATRIC LITERATURE

Radiation Exposure during Pediatric ERCP

May 2021 • Volume XLV, Issue 5

Read Article

Endoscopic retrograde cholangiopancreatography (ERCP) is increasing as a pediatric gastrointestinal diagnostic and therapeutic modality. However, ERCP is associated with ionizing radiation exposure, and in adult gastroenterology literature, radiation exposure is reduced if procedures are performed by high-volume endoscopists. It is unknown if this same finding occurs with pediatric gastroenterologists who perform ERCP.

The authors of this study performed a retrospective review of all pediatric ERCPs completed at a single, large children’s hospital over a 15-year period (2002-2017). ERCPs in this setting were performed by both adult and pediatric gastroenterologists, and a “highvolume gastroenterologist” was defined as one who performed greater than 100 adult and pediatric ERCPs per year while a “low-volume gastroenterologist” was defined as one who performed less than 100 such procedures. Each gastroenterologist had ERCP data reviewed including obtaining information about each pediatric patient (age, sex, diagnosis, and ERCP intervention). Fluoroscopy time during ERCP was compared between high-volume and low-volume gastroenterologists.

A total of 385 ERCPs were performed on 321 patients by 8 gastroenterologists (5 adult; 3 pediatric). Three adult gastroenterologists and one pediatric gastroenterologist were high-volume providers while the rest were low volume. A separation into high- versus low-volume providers demonstrated that 175 ERCPs were performed by low-volume gastroenterologists and 210 were performed by high-volume gastroenterologists. The average patient age was 13.4 years with 51% of patients being Caucasian. All patient variables did not differ significantly between low-volume and high-volume gastroenterologists. Throughout the study, the proportion of therapeutic ERCPs increased significantly over time. Median fluoroscopy time per procedure was 4.85 (± 2.68) minutes. High-volume gastroenterologists had a median fluoroscopy time of 2.04 minutes which was significantly lower than low-volume gastroenterologists who had a median fluoroscopy time of 5.21 minutes. Univariate and multi-variate analyses also demonstrated significantly increased fluoroscopy time for patients who needed an ERCP for a pancreas disorder, for patients with any type of ductal stricture, and for any patient less than 4 years of age or greater than 16 years of age. Significantly decreased fluoroscopy time was associated with patients who had undergone prior ERCP. The ASGE Procedure Complexity Scale for patient procedures did not predict fluoroscopy time although the Stanford Fluoroscopy Complexity Scale did show a significant correlation between total fluoroscopy time and increasingly complex pediatric procedures. Finally, ERCPs with fluoroscopy controlled by a radiology technician or radiologist had significantly higher fluoroscopy time compared to endoscopist-controlled fluoroscopy, and C-arm use was associated with significantly more fluoroscopy time compared to use of a fixed fluoroscopy unit.

This study demonstrates that high-volume endoscopists who perform ERCP utilize less fluoroscopy time comparted to low-volume endoscopists. Also, the person controlling the fluoroscopy and type of machine providing imaging appears to effect exposure time. Multicenter as well as prospective studies are needed to confirm these important findings This study demonstrates that high-volume endoscopists who perform ERCP utilize less fluoroscopy time comparted to low-volume endoscopists. Also, the person controlling the fluoroscopy and type of machine providing imaging appears to effect exposure time. Multicenter as well as prospective studies are needed to confirm these important findings

Download Tables, Images & References

The Risk of Cancer in Children with Inflammatory Bowel Disease

May 2021 • Volume XLV, Issue 5

Read Article

Inflammatory bowel disease (IBD) in children is associated with chronic inflammation, and such inflammation increases the risk of cancer development. Since IBD incidence is increasing in children, the authors of this study performed a meta-analysis regarding the potential cancer risk in children with IBD using PRISMA guidelines. Potential articles and abstracts evaluating the risk of cancer in pediatric patients with IBD (defined as occurring under 25 years of age) were obtained from PubMed, Google Scholar, Scopus, Cochrane Central Register of Controlled Trials as well as from major cancer and gastroenterology meetings. IBD terms such as “Crohn’s disease”, “ulcerative colitis”, and “inflammatory bowel disease” combined with various potential cancer terms including “childhood”, “cancer”, “malignancy”, as well as several types of malignancy were searched via these databases. Each potential data source was reviewed by 2 authors, and the Jadad score and the Cochrane Risk of Bias Assessment Instrument were used to determine randomized controlled trial quality. The NewcastleOttawa Scale was used to assess observational study quality. GRADE criteria (Grading of Recommendations, Assessment, Development and Evaluation) were used to determine risk of bias. The primary outcome was to determine the risk of cancer noted in studies using standardized incidence ratios. Secondary outcomes included the pooled incidence rates of all cancers as well as site-specific cancers. Meta-regression analysis was performed to determine if medication type influenced cancer development.

A large number of potential studies (total of 969,127) was initially identified; however, only 66 studies including 38,092 patients were included in the final analysis. A total of 44 studies evaluated patients with Crohn’s disease; 31 studies evaluated patients with ulcerative colitis; and 5 studies evaluated patients with IBD (no distinction given). Patients less than 18 years of age were included in 50 studies (75.76%) while the remainder of the studies included patients 18 to 24 years of age. A total of 14 of the 62 observational studies had a Newcastle-Ottawa score of 6 or higher. All randomized controlled trials had a Jadad score of 2 or 3. No inter-rater disagreement for data scoring was noted between the study authors.

A total of six retrospective observational studies including 17,450 patients evaluated the standardized incidence ratio of cancer occurrence. At least 125 patients developed a malignancy although the final number of patients with a malignancy was not clear. Four of these studies evaluated patients with Crohn’s disease and noted a 2.4-fold increased risk of cancer (pooled SIR 2.42, P < .0001, 95% CI 1.90-3.06; meta-analysis heterogeneity score (I2) = 0%) while five of these studies evaluated patients with ulcerative colitis and noted a 2.1-fold increased risk of cancers (pooled SIR 2.10, P < .0001, 95% CI 1.51-2.90; I2 = 41.54%). A pooled standardized risk ratio for all pediatric patients with IBD was 2.39 (P < .0001, 95% CI 2.00-2.86; I2 = 0%). The pooled incidence of overall pediatric cancers came from 9 prospective and 44 retrospective studies. The pooled incidence rate of overall cancers in patients with Crohn’s disease was 0.014 (95% CI 0.0087- 0.021; I2 = 78.90%) while the pooled incidence rate of overall cancers in patients with ulcerative colitis was 0.031(95% CI 0.018-0.052; I2 = 91.59%) and the pooled incidence rate of overall cancers in all of the included studies was 0.018 (95% CI 0.013-0.025; I2 = 89.10%). A metaregression analysis determined that follow-up study duration positively correlated with cancer development risk, and this finding was statistically significant. No such association was seen with various medications used to treat pediatric IBD including use of steroids, immunomodulators, and anti-tumor necrosis factor medications.

Regarding specific cancer development, not enough data was available to perform a metaanalysis for the development of colorectal cancer. However, the pooled incidence rate of colorectal cancer in CD was 0.0075 (95% CI 0.0049-0.011; I2 = 41.30%) while the pooled incidence rate of colorectal cancer in ulcerative colitis was 0.020 (95% CI 0.012-0.034; I2 = 87.95%) and the pooled incidence rate in all pediatric IBD patients was 0.010 (95% CI 0.0074-0.014; I2 = 81.30%). There appeared to be a statistically significant and positive correlation between male patients and the risk of colorectal cancer while a statistically significant and negative correlation was seen between age of IBD diagnosis / onset and risk of colorectal cancer with younger patients at time of diagnosis having an increased risk of colorectal cancer long term. Only one study provided standardized incidence ratio data on hematologic cancers in the setting of IBD. However, enough studies were present to determine the pooled incidence rate of pediatric patients with Crohn’s disease and ulcerative colitis. Patients with Crohn’s disease had a pooled incidence rate of 0.0061 (95% CI 0.0040-0.0090; I2 = 27.14%) while patients with ulcerative colitis having a pooled incidence rate of 0.0045 (95% CI 0.0040-0.0090; I2 = 31.66%).

The pooled incidence rate of all pediatric patients with IBD was 0.0054 (95% CI 0.0039-0.0075; I2 = 35.25%). Meta-regression analysis showed no risk of hematologic cancers in patients having received steroids, immunomodulators, or antitumor necrosis factor medications. Finally, cumulative meta-analyses showed that all cancer types had a decreasing incidence over time.

This study shows that pediatric patients with IBD do have an inherent cancer risk, but it is reassuring that the risk of cancer is not associated with standard IBD therapy. It also is helpful to know that the incidence of cancer in this study decreased over time suggesting pediatric patients with IBD may be maintaining good disease control over time. However, the range of heterogeneity of meta-analyses in this study suggests that better data is needed to answer this question more clearly.

Komaki Y, Komaki F, Yamada A, Micic D, Ido A, Sakuraba A. Risk of cancers in patients with pediatric inflammatory bowel diseases: a systemic review and meta-analysis. Journal of Pediatrics 2021; 229: 102-117.

jojobethacklinkmarsbahiscasibomJojobet GirişcasibomJojobet GirişCasibomCasibomvaycasinoholiganbetcasibommarsbahis girişJojobettaraftarium24madridbet güncel girişmadridbet girişmadridbetGrandpashabet